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J Neurol (2007) 254 [Suppl 3]: III/1–III/212 DOI 10.1007/s00415-007-3001-6

Seventeenth Meeting of the European Neurological Society 16–20 June 2007, Rhodes, Greece Symposia and Free Communications

The abstracts have been reviewed by: Z. Argov, O.A. Bajenaru, R. Baringer, C. Bassetti, H. Cock, G. Comi, M. Dieterich, V. Dietz, M. Eraksoy, F. Fazekas, M. Filippi, O. Hardiman, C. Krarup, G.L. Lenzi, R. Lisak, I. Milonas, G. Moonen, D. Pareyson, Y. Parman, H. Reichmann, G. Said, E. Scarpini, A. Sena, V. Silani, R. Soffietti, C. Sommer, A. Steck, M.J.D. Vidailhet

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Contents Presidential symposium Axonal protection in chronic inflammatory demyelinating diseases III/3

Symposia Mitochondrial disorders 2007: diagnosis, treatment and implications for common neurological diseases III/4 Repair of brain and spinal cord injuries: promises and challenges III/5 Stroke prevention III/6

FREE COMMUNICATIONS Oral Sessions Session 1: Neuro-otology III/7 Session 2: Neuro-oncology III/7 Session 3: Muscle disorders III/9 Session 4: Dementia 1 III/11 Session 5: Cerebrovascular disorders 1 III/12 Session 6: Multiple sclerosis 1 III/13 Session 7: Movement disorders 1 III/15 Session 8: Peripheral neuropathy 1 III/16 Session 9: Genetics 1 III/18 Session 10: Rehabilitation III/20 Session 11: Cerebrovascular disorders 2 III/21 Session 12: Multiple sclerosis 2 III/23 Session 13: Movement disorders 2 III/25 Session 14: Peripheral neuropathy 2 III/26 Session 15: Genetics 2 III/28 Session 16: Infection III/30 Session 17: Investigating patients after stroke III/31 Session 18: Epilepsy III/32 Session 19: Higher function disorders III/33 Session 20: Multiple sclerosis 3 III/35 Session 21: General neurology 1 III/37 Session 22: Pain III/38 Session 23: Child neurology III/39 Session 24: Clinical neurophysiology III/41 Session 25: Dementia 2 III/42 Session 26: Multiple sclerosis 4 III/44 Session 27: General neurology 2 III/46 Session 28: Headache III/48 Session 29: Epilepsy and sleep disorders III/49 Session 30: Cerebrovascular disorders 3 III/51 Session 31: Motor neuron disease III/53 Session 32: Treatment of acute stroke III/54 Session 33: Management of the MS patient III/55

POSTER SESSIONS Poster Session 1 Cerebrovascular disorders III/56 Neuro-ophthalmology III/59 Extrapyramidal disorders III/62 Rehabilitation III/65 Genetics III/68 Multiple sclerosis III/71 General neurology III/75 Neuro-oncology III/77 Peripheral neuropathy III/81 Poster session 2 Cerebrovascular disorders III/84 Clinical neurophysiology III/90 Extrapyramidal disorders III/92 Child neurology III/95 Infection III/98 Multiple sclerosis III/100 Neuro-biology III/106 Peripheral neuropathy III/109 Poster session 3 Cerebrovascular disorders III/112 Clinical neurophysiology III/119 Extrapyramidal disorders III/122 Epilepsy III/125 Peripheral neuropathy III/129 Multiple sclerosis III/133 General neurology III/138 Poster session 4 Cerebrovascular disorders III/141 Dementia/Higher function disorders III/145 Muscle disorders III/151 Epilepsy III/156 Infection III/161 Multiple sclerosis III/163 General neurology III/167 Poster session 5 Cerebrovascular disorders III/169 Dementia/Higher function disorders III/171 Pain and headache III/176 Motor neuron disease III/181 Infection III/186 Multiple sclerosis III/188 General neurology III/192 Sleep disorders III/196

Author index

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Presidential symposium Axonal protection in chronic inflammatory demyelinating diseases 1 Acute inflammation and late axonal degeneration: is there a link? G. Comi IRCCS San Raffaele (Milan, IT) Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, predominantly, but not exclusively, involving the normal appearing white matter. Nervous damage is explained by both an acute and chronic axonal loss inside and outside the lesions. Acute axonal loss is predominant in lesions appearing in the early phases of the disease and decreases over time. A high amount of damage occurs in area with large infiltration of T lymphocytes (especially CD8+ T cells) and the extent and macrophages indicating a correlation between inflammation and axonal damage, a relationship demonstrated also by magnetic resonance studies. Many studies, using variable MRI techniques, showed irreversible nervous damage in CIS and early RRMS patients. Clinical trials performed in CIS and early RRMS patients demonstrated that reducing the number of inflammatory lesions there was a decrease in the progression of brain atrophy. There are pathological, electrophysiological and MRI evidences that a “chronic axonal damage” is also an important contributor to MS disability. Both transversal and longitudinal studies using magnetic resonance markers of tissue damage revealed that both inside the lesions and in the so called normal appearing white matter there is an ongoing process of degeneration, more pronounced in the progressive phase of the disease. The amount of this secondary degeneration, compared to the acute axonal loss occurring in the active lesion is unknown. The clinical observation that the topographic pattern of irreversible, progressive neurological deficits in MS frequently depends on the localization of the previous attacks supports the role of lesions also in the progressive phase of the disease. In the same direction, the evidences that the MRI lesion load in CIS predicts the long term disability. Many interpretations have been proposed for the secondary axonal degeneration taking place in the inactive lesions. Naked, demyelinated axons may be more susceptible to degeneration because of the lost of the trophic support from the oligodendrocyte, an hypothesis supported by the observation that remyelinated axons are protected from further damage. Demyelinated axons are also more susceptible to soluble or cellular mediators present in the chronic plaque and may degenerate because of the abnormal expression of sodium channel subtypes which alter the membrane excitability. The secondary degeneration may also occur because repeated episodes of demyelination exhausted the availability of oligodendrocyte precursor or decreased their remyelinating efficiency. A primary pathology of oligodendrocytes could also explain the inefficient remyelination in some cases, an explanation which has been proposed for patients with primary progressive MS. Repeated episodes of focal inflammation leading to an exhaustion of remyelination. The mechanisms responsible of the axonal degeneration in the normal appearing brain tissue are even more disputable. Axonal loss may simply reflect the anterograde degeneration of nerve fibres transected or degenerated in the lesion: the axonal loss in the corpus callosum of progressive MS patients is significantly correlated to the lesion load in the hemispheres and the longitudinal changes of the cortical grey matter is related to the subcortical lesion load.Alternative mechanisms include a retrograde axonal degeneration, transynaptic neuronal degeneration and axonal degeneration due to low grade diffuse inflammation. Finally, we should consider the extreme hypothesis that MS is a primary progressive degenerative disease, with a secondary inflammatory response. There are accumulating evidences that the pathogenetic mechanisms may differ in the early and in the late phase of the disease. Early MS is associated with recruitment of systemically derived immune cell populations and inflammatory lesions. Late MS inflammatory responses appear to be modest, mostly at the edge of pre-existing lesions, locally regulated as suggested by the secondary lymphoid organization within the Virchow-Robin spaces, the ectopic follicles containing B cells and plasmacells in the meninges and memory B lymphocytes higher in CSF than in peripheral blood. Moreover, there is an extensive cortical demyelination, a diffuse microglial activation and a widespread axonal injury. All these data indicate a compartimentalised immunological response in the progressive phase of the disease.

2 Mechanisms of axonal degeneration in CIDP and MS B. Trapp Cleveland Clinic Foundation (Cleveland, US) Neurodegeneration is the major cause of permanent neurological disability in individuals with the demyelinating disease, multiple sclerosis (MS). The continuous and irreversible neurological decline that occurs during the latter stages of MS is thought to result from degeneration of chronically demyelinated axons. The molecular mechanisms responsible for the degeneration or dysfunction of chronically demyelinated axons are poorly understood. This presentation will review some of the mechanisms that are thought to be responsible for the degeneration of chronically demyelinated axons. Proof of principle for degeneration of chronically demyelinated axons comes from studies of mice in which myelin proteins have been eliminated. Mice deficient in the myelin proteins, myelin associated glycoprotein (MAG), 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNP), and proteolipid protein (PLP) have little myelin pathology but develop primary axonal pathology which precedes axonal degeneration and development of neurological disability. In addition to facilitation of saltatory conduction, myelin provides trophic support essential for long term axonal survival. To identify possible neuronal changes that may contribute to degeneration of chronically demyelinated axons, we compared gene expression profiles in control and MS motor cortex obtained by rapid autopsy. Twenty-six nuclear encoded mitochondrial genes and the activity of mitochondrial respiratory chain complexes I and III were significantly decreased in MS motor cortex. Reduced mitochondrial gene expression was specific for neurons Since the energy demands of nerve conduction are greater in demyelinated axons, supply of defected mitochondrial could result in failure of ionic homeostasis and result in increased axonal Ca and Ca-mediated axonal degeneration. The ionic imbalance that results in degeneration of chronically demyelinated axons is thought to involve dysfunction of the Na+/K+ ATPase. Since little is known about the distribution of this pump in MS brains, we determined the distribution of Na+/K+ ATPase subunits in normal human white matter and demyelinated lesions in multiple sclerosis brains. Na+/K+ ATPase subunits alpha1, alpha3 and beta1 were detected in the internodal axolemma and absent from the nodal axolemma of myelinated fibers in the adult human brain. Following demyelination, all three subunits were initially detectable on demyelinated axolemma. In contrast, demyelinated axons in some chronic lesions of multiple sclerosis contained little or no Na+/K+ ATPase immunoreactivity. As a result, these chronically demyelinated axons cannot exchange axoplasmic Na+ for extracellular K+ and their axolemma remains in a depolarized state and incapable of nerve transmission. We propose that loss of axonal Na+/K+ ATPase is a major contributor to continuous neurological decline in multiple sclerosis patients. 3 The protective role of myelin D. Delaunay, K. Heydon, A. Cumano, M. H. Schwab, J. L. Thomas, U. Suter, KA. Nave, N. Spassky, B. Zalc Hôpital Pitié Salpêtrière (Paris, FR); Université Pierre et Marie Curie (Paris, FR); Max-Planck-Institute (Goettingen, DE); Swiss Federal Institute of Technology (Zurich, CH) One of the most fundamental problems of mammalian brain development is “how are neurons and glial cells specified?”, a question with a long history that has led to two still undecided models: (1) Neuroepithelial stem cells are rather uniform,but they first give rise to neurons and later to glial cells.Thus, ventricular zone stem cells uniformly “switch” their potential as development proceeds (“switching model”). (2) The alternative model assumes that ventricular zone cells segregate very early in development and become intrinsically committed to generate either neurons or glial cells (“segregating model”). This idea was first put forward by W. His as early as 1889. We have undertaken a conditional genetic approach with a combination of in vitro and in vivo studies, using the diencephalon as a model. In the mouse diencephalon, plp gene transcripts mark diencephalic neuroepithelial stem cells at E 9.5, and a subpopulation of radial glial cells by E13.5. Using Cre/loxP fate mapping, we reveal that plp expressing cells give rise to all three types of neural cells, i. e., astrocytes, oligodendrocytes, and neurons. When these plp+ stem cells were isolated (by FACS) from the diencephalon of transgenic plp-GFP mice at E9.5, they formed neurospheres and behaved in vitro as tri-potent neural stem cells. However, when isolated at E13.5 plp+ cells were glial-restricted progenitors. Also clones derived in vitro from FACS purified plp+ stem cells showed either restricted neuronal (at E9.5) or glial cell fate (at E13.5). This restriction was then confirmed in vivo, using an inducible plp-CreERT2/loxP mice fate mapping strategy: when Tamoxifen was administered at E9.5, a large majority of neurons were generated, – when Cre was induced at E13.5, only glial cells were labeled. Importantly, we could

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also demonstrate that the radial glial cells expressing plp in the diencephalon were not the progeny of neuroepithelial cells expressing plp at E9.5. When combined, our results demonstrate directly the presence of two distinct types of neural progenitor cells: One earlier progenitor (at E9.5) has a restricted neuronal fate of differentiation, the later progenitor (at E13.5) is restricted to the glial cell fate and distinct from the earlier progenitor. Therefore, W. His was correct, in that there is a very early segregation of neuroblasts and glioblasts within the ventricular zone of the developing brain.

childhood, for these families then identifying the genetic defect and prenatal diagnosis is an option. There are many different studies published looking at ways to correct the genetic defect in patients with mtDNA disease – however, few has come through to clinical practice. Exercise, both endurance and strength training, has been proposed as a therapy for mitochondrial myopathies and preliminary studies in this area are encouraging. For patients with mtDNA disease, preventing the transmission of the disease is also being explored. Treatments specifically correct the genetic defects or the consequences of these defects on cell metabolism have either been considered for clinical trials or undergoing investigation at present.

Symposium

18 Novel nuclear genes: the tip of the iceberg? M. Zeviani “C. Besta” Neurological Institute – Foundation IRCCS (Milan, IT)

Mitochondrial disorders 2007: diagnosis, treatment and implications for common neurological diseases 16 How common are mitochondrial diseases and how do they present in the neurology clinic? P. Chinnery Mitochondrial Research Group (Newcastle upon Tyne, UK) Epidemiological studies carried out over five years ago established that, as a group, mitochondrial disorders are amongst the most common genetic diseases, affecting at least 1 in 5000 of the population. Many patients either present with nervous system involvement or develop neurological features as the disorders progress, causing substantial morbidity and mortality.A number of epidemiological surveys supported the then prevailing view that nuclear gene mutations were uncommon in adults presenting with mitochondrial disease. However, recent clinical and genetic studies indicate that mutations in POLG, the gene coding for the mitochondrial DNA polymerase (poly) are a major cause of progressive neurological disease in adults, with a broad range of clinical presentations hitherto unrecognised. These overlap with common neurological disorders, including migraine, epilepsy, ataxia and Parkinsonism. Paradoxically, the more we understand about the aetiology of mitochondrial disease, the more difficult it is to identify or exclude in a busy general Neurological practice. This session will move beyond the traditional mitochondrial clinical syndromes, and provide a contemporary overview of the symptoms and signs that should alert the Neurologist to an underlying mitochondrial disorder. An efficient approach to investigation will also be presented, whilst pointing out the potential pitfalls. 17 Investigation and management of mitochondrial disorders D. Turnbull The Medical School Newcastle University (Newcastle upon Tyne, UK) The investigation of patients with mitochondrial disease involves both clinical tests to assess the likelihood of mitochondrial involvement, and histochemical, biochemical and molecular biology techniques specifically to assess mitochondrial function. It is essential that these tests are led by the clinician involved or there will either be unnecessary or inappropriate investigations performed. In some patients the molecular genetic diagnosis can be made on a blood or urine sample, whereas in others a muscle biopsy is required. Muscle is an appropriate tissue to biopsy in many patients cases since it is often involved clinically,but even if not,characteristic changes may be present; for example cytochrome c oxidase deficient muscle fibres or accumulation of abnormal mitochondria. In recent years there have been many advances in the molecular genetic analysis of mitochondrial disease including the finding of new nuclear genes causing mitochondrial deficiency and efficient methods to sequence the entire mitochondrial genome. The management of patients with mitochondrial disease is challenging since for the majority of patients there is no specific curative treatment. Rare patients with ubiquinone deficiency usually respond to therapeutic doses. However, as with many other neurological disorders it is very important to try and detect treatable complications early. Patients with may present with neurological disease but often have involvement of several other systems, for example cardiomyopathy, bowel mobility problems and diabetes, all of which require specific help to avoid long-term complications. Genetic counselling is often challenging for patients with mitochondrial disorders and for many patients best done by clinicians with experience in this area. Since many mitochondrial conditions are potentially disabling or fatal in early

Mitochondrial disorders are clinical phenotypes associated with abnormalities of the terminal component of mitochondrial energy metabolism, i. e. oxidative phosphorylation (OXPHOS). Recent epidemiological studies have shown that ~1 in 5000 individuals in European populations have an OXPHOS disorder causing significant morbidity and mortality. Not only OXPHOS defects are, as a group, one of the commonest inherited neurological diseases in Western Countries, they also have a broad impact on public health, as they are reported to contribute to or be the leading cause in cardiovascular disease, diabetes, age-related neurodegenerative diseases and cancer. Genes that encode the structural components of OXPHOS are contained in two spatially and functionally separated genomes, the nuclear genome and the mitochondrial genome (mtDNA). As a consequence of this dual genetic control, mitochondrial disease can be due to mutations in mtDNA or nuclear DNA genes. An impressive and ever expanding number of pathogenic mutations of mtDNA have been building up in the last two decades, in association with a wide spectrum of clinical presentations.Albeit at a lesser rate, substantial progress has also been made in the characterization of nuclear OXPHOS-related genes responsible for mitochondrial syndromes. A clinical-genetic classification of nucleus-driven mitochondrial disorders includes the following main groups: (i) disorders due to mutations in respiratory chain subunits; (ii) disorders due to mutations in ancillary proteins involved in RC formation; (iii) disorders due to faulty intergenomic communication affecting the maintenance and expression of mtDNA; (iv) disorders due to defects in non-protein components of the respiratory chain; (v) disorders due to gene defects encoding proteins indirectly related to OXPHOS. However, approximately 60 % of biochemically defined OXPHOS disorders fail to be diagnosed at the molecular level. The vast majority of these disorders are likely due to nuclear gene mutations. Recent data from studies based on integrative genomics has established the human mitochondrial proteome to consist of approximately 1500 gene products. The number of candidate genes potentially able to determine a mitochondrial disease is believed to coincide, and possibly outnumber, this figure. These considerations help understand what a formidable task is facing the clinical research in this area. On a practical side, this scenario requires an effort to optimize efficient and accurate diagnosis of mitochondrial diseases, to establish best practice for the clinical investigation and management of patients and families in order to prevent the transmission of mitochondrial disorders.Accurate and rational diagnostics is extremely important and often underestimated. It will provide reassurance for patients and families when the results are negative, it is essential for prognostic and genetic counseling, and can avoid waste of time and money due to unneeded tests. 20 Implications of mitochondrial dysfunction in common neurological disorders N. G. Larsson Karolinska Hospital (Stockholm, SE) The main task of the mitochondrial network is to convert food and oxygen into the cell’s main energy currency,adenosine tri-phosphate,ATP.This it accomplishes through the process of oxidative phosphorylation. Disturbance in the mitochondrial function is an important cause of human disease; one in 10,000 newborns suffer from some kind of mitochondrial disease. Impaired mitochondrial function has also been implicated in several age-associated diseases, such as diabetes type 2, heart failure and Parkinson disease, as well as to the normally occurring ageing process. The mitochondrial function is fully dependent upon proteins encoded by the mitochondrial DNA, mtDNA. Point mutations and deletions of mtDNA accumulate in a variety of tissues during ageing in humans, monkeys and rodents. In terms of the ageing process, their possible causative effects have been intensely debated be-

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cause of their low abundance and purely correlative connection with ageing. To study the link between mtDNA mutations, mitochondrial dysfunction and ageing, we generated mice expressing an error-prone form of the catalytic subunit of the mtDNA polymerase, PolgA. These mice have an “mtDNA mutator” phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide the first experimental evidence for a causative link between mtDNA mutations and ageing phenotypes in mammals.

Repair of brain and spinal cord injuries: promises and challenges 21 Neuronal plasticity after spinal cord injury: consequences for rehabilitation V. Dietz Balgrist University Hospital (Zurich, CH) After a spinal cord injury (SCI) of the cat or rat, neuronal centers below the level of lesion exhibit plasticity than can be exploited by specific training paradigms. In individuals with complete or incomplete SCI, human spinal locomotor centers can be activated and modulated by locomotor training (facilitating stepping movements of the legs using body weight support on a treadmill to provide appropriate sensory cues) (for review see Dietz 2002, 2003). Individuals with incomplete SCI benefit from locomotor training such that they improve their ability to walk over ground. Load- or hip jointrelated afferent input seems to be of crucial importance for both the generation of a locomotor pattern and the effectiveness of the training (Dietz et al. 2002). However, it may be a critical combination of afferent signals that is needed to generate a locomotor pattern after severe SCI. Mobility of individuals after a SCI can be improved by taking advantage of the plasticity of the central nervous system and can be maintained with persistent locomotor activity. In the future, if regeneration approaches can successfully be applied in human SCI, even individuals with complete SCI may recover walking ability with locomotor training (Curt et al. 2004). During the past few years, several approaches to spinal cord repair have been successfully established in animal models. For their use in clinical trials of SCI in human beings, specific difficulties that affect the success of clinical trials have to be recognised (Dietz and Curt 2006). First, transection of the spinal cord is commonly applied in animal models, whereas contusion, which generally leads to injury in two to three segments, represents the typical injury mechanism in human beings. Second, the quadrupedal organisation of locomotion in animals and the more complex autonomic functions in human beings, challenge translation of animal behaviour into recovery from SCI in people. Third, the extensive damage of motor neurons and roots associated with spinal cord contusion is little addressed in current translation studies. Fourth, there is increasing evidence for a degradation of neuronal function below the level of the lesion in chronic complete SCI. This degradation might have a considerable impact in chronic SCI subjects for a regeneration-inducing treatment. Therefore, it’s relevance needs to be investigated. References Curt A, Schwab ME, Dietz V (2004) Providing the clinical basis for new interventional therapies: Refined diagnosis and assessment of recovery after spinal cord injury. Spinal Cord 42:1–6 Dietz V (2002) Proprioception and locomotor disorders. Nature Reviews Neuroscience 3:781–790 Dietz V (2003) Spinal pattern generators for locomotion. Clinical Neurophysiology (Review) 114:1379–1389 Dietz V, Curt A (2006) Neurological aspects if spinal cord repair: promises and challenges. Lancet Neurology (Review) 5:688–694 Dietz V, Müller R, Colombo G (2002) Locomotor activity in spinal man: Significance of afferent input from joint and load receptors. Brain 125:2626–2634

22 Achievements in basic research on regeneration M. E. Schwab University of Zurich (Zurich, CH) Nerve fibre growth in the adult brain and spinal cord is restricted to distances of 0.2–2mm, both in the intact CNS and after injury. Specific neurite growth inhibitory factors play a key role for the inability of injured axons to regenerate over long distances. CNS myelin contains several of these neurite growth inhibitors, among which the very potent membrane protein Nogo-A. Function blocking antibodies have been generated and applied to rats and macaque monkeys with spinal cord injuries as well as animals with MCAO strokes. Biochemical readouts showed an upregulation of growth specific proteins. On the anatomical level, injured fibres showed enhanced regenerative sprouting and, for 10–20 % of spinal descending tract fibres, long-distance regeneration with formation of large terminal arbors. Simultaneously, spared fibre tracts showed enhanced compensatory sprouting, often covering long distances. In stroke models, fibres from the intact corticobulbar or corticospinal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord under the influence of anti Nogo-A antibodies.Behavioural experiments for locomotion,grid and beam walk,swimming, as well as skilled fore limb reaching showed marked improvements of functional recovery in the Nogo-A antibody treated injured animals. In collaboration with Novartis, a human anti-human Nogo-A antibody was generated and extensively tested toxicologically. The antibody enhances regeneration of corticospinal fibres and recovery of precision movements of the paralysed hand after high cervical hemisections in adult monkeys. A Phase I clinical trial is currently ongoing in a European Network of Spinal Cord Injury Centres (EM-SCI, coordinated by V. Dietz, Zurich), using this anti NogoA antibody in acutely injured paraplegic patients. 23 Some advances in experimental spinal cord injury and their relevance to the clinical situation G. Brook Aachen University Hospital (Aachen, DE) The use of experimental animal models has resulted in major advances in our understanding of the pathophysiology of spinal cord injury (SCI). Traumatic SCI initiates a complex cascade of events which acts over a period of hours, days and weeks before a stable lesion site, consisting of connective tissue, astroglial scarring and cystic cavitation has developed. Despite these advances in the experimental domain, relatively little is known about the correlative events that take place in traumatically injured human tissues. In an attempt to address this imbalance, we have been investigating the expressing of a range of axon-growth promoting and axon-growth inhibitory molecules at- and around the lesion site in post mortem material obtained from patients who died following neurologically “complete”, maceration-type SCI. This has allowed us to highlight the similarities as well as some important differences in the tissue response to injury exhibited by laboratory rodents and humans. A better understanding of the cellular and molecular mechanisms responsible for the failure of any functional axonal regeneration has led to the development of a wide range of novel intervention strategies. The main goal of these strategies is to improve function by either (i) reducing secondary tissue degeneration, (ii) restoring the function of spared, demyelinated axons, (iii) promoting compensatory sprouting by spared axons or (iv) inducing regeneration of damaged axons. Some of the most promising of these strategies have entered early clinical trials. In the context of improved function through enhanced tissue sparing, high dose methylprednisalone was reported to be efficacious. However, this has been subject to considerable scepticism and there still remains no widely accepted acute treatment for spinal cord injured patients. A wide variety of alternative agents have been used to demonstrate efficacy in promoting tissue sparing. However, most would require a number of years further development before entering the clinical domain. We have addressed the possibility of using pharmacological agents that were designed for completely other purposes than for the treatment of SCI, but which have, importantly, already successfully passed through clinical trials. To this end, 2 drugs rolipram and thalidomide were chosen for their anti-inflammatory effects. The acute administration of both drugs improved the motor function of rats that were subjected to a moderate contusion injury. This effect was correlated to a reduction of pro-inflammatory cytokine (TNF-alpha and IL-1β) production following the insult and an increase in white matter tissue sparing at the lesion epicentre. Although this particular combination of drugs may not be the most efficacious for reducing secondary tissue degeneration, the value of investigating such an “off-the shelf ” approach is evident. Finally, the potential of tissue engineering strategies to contribute to the bridging of axonal regeneration across the scarring and cavitation of spinal cord lesion sites is

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becoming more widely appreciated. We have investigated the ability of a novel porcine type I collagen scaffold to act as a cell carrier for olfactory nerve ensheathing cells and to promote orientated axonal regeneration and functional repair. The possible future clinical benefit of adopting such strategies will be discussed. 24 Brain plasticity after damage C. Weiller Neurologische Universitätsklinik (Freiburg, DE) Recovery of functions of the brain after localised lesions is related to a reorganisation of the brain, which is individually different. It is influenced by behavioural and pharmacological treatment. Longitudinal studies with fMRI differentiated two types of reorganisation related to training induced improvement of motor function: patients with damage to the motor cortex or the pyramidal tract showed an abnormal increase of BOLD effect in the motor cortex during training, whereas patients with intact M1 and its major outflow tract showed a u-shaped development of activity over time with a decrease during treatment and an increase during the following consolidation. This pattern seems to be related a more normal learning and these patients only were able to keep up the improvement in daily living. In recovery from aphasia both hemispheres play a role. According to recent datas.Another recent study on 14 patients with aphasia with fMRI starting very early and following up to 1 year differentiated three stages of brain reorganisation. In an initial phase of “shock” loss of function is associated with very little if any activation in remaining left frontal language related regions. This is followed by a phase of “hyperactivation” with strong BOLD increases, especially in the right homologue frontal areas, related to considerable improvement of function. This is followed by a phase of gradual normalisation. Different therapeutic approaches may apply in the different stages of recovery.

Stroke prevention 36 Preventing early recurrences after a cerebral ischaemic event H-C. Diener University Duisburg-Essen (Essen, DE) Patients with a TIA have a high stroke risk with 50 % of early strokes happening in the first 48 hours. In patients with established ischemic strokes, 50 % of recurrent ischaemic events occur in the first seven days. This explains why secondary prevention has to be initiated as quickly as possible. Within the group of antiplatelet drugs only aspirin has shown efficacy in the first 2 weeks after the ischaemic event. The number of events prevented (7/1000), however, is small. The use of the combination of dipyridamole and aspirin in early stroke prevention is presently investigated in the PRoFESS trial. Oral anticoagulation should be initiated early in patients with cardiac source of embolism and mild to moderate stroke severity. Heparin, low molecular weight heparin and heparinoids decrease the rate of recurrent ischaemic events. They are, however, associated with an increased risk of cerebral haemorrhages cancelling out the benefit. Endarterectomy or stenting with or without balloon angioplasty should be performed as early as possible after a TIA or mild to moderate stroke in cases of high degree carotis stenosis. Initiation of antihypertensive therapy immediately after stroke with angiotensin receptor blockers is safe. Early initiation of statin therapy also reduces the risk of early recurrent stroke. Treatment with vitamins or folic acid is not effective. 38 Stroke prevention in women V. Caso Clinica Neuropsichiatria-Neurologia (Perugia, IT) Stroke is more prevalent in men than in women and men have also a higher age-specific stroke incidence rates (based on age-specific rates calculated from strata defined by race/ethnicity). The only exceptions are in 35- to 44year-olds and in those > 85 years of age-groups in which women have slightly greater age-specific stroke incidence than men. Factors such as oral contraceptive use and pregnancy contribute to the increased risk of stroke in young women, and the earlier cardiac-related deaths of men with cardiovascular disease may contribute to the relatively greater risk of stroke in older women. However, beside these risk-factors such as age and hormonal

fluctuation who are clearly sex-related, women have also different response to vascular risk-factors: Symptomatic and asymptomatic carotid stenosis: Sex-based differences in the overall results of endarterectomy are of particular interest. Because of a higher operative risk in women and a lower risk of stroke without surgery, CEA for symptomatic stenosis is less beneficial for 70 % to 99 % stenosis in women than in men and of no benefit in women with 50 % to 69 % stenosis (overall interaction P = 0.003).Women had a lower risk of ipsilateral ischemic stroke on medical treatment and a higher operative risk than men. The same patterns were also shown in a large trial of carotid endarterectomy for asymptomatic stenosis. Consequently, this procedure for asymptomatic stenosis was beneficial in men but not in women (ACAS). The ACST trial reported a benefit with women, but their subgroup analysis was performed as a comparison of outcome in the medical group versus the outcome in the surgical group after the 30-day perioperative period. Perioperative complications were not included in their subgroup analyses. Atrial Fibrillation: Atrial Fibrillation is an important risk factor for stroke. Wafarin treatment reduces the incidence of stroke in primary and secondary prevention. Women with atrial fibrillation had more commorbidities, more heart failure with preserved systolic function, and a lower QoL and are older than men. Additionally, women tend to be treated more conservatively with less rhythm control and less electrical cardioversion. Data about the use of anticoagulation treatment are controversial considering different studies. However, women tend to be treated less with wafarin compared to men. Hyperlipidemia: Statins have been shown to be effective in secondary stroke prevention. Statins tend to have more side-effects in women than in men and a higher presence of myopathies has been observed. There seems to be no differences in efficacy between sexes. Antiplatelets: The earlier Physicians’ Health Study showed that aspirin in males significantly reduced the risk of myocardial infarction but not stroke. In comparison, a recent Women’s Health Study with 39 876 healthy women receiving 100 mg daily aspirin in primary prevention on alternate days or placebo demonstrated that in women < 65 years of age, low-dose aspirin gave a 17 % reduction in the risk of stroke overall (24 % reduction for ischemic stroke) but has no significant effect on the risk of myocardial infarction or death from cardiovascular causes. In women an increase of 15-epi-lipoxin A4 (increase of 0.37 ng/mL per decade) was observed. This may provide a molecular rationale for low-dose aspirin therapies in elderly women to reduce inflammation-related disorders. 39 Secondary prevention after an ischaemic stroke in young adults D. Leys Hôpital Roger Salengro (Lille, FR) Although the median age of stroke patients is approximately 75 years in western countries, stroke may also occur in young persons. The 3 main characteristics of ischaemic stroke in young persons are their causes, the overall good outcome, and interference in women with hormonal life (contraception, pregnancy and future menopause). These specificities influence the secondary prevention after stroke. As for elderly subjects, secondary prevention measures manly depend on the presumed cause. For this reason, an extensive and early diagnostic work-up is required, as well as an extensive evaluation of risk factors. Stroke prevention measure should take into account that short- and long-term mortality rates are low, and that the overall risk of new vascular events is also low. The overall management of secondary prevention is based on similar principles than in elderly subjects, i. e. an optimal management of vascular risk factors, an appropriate antithrombotic therapy (oral anticoagulation and antithrombotic agents depending on the cause, and removal of the source in specific cases (severe internal artery stenosis, cardiac myxoma etc.). The specificities of stroke prevention in young adults are the following: (i) oral contraceptive therapy should be avoided in most cases; (ii) in the absence of evidence-based data, cervical artery dissections may be treated either by antiplatelet therapy or by anticoagulation, but, because of the low rate of recurrence after the 4th week, there is no reason to give oral anticoagulation for more than a few weeks or in patients at increased risk for bleeding; (iii) patients who have a negative diagnostic work-up but a patent foramen ovale (PFO) at risk (large PFO, or PFO associated with and inter-atrioseptal aneurism) have a 4-fold increased risk of recurrence under aspirin, and should preferably be randomised in trials comparing oral anticoagulation and closure; (iv) the association aspirin plus dipyridamole is the standard therapy for patients who can tolerate aspirin, have no clear cardiac indication for clopidogrel, and do not develop headache; (v) randomized controlled trials suggesting that estrogens increase the severity of ischemic

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strokes, patients should be informed that hormonal replacement therapy will not be recommended when the menopause will occur, if there is no new data showing that this attitude is inappropriate at that time; (vi) young women should be informed what to do in case of pregnancy (continue aspirin except during the last 6 weeks, replace oral anticoagulation by subcutaneous heparin in case of pregnancy). An important question that remains unanswered is how long should young patients receive antiplatelet therapy after an ischaemic stroke when the diagnostic work-up is negative. Due to the low risk of recurrence in patients without any risk factor, the reason to continue antiplatelet therapy more than a few years is rather weak.

FREE COMMUNICATIONS Oral Sessions Oral session 1 Neuro-otology

to the type of vertigo: (A) benign paroxysmal peripheral vertigo (BPPV, n = 19), (B) vestibular neuritis (VN, n = 14), (C) vestibular migraine (VM, n = 27), and (D) Menière’s disease (MD, n = 8). All patients underwent clinical neurological and standardized neuro-otological examinations including electro-oculography with caloric and rotatory testing, measurements of the subjective visual vertical, and ocular torsion for otolith testing, as well as two standardized interviews and a psychometric examination battery. Overall, the patients were evaluated at five different times (T0–T4) over 1 year (day 0, after 30 days, after 3 months, after 6 months, and after 12 months). Results: The prevalence of psychiatric disorders at baseline T0 did not differ between the four subgroups (A-D). After 1 year patients with VM expressed higher distress due to subjectively perceived vertigo than all other patients (T4: VM in 85 %, all others in 38 %, p = 0.007). Furthermore, the VM patients revealed a significantly elevated risk for somatoform disorders (T4: p = 0.019). Patients with a positive history of psychiatric disorders before disease onset showed a significantly increased risk for developing a reactive psychiatric disorder after a vestibular vertigo syndrome compared to patients with a negative history of psychiatric disorders (p = 0.001). The extent of vestibular deficit did not have any influence on the further course of the vestibular disease and also did not correlate with the amount of psychological strain. Conclusion: A positive history of psychiatric disorders is a strong predictor for the development of reactive psychiatric disorders following a vestibular vertigo syndrome. Especially patients with vestibular migraine are at risk for developing a somatoform disorder, which may be due to the unpredictive character of their vertigo attacks. References

O40 Aetiology of downbeat nystagmus – a retrospective survey of 117 patients J. N. Wagner, M. Glaser, T. Brandt, M. Strupp Klinikum Großhadern (Munich, DE) Objective: DBN is the most common form of acquired involuntary ocular oscillations overriding fixation. According to previous studies the cause of DBN remained unsolved in up to 44 %; craniocervical malformations and cerebellar atrophy were found to be the most frequent aetiologies. We reviewed 117 patients to establish whether the analysis of a large collective and improved diagnostic means would reduce the number of cases with “idiopathic DBN” and change the spectrum of underlying aetiologies. Methods: The medical records of all patients diagnosed with DBN in our Neurological Dizziness Unit between 1992 and 2006 were reviewed. In the final analysis only those patients with documented cranial MRI were included. Their workup comprised a detailed history and a standardized neurological, neuro-otological and neuro-ophthalmologic examination and further laboratory tests where applicable. Results: In 62 % of patients, a causative factor could be identified (“secondary DBN”). The most frequent single identifiable causes were cerebellar degeneration (21 %, n = 24), posterior fossa ischaemia (9 %, n = 10), and craniocervical malformations (7 %, n = 8). In 38 % (n = 45) of all patients with DBN, no causative factor could be identified (“idiopathic DBN”). The latter, however, frequently concurred with bilateral vestibulopathy, other cerebellar signs and/or peripheral neuropathy. Conclusions: The proportion of idiopathic DBN remained high despite of improved diagnostic techniques. Based on our findings we propose two groups of patients with “idiopathic DBN”: those with “pure” DBN and a syndromatic form of DBN associated with one or more of the following: bilateral vestibulopathy, cerebellar signs in the absence of cerebellar pathology on MRI and/or peripheral neuropathy. This form of DBN may be caused by a multisystem neurodegeneration. O41 The influence of peripheral vestibular function and pre-existing psychiatric morbidity on the course of vestibular disorders: results of a longitudinal study C. Best, A. Eckhardt-Henn, R. Tschan, S. Bense, M. Dieterich Johannes Gutenberg-University (Mainz, DE); Bürgerspital (Mainz, DE) Objectives: High rates of coexisting vestibular deficits and psychiatric disorders have been reported in patients with vertigo [1]. Hence, a causal linkage between the vestibular system and emotion processing systems has been postulated [2, 3]. The aim of this study was to evaluate the impact of vestibular function and deficits as well as preexisting psychological pathologies on the course of vestibular disorders. Methods: The interdisciplinary longitudinal study included a total of 68 patients with vestibular disorders. Four subgroups were formed according

1. McKenna et al., 1991 2. Jacob and Furman, 1996 3. Balaban and Thayer, 2001 The study was supported by DFG EC 220/2-1.

Oral session 2 Neuro-oncology O42 Initial radiographic response predicts favourable outcome to chemotherapy in primary CNS lymphoma H. Pels, A. Jürgens, I. Schiergens, A. Glasmacher, H. Schulz, A. Engert, V. Diehl, M. Linnebank, G. Schackert, H. Reichmann, F. Kroschinsky, M. Vogt-Schaden, G. Egerer, U. Bode, M. Deckert, R. Fimmers, K. Fliessbach, P. Calabrese, T. Klockgether, I. G. H. Schmidt-Wolf, U. Schlegel University of Bochum (Bochum, DE); University of Bonn (Bonn, DE); University of Cologne (Cologne, DE); University of Dresden (Dresden, DE); University of Heidelberg (Heidelberg, DE) Objective: The identification of prognostic factors in primary CNS lymphoma (PCNSL) is useful for treatment stratification in randomized trials and for decision making in the individual patient. Prognostic factors in PCNSL are age and performance status and possibly others. To evaluate the prognostic impact of tumor response to initial systemic and intraventricular chemotherapy cycles during ongoing treatment as assessed by magnetic resonance imaging (MRI). Patients and Methods: From 09/1995 to 12/2002, 88 patients with PCNSL were enrolled in a pilot/phase II study evaluating MTX-based high-dose chemotherapy without radiotherapy (“Bonn-Protocol”). MRI-scans were performed after two and after six courses of chemotherapy and radiographic response was assessed according to the Macdonald criteria. Overall survival (OS) and time to treatment failure (TTF) were measured. Median follow-up is 42 months (range: one to 124 months). Results: Patients achieving a complete radiographic response already after two courses of chemotherapy (n = 18) had a significantly longer median OS (not reached) and median TTF (not reached) than patients with complete response after termination of treatment (n = 24) (OS: 55 months; TTF: 32 months) (p = 0.01). Conclusion: Early tumor response assessed by MRI already in the early stage of treatment was shown to be a highly predictive prognostic factor for both OS and TTF in patients with PCNSL treated with combined systemic and intraventricular chemotherapy. Patients without such an early response

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to chemotherapy possibly should be switched to alternative treatment strategies. O43 Retrospective Italian study on natural history and treatment of brain stem gliomas in adults A. Salmaggi, L. Fariselli, I. Milanesi, E. Lamperti, A. Silvani, A. Bizzi, C. Maccagnano, E. Trevisan, E. Laguzzi, R. Rudà, A. Boiardi, R. Soffietti Istituto Neurologico C. Besta (Milan, IT); Univ. and S. Giovanni Battista Hospital (Turin, IT) Objectives: To investigate the clinical course, prognostic factors and management in adult patients with brain stem gliomas. Methods: We retrospectively evaluated a group of 34 adult patients with either histologically-proven or clinico-radiologically diagnosed brainstem glioma followed at 2 Centers in northern Italy. Results: Median age was 31 years. In 22 of the patients histology was obtained, it was informative in 21 (2 pylocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma, 1 glioblastoma). Contrast enhancement at MRI was present at onset in 14 patients. All the 9 patients undergoing spectroscopy-MRI at diagnosis showed an increased Cho/NAA ratio. In 8 patients, an initial wait-and-see policy was adopted, while 24 were treated with radiotherapy alone (4) or radiotherapy and chemotherapy (20). Only minor radiological responses were observed after treatment, while clinical improvement was observed in 9 out of 15 radiologically stable patients.After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died. Median overall survival time was of 59 months. Investigation of possible prognostic factors showed that a short time interval between disease onset and diagnosis was predictive of a signficantly shorter survival. No differences in survival emerged between the group of patients having undergone or not histologic assessment. Conclusions: Brainstem gliomas in adults are clinically and radiologically heterogeneous; a short time lapse between disease onset and diagnosis is associated with a shorted survival. The need for histologic assessment should be evaluated on the basis of local rates of complications of the procedures and keeping into consideration MRI and spectro-MRI results. Radiotherapy induces clinical responses in approximately 70 % of the patients, although these responses are transient and only seldom parallel minor radiological responses. Addition of chemotherapy is well tolerated but no striking advantages are obtained in comparison to radiotherapy alone. O44 The profile of paraneoplastic antibodies and clinical patterns in a cohort of patients with paraneoplastic neurological syndromes in the Czech Republic P. Stourac, J. Bednarova Masaryk University (Brno, CZ); Faculty Hospital (Brno, CZ) Objectives: To describe the association of various well-defined onconeural antibodies and to evaluate corresponding clinical patterns in individual patients in the Czech Republic during the period 2000–2006. Methods: We clinically evaluated 18 patients(n-18) with neurological paraneoplastic syndromes and tried to find any distinctions in clinical patterns of the individual patients regarding to positivity of only one vs. more of the well-defined onconeural antibodies. We used indirect immunofluorescence on mouse tissue substrate (MeDiCa,USA) and immunoblot (Ravo Diagnostics, Germany)for screening and confirmation of onconeural antibodies. The laboratory and clinical diagnoses were established according to the “Recommended diagnostic criteria for paraneoplastic neurological syndromes” published in J Neurol Neurosur Psychiatry 2004. Results: We found 6 patients (n-6), i. e. approximately 33 % positive for two or three well-defined onconeural antibodies in parallel in serum and/or in cerebrospinal fluid. The following antibodies were combined: anti-Hu+ anti-Ri(n-2),(subacute sensory neuronopathy,encephalomyelitis);anti-Hu+ anti-Yo+ anti-Ri(n-2),(subacute sensory neuronopathy, encephalomyelitis); anti-Hu + anti-Yo (n-1), (brainstem encephalitis); anti-Yo+ anti CV2(n-1), (subacute cerebellar degeneration). The other patients were positive for anti-Hu (n-8), (sensory neuronopathy, encephalomyelitis); anti-Ri (n-2), (encephalomyelitis); anti-Yo (n-2), (subacute cerebellar degeneration). Conclusion: The association of various well-defined onconeural antibodies in patients with paraneoplastic neurological syndromes is not uncommon. Approximately about one third of the patients in our cohort harboured two or more such antibodies. We only hypothesize about the pathophysiological relevance which could likely mirror polyclonal B cells activation like in other neurological autoimmune conditions ›for instance in multiple sclerosis. It is not probable that antibodies association change the

clinical pattern which was in all cases(except one) represented by classical paraneoplastic neurological syndrome. The clinical pattern did not reflect the most prominent clinical features of all associated antibodies, but only of the dominant antibody associated with typical tumour. Supported by MSMT 0021 622 404 ›QLG1 -CT-2002–01756-PNS Euronetwork. O45 Efficacy of topiramate in patients with gliomas R. Rudà, E. Laguzzi, E. Trevisan, B. Leoncini, D. Guarneri, R. Soffietti University of Turin (Turin, IT) Objective: Conventional anti-epileptic drugs (AEDs) have an increased risk of side effects in brain tumour patients, and most of them interact with antineoplastic drugs. Few studies are available addressing the role of new AEDs in patients with gliomas. The aim of this study was to evaluate the efficacy and toxicity of Topiramate (TPM) as add-on therapy in a cohort of patients with gliomas and persisting seizures despite conventional AEDs both in follow-up after treatment or with tumor progression under antineoplastic therapy. Results: Fifty patients with biopsy proven gliomas have been treated. A reduction > 50 % in seizure frequency attributable to TPM was obtained in 19/50 (38 %) patients with 4 patients seizure free leading to concomitant AEDs reduction or withdrawal. A significant seizure reduction attributable to either chemotherapy or radiotherapy was observed in other 6/50 patients. Toxicity of TPM was mild with 9 % of patients who discontinued the drug due to somnolence and/or fatigue. Conclusions: TPM is an effective and well tolerated add-on treatment in patients with glioma. Further investigation on the role of TPM as monotherapy is warranted. Considering the potential benefit of radiotherapy and chemotherapy on tumor-related seizures, future trials should distinguish the role of AEDs from the effect of antitumor therapies. O46 Paraneoplastic stiff-person syndrome and anti-Ri antibodies in metastatic breast cancer L. A. Hoffmann, N. Ditsch, T. Kuempfel, C. Dudel, M. Wick, R. Voltz Ludwig Maximilians University (Munich, DE); University Hospital (Cologne, DE) Objectives: We describe a patient with the unusual combination of paraneoplastic Stiff Person Syndrome (SPS), breast cancer and anti-Ri antibodies, to our knowledge for the first time Patients and methods: A 43-year-old saleswoman experienced fluctuating muscle rigidity in her trunk and legs and stimuli sensitive muscle spasms provoked sudden falls. Neurological examination showed increased muscle tone with rigidity (upper limb > lower limb, proximal > distal), especially when initiating movements and significantly worsening with stress and anxiety, increased clonic tendon reflexes, a marked action tremor and a bizarre broad based insecure gait. The neurological symptoms were progressive and after a short period of time she was wheelchair bound. Increased sweating, mydriasis, urinary retention and constipation indicated vegetative dysregulation. Neuropsychologically, a depressive mood, anxiety and emotional lability were prominent. Electromyographic tests demonstrated characteristic continuous tonic motor unit activity. Antibody testing for anti-GAD and anti-amphiphysin was negative. Because of a history of breast cancer 13 years ago, which was operated and treated with chemotherapy and a local recurrence 4 yrs ago, a whole body FDG-PET-CT was performed and showed hypermetabolism in cervical lymphnodes which were histologically diagnosed as metastases of breast cancer. Indirect immunofluorescence titres were determined from serum samples in serial dilutions on a panel of commercial tissue slides including monkey cerebellum and Hep-2-cells, which revealed anti-neuronal nuclear antibodies (ANNA), antiRi reactivity was confirmed qualitatively by a commercial immunoblot. Repeated courses of chemotherapies induced temporary remissions of the breast cancer and were associated with an improved neurological condition. Furthermore the neurological symptoms partially responded to immunosuppressive and symptomatic treatment. Conclusion: In our case the clinical and electrophysiological features were consistent with SPS plus additional brainstem and pyramidal signs. The patients’ clinical presentation with an unusual SPS of unknown etiology, in correlation with a history of tumor disease, detection of metastases and with the positive antibody tests validates the paraneoplastic etiology according to the definition of paraneoplastic neurological syndromes. To our knowledge this is the first case of a paraneoplastic SPS in a patient with breast cancer and anti-Ri reactivity.

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O47 Multimodal evaluation of brain tumour – FET-PET, fMRI and cortical stimulation mapping for tailoring therapy J. Nickel, M. C. Sabel, F. W. Flöth, G. Stoffels, K. J. Langen, R. J. Seitz University Hospital Dusseldorf (Dusseldorf, DE); Research Center Julich (Julich, DE) Objective: To illustrate the potential of multimodal image fusion with integration of functional magnetic resonance imaging (fMRI) and metabolic information obtained from [18F]fluoroethyl-tyrosine positron emission tomography (FET-PET) in the examination of patients with brain tumours in eloquent cortex. Methods: FET-PET (ECAT EXACT HR+ Scanner, tumour metabolism) and fMRI (1.5 T Siemens Magnetom Vision, sentence completion task with inflectional processing of verbs) were co-registered on a structural MRI. Quantification was done using commercially available PMOD and BrainVoyager software. Intraoperative cortical stimulation mapping (CSM) was navigated by use of multimodal image fusion. Results: When the right-handed, male patient with a left frontotemporal tumour was examined at the age of 35 years, FET-PET showed a mean tumour-to-brain ratio (TBR) of 1.6 and biopsy confirmed the diagnosis of diffuse isomorphic astrocytoma (WHO°II). Two years later he underwent language testing and fMRI for the first time. The sentence completion task induced activation remote and adjacent to the tumour that had increased in volume but still showed a TBR of 1.6. Language tests showed reduced verbal memory and fluency. Due to the space-occupying effect, the patient underwent cytoreductive surgery within limits of the fMRI activation. Analysis of the resected specimen confirmed WHO°II, no postoperative deterioration of speech was found. Aged 40, tumour relapse with suspicion of secondary malignancy led to re-evaluation. TBR in PET had increased to 2.3, language testing confirmed reduced verbal fluency and fMRI showed displaced language areas within the left hemisphere. Activation in the left dorsolateral prefrontal cortex occurred, which was functionally relevant as evident from CSM, while no effect was seen in the left inferior frontal cortex. After resecting 90 % of the FET-uptake volume (TBR > 1.6), including the inferior frontal region, there was no significant change in language tests or fMRI activation pattern. Histology revealed an anaplastic astrocytoma (WHO°III). Postsurgical PET showed a small rest of FET-positive tumour (TBR 2.0). Multimodal image fusion was performed to target irradiation therapy. Conclusion: Multimodal integration of FET-PET, fMRI and CSM is a promising approach for the evaluation of patients with brain tumours in eloquent areas. It seems to be suited to tailor surgical and irradiation therapy with respect to maintenance of eloquent brain functions. The work of Dr. Nickel is funded by the “Forschungskommission” of the Medical Faculty of the Heinrich-Heine-University, Düsseldorf (Germany).

Oral session 3 Muscle disorders O48 Enzyme replacement therapy in adult-onset type II glycogenosis S. Ravaglia, A. Repetto, A. Pichiecchio, A. Costa, C. Danesino, M. Rossi, P. Fratino, A. Lozza, E. Alfonsi, S. Bastianello, A. Moglia Institute of Neurology C. Mondino (Pavia, IT); ASL Pavia (Pavia, IT) Objective: To evaluate the effects of recombinant lysosomal alpha-glucosidase (GAA) derived from Chinese hamster ovary cells in adult adult-onset type II glycogenosis (GSDII). Background: GSDII is an autosomal recessive disease caused by GAA deficiency. Infantile, juvenile, and adult variants are known. The adult form is restricted to skeletal muscle involvement and characterized by slowly progressive girdle and diaphragm weakness. Muscle damage is not completely explained by intralysosomal accumulation of glycogen; increased muscle protein breakdown due to improper utilization of glycogen is thought to play a role. The effectiveness of enzyme replacement therapy (ERT) with recombinant-GAA, while proven in infantile GSDII, is still under investigation for adult GSDII. Design/Methods: We started an open label trial on six GSDII patients aged 58 ± 13.3 years with severe respiratory failure and moderate to severe limb girdle involvement. ERT (20 mg/kg every 2 weeks of Myozyme-Gen-

zyme) started between July 2005 and March 2006 and has been continued to now (October 2006). All patients carried the IVS1(-13T-G) mutation. Outcome indices included evaluation of segmental muscle strength (manuaal muscle testing, MMT), vital capacity (CV), 6-minutes walking test when applicable, muscle MRI.A 3 to 5 years pre-treatment follow-up had shown progressive worsening. Results: No patients reported treatment-related adverse effects. In 4/5 patients the respiratory function improved, up to 100 % of basal values in the patient with the longest follow-up (1 year). MMT score improved in pelvic muscles in 3/5 patients and in leg and thigh muscles in all patients. Muscle MRI showed increased muscle bulk. Two patients with low body mass index before treatment (12 kgm[sup-2]) increased upon ETR to 17 Kgm[sup-2], mainly in lean mass. Laboratory parameters indicating protein synthesis also improved. Conclusions/Relevance: Preliminary results indicate significant improvement of adult GSDII patients upon ERT, on different functional, metabolic and anatomical indices, including muscle mass, body weight, nutritional status and muscle strength. This data encourage the continuation of ERT therapeutic trial and recruitment of additional patients. O49 BiPAP prevents prolonged ventilation in myasthenic crisis J. Seneviratne, J. Mandrekar, E. Wijdicks, A. Rabinstein Mayo Clinic (Rochester, US) Objectives: To assess predictors of ventilation duration (VD) in myasthenic crisis (MC). Methods: We retrospectively identified patients with MC treated at Mayo Clinic between 1987–2006. Patients treated with either bi-level positive airway pressure (BiPAP) non-invasive ventilation or tracheal intubation were included in the analysis. We collected patient’s demographic information, baseline and pre ventilation measurements of forced vital capacity (FVC), maximal inspiratory and expiratory pressures (MIP, MEP), arterial blood gases, immunotherapy, medical complications, VD and hospital length of stay (LOS). Statistical analysis was performed using univariate logistic regression. All tests were two-sided and p-values < 0.05 were considered significant. Results: We identified 60 episodes of MC (in 52 patients) initially treated with BiPAP (24 episodes) or ET (36 episodes). Patient demographics were comparable to previously reported studies in MC. In 14 episodes treated with BiPAP (59 %) intubation was avoided. Mean duration of BIPAP use was 3.1 days. FVC, MIP, MEP and PO2 on admission or upon starting BIPAP failed to predict outcome of BIPAP. The only predictor of BiPAP failure (i. e. requirement for intubation) was PCO2 ≥ 45 mmHg upon BiPAP initiation (P = 0.037). Mean VD was 10.4 days. Longer VD associated with lower MEP on arrival (P = 0.024), intubation (P = 0.015) and atelectasis (P = 0.0046). ICU LOS (P < 0.0001) and hospital LOS (P < 0.0001) significantly increased with VD. The only variable associated with decreased VD was BIPAP treatment (p = 0.0066). When the groups of episodes initially treated with BIPAP and intubation were compared there were no baseline differences in patient demographics, arterial gases or respiratory parameters. Conclusions: BIPAP was the only variable significantly associated with reduced VD. We conclude that timely BIPAP initiation in MC patients before they develop hypercapnia (PCO2 ≥ 45 mmHg) can prevent intubation and prolonged ventilation, thus reducing pulmonary complications and length of ICU and hospital stay. O50 Predictors of prognosis in autoimmune myasthenia gravis G. Galassi, A. Ariatti, F. Girolami, F. Barbieri, U. Morandi, C. Lavini, P. Faglioni Institute of Neurosciences (Modena, IT) Objective: Several factors including age of onset, severity at diagnosis, immunological characteristics, thymectomy, thymic pathology may influence prognosis of MG. Methods: We reviewed our experience on 130 Caucasian MG patients (mean age 64.9 y; range 20.6–91.3). 57 were males (43.8 %; mean age 66.7 y; range 23.5–86.2), 73 females (56.2 %; mean age 63.5 y; range 20.6–91.3) followed during the observational time of 72 months. Mean duration of illness was 87.2months, range 1–558. Patients fulfilled criteria for acquired MG. Disease severity was defined according to Osserman’s, Myasthenia Gravis Foundation of America (MGFA) clinical classification. Onset of symptoms was defined late(102 patients; 78.5 %) when patients were aged equally or more than 40 years and early late when aged less than 40 years (28 patients; 21.5 %). Presence of anti-AChR antibodies (pmol/ml) was tested at time of diagnosis and yearly: 94 patients were seropositive (72.3 %; 50 females, 44

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males) and 36 seronegative (27.7 %; 24 females and 12 males). 45 patients (34.6 %; 26 females, 19 males) underwent thymectomy either for neoplastic (n = 23; 12 females, 11 males) or for hyperplastic thymus (n = 22; 14 females, 8 males). At diagnosis, 60 cases were classified in grade I (46.1 %; 29 females, 31 males), 40 were scored as IIA (30.8 %; 26 females, 14 males), 29 as IIB (22.3 %; 18 females, 11 males), 1 men was in grade III (0.8 %). None were asymptomatic or in grade IV and V at time of diagnosis. According to actual severity, 6 patients were asymptomatic (4.6 %; 5 females, 1 men), 60 were in stage I (46.1 %; 30 females, 30 males), 46 were in stage IIa (35.4 %; 29 females, 17 males), 17 in IIB (13.1 %; 9 females, 8 males) and 1 men in stage III (0.8 %). Improvement was evaluated in relation to age at diagnosis, severity at onset, presence of AChR antibodies in serum and thymectomy either for neoplastic or hyperplastic thymus Results and conclusion: Factors relevant for prognosis were tested by means of binary logistic regression analysis. Results are as follow: 1) MG patients with early onset had significantly better prognosis: (P < 0.0135)2) 2) In patients more severely affected at diagnosis, degree of severity contributed significantly to improvement (P = 0.00001). 3) Positive anti AChR titre did not contributed significantly to clinical improvement (P = 0.2282). 4) Thymectomy in cases with hyperplastic thymus raised the chances of improvement (P < 0.0364 one tailed). O51 The distribution of NF-kB and its inhibitor in the idiopathic inflammatory myopathies J. L. De Bleecker, K. K. Creus, B. De Paepe Ghent University Hospital (Ghent, BE) Objectives: Sustained activity of the pivotal transcription factor Nuclear Factor-kappa B (NF-kB) regulates chronic inflammation. Inactive NF-kB is a cytoplasmic dimer most often composed of a p50 and p65 subunit, linked to its inhibitor I-kappaB. Following stimulation by pro-inflammatory factors, I-kappaB is degraded, and active NF-kB translocates to the nucleus where it induces the expression of target genes. We studied NF-kB subunits and I-kappaB alpha (I-kB) in the idiopathic inflammatory mypathies (IM) namely dermatomyositis (DM), polymyositis (PM) and sporadic inclusion body myositis (IBM). Methods: p50, p65 and I-kB protein and mRNA distribution was studied in skeletal muscle biopsies from IM patients and controls with immunohistochemistry, immunofluorescence and in situ hybridisation. Results: Muscle tissue from all diagnostic groups displayed myonuclear p50 and p65. In disease controls, the sarcoplasm of atrophic muscle fibers showed an enhanced p65 signal. Regenerating muscle fibers displayed an increased signal for both p65 and p50. NF-kB subunits were expressed in the blood vessels of each diagnostic group, but they were upregulated in DM. Normal muscle fibers display slight homogeneous sarcoplasmic and sarcolemmal staining for I-kB. The inhibitor was abundantly distributed in the majority of abnormal perifascicular muscle fibers in DM, nonnecrotic invaded muscle fibers in PM/IBM and a subset of regenerating fibers in all IM. The I-kB signal was very strong in CD68+ macrophages in PM, IBM and DM and weaker in muscular dystrophy disease controls. CD8+ cytotoxic T cells in PM/IBM were strongly positive, CD4+ cells were weakly positive in all IM, and B cells in DM were mainly negative or very weakly positive. In IBM we detected I-kB in the inclusions. Conclusion: Our results lead us to presume that NF-kB activity is required for normal muscle physiology. In DM, p50 and p65 are probably involved in the endotheliopathy associated with this disorder. I-kB distribution in affected muscle tissue together with the observations for NF-kB subunits suggests that I-kB sequesters NF-kB in the sarcoplasm, which could counteract NF-kB transcriptional activity. Vascular expression of I-kB does not seem to be involved in the immunopathogenesis of IM. Further phenotyping of inflammatory cells expressing I-kB is still under way. The presence of the inhibitor in IBM inclusions might signify a non-specific event in which it is drawn to ectopically accumulated proteins. O52 Effects of rituximab treatment in two patients with dysferlin-deficient muscular dystrophy C. Marchesi, M. Belicchi, M. Meregalli, A. Farini, D. Parolini, M. Guglieri, M. G. D’Angelo, N. Bresolin, Y. Torrente Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena (Milan, IT); IRCCS E. Medea (Bosisio Parini, IT) Objectives: To investigate whether rituximab (anti-CD20 monoclonal antibody) improves muscle strength and influence the disease course in dysfer-

linopathies (recessive inherited muscular dystrophies caused by mutations of the dysferlin gene). In such conditions, in which the two main phenotypes recognized are Miyoshi myopathy (MM) and Limb-Girdle muscular dystrophy type 2B (LGMD2B), there are some evidences proving an involvement of immune system. In fact it was demonstrated the presence of muscle inflammation and a downregulation of the complement inhibitory factor CD55. Moreover recently it was reported an improvement in muscle strength in one patient affected by LGMD2B treated with Ig i. v. Methods: As compassionate use two male patients (41 and 30 years old) with Miyoshi myopathy were treated with four weekly infusions of rituximab (MabThera®, Roche, Hertfordshire, UK) at the standard dosage of 375 mg/m2 body surface area, after informed consent was obtained. Their laboratory (CD 20+, CD19+cells levels) and clinical response (muscle strength assessed by manual muscle testing and spirometry) were evaluated immediately after each infusion, 7 days and three months after the end of the treatment. Results: the treatment was tolerated well. Laboratory parameters showed that in both patients the percentages of circulating CD20+ and CD19+ cells were suppressed at 0–0.01 % to 3 months after infusion (percentages before the treatment were 2.9–7.3. Both patients reported an improvement in their ability of movement in the lower limb and an increased strength in the forearms and in the hands. Clinical follow-up showed a partial recovery of muscle strength in the dystal upper limb muscles (wrist flexors and extensors increased from 2–2/3 to 3–3/4) and a low amelioration of vital capacity values at the spirometry three months after the end of the treatment. Conclusion: The response to the treatment was safe and rituximab appears to be beneficial in these two patients. The effect of rituximab in LGMD2B and MM should be tested in a controlled clinical trial. O53 Myohistological mitochondrial changes in patients with different forms of idiopathic myositis P. Tacik, K. Traufeller, M. Deschauer, J. Weis, S. Zierz University of Halle Wittenberg (Halle, DE); RWTH Aachen University (Aachen, DE) Objectives: Myohistological mitochondrial changes were frequently reported in inclusion body myositis (IBM) and occasionally in dermatomyositis (DM) as well as in polymyositis (PM). The aim of this study was to analyse frequencies of myohistological mitochondrial changes in clinically well-described patients with IBM, DM and PM compared to normal controls. Methods: Quantitative examination of myohistological mitochondrial changes in 31 patients (6 IBM, 14 PM, 11 DM) was carried out and balanced against 11 controls. Muscle biopsies were stained for cytochrome c oxidase/succinate dehydrogenase (COX/SDH) to identify COX-negative fibres (CNF) and with modified Gomori’s trichrome staining to detect ragged red fibres (RRF). The quantitative analysis of at least 1000 muscle fibres of each patient per staining method was performed by one investigator. Results: In the control group 0.045 % of CNF were identified. A significant increase of CNF was seen in the IBM group (mean 3.9 %; range 0.3 %–11.5 %, p < 0.045 vs. controls) and in the DM group (0.4 %; 0 %–1.4 % p < 0.034), being not significant in the PM group (1.4 %; 0–5.4 % p < 0.107). Among the PM patients, two subgroups were differentiated: 8 patients showing no significant increase of CNF (0.02 %; 0–0.098 %, p < 0.559) and 6 patients with numerous CNF (3.3 %; 0.9 %– 5.4 %, p < 0.006). There was no significant increase of RRF compared to controls neither in any form of idiopathic myositis nor in the PM subgroups. Immunosuppressive treatment with azathioprine and steroids was effective in 6 out of the 8 PM patients without CNF compared to only 2 out of the 6 PM patients with CNF. Conclusions: 1. The cytochrome c oxidase/succinate dehydrogenase staining is a more sensitive method for detecting mitochondrial changes than modified Gomori’s trichrome staining. 2. Different degrees of mitochondrial changes were found in patients with different forms of idiopathic myositis being most prominent in IBM but also present in DM and in a subgroup of PM. 3. It can be speculated that mitochondrial changes contribute to a poor response to immunosuppressive treatment

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Oral session 4 Dementia 1 O54 ApoE e2 decreases the susceptibility to develop Alzheimer’s disease but not frontotemporal lobar degeneration, Lewy body disease or vascular dementia D. Galimberti, C. Lovati, E. Venturelli, P. Bertora, I. Guidi, C. Fenoglio, F. Cortini, G. Cislaghi, F. Clerici, G. Forloni, N. Bresolin, C. Mariani, E. Scarpini University of Milan, Ospedale Maggiore (Milan, IT); University of Milan, Ospedale Sacco (Milan, IT); Istituto di Ricerche Farmacologiche M. Negri (Milan, IT) Background: The e2 allele of Apolipoprotein E (ApoE) gene has been proposed as protective factor for the development of Alzheimer’s disease (AD). Whether it influences other neurodegenerative disorders is still debated, as, given its low frequency, extensive population studies in different types of dementias are still lacking. Objective: To determine the distribution of the ApoE alleles in a population of patients with AD as compared with age-matched controls as well as with patients with other types of dementia, including Frontotemporal Lobar Degeneration (FTLD), Lewy Body Disease (LBD) and Vascular Dementia (VaD). Methods: Seven hundreds thirty-five patients with probable AD, 212 with other types of dementia (75 with FTLD, 40 with LBD, 97 with VaD) and 506 age- and ethnicity-matched subjects without dementia were genotyped by Restriction Fragment Length Polymorphism (RFLP) technique. Chi square test was used for comparisons. OR was calculated along with its CI. Results: The frequency of the ApoE e2 allele was significantly lower in patients with AD than in controls (2.8 % versus 6.4 %, P < 0.001, OR: 0.41, CI:0.27–0.62). Similar results were obtained comparing AD with FTLD (2.8 versus 6.7 %, P < 0.01, OR: 0.37, CI: 0.18–0.77), but not with VaD or LBD (P> 0.05). The frequency of the ApoE e4 allele was significantly increased in patients with AD as compared with CON (25.1 versus 8.2 %, P < 0.001, OR: 4.24, CI: 3.20–5.61), as well as FTLD (25.1 versus 11.3 %, P < 0.001, OR: 2.67, CI: 1.53–4.67), VaD (25.1 versus 11.8 %, P < 0.001, OR: 3.02, CI: 1.81–5.04), or LBD (25.1 versus 13.8 %, P = 0.048, OR: 2.07, CI: 1.02–4.21). The frequency of the e4/e4 genotype was significantly increased in AD patients as compared with controls (6.3 versus 0.8 %, P < 0.001, OR: 8.38, CI: 3.00–23.43). Conclusions: the presence of the e2 allele is a protective factor towards the development of AD, but not FTLD. The e4 allele is a specific risk factor for AD, but not for FTLD, VaD or LBD. The presence of two copies of the e4 allele increases the risk to develop the disease by almost ten fold. O55 Frequency of mutations in progranulin gene in frontotemporal lobar degeneration J. Fortea, A. Lladó, M. Ezquerra, R. Sanchez-Valle, J. Molinuevo Hospital Clinic (Barcelona, ES) Objective: To determine the frequency of mutations in progranulin (PGRN) gene in patients with clinical or pathological diagnosis of frontotemporal lobar degeneration (FTLD). Methods: We studied 10 patients who fulfilled clinical criteria of FTLD and 11 cases with pathologically proven FTLD ubiquitin-posive tau-negative (FTLD-U) selected from the University of Barcelona/Hospital Clínic brain bank. Three of the FTLD-U cases presented neuronal intranuclear inclusions (NII). Patients were classified clinically according to Neary’s criteria as frontotemporal dementia (FTD), semantic dementia (SD) or progressive nonfluent aphasia (PNFA). Patients who presented signs of motor neuron disease were classified as FTLD-MND. Familial history of disease was considered when at least one first-degree relative presented dementia. An autosomal dominant (AD) pattern of inheritance was defined by the presence of three members affected in two generations. All patients lacked mutations in the MAPT gene. Clinical histories of the pathologically proven cases were retrospectively reviewed and clinically classified according to the same criteria. The12 coding exons and the non coding exon 0 of PGRN gene were screened by direct sequencing in all cases. Results: 4 patients with clinical FTLD and 4 patients with FTLD-U pathology presented familial history of disease (1 and 2 cases with AD pattern, respectively). PGRN mutations were not identified in any of the 10 FTLD patients (4 FTD, 5 SD and 1 PNFA). The clinical diagnosis of 11 FTLD-U was: 6 FTLD-MND, 3 SD and 2 FTD. The study disclosed a PGRN mutation in one FTLD-U sample with NII clinical FTD diagnosis and AD

pattern of inheritance. The mutation was a deletion in exon 8, that causes a frameshift at codon 303 introducing a premature termination at the aminoacid 360 (A303AfsX57), leading to a truncated protein. Conclusions: The frequency of PGRN mutations was 5 % in the whole cohort, 9 % in pathologically proven FTLD-U and 33 % in FTLD-U with NII.We did not find PGRN mutations in our clinical series or in FTLD-U without NII presenting clinically as FTLD-MND. We found a new PGRN mutation in a patient with a clinical diagnosis of familial FTD and FTLD-U with NII in the neuropathological exam. O56 The efficacy, safety effect of tramiprosate in the treatment of mild-to-moderate Alzheimer’s disease: results of an 18-month Phase III trial S. Gauthier, P. Aisen, B. Vellas, R. Briand, D. Saumier, G. Soulban, J. Laurin, D. Garceau McGill Centre for Studies in Aging (Montreal, CA); Georgetown University Medical Center (Washington, US); University of Toulouse Hospital (Toulouse, FR); Neurochem Inc. (Laval, CA) Objectives: To assess the efficacy, safety, and disease modification effect of tramiprosate, a novel anti-amyloid compound intended for the treatment of Alzheimer’s disease (AD). Methods: The study was a North American multi-centre, randomized, double-blind and placebo controlled Phase III trial. Patients (n = 1052) with mild-to-moderate AD (with baseline Mini Mental State Examination [MMSE] scores of 16–26) were randomized to receive either tramiprosate 100 mg BID, 150 mg BID or placebo BID for 18 months, which included a 1–2 month dose titration period. Patients were required to be on stable doses of acetylcholinesterase inhibitors, which could be combined with memantine, for a minimum of 4 months prior to screening. Efficacy assessments were performed every three months after study entry. Primary efficacy measures were the Alzheimer’s disease Assessment Scale, cognitive subscale (ADAScog), and Clinical Dementia Rating-Sum of Boxes (CDR-SB). The MMSE, Clinician’s Interview Based Impression of Change, plus Caregiver Interview (CIBIC-plus), Neuropsychiatric Inventory (NPI) and Disability Assessment for Dementia (DAD) served as secondary efficacy measures. Safety assessments included adverse events reporting, laboratory parameters, electrocardiograms, and physical exams. Brain volumetric MRI was performed at screening and month 18 visits to assess the disease modification effect of tramiprosate. Patients who fully completed the double-blind study were offered participation in an 18-month open-label extension trial of tramiprosate. Results: Patients enrolled had a mean age of 74.0 ± 8.6 years and a mean MMSE baseline score of 21.0 ± 3.2 points. Primary efficacy endpoints will include changes from baseline in ADAS-cog and CDR-SB scores. Score changes from baseline to each visit for the MMSE, CIBIC-plus, NPI and DAD will serve as secondary endpoints. Changes in volumetric MRI measures and rates of cognitive decline over the course of the study will be presented to address disease modification. A description of tramiprosate’s safety results will also be provided, along with data obtained from the open-label extension trial. Conclusion: Tramiprosate represents a potential new class of therapeutic agent for AD. The results presented will provide evidence for tramiprosate’s safety, efficacy and potential to slow AD progression. These results will be discussed in the context of an ongoing European Phase III trial of tramiprosate. Drs. Gauthier, Aisen and Vellas are consultants for and have received grants from Neurochem Inc. Drs Briand, Saumier, Soulban, Laurin and Garceau are employees of Neurochem Inc. O57 Ten-year surveillance of Creutzfeldt-Jakob disease in Taiwan S-S. Chen, S-L. Lai, W-C. Shyu, C-J. Lu Taiwan Neurology Society (Kaoshiung, TW); Kaohsiung Chang Gung Memorial Hospital (Kaoshiung, TW); Chang Gung University (Kaoshiung, TW) Objectives: The national surveillance program for Creutzfeldt-Jakob disease (CJD) in Taiwan was initiated in 1996 and well established in 1997 at Department of Health (DOH), Execute Yuan, Taiwan. Epidemiological data, clinical and risk factor analysis, results of polymorphism study and therapeutic trial will be presented. Methods: A retrospective review of the past CJD cases was made in 1996, and a total of 37 cases were enrolled based on the WHO criteria for the clinical diagnosis of probable CJD and then a prospective survey was starting from 1997. In 1998, the National Surveillance Unit for CJD and and other Human Transmissible Spongiform Encephalopathies was submitted from DOH

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to Taiwan Neurological Society. The information presented in this study provides evidence of a clincal level of case ascertainment. The study period and data collection in this presentation started from 1997 till end of 2006. Results: Till end of 2006, a total of 175 cases; including 83 males and 92 females had been confirmed, and 93.1 % of cases were beyond 50 years old. The gender difference is not statistically significant. No case of vCJD has been found. The annual incidence rate were: 0.28, 0.59, 0.55, 0.50, 0.54, 0.58, 0.36, 0.75, 0.40, 0.70 per million population from 1997 till 2006. Mortality rates ranged 0.23~0.76 /million/year. These rates are not higher than those observed in other countries elsewhere in the world. There was some variation in the observed incidence rates between the different areas but this variation is not statistically significant. Besides the age, there was no siginificant risk factors. The autopsy rates of suspected CJD patients were lower due to cultural against with the post-mortem autopsy. This is reflected in the lower number of brain specimens examined in this country. A polymorphism study of methionine homozygosity at codon 129 of the prion protein gene is also serving the key mark for CJD from 2004, 52 cases of CJD cases with available genetic analysis have all been methionine homozygotes. In addition to the clinical presentation, EEG,.DWI of MRI and CSF 14-3-3 are the most sensitive diagnosis tool. Finally, so far, no medication, including Quinacrine, was proved to be effective for the treatment of CJD. Conclusion: The annual incidence rate and mortality rates of CJD were below 0.80/million/year in Taiwan. No vCJD was found. All of the cases were methionine homozygous. EEG, DWI of MRI and CSF 14-3-3 protein were sensitive diagnostics. No medication was proved to be effective for CJD.

Oral session 5 Cerebrovascular disorders 1 O58 Clinical spectrum of posterior reversible encephalopathy syndrome O. S. Kozak, A. Rabinstein Mayo Clinic (Rochester, US) Background and Purpose: Posterior reversible encephalopathy syndrome (PRES) is a well-recognized clinical entity characterized mainly by headache, seizures, and visual changes along with typical imaging features, primarily in the territories of the brain supplied by the posterior circulation. The still considerable debate exists on the etiology (PRES). Recently several new settings were added to the list of the potential clinical triggers. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES. We have aimed to identify several underlying factors and their effect on the outcome. Methods: The clinical presentation and neuroimaging features of 81 patients who developed PRES between years of 1999–2007 at the Mayo Clinic were retrospectively evaluated in detail. Results: We have identified 81 patients (49 females, 32 males) with PRES. Presumed etiology was severe hypertension in 54 (67 %), eclampsia in 8 (10 %), immunosuppressive medication in 9 (10 %), sepsis in 5 (6 %). Significant comorbid conditions included renal failure (42 %), autoimmune disorder (22 %), and organ transplantation (18 %). Recurrent PRES was observed in 4 patients. Effects of comorbid conditions on outcome were evaluated. Conclusion: We report a large clinical series of PRES. PRES is becoming a more commonly diagnosed condition with the frequent use of advanced imaging studies. It is important to identify the potential causes of PRES and associated comorbid conditions for prevention, earlier diagnosis and treatment. O59 Anosmia after aneurysmal subarachnoid haemorrhage M. Wermer, M. Donswijk, P. Greebe, B. Verweij, G. J. E. Rinkel University Medical Centre Utrecht (Utrecht, NL) Objective: Anosmia has an important impact on well-being, but is often neglected by physicians. In patients with subarachnoid hemorrhage (SAH) it has been reported mainly after surgery for aneurysms of the anterior communicating artery (ACA). In SAH patients we studied the prevalence, predisposing factors (aneurysm site and type of treatment), impact and prognosis of anosmia.

Methods: From those SAH patients who resumed independent living, we included all patients treated by coiling between 1997 and 2003 and a sample of patients treated by clipping between 1985 and 2001. Patients underwent structured interviews regarding the presence and duration of anosmia. The impact of anosmia was scored on a visual analog scale (VAS) ranging from 0 (no influence) to 100 (the worst thing ever). Risk factors for anosmia were assessed by logistic regression analysis. Results: Overall 89 (28 % [95 % CI 23–34 %]) of the 315 interviewed patients reported anosmia after the SAH (mean follow-up 7.4 years); 10 (15 %) of the 67 coiled patients and 79 (32 %) of the 248 clipped patients. The median VAS impact score was 53 (range 0–100). In 20 of the 89 patients (23 % [95 % CI 15–33]) the symptoms had improved over time. Risk factors for anosmia were treatment by clipping (OR 2.7 [95 % CI 1.3–5.7]) and ACA aneurysms (OR 2.0 [95 % CI 1.2–3.3]) Conclusion: Anosmia after SAH has a high prevalence, a considerable impact and a poor prognosis. Its occurrence after coiling suggests that not only damage to the olfactory nerve by clipping but also the SAH itself plays a role in its pathogenesis. O60 Previous treatment with angiotensin II receptor blockers: possible protector effect in acute cerebral infarct M. A. Ortega-Casarrubios, B. Fuentes, B. San José, M. J. Aguilar-Amat Prior, I. Ybot, P. Martinez-Sanchez, E. Díez-Tejedor Stroke Unit, Hospital Universitario La Paz (Madrid, ES); Biostatistics, Hospital Universitario La Paz (Madrid, ES) Objectives: Previous studies with angiotensin II receptor blockers (ARB) have demonstrated a protective effect in spontaneously hypertensive rats from cerebral ischemia. It is not known if all the hypotensor drugs share this property. Our goal is to analyse the impact of pre-stroke use of hypotensor drugs in stroke severity and outcome. Methods: Observational study from the Stroke Unit data bank of the Department of Neurology, with inclusion of consecutive stroke patients (January 2000-October 2005). Parameters analysed: Risk factors, previous hypotensor drug treatment, severity on admission (Canadian Stroke Scale, CSS), in-hospital complications, mortality and functional state at discharge (Modified Rankin Scale, mRS) Results: 1738 patients were included in the study, 55.9 % were men. Average age: 69.61 ± 12 years. 63.3 % had high blood pressure and 27.9 % DM. 39.4 % received hypotensor drugs (90.2 % of them for hypertension). Patients with ARB presented lower stroke severity on admission (EC ≤ 6: 16 vs. 29.4 %, p = 0.011) and better functional state at discharge (mRS ≤ 2: 78 vs. 63.6 %, p = 0.008) The multivariate logistic analysis showed that ARB pretreatment was a predictive factor of lower stroke severity, independent of age, sex and stroke subtipe (OR 0.4; 95 % IC 0.2–0.7) Patients treated with diuretic drugs had higher severity on admission (EC ≤ 6: 34.5 vs. 27.3, p = 0.023) and worse outcome (mRS ≤ 2: 58.9 vs. 65.8 %, p = 0.044). Other groups of hypotensor drugs did not show significant benefit on stroke severity. Conclusions: Previous treatment with ARB was associated with a lower acute stroke severity on admission and better evolution, being an independent predicitive factor of lower stroke severity. More studies are needed to confirm this posible protector role. O61 Lacunar infarcts benefit the most from statins treatment P. Martinez-Sanchez, C. Rivera-Ordoñez, B. Fuentes, M. Ortega-Casarrubios, E. Diez-Tejedor Hospital Universitario La Paz (Madrid, ES) Background and Purpose: Statins have a neuroprotective effect after ischemic stroke in observational studies. However, this effect has never been assessed according to etiological subtypes. Our goal is to evaluate if statin pretreatment improves outcome in the different stroke subtypes. Methods: Observational study from the Stroke Unit Data Bank with inclusion of consecutive patients with cerebral infarct (January 1998-October 2005). We analyzed: demographic data, cardiovascular risk factors, treatment with statins at the stroke onset, stroke severity (Canadian Stroke Scale), stroke subtype, in-hospital complications, and functional status at discharge (modified Rankin Scale [mRS]). Results: A total of 2,344 patients were included, 1313 were men. Mean age was 69.28 ± 12.35 years. 216 patients (9.1 %) were receiving statins when admitted. Unfavorable outcomes at discharge (mRS ≥ 2) were less frequent in the statin group (OR, 0.740; 95 % CI, 0.559 to 0.980) for all strokes and for patients with stroke of arterial origin infarct (lacunar plus atherothrombotic infarct) (OR, 0.675; 95 % CI, 0.467 to 0.976). However, only the lacunar sub-

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type reached statistical significance separately (OR, 0.497; 95 %, CI 0.272 to 0.908). The logistic regression analyses showed that previous treatment with statins was an independent predictor for better outcome at discharge among all strokes (OR, 0.646; 95 % CI, 0.454 to 0.920) and for lacunar infarcts (OR, 0.487; 95 % CI, 0.259 to 0.915) after adjustment for demographic data, risk factors, stroke subtypes, stroke severity and in-hospital complications. Conclusions: Previous treatment with statins is an independent factor for good outcome in patients with ischemic stroke. Lacunar infarct has the greatest benefit. O62 Are there any differences between intracranial vascular malformations in the characteristics of their presenting haemorrhages? A prospective, population-based study C. Cordonnier, R. Al-Shahi Salman, J. Bhattacharya, C. Counsell, V. Papanastassiou, V. Ritchie, R. Roberts, R. Sellar, C. Warlow Lille University Hospital (Lille, FR); Division of Clinical Neurosciences (Edinburgh, UK); Institute of Neurological Sciences (Glasgow, UK); Department of Neurology (Aberdeen, UK); Fauldhouse Health Centre (Edinburgh, UK); Department of Neurology (Dundee, UK) Background: Intracerebral haemorrhage (ICH) accounts for 10–20 % of stroke. Intracranial vascular malformations (IVM) are the leading cause of ICH in young adults, but they occasionally cause ICH deep in the brains of hypertensive elderly people. The choice of brain and vascular imaging to detect the cause of ICH may be influenced by the type of IVM that is thought likely to underlie the ICH. Objective: We sought to determine the brain imaging characteristics of presenting ICHs, subsequently found to be due to an IVM, for the first time in a contemporaneous, prospective, population-based study design. We hypothesized that haemorrhages due to cavernous malformation (CM) are smaller than those due to brain arteriovenous malformation (BAVM) or dural arteriovenous fistula (DAVF). Methods: The Scottish Intracranial Vascular Malformation Study (SIVMS) is a prospective, population-based study of all adults resident in Scotland and diagnosed for the first time with an IVM between 1999–2003. We compared the morphological characteristics and volume (calculated using the ABC/2 formula) of ICHs on presentation imaging that were subsequently found to be due to BAVM, CM, or DAVF. Results: Of 394 adults in SIVMS, 141 presented with intracranial haemorrhage, of which 115 were ICH (with or without subarachnoid, intraventricular or subdural extension). The median volume was larger for BAVM (16.0 cm3, inter-quartile range (IQR) 4.7 cm3 to 42.0 cm3) and DAVF (14.1 cm3, IQR 4.9 cm3 to 21.5 cm3) than for CM (1.8 cm3, IQR 1.3 cm3 to 4.3 cm3) (Kruskal-Wallis, p < 0.0001). Excluding ICH due to CM, the volume of BAVM and DAVF ICH were similar (Mann-Whitney, p = 0.622). However, small ICH volumes (for example, 2.5 cm3) occurred among all IVM types, while the largest CM ICH was 12 cm3. Pure ICH accounted for all CM haemorrhages, but only 50 % of BAVM and DAVF bleeds (the rest extended into ventricular, and/or subarachnoid and/or subdural spaces). Discussion: We have confirmed the common clinical perception that BAVM and DAVF ICH are in general larger than ICH due to CM.While small ICH may be due to any IVM type, we have not found ICH > 12cm3 to be due to CM. Both magnetic resonance and angiographic imaging are still necessary to determine the cause of ICHs when any type of IVM is suspected as the underlying cause of ICH. Charlotte Cordonnier was funded by the European Neurological Society, the Journées Neurologiques de Langue Française, the Stevenson Exchange Scholarship, and the Fondation Bettencourt Schueller. O63 White matter and pulvinar signal abnormalities in Fabry disease: data from the Fabry Outcome Survey R. Manara, L. Ginsberg, M. Severino, A. R. Valentine, B. Kendall, J. T. R. Clarke, A. Metha, A. P. Burlina for the European FOS Investigator Group Background: Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the activity of alpha-galactosidase A. CNS manifestations occur in a significant proportion of patients and Fabry disease is known to be associated with stroke, particularly in the young population. MRI abnormalities are frequent and involve mostly the white matter and the posterior region of the thalamus but the meaning of these findings is not well understood. We present data on the frequency of these abnormalities in the Fabry Outcome Survey (FOS). Methods: among 1273 patients enrolled in FOS database, brain MRI scans of 84 Fabry patients (48 males, 36 females, mean age 41, range 4–71)

were centrally analyzed. We recorded pulvinar T1 hyperintensity and ischemic lesions; moreover, white matter abnormalities were graded as absent, 1–5, 6–10, and more than 10 or confluent lesions. Results: 44 patients (52 % of the studied population, 28 males, 16 females) had an abnormal brain MRI; 6 patients had an ischemic stroke, 2 a haemorrhage, 18 dolichoectasia of the basilar artery. The most frequent MRI finding was the presence of white matter abnormalities (WMA) which were found in 38 subjects (45 % of the studied population, 23 males); severe WMA (more than 10 or confluent lesions) were detected in 29 patients (17 males, mean age 28–71). WMA increased in number and frequency with age but there was no difference between genders. Bilateral pulvinar sign was present in 13 patients (12 males – 1 female, mean age 43), 9 of whom presented severe WMA. Cardiac complications correlated with severe WMA (p < 0.05). No correlation between the pulvinar T1 hyperintensity and end stage renal failure (ESRF) was detected. There is a correlation between the pulvinar sign and the presence of severe WMA (p = 0.009, Fisher Exact test). Conclusions: White matter and pulvinar abnormalities are frequent in young Fabry patients, including females. The identification of a typical Fabry pattern of brain MRI could be helpful in defining the cause of cerebrovascular events in the young.

Oral session 6 Multiple sclerosis 1 O64 Addressing the enigma of invisible pathology in multiple sclerosis: a multimodal approach to characterise “normal appearing” and diffusely abnormal white matter A. Seewann, H. Vrenken, E. L. A. Blezer, C. van Urk, A. van der Toorn, J. A. Castelijns, C. H. Polman, P. J. W. Pouwels, F. Barkhof, L. Boe, J. J. G. Geurts Medical University Graz (Graz, AT); VU University Medical Center (Amsterdam, NL); University Medical Center Utrecht (Utrecht, NL) Objective: to reveal and histopathologically characterize subtle tissue changes in the normal appearing white matter (NAWM) and diffusely abnormal white matter (DAWM), also known as “dirty white matter”, of multiple sclerosis (MS) patients. Additional pathology beyond MR-visible focal lesions may contribute to the clinicoradiological dissociation. This may be remedied by increasing MRI sensitivity to subtle tissue changes in the NAWM, and characterizing DAWM (as detected on T2-weighted MRI) which could be an expression of (severe) histopathologic damage. Materials and Methods: 22 formalin-fixed, coronally cut brain slices from 15 patients with chronic MS (seven females) and three slices from two control subjects (1 female) without neurological disease were examined both with qualitative MRI (dual-echo T2 spin-echo at 1.5T and a proton density [PD] weighted sequence at 4.7T) and with quantitative MRI (1.5T; magnetization transfer (MT)and diffusion tensor (DT) imaging, T1 mapping, T2 mapping. In NAWM, focal lesions, and DAWM, a total of 39 regions of interest (ROIs) were placed. These ROIs were compared with corresponding ROIs on the 4.7T PD and histological slices (10micron). MTR, DTI, and relaxation time measurements are currently being correlated with histopathological findings. Histopathology (both quantitative and semiquantitative ratings) includes: axonal density (Bodian silver stains), myelin density (LFB, astrogliosis (GFAP, microglial reactivity (MHC class II, acute axonal pathology (APP, and blood-brain barrier leakage (fibrinogen. Results: so far, we have found that DAWM at 1.5T is also diffusely abnormal at high-field (4.7T. This suggests that DAWM at 1.5T is not simply a confluent, multifocal lesional pattern, but that it may reflect a pathological process separate from the typical focal lesions. All histopathological analyses will be completed within the coming three months. Conclusion: with this comprehensive approach, using different MR fieldstrengths, as well as qualitative and quantitative MRI and histopathology, we aim to elucidate the histopathological correlates of DAWM. Furthermore, the question whether NAWM at clinical field-strength (1.5T) is still “normal-appearing” at 4.7T, and normal in histopathological terms, will be investigated. Finally, it will be assessed whether quantitative MRI at 1.5T increases both sensitivity and specificity with respect to pathology in NAWM and DAWM, compared to qualitative 1.5T and 4.7T MR imaging. The MS Center Amsterdam is financially supported by the Dutch MS Research Foundation (grant no: 06–358 c)

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O65 Extent of deep grey matter atrophy in patients with multiple sclerosis. A case control study D. P. Ramasamy, D. Fritz, J. L. Cox, N. Abdelrahman, S. Hussein, M. G. Dwyer, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, US) Background: It has been shown that selective thalamic, caudate and putamen atrophy is present in patients with multiple sclerosis (MS). The role of hippocampal atrophy in MS is unknown. FreeSurfer software, a set of voxelbased automated tools for brain reconstruction, offers an opportunity to investigate the influence of tissue-specific deep gray matter (DGM) atrophy in MS Objective: To investigate the extent of DGM atrophy in patients with MS. To examine the relationship between DGM atrophy and disease severity. Design/Methods: We examined 82 MS patients [46 relapsing-remitting (RR), 18 secondary-progressive (SP) and 18 primary-progressive (PP)], 22 normal controls (NC) and 17 patients with clinically isolated syndrome (CIS). Segmentation was performed on 3D SPGR T1-weighted 1mm MRI 1.5T images. Region-specific tissue volumes were calculated for the thalamus, caudate, putamen, pallidum, hippocampus, amygdala and accumbens regions. Mean scan-rescan COV was 2.9 %. Logistic regression and general linear model (GLM) analyses, adjusted for age, were conducted to investigate differences between NC, MS and CIS patients, and according to the disease course groups. Results: In GLM analysis, thalamus, putamen, hippocampus, caudate and amygdala volumes were significantly lower in the MS group than in NC. Logistic regression analysis included only the thalamus (p < 0.0001) and caudate (p = 0.003). In CIS patients, only the thalamus (p = 0.007) showed a lower volume than NC. RR, SP and PP patients showed lower thalamic, putamen, hippocampus and caudate volumes than CIS. DGM volumes were not significantly different between different disease subtypes. All DGM structures correlated with disease duration (r = 0.28 to 0.49) and disability (as measured by EDSS) (r = 0.21 to 0.39). Conclusions/Relevance: This study confirms selective thalamic atrophy in CIS patients. DGM atrophy is common in MS patients and selective for the thalamus, caudate, hippocampus and putamen regions. Lower volumes in these structures are related to more severe disease outcome. O66 Macroscopic and microscopic changes in deep grey matter structures of patients with multiple sclerosis V. Durastanti, F. Tovar-Moll, I. Evangelou, S. Pellegrini, J. Ohayon, M. Ehrmantraut, D. Gaindh, F. Cantor, H. McFarland, F. Bagnato National Institutes of Health (Bethesda, US) Objectives: To investigate the correlation between macroscopic (volume reduction) and microscopic (diffusion tensor imaging [DTI] measurements) changes in the thalamus, caudate, and putamen in patients with multiple sclerosis (MS). Methods: Sixteen patients (12 females and 4 males, mean age = 42.06 ± 7.94 years) with clinically definite relapsing remitting (RR) (n = 9) and secondary progressive (SP) (n = 7) MS (mean Expanded Disability Status Scale [EDSS] = 3.9 ± 2.23 and disease duration = 14.25 ± 6.99) were enrolled in the study. Seventeen age-and gender-matched healthy volunteers (HVs) were also recruited. Magnetic resonance (MR) images of the whole brain were acquired on a 3.0 Tesla GE Excite scanner with an 8-channel array coil using the following sequences in the axial plane: (1) T1 weighted (T1W) 3D – Inversion Recovery Spoiled Gradient Echo (IR-SPGR) with TE/TR/TI = 3/7.5/750 ms, voxel size = 1 mm3, repeated three times and (2) DTI with 33 isotropic directions with b-value = 1000 s/mm2, 3 images with b-value = 0, TR/TE = 13000/76 ms, voxel size = 2.5 mm3, repeated twice. For each examined structure, volume measurements were obtained using Freesurfer. Regions of Interest (ROI) were placed in 3 consecutive slices for the thalamus (size = 8 x 10 pixels), in 1 slice for the caudate and putamen (size = 4 x 4 pixels) and fractional anisotropy (FA) and mean diffusivity (MD) measurements were computed using DTI-studio in these ROIs. Mean differences in volume, FA and MD values were investigated using an unpaired t-test whereas correlations between them were evaluated using the Pearson correlation coefficient. Results: Significant changes (p ≤ 0.05) between patients and HVs were found in mean values of volume and FA, but not MD, of the thalamus, caudate and putamen. Significant negative correlations arose only between the mean volume and FA of caudate (p < 0.01, r = –0.66). Conclusion: These results illustrate the presence of both microscopic (increased FA) and macroscopic (reduced volume) changes in patients with MS. Increased FA in the caudate may be the result of axonal degeneration

and neuronal loss thus correlating with volume loss. In the thalamus, where a higher number of white matter fibers intersect, increased FA may be the result of plasticity repairing mechanisms explaining the lack of correlations with the volume loss. O67 Hippocampal atrophy does not correlate with cognitive decline in patients with multiple sclerosis R. Benedict, D. P. Ramasamy, J. L. Cox, M. G. Dwyer, D. Fritz, F. E. Munschauer, B. Weinstock-Guttman, R. Zivadinov Jacobs Neurological Institute (Buffalo, US); Buffalo Neuroimaging Analysis Center (Buffalo, US) Background: Failures in processing speed and new learning are the cardinal features of multiple sclerosis (MS)-associated dementia. Previous work was shown that frontal and temporal lobe atrophy are correlated with tests measuring learning and memory. Objective: To explore brain/behavior and deep gray matter atrophy in patients with MS, using FreeSurfer software, a set of voxel-based automated tools for brain reconstruction developed by the Harvard-Massachusetts Institute of Technology. Design/Methods: We studied 49 clinically definite MS patients [age 45.8+8.6; 87.8 % female; 65 % relapsing course]. Cognitive tests measuring processing speed [Symbol Digit Modalities Test (SDMT)] and learning/memory [California Verbal Learning Test-II; Brief Visuospatial Memory Test-Revised] were applied. Segmentation of 3D SPGR T1-weighted 1 mm3 MRI [1.5T] images was performed for subcortical structures and hippocampus. Region specific tissue volumes were calculated by registering MRI volumes to Talairach space and labeling output segmentation masks using a probabilistic atlas where each voxel was assigned to the following areas: thalamus, caudate, putamen, third ventricle volume (3VV), hippocampus. Mean scan-rescan COV was 2.9 %. Linear measurement of third ventricle width (3VW) was also performed. Results: Correlations were calculated controlling for the effects of age. 3VW was strongly correlated with 3VV (r = 0.83). Consistent with prior work, 3VW was strongly correlated with SDMT. Correlations between SDMT and deep gray matter regions were significant with thalamus showing the strongest relationship (right 0.50, left 0.63). There were no correlations between any test and hippocampal volume. Controlling for the effects of education and depression did not alter the findings. Conclusions/Relevance: Disruption of frontal/subcortical circuitry is responsible for MS-associated defects in processing speed, but not episodic memory. Amnesia in MS is not directly related to hippocampus atrophy, as might be anticipated from the literature showing that memory failures in MS are not due to impaired consolidation. O68 Is magnetic resonance imaging a reliable tool for prediction of disability progression in patients with early relapsing-remitting multiple sclerosis? A 5-year longitudinal study D. Horakova, M. G. Dwyer, E. Havrdova, J. L. Cox, O. Dolezal, N. Bergsland, B. Rimes, J. Krasensky, M. Vaneckova, R. Zivadinov Charles University (Prague, CZ); Buffalo Neuroimaging Analysis Center (Buffalo, US) Objective: The value of MRI measurement over the long term in predicting clinical progression in multiple sclerosis (MS) has not been fully elucidated. Therefore, the objective of this analysis was to assess the relationship between MRI metrics and clinical status in a group of highly active, early relapsing-remitting MS patients over 5 years. Methods: 181 patients from the original Avonex-Steroids-Azathioprine study were included in the analysis. Mean age was 30.7 years, disease duration was 5.5 years and Expanded Disability Status Scale (EDSS) score was 1.9. Clinical (EDSS and relapse rate) and MRI assessments were performed every 2 months in the first 24 months and then clinical examination was performed every 3 months and MRI annually in the 3-year extension study. Whole and tissue-specific brain atrophy measures were calculated using SIENA/X. T2-lesion volume (T2-LV) and central atrophy also were measured. Patients were classified according to their clinical status as Stable or Reached Confirmed Sustained Progression (RCSP) (24 weeks sustained disability) at each study time point. Results: At baseline, there were no significant differences in clinical or MRI variables between the Stable and RCSP groups. At each study time point, the RCSP group had a significantly larger percent brain volume change (PBVC) than the Stable group. The highest difference was at 0–24 months (–2.3 % vs. –1.2 %, p < 0.0001). In regression analysis, at 0–6 months PBVC and gray matter volume (GMV), at 0–12 months PBVC, GMV and T2-

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LV, at 0–24 months PBVC and GMV, at 0–36 months PBVC, GMV and T2-LV, and at 0–48 months PBVC predicted the differences between the RCSP and Stable groups. Stable patients who presented with ≥ 3 relapses had similar PBVC compared with the RCSP group over 5 years (–5.3 % for both groups). Conclusions: PBVC progression was the strongest marker of clinical deterioration. Among regional atrophy markers, GMV predicted the best clinical status. A greater change in brain atrophy was shown in the Stable group of patients with a higher number of relapses. This study was supported by Biogen Idec, Inc. O69 Rebif® New Formulation (RNF; interferon beta-1 a): 1-year results of a phase IIIb study in patients with relapsing forms of multiple sclerosis P. Sørensen, O. Barbarash, F. Casset-Semanaz, G. Giovannoni, J. King, L. Metz, G. Pardo, J. Simsarian, B. Stubinski on behalf of the RNF Study Group Objectives: Rebif® New Formulation (RNF; interferon [IFN] beta-1 a), which is free from human- or animal-derived components, has been developed to maximize treatment benefit by improving injection tolerability and reducing immunogenicity. This study was designed to investigate the safety and immunogenicity of RNF 44mcg/0.5mL injected subcutaneously (sc) 3 times weekly (tiw). Methods: This 48-week analysis compares data from an ongoing 96week, Phase IIIb, multi-centre, single-arm, open-label study of RNF with historical data on IFN beta-1 a, 44mcg sc tiw (Rebif®), from the EVIDENCE study. Patients in both studies were aged 18–60 years, diagnosed with relapsing multiple sclerosis and had an EDSS < 6.0. Patients with neutralizing antibody (NAb) titres ≥ 20NU/mL were considered NAb+. Safety analyses included assessment of 8 pre-specified adverse event groups of interest. The proportion of patients who were relapse-free up to week 48 was also assessed. Results: At week 48, 227/260 patients (87.3 %) remained on the study. A smaller proportion of RNF-treated patients were NAb+ at week 48 (13.9 % [95 % CI:9.9–18.7]) than in EVIDENCE (24.4 % [95 % CI:19.9–29.4]; last observation carried forward). Of the patients who were NAb+, the proportion of RNF-treated patients (11 %) who had high NAb titres (> 1000NU/mL) was also lower than in EVIDENCE (20 %). Also, a smaller proportion of patients receiving RNF were NAb+ at both 24 and 48 weeks (2.5 % [95 % CI:1.0–5.4]) than in the EVIDENCE study (14.3 % [95 % CI:10.7–18.6]). The incidence of 7/8 pre-specified adverse event groups was similar or lower in the RNF study, compared with EVIDENCE: injection-site reactions (30 % vs. 84 %, respectively; a threefold reduction); cytopenia (10 % vs. 12 %); depression and suicidal ideation (6 % vs. 20 %); hepatic disorders (13 % vs. 17 %); skin rashes (5 % vs. 12 %); thyroid disorders (2 % vs. 5 %); and hypersensitivity reactions (5 % vs. 3 %). The incidence of flu-like symptoms was higher with RNF than for historical data (71 % vs. 48 %); however, most events were mild in severity. At week 48, 67 % of RNF-treated patients were relapse-free; in the EVIDENCE study, 58 % were relapse-free. Furthermore, the mean relapse rate during the 12 months prior to informed consent for the RNF study was 1.03 (95 % CI: 0.53–2.30) and reduced to 0.37 (95 % CI: 0.22–0.71) at week 48, representing a 64 % reduction. Conclusion: These data suggest that RNF has an improved overall tolerability and safety profile and a lower immunogenic potential. This study was supported by Merck Serono

Oral session 7 Movement disorders 1 O70 Evidence for grip force scaling deficits in focal dystonia patients M. Obermann, O. Yaldizli, A. de Greiff, E. R. Gizewski, H.-C. Diener, M. Maschke University Duisburg-Essen (Essen, DE) Objective: To evaluate the generation of applied grip forces in patients with blepharospasm and cervical dystonia compared to healthy controls using functional magnetic resonance imaging (fMRI). Methods: Twenty focal dystonia patients (10 blepharospasm, 9 cervical dystonia) and 12 healthy controls were investigated with functional MRI performing a simple forearm contraction task. Subjects were asked to alter-

nately press a custom made grip force handle light and strong. The applied grip force was recorded and included as covariate in the fMRI analysis design. Results: Patients with focal dystonia showed similar mean grip force results and similar activation patterns in the contralateral pre-motor, primary motor and primary sensory cortex as well as the ipsilateral cerebellar hemisphere compared to healthy controls, but recruited considerably larger cortical resources performing both light and strong conditions. Moreover, the light condition that required more accurate generation of applied grip forces showed a much larger activation in focal dystonia patients and almost no difference to the strong condition in both patient groups. Conclusion: The disturbance of sensory-motor function in patients with focal dystonia is thought to be responsible for the generation of inefficiently high grip forces in relation to the underlying task. We were able to demonstrate this grip force scaling deficit in patients with two common forms of focal dystonia using fMRI. The here reported cortical changes exceeded the direct cortical representation of the affected dystonic musculature indicating a generalised affection of sensory-motor systems in focal dystonia. O71 Propriospinal myoclonus: utility of magnetic resonance diffusion tensor imaging and fibre tracking E. Roze, E. Apartis, M. Vidailhet, V. Cochen, Y. Beaugendre, J.-M. Trocello, P. Lasjaunias, D. Ducreux Saint Antoine Hospital (Paris, FR); Bicêtre Hospital (Paris, FR) Objective: Propriospinal myoclonus is a rare movement disorder characterized by involuntary spinal-generated muscular jerks that spread rostrally and caudally to other spinally innervated muscles. Most patients have no clear etiology, and conventional MRI of the spinal cord is generally normal. Here we report the use of magnetic resonance (MR) diffusion tensor imaging (DTI) and fiber tracking (FT) to detect tract-specific abnormalities in a patient with propriospinal myoclonus. Methods: MRI was performed with sagittal T2-STIR sequences, followed by a sagittal spin-echo single-shot echo-planar parallel Grappa diffusionweighted sequence with an acceleration factor of 2 and twenty-five noncollinear gradient directions with two b values (b = 0 and 500 s/mm2) (field of view = 17.9 ⫻ 17.9 cm; image matrix = 128 ⫻ 128; 12 slices with section thickness = 3 mm, nominal voxel size = 1.4 ⫻ 1.4 ⫻ 3 mm; TR/TE = 4600/83 ms). The DTI sequence lasted 3 min 10 s. The raw DTI images were analyzed with DPTools software and 3D fiber-tracking reconstructions. Results: In our patient, whereas conventional MRI was normal, colorcoded tracts analysis showed asymmetry and thinning of the posterior lemniscal tracts and corticospinal posterolateral tracts from spine levels C6 to T10, that predominate on the left side. In the patient the total numbers of visible fibers at level T10 were 168 and 173 for the posterior lemniscal tracts and posterolateral corticospinal tracts, respectively. By comparison, the mean values were 571.5 and 270.5 in a panel of five healthy volunteers. Conclusion: MR-DTI-FT may be useful for detecting spinal cord abnormalities in patients with propriospinal myoclonus. Tract-specific analyses of more patients are needed to determine the range of structural abnormalities associated with propriospinal myoclonus, and to further unravel the pathophysiology of this disease. O72 Who knows about cues in Parkinson’s disease? H. Laird, F. Gibson, A. Leake, M. Marion St. George’s, University of London (London, UK); St. George’s Hospital (London, UK) Objectives: Freezing is experienced by 20–60 % of patients with advanced Parkinson’s disease (PD) and is a major risk factor for falls, fracture, loss of independence and therefore reduced quality of life. The aim of the study is to establish if people with PD who experience the symptom of “freezing” are given adequate information on “cues” which are simple strategies which can be used by the patient or carer to overcome freezing using visual, rhythmic, acoustic or even mental stimuli. Methods: Questionnaires were administered to patients with PD who attended the movement disorder clinics at St. George’s, Lewisham University and King’s College hospitals between July and August 2006 and who had experienced freezing. Participants were asked if they were aware of cues, where they had found out about them and if they were happy with the information they had received. At the end of the questionnaire participants were then asked if they would find more information about cues useful. Participants were given examples of types of cue and were asked which they had tried and how well they worked. Results: Of the 41 patients interviewed, 21 (51 %) had experienced freez-

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ing and went on to complete the questionnaire. 4 (19 %) of those 21 who had experienced freezing were completely unaware of cues. The majority 13 (76 %) of patients who were aware of cues heard about cues from a health care professional, 9 (53 %) discovered it themselves, through a carer or another patient, 3 (18 %) heard about cues through the Parkinson’s Disease Society. Whilst 19 (90 %) patients were happy or neutral about the information they had been given on cues at the beginning of the questionnaire, 16 (76 %) wanted more information about cues at the end of the questionnaire. Of the 11 patients who had heard of cues from a health care professional, the majority 6 (55 %) had been informed by physiotherapists, the others were informed by neurologists, specialist nurses and occupational therapists respectively. Of the 17 patients who were aware of cues, only 4 (24 %) had been offered support to help improve their cueing techniques. Conclusion: 19 % of patients were unaware of cues. Of the 81 % who were aware of cues, only 24 % were offered support and encouragement to improve their techniques. 76 % of those who froze would find more information on cues useful. A patient education strategy with oral and written information will provide patients with the support they need to maintain their mobility and independence. O73 Anhidrosis in multiple system atrophy: a preganglionic sudomotor dysfunction? R. Liguori, M. Nolano, M. Elam, L. Santoro, P. Montagna, V. Provitera, A. Baruzzi, V. Donadio University of Bologna (Bologna, IT); Department of Neurology (Telese, IT); University of Goteborg (Goteborg, SE); University of Naples (Naples, IT) Objectives: Anhidrosis occurs in the majority of patients with Multiple System Atrophy (MSA) but the underlying mechanism is not well established. The aim of our study was to test in patients with MSA and anhidrosis whether skin biopsy associated with microneurography were effective in detecting the underlying sudomotor lesion site. Methods: We describe three patients with long-standing MSA and anhidrosis diagnosed on the basis of clinical findings and thermoregulatory test. Patients underwent to immunofluorescence analysis of sweat gland innervation and microneurographic recording of skin sympathetic nerve activity (SSNA) from the peroneal nerve to prove the integrity of postganglionic fibres in two patients. Results: Immunofluorescence analysis of sweat gland innervation detected a fair amount of sudomotor cholinergic fibres around sweat glands which showed a normal pattern of innervation encircling the tubules in all patients. No sudomotor innervation differences were found between distal and proximal lower limb sites. Skin sudomotor activity was absent suggesting a functional inactivity of postganglionic sudomotor fibres. Conclusions: Immunofluorescence analysis of sweat gland innervation excluded postganglionic sudomotor damage supporting the hypothesis of a preganglionic nerve fibre lesion underlying anhidrosis in our MSA patients. O74 Neuropsychological differences between Parkinson’s disease patients with mild cognitive impairment and early stage of dementia M. Petrova, Y. Zhelev, M. Raycheva, S. Mehrabian, L. Traykov Medical University (Sofia, BG) Background: In recent years, practical as well as theoretical considerations have engendered a strong interest in recognizing Parkinson’s disease dementia (PDD) at a very early stage. Recent studies suggest that onset of PDD is preceded by a phase known as Parkinson’s disease mild cognitive impairment (PD-MCI). However, the differences in the neuropsychological profile between patients with PD-MCI and mild PDD are still unclear. Objective: To determine the specific differences in the cognitive impairment between patients with PD-MCI and mild PDD. Methods: We investigated 43 patients with PD-MCI (modified Petersen’s criteria), 21 patients with early stage of PDD (DSM-IV) and 25 normal elderly controls. All subjects underwent a comprehensive neuropsychological assessment. Results: Relative to controls, PD-MCI group showed significant deficits in immediate (p < 0.0001) and delayed free recall (p < 0.0001) of the Free and Cued Selective Reminding Test, digit span forward (p < 0.002), phonemic (p < 0.0001) and semantic fluency (p < 0.0001), TMTB (p < 0.0001) and digit span backward (p < 0.0001). However, this group was unimpaired on recognition memory, Boston naming test,Wisconsin sorting test and copy of complex designs. Compared to PD-MCI, patients with mild PDD demonstrated significantly lower scores on all cognitive measures except the TMTB and the digit span forward. Conclusion: Impairments in episodic memory and attention/executive

functions are the most prominent features in the cognitive profile of PDMCI patients, while deficits in recognition memory, naming, concept-formation and constructional praxis are observed only in patients with PDD. The most affected executive subcomponents in PD-MCI group were initiation and strategic searching, cognitive flexibility and inhibitory control. Moreover, we found that the psychomotor speed and the selective attention are significantly affected in the stage of MCI and do not considerably progress with the cognitive deterioration. More prospective studies are needed to understand the longitudinal course of early cognitive changes in PD and to determine which of them represent a precursor to a more widespread dementia. O75 More than 10 years of botulinum toxin a treatment is effective and safe in patient with facial hemispasm M. T. Pérez-Saldaña, V. Parkhutik, M. Boscá, B. Claramonte, J. A. Burguera Neurología Hospital General de Castellón (Castellón, ES); Hospital La Fe de Valencia (Valencia, ES) Objective: Facial hemispasm (HFS) is defined by involuntary, unilateral, irregular, tonic or clonic contractions of muscles innervated by the ipsilateral facial nerve. Botulinum toxin A (BTA) injection has been the most important revolutionary therapeutic option of the new age. Short term benefits and benign side effects of BTA are well known. But there are few reports showing the effectiveness on long lasting therapy. Methods: We reviewed the demographics and the clinical features of 106 patients with HFS. We analyzed changes in doses, frequency of visits and side effects of BTA treatment, focussing on those with more than 10 years of treatment (1990-January 2007). Results: The mean age at onset was 59.21 ± 12.7 years (range: 24–86) and the mean duration of symptoms was 5.8 ± 6.2 years (range: 0.3–25). They were predominantly women (69.8 %). The right side was the most common affected (52 %). The orbicularis oculi was the most common muscle involved (85.8 % of patients), followed by risorio (69.6 %) and nasalis (61.3 %). The symptoms were exacerbated mostly by stress, and by specific actions like talking and reading. The symptoms appeared more than 50 % of time during the day. The mean score in Disability Scale was 8.89 ± 3.8 (range: 0–20). The most common cause was idiopathic (80.2 %). There was a prior history of Bell’s palsy in 11.3 % of the patients. The percentage of patients with more than 10 years of treatment was 54 %. The rate of discontinuation per year was higher the first seven years of experience with BTA treatment but it decreased after 1997. The mean dose of BTA per session increased significantly (p ≤ 0.05) thorough the years with an S shape curve. The number of visits per year increased progressively after the first visit also with sine curve shape and it kept constant between 2–4 and 11–15 years of treatment (p ≤ 0.05). Secondary effects occurred at 43 % of patients. Ptosis (81 %) was the most common of them, followed by haematoma (12.5 %) and facial weakness (12.5 %). They occurred mostly during the first years of treatment (mean 32.3 ± 30 months). There was a significant correlation between duration of treatment and occurrence of secondary effects (p = 0.042). Conclusion: BTA is an effective and safe option (with few and benign secondary effects) of treatment for patients with HFS. There is a trend to stability in mean doses per year and in frequency thorough the years that could be explained by stabilization of the disease.

Oral session 8 Peripheral neuropathy 1 O76 Different patterns of cytokines in chronic inflammatory polyneuropathies M. Gironi, M. Saresella, I. Marventano, F. r. Guerini, L. Ceresa, G. Antonini, S. Morino, P. Ferrante, E. Beghi, R. Nemni Don Carlo Gnocchi Foundation (Milan, IT); University of Rome La Sapienza (Rome, IT); Institute for Pharmacological Research Mario Negri (Milan, IT) Background: Immunological mechanisms underlying the heterogeneity of chronic inflammatory polyneuropathy (CIP) are still unsolved. In vitro and in vivo evidence suggests a clear role of pro and anti inflammatory cytokines in damage and protection of peripheral myelin and axons. We investigated

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whether Th1 and Th2 cytokines patterns could correlate with different clinical and histopathological patterns in CIP. Methods: This study was conducted in 65 patients with possible CIP (EFNS 2006). Exclusion criteria were any toxic, metabolic, neoplastic, hereditary or infective cause of neuropathy or an associated autoimmune disease. Included were patients aged 30 through 90 years in stable clinical conditions. With reference to clinical, electrophysiological and biochemical findings, 36 patients were classified as Chronic Inflammatory Demyelinating Neuropathy (CIDP), 19 as chronic idiopathic neuropathy (CIN), and 10 as IgM antiMAG polyneuropathy (antiMAG). The percentage of unstimulated and SEB+anti CD28 stimulated IL1, IL2, IFNg, IL10 and TNFa producing CD4+ and CD8+ and IL1, IL10, IL6 and TNFa producing CD14+ cells were analyzed by flow-cytometry. Mean cytokine values were compared in the three diagnostic categories by one-way analysis of variance (ANOVA). The direction of the statistical significance was tested by the Scheffe post-hoc test. Results: Significant differences across diagnostic categories were found for IL1 and IL10-producing CD4 cells (p < 0.0001), for IL1, IFNg, TNFa, IL10producing CD8 cells (p < 0.005 to p < 0.0001), and for IL1 and IL6-producing CD14 cells (p < 0.05). Post-hoc tests showed highest IL1 and IL10 CD4+ values and highest IL1 CD8+ values with anti-MAG. IFNg and TNFa CD8+ values were higher with CIDP and anti-MAG compared to CIN and particularly IFNg CD8+ values were highest with anti-MAG. The greatest differences in the IL1 and IL6 CD14+ values were seen between CIDP and anti-MAG (highest) and between CIN and anti-MAG (lowest). Discussion: A different pattern and maybe a different role of cytokines in nerve injury can be speculated for CIN, CIDP and anti-MAG. These immunological findings are consistent with morpho-immunological reports showing anti-MAG neuropathy as a different peculiar inflammatory neuropathy. The role of age, sex and disease duration will be also assessed with multivariate analysis models. O77 Gene expression profiling in vasculitic neuropathy J. Kinter, L. Broglio, M. Tolnay, P. Fuhr, N. Latov, D. Kalbermatten, A. J. Steck, N. Schaeren-Wiemers, S. Renaud University Basel (Basel, CH); University Hospital Basel (Basel, CH); Weill Medical College Cornell University (New York, US) Background: DNA microarray analysis is a powerful tool for simultaneous analysis and comparison of gene regulation in normal and diseased tissues. Vasculitic neuropathy occurs as a primary or as a secondary phenomenon and can be restricted to the peripheral nervous system only. Little is known about pathomechanisms and in particular in non-systemic vasculitis there are no disease markers. Objective: To demonstrate distinct gene expression patterns in archived frozen nerve biopsies of patients with vasculitic neuropathies compared to control nerve by DNA microarray analysis. Methods: Nerve biopsies from 8 patients with vasculitic neuropathy were included in this study. Two patients were suffering from virus associated nerve vasculitis, another two had non-systemic vasculitic neuropathy and the remainder were suffering from nerve vasculitis due to systemic disease. As controls, biopsy specimens were obtained from individuals who did not suffer from polyneuropathy, but from muscle dystrophy, dermatomyositis or who received reconstructive surgery in their legs. One control specimen was a sural nerve from an autopsy case. Total RNA was isolated and a biotin-labelled cRNA was generated for differential expression analysion on the Hu 133A 2.0 Affymetrix chip. Data analysis was performed using the Genespring package and Excel. Normalization was performed using robust multi-array analysis (RMA). For further analysis genes were selected, which were differentially expressed in more than half of the vasculitis specimens.A fold change threshold was set for further filtering and finally a Students t-test was performed to determine differentially expressed genes. Results: In vasculitic nerve 201 genes were differentially regulated compared to control nerves. There was a striking upregulation of mRNA of genes involved in immune regulation and inflammation. Of special interest are members of the complement familiy (complement component 1 and 4A), members of the MHC class II group, proteolytic enzymes like granzyme K, and granzyme A and matrixmetalloproteinase 9, adhesion molecules like CD52, immunoglobulins, TNF-beta and the chemokine family. Conclusion: We demonstrate an impressive up regulation of genes involved in immunity and inflammation in vasculitic neuropathy. Thus gene expression profiles may reveal mechanistic clues to the molecular pathogenesis of vasculitic neuropathies.

O78 Circulating levels of VEGF in POEMS syndrome and in immune-mediated neuropathies C. Giannotta, F. Terenghi, C. Casellato, F. Gallia, E. Nobile-Orazio Milan University IRCCS Istituto Clinico Humanitas (Milan, IT) Objective: To determine whether increased serum vascular endothelial growth factor (VEGF) levels are specifically associated with the POEMS syndrome (characterized by the association of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes), or may be also found in patients with other neuropathies. Background: Markedly increased serum VEGF levels have been reported in POEMS syndrome, representing a useful marker especially in patients without all typical clinical manifestations. Only few patients with other neuropathies have been however investigated so that their specificity for POEMS among neuropathy patients remains unclear. Methods: We measured serum VEGF in 172 patients with different neuropathies or related syndromes including 6 with POEMS, 12 Guillain-Barré syndrome (GBS), 32 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 11 multifocal motor neuropathy (MMN), 19 neuropathy and IgM-MGUS (PN+IgM) with anti-MAG (18) or sulfatide reactivity, 49 other neuropathies (OPN),24 motor neuron disease (MND),19 myeloma or MGUS without PN, and in 21 healthy subjects (NS). VEGF levels were determined by ELISA using a commercially available system (Research & Diagnostic Systems, Minneapolis, MN) and according to manufacturer’s instructions. The upper normal limit for serum VEGF levels was calculated in NS sera as the mean + 3 standard deviation (SD). Results: Serum VEGF levels were significantly higher (p < 0.0001) in patients with POEMS (mean/ SD: 6448/2930 pg/ml) compared to NS (272/229), GBS (1017/985 pg/ml), CIDP (668/377 pg/ml), MMN (448/311), PN+IgM (738/598), ONP (450/508), MND (485/245), and myeloma or GUS without PN (403/245). A significant though less marked increase of VEGF was also observed in GBS, CIDP and PN+IgM compared to NS (p < 0.001) and to all other patients’ groups (p < 0.025–0.005). VEGF values above upper normal limit (959 pg/ml) were found in all POEMS (range 3602–11 560 pg/ml), 5 GBS (42 %, range of positive 1094–3391), 7 CIDP (22 %, 1036–1304), 5 PN+IgM (26 %, 1125–2579), but only one with vasculitic PN (3489) and one NS (1092). Conclusion: even if markedly increased serum VEGF levels were almost invariably associated with POEMS, a less pronounced though significant increase was also found in a consistent proportion of patients with inflammatory or immune mediated neuropathies and may therefore help in the diagnosis of these neuropathies. O79 Clinicopathological aspects and long-term follow-up of patients with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) D. Adams, P. Lozeron, C. Lacroix, I. Brault, Y. Taoufik, C. Denier, V. Ribrag, C. Theodore, G. Said CHU de Bicêtre (Kremlin Bicêtre, FR) The POEMS syndrome is a disabling, life threatening syndrome that may respond to treatment of plasma cell dyscrasia. Objective: To describe the spectrum and the course of the neuropathy in patients with POEMS syndrome and outcome after treatment. Methods: Retrospective study of 25 POEMS patients referred between 1980 and 2005, followed in our center. All patients fulfilled recent criteria for POEMS (Dispenzieri et al, 2003). Nerve biopsy was performed in 22 patients. Serum vascular endothelial growth factor (VEGF) was assessed by ELISA Test (R D Systems) in 7 patients. We used the Kaplan-Meier analysis of survival. Therapy included radiation for solitary plasmacytoma, chemotherapy, autologous peripheral blood stem cell cells transplantation (APBSCT). Results: The mean age at referral was 56 years (extremes: 27–83). The neuropathy was inaugural in 18/25 (72 %), mimicking CIDP in 19; subacute onset in 4, distal symmetrical polyneuropathy in 1. The mean interval between first symptom and referral was 9 months (extremes: 1 month–3 years). All patients complained of walking difficulties; 9 walked with aid, 3 were wheelchair bound or bedridden. Nerve biopsy showed reduction of density of myelinated fibers in 18 patients and teased fibre preparation a mixture of axonal degeneration and demyelination in 13; one patient had marked endoneurial monuclear cell infiltration predominating around capillaries; endoneurial oedema was common finding. Serum monoclonal IgGl or IgAl were found in 19 patients, biclonal gammopathy in 4. Bone lesions (BL) in 11 patients including solitary plasmacytoma in 7; multiple myeloma in 8 and Castleman s disease in 8. The course was progressive in 64 %. Twenty patients were treated, including 5 with APBSCT; 17/20 improved including 4/6 who were quadriplegic. The disease relapsed in 5 patients.

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Serum VEGF level was high in 7/7patients including 4 without BL, and dramatically decreased after treatment. The median survival was 7 years; 13 patients died usually from the progression of the disease. Conclusions/Relevance: Neuropathy in POEMS usually mimics a rapid and aggressive CIDP associated with a seemingly benign IgGl or IgAl. Accurate investigations and therapy can favourably influence the course of this life-threatening syndrome. O80 Diagnostic criteria and acquired sensory neuronopathy G. Jousserand, J. P. Camdessanche, J. Honnorat, P. Petiot, C. Vial, J. C. Antoine CHU Saint-Etienne (Saint-Etienne, FR); CHU Lyon (Lyon, FR) Aim: To test the criteria commonly used for the diagnosis of ASN. Background: There are no validated criteria for the diagnosis of ASN. A severe non length dependent sensory neuropathy with almost normal motor velocities (MCV) is usually retained. Material and Methods: Case records of 76 patients with a final diagnosis of ASN were reviewed. They were classified into three etiological groups: group 1, paraneoplastic (anti-Hu); group 2, toxic (cisplatin); and group 3, dysimmune or idiopathic. Clinical symptoms and signs, modality of installation, topography and distribution, the type of altered sensory modalities, ataxia or dysautonomia, and electrophysiological absence or reduction of sensory action potentials (SAP), and MCV were analyzed. In a first step, the three groups were compared using logistic regression and exact Fisher’s test. Then, the sensitivity of usual ASN criteria was evaluated. Selected items were a pure sensory neuropathy (C1), a non length dependant distribution determined clinically (C2 a) or clinically and electrophysiologically (C2 b), absence (C3 a) or absence/ reduction of SAP (C3 b), ataxia (C4), and absent (C5 a) or mildly altered MCV (C5 b). Results: 33 patients were in group 1, 11 in group 2, and 32 in group 3. There was no group difference concerning sensory manifestations and SAP abnormalities. In group 1, acute onset, abnormal CSF and mildly abnormal MCV were more frequent. In group 2, subacute onset and pain, and in group 3, progressive course and normal CSF were more frequent. Sensitivity was 100 % for C1, 76.3 % for C2 a, 86.8 % for C2 b, 53.9 % for C3 a, 100 % for C3 b, 69.7 % for C4, 56.6 % for C5 a, and 89.5 % for C5 b respectively. Patients not fulfilling all these criteria occurred in the three groups. Conclusion: ASN has a homogenous clinical and electrophysiological pattern. The commonly accepted diagnosis criteria have important limitations. There is a need for more sensitive and specific criteria.

Oral session 9 Genetics 1 O81 Penetrance estimation and haplotype analysis of TTR val30met mutation in Brazilian families with familial amyloidotic polyneuropathy type I M. Saporta, C. André, C. Zaros, M. Misrahi, G. Said, E. Génin, C. Bonaïti-Pellié, V. Planté-Bordeneuve, M. W. Cruz HUCFF/UFRJ (Rio de Janeiro, BR); CHU Bicêtre (Paris, FR); Unité INSERM 535 (Paris, FR) Objectives: To estimate the penetrance of Familial Amyloidotic Polyneuropathy (FAP) in Brazilian families using a statistical model and to determine the presence of a founder effect in this sample, both important information to better understand the disease and provide proper genetic counselling. Methods: This protocol was approved by both local and national ethics committees. Genealogical investigations, clinical information on symptomatic cases and genotyping of 106 voluntary patients and asymptomatic family members were obtained in 15 Brazilian kindred. Epidemiological data from another 7 families was added for the statistical analysis. Penetrance estimation was performed applying a method previously described based on maximum likelihood, using a survival analysis approach, and corrected for ascertainment bias. For the haplotype analysis, eleven polymorphic microsatellite markers encompassing a region of c. a.15Mb around the TTR region (18q12) were used. The most likely haplotypes were reconstructed using PHASE v2.1.1 software. The age of the Most Recent Common Ancestor (MRCA) of Met30 mutation carriers in this sample was estimated

by a likelihood-based method using multilocus marker data from patients (ESTIAGE). Results: Data from 623 individuals from 22 families were obtained for penetrance estimation. Val30Met was the only pathogenic transthyretin variant in the families tested. The penetrance of FAP was estimated as 19 % at 30 years, 52 % at 40 years, 76 % at 50 years, reaching a plateau of 83 % at 60 years. Microsatellite marker analysis was performed in 13 unrelated probands and 22 controls. We found that Val30Met-carrier haplotypes share the same alleles at markers surrounding the Val30Met locus and that was not demonstrated in the control group, thus suggesting a founder effect in the Brazilian FAP sample. Using ESTIAGE program, the age of the MRCA of Val30Met mutation carriers was estimated to be 26 (95 % CI: 17–40) generations. If we assume 25 years per generation, the MRCA is 650 (95 % CI: 425–1000) years old. Conclusions: As expected, the penetrance estimated in Brazilian families was high and incomplete, reaching its maximum value of 83 % around the age of 60 years. Our results are very similar to those previously reported on Portuguese families, with a similar mean age of onset. A founder effect was demonstrated in our sample. The results from our work provide useful information for genetic counselling of Brazilian families with FAP. Dr. Saporta received a travel grant from the European association of Young Neurologists and Trainees O82 Clinical and genetic findings in two Italian families with DYT5 dystonia R. Fancellu, C. Barzaghi, E. Pagliano, B. Garavaglia, S. DiDonato, C. Mariotti Istituto Nazionale Neurologico C.Besta (Milan, IT) Objectives: DYT5 dystonia is autosomal dominant inherited disease, characterized by early-onset foot dystonia, marked diurnal fluctuation, and response to levo-dopa treatment. DYT5 dystonia is caused by mutations in the gene encoding for the enzyme Guanosine Triphosphate Cyclohydrolase 1 (GCH1). This enzyme catalyzes the rate-limiting step in the synthesis of tetrahydrobiopterin, which is a cofactor for tyrosine hydroxylase, involved in the production of dopamine. Methods: We studied two familial cases of DYT5. Molecular analysis of GCH1 gene was performed by direct DNA sequencing of coding regions. Results: In both families, the probands had an initial clinical diagnosis of hereditary spastic paraplegia. In the first pedigree, the proband was a 39year-old woman who noticed difficulties in walking and progressive lower limb weakness at the age of 13. Neurological examination revealed mild spastic gait and hyperreflexia. In the family history, she had two paternal aunts presenting a progressive gait disorder associated with pes cavus. Her 9-year-old daughter had minimal walking difficulties, while her father was asymptomatic at the age of 68. Molecular analysis of GCH1 gene revealed the presence of a novel mutation consisting in a 7 bp deletion in exon 4 (520–526delATCTATA), causing a frame-shift and a premature stop codon (E173fsX189). In the second family, the proband was a 53-year-old woman, who had the first manifestation of the disease at the age of 8, with the occurrence of progressive gait difficulties and disequilibrium. She noticed diurnal fluctuation of the symptoms. Also her mother had gait disturbances since the age of 8. Neurological examination revealed mild horizontal gazeevoked nystagmus, paraparetic gait, lower limb rigidity, increased deep tendon reflexes, bilateral extensor plantar responses, and right foot dystonia, In this family we found the previously described 631–632delAT mutation in exon 6 of GCH1 gene. The same mutation was found in her 29-year-old son and in a 41-year-old brother, who were clinically asymptomatic. In both families a marked improvement in dystonia and gait spasticity was observed with levodopa treatment. Conclusion: Our data confirm clinical features and the response to treatment in DYT5 patients. A novel mutation in the GCH1gene is described. In both DYT5 families we observed a reduced penetrance in male carriers, and in symptomatic women a phenotype mimicking familial spastic paraplegia. O83 Clinical and MRI findings in adult-onset Alexander’s disease D. Pareyson, L. Farina, I. Ceccherini, C. Mariotti, A. Salmaggi, L. Grazzi, S. Romano, G. Gattellaro, R. Fancellu, M. Savoiardo C.Besta Neurological Inst. (Milan, IT); Gaslini Institute (Genoa, IT); La Sapienza University (Rome, IT); L.Sacco Hospital (Milan, IT) Objective: To describe the clinical and MRI findings of adult-onset Alexander’s disease (AOAD), that are remarkably different from those of the infantile form. Diagnosis of AOAD can now be confirmed by molecular analysis of the GFAP gene, thus avoiding the need of biopsy searching for Rosenthal’s fibres. Patients/methods: Seven patients (3 females, 4 males, age 26–61 yrs., age

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at onset 13–57 yrs.), presented with mild to moderate brainstem or cerebellar dysfunctions (including palatal myoclonus in two of them), except for one asymptomatic subject studied for headache. All had brain and cervical spinal cord MRI. All but one had postcontrast examination. Results: In all patients the diagnosis of AOAD was suggested by the MRI abnormalities. All patients had atrophy and signal changes in the medulla oblongata extending to C1-C2 segments. Atrophy of the cervical spinal cord without signal abnormalities extended to its lower segments. Minimal changes were present in the dentate nuclei (six cases). In one patient, appearance and progression of medullary atrophy was documented over seven years. Minimal to moderate symmetrical periventricular signal changes were present in all the patients, with “garlands” in two (van der Knaap, Neurology 2006). Patchy, postcontrast enhancement only in brainstem and cerebellum was seen in four patients. In all patients the diagnosis was confirmed by sequencing the GFAP gene. Previously reported mutations were found in two subjects, while two additional patients carried missense substitutions at codons already known to be affected in Alexander disease. Finally, in three patients new mutations could be detected. Conclusions: AOAD may have its onset late in life (as late as at age 57 in our series). MRI characteristic findings are: signal changes and atrophy of the medulla and upper spinal cord with abnormal blood-brain barrier, probably related to the abundance of Rosenthal fibres in the endfeet of perivascular astrocytes. Periventricular white matter abnormalities in a disease known as a diffuse leukodystrophy in children are remarkably inconspicuous. Awareness of this peculiar MRI pattern should prompt search for a GFAP mutation. In our series, diagnosis was genetically confirmed in 7 out of seven cases, including an asymptomatic patient. O84 Characterisation of COX16, a novel human gene required for cytochrome c oxidase assembly S. Sacconi, E. Trevisson, A. Casarin, G. Casagrande, C. Desnuelle, L. Salviati Fédération des maladies neuromusculaires (Nice, FR); Padua University (Padua, IT) Objectives: To characterize the human homologue of COX16 a gene required for cytochrome c oxidase (COX) biosynthesis in yeast. Methods: The human gene was identified in the expressed sequence tags (EST) database using a cyberscreening method. The human cDNA was cloned by traditional RT-PCR into appropriate expression vectors, and used as a probe for Northern blot analysis. A hemagglutinin tagged version was synthesised using specific PCR oligonucleotides. The transcript was characterized by Rapid Amplification of CDNA Ends analysis. Gene silencing was carried out using specific siRNA by transient transfection. Results: Human COX16 is comprised of 4 exons on chromosome and encodes for a 106 aminoacids protein with a N-terminal putative transmembrane domain and a C-terminal hydrophilic domain, with no homology to any known family of proteins. The gene is expressed ubiquitously with highest levels in muscle, heart, and liver. We found multiple transcription initiation sites,the most upstream of which is located 100 base pairs from the ATG. The COX16 protein is located in mitochondrial, presumably in the mitochondrial inner membrane. Overexpression of COX16 in HeLa cells determined an increase in COX activity, while other respiratory chain complexes were unaffected. Similarly silencing of the COX16 transcript by siRNA caused a reduction of COX activity after 48 hours in transfected cells. Conclusion: COX16 is a novel human COX-assembly gene whose precise function is unknown. Its small size suggests that it doesn’t have a catalytic role, but rather that it could act by stabilizing nascent COX subcomplexes in analogy to PET100. The effect of COX16 silencing on COX activity is striking, suggesting that COX16 may play an important role in the regulation of the COX assembly process. The role of COX16 in COX deficiency has yet to be determined. A previous study failed to detect mutations in patients with isolated COX deficiency; we are now screening a novel cohort of patients for mutations in this gene. O85 Molecular and functional analysis of paraplegin gene (SPG7) mutations in patients with familial and sporadic spastic paraplegia D. DiBella, C. Mariotti, M. Plumari, F. Lazzaro, M. Muzi-Falconi, V. Fracasso, R. Fancellu, S. DiDonato, S. Baratta, C. Gellera, F. Taroni Fondazione IRCCS Ist Neurologico C.Besta (Milan, IT); University of Milan (Milan, IT) Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders. Mutations in the SPG7 gene

are responsible for autosomal recessive HSP with both “pure” and “complex” phenotypes. This gene encodes paraplegin, a major component of the mitochondrial mAAA metalloprotease. Objectives: To screen a large HSP patient sample for SPG7 mutations and to functionally characterise missense mutations in a yeast model. Methods: We have sequenced the paraplegin gene in 74 unrelated index cases, including 53 sporadic cases and 21 cases compatible with an autosomal recessive pattern of inheritance. The majority of patients exhibited a “complex” phenotype characterized by spastic gait and signs of cerebellar involvement. Paraplegin expression was investigated in the cell lines of mutated patients using polyclonal antibodies raised in our laboratory. Results: Pathogenic mutations (3 frameshift, 4 nonsense, 1 in-frame exon deletion, 1 splicing, and 5 missense including the Ala510Val) were found in 14 sporadic patients and in 1 familial case. The mutations were not found in a large control population. Ten patients in the sporadic group (10/53, 18.9 %) and only 1 patient in the familial group (1/21, 4.8 %) had mutations on both alleles, with an overall frequency of 14.9 % (11/74). The remaining 4 sporadic patients carried a mutation on a single allele. Western blot analysis demonstrated the absence of paraplegin protein in the 4 patients carrying two null alleles. Interestingly,Western blot analysis of lymphoblast from a patient homozygous for the Ala510Val missense mutation showed a great reduction of protein levels. Although this mutation had been previously described as a polymorphism, it has been more recently identified in numerous HSP patients (Elleuch 2006) and is present in 6 patients in our series. We have modelled the identified SPG7 missense mutations in a yeast system in which the human m-AAA is functionally reconstituted. Notably, functional analysis clearly indicated that the Ala510Val produces a respiratory-deficient phenotype in yeast cells expressing the mutant protein. Conclusion: In our study, SPG7 mutations account for 14.9 % of HSP patients, an overall frequency higher than that in previously reported series. Western blot analysis and functional studies demonstrated that the frequent Ala510Val substitution is a disease-causing mutation. Partly supported by Telethon GUP04 009 and Fondazione Mariani R0544 grants to FT. O86 A new locus for the Silver syndrome variant of hereditary spastic paraplegia An. Orlacchio, C. Patrono, F. Gaudiello, A. Borreca, V. Moschella, Al. Orlacchio, R. Floris, G. Bernardi, T. Kawarai CERC-IRCCS Santa Lucia (Rome, IT); Università di Roma Tor Vergata (Rome, IT); Università di Perugia (Perugia, IT); Hyogo Brain and Heart Center (Himeji City, JP) Objectives: Silver Syndrome (SS) is a complicated form of hereditary spastic paraplegia (HSP) associated with amyotrophy and weakness of the intrinsic hand muscle.A recent genetic study has shown that SS can be caused by mutations in the BSCL2 gene (seipin) on chromosome 11q12-q14 (SPG17). In this context, investigating the genotype-phenotype correlations is essential to understand the mechanism(s) of the disease. In order to evaluate the genotype-phenotype associations, we carried out a clinical and genetic study of two large Italian families with SS (RM-36 and RM-51). Methods: Neurological evaluations, neurophysiological and neuropsychological assessments, neuroimaging studies, linkage study, and sequencing. Results: Linkage analyses demonstrated that the two families are excluded for linkage to the BSCL2 locus. Sequence of the seipin gene revealed no disease-causing nucleotide substitution. Having excluded the multiple known HSP loci in the pedigree RM-36, we performed a genome-wide search for linkage of SS, which showed a novel SS locus on the long arm of chromosome 4. The clinical features of this family are comparable to those in SS. Linkage analyses at the currently-known ADHSP loci showed evidence of linkage to SPG4 in the pedigree RM-51. SPG4 sequence analysis revealed a novel frameshift mutation in exon 6 (c.961insG) resulting in premature termination at the codon 326 (p.N326X). PCR-RFLP analysis showed that the mutation segregates with the disease and the mutation was not found in 200 control chromosomes. Clinical investigations in the family carrying the frameshift mutation in SPG4 demonstrated decreased vibration sense in lower and upper limbs, pes cavus, cognitive dysfunctions, and temporal lobe epilepsy (TLE), in addition to SS typical clinical manifestations. Analysis of age at onset and degree of disease severity among generations revealed a general impression of genetic anticipation. Electrophysiological studies revealed the involvement of lower motor neurons as well as upper motor neurons. Conclusion: The data presented in this study identify a second locus for the SS variant of HSP. Our study demonstrates also that SPG4-HSP may include clinical features observed in SS and widen the spectrum of genetic abnormalities of the disorder.

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Supported by grants from the “Comitato Telethon Fondazione Onlus” – Italy – (GGP06209), the Italian “Ministero della Salute” (PS04.2O and RF04.125O), and the Lundbeck Foundation – Denmark – (COFIN04.125O).

Oral session 10 Rehabilitation O87 Activation in dominant and non-dominant brain regions in relation to language performance in chronic aphasic stroke patients C. A. M. M. van Oers, M. Vink, M. J. van Zandvoort, H. B. van der Worp, E. H. de Haan, L. J. Kappelle, N. F. Ramsey, R. M. Dijkhuizen UMC Utrecht (Utrecht, NL); University of Utrecht (Utrecht, NL) Objectives: Recovery from aphasia after stroke is optimal when the ipsilesional dominant hemisphere can regain its role in language processing. In the earlier phases after stroke, functional neuroimaging studies have shown extensive activation in the non-dominant hemisphere not correlated to recovery. This may lead to novel therapeutic strategies, such as use of transcranial magnetic stimulation(TMS). The non-dominant side may still contribute to language performance in the chronic phase. The aim of our study was to identify the contribution of left and right brain areas to language function in chronic stroke patients and controls. Methods: We examined 11 chronic aphasic stroke patients and 12 controls using 3 fMRI language paradigms: verb generation(VERB), picture word matching(PWM), and semantic decision(SD). SPM2 was used for dataanalysis. The number of activated voxels (NAV) and lateralization index(relative contribution of the left hemisphere (LI)) were calculated in different regions-of-interest(ROIs). The Aachen Aphasia Test was used as a measure of aphasia severity, and was correlated with NAV and LI in ROIs. Results: LI for all ROIs combined was lower in the patient group for the following language tasks: PWM (LI = 0.39 (controls) vs. 0.09 (patients); p = 0.002), and VERB (0.37 vs. 0.20; p = 0.07). LI in cerebellum was higher in patients for the language tasks SD (–0.27 vs. 0.14; p = 0.001), and VERB (–0.35 vs. –0.01; p = 0.003). A positive correlation between performance and LI for all ROIs combined was found for PMW (p = 0.01), and SD (p = 0.071). In PMW mainly posterior ROIs were responsible (p = 0.008). NAV in the left supramarginal gyrus (SMG) tended to be positively correlated with performance for VERB (p = 0.080). Conclusions: In agreement with previous findings, we found relatively more active left cerebellar and right cerebral hemispheres in patients. Within the patient group language performance was positively correlated with LI in language areas. Particularly posterior areas contributed to this correlation. NAV in the left SMG correlated positively with language performance for VERB. Our data suggest that activation in the ipsilesional left hemisphere, especially posterior regions, is most important in language recovery.We found no clear evidence for a contribution of the right, non-dominant hemisphere to language performance in chronic ischemic stroke patients. Supported by the Dutch Heart Foundation, grant 2003B196. O88 Measuring intentional mental imagery – and hence consciousness – in noncommunicative brain injured patients using fMRI M. Boly, M. Coleman, M. Davis, A. Hampshire, D. Bor, P. Maquet, J. Pickard, G. Moonen, A. Owen, S. Laureys Coma Science Group (Liège, BE); University of Cambridge (Cambridge, UK); Cyclotron Research Centre (Liège, BE); CHU Neurology (Liège, BE) Introduction: The assessment of voluntary behaviour in non-communicative brain injured patients is often challenging due to the existence of profound motor impairment. In the absence of a full understanding of the neural correlates of consciousness, even a normal activation in response to passive sensory stimulation cannot be considered as proof of the presence of awareness in these patients. In contrast, predicted activation in response to the instruction to perform a mental imagery task would provide evidence of voluntary task-dependent brain activity, and hence of consciousness, in non-communicative patients. However, no data yet exists to indicate which

imagery instructions would yield reliable single subject activation. The aim of the present study was to establish such a paradigm in healthy volunteers. Methods: Two exploratory experiments evaluated the reproducibility of individual brain activation elicited by 4 distinct mental imagery tasks. The two most robust mental imagery tasks were found to be spatial navigation and motor imagery. In a third experiment, where these two tasks were directly compared, differentiation of each task from one another and from rest periods was assessed blindly using a priori criteria and was correct for every volunteer. Results: The spatial navigation and motor imagery tasks described here permit the identification of volitional brain activation at the single subject level, without a motor response. Conclusion: Volunteer as well as our reported patient data (Owen et al., Science 2006) strongly suggest that this paradigm may provide a method for assessing the presence of volitional brain activity, and thus of consciousness, in non-communicative brain-injured patients. The Belgian National Fund for Scientific Research (FNRS), an MRC programme grant, Commission of the European Communities (contract # 043457), Marie Curie Training Networks (contract # MRTN-CT-2006–0359) and the Mind Science Foundation funded this work. O89 Comparison of the admission policies to stroke rehabilitation units and of the aftercare situation in four European centres. Data from the CERISE study W. Schupp, K. Putman, L. De Wit, W. Jenni, P. Berman, E. Dejaeger Fachklinik Herzogenaurach (Herzogenaurach, DE); Vrije Universiteit Brussel (Brussels, BE); Katholieke Universiteit Leuven (Louvain, BE); RehaClinic (Zurzach, CH); City Hospital (Nottingham, UK); University Hospital (Pellenberg, BE) Objectives: The CERISE (Collaborative Evaluation of Rehabilitation in Stroke Across Europe) study aimed in part examing differences in the amount and content of therapy, in organisational characteristics and staff input, in regional networking for admission and aftercare in four European stroke rehabilitation units (SRUs). On the last ENS meeting we reported on the impact of the therapeutic activities on outcome. Now, we present data on the networking with acute clinics and the aftercare services. Methods: In each of the four centres, questionnaires and semi-structured interviews were performed by a single researcher with the medical consultants exploring the importance of factors related to the patients, factors related to the network between facilities and the referring acute hospital in the decision-making process concerning admission. Home visits at 6 months post-stroke were conducted to monitor the services patients receive at home. Together with the outcome data of the SRUs we can provide a synopsis on the network for acute treatment, rehabilitation and aftercare in stroke in each region of the SRUs. Results: In the GB-SRU, severely disabled patients were admitted significantly earlier after stroke compared to the other units. Pre-morbid conditions were frequently more taken into account in BE-, CH- and, DE-SRU. Networks between the acute facilities and the respecitive SRUs also influenced their decision-making on admission. Between 66 % (CH) and 75 % (DE) of the patients lived at home 6 months post-stroke. They differed significantly in their motor and functional status. The most contacted professional caregivers were general practitioners (89 % (CH)–43 % (GB)), followed by the physiotherapists (82 % (B)–47 % (CH)) and the nurses (42 % (B)–4 % (D)). The aftercare situation showed hereby also significant differences, which could not be fully explained by the patients’ status. Conclusion: Regional networking with acute clinics and shared decision making on patients’ conditions can facilitate the admission to SRUs. Improving the aftercare situation can be obtained by the cooperation between the SRUs and mainly general practitioners, physiotherapists and nursing services in the region. Networking for acute treatment, rehabilitation and long term (after)care in stroke should include all these partners. The study was performed within the framework of the research “Collaborative Evaluation of Rehabilitation in Stroke across Europe (CERISE)”, Quality of life, key action 6, 2001–2005, contract number QLK6-CT2001–00 170 funded by the

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O90 Quantitative evaluation of selective trunk rehabilitation in stroke patients E. Milano, F. Menegoni, C. Trotti, M. Galli, S. Baudo, L. Pianta, G. Miscio, A. Mauro IRCCS “Italian Auxologico Institute” (Piancavallo (VB), IT); Polytechnic of Milan (Milan, IT)

O92 The validity, reliability and clinical importance of changes in spasticity severity measured on a 0–10 Numerical Rating Scale J. T. Farrar, A. Troxel, C. G. Stott, P. Duncombe University of Pennsylvania (Philadelphia, US); GW Pharma Ltd (Salisbury, UK)

Objective: The aim of this study was to evaluate the effect of rehabilitative protocol with trunk control exercises in hemiparetic patients and to determine the relationship between clinical evaluations and quantitative gait analysis. Methods: 8 post stroke patients with chronic lesion were enrolled (5 males, 3 females; mean age: 54.1±16.7 years). The study has been approved by the local ethic committee. Each patient was evaluated with clinical and functional scales (Trunk Control Test [TCT], Motricity Index [MI], Functional Ambulatory Category, Walking test [WT], Berg Scale [BS], and FIM_) and was analysed by quantitative gait analysis (VICON system, UK), and superficial EMG (STEP-PC 32) at trunk muscles (lastissimus dorsi (LD), rectus abdominis (RA) and obliquus externus (OE)). Rehabilitation program was composed by one hour of Bobath concept treatment and thirty minutes of specific trunk training. The proposed program was applied for 21 days and clinical and instrumental evaluations were performed before (pre) and after (post) it. Statistical analysis was conducted using parametric and non parametric tests (P < 0.05). Results: The most important results with regard to quantitative gait analysis were in terms of walking speed (pre = 0.54m/sec, post = 0.70m/sec) and stride length (pre = 0.80 m, post = 0.93 m) which increased in 6 out of 8 patients. Kinematics results showed reduced equinus of the foot and reduced pre-treatment hyperextension in stance phase. Clinical results demonstrated some disparity. Berg scale and walking test reported scores comparable to gait analysis results (BS P = 0.027; WT P = 0.03), while FAC, TCT, FIM and MI did not reveal significant changes. EMG activity showed asymmetric activation in LD, spreading of activation during flexion trunk (RA, LD) and hyperactivity LD in paretic side. Conclusion: Even if trunk control is required to maintain postural control and gait stability, little is known about the stroke effects on trunk muscle activity. This study suggests that not only the quantitative gait analysis can be used to assess patient status before and after rehabilitation program but also the proposed rehabilitation program improves the performance of all subjects. Clinical tests were not always in accord with one another nor with respect to gait analysis; these findings could partly have been the result of the test scores of the less involved subjects who had the highest in both evaluations.

Objectives: The aim of this study was to determine the reliability and validity of the use of a 0–10 Numerical Rating Scale (NRS) when used by patients to self-rate the severity of their spasticity on a daily diary card and to define the Minimal Clinically Important Difference (MCID) for the NRS in spasticity. Methods: The reliability and validity of the 0–10 NRS for spasticity was assessed using accepted methodology.An MCID for the NRS spasticity scale was determined by relating it to the Patient’s Global Impression of Change (PGIC) using established, anchor-based methodology, utilising data from a large randomised, double-blind, placebo-controlled study of Sativex in 189 MS patients with spasticity. Results: Test re-test reliability was demonstrated by a highly correlated relationship between the mean NRS spasticity scores at the beginning and end of the baseline (BL) period (correlation co-efficient, r = 0.828, p < 0.0001). Face validity was evident from the patient’s daily diary question: “On a scale of 0–10 please indicate your level of spasticity over the last 24 hours” (where 0 = No spasticity and 10 = Worst ever spasticity). Content validity was demonstrated as the question asked the patient about the level of perceived spasticity over the previous 24 hours, which covers the entire construct of the symptom of spasticity. Construct validity was apparent following a statistically significant improvement between treatments in mean NRS values in the same study. Criterion validity was confirmed by statistically significant correlations between the spasticity NRS and a number of spasticity-related variables (spasm frequency scale: r = 0.626, p < 0.0001; PGIC: r = 0.469, p < 0.0001) and an association with the Ashworth Scale (r = 0.14, p = 0.06). Receiver Operating Characteristic (ROC) analysis for change in Spasticity NRS Score versus PGIC response indicated that the MCID was -0.9 for the raw data and –18 % for the % improvement from BL. A similar analysis defined the Clinically Important Difference (CID) as –1.27 for the raw data and –29.5 % for the % improvement from BL. Conclusion: The 0–10 NRS is an appropriate and valid measure of spasticity and appears to be more reliable and sensitive in terms of reporting the symptom of spasticity than the Ashworth Scale. The change in 0–10 NRS that best represents the MCID for spasticity is a change of -0.9 NRS units or a % change of –18 %. The corresponding values for the CID are –1.27 NRS units or a % change of –29.5 %. A research grant of $15.000 was paid to the University of Pennsylvania for this work, sponsored by GW Pharma Ltd

O91 FMRI correlates of lower limb function in subjects with gait impairment due to stroke C. Enzinger, H. Johansen-Berg, H. Dawes, M. Bogdanovic, J. Collett, C. Guy, S. Ropele, U. Kischka, D. Wade, F. Fazekas, P. Matthews Medical University (Graz, AT); University of Oxford (Oxford, UK); Oxford Brookes University (Oxford, UK); Nuffield Orthopaedic Centre (Oxford, UK); Imperial College (London, UK) Objective: Whereas knowledge concerning cortical reorganisation related to upper limb function after ischemic brain damage is growing, analogous data for lower limb movements are limited. Here, we report on use of an ankle movement fMRI paradigm to characterize changes in neocortical gait control after stroke. Subjects and Methods: Eighteen patients (8F/10M; mean age 59.9±13.5, range 32–74 yrs) with chronic residual gait impairment due to a single subcortical ischemic stroke and 18 age- and sex-matched healthy controls underwent FMRI at 3.0T (EPI TR = 3000ms, TE = 30ms, FOV = 256x256, matrix = 64x64) during active and passive ankle dorsiflexion movement. Results: We observed substantial and essentially similar neocortical activity associated with foot movement in the stroke patients and in the healthy controls. There was, however, increased cortical activation with increasing functional impairment in the patients, particularly in the primary sensorimotor cortex of the unlesioned hemisphere. The changes were most prominent with the active movement task. In contrast to changes reported after studies with upper limb movement, premotor activation did not appear to contribute significantly to the recovery of control of the lower limb movements. Conclusions: These findings suggest that the pattern of brain activation associated with this simple movement may be predictive of gait impairment after stroke. Brain activity during passive ankle movement was similar to that with active ankle movement, suggesting that passive movements might be used similarly across the full spectrum of injury to elicit clinically relevant brain activation measures.

Oral session 11 Cerebrovascular disorders 2 O93 An analysis of cognitive disorders in patients with anterior choroidal artery infarction M. Rousseaux, M. Cabaret, T. Bernati, O. Kozlowski, W. Daveluy CHRU de Lille (Lille, FR) Objective: Infarction of the anterior choroidal artery (IAChoA) usually results in pure motor hemiplegia. Hypoesthesia and visual field defect are possible but rare. However, little is known about cognitive disorders of these patients. Our objective was to investigate these cognitive disorders in a relatively large cohort of patients. Methods: Participants were 20 patients suffering from a relatively recent and isolated IAChoA (left side: 13; mean delay = 47.4 days; M: 10; mean age = 59.6 years; mean education level, EL = 10.3) who were admitted to neurological rehabilitation. We assessed attention (alertness, Go Nogo, divided attention and visual vigilance from the computerized test TEA), orientation (verbal, spatial), short-term memory (STM: forward and backward spans, spatial span, Peterson paradigm), long-term memory (LTM: Buschke verbal test, Batterie 144 of Signoret for verbal and visuo-spatial memory), retrograde memory (RM: questionnaire on famous events), executive functions (WCST, TMT A and B, categorical and literal evocation), spatial attention

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(bell test for neglect), and verbal abilities (naming and word comprehension). Their performance was compared with that of 20 control subjects matched in age and EL. Results: IAChoA patients showed a significant deficit (p < 0.05) in attention, because of slowness (simple RT, Go Nogo) and increase in omission and error rate (most tests), in LTM, especially for verbal recall (Buschke and B144) and in executive functions (slowness and errors in TMT B; reduced categorical and literal evocation). Conversely, we found preservation of orientation, STM, RM, WCST, spatial neglect and naming. Patient performance partially correlated with age and EL, but not with the volume and side of the infarct (MRI) neither with the severity of leucoaraïosis and cortical atrophy. Conclusions: Limited subcortical stroke lesion can result in cognitive slowness, and discrete disorders of focused and divided attention, verbal recall and executive functions. These are more severe in older age. This profile is somewhat different from what is usually described in thalamic and cortical lesions, namely aphasic disorders and spatial neglect. O94 Wingspan stent system for ICAD: U. S. registry results after one year G. Pride on behalf of the Neuroendovascular Research Collaboration Objectives: The Wingspan is a flexible, self-expanding, microcatheter-delivered, microstent designed specifically for the treatment of intracranial atherosclerotic disease (ICAD). This report details our current experience with this device in 116 patients. Methods: All patients undergoing angioplasty and stenting with the Gateway Balloon-Wingspan stent system were prospectively tracked in our collaborative five institution endovascular database. Patient data, lesion characteristics, procedural details, pre and peri-procedural anti-thrombotic pharmacology, and clinical and imaging follow up were recorded. Results: Over a 15 month period 116 patients (52 females, 64 males; average age 62.7 years, range 35–85 years) with 124 intracranial atheromatous lesions were treated with the Wingspan stent system. Stents were delivered with a 98.4 % first session technical success rate. The treated lesions involved the internal carotid (n = 43; 12 petrous, 12 cavernous, 16 supraclinoid segment, 3 terminus), vertebral (n = 23; V4 segment), basilar (n = 25), and middle cerebral (n = 32) arteries. The average pre-treatment stenosis was 74.5 percent, improving to 44.4 percent after Gateway balloon angioplasty and to 27.6 percent after Wingspan stent placement (with or without post-dilation). 82 of 124 lesions treated were > 70 % stenotic. Of these 124 lesions treated, there were 6 major neurological complications (4.8 %), 4 of which resulted in patient death within 30 days of the procedure. Imaging follow up is available for 68 lesions (53 angiography, 12 CTA, 3 MR only). 19 lesions demonstrated in-stent restenosis (ISR), 6 of which have been symptomatic and 11 of which have been re-treated. Two stent constructs were thrombosed at follow up (one of which was symptomatic). During re-treatment, 3 in-stent dissections occurred, 2 of which required placement of an additional Wingspan stent, 1 re-perfusion hemorrhage occurred after re-treatment. ISR rates were much higher in the anterior circulation (ICA 37.5 % and MCA 47.1 %) than the posterior circulation (basilar 9.1 % and vertebral artery 8.3 %). Conclusion: Treatment of symptomatic ICAD can be performed with the Wingspan stent system with a high technical success rate and relatively low peri-procedural morbidity. However, many of the periprocedural complications were severe, resulting in patient death within 30 days. ISR occurs at a rate higher than initially anticipated, particularly affecting stents placed within the anterior circulation. Registry supported by a grant from Boston Scientific Corp. O95 Long-term mortality and vascular event risk after aneurysmal subarachnoid haemorrhage M. J.H Wermer, P. Greebe, A. Algra, G. J. E. Rinkel University Medical Centre Utrecht (Utrecht, NL) Objective: Hypertension and smoking are risk factors shared between aneurysmal subarachnoid haemorrhage (SAH) and vascular disease in general. Patients with a history of SAH may therefore be at increased risk for vascular events and excess mortality. We studied the overall mortality and long-term risk of vascular events after SAH. Methods: We interviewed 752 patients (mean age 50 years, 67 % women, mean follow-up 8.1 years) with SAH who had been discharged home or to a rehabilitation facility between 1985 and 2001 about new vascular events (ischemic/haemorrhagic stroke, myocardial infarction or vascular death). If patients had died during follow up, we retrieved the cause of death. We compared the age and sex-specific mortality after SAH with that of the general population by means of standardized mortality ratios. The incidence of vascular events in SAH patients was compared with that in patients with a mi-

nor ischemic stroke (including transient ischemic attack) by Kaplan-Meier curves and Cox regression analysis (adjusted for age and sex). Results: The standardized mortality ratio for SAH patients was 3. In the first 10 years after the SAH the cumulative incidence of a vascular event was 10.8 % (95 % CI 7.8–13.8), which was lower (HR 0.43, 95 % CI 0.33–0.56) than that in patients with a minor stroke. Conclusion: Patients who recovered to a functional independent state after SAH have an excess mortality compared with the general population. The risk of vascular events after SAH is lower than after minor stroke, but higher than the population risks reported in the literature, and therefore probably contributes to the excess mortality. O96 Stroke in the United Kingdom: what is the latest evidence on mortality,morbidity and treatment costs? M. C. Christensen, V. Munro Novo Nordisk A/S (Bagsvaerd, DK); Novo Nordisk Ltd (Crawley, UK) Objectives: Stroke is the third leading cause of death and one of the most important causes of adult disability in the United Kingdom, yet little information exists on current treatment patterns, their outcomes and cost. This study assessed survival, morbidity and cost of hospitalisation in a cohort of patients experiencing a first-ever intracerebral hemorrhage (ICH) or ischemic stroke (IS) in the United Kingdom. Methods: We used a population-based retrospective inception cohort design using data from the Hospital-Record Linkage System in the National Health Service (NHS) in Scotland. Individuals were included if they had been admitted to a hospital with a primary first-ever diagnosis of ICH and IS based on the International Classification of Disease Codes (ICD10 161 for ICH and ICD10 163 for IS) between April 2004 and March 2005 inclusive. Patients were followed for twelve months during which survival, morbidity, treatment and cost of treatment provided in hospitals were evaluated. Results: A total of 1,013 patients with an incident ICH and 4.305 with an incident IS were identified. The mean age was 69.8 years (SD 14.7) for ICH and 72.6 years (SD 12.8) for IS at stroke onset. The gender ratio (males/females) was similar for both ICH and IS: 49.7 %/50.3 % for ICH and 48.2 %/51.8 % for IS. Acute in-hospital mortality was 42.5 % for ICH and 13.4 % for IS. Mortality at three months was 46.5 % and 19.9 % for ICH and IS respectively, mortality at six months was 50 % and 22.1 % for ICH and IS respectively, whilst 53.1 % of ICH patients and 27.2 % of IS patients were dead at 1 year after stroke onset. 52.6 % of all ICH patients discharged alive were readmitted to hospital during the first year after stroke onset compared to 54.7 % of IS patients. 7.4 % of the ICH cohort was hospitalized for recurrent stroke during the first year, 1.2 % for myocardial infarction and 1.5 % for heart failure compared to 8.2 %, 1.2 %, and 1.8 % of the IS cohort, respectively. Mean length of stay during initial hospital care was 17.3 (SD 31.9) days for ICH and 18.2 (SD 32.4) days for IS. This resulted in costs attributable to initial hospital care of ≤£5.197 (SD 8.922) for ICH and ≤£4.949 (SD 8.437) for IS. Conclusion: Individuals experiencing a first-ever ICH have a poorer short-term prognosis than individuals experiencing a first-ever IS as reflected in the much higher mortality rate, yet both types of stroke utilise considerable health care resources and require significant follow-up care. This study was funded by Novo Nordisk Ltd O97 Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting C. Cordonnier, R. Al-Shahi Salman, J. Wardlaw Lille University Hospital (Lille, FR); Division of Clinical Neurosciences (Edinburgh, UK) Background and objective: Brain microbleeds (BMBs) are seen as small, homogeneous, round foci of low signal intensity on magnetic resonance imaging T2* sequences. BMBs might only be a biomarker for microangiopathy, or alternatively BMBs might provide useful diagnostic and prognostic information, potentially with therapeutic implications for the treatment of stroke. Methods: Because of the rapid expansion in recent BMB research, we systematically reviewed and critically appraised the published literature according to QUADAS, STARD and Cochrane principles. Results: Our selection criteria were met by 54 studies of 53 case series involving 9.073 participants, 4.432 of whom were people with cerebrovascular diseases. There were significant biases in many of the studies. By pooling data from similar studies, we found that the prevalence of BMBs was 5 % (95 % confidence interval (95 % CI) 4 to 6) in healthy adults, (34 %, 95 % CI 31 to 36) in people with ischaemic stroke, and 60 % (95 % CI 57 to 64) in people

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with non-traumatic intracerebral haemorrhage (ICH). In the studies where a distinction could be made, BMBs were more prevalent among recurrent strokes than first-ever strokes: they affected 23 % (95 % CI 18 to 29) with first-ever ischaemic stroke but 44 % (95 % CI 34 to 54) with recurrent ischaemic stroke, and 52 % (95 % CI 47 to 56) with first-ever ICH but 83 % (95 % CI 71 to 90) with recurrent ICH. By pooling data that could be extracted from similar studies, it appears that BMBs are associated with hypertension (OR 3.9, 95 % CI 2.4 to 6.4) and diabetes mellitus (OR 2.2, 95 % CI 1.2 to 4.2) in otherwise healthy adults, and that they are associated with hypertension (OR 2.3, 95 % CI 1.7 to 3.0) in adults with any cerebrovascular diseases. The association with hypertension was robust in sensitivity analyses. Discussion: There is a pressing need for better designed studies to assess the diagnostic utility of BMBs, disentangle the many likely influences on their occurrence, and determine their prognostic utility and whether they should influence treatment. We conclude by proposing criteria for ideal study design and reporting. Charlotte Cordonnier was funded by the European Neurological Society, the Journées Neurologiques de Langue Française, the Stevenson Exchange Scholarship, the Fondation Bettencourt Schueller and the EA2691. O98 Glutathione peroxidase 1 C593T polymorphism and APOE common polymorphism in primary intracerebral haemorrhage J. Pera, A. Slowik, T. Dziedzic, R. Pulyk, D. Wloch, A. Szczudlik Jagiellonian University (Cracow, PL) Background: Oxidative stress is an important player in vascular injury related to hypertension and age. It also contributes to pathogenesis of primary intracerebral hemorrhage (PICH). Among enzymes involved in antioxidant protection selenium-dependent glutathione peroxidase (GPX1) play a key role by detoxifying hydrogen and lipid peroxides. T allele of the GPX1 C593T polymorphism (rs1050450) is less responsive to the stimulation of GPX1 enzyme activity and associated with sensitivity to oxidative damage by H2O2, and an increased risk of cardiovascular diseases in diabetic patients. The significance of this polymorphism in PICH is unknown. Studies suggest that the possession of apolipoprotein E (APOE) epsilon2 and/or epsilon4 alleles is associated with lobar PICH and epsilon4/epsilon4 carriers are the most susceptible to oxidative protein damage. In this context we sought to investigate if the C593T GPX1 polymorphism is involved in the genetic susceptibility to PICH in a Polish population. Moreover, we analyzed whether there is a relation between this polymorphism and APOE common polymorphism. Methods: We prospectively enrolled 192 PICH patients, and 197 unrelated controls with no apparent neurological disease, matched by age and sex. All patients underwent computed tomography (CT) and angioimaging (CTA and/or MRA and/or DSA). All participants were Caucasians. Demographic data and information on vascular risk factors were collected. GPX1 and APOE genotypes were determined by PCR-RFLP method. Results: The distribution of the GPX1 and APOE genotypes was in Hardy-Weinberg equilibrium in studied groups. In univariate analysis genotypes with the T allele were significantly over-represented in patients with lobar (cases: 73 % vs. controls 54.3 %, p = 0.004) but not in non-lobar PICH (57.6 %). Genotypes with epsilon2 or epsilon4 alleles were also over-represented in lobar PICH (38 % vs. controls 26.8 %, p < 0.05). Logistic regression analysis showed that possession of the genotype with T allele (OR = 2.29, 95 % CI: 1.20–4.39; p = 0.01) was an independent risk factors for lobar PICH. This was also true after adjustment for APOE genotypes. Discussion: Our results supports the association of the genetically determined GPX1 activity with PICH.

Oral session 12 Multiple sclerosis 2 O99 Altered functional and structural connectivities in patients with multiple sclerosis: a fMRI and MR tractography study at 3 T M. Rocca, M. Absinta, E. Pagani, P. Valsasina, A. Falini, G. Scotti, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, IT); CERMAC (Milan, IT); IRCCS San Raffaele (Milan, IT) Background: Using functional magnetic resonance imaging (fMRI), abnormal patterns of movement-associated cortical activations have been demonstrated in patients with multiple sclerosis (MS). Objectives: To determine the functional and structural substrates of motor network dysfunction in patients with relapsing-remitting (RR) MS, using analysis of functional connectivity and MR tractography. Methods: Using a 3 Tesla scanner, in 12 right-handed patients with RRMS and 14 sex- and age-matched healthy volunteers, we acquired, dual-echo (DE), diffusion tensor (DT) MRI and fMRI during the performance of a simple motor task with the dominant hand. DT MRI tractography was used to construct, from healthy volunteers data, probability maps for the corpus callosum, the corticospinal tract (CST), the optic radiation, the superior frontooccipital fasciculus, the uncinate fasciculus, the dentatorubrothalamic (DRT) tract, the cingulum and the superior longitudinal fasciculus. Then, these maps were applied to patients data to calculate DT-derived metrics of the bundles of interest. Using SPM2 and dynamic causal modelling a functional connectivity model was built, assuming the effect of the task entering the network via the left (L) primary sensorimotor cortex (SMC). Results: Compared to control, MS patients had significantly higher MD and lower FA of all the white matter bundles studied. Compared to controls, MS patients had more significant activations of the contralateral supplementary motor area (SMA), the contralateral primary SMC, and the ipsilateral anterior lobe of the cerebellum. They also had increased functional connectivity between the right (R) primary SMC and the R cerebellum (p = 0.01) and between the SMA and the L primary SMC (p = 0.04). Strong correlations were found between coefficients of altered connectivity and structural MRI metrics of tissue damage of the CST and the DRT tract (r values ranging from –0.73 to 0.85). Conclusions: The correlations found between measures of functional connectivity and structural damage to some of the major brain motor white matter bundles suggests an adaptive role of functional connectivity changes in limiting the clinical consequences of structural damage in MS. This study also indicates that combining measures of altered functional and structural connectivities of specific brain networks is a promising tool to better elucidate the mechanisms responsible for the clinical manifestations of CNS damage. O100 In vivo assessment of cervical cord damage in multiple sclerosis patients: a longitudinal diffusion tensor magnetic resonance imaging study F. Agosta, M. Absinta, M. P. Sormani, A. Ghezzi, A. Bertolotto, E. Montanari, G. Comi, M. Filippi Scientific Institute and University Ospedale San Raffaele (Milan, IT); University of Genoa (Genoa, IT); Gallarate Hospital (Gallarate, IT); Orbassano Hospital (Orbassano, IT); Fidenza Hospital (Fidenza, IT) Objectives: We used conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) to: a) define the temporal evolution of intrinsic tissue injury and atrophy in the cervical cord from multiple sclerosis (MS) patients, b) investigate how these two aspects of cord damage are interrelated, and c) assess the correlation of cord MRI metrics with concomitant brain damage and disability. Methods: Conventional and DT MRI of the brain and cervical cord were obtained from 42 MS patients and nine healthy controls at baseline and after a mean follow-up of 2.4 years. At each time-point, we measured: cervical cord lesion number, cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA). Brain T2 lesion volume, grey matter MD, normal appearing white matter (NAWM) MD and FA, as well as longitudinal normalised percentage brain volume changes were also measured. Results: In MS patients, cervical cord cross-sectional area (p < 0.001) and FA (p = 0.01) decreased, and cervical cord MD increased (p < 0.001) during follow up. Cord FA decrease, but not cord cross-sectional area and MD, was significantly higher (p = 0.05) in primary progressive MS patients than in those with either relapsing-remitting and secondary progressive MS. At

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baseline and follow up, moderate correlations were found between intrinsic cord diffusivity abnormalities and cord cross-sectional area (r values ranging from 0.34 to 0.58), but not between their changes over time. No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of cord T2-visible lesions. Brain NAWM MD (p = 0.03) and brain volume (p < 0.001) also changed in patients. There was no significant correlation between cord and brain MRI metrics at both time-points, as well as between their changes occurred over the follow up. Baseline cord crosssectional area (r = –0.40, p = 0.01) and FA (r = –0.40, p = 0.03) correlated with increase in disability at follow up. Conclusions: This study shows that both progressive tissue loss and injury to the remaining tissue occur in the cervical cord of MS patients, and that these two components of cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage. MS cord pathology also seems to be independent of concomitant brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual. O101 Functional magnetic resonance imaging of the cervical cord in patients with multiple sclerosis F. Agosta, P. Valsasina, S. Sala, E. Judica, D. Caputo, P. W. Stroman, M. Filippi Scientific Institute Fondazione Don Gnocchi (Milan, IT); Scientific Institute Ospedale San Raffaele (Milan, IT); Queen’s University (Kingston, CA) Objective: To assess and compare the extent of the activations in the cervical cord of patients with relapsing multiple sclerosis (MS) and healthy controls, during the performance of a passive motor task, and to investigate the magnitude of the correlation between cervical cord functional recruitment and structural damage. Methods: Cervical cord conventional, diffusion tensor, and functional (proton density-weighted spin echo sequence) magnetic resonance imaging (MRI) were acquired from 24 right-handed relapsing MS patients (17 women, seven men; mean age = 40.7 years; median disease duration = 12 years; median EDSS = 3.5) and 10 matched controls. Cervical cord T2 lesions were identified, and mean diffusivity (MD) and fractional anisotropy (FA) histograms were produced. Using a block design, subjects were scanned when performing a passive motor task consisted of the flexion-extension of the right wrist. Functional MRI (fMRI) analysis was performed using a General Linear Model. Statistical maps were generated for all subjects (p = 0.02). The task-related mean intensity signal change was computed for all activated voxels within the cervical cord. A Student t test for paired data was used to compare MRI quantities between controls and patients. Univariate correlations were assessed using the Spearman Rank Correlation Coefficient. Results: Three patients were excluded prior to MRI analysis for the presence of motion artifacts in the fMRI.All controls and 16 patients had no cervical cord T2 lesions, whereas three patients had one lesion, one patient two lesions, and the remaining patient three lesions. MS patients had significantly higher cervical cord MD (p = 0.009) and significantly lower FA (p < 0.001) compared to controls. During the passive motor task, the average cord signal changes were 2.5 % (SD = 0.2) for controls and 3.2 % (SD = 0.9) for patients (p = 0.03). Cervical cord FA (r = –0.51, p = 0.005) was significantly associated to cervical cord average signal change. In MS patients functional cervical cord changes also significantly correlated to disease duration (r = 0.46, p = 0.03) and EDSS (r = 0.48, p = 0.03). Conclusions: During a passive motor task, MS patients showed an abnormal functional recruitment of the cervical cord compared to controls. The correlations between cervical cord functional changes and cord structural damage and clinical disability might suggest an adaptive role of cord reorganization contributing to the maintenance of normal functional capacity in MS patients. O102 Regional volumetry and diffusivity changes in patients with benign and relapsing-remitting multiple sclerosis A. Ceccarelli, E. Pagani, M. Rocca, A. Ghezzi, R. Capra, M. Rodegher, A. Falini, G. Scotti, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, IT); Ospedale di Gallarate (Gallarate, IT); Ospedale di Brescia (Brescia, IT); IRCCS San Raffaele (Milan, IT); CERMAC (Milan, IT) Objectives: To obtain new insight into benign (B) multiple sclerosis (MS) pathophysiology by comparing regional gray matter (GM) loss and GM and white matter (WM) diffusivity changes between patients with BMS and those with relapsing remitting (RR) MS.

Methods: Using a 3 Tesla scanner, dual-echo, magnetization-prepared rapid acquisition gradient echo (MP-RAGE) and diffusion tensor (DT) scans were acquired from 20 healthy volunteers (HV), 19 BMS and 16 RRMS patients, with similar disability. An optimised voxel-based morphometry analysis was performed using SPM2 and an ANCOVA model. Results: Compared to HV, MS patients had GM loss in the left (L) parietal (PL) and frontal (FL) lobes and the thalamus, bilaterally (p < 0.05). BMS patients also showed GM loss in the cingulum (CG) (p < 0.05). GM loss in the previous structures was more pronounced in BMS rather than RRMS patients (p < 0.001). Compared to HV, MS patients had increased mean diffusivity (MD) values in the splenium of CC, the CG, the R corona radiata, pons and occipital lobe (OL) and bilaterally in the FL and temporal lobe (TL), and cerebellum (p < 0.05). BMS patients had also increased MD in the L precuneus (p < 0.05), while RRMS patients had increased MD in the L internal capsule and CG (p < 0.001). Compared to HV, MS patients had decreased fractional anisotropy (FA) values in the splenium of corpus callosum (CC), the bilateral occipito-temporal fibers, and the R pons (p < 0.05). No differences were found between BMS and RRMS patients. Conclusions: Patients with BMS have a pattern of brain regional damage very similar to that of RRMS patients. This suggests that brain damage development remains restricted to areas involved early by the disease, and therefore, might contribute to explain the absence of clinical disability in BMS.

O103 Syrinx like formations: a rare feature of spinal cord involvement in multiple sclerosis K. Weier, Y. Naegelin, A. Thoeni, J. Hirsch, E. W. Radue, L. Kappos, A. Gass University Hospital Basel (Basel, CH) Introduction: Syrinx formations within the spinal cord (SC) occur most commonly in association with congenital-idiopathic diseases or aquired pathology (post-traumatic, neoplasm, inflammatory arachnoiditis). Symptomatic syringomyelia usually causes the clincal picture of dissociated sensory loss at the level of the cord pathology and may require surgical intervention.We report syrinx like formations in the spinal cord in a large cohort of MS patients who underwent 2 brain and SC MRI examinations 1 year apart. Methods: Standardised brain and SC MRI of 202 MS patients (140 w, 62 m, 24–74 years old, EDSS 0–7.0) with different MS subtypes (CIS, RRMS, SPMS and PPMS) was analysed. SC MRI included images in the sagittal and transverse plane of the whole cord employing multi-array-coils and parallel imaging technology. Results: SC MRI demonstrated the typical sequelae of inflammatory-demyelinating disease: focal lesions, diffuse abnormalities and the combination of both, furthermore focal and generalised atrophy was seen. In 7/202 patients (3.5 %) syrinx like formations were identified. All syrinx like formations presented as a non-communicating, isolated dilation of the central canal with CSF signal intensity in sagittal and transverse planes. There was a slight enlarging effect on the cord at the level of the syrinx. The size varied from 2.5–17 cm in length and 15–50 mm in diameter. In 7/7 patients there were concomitant typical SC MS lesions. Lesions could be close to the syrinx, above or below the cavitation, but there was no obvious pattern of immediately adjacent lesions. Five patients showed slight degenerative changes of the vertebral column, but none causing cord compression. F/u MRI demonstrated in all cases unchanged phenomenology of the syrinx. Careful clinical examination showed in none of the cases dissociated sensory loss or suggested a focal functional deficit arising from the syrinx level. Conclusion/Discussion: Noncommunicating oligo/asymptomatic syrinx like formations rarely occur in MS patients. Unlike disc disease, intramedullary tissue changes are usually not noted in normal controls. In this 202 patient cohort they did not cause obvious clinical symptoms or signs. Displacement of SC tissue was noted without major compressive effect and without a tendency to increase in size over 1 year.

O104 Distinct shift in immune cells counts and cerebrospinal fluid oligoclonal bands number after natalizumab treatment in multiple sclerosis E. Krasulova, E. Havrdova, H. Mareckova, P. Racek, P. Nytrova First School of Medicine (Prague, CZ) Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) often leading to severe disability. Many immunopathological processes have been described in MS pathophysiology including role of CD4+ T-cells, CD19+ B-cells and various anti-bodies production. Intrathecal production of oligoclonal IgG bands (OCBs) is used for

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MS diagnosis verification, however strong correlation between OCBs number and disease acitivity or treatment efficacy has not been described yet. So far the most efficacious MS drug with 68 % drop in relapse rate seems to be a monoclonal antibody against adhesive molecule alfa4beta1 integrin expressed on lymphocytes, interfering with lymphocyte migration to the site of inflammation (CNS). In our study we have investigated natalizumab effects on CD4+ and CD19+ cells in peripheral blood and cerebrospinal fluid (CSF) as well as effect on OCBs number in MS patients during the treatment and 16 months after the drug withdrawal. Methods: Peripheral blood and CSF was taken, immunophenotyping was performed and OCBs assessed in 15 MS patients after at least 6 months of open label safety natalizumab study (4 weeks after last administration). Same examinations were repeated 16 months after natalizumab withdrawal. Flow cytometer FACSCalibur and monoclonal antibodies BD Bioscience were used (CD4, CD19), OCBs were detected by isoelectric focusation. Student’s t test was used for statistical analysis. Results: 16 months after natalizumab withdrawal significant increase of total elements count in CSF was found (p = 0.002). There was significant decrease of CD19+ cells in peripheral blood (p = 0.01) and increase of this subpopulation in CSF (p = 0.006), we have shown increase of OCBs number in CSF as well (p = 0.002). Significant increase of CD4+ cells in peripheral blood (p = 0.0003) as well as in CSF (p = 0.0001) was shown 16 months after natalizumab withdrawal. Conclusion: Natalizumab is a potent novel MS drug with obvious immunological effects. It can reduce both CD4+ T-cells and CD19+ B-cells in CSF compartment and this had the same trend with OCBs number decrease in CSF. There was also decrease of CD4+ cells in peripheral blood, here we can hypothesize other effects of natalizumab on T-cells, e. g. apoptosis increase after not reaching relevant antigen in the CNS. Further systematic immunological investigations are needed for better use of the drug and cautious handling with potential adverse events. Supported by IGA MZ NR/9375–3/2007.

Oral session 13 Movement disorders 2 O105 Clinical outcome predictors of pallidal deep brain stimulation for primary dystonia I. U. Isaias, R. Alterman, M. Tagliati University of Milano Bicocca (Monza, IT); The Mount Sinai School of Medicine (New York, US) Background: Pallidal DBS is currently the most effective treatment for medically refractory dystonia. However, patient selection criteria are not well defined. The cost and potential risks of pallidal DBS warrant a better determination of patients that will likely have optimal postoperative outcomes. Methods: We reviewed clinical records of 31 patients with medically refractory primary dystonia (20 DYT1+) who underwent stereotactic pallidal DBS implants. Twenty-nine were implanted bilaterally (17 males) and two unilaterally (1 male). Three patients had multiple thalamotomies before DBS. The Burke-Marsden-Fahn Dystonia Rating Scale (BMFDRS) scores at baseline and 12 months after DBS were used to evaluate clinical outcome. Several possible outcome predictors, including demographic (age, gender) and clinical factors (duration and severity of disease, anatomical site of involvement, previous ablative surgery) were correlated with BFMDRS score changes using Pearson correlation coefficients. Results: Pallidal DBS was successful in every patient, with an average improvement of 69.4 % at 12 months. Previous thalamotomy and involvement of speech and swallowing were the only factors showing a significant negative correlation with clinical outcome (p < 0.01 and p < 0.05, respectively). Disease duration also showed a negative correlation trend (p = 0.06). Even when the 3 patients with multiple thalamotomies were excluded, involvement of speech and swallowing showed a negative corelation with outcome (p = 0.05) and disease duration showed a negative correlation trend (p = 0.06). None of the other analyzed factors showed any correlation with clinical outcome. Conclusions/Relevance: A history of multiple thalamotomies is a negative outcome predictor for pallidal DBS in patients with dystonia. Similarly, patients with involvement of speech and swallowing muscles and longer dis-

ease duration of disease may expect less than optimal outcomes. Age at onset and at surgery, gender, DYT1 status, dystonia severity and involvement of axial and limb muscles do not predict DBS outcome. O106 Influence of tremor on the quality of life A. Vaitkus, A. Kiseliova, A. Sasnauskaite, O. Fomina Kaunas University of Medicine (Kaunas, LT) Purpose: to evaluate the between different age groups. Objectives: 1)To find out what kind of tremor and how often disturbs patients, 2)what are the reasons of tremor, 3) what kind of treatment can be performed and what is the effect 4)what is the effect of tremor on rutine life. Methods: The research was performed among therapic patients at the Clinical Hospital and among students of Kaunas University of Medicine. Questionnaire based surveys was performed. 472 respondents were questionned. The data were analysed with SPSS programs. (ö2) criterion was used to check hypothesis about correlation of features. Results: 67 % stated that tremor disturbed them, 33 % -that it didn’t. All respondents were classified by age into grupes: 33.5 % < 25years, 6.8 % – 26–35years, 5.5 % 36–45years, 12.1 % 46–55years, 12.3 % 56–65 years and 29.9 % > 65 years old. Tremor occurrence between different grupes of age was: 65.8 %– < 25 y., 78.1 %– 26–35 y., 61.5 %– 36–45 y., 54.4 %– 46–55 y., 77.6 %– 56–65 y., 64.2 %– > 65 y. Tremor of head, voice, chin and legs statistically depended on age (p < 0.05). Respondents stated those factors that induced tremor most often: stress- 70.3 %, physical work- 25.2 %, fatigue34.8 %. Tremor’s reasons depended on age and sex (p < 0.05). Respondents tried those methods of management: 22.4 % medications, 45.7 % relaxation, 16.3 % relaxing exercises, but 33.5 % did nothing. 65.6 % stated chosen methods as effective, 11.5 %–ineffective, 23 %– of unsufficient efficiency. Efficiency of treatment depended on chosen method (p < 0.05): physiotherapy, folk medicine were stated as ineffective, whereas decreasing of alcohol and coffeine usage, relaxation and relaxing exicises- as effective. 48.6 % stated short-term tremor, 42.4 %–intermitent, 9.3 %–persistent. 22.4 % noticed that tremor disturbed their every day life, 54.3 %–that it didn’t, 23.3 %– that it disturbed their life partially. Tremor’s influence on every day life depended on treatment efficiency, character of tremor and it’s progression (p < 0.05). Conclusions: 1. About 2/3 complained of tremor, which was short-term and intermitent; 2. Stress, fatigue, physical work were the most frequent tremor inducing factors; 3. Relaxation, medications and relaxing exicises were the most frequent and effective methods of treatment; 4. Every day life of half of respondents, complaining of tremor, did not change. O107 Gilles de la Tourette syndrome – clinical analysis of 126 Polish patients A. Kalbarczyk, M. Sitek, M. Zach, P. Janik Medical University of Warsaw (Warsaw, PL); SP CSK (Warsaw, PL) Objective: Gilles de la Tourette syndrome (TS) is characterised by the presence of multiple motor and vocal tics. The objective of this work is to compare clinical and demographic symptomatology of Polish TS patients with other cohorts. Methods: 126 TS patients were studied and compared with the international database of 3500 patients from 22 countries (Freeman et al., 2000). The same data entry form including demographic and clinical data was used in both studies. Results: TS was four times more frequent in males in both cohorts. Paternal inheritance dominated in our patients in contrast to maternal inheritance in the international study. As compared to the international database in our patients, there were more frequently seen: significant prenatal/perinatal problems (29 % vs. 20 %; p < 0.05); abrupt onset or upsurge after infection (11 % vs. 5 %; p < 0.01); later age at onset (7.6 ± 3.5 years vs. 6.4 ± 2.9 years); earlier diagnosis (11.8 ± 5.5 lat vs. 13.2 ± 9.6 lat); more severe tics needed to be treated (85 % vs. 69 %; p = 0.0001); tics without comorbidity (23 % vs. 12 %; p < 0.001); greater comorbidity score (2.6 vs. 2.06); learning disorder (34 % vs. 23 %; p < 0.001), coprolalia (36 % vs. 14 %; p < 0.001), selfinjurious behaviour (33 % vs. 14 %; p < 0.001), sleeping problems (33 % vs. 25 %; p < 0.05). The most commonly reported comorbidity was attention deficit hyperactivity disorder (59 % vs. 60 % patients; p = ns). Polish patients were more often given symptomatic treatment (77 % vs. 60 % patients; p < 0.001).Among our patients haloperidol was used most frequently in contrast to international database where clonidine was the drug of choice. Conclusion: Intensity of tics and comorbidities were more severe in Polish patients, which may result from the differences in inheritance and increased influence of environmental factors.

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O108 The influence of the lesion in STN on clinical characteristics of the patients with hemiballism due to stroke A. J. Ristic, N. Dragasevic, G. Trajkovic, M. Svetel, V. S. Kostic Institute of Neurology (Belgrade, RS); School of Medicine (Kosovska Mitrovica, RS) Objective: To determine the role of lesion of the STN in patients with hemiballism due to stroke regarding degree of functional disability, treatment response and outcome. Methods: In 41 patients with hemiballism due to stroke we determined level of functional disability using quantitative scale from 0 to 4 (0-without involuntary movements, 1-mild involuntary movements, 2-moderate involuntary movements without functional disability, 3-moderate involuntary movements with moderate functional disability, and 4-severe involuntary movements with severe functional disability), treatment response and short term outcome. We found identifiable lesion in 33 patients. In 8 patients with normal imaging stroke was suspected due to risk factors and sudden onset. Results: We recorded hemiballism in 38 patients, in 2 patients monoballism, and biballism in one patient. Chorea as additional movement disorder was estimated in 70.7 % of patients. 9 patients had lesions in STN. We found no statistically significant difference between patients with and without lesion in STN regarding the degree of functional disability (Mann-Whitney U = 100.5, p = 0.76). There was no significant difference between patients with and without lesion in STN regarding parameters concerning treatment response (full cessation of involuntary movements with treatment; no response to haloperidol). Clinical improvement in group with lesion in STN was registered after 6 days, and in group of other locations after 10.5 days (log-rank test statistics = 0.11, p = 0.91). 2 patients with lesion in STN of 5 followed and 4 patients with lesions out of STN of 14 died during long-term follow-up. Conclusion: Lesion in STN doesn’t impact certain clinical characteristics in patients with hemiballism due to stroke. O109 Neurophysiological evidence of executive dysfunction in Parkinson’s disease: a study using event-related potentials to a Stroop task L. Leocani, N. Amato, G. Magnani, S. Lalli, D. Ceppi, F. Spagnolo, G. Comi, M. A. Volonté IRCCS S. Raffaele (Milan, IT) Objective: In addition to the cardinal motor symptoms, cognitive involvement is frequently reported in patients with Parkinson’s disease (PD), predominantly concerning executive function. Subcortical dementia develops in 10 to 20 % of patients. The aim of the present study was to investigate the bioelectrical correlates of executive functions in non-demented patients with PD. Methods: Twenty-nine non-demented (MMSE 27.8 ±1.2, range 26–30) patients with PD (age:62 ± 8; UPDRSIII score 22±11 on, 34.55±14 off; H&Y score: 2.3±0.57 on, 2.8±0.98 off) under L-DOPA treatment, and in 22 healthy subjects (age: 58±7) were included. Simple and complex manual reaction times (RTs) to the Stroop test, a test investigating executive functions, were included. Simple and complex reaction times to the Stroop color/word task, a test investigating executive functions, were measured using a computerized system. In complex RTs (go/no go and choice), a different response was required for congruent and incongruent color/word stimuli. Event-Related Potentials (ERPs) to the same stimuli were obtained from 29 channel EEG, during mental discrimination between congruent and incongruent stimuli. Multivariate analysis was performed on ERPs latencies of N1, P2, N2, P3 and N4 components; topographic differences were searched with low resolution brain electromagnetic tomography (LORETA). Results: Reaction times did not significantly differ between the two groups, but in the PD group the speed of RT was significantly correlated with the UPDRSIII score ‘on’ in the choice RT (r = 0.672; p = 0.006). The latency of early ERPs components (N1, P2) did not show significant group effect, while N2, P3 and N4 latencies were significantly delayed in PDs compared to controls (p < 0.0001). LORETA voxel-wise ERPs analysis showed that, compared to controls, PD patients had reduced activation of the superior, middle and inferior frontal gyrus, the orbital gyrus, the anterior cingulate and the left inferior and middle temporal gyrus in latencies between N2 and P3; in the N4 time window, in the inferior and medial frontal gyrus, the orbital gyrus and the anterior cingulate. Conclusions: The finding of delayed ERPs latencies of late component, together with reduced expression over the frontal regions in treated, non-demented PD patients with normal behavioural responses to the Stroop test, suggest that bioelectrical activity may be useful in detecting subclinical frontal lobe impairment in this disease.

Oral session 14 Peripheral neuropathy 2 O110 Diaphragm muscle electrophysiological study predicts respiratory evolution in patients with amyotrophic lateral sclerosis J. P. Camdessanche, A. Poujois, F. Costes, I. Court-Fortune, J. C. Antoine CHU Saint-Etienne (Saint-Etienne, FR) Objective: To evaluate the interest of electrophysiological diaphragm muscle recording to predict respiratory insufficiency in patients with amyotrophic lateral sclerosis (ALS). Background: Respiratory insufficiency considerably affects survival in ALS. Bolton (1993) has proposed a simple method to record diaphragm muscle with a surface electrodes placed on the abdomen after phrenic nerve stimulation at the neck. This method has showed prolonged distal latencies or unrecordable muscles in ALS patients with respiratory signs (Evangelista et al., 1995). Methods: We prospectively recorded right and left diaphragm muscles according to Bolton’s method in 23 healthy volunteers and in 21 patients with definite ALS referred to the ALS center of Saint-Etienne. None of them had clinical respiratory signs, at referral time. In ALS patients, ALS-FRS, respiratory functional tests, arterial-blood gas studies, recourse to non-invasive ventilation and survival were evaluated every three months during the first year of follow-up. Statistics were performed with non parametric tests. Results: Values of distal latencies (DL) and compound motor action potentials (CMAP) were similar in healthy volunteers to that published by Bolton. In ALS patients at referral time, CMAPs were reduced comparatively to healthy volunteers (0.24 ± 0.11 vs. 0.55 ± 0.22 mV; p < 0.01). CMAP amplitude at referral time was correlated with survival (p < 0.05), O2 pressure rate at 9 (p < 0.05) and 12 months (p < 0.01), PO2 pressure rate at 9 and 12 months (p < 0.01) and forced vital capacity at 12 months (p < 0.01) with the Spearman correlation test. There was no correlation between CMAP amplitude at referral time and delay between the onset of symptom and referral time. Conclusions: Recording of diaphragm muscle with Bolton method is simple and may be useful to identify ALS patients at risk to rapidly develop respiratory insufficiency needing early non-invasive ventilation. O111 Sensory profiles in painful versus non-painful chemotherapy-induced polyneuropathy C. Geber, C. Egenolf, M. Dieterich, R. Treede, F. Birklein, T. Vogt Johannes-Gutenberg University (Mainz, DE) Objectives: Chemotherapy-induced polyneuropathy (CINP) is a common negative side effect of antineoplastic therapy. Besides sensory loss (“numbness”), patients often report accompanying pain which is often neuropathic. Clinical symptoms and signs in patients with painful and painless CINP were assessed, sensory dysfunction objectified using electroneurography and sensory profiles assessed using quantitative sensory testing (QST) according to the DFNS protocol (Rolke 2006). The aim of this study was to point out differences in sensory dysfunction which might play a role for the development of pain in some but not all patients and to elucidate the underlying pathophysiological mechanisms. Methods: 40 patients (m: 15; f: 25) aged between 26–70 (mean 56) years with malignant solid and non-solid tumors of different aetiologies (gastrointestinal, gynaecological tumors, Hodgkin-/Non-Hodgkin lymphomas) and clinical signs of persisting CINP were included. Sensory symptoms and signs were clinically assessed and an electroneurography of the sural and peroneal nerve was performed. QST was performed on the right foot. It comprises 13 parameters including thermal and mechanical detection and pain thresholds, unmasks large- and small-fiber dysfunction and can detect hypo- as well as hyperphenomena, e. g. thermal or mechanical hyperalgesia. For both subgroups (painful and painless CINP, each n = 20) sensory profiles were plotted and compared to a control group matched for age and gender. Statistical analyses were performed using t-tests and ANOVAs. Results: Electroneurography detected sensory neuropathy in both CINP subgroups. In the QST a significant reduction of thermal (cold- and warm) detection (each p < 0.01)was found but perception of thermal pain was not altered in both groups. Congruently, there was a significant (p < 0.01) reduction of mechanical detection (touch) and vibration. However, mechanical pain detection was significantly reduced (p < 0.05) only in the painful CINP group. Conclusion: Electroneurography as well as QST detected sensory dysfunction in both groups. Sensory profiles of both –painful and painless–

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CINP were largely overlapping showing deficits in small- and large fiberfunction. The fact that the mechanical pain detection, which represents the function of an A-Delta-fiber subgroup, was more affected in the painful CINP group could be of pathophysiological relevance for the development of pain. Supported by the DFNS (BMBF-grant 01EM0506) and the “Stiftung Rheinland-Pfalz für Innovation”. O112 Molecular analysis of the MFN2 gene in familial and sporadic axonal Charcot-Marie-Tooth disease type 2 M. Milani, D. Pareyson, F. Taroni Fondazione IRCCS Ist Neurologico C.Besta (Milan, IT) Axonal CMT (CMT2) is genetically highly heterogenous, with at least 14 loci and 10 genes identified thus far. Mutations in the gene encoding the mitochondrial protein mitofusin-2 (MFN2) have been shown to be responsible for autosomal dominant CMT2 type A2 (CMT2A2). The MFN2 gene maps to chromosome 1p36.2 and encodes a 757-amino acid protein which is an essential component of mitochondrial fusion in mammalian cells. The CMT2A2 phenotype is largely indistinguishable from that of CMT2A1 (KIF1B), CMT2E (NEFL), and CMT2F (HSPB1). However, in a subset of CMT2A2 patients, pyramidal involvement and visual impairment have been reported. The disease exhibits reduced penetrance: studies in large families have shown that individuals with MFN2 mutations may present no signs of disease even at the electrophysiological examination. Objectives: To screen a large CMT2 patient sample for MFN2 mutations. To analyse the mutation spectrum and frequency and to assess the phenotypes associated with the MFN2 gene. Methods: We studied 173 index patients with axonal CMT. Familiarity was reported in one third of the cases only. The 17 MFN2 exons and exon-intron boundaries were screened by DHPLC. Fragments showing an altered profile were directly sequenced. Results: Nine novel and 2 previously reported mutations were found in heterozygous form in 11 unrelated index cases. There were 9 missense and 1 frameshift mutations,and 1 amino acid deletion.The majority of cases (7/11, 63.6 %) were sporadic. Age at onset ranged from 4 years to adulthood. Clinical presentations included clinical and electrophysiological sparing of the upper limbs, pyramidal signs, tremor, and optic atrophy in two cases. Two familial cases were characterized by early-onset, severe progression, and proximal involvement. Conclusion: Our results indicate that in a raw series of axonal CMT patients the minimum frequency of MFN2 mutations is approx. 7 %, thus indicating that genetic testing for CMT2 should begin from the MFN2 gene. The age at onset and the phenotypic spectrum is broad. The results also show that MFN2 mutation analysis should be performed in both familial and sporadic cases. Supported by Telethon-UILDM (GUP04009) and Fondazione Mariani (R-05–44) O113 Ten-year experience with liver transplantation for familial amyloidotic polyneuropathy type I in Rio de Janeiro, Brazil M. W. Cruz, M. Saporta, C. André, S. A. P. Novis, J. Ribeiro Federal University of Rio de Janeiro (Rio de Janeiro, BR) Objectives: To describe the results of neurological and electroneuromyography (ENMG)evaluations done both before and after liver transplantation (LT) in FAP type I patients followed since April 1997. Methods: Patients were annually submitted to neurological and ENMG evaluations addressing the most relevant aspects of FAP type I before and after LT. Results: 51 patients (28 men, 23 women) were considered eligible for LT since 1991. Forty two patients were Caucasian and 9 Afro-Brazilian. 39 patients belonging to 33 families were from Portuguese ancestry. The mean age of disease onset was 34.7 years (19–50) in women and 28 years (20–38) in men. A pathogenic transthyretin variant Val30Met mutation was confirmed in 29 patients. 28 patients were annually evaluated up to the forth year before LT: during the first year before LT 60 % of these patients exhibited clinical worsening and 77 % had increasing ENMG abnormalities. The corresponding results in the second, third and fourth years were: 40 % and 42 %, 71.4 % and 57.1 %; and clinical deterioration of one of the two remaining patients. There was evidence of deterioration of 53 % (26) in a total of 49 clinical evaluations, and of 60 % (46) of ENMG exams. Cadaveric LT was performed in 34 patients, mostly in Rio de Janeiro (22). In 2 patients, cadaveric LT followed previous living donors LT. The mortality rate after LT was 21 % (7 / 34) mostly related to infectious causes. The mean time of disease onset

at LT was 4.8 years (1–9) and the mean time of last evaluation before LT was 8.7 months (1–24). Fourteen patients could not be evaluated after LT: 7 died, 4 LT have only recently been done and 3 patients were lost to follow-up. In 20 patients evaluated up to sixth years after LT, clinical stability could be demonstrated in: 7 out of 11 in the first year; 7 out of 9 in the second year, 1 out of 2 patients in the third year, and 3 out of 3 in the forth year. The corresponding rates for ENMG non- progression were: 4 out of 10; 1 out of 8; 1 out of 2; and 1 out of 2. During the sixth year the only patient followed did deteriorate clinically. Conclusion: Brazilian patients with FAP type I progressively deteriorate without LT. After LT patients tended to remain clinically stable but ENMG increasing abnormalities suggest an ongoing process and a longer period of follow-up is needed to better ascertain their prognosis. In this particular series of cases disease duration before LT did not influence the prognosis after the procedure. O114 Decreased cardiac 123I-MIBG uptake in sporadic late-onset familial amyloid polyneuropathy type I (TTR Met 30) patients without signs or symptoms of cardiovascular autonomic involvement O. J. M. Nascimento, G. Quintanilha, M. R. G. de Freitas, J. C. Azevedo, C. T. Mesquita, P. L. Correa Universidade Federal Fluminense (Rio de Janeiro, BR) Recently, reports of late onset sporadic familial amyloid polyneuropathy (LOS-FAP) cases presenting with a phenotype similar to that observed in senile systemic amyloidosis have emerged. Cardiovascular autonomic involvement is commonly seen in LOS-FAP patients, mainly the sympathetic ones. Metaiodobenzylguanidine (MIBG) an analog of the false neurotransmitter guanethidine, when tagged with 123I can be used to image adrenergic receptors in many organs, including the heart. The major advantage of 123IMIBG myocardial scintigraphy is its ability to directly and no invasively assess cardiac sympathetic innervations, which cannot be accomplished by the traditional autonomic tests. Objective: Report the myocardial sympathetic nervous activity findings in LOS-FAP patients presenting a small fiber polyneuropathy (SFPN). Patients and method: Three patients, a 58 y. o. man, and 2 women, respectively with 56 y. o. and a 62 y. o. were referred to us with a SFPN with no familiar history. Presenting symptoms were sensory in all, being pain in the distal lower limbs the most prominent. Duration of symptoms was 6. 10, and 24 months, respectively. There was no autonomic dysfunction or cardiac involvement assessed by the standard bedside tests. Electrophysiological and laboratorial examinations had been performed. Results: Sural nerve biopsy revealed amyloid deposits in all cases. DNA TTR Met 30 mutation test was positive in all cases pointing to LOS-FAP diagnosis. 123I – MIBG scintigraphy was performed to analyze sympathetic nervous activity. There was an accentuated decrease in the accumulation of 123I-MIBG in the heart, suggesting that severe glandular and visceral autonomic dysfunctions had occurred in our three patients. Conclusion: MIBG is an useful non invasive test for the detection of cardiac sympathetic denervation before the current diagnostics tests in patients with LOS-FAP without symptoms of autonomic dysfunction. O115 Reduced post-tetanic hyperpolarization in WldS mice M. Moldovan, S. Alvarez, C. Krarup Panum Institute, University of Copenhagen (Copenhagen, DK); Rigshospitalet, University of Copenhagen (Copenhagen, DK) Wallerian degeneration of injured neuronal axons and synapses is delayed in WldS mice due to a mutation mapped to distal chromosome 4. The protein product of the WldS was localized to neuronal nuclei. The mechanism accounting for axonal protection remains poorly understood. It is recognized that a large increase in intra-axonal Na+ could trigger axonal degeneration. The ATP-dependent Na+/K+ pump is the major defense mechanism against a lethal Na+ load. The pump expels 3 Na+ ions in exchange for 2 K+ resulting in hyperpolarization.With conduction of high frequency trains of action potentials, the restoration of Na+ equilibrium lags behind repolarization. The intra-axonal Na+ accumulation drives the Na+/K+ pump activity beyond the end of the train resulting in post-tetanic hyperpolarization (PTH). Objectives: The aim of this study was to investigate in vivo PTH in WldS mice. Methods: Experiments were carried out under anesthesia in adult C57BL/WldS mice (n = 5) and age-matched control (C57BL/6J, n = 5) female mice. Tibial nerves were stimulated at ankle and the evoked CMAPs were recorded from the plantar muscles using subcutaneous needle electrodes.

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The motor threshold was defined as the current required to elicit a 40 % submaximal CMAP. The changes in CMAP and motor thresholds following a 5 minute train of supramaximal impulses (0.2 ms, 100Hz) were monitored using the MTRACK threshold-tracking system (Moldovan & Krarup 2006, J. Neurosci. Methods. 15:155). Temperature was maintained with a heating pad. Results: At low (1 Hz) frequency stimulation CMAPs amplitudes, latencies and motor thresholds were similar in the WldS mutant and control mice. In all mice, CMAPs were largely suppressed during the 100 Hz stimulation but recovered promptly when the low frequency stimulation was resumed after the train.An increase in threshold consistent with PTH was detected in all mice. After 3 minutes of recovery, the increase in motor threshold was ~ 25 % in control mice and only ~ 15 % in WldS mutant mice (p < 0.05). The reduced PTH in WldS mutant mice was apparent for more than 5 minutes after the train and could not be explained by differences in CMAP recovery. Conclusion: Our data suggest that intra-axonal Na+ accumulation driving the PTH is lower in WldS than controls. It is therefore likely that WldS mutant mice have a better ability to cope with the Na+ load, and this may contribute to the observed delay in axonal degeneration. O116 Accessory deep peroneal nerve – a clinically significant anomaly? S. Owsiak, A. Kostera-Pruszczyk, K. Rowinska-Marcinska Medical University of Warsaw (Warsaw, PL) Objectives: Accessory deep peroneal nerve (ADPN), a variant of peroneal nerve, may give motor branches to extensor digitorum brevis muscle (EDB) and active search during nerve conduction studies (MNC) detects this nerve in 19–28 % of general population and in up to 78 % in familial cases. There is little data however on the extent to which this variant influences MNC results of the peroneal nerve. The aim of our study was to evaluate its significance. Methods: The occurrence of the ADPN was analyzed in three groups. Group I consisted of 310 subjects (147 men, 163 women, mean age 39.2 yrs), without polyneuropathy or motor neuron disease, whose routine peroneal MNC recordings were analyzed retrospectively. In group II consisting of 24 healthy volunteers (7 men, 17 women, mean age 48.3 yrs) additional stimulation behind the lateral malleolus was performed. Additionally 8 relatives of a healthy control with large ADPN (group III) were tested. An increase of amplitude and area of CMAP from EDB muscle exceeding 10 % between proximal and distal stimulations in a routine MNC was considered to be consistent with presence of the ADPN. Results: Routine MNC disclosed ADPN in 7.7 % of patients in group I and 12.5 % in group II. Stimulation behind the lateral malleolus detected the ADPN in 25 % of group II and in 50 % of relatives of a patient with this anomaly. The highest CMAP amplitude obtained by stimulation of the ADPN was 3.71 mV in group III and 2.5 mV in group II, and equalled 51 % and 44 % of the total EDB response respectively. Conclusions: The presence of the ADPN significantly influences routine MNC of the peroneal nerve in 7.7–12.5 % of patients. Stimulation behind the lateral malleolus doubles the sensitivity of detecting ADPN (25 % vs. 12.5 %). Innervation of the EDB by ADPN may be important for preserving function of the EDB in some cases of peroneal neuropathies with conduction block (CB). Pedigree analysis of group III suggests autosomal dominant transmission of the ADPN with incomplete gene penetrance.

Oral session 15 Genetics 2 O117 SYNE1-related autosomal recessive cerebellar ataxia J.-P. Bouchard, N. Dupré, F. Gros-Louis, G. A. Rouleau Laval University (Quebec City, CA); University of Montreal (Montreal, CA) Objectives: Define the phenotype and genotype of French-Canadian families with a pure cerebellar ataxia referred to as autosomal recessive cerebellar ataxia type 1 (ARCA1), formerly known as recessive ataxia of Beauce. Methods: We have ascertained the probands and affected members of 27 families from South-Eastern Quebec and completed detailed clinical history,

neurological examination, brain imaging, and nerve conduction studies on all available affected subjects and relatives. A genome-wide scan was conducted on five multiplex families with 20 affected individuals. Candidate genes were screened within the mapped area on chromosome 6q. Results: Based on the study of these families, ARCA1 is characterized by: recessive transmission; middle-age onset (mean 30.4, range 17–46 years); initial symptoms as gait ataxia and/or dysarthria; slow progression and moderate disability; mild ocular saccade abnormalities; occasional brisk reflexes in the lower limbs; no sensory involvement; normal nerve conduction studies; early diffuse and severe cerebellar atrophy on imaging. Mutations in the SYNE-1 gene were detected in all affected individuals and obligate carriers. The predominant genotype was present in only 50.8 % of chromosomes and a total of seven mutations segregating on founder haplotypes were identified, providing evidence of wide genotypic heterogeneity in this population from the same region. Conclusion: We have identified a new recessive ataxia of middle-aged onset and of relatively pure cerebellar type, related to mutations in the SYNE1 gene. The function of this gene seems critical in the maintenance of cerebellar structure in humans, and this allows us to place ARCA1 in a new category of hereditary ataxias caused by genes with large spectrin domains. We expect that mutations in the SYNE1 gene will be a common cause of recessive ataxia worldwide. O118 Spinocerebellar ataxia type 28 (SCA28): clinical and genetic characterisation of a novel form of autosomal dominant cerebellar ataxia D. DiBella, C. Mariotti, C. Gellera, M. Plumari, V. Fracasso, R. Fancellu, C. Cagnoli, A. Brusco, F. Lazzaro, M. Muzi-Falconi, S. DiDonato, F. Taroni Fondazione IRCCS Ist Neurologico C.Besta (Milan, IT); University of Turin (Turin, IT); University of Milan (Milan, IT) The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative disorders characterized by progressive cerebellar ataxia associated with other neurological features. We have recently mapped the SCA28 locus on chromosome 18p11.22 in a 4-generation Italian family with a novel form of autosomal dominant cerebellar ataxia, characterized by juvenile onset, slowly progressive gait and limb ataxia, and oculomotor abnormalities including nystagmus and ophthalmoparesis. Direct sequencing of candidate genes within the 7.9-Mb critical interval led to the identification of an heterozygous point mutation in one of them. The mutation segregated with the disease phenotype in all affected members of the family and is not present in more than 500 control chromosomes. We have analysed the SCA28 gene, with a dHPLC/direct sequencing approach, in our large collection of families and patients with spinocerebellar ataxia negative for mutations in known SCA genes (129 index cases with autosomal dominant ataxia, 51 index cases compatible with autosomal recessive inheritance), and in 150 sporadic cases. We have raised polyclonal antibodies against the SCA28 protein and generated a cellular model for functional studies. A number of polymorphic variants were identified. Four putative disease-causing mutations (ie, not found in control subjects and segregating with the disease in the family) were found in 4 families with autosomal dominant inheritance. The mutations cause amino acid changes in evolutionarily conserved residues in the same functional domain of the SCA28 protein. Phenotypic analysis of the patients harbouring a mutation in the SCA28 gene showed a relatively uniform ADCA1type clinical presentation characterized by slowly-progressive cerebellar ataxia with cerebellar atrophy and a frequent occurrence of oculomotor dysfunction (slow saccades and ophthalmoparesis) and pyramidal signs. Western blot analysis of protein expression in patients’ cell lines demonstrated a modest reduction of protein levels, consistent with the heterozygous nature of the mutations. Functional studies demonstrated a pathogenic role of the identified mutations. Conclusion: We have identified the SCA28 gene. SCA28 is the sixth recognized SCA caused by point mutations. The phenotype is characterized by ataxia and oculomotor dysfunction. Mutation screening allowed to establish a minimum frequency of 3 % for SCA28 in ADCA of unknown origin. Partly supported by an FP6-EUROSCA cloning grant to FT O119 A novel voltage-sensing mutation in Kv1.1 is associated with episodic ataxia type 1 T. D. Graves, S. Schorge, H. Morris, D. M. Kullmann, M. G. Hanna Institute of Neurology (London, UK); School of Medicine, University of Cardiff (Cardiff, UK) Objectives: To identify a KCNA1 mutation in a patient with episodic ataxia type 1 (EA1) and characterise the functional consequences of the mutation.

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EA1 is a rare autosomal dominant disorder characterised by brief attacks of ataxia on a background of continuous myokymia. It is due to mutations in the voltage-gated potassium channel Kv1.1, encoded by KCNA1. Nineteen mutations have been described throughout the gene. All lead to amino acid substitutions, except for one nonsense mutation. These mutant channels show reduced potassium current density as well as other subtle effects. However, the biophysical consequences have mainly been studied in Xenopus laevis oocytes, which do not always reproduce mammalian cell biology. Therefore, we decided to analyse EA1 mutations in human cells to measure whether the differences observed are consistent with those seen in oocytes. Methods: A patient with EA1 was identified. DNA was extracted using standard techniques. The entire KCNA1 gene was directly sequenced. A novel missense mutation, R307C was identified. This was inserted into a cDNA construct of KCNA1 contained within the mammalian expression vector, pMT2LF, using site-directed mutagenesis. Human embryonic kidney (HEK-293) cells were transiently transfected using standard techniques. Potassium currents were measured using whole-cell patch clamp recordings with potassium gluconate-based internal solution and standard mammalian Ringer’s solution. Results: A novel c to t transversion leading to R307C was identified. The mutation changes a highly conserved amino acid and was not found in 228 control chromosomes. R307C is located in the S4 transmembrane segment and removes one of the invariant, positively-charged residues which constitute the voltage-sensor of the channel.As such, R307C is predicted to disrupt voltage sensing in the channel. Physiological experiments are ongoing and data will be presented. Conclusions: Until very recently, no mutations in the S4 segment of Kv1.1 were known and none have been studied functionally. This is the first mutation reported in the voltage-sensor of Kv1.1, and it is predicted to have a dramatic effect on voltage sensing in the potassium channel. TDG has an Action Medical Research Training Fellowship and was previously finded by the Guarantors of Brain O120 A phase 2 double-blind, placebo-controlled study of idebenone in patients with Friedreich’s ataxia N. Di Prospero, A. Baker, N. Jeffries, K. Fischbeck National Institutes of Health (Bethesda, US) Objective: To examine the safety and efficacy of the antioxidant idebenone in ambulatory children and adolescents with Friedreich’s ataxia (FRDA). Methods: This was a 6-month, randomized, double-blind, placebo-controlled study in subjects with genetically-confirmed FRDA. The subjects were assigned to receive either placebo, low, intermediate, or high dose idebenone (given as a fixed dose approximating 5, 15, or 45 mg/kg/day) divided in 3 daily doses. The primary endpoint measure was urinary 8-hydroxy-2-deoxyguanosine (8OH2’dG), a marker of oxidative DNA damage. Secondary endpoints included the International Cooperative Ataxia Rating Scale (ICARS), Friedreich’s Ataxia Rating Scale (FARS), and a survey of activities of daily living (ADL). Results: Forty-eight subjects with FRDA (25 male, 23 female; age range 9–18 years) were assigned to placebo (n = 11), low (n = 12), intermediate (n = 13), or high (n = 12) idebenone dose groups. All subjects completed the study, and the idebenone was generally well tolerated with similar types and frequency of adverse events across all groups. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved with discontinuation of the drug. The levels of 8OH2’dG were not elevated, in contrast to previous reports, and did not significantly change following idebenone treatment. Although an overall statistical analysis did not reach significance for ICARS, FARS or ADL total score, there was an indication of a dose-dependent response for ICARS (p < 0.05). A pre-determined subset analysis excluding the most severely affected subjects (those requiring wheelchair assistance) revealed a trend toward improvement in ICARS (p < 0.01) and a dose related response in ICARS, FARS, and ADL scores (p < 0.05). Conclusion: Treatment with idebenone was generally well tolerated and associated with trends toward improvement in neurologic function and activities of daily living in subjects with FRDA. The degree of improvement appeared correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurologic function.

O121 Genetic and clinical features of juvenile patients with spinocerebellar ataxia type 2 in Poland M. Rakowicz, E. Zdzienicka, R. Rola, A. Sulek-Piatkowska, M. Niewiadomska, M. Wieclawska, J. Zaremba Institute of Psychiatry and Neurology (Warsaw, PL) Objectives: Spinocerebellar ataxia type 1 (SCA1) and type 2 (SCA2) are the most common forms of ADCA in Poland. Expanded CAG repeats in the ATX2 gene are the genetic cause of SCA2. This phenotype is highly variable and includes trunk and limb ataxia, dysarthria, gaze palsy, slow saccades, axonal neuropathy and extrapiramidal signs. The aim of the study was to assess the influence of the transmission pattern on genetic and clinical features of juvenile SCA2 patients. Methods: 49 SCA2 patients from 22 families were analysed retrospectively. The mean age at onset was 31.5 ±11.0, ranging from 11 to 71 years, and the average CAG repeats in affected family members was 44.7 ±3.3, ranging from 36 to 52. Paternal transmission was prominent in 65 % of cases. In 10 SCA2 families with the juvenile form, the relation of clinical severity, sex, CAG repeats number and age of disease onset of transmitting parents was analysed. The International Cooperative Ataxia Rating Scale (ICARS), MRI and electrophysiological examinations in parent – child pairs were analysed. Results: In both transmission patterns a lack of relation between the age at onset and disease duration in juvenile cases was observed: mean age of 15.4 y. – paternal vs. 16 y. maternal and 5.9 vs. 5.3 y. respectively, whereas mean age at onset of fathers was 36.9 y. and of mothers – 24.3y. The anticipation was more prominent in subjects with paternal than with maternal transmission: from 13 to 28y., mean 21.4y., and from 4 to 15y., mean 8.3 years per generation respectively. In juvenile cases the CAG repeats number was not different based on transmission pattern, however the CAG repeats number was higher among mothers 42.3, than among fathers 39.3. Severity of ataxia was more pronounced in children with paternal transmission (ICARS 42.0) than those with maternal (35.3). MRI revealed cerebellar atrophy in all juvenile cases, without shrinkage of cervical spinal cord observed in six parents. The occurrence of non-cerebellar signs such as extrapiramidal rigidity, fasciculation, absent reflexes and distal sensory loss was detected in 70 % of juvenile cases. Axonal neuropathy, most prominent in sensory nerves was revealed to the same degree in juvenile cases and parents. Somatosensory evoked potentials documented involvement of the posterior columns in all but two patients. Conclusions: In our SCA2 patients the paternal transmission results in more prominent anticipation per generation than maternal. The research was supported by grant 3PO5B 019 24 from the Polish Ministry of Science and partly by the European Integrated Project on Spinocerebellar Ataxias: grant EUROSCA/LSHM-CT-2004–503304. O122 Muscle coenzyme Q10 levels in ataxia with oculomotor apraxia type 1 C. Mariotti, C. Gellera, M. Rimoldi, R. Fancellu, D. Pareyson, S. Allievi, B. Castellotti, S. DiDonato, F. Taroni Istituto Nazionale Neurologico C.Besta (Milan, IT) Objectives: Ataxia with Oculomotor Apraxia type1 (AOA1) is an autosomal recessive disease characterized by early-onset slowly progressive cerebellar ataxia, areflexia, and peripheral neuropathy. In adult stages hypoalbuminemia and hypercholesterolemia are detected. AOA1 is caused by mutations in the APTX gene (9p13.3) encoding a nuclear protein named aprataxin. Recently, reduced levels of muscle coenzyme Q10 (CoQ10) have been observed in a group of patients with AOA1. Methods: We analyzed CoQ10 levels in plasma, fibroblasts and muscle tissue from 6 unrelated Italian patients with APTX gene mutations. Age at onset ranged from 3 to 7 years, and age at examinations from 18 to 30 years. All patients had gait and limb ataxia, dysarthria, sensory-motor neuropathy, hypercholesterolemia and reduced plasma albumin. Four patients were homozygous for the W279X mutation, 1 patient was homozygous for the R306Xmutation, 1 patient was a compound heterozygote for the W279X/Q181X mutations, and 1 patient was homozygous for the W279R missense mutation. CoQ10 levels in muscle homogenates, fibroblasts and plasma were analyzed by reversed-phase HPLC on Synergi Polar RP. Detection was done with an Applied Biosystem API 2000 triple-quadrupole mass spectrometer (MS). CoQ9 was used as internal standard. Quantitative MS/MS data were obtained by multiple reaction monitoring mode. Results: Morphological analysis of muscle tissue revealed mild neurogenic changes in all cases. Muscle CoQ10 levels, measured in 4/6 patients, were within the normal values in two cases (180 and 260 pmol/mg of protein; normal values 174 ± 20 pmol/mg); below the normal range in one patient (100 pmol/mg), and in the low normal range in the other patient (154 pmol/mg). Preliminary data on plasma samples showed normal CoQ10 lev-

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els (mean 1.89 ± 0.14 mmol/L; normal values 1.17 ± 0.34 umol/L; n = 5). Measurements of CoQ10 levels in two remaining muscle biopsies and in cultured fibroblasts are in progress. Conclusion: Our results indicate that in some patient APTX gene mutations are associated with a partial defect of CoQ10 in muscle tissue. However, CoQ10 levels did not seem to correlate with genotype, as all the 4 patients tested had nonsense mutations predicting absence of the protein. In particular, only one of the two patients homozygous for the W279X mutation had reduced levels of CoQ10. Mechanism and pathogenic role of muscle CoQ10 deficiency in AOA1 patients need to be further investigated.

Oral session 16 Infection O123 Recurrent myelitis in patients with hepatitis C virus infection S. Ravaglia, M. Ceroni, E. Tavazzi, E. Marchioni Institute of Neurology C. Mondino (Pavia, IT) Objective: To evaluate the association between HCV-infection and non-MS recurrent transverse myelitis (TM). Background: CNS abnormalities, including myelitis, are a rare complication of hepatitis C virus (HCV) infection. The pathogenetic mechanism is unknown. Design/Methods: HCV was sought for in a cohort of 59 consecutive nonMS inflammatory TM by using immunological and PCR-based methods. Compression, vascular, radiation, infectious and autoimmune disorders were excluded. All patients had normal visual evoked potentials and brain MRI, neither oligoclonal band nor NMO-IgG antibodies.21/59 of our patients (36 %) showed at least one relapse; of them, 7/21 (33 %) had HCV-infection. Search for HCV was negative in 32 cases characterized by monophasic course. Results: The 7 HCV-positive patients had 2 to 5 episodes of myelitis during a median 41 months follow-up.When the first episode occurred, only one patient was aware to be HCV-positive. Routine blood analyses were normal except for high transaminases in one patient. Two patients showed mixed cryoglobulinemia (MC). Another patient had detectable HCV-RNA (genotype 1 b) in the CSF. Poly-radiculo-neuritis was detected in 6/7 patients. All patients received high-dose steroid treatment, that was ineffective in 4 patients but two of them improved after a 5-day cycle of immunoglobulins (IVIg). One patient was treated with alpha-interferon (alfa-IFN) after the third relapse and continued for 2 years. Two further relapses occurred after alfa-IFN discontinuation. Conclusions/Relevance: We found high prevalence of HCV in Italian patients with recurrent TM (12 %). Casual association is unlikely, given the rarity of HCV-infection in the general population of Northern Italy (3 %). The pathogenesis of CNS injury during HCV-infection is unclear: only two patients had MC, possibly responsible for a vasculitic mechanism. The recurrent course and the response to immunomodulating treatments support the hypothesis of a virus-mediated autoimmune response rather than a direct effect of the virus, the presence of which was detected in the CSF of only one patient. O124 Borrelia garinii induces CXCL13 production in human monocytes through TLR2 T. Rupprecht, C. Kirschning, B. Popp, S. Kastenbauer, V. Fingerle, H-W. Pfister, U. Koedel Klinikum Grosshadern (Munich, DE); Technical University Munich (Munich, DE) Objectives: Recent studies have suggested an important role of the B-cell attracting chemokine CXCL13 in the B-cell dominated cerebrospinal fluid (CSF) infiltrate in neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB-patients. As it has been unclear, however, whether high CSF-CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well, the CXCL13 levels in CSF/serum pairs from patients with NB, neurosyphilis (NS), syphilis without CNS involvement (S) and pneumococcal meningitis (PM) were evaluated. Furthermore, the mechanisms leading to the observed CXCL13 expression have not yet been identi-

fied. Therefore, the interaction of the responsible pathogens, namely Borrelia garinii (Bg – the Borrelia strain most frequently found in NB-patients), Treponema pallidum (Tp) and Streptococcus pneumoniae (Sp) with monocytes has been analysed in vitro. Methods: The CXCL13 levels (in vivo and in vitro) have been measured by ELISA. Human monocytes have been isolated from whole blood by density centrifugation and a CD-antibody coupled magnetic beads system (MACS). The interaction of monocytes with the different bacteria has been analysed using recombinant bacterial surface proteins and an anti-human monoclonal TLR2-antibody. Results: As observed in the CSF of NB patients (mean CSF-concentration: 344.2ng/g total CSF-protein), we also measured elevated CSF-CXCL13 levels in patients with NS (134.1ng/g), while noninflammatory controls (0.25ng/g), S (2.7ng/g) and PM (1.9ng/g) patient’s CSF lack high CXCL13 content. In parallel, challenge of human monocytes in vitro with both of the spirochetal causatives, Bg and Tp, but not Sp induced the CXCL13 release. This implicates a common spirochetal motif as CXCL13 inducer.Accordingly, we found the lipid moiety Pam3Cys (three palmitoyl rests bound to N-terminal cystein) of the spirochetal lipoproteins to be critical for the CXCL13 induction in monocytes. In addition, blocking the receptor of Pam3Cys, the toll-like receptor TLR2 of the innate immune system, using a TLR2-antibody, significantly reduced (60 % vs. the isotype control) the borrelia induced CXCL13 secretion. Conclusion: High CSF CXCL13 levels can be found in both major spirochetal CNS diseases. The interaction of the spirochetal lipoproteins with the TLR2 receptor on the surface of human monocytes appears to be a critical step in the observed spirochetal induced secretion of this chemokine in vitro. O125 Alpha- and beta-herpesvirus co-infection in human sensory ganglia K. Hüfner, V. Arbusow, S. Himmelein, T. Derfuss, M. Strupp, T. Brandt, D. Theil Ludwig-Maximilians University (Munich, DE) Introduction: Herpesviruses such as herpes simplex virus type-1 (HSV-1) and varicella zoster virus (VZV) have the ability to persist for life in human sensory ganglia. When reactivated, they may cause a wide spectrum of clinical manifestations, ranging from asymptomatic viral shedding to fatal disease. Human herpes virus 6 (HHV-6) has recently been shown to persist in the central nervous system, but its prevalence in the peripheral nervous system (PNS), known to be the preferred latency site for herpesviruses, has not been studied. Methods: Using nested PCR, we determined the distribution of HHV-6 and its colocalization with alpha-herpesviruses (HSV-1 and VZV) in ten human trigeminal (TG), 20 geniculate (GG), 20 vestibular (VG), and in 11 dorsal root ganglia (DRG). The presence of infiltrating T-cells in the respective ganglia was determined via immunohistochemistry. Results: HHV-6 was present in 30 % of the TG, 40 % of the GG, 25 % of the VG, and 55 % of the DRG. It co-occurred with alpha-herpesviruses in 91 % of the HHV-6 positive ganglia. Only two ganglia were solely positive for HHV6 (9 %). Chi-square statistics showed that the infection of a sensory ganglion with HHV-6 was associated with infection of another herpesvirus (either HSV-1 or VZV; p < 0.05). This was largely due to a co-infection of HHV-6 positive ganglia with VZV. The co-occurrence of HSV-1 and VZV in the ganglia was not statistically significant (p> 0.05).The presence of HHV-6 did not correlate with the persistence of inflammatory cells,which are known to harbor HHV-6. Conclusion: This study presents evidence that HHV-6 is prevalent in the peripheral nervous system. All the human sensory ganglia, e. g., TG, GG,VG, and DRG, show similar frequencies for the presence of HHV-6 (25 %–55 %). The lack of correlation between HHV-6 and inflammatory cells suggests that HHV-6 resides in human sensory ganglia themselves. It is possible that HHV-6 is the first of the herpesviruses to infect the ganglia, since infection occurs quite early, usually within the first year of life. In contrast, HSV-1 and VZV infections occur later. Latent HHV-6 could create an environment in the ganglia which facilitates the invasion of other viruses. In point of fact, it has been demonstrated that HHV-6 can interact with a number of other viruses during active infection, latency, and reactivation. O126 Role of the chemokine CXCL16 in pneumococcal meningitis B. Obermaier, M. Klein, B. Angele, B. Popp, H. W. Pfister, U. Koedel Ludwig-Maximilians-University (Munich, DE) Objectives: CXCL16 is a recently discovered chemokine functioning as scavenger receptor, adhesion molecule and chemoattractant for activated T cells. Protein array analysis of the chemokine expression pattern in a mouse

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model of pneumococcal meningitis (PM) revealed upregulation of CXCL16. This study was performed to further characterize the expression pattern of CXCL16 and its functional role in PM. Methods: CXCL16 expression was determined by ELISA in brain homogenates of mice infected with Streptococcus (S.) pneumoniae, in supernatants and cell lysates of RAW 264.7 macrophages exposed to S. pneumoniae as well as in the cerebrospinal fluid (CSF) of patients with PM (n = 20; compared to patients with non-inflammatory neurologic diseases, n = 16). To assess the functional role of CXCL16, mice infected with S. pneumoniae were treated intraperitoneally with a CXCL16 neutralizing antibody (together with an antibiotic) 24 hours after infection. Results: In brains of infected wild type (WT) mice CXCL16 was significantly upregulated 24 hours after infection, the maximum concentration was reached 48 hours after infection. Compared to infected WT mice, no upregulation of the chemokine was observed in mice lacking the Toll-like receptor/interleukin1 receptor adaptor molecule MyD88. Next, we examined CXCL16 expression in humans with PM. CXCL16 was significantly upregulated in the CSF of patients with PM (13.0 ng/ml) compared to low levels of CXCL16 in control patients (2,7 ng/ml, p = 1.3x10–6). Statistical analysis showed a correlation between CSF CXCL16 levels and CSF white blood cell (WBC) count. In vitro, we found a two-fold increase of CXCL16 release in the supernatant of RAW 264.7 macrophages exposed to S. pneumoniae. In infected WT mice, anti-CXCL16 antibody treatment resulted in higher CSF WBC counts. Conclusions: Taken together, these results show a MyD88-dependant upregulation of CXCL16 in PM in humans and mice. Our data suggest that CXCL16 is released by infiltrating leukocytes and that it exerts an antiinflammatory effect.

Objective: To determine the course and characteristics of patients with a clinically isolated syndrome (CIS) of the spinal cord and a normal brain MRI and to look for factors predicting later outcome. Material: Charts of patients with APTM who were older than 18 years and had been admitted to our hospital from January 1999 to June 2005 were reviewed. 34 patients (22 women) with a mean age ± SD of 38.1 ± 9.77 years were identified. Clinical findings were reassessed within 3 months after APTM, and then patients were followed for a mean of 3.5 years (±1.63). Results: 29.4 % patients converted to clinically definite MS (CDMS), 14.7 % had a recurrent myelitis and in 55.9 % there were no recurrent symptoms or signs. CDMS was diagnosed after a mean time of 9.9 months (±14.4) and myelitis recurred after 4 months (± 8.0) on average. 2 of the MS patients developed MS-typical brain MRI lesions. Sensory symptoms were present in all but one patient and motor disturbances were found in 30 % of patients later converting to MS, in 73.7 % with monosymptomatic myelitis and in 40 % with recurrent myelitis. 38.2 % had bladder dysfunction, in monosymptomatic APTM in 40 %, in MS in 20 % and in recurrent myelitis in 10 %. A complete recovery within 3 months was observed in 50 %, the remainder recovered incompletely. Age, sex and time to a second event was not different between the groups. Conclusion: Approximately a third of our patients with APTM and a normal brain MRI converted to MS during follow-up and some showed also MStypical brain lesions on repeat scans. Most frequently, however, APTM remained an isolated manifestation. Recurrent myelitis was observed in a minority of patients. Clinical outcome 3 months after APTM was rather favourable and not different between the three groups. There were no clinical or demographic factors predicting the course. Therefore, further studies are needed in order to identify reliable surrogate markers with predictive value.

O127 Natural history of HTLV-2-associated myelopathy M. Menna-Barreto PUCRS (Porto Alegre, BR) Background: HTLV-2-associated myeloneuropathy has been documented among monoinfected individuals living in Porto Alegre city, southern Brazil. Both subtypes A and B were seen in those individuals. The prevalence of HTLV-1/2 infection is 1.2 % among blood donors in this metropolitan area. Objective: To analyse the natural history of HTLV-2-associated myeloneuropathy. Design: 13-year follow-up study. Patients and methods: 194 HTLV-2-infected individuals, 62 coinfected with HIV-1, were seen three times a year since 1994, providing clinical and laboratory data. Magnetic resonance imaging, electrophysiological studies (somatosensory and visual evoked potentials, electromyography) and cerebrospinal fluid analysis were performed whenever necessary. Results: 37 HTLV-2-infected patients with myeloneuropathy were studied; HIV-1 and syphilis were excluded. Risk factors as intravenous drug use in nine individuals (eight HCV-coinfected out of them), south amerindian descendant in three and occupational transmission by a needlestick accident in one health care worker were identified. No one died but four were lost for the follow-up. A dorsal spinal cord tumor had developed in one patient, with full recovery after surgical intervention. Connective tissue disorders (Sjogren syndrome and systemic lupus erithematosus) were identified in five patients. Devic’s syndrome (relapsing neuromyelitis optica) has developed in one caucasian HTLV-2b-infected male whose wife (also HTLV2b-infected) were also diagnosed with systemic lupus erythematosus. Gait disorders (spastic paraparesis and sensory ataxia), dysautonomy (neurogenic bladder, erectile dysfunction, constipation and fecal incontinence), radicular pain and cognitive impairment were the main disabling sigs of HTLV-2-associated disease. Conclusion: HTLV-2-associated myeloneuropathy is a slowly disabling disease, characterized by sensory ataxia, radicular pain and bladder dysfunction. O128 Outcome of patients with a clinically isolated syndrome of the spinal cord and normal brain MRI: monosymptomatic event, recurrent myelitis or conversion to multiple sclerosis? N. Luethi, J. Sellner, R. Buehler, A. Gebhardt, H.-P. Mattle Inselspital, University Hospital Berne (Berne, CH) Background: Multiple Sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS). Diagnosis is based on neurological symptoms in relation to time and space. Acute partial transverse myelitis (APTM) can be the first manifestation of MS even when brain MRI is normal. It can also remain a monosymptomatic event or recur.

Oral session 17 Investigating patients after stroke O129 T. A. C. E.T. – The Austrian Paradoxical Cerebral Embolism Trial S. Horner for the Austrian PFO Study Group and the Austrian Society for Stroke Research Objectives: To document the baseline characteristics and results of diagnostic and medical or interventional treatment strategies in a cohort of stroke patients who have cardiac or pulmonary right-to-left shunting (RLS) with presumed paradoxical embolism. Methods: A prospective, national, multi-center, non-randomized, clinical trial in patients aged ≤ 55 years who presented with recent TIA/stroke, in whom contrast transesophageal echocardiography (cTEE) demonstrated cardiac or pulmonary RLS, and who underwent contrast transcranial Doppler sonography (cTCD). Primary outcome was the incidence of recurrent TIA/stroke during medical and/or interventional therapy. All patients are intended to have 5 clinical visits during a 2-year follow-up period which is expected to end in June 2007. Results: The recruitment period ended 2005 with 200 patients (105 males, 95 females, mean age: 41.3 yrs) enrolled in 15 centers. Qualifying inclusion criteria were: stroke (117, 58.5 %) or TIA (83, 41.5 %) combined with cardiac (193, 96.5 %) or pulmonary (7, 3.5 %) RLS. The sensitivity of cTCD for RLS detection was 93.5 %. The overall 12-month recurrence rate of a cerebrovascular event was 7.5 % with 2 strokes and 10 TIA encountered, 11 with cardiac and 1 with pulmonary RLS. Patients and physicians opted for initially conservative treatment 106 instances and 94 for transcatheter closure. This was associated with a repeat cerebral ischemic episode in 10 patients with conservative treatment (2 strokes, 8 TIA) and in 2 after intervention (both TIA) within the 1 year of follow-up. Conclusion: Preliminary results of T. A. C. E.T. suggest a non-significantly (p = 0.074) lower frequency of recurrent cerebrovascular events after transcatheter closure. Long-term follow-up is needed to confirm these results. www.meduni-graz.at/neurologie/TACET/Home.htm.

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O130 Remote evaluation of acute ischaemic stroke (REACH); 3 years of real life telemedicine stroke consultation R. J. Adams, J. A. Switzer, H. Gross, F. T. Nichols, C. H. Hall, S. Wang, W. B. Hamilton, D. C. Hess Med College Georgia (Augusta, US) Objective: We evaluated our system (now commercialized as REACHMDC.com,Augusta Georgia) linking 9 rural sites to an academic Stroke Center (Medical College of Georgia Hospital) with an eye towards overall performance and improving efficiency. The remote hospitals (10–72 beds, ED visits per year ranged from 3,302–11,872) have no on site Neurology coverage but Emergency Departments (ED), wireless capabilities, computed tomography (CT) scanners (capable of digital output) and fast internet. Methods: REACH provides video and audio via a secure web based system with imbedded decision support and digital CT scan review. The system was queried for operational data from the years 2004, 2005 and 2006. The consults, tissue plasminogen (tPA) recommendations, treatment times and complications were analyzed in terms of the number of ED visits/year. Results: Sites were instructed to call for any suspected stroke < 5 hours from onset. In 2004, from 6 sites 13 tPA treatments were recommended after REACH consultation from 104 total consults (13 %), in 2005 at 7 sites 26 tPA treatments were recommended from 124 total consults (21 %) and in 2006 at 9 sites 30 tPA treatments were recommended from 148 total consults (20 %). In 2006 (all 9 sites) consults/month ranged from 0.5–3.3 and the fraction of consults resulting in tPA recommendation varied from 0–39 %.With the first 76 tPA treatments, the onset to treatment (OTT) recommendation time was 129 minutes (symptomatic hemorrhage rate 2 %). Reasons for not recommending tPA were: beyond time window 28 %; rapid improvement 22 %; minimal deficit 26 %, intracranial hemorrhage 12 %, other 12 %. Only two tPA treatments were generated from the 3 smallest sites in 2006 each with less than 6500 ED visits/year.While the ratio of tPA treatments to ED volume varied from 1:1197 to 1:5612 ED volume appears to be a better indicator of likely activity using REACH than bed size. Conclusions: About 20 % of the consults result in tPA treatment. OTT is excellent in relation to other reported times indicating that even these small sites can function effectively in a limited paradigm of emergent stroke care. Cost effectiveness concerns may dictate limiting the system to sites that have at least 7500 or more ED visits per year depending on resources.We and others have demonstrated that this program works and delivers tPA safely with low delay times. More work will be needed to optimize and scale the system for larger applications and clinical trials. The REACH system used in this report was a pilot system supported by Medical College of Georgia Hospital and Clinics. O131 Ischaemic stroke due to acute internal carotid artery occlusion: comparison of 1-year clinical outcome in patients treated by emergent carotid disobliteration versus intravenous thrombolysis M. Kral, R. Herzig, P. Olivier, D. Sanak, P. Bachleda, P. Utikal, S. Burval, D. Skoloudik, I. Vlachova, A. Bartkova, R. Opavsky, P. Hlustik, P. Kanovsky, P. Michel Palacky University and University Hospital (Olomouc, CZ); CHUV (Lausanne, CH) Objectives: Acute ischemic stroke (AIS) caused by an acute internal carotid artery occlusion (ICAo) is often associated with a severe and persistent neurological deficit and a high mortality rate. Intravenous thrombolysis (IVT) performed within 3 hours since AIS onset is the only standard treatment method. An emergent carotid endarterectomy (CEA) can be used alternatively. The aim was to compare 1-year clinical outcome in patients treated by CEA and IVT. Methods: A retrospective, hospital-based, two-center study was used. CEA group consisted of 29 patients (20 males, 9 females; age 39–79, mean 63.6 ± 10.3 years) in one center, and the IVT group of 20 consecutive patients (11 males, 9 females; age 32–88, mean 70.9 ± 13.0 years) in the other. Clinical assessment was quantified by admission NIHSS score and 1-year modified Rankin scale (mRS).A poor outcome was defined as a mRS > 2. Independent samples t-test was applied when assessing the difference in age and admission NIHSS, and chi-square test when assessing the difference in sex and 1year clinical outcome in CEA and IVT patients. Results: CEA patients were significantly younger than IVT patients (p = 0.033). Sex was not significantly different between both groups (p = 0.32). Admission NIHSS was significantly lower in CEA (3–18, mean 10.2 ± 4.7 points) versus IVT (12–31, mean 19.8 ± 4.2 points) patients (p < 0.001). Good 1-year clinical outcome was significantly more frequent in CEA (48.3 %) versus IVT (20 %) patients (p = 0.044). When restricting the analysis to the subgroups of patients with admission NIHSS 10–20, no sig-

nificant difference in age (p = 0.07) and sex distribution (p = 0.43) was found; good 1-year clinical outcome was present in 35.7 % of CEA versus 14.3 % of IVT patients in this subgroup (p = 0.19). Conclusion: In this two-center retrospective comparison, emergent CEA in patients with AIS caused by acute ICAo is associated with a more favorable clinical outcome when compared to standard IVT, particularly in younger subjects with milder neurological deficit. Supported by the IGA MH CR grant NR/8579–3/2005.

Oral session 18 Epilepsy O132 Electroclinical characteristics and seizure outcome in patients with ganglioglioma G. Kuchukhidze, I. Unterberger, J. Dobesberger, N. Embacher, G. Walser, F. Koppelstaetter, T. Gotwald, H. Maier, M. Ortler, S. Felber, G. Bauer, E. Trinka Innsbruck Medical University (Innsbruck, AT) Objectives: Ganglioglioma (GG) is a dysplastic CNS tumour comprised of mixture of glial cells and differentiated neurons. It is commonly located in temporal lobe and associated with pharmacoresistant partial seizures. The controversy about the optimal surgical treatment for GG has not been fully resolved.We aimed to analyse electroclinical characteristics and seizure outcome in patients with GG. Patients and Methods: We retrospectively reviewed 18 patients (13w/5 m) with GG and epilepsy from the large database of our department.All patients were clinically examined, underwent high resolution MRI, EEG recordings and neuropsychological testing. Thirteen patients underwent surgery and subsequent histological analysis of tumour tissue. Results: Mean age of patients was 34 years (5–66 years) at reassessment time. Mean age at seizure onset was 16 years (2–30 years). All patients had partial seizures: 15 – with temporal lobe and 3 – with frontal lobe epilepsy. All had SPS and CPS, secondary generalisation was observed in 13 (72 %) patients. Seizure frequency varied from daily attacks to sporadic seizures. Sixteen had focal and 2 – diffuse slowing on interictal EEG, in 3 of those interictal epileptiform potentials were registered. Three patients had mild neurological deficits, 7 (39 %) – suffered from psychiatric comorbidity, either depression or psychosis. GG were temporal in 13 and extratemporal in 5 cases. Thirteen patients underwent surgery with histological diagnosis of GG. Nine patients had total resection of tumour, one – subtotal resection and 3 – initial subtotal and subsequent total resection. Postsurgical follow-up period ranged from 1 to 17 years (mean 6 years). Ten patients (56 %) were seizure free after surgery for at least one year; seven corresponding to Engel class I, 3 patients – to Engel class II. The longest seizure free period – 8 years. Three patients with initial subtotal resection were reoperated because of recurrent seizures, two of them became seizure free after the second surgery. All patients with initial total resection were seizure free postoperatively. Five patients were not operated on because of high risk of postsurgical deficits, all of them suffered from pharmacoresistant seizures. Conclusions: Psychiatric comorbidity is often encountered in patients with GG and epilepsy. Total surgical resection of tumour determines seizure freedom in most cases, whereas subtotal removal of GG is associated with recurrent seizures. O133 Longitudinal follow-up studies in tumour-like lesions induced by presenting status epilepticus N. Canas, R. Pestana, S. Calado, P. Soares, C. Ribeiro, J. Vale Hospital de Egas Moniz (Lisbon, PT) Objective: reversible TLL induced by SE have been rarely described. Their etiology (SE or ongoing epilepsy), long-term consequences and pathophysiology are still unclear. Follow-up studies in non-epileptic patients with TLL induced by a presenting SE could contribute to the clarification of these questions. We describe the clinical, EEG and MRI follow-up studies in patients with tumor-like lesions (TLL) induced by a presenting status epilepticus (SE). Methods: we identified 4 non-epileptic patients with a presenting SE associated with tumor-like MRI signal abnormalities that completely/ par-

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tially reversed in a second MRI (after 12.3 weeks; 5–18). Follow-up MRI, clinical and EEG studies were performed to investigate their long-term consequences (24.3 months; 7–60). Results: 3 patients presented with convulsive SE (generalized tonicclonic seizures in 2, partial motor in 1) and 1 with partial-complex SE. Patients with partial seizures had clinical-lesional correlation (hippocampus/ precentral lesions); temporal/ parieto-occipital lesions were disclosed in the patients with generalized seizures. Initial MRI (within 24 h pos-SE) showed cortico-subcortical (2/4)/ subcortical (2/4) signal abnormalities, increased in T2-weighted (4/4), FLAIR (4/4) and diffusion-weighted (3/3) images, and decreased in the ADC (2/2) and T1-weighted (4/4) images (1/2 with contrast enhancement); MR spectroscopy (MRS) disclosed decreased N-acetylaspartate and elevated choline (2/2) and lactate (1/2); all had sulci effacement. In the follow-up studies, none patient had seizure recurrence or EEG epileptiform abnormalities, even without antiepileptic treatment; neurological examination was unremarkable; MRIs showed complete reversal of the tumorlike signal abnormalities. 3 patients had cerebral atrophy in the regions previously affected, with MRS showing a mild recovery of choline/ NAA levels and lactate normalization. 2 patients had marked generalized cerebral atrophy. Conclusion: SE per-se may induce reversible TLL. Their signal abnormalities resemble those of isquemic stroke, but do not respect vascular territories; the absence of significant mass effect/ contrast enhancement may help in the differential diagnosis with neoplastic lesions. MRI features suggest that reversible brain edema/ metabolic dysfunction are involved in their pathophysiology; they have a benign prognosis, although subsequent brain atrophy and NAA decrease discloses permanent neuronal loss. O134 Status psychosus epilepticus: a special type of non-convulsive status epilepticus N. Kitchener General Organization for Teaching Hospitals (Cairo, EG) It has long been stated that psychotic behavior may be the only presenting symptom in psychomotor (complex partial) epilepsy. Those epileptic equivalents last for a few minutes. This work is aiming at defining a special type of non convulsive status epilepticus, that can be called “status psychosus epilepticus”(SPE), which is defined as a Prolonged disturbed behavior due to disturbed brain electrical activity and characterized by: (1) Psychotic behavior as the only presenting manifestations. (2) Persistent for weeks (one to six weeks in the present study) (3) Complete and persistent response of the Psychotic behavior, in these epileptic states, to antiepileptic drugs, alone. Subjects and methods: 37 patients, (17 male and 20 female) with age range from 14 to 36 years, present with psychotic manifestations for at least one week, and drug naïve. They were subjected to full clinical and psychological assessment, in addition to EEG. Results: Clinical examination was unremarkable; MMSE range from 26 to 13. EEG showed periodic lateralized left epileptiform activity in 13 patients (35 %); bilateral independent periodic lateralized epileptiform activity in 8 patients (22 %), and generalized periodic epileptiform discharges in 16 patients (43 %). IV diazepam improved 23 patients (62 %). 25 patients (67.6 %) returned to their normal after four weeks of anti-epileptic drug treatment; monotherapy, 28 patients (75.7 %) returned to their normal after eight weeks of anti-epileptic drug treatment, monotherapy. The rest (9 patients, 24 %) needed addition of another antiepileptic to be controlled. Conclusions: SPE may last for weeks (one to six weeks in the present study). SPE can be misdiagnosed as Brief psychotic disorder, or even as Schizophrenia; if clinical examination (including MMSE) and EEG was not done for every suspicious case. Monotherapy is effective in 75.7 % of cases, with complete and persistent response of the psychotic behavior, in those epileptic states to antiepileptic medications alone. O135 Epileptic seizure control in pregnancy F. J. E. Vajda, A. Hitchcock, J. Graham, C. M. Lander, T.J O’Brien, M. J. Eadie Monash University (Clayton, AU); Queensland University (Brisbane, AU); Melbourne University (Parkville, AU) Objective: To study the behaviour of antiepileptic drug-treated, and untreated epileptic seizures during pregnancy in women enrolled in the Australian Pregancy Register Method: Register established in 1999 to collect data on foetal malformations in the offspring of pregnancies exposed to antiepileptic drugs (AEDs) [1]. Information from 3 categories of pregnancies.

(i) AED-treated pregnancies in women with epilepsy, (ii) pregnancies in women with epilepsy not on AEDs. (iii) AED-treated non epileptic pregnancies Recruitment into the Register is entirely voluntary, pregnant women becoming aware of it from doctors, lay organisations, nurses or patients. Contact is by telephone, with interviews at recruitment, at 30 weeks of pregnancy, at 4 weeks post-partum, and at 1 year from childbirth. Data are recorded in a computerised pro-forma. Patients’ identifying details are kept in a separate register, linked only by means of a numerical identifying system, for confidentiality. Relevant details are extracted from the data base into Excel spreadsheets, and analyses of statistical significance carried out by confidence interval methods. Results: There were 841 antiepileptic drug- treated pregnancies, and 83 pregnancies not treated with AEDs, at least in the first trimester. Behaviour of the seizure disorders appeared similar in the AED exposed and unexposed pregnancies. The risk of seizures during pregnancy was 50–70 % less, if the pre-pregnancy year was seizure free. The cumulative percentages of pregnancies in which seizures of any type had occurred correlated with the interval of freedom from seizures prior to pregnancy in pregnancies in which antiepileptic drugs were taken. Seizures in AED untreated pregnancies and AED untreated women had statistically significantly longer durations of seizure freedom prior to pregnancy, and shorter durations of their epilepsies, but no differences in other parameters compared. Conclusion: The duration of freedom from seizures before pregnancy related to chances of being seizure-free during all phases of pregnancy. The risk of seizures in pregnancy was substantially reduced once there had been one year’s freedom from seizures prior to pregnancy, and relatively little further reduction in risk with longer periods of seizure freedom. There appears little point in deferring pregnancy to avoid seizures returning after a year of seizure freedom. The Australian Pregnancy Register is supported by the Epilepsy Society of Australia, Epilepsy Association, Sanofi-Aventis, Pfizer, UCB Pharma, Novartis, Janssen-Cilag, and GSK. Reference 1. Vajda F. et al. (2006) Eur J Neur 13:645–654

Oral session 19 Higher function disorders O136 Presentation of affective pictures induces subjective stress but no relevant autonomic arousal compared to other mental stress tasks M. Fechir, T. Schlereth, T. Purat, S. Kritzmann, M. Gamer, M. Dieterich, F. Birklein Neurologische Klinik (Mainz, DE); Psychologisches Institut (Mainz, DE) Objectives: Stress tasks are commonly used in studies with the aim to further characterize autonomic arousal. Nevertheless it is not clear which of the different tasks evokes the highest reaction for which parameters. Therefore we compared the following tasks concerning their effects on autonomic parameters: the presentation of negative, positive, and – as a control condition – neutral affective pictures, the Color-Word Interference test by Stroop (CWT), serial subtraction, singing a song aloud, and holding a spontaneous speech. Methods: We exposed 11 healthy subjects (mean age 25.3 years) towards the tasks mentioned above and recorded multiple autonomic parameters: quantitative sudometry, peripheral vasoconstriction, cardio-vascular parameters, electromyographic activity of the trapezius muscle, and skin conductance level. Moreover, subjects rated every task concerning their individual sensation of stress on a visual analog scale. Results: As expected, the presentation of negative affective pictures evoked a higher sensation of stress than neutral pictures (4.5 vs. 2.0 cm VAS; p < 0.01). Presentation of positive affective pictures (3.6 cm VAS; p < 0.05 vs. neutral), and the other stress tasks resulted in increased subjective stress levels, too. In contrast, presentation of negative, or positive affective pictures did not result in any statistically significant changes of the recorded parameters whereas all the others tasks were able to evoke activation of auto-

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nomic parameters. Among these tasks different patterns of activation could be determined. In detail, serial subtraction resulted in high levels of emotional sweating (p < 0.001 vs. neutral) but had only small effects on peripheral vasoconstriction and on electromyographic activity of the trapezius muscle. CWT caused highest activations in most of the parameters, which were quite stable. Conclusion: In conclusion, our results show that presentation of affective pictures is considered to be stressful by subjects but does not result in any relevant alteration of autonomic parameters. The other tasks induce higher arousal; the extent of recorded stress reactions is different for every task. CWT seems to lead to the strongest, most reproducible autonomic arousal, which will be further characterized. Supported by DFG.

O137 Clinical, neuropsychological, structural and functional imaging characteristics of patients with posterior cortical atrophy syndrome D. A. Drubach, D. I. Drubach Mayo Clinic and College of Medicine (Rochester, US) Objectives: To delineate the clinical, neuropsychological, structural and functional imaging characteristics of patients with Posterior Cortical Atrophy Syndrome (PCAS). Methods: We performed a retrospective chart review of 14 patients diagnosed with posterior cortical atrophy syndrome evaluated at a tertiary Behavioral Neurology Program between 2002 and 2007.All patients had a neurological evaluation by an experienced behavioral neurologist, a full battery of neuropsychological testing by an experienced neuropsychologist as well as at least one MRI of the brain. All patients underwent functional brain imaging (either SPECT or PET scanning) and most patients underwent an EEG. Results: All patients presented with visual perceptual complaints as the main symptom that drove them to seek medical attention. Most patients had been repeatedly evaluated by ophthalmologists or optometrists prior to seeking attention with a neurologist. Clinical exam was significant for prominent visual perceptual difficulties, including optic ataxia and apraxia, simultagnosia, visual agnosia, evidence of “selective” cortical blindness and visual distortions. Both ideational and ideomotor apraxia was seen in several of the patients. Visual hallucinations were very rare. Neuropsycholgical testing in all patients showed difficulty with visual-spatial tasks and relatively sparing of language, attention, memory and executive function. MRI scanning showed selective mild to moderate atrophy involving posterior parietal a most prominently, occipital cortex. Functional brain imaging demonstrated decreased blood flow or FDG metabolism in posterior cortex, and many showed prominent involvement of primary visual cortex. EEG findings ranged from normal to severe dysrrhythmias. Conclusions: PCAS is a discrete clinical entity with characteristic neuropsychological as well as structural and functional brain imaging characteristics. While studies have shown that various underlying neuropathological entities can cause this syndrome, Alzheimer’s disease pathology is most frequently found. However, the clinical characteristics and specific functional impairments differ from those commonly seen in Alzheimer ’s disease, which has prominent treatment implications. We discuss a number of visual rehabilitation interventions which may be of help in this population of patients.

O138 Infarct volume and apraxia of speech in acute ischaemic hemispheral stroke S. Murphy, C. Doherty, J. Moroney Beaumont Hospital (Dublin, IE); St James Hospital (Dublin, IE) Objective: To determine the relationship between apraxia of speech (AOS) and infarct volume in patients presenting with acute hemispheral ischaemic stroke (AHIS). AOS is a motor programming disorder affecting the timing and duration of utterances integral to suprasegmental speech processing. Methods: We recruited consecutive patients hospitalised with AHIS as part of a prospective study on the investigation of AOS. We determined the presence and severity of AOS using a standardised test battery. Clinical stroke severity was measured using the National Institute of Health Stroke Scale (NIHSS). Stroke-protocol MRI was performed on all patients. Infarct volume was measured using a stereology grid technique. Results: Fifty patients were recruited, 29 (58 %) were male, mean age was 65.9 years. Forty-eight (96 %) were right-handed while 15 (30 %) had right and 35 (70 %) had left hemispheral infarction. We found AOS in 19 patients (38 %): ranging from mild to severe. All patients with AOS had left hemispheral infarction. After controlling for NIHSS, infarct volume was signifi-

cantly greater in the patients with left hemisphere stroke and AOS than in those without AOS. Conclusions: We found that AOS was common after AHIS and that it only occurred in patients with left hemisphere infarction. Infarct volume was significantly greater in patients with AOS compared with patients without AOS. Further investigation is ongoing to determine whether AOS affects stroke outcome, in particular, recovery of functional language skills at six months. This study was supported by a grant from the Irish Heart Foundation.

O139 Influence of neglect, hemianopia and delay after stroke on the subjective straight ahead A. Saj, J. Honoré, T. Bernati, M. Rousseaux CHRU de Lille (Lille, FR) Objective: In patients with spatial neglect, a translation of the subjective straight ahead (SSA), without rotation, has been suggested (Richard et al., 2004). However, Ferber and Karnath (1999) suggested that hemianopia could be responsible for a counterclockwise rotation of this egocentric reference, and neglect for a clockwise deviation. Furthermore, nothing is known about the time course of this misorientation. Here, we aimed at disentangling the relative effects of neglect, hemianopia, and delay on the representation of SA, using a method which analyses translation and rotation in parallel. Patients and methods: We included patients with a right hemisphere stroke. Eight had neglect and hemianopia (N+H+), 13 neglect only (N+H), 3 hemianopia only (N H+), and 12 neither one nor the other (N H). Controls (C) were fifteen. Participants had to adjust a bar, movable in translation and rotation, straight ahead of the navel, and in darkness. The task was performed twice with a delay of 5–7 weeks. Results: The translation of SSA differed significantly among the groups, and the differences depended on the session. In the first session, and in comparison with C (0.1 cm), a significant rightward translation was found in the N+H+ (6.2), N+H- (4.8) and N H+ (3.8), but not in the N H (0.9) patients. In the second session, a translation was still significant in the N+H+ (3.5 cm) and N+H- (4.3), but had disappeared in the N-H+ (0.2; N-H-: 1.0; C: 0.1); furthermore, the N+H+ and N-H+ improved significantly. As regards the rotation of SSA, both groups with hemianopia showed a counterclockwise deviation in the first session (N+H+: 2.6°; N H+: 1.2°), which reversed in the second session for N+H+ group (2.0°; significant difference), while it remained stable for N H+ (1.2°). The translation significantly correlated with clinical scores of neglect and lesions of the parietal cortex and centrum semiovalum. Conclusions: The translation of the egocentric reference is a main problem in patients with neglect. This phenomenon can also be found in patients with pure hemianopia, but it disappears in a few weeks. Furthermore, a discrete counterclockwise rotation of the SSA can be observed in hemianoptic patients, whether neglect or not, but is more persistent in case of pure hemianopia.

O140 Transient global amnesia – insights from cerebral diffusion weighted imaging C. Enzinger, F. Thimary, S. Ropele, F. Ebner, P. Kapeller, F. Fazekas Medical University (Graz, AT); Department of Neurology (Villach, AT) Purpose: The pathogenesis of Transient Global Amnesia (TGA) is still unclear. Recently, a hypoxic-ischemic origin has again been suggested based on the observation of mesiotemporal diffusion weighted imaging (DWI) abnormalities.We wished to probe this hypothesis by comparing DWI positive and negative subjects for the associations of this finding with vascular risk factors and MRI markers of cerebral small-vessel disease (cSVD). Methods and Materials: We retrospectively identified hospitalized patients with TGA (2002–2006). MRI of the brain (T2, FLAIR, T1) at 1.5T including DWI was available in 87 patients (age 66+/-10 yrs). MRI scans were assessed for unco-hippocampal DWI positive lesions (verified by ADC maps),white matter hyperintensities (WMH),and chronic ischemic infarcts. Vascular risk factors, precipitating events, and other ancillary investigations (duplex sonography, EEG, ECG, laboratory findings) were recorded. Results: DWI positive lesions were found in 10 individuals (11.5 %; age: 68.3±5.4 yrs; F/M: 8/2). The interval between symptom onset and MRI was non-significantly shorter in this group compared to DWI negative subjects (age 65.6±11.4 yrs; F/M: 46/31; interval: 59±30 vs. 79±57 hrs; p = 0.06). The vascular risk profile was generally favorable in the entire cohort and did not show significant between-group differences. The proportion of subjects with confluent WMH was also not significantly different between subgroups

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(10 % vs. 11.7 %). Chronic ischemic infarcts were present in 2 subjects only (all DWI negative). Conclusion: These findings appear to argue against a “classical” vascular mechanism of DWI positivity in TGA patients. However, the overall low frequency of DWI lesions observed and subgroup differences in the delay between symptom onset and MRI potentially limit this conclusion. O141 The mirror-neuron system and handedness: a “right” world? M. Rocca, A. Falini, G. Scotti, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, IT); CERMAC (Milan, IT); IRCCS San Raffaele (Milan, IT) Objective: To test how actions performed by others are represented in brain of left-handed (LH) subjects and the relationship between action representation processed by the mirror-neuron system (MNS) and simple motor act processing. Methods: Using a 3T scanner, we acquired functional magnetic resonance imaging from 11 right-handed (RH) and eight LH subjects to identify regions involved in the processing action of the right and left upper limbs and right lower limb, respectively. Subjects performed flexion-extension movements of the right hand and foot, separately, (execution task) alternated with period of rest and looked at a movie showing the hand or the foot of another subject while performing the previous task (observation task). Results: During the execution tasks, LH subjects had a more bilateral pattern of activation than RH. Different lateralizations of the MNS and motor system activations were found in RH and LH subjects during the observation tasks of the dominant and non-dominant limbs. The comparison of the execution vs. observation task demonstrated that during the execution task with their dominant limbs, RH subjects activated areas of the motor system in the left hemisphere, whereas LH subjects also activated areas of the MNS. During the execution task with the non-dominant limbs, both groups activated regions of the MNS and motor system. Conclusions: The patterns of MNS activations observed in RH and LH subjects support the theory that suggests that this system is involved in brain functions lateralization. In LH people, this system might contribute to their adaptation to a world essentially built for right-handers through a mechanism of mirroring and imitation.

Oral session 20 Multiple sclerosis 3 O142 Phenotypic and functional characterisation of T cell subsets in multiple sclerosis patients treated with the novel immunomodulator FTY720 (Fingolimod) M. Mehling, V. Brinkmann, N. Goebels, R. L. P. Lindberg, L. Kappos University Hospital (Basel, CH); Novartis Pharma AG (Basel, CH); University Hospital (Zurich, CH) Background: FTY720 is an oral immunomodulator, which showed clinical and MRI efficacy in a 6-month, placebo-controlled phase-II clinical trial in patients with Multiple Sclerosis (MS). FTY720 functionally antagonizes the Sphingosine-1-phosphate receptor-1 on human T cells, thereby inhibiting lymphocyte egress from secondary lymphoid organs. Little is known about effects of long term mono-therapy with FTY720 on peripheral T cells. Objective: To determine in MS patients the effect of FTY720 on blood Tcell subset composition and function compared to Interferon-beta (IFNb) treated patients and healthy donors (HD). Methods: T cell subsets were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMC) from MS patients treated with FTY720 (n = 10) or IFNb (n = 7) and in HD (n = 9). Activation and intracellular IFNgamma (IFNg) production of T cells was studied after stimulation with antiCD3/CD28 monoclonal antibodies (mAbs), and anti-CD28 mAb/antiCD49 d mAb/Staphylococcus enterotoxin B for recall stimulation of memory T cells. Results: In FTY720 patients, percentages of CD4+ (4.3 %) and CD8+ (8 %) T cells in PBMC were reduced compared to IFNb patients (CD4+: 36.4 %; CD8+: 21.1 %) and HD (CD4+: 38.7 %; CD8+: 23.4 %), and a reduced CD4/CD8 T cell ratio was observed (FTY720: 0.54; IFNb: 1.72; HD: 1.65). In

FTY720 patients the composition of CD4+ T cells was as follows: 16.2 % naïve, 7.9 % central memory T cells (TCM) and 45.6 % peripheral/effector memory T-cells (TEM); in IFNb: 44.8 % naïve T cells, 33.8 % TCM and 12.8 % TEM; in HD: 48.6 % naïve T cells, 31.3 % TCM and 12.7 % TEM. Production of IFNg in CD4+ and CD8+ T cells was similar in all groups, indicating full functionality. Conclusion: FTY720 lowers numbers of peripheral blood T cells, and reduces the CD4/CD8 ratio. Further, the drug alters the composition of peripheral blood T cell subsets substantially. Importantly, T cells in MS patients treated with FTY720 are fully functional, supporting an immunomodulatory action rather than a general immunosuppressive effect of the drug. O143 Change in lymphocyte gene expression induced by Campath-1H treatment of multiple sclerosis J. A. Somerfield, J. L. Jones, V. H. Robertson, D. A. S. Compston, A. J. Coles University of Cambrige (Cambridge, UK) Objectives: Campath-1H, a humanised monoclonal antibody to CD52, causes profound lymphopenia. It significantly reduces the relapse rate of multiple sclerosis and, intriguingly, results in reduced EDSS scores at 36months. This study aims to identify changes in peripheral lymphocyte gene expression associated with this improvement in disability after Campath-1H treatment. Methods: Blood was obtained from patients with early, aggressive, RRMS participating in one of two clinical trials of Campath-1H treatment: CAMMS-223 and CAMMS-224. CD4+ peripheral blood mononuclear cells were isolated and total RNA extracted. An Affymetrix microarray was performed and genes were identified that were increased or decreased by a factor of greater than 1.5. RNA was then reverse transcribed to cDNA and quantitative real-time polymerase chain reaction (PCR) was performed. Results: The Affymetrix microarray on four patients identified 42 upregulated genes and 8 down-regulated genes. 16 of these genes with a role in neuronal repair were validated by real-time PCR on a total of 8 patients and 5 healthy controls. Conclusion: Analysis of RNA from lymphocytes of patients with RRMS treated with Campath-1H show an up and down-regulation of genes that contribute to neuronal repair. Jennifer Somerfield’s salary was paid for by the Neurological Foundation of New Zealand. O144 Multiple sclerosis and genetic polymorphism in type III promoter of CIITA gene T. Mihalova, A. Barton, S. Eyre, J. Bowes, M. J. Stone, N. Rukin, A. A. Fryer, M. D. Boggild, C. Young, P. Hoban, J. Worthington, R. Strange, C. P. Hawkins on behalf of the North West MS Genetics Group Objectives: Multiple sclerosis (MS) is a chronic inflammatory neurological condition of complex aetiology, where susceptibility is significantly regulated by the major histocompatibility complex (MHC) class II genes. MHC class II plays an important role in T-cell dependent immunity and inflammatory response. MHC class II expression is controlled by MHC class II transactivator (CIITA) gene. Type III promoter(CIITA-III), situated on chromosome 16p13, is the principal promoter of CIITA employed by human activated T-cells. Single nucleotide polymorphism (SNP) in the 5’flanking region of CIITA-III (rs3087456) was reported to be associated with rheumatoid arthritis, multiple sclerosis and myocardial infarction in a Swedish population. Our study was designed to test for association between the CIITAT-III region and MS susceptibility in the previous described SNP and four additional SNPs in a UK population. Methods: Following 5 SNPs spanning the 5’flanking region of CIITA -III were selected: SNP1: G -7213/C (rs7501204); SNP2: T-6952/G (rs6498114); SNP3: T5473/C (rs6416647); SNP4: C-4591/T (rs7404672) and SNP5: A-168/G (rs3087456). Genotyping was performed in 474 MS cases and 775 population controls, using a Sequenom MassArray platform according to manufacture’s instructions. Genotype frequencies were compared at each locus using logistic regression in Stata, Version 8. Estimated haplotype frequencies were generated using the EM algorithm on HelixTree and compared between cases and controls. The risk association with individual haplotypes was evaluated using logistic regression in Stata, Version 8. Results: Genotype analysis detected no significant differences between genotype frequencies in MS cases and controls. SNP4: C-4591/T (rs7404672) showed to be non-polymorphic. Four remaining SNPs were in moderate to strong linkage disequilibrium (LD) with D-prime values: D’ = 0.73–0.99 for

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controls and D’ = 0.63–0.91 for MS cases. Two copies of haplotypes comprising SNP1-2-3-5: G-T-T-A (Odds ratio (OR) = 0.42, 95 % confidence interval (CI) = 0.21–0.86, p = 0.018) and SNP1–3-5: G-T-A (OR = 0.39, 95 % CI = 0.196–0.813, p = 0.011) were associated with reduced risk (reference, no copies of the haplotypes). Conclusion: We confirm that genetic polymorphism in type III promoter of CIITA gene is associated with MS susceptibility. Polymorphism in CIITAIII gene may influence a differential MHC molecule expression and contribute to the complex genetic aetiology of MS. O145 Liver X receptors counteract T cell activation and 7-ketocholesterol-induced neurodegeneration: implication for multiple sclerosis G. Porcelli, M. Giorelli, M. Ruggieri, C. Pica, P. Livrea, M. Minervini, M. Trojano Università degli Studi di Bari (Bari, IT); Casa Divina Provvidenza (Bisceglie, IT) Background: Liver X receptors (LXRalpha and LXRbeta) are nuclear transcription factors involved in the regulation of cholesterol metabolism. LXRs are greatly expressed in leukocytes and in the Central Nervous System. Activation of LXRs inhibits expression of metalloproteinase9 (MMP9) while inducing HMGCoA reductase in LPS-activated macrophages (Joseph et al., 2003), and exerts relevant neuroprotective effects in vitro (Sun et al., 2003). Objectives: The aim of this work was to analyse the expression of LXRbeta in peripheral blood mononuclear cells (PBMCs) from MS patients and controls, and to study the immunomodulatory and neuroprotective effects of LXRs activation. Methods: Expression levels of LXRbeta mRNA were measured by semiquantitative RT-PCR on PBMCs from 20 MS patients together with 10 people affected by Other Neurological Deseases(OND) and 7 Healthy Controls (HC). Cultures of PBMCs were treated in vitro with the synthetic LXRs ligand TO901 317 (2 and 20 microM) for 24 hours and then activated with antiCD3 + anti-CD28 for additional 72 hours. IFN gamma content was measured on supernatants (ELISA) and cell-based ELISA measured the cellular proliferation rate. The human neuroblastoma cells SH-SY5Y were treated in vitro for 24 hours with either 50 mg/l or 100 mg/l of 7-ketocholesterol, a myelin breakdown product (Diestel et al., 2003), with or without 2 microM of TO901 317 in the previous 24 hours. Extent of neurodegeneration was evaluated by mitochondrial conversion of tetrazolium into formazan (ELISA). Results: PBMCs from MS patients were found to express mRNA levels of LXRbeta four folds higer as average than those observed either in OND and HC individuals. In vitro pre-treatment of PBMCs cultures with 20 microM TO901 317 reduced the proliferaton rate (p < 0.01), and the INF gamma secretion from the same cells (p < 0.001), while increasing expression of HMGCoA reductase mRNA(150 %). Pre-treating SH-SY5Y cells with 2 microM of TO901 317 for 24 hours partially counteracted the extent of neuronal death induced by both 50 mg/l (p0.01) and 100 mg/l (p 0.05) of 7-ketocholesterol. Conclusion: Over-expression of LXRbeta in PBMCs from MS patients strongly suggests the involvement of this transcription factor in MS pathogenesis. The observed inhibitory effects of agonist-specific stimulation of LXRs on T cell activaton, INF gamma secretion, and on 7-ketocholesterol-induced neurodegeneration may open novel therapeutic avenues in MS. O146 Host brain reaction following transplantation of bone marrow stromal cells in experimental allergic encephalomyelitis E. Polyzoidou, A. Giannakopoulou, K. Kotta, O. Touloumi, A. Lourbopoulos, C. Simeonidou, E. Spandou, D. Karussis, N. Taskos, I. Milonas, N. Grigoriadis Aristotle University of Thessaloniki (Thessaloniki, GR); Hadassah University Hospital (Jerusalem, IL) Objective: Bone marrow stromal cells (BMSCs) are non-haematopoietic multipotent stem cells. BMSCs can differentiate into bone-related cells (bone, cartilage and adipose tissue cells); as well as muscle cells, and even neurones and astrocytes in vitro and in vivo. They have common characteristics with other stem cells, as they have the ability to renew and differentiate. BMSCs transplantation as potential cell therapy in autoimmune demyelinating disorders was studied here in Experimental Allergic Encephalomyelitis (EAE), the animal model of multiple sclerosis. Methods: BMSCs were isolated from Green Fluorescent Protein (GFP) transgenic mice with a C57Bl/6 background. EAE was induced with MOG 35–55 in five-six week old female C57Bl/6 mice, using standard protocols. On day 7 post-induction of EAE, a number of animals were used as recipients of GFP+ BMSCs which were stereotactically administered in both lateral ventricles, each with 106 cells. EAE animals that were injected with the culture medium only, were used as controls. Both groups of animals were

clinically followed up and sacrificed during the acute and the chronic phase of their disease. Cryostat sections were evaluated with immunofluoresence labelling for neuronal and glial cell markers. Statistics were performed using t-test (unequal variances assumed). Results: BMSCs transplanted animals presented a better clinical course versus the control group. Statistical significant differences (p < 0.05) appeared from day 29 until 47. Pathological study of the fate of BMSCs revealed that the majority of the cells turned to NG2+ cells (97.3 %) and a small percentage of them became GFAP+ cells (2.7 %). Notably, the transplanted cells migrated toward the areas with inflammatory lesions and were found to be strongly positive for BDNF.A remarkable accumulation of cells surrounding the migrated BMSCs in homocentric circle distribution was noticed in a number of animals.The inner layers of these cells were positive for F4/80 and Mac3 (activated microglia), whereas the outer were host astrocytes (GFAP+ and GFP– cells). Conclusion: BMSCs significantly attenuated the disease burden both during the acute and the chronic phases of EAE. BMSCs survive and migrate within the inflamed brain and the majority of them become NG2+ oligodendrocyte progenitor cells. In addition, the idiotypic distribution of host glial cells around the transplanted BMSCs may indicate a cross-talk between these cells, which needs to be clarified. The study was supported by the Pythagoras research grand from the General Secretary for research and technology of the Greek Ministry for Development O147 Devic’s neuromyelitis optica: a prospective study M. Eraksoy, G. Akman-Demir, M. Kurtuncu, Z. Yapici, M. Mutlu, B. Topcular, H. Durmus, H. Ozcan Istanbul University (Istanbul, TR) Although Devic’s neuromyelitis optica (DNMO) has been encountered in Turkish patients, its precise frequency is unknown.The geographic location of Turkey has been bridge between West and East and Turkish population has a different ethnic genetic background. Therefore, it would be informative to document the frequency and the characteristics of DNMO and opticospinal multiple sclerosis (OSMS) and their relationship with classical RRMS patients presented with unilateral optic neuropathy/bilateral optic neuropathy (ON/ BON) or transverse myelopathy (TM). In this study we describe the frequency, clinical, MRI, CSF and the laboratory findings of 34 patients with diagnosis of DNMO according to new criteria. We compared the first two interattack intervals and the time to reach EDSS 6.0, CSF and MR findings in DNMO group and in two groups of patients with OSMS presented with ON/ BON or TM/ partial spinal cord syndrome in our hospital-based cohort. Three thousand and fifty patients with CDMS, clinically isolated syndromes(CIS) and other demyelinating disease were assessed and their records were updated at our MS unit.Thirty-four patients fulfilled the diagnostic criteria for DNMO (1 %), 152 patients (%5) met the OSMS criteria and 4 of 34 patients (12 %) (0.1 % of 3050 patients) exhibited transitional clinical, radiological and CSF findings between DNMO and OSMS. The age at onset ranged between 5 to 44 years. F:M:5/1. Twenty-five patients presented with ON/BON, 7 patients developed ON/BON and TM, and 2 patients had TM as an index event.Thirty patients had multiphasic, 4 patients had monophasic DNMO. The brain parenchyma was normal 19 of 27 initial MRI.Two patients developed large, tumor-like brain lesion during the follow-up. Mean disease duration was 11.4 years and duration of follow up was 10.7 years.The mean EDSS score was 4.86 Oligoclonal bands were negative except for 4 OSMS like patients. This study revealed that DNMO in Turkish patients was not frequent and most of the patients developed multiphasic DNMO in the long term followup. There was transitional forms between DNMO and OSMS. Mean interval between first two relapses were shorter in multiphasic DNMO and prognosis was poor than OSMS patients presented with ON/ BON o r TM. The genetic and environmental factors which modify the acutness and speed of the process might explain the differences of the outcome.

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Oral session 21 General neurology 1 O148 Anthropometric variables and physical activity in relation to cognitive function in a general population sample of elders: the Greek EPIC cohort A. Kyrozis, T. Psaltopoulou, P. Stathopoulos, D. Trichopoulos, D. Vassilopoulos, A. Trichopoulou University of Athens (Athens, GR) Objectives: Cognitive impairment can be a serious problem among the elderly with considerable public health implications, accentuated by the rapid aging of the populations worldwide. In order to identify anthropometric and lifestyle parameters that may be associated with cognitive function in the elderly, volunteers from the general population in the Attika region of Greece were prospectively studied. Methods: A sample of 732 men and women, 60 years or older, participating in the EPIC-Greece cohort and residing in the Attika region had anthropometric, lifestyle, dietary, sociodemographic and medical variables ascertained at enrollment (1993–1999). Six to 13 years later, cognitive function was evaluated through the Mini-Mental State Examination (MMSE) score and affective state through the Geriatric Depression Scale (GDS). The data were examined separately for men and women, as well as overall. In multivariate linear regression, MMSE was used as the dependent variable, controlling for age, gender, marital status, years of education, smoking, alcohol intake, energy intake, diet and presence of commorbidities, such as hypertension, diabetes and depression. Results: MMSE score was significantly positively associated with height and physical activity in both genders, and negatively associated with waistto-hip ratio in women. Body mass index (BMI) did not have a significant association with MMSE in either gender. Conclusion: Among anthropometric and lifestyle variables modifiable in adulthood, physical activity and (in women) waist-to-hip ratio were significantly associated with cognitive function in the elderly. Height, possibly reflecting nutrition in early life, was also a significant predictor. Though obesity was not related to mental performance in the elderly, central adiposity tended to be associated with poorer mental performance, particularly among women. Co-funded by the European Social Fund and National Resources – (EPEAEK II) PYTHAGORAS. O149 Paroxysmal sympathetic hyperactivity in the neurological intensive care unit A. Rabinstein Mayo Clinic (Rochester, US) Objective: Assess the incidence and associations of paroxysmal sympathetic hyperactivity (PSH) among febrile patients in the neurological intensive care unit. Methods: Prospective data collection of consecutive patients admitted to an academic neurological-ICU for > 48 hours. Fever was defined as body temperature > 38.3° C (101.0° F) on at least one measurement for two consecutive days. PSH was defined by the transient presence of 4 of the following 5 criteria: fever, tachycardia, hypertension, tachypnea, excessive diaphoresis, and extensor posturing or severe dystonia in the absence of other potential causes for these clinical signs. Results: 93 patients were included. Traumatic brain injury (TBI) was the primary diagnosis in 43 patients (46 %). PSH were diagnosed in 17 patients (18 %). It occurred in 14/43 patients (33 %) with TBI but only 3/50 patients (6 %) with other primary disorders (p = 0.01). Patients with PSH were younger (mean 35 ± 14 years vs. 51 ± 18 in the rest of the population) (p = 0.01), although the difference did not reach statistical significance when only TBI patients were included in the analysis (mean age 35 ± 15 in TBI patients with PSH vs. 46 ± 19 in TBI patients without PSH; p = 0.07). Duration of fever in patients with PSH (mean 10.5 ± 7 days; median 9 days) was significantly longer than in the rest of the population (mean 5.1 ± 3 days) (p < 0.001); the difference remained significant when the analysis was restricted to TBI patients (p = 0.001). Conclusions: Episodes of PSH occur in one third of TBI patients but are rare in other acute neurological conditions. They are more frequent in younger patients and are associated with prolonged duration of fever.

O150 Neurocysticercosis in a university hospital, Madrid, 1996–2006 J. Fernández Domínguez, L. Gabaldón Torres, J. Salas Felipe, M. Aguilar-Amat Prior, M. Abenza Abildúa, F. J.Arpa Gutiérrez Hospital Universitario La Paz (Madrid, ES) Introduction and objectives: Neurocysticercosis is the most common parasitic infection of the central nervous system. Neurocysticercosis was endemic to only Latin America, Eastern Europe, Asia, and Africa, although increasing numbers of cases are being recognized in Spain,particularly among Hispanic immigrants. We reviewed the sociodemographic characteristics, incidence, clinical features, imaging, diagnosis and management of patients after being admitted to the La Paz University Hospital of Madrid for the last ten years. Patients and methods: We reviewed the clinical records of 38 patients with the diagnosis of Neurocysticercosis in our hospital from January 1st 1996 to December 31st 2006.A total of 30 patients showed neurological manifestations on admission, being 2 of them children. Results: The most frequent clinical manifestations at onset were seizures (n = 18), unspecific headache (n = 6), trigeminal neuralgia (n = 1), cephalea associated to hydrocephalus (n = 2) and psychomotor development delay (n = 1). In one case the cystic cerebral lesions were CT casual findings. Neurocysticercosis is more common among immigrants from Latin America, mainly from Ecuador (n = 15). Neuroradiological sings of active Neurocysticercosis were found in 25 patients. Albendazole, associated or not to corticosteroids and phenytoin, has been used as treatment in 19 patients. Conclusions: Neurocysticercosis is more common among immigrants from endemic areas. The most frequent first manifestation is seizure. Treatment with albendazole results in complete resolution or significant regression of cystic lesions and showed a significant reduction of seizures rate as well. Risk of recurrence was lower in treated patients. O151 Risk of osteoporosis in an aging polio population. Audit 2006 A. Mohammad, K. Khan, L. Galvin, O. Hardiman, P. G. O’Connell Beaumont Hospital (Dublin, IE) Introduction: The osteoporosis (OP) risk in polio survivors (PS) is unknown. Polio results in muscular weakness/immobility, leading to reduce mechanical stress on bone (1), thus increasing risk of OP. There is a well known correlation between bone mineral density (BMD), and muscle mass (2, 3). In 2006 we undertook an audit of PS attending outpatient clinics of a university teaching hospital. Our aim was to determine the risk of falls, fractures, and OP in this cohort. Methods: Retrospective chart-audits conducted over a 6-month period on 25 PS attending outpatient-clinics of Rheumatology and Neurology. Demographic data/details of treatment extracted. The following details regarding polio were extracted; age of polio onset, disability/use of braces/ modified shoes, a history of falls/fractures in the last 6 months and 5 yrs. Other OP risk factors were assessed. Women ≥ 55 yrs were classified as postmenopausal (PM). All patients underwent DXA scanning. Z-score was used for patients ≤ 55 yrs, and T-score for ≥ 55 yrs to diagnose OP. Results: 25 PS were screened; 17 (68 %) were females (13 were PM), and 21 developed polio at age ≤ 10 yrs. Currently, 15 (60 %) patients were using braces/modified shoes. 22 (88 %) of the patients had falls in the last 5 yrs vs. 17 (68 %) in the last 6 months. The number of the falls varied from 2–5. Of the patients, 10 (40 %) had a bone fracture in the last 5 years (3 wrist, 3 neck of femur, 2 vertebral, 3 ankle). Overall 23 (92 %) underwent DXA scanning, and 13 (52 %) were diagnosed with OP (including 9 PM women), and 7 (28 %) had osteopenia, i. e. 80 % (20) had osteopenia or OP on BMD testing. Of the patients, 11 (44 %) received some bone protection, 11 (44 %) ca/ vitamin D, but only 4 (16 %) received a bisphosphonate. Of the 10 patients who had a fracture, 4 (40 %) had OP, and 6 (60 %) had osteopenia on DXA scanning. Conclusions: This is first study providing OP data on polio survivors. PS represent a high-risk fracture group (40 % in 5 yrs) due to presence of multiple risk factors i. e. OP, muscle weakness, immobility, and recurrent falls. Of those in whom the BMD was measured 80 % (20) either have OP or osteopenia, and 40 %(10) had fractures, but only a small number was on anti-resorptive therapy, suggesting that BMD should be checked in all PS, and bone protection commenced in case of osteopenia or OP.Weight bearing exercise, lifestyle changes to reduce OP risk, and strategies to reduce risk of falls should be part of the healthcare of all polio survivors.

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O152 Clinical and immunological features of patients with anti-glial nuclear antibodies M. Tschernatsch, O. Gross, N. Kneifel, I. Krasenbrink, V. Novakova, M. Kaps, F. Blaes Justus-Liebig University (Giessen, DE) Recently, anti-glial nuclear antibodies (AGNA), which react with a special cerebellar glial cell type, have been described in patients with paraneoplastic neurological syndromes (PNS). We retrospectively analysed our serum bank and found 12 patients with AGNA. Seven patients had sensorimotor neuropathy, 3 had Lambert-Eaton myasthenic syndrome (LEMS), 1 limbic encephalitis and 1 had astrocytoma. 7/12 patients had an extracerebral tumour (5 small cell lung cancer, 2 carcinoma of unknown primary). The four patients without tumour had all peripheral neuropathy. However, these four patients had a follow-up of only 1–2 years. Serum was available from 9 patients and were negative for known antineuronal antibodies with exception of the LEMS patients, who had antiVGCC. Western Blot analysis of human cerebellar and an astrocytoma cell line protein fractions did not reveal a common reactivity. In contrast, using the SCLC cell line NCI-H510A, we could detect a common reactivity at about 70 kD, which was not detectable in healthy controls or other PNS patients. Anti-glial nuclear antibody represent a new mainly paraneoplastic syndrome-related autoantibody, which is associated predominantly with SCLC. Most observed clinical syndromes are LEMS and axonal neuropathy. The autoantibodies cross-react with a new 70 kD protein in small cell lung cancer cells.

Oral session 22 Pain O153 Neurophysiological study of central pain in patients with Parkinson’s disease P. Schestatsky, H. Kumru, J. Valls-Solé, F. Valldeoriola, M. J. Marti, E. Tolosa, M. L. Chaves CAPES (Brasília, BR); Clinica Guttmann (Barcelona, ES); Hospital Clínic Barcelona (Barcelona, ES); Hospital de Clínicas de Porto Alegre (Porto Alegre, BR) Background: Patients with Parkinson’s disease (PD) may present with various types of pain. Primary central pain (PCP) is defined as pain that does not appear to be secondary to known causes. Objectives: To evaluate the possibility of dysfunction in pain pathways in PD patients with PCP (PD-PCP), we carried out quantitative sensory testing (QST) and neurophysiological studies using thermal probes and laser stimuli. Methods: The study was carried out in 9 PD-PCP patients, 9 PD patients without pain (PD-NoP) and 9 healthy control subjects. We assessed the clinical characteristics of pain, performed QST, and recorded laser-evoked cortical potentials (LEPs) and laser-induced sudomotor skin responses (l-SSR). Results: In off condition, PD-PCP patients had lower heat pain and laser pinprick thresholds, higher LEP amplitudes, and less habituation of the lSSR in comparison to PD-NoP patients and control subjects. Abnormalities were more marked in the most affected side in comparison to the less affected side. In on condition, differences on QST and neurophysiological data disappeared or were significantly attenuated. Conclusion: Conduction of pain inputs along the peripheral and central nociceptive tracts is normal in PD patients with or without PCP. However, PD-PCP patients had a higher score in subjective sensation of pain and exhibited an abnormal effect of pain inputs on autonomic centers generating the sympathetic skin response. These abnormalities were partially modified by L-dopa, suggesting that the dysfunction may lie in dopamine-dependent centers regulating both autonomic function and inhibitory modulation of pain inputs.

O154 Pain inhibition by brush stroking may be mediated by unmyelinated tactile afferents H. H. Krämer, L. Lundblad, F. Birklein, M. Elam, H. Olausson University Mainz (Mainz, DE); University Gothenborg (Gothenborg, SE) Human (hairy but not glabrous) skin contains low-threshold unmyelinated tactile (CT) afferents that respond vigorously to soft brush stroking but not to vibration, and are suggested to serve emotional aspects of tactile sensation. Animal studies suggest that CT fiber input inhibits C nociceptor messages in the spinal cord. We have now studied if CT activation inhibits pain in humans. Eleven healthy subjects (mean 32 years, 6 women) participated in a psychophysical study. We applied heat stimulation (pain threshold + 0.5 °C) on the right thigh and tactile stimulation (slow stroking with a soft brush, or vibration 50 Hz) in the same dermatome (L 3) on both thighs, or on the left arm. In another session we applied heat and tactile stimulation on the right palm. Subjects were continuously rating perceived pain intensity on a visual analogue scale. There was a significant pain reduction (ANOVA, P < 0.001) when heat was combined with brushing in the same dermatome on the thigh but not on the palm. There was a significant pain reduction (P < 0.05) when heat was combined with vibration for both thigh and palm, but on the thigh the effect was smaller than for brushing (P < 0.001). There was no significant pain inhibition when heat on the thigh was combined with tactile stimulation on the arm. CT fibers seem to be particularly important for tactile inhibition of pain since the inhibition was more pronounced for brush stroking (activates CT) than vibration (does not activate CT). Further, the inhibition by brush stroking was only present at hairy skin (where CT fibers are abundant) and not on glabrous skin (where CT fibers are lacking). ENS fellowship 2005. O155 Dissociable neural activity to self vs. externally administered heat allodynia: a parametric fMRI study S. Leyendecker, C. Mohr, C. Helmchen University of Lubeck (Lubeck, DE) Cognitive strategies help to modulate neural responses in the human brain to ameliorate pain, e. g., by predicting the sensory consequences of impending acute painful stimuli. It is unknown whether these strategies are applicable in tonic pain models. We compared pain-evoked neural responses of self- and externally administered thermal allodynia in the experimental capsaicin model. Using fMRI, seventeen healthy male subjects were investigated in a parametric design with thermal stimuli (37°, 40°, 43°C) at the right thigh which was sensitized by topically administered capsaicin (1 % solution).In contrast to the external stimulation self-administered pain was made controllable. For both conditions thermode application trials without noticable thermal stimulation were introduced (high-level baseline, HLB) to account for the tonic capsaicin-induced pain and other covariables (e. g., predictability). Following subtraction of the HLB, the anterior insula and the anterior cingulate cortex (ACC) but not the somatosensory cortices maintained to show parametric increases of neural responses to heat allodynia. A stronger parametric increase of pain-related activity during self-administered stimuli was observed in the posterior insula. In contrast, the prefrontal cortex and cerebellum showed stronger increases to external heat stimuli. This study shows parametric, pain-intensity encoding neural responses in heat allodynia. Interestingly, particularly pain-intensity encoding regions (e. g., anterior insula, ACC) but not those with sensory discriminative functions (SI, SII) were parametrically activated during heat allodynia. Moreover, some areas were able to dissociate between self- and externally administered stimuli in heat allodynia. Thus, cognitive mechanisms maintain the capability of dissociating external from self generated states of injury in heat allodynia and may help to understand how cognitive strategies potentially alleviate chronic pain syndromes. O156 fMRI study of hypnosis-induced analgesia M. Boly, E. Balteau, C. Schnakers, R. Kupers, A. Luxen, P. Maquet, S. Laureys, M. E. Faymonville University of Liège (Liège, BE); PET Unit & Dept. Surgical Pathophysiology (Copenhagen, DK); CHU Pain Clinic (Liège, BE) Introduction: The neural mechanisms underlying the antinociceptive effects of hypnosis remain badly understood. We here used fMRI to study the effect of hypnosis on thulium-YAG laser induced pain in volunteers.

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Methods: 13 healthy subjects underwent 2 randomized fMRI sessions, one in normal, and one in hypnotic state. During each session, 200 laser stimuli with intensity ranging from 300 to 600 mJ were administered on the left hand. Subjects rated their sensations as P0: nothing perceived, P1: perceived, non painful, P2: mild pain, P3: moderate pain, P4: intense pain. fMRI data were preprocessed and analyzed using statistical parametric mapping (SPM2). Analyses compared activation induced by matched intensity laser stimulation in normal and in hypnotic state. Results were thresholded at small-volume corrected p < 0.05 within the previously identified pain matrix. Results: A significant difference in sensation was found between normal and hypnotic state for the painful intensity range of stimulation (mean score 1.9 ± 0.3 SD vs. 1.2 ± 0.4, respectively), but not for the non-painful range of intensity (mean score 0.5 ± 0.2 SD vs. 0.4 ± 0.3, respectively). In the normal state, high intensity (painful) compared to low intensity (non-painful) stimuli activated bilateral thalamus, primary somatosensory cortex (S1), insula, and anterior cingulate cortex (i. e., the pain matrix). In the hypnotic state, high intensity compared to low intensity stimuli only identified significant activation in S1. Bilateral thalamus, left insula and bilateral anterior cingulate cortex showed significant less activation in the hypnotic state as compared to the normal state. Conclusion: Our parametric event-related fMRI study investigating the effects of hypnotic suggestion on pain intensity perception in healthy volunteers demonstrated decreased pain perception during hypnosis, while leaving sensory non-painful perception unaltered. This hypnosis-induced decreased pain perception correlates with a decreased activation in thalamus, insula and anterior cingulate cortex. Supported by Belgian Fonds de la Recherche Scientifique – FNRS. O157 Onset and duration of pain relief with pregabalin treatment for painful diabetic peripheral neuropathy and postherpetic neuralgia: analyses of short- and long-term trials M. Rowbotham, R. Portenoy, T. Murphy, J. Young University of California (San Francisco, US); Beth Israel Medical Center (New York, US); Pfizer Inc (New York, US); Pfizer Global R&D (Ann Arbor, US) Objectives: Pregabalin has demonstrated robust efficacy as treatment of neuropathic pain. We report on time to onset and duration of pain relief associated with pregabalin treatment for painful diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN). Methods: Data from 9 placebo (PBO)-controlled trials (5–13 weeks; 300 or 600 mg/d pregabalin for DPN; 150, 300, or 600 mg/d for PHN; pregabalin, N = 1205; PBO, N = 772) and 4 open-label (OL) extension trials (duration = 2 years; flexible dosing; N = 444 with dose data and N = 251 with pain data) were evaluated in secondary analyses. Meaningful pain relief in the PBOcontrolled trials was defined as ≥ 1-point improvement in mean pain score (MPS, on a daily 0–10 numeric rating scale) among patients who were also responders (≥ 30 % improvement in MPS from baseline) at endpoint. Time, in days, to onset of such relief was determined for the 25th and 50th percentiles of all patients in pregabalin and PBO groups. Long-term outcomes from the 4 OL trials included change in pregabalin dosages and corresponding pain levels (0–100 mm visual analog scale). Results: 25 % of DPN and PHN patients treated with pregabalin had onset of meaningful pain relief by Day 1 or 2, while among PBO patients, onset was Day 4 for DPN and Day 18 for PHN patients (P <.0001). 50 % of DPN patients had onset of meaningful pain relief by Day 4 (300 mg/d) and Day 3 (600 mg/d), while < 50 % of patients receiving PBO had meaningful pain relief (P <.0001). Among PHN patients, 50 % of those treated with 300 or 600 mg/d had onset by Day 5, while < 50 % of PBO and of 150 mg/d patients met the criteria (P <.0001 for 300 and 600 mg/d vs. PBO). Among patients in the OL trials, pain remained consistent from the first quarter (29.1 ± 21.9) to 2year follow-up (28.3 ± 25.2), with no clinically meaningful variations in mean dosage (Q1 = 361, 2-year [Q8] follow-up = 375 mg/d; median 300 mg/d).Pregabalin’s long-term AE profile in these OL trials was similar to that reported in short-term trials. Conclusions: Pregabalin showed rapid onset of meaningful pain relief, by treatment Day 1 or 2, in 25 % of DPN and PHN patients in placebo-controlled trials. In long-term OL trials, patients’ pain levels remained consistent, without clinically meaningful dose variations, for 2 years. Pfizer sponsored this study.

Oral session 23 Child neurology O158 The use of IFNB-1 b therapy before and after 16 years of age in children with multiple sclerosis: a prospective follow-up M. Eraksoy, G. Akman-Demir, Z. Yapici, M. Kurtuncu, M. Mutlu, B. Topcular, H. Durmus, H. Ozcan Istanbul University (Istanbul, TR) Early diagnosis and therapy of multiple sclerosis (MS) might be positive effect on the prognosis and outcome of the disease. The objective of this study was to assess efficacy, safety and tolerability of every-other-day interferon beta-1 b therapy before and after 16 years of age in children with MS, prospectively. Of 3297, 140 (~ 4.2 %) patients have childhood-onset MS in our MS unit (January 2007). Seven children with MS started to IFN-1 b therapy before 16 years of age (9 to 15) (GI); 13 patients with childhood-onset MS began to receive IFNB-1 b after 16 years (17 to 39) (G2). In the first group (GI), there were one boy and 6 girls, and median age at onset was 13 yrs (6 to 15).All the children had relapsing-remitting MS (RRMS), median age at initiation of therapy was 13 yrs, median relapse rate 2 years before the therapy was 2 and median EDSS was 1.0. Median duration of therapy was 3 years (1 to 7); the relapse rates 2 and 5 years after the initiation of therapy were1 (3/7 pts). Disability score(s) were 1.0 (6/7 pts.) and was 6.0 (1/7pt) at January 2007. As the side-effects, dose titration was performed in three patients because of elevation in liver enzymes and fatigue in the first three months. Two patients were relapse-free after the 5 years, in spite of neutralising antibodies were positive at 5 years of the disease in a patient. All the patients in this group have been receiving IFNB-1b. In the second group (G2), there were 5 men and 8 women (n = 13).The age of MS onset was 14 yrs. The median age at initiation of IFNB-1 b was 25 yrs; median relapse rate 2 years before therapy was 2; median EDSS at the initiation of therapy was 3.0 (1.0 to 5.5); median duration of therapy was 7 yrs (3 months to 9 yrs). The relapse rates 2 and 5 years after therapy was 1 and 2 respectively in 10 patients. Three patients developed secondary progressive MS and stopped the therapy. Two patients had severe flu-like symptoms, fatigue and elevation in liver enzymes in 3 and 7 months. Four patients have been using IFNB-1 b with mild relapses and had EDSS 1.0 although median disability score at 2007 was 6.0 in whole group. In conclusion, this study revealed that IFNB-1 b was safe and tolerable in children with MS in short and long-term (after 5 years) follow-up and at least half of the patients in both groups had decreased relapse rates and unchanged disability at the last follow-up. O159 Childhood multiple sclerosis: clinical presentation and disease course S. N. Tenembaum, M. Segura Hospital de Pediatria J. P. Garrahan (Buenos Aires, AR) Objectives: to define the full spectrum of clinical presentation and disease course of childhood Multiple Sclerosis (MS). Methods: patients under the age of 10 years at clinical onset and fulfilling Poser criteria for clinically definite MS and/or McDonald MRI diagnostic criteria were eligible for inclusion. Children were collected from the Pediatric Demyelinating Disease Program at one clinical site in Buenos Aires. Prospectively acquired data reviewed for each children included: age at onset, sex, clinical characteristics and course, relapse history, disability assessment by Expanded Disability Status Scale (EDSS) and all available brain and spine MRI scans. Results: Thirty children fulfilled diagnostic criteria for MS. Mean age at clinical onset was 4.9 years (1.5–9.5 years), including 14 children with age onset under 5. The female: male ratio was 0.6. An acute disseminated encephalomyelitis (ADEM)-like phenotype was the most frequent presentation observed in 12/30 (40 %) children, including focal seizures in 3 patients and optic neuritis in 5. A polysymptomatic onset without encephalopathy was observed in 3/30 (10 %). The frequencies of clinically isolated syndrome presentation observed in the other 15 children were: brainstem-cerebellar syndrome (17 %), transverse myelitis (13 %), optic neuritis (10 %) and hemimotor syndrome (10 %). Of the 23 children with available MRI scan at first event, 78 % fulfilled McDonald MRI criteria for dissemination in space. All children underwent MRI at the MS defining event and subsequent attacks, and 97 % fulfilled MRI criteria for dissemination in time. After a mean follow-up of 7.6 years (1–12.8 years), 67 % of patients had

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a relapsing-remitting MS, 30 % a secondary progressive MS, and 1 child (3 %) had Marburg disease. The mean number of relapses was 2.15 (1–5) during the first year of disease, and 3 (1–11) during the second year. The number of children reaching confirmed EDSS 3 was 14 (47 %) during the first year, 18 (60 %) during the second year, and 20 (67 %) at last visit. The median EDSS at last visit was 3.5 (1–10), with 20 % of children reaching EDSS ≥ 6. Conclusions: Clinical presentation features of childhood MS are unique, with atypical symptoms like encephalopathy and multifocal deficits. The high relapse rate and early age of sustained disability observed in this young cohort of MS patients reflect an active inflammatory process, in which early initiation of disease modifying therapies should be considered. O160 Reciprocal inhibition in children with cerebral palsy compared to healthy controls M. Hodapp, J. Rosset, J. Vry, V. Mall, M. Faist University Hospital (Freiburg, DE) Objectives: Reciprocal inhibition (RI) onto soleus motoneurons is reduced in patients suffering from spasticity after bilateral spinal and unilateral cerebral lesion (Crone et al., 2003), while presynaptic inhibition (PI) of soleus Ia afferents is only reduced after bilateral spinal lesions but not after unilateral cerebral lesion (Faist et al., 1994; Aymard et al., 2000). Reciprocal inhibition may be restored in patients with good functional outcome after unilateral cerebral lesion. In children with cerebral palsy (CP) the bilateral supraspinal lesion occurs before the maturation of the CNS is accomplished. In CP a lack of age dependent development of reflex pathways has been described. The question arises, if there are any age dependent changes of RI or PI in healthy children and if there are differences to children with CP Methods: A total of 51 healthy children aged 5–16 years and 5 diplegic CP children aged 8–11 years were investigated. Soleus H-reflexes were conditioned by common peroneal nerve stimulation at 1.0 motor threshold. At least 20 reflexes for each conditioning-test (c-t) interval were recorded and averaged. ANOVA for differences between age groups and between CP and healthy children was used for statistical analysis. Reciprocal inhibition was assessed at c-t intervals 2–3 ms, presynaptically mediated D1 inhibition was expected at c-t intervals 10–20 ms Results: No significant differences were found of Hmax/Mmax ratio between children aged 5–12 and 13–16 years or children with CP. Reciprocal inhibition and presynaptic D1 inhibition were present in healthy children at the age of 5–12 years. There were no statistically significant age dependent changes. In CP children reciprocal inhibition was not reduced at all, while presynaptic D1 inhibition was significantly decreased. Conclusions: The ongoing maturation of the corticospinal tract in healthy children seems to have no impact on reciprocal or presynaptic D1 inhibition, at least in the resting condition. Our results may indicate that reciprocal inhibition requires an intact spinal or brainstem level while the development of presynaptic inhibition requires at least one intact side of the corticospinal tract. References Crone C, Johnsen LL, Biering-Sorensen F, Nielsen JB (2003) Brain 126: 495–507 Faist M, Mazevet D, Dietz V, Pierrot-Deseilligny E (1994) Brain 117: 1449–1455 Aymard C, Katz R, Lafitte C, Lo E, Penicaud A, Pradat-Diehl P, Raoul S (2000) Brain 123:1688–1702 O161 New evidences of genotype-phenotype correlation in metachromatic leukodystrophy F. Fumagalli, A. Biffi, M. Cesani, U. Del Carro, C. Baldoli, S. Gerevini, S. Amadio, M. Falautano, S. Canale, G. Comi, M. G. Roncarolo, M. Sessa San Raffaele Scientific Institute (Milan, IT) Objectives: Metachromatic Leukodystrophy (MLD) is a rare and fatal demyelinating lysosomal storage disorder with no effective treatment. Because of its rarity, little is known about the natural history of different clinical variants. Our aim was to enlarge knowledge about disease progression and to identify reliable prognostic factors instrumental for accurate patients’ selection in current and new therapeutic protocols such as gene therapy. Methods: We characterized a large cohort of 27 MLD patients by biochemical evaluation of residual enzymatic activity and complete sequencing of the coding region of the ARSA gene. Patients were clinically followed along a four-years period by means of motor (Gross Motor Function Mea-

sure) and neuropsychological (Bayley Scale of Infant Development, Stanford-Binet Scale, Wechsler Intelligence Scale) scales, and neurophysiological and neuroradiological studies. An NCV index was calculated as the average of z-scores (patient’s nerve conduction velocity (NCV) – normal donors’ mean NCV / normal donors’ NCV standard deviation) of the four tested nerves. For scoring of MR studies we adapted the Loes’ scoring system developed for adrenoleukodystrophy. Results: Residual enzymatic activity, as routinely tested for diagnostic and prognostic indications, results poorly informative. Indeed, we demonstrate the existence of a precise correlation between mutations in the ARSA gene and patients’ phenotype.We show that this correlation, already demonstrated for common mutations, applies also to rare ones. Moreover, the involvement of the peripheral nervous system (low NCV index) since disease onset is associated with a rapid and more severe disease progression. We also found that the evolution of MRI score is significantly different in groups of patients having different genotypes: it increase more rapidly and progressively in patients carrying at least one severe mutation. Conclusions: This work demonstrates the unique prognostic value of gene sequencing and rare mutation analysis in MLD. Moreover, it reveals the importance of peripheral nervous system evaluation in the diagnostic work up at disease onset in order to accurately predict patients’ phenotype and to elaborate a correct prognosis. Further, MRI represents a useful and quantitative tool for monitoring disease natural history and for evaluating the efficacy of current or new therapeutic protocols. This research was supported by grants from the Italian Telethon. O162 Alpha-synuclein levels in Gaucher disease T. Papasilekas, M. Moraitou, E. Michelakaki, L. Stefanis IIBEAA, Academy of Athens (Athens, GR); Child’s Health Institute (Athens, GR) Objective: Gaucher disease is a Mendelian disorder resulting from the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GBA) and classically divided into three clinical types. A link between Gaucher disease and Parkinsonism became evident during recent years from the recognition of rare patients with early onset, treatment refractory Parkinsonism. Although many possible mechanisms for the association of the two entities have been proposed, nothing is really known yet. Perhaps the most convincing explanation is that GBA mutations cause lysosomal dysfunction and this interferes with clearance of alpha-synuclein. Our study’s objective is to determine whether the presence of GBA mutations, whatever the cause, leads to increased intracellular levels of alpha-synuclein or perhaps the appearance of potentially toxic oligomers, risk factors both related to parkinsonism. Methods: In our study we plan to examine Red Blood Cells, White Blood Cells and Fibroblasts from 30 Gaucher patients, 30 GBA mutation carriers and 30 age and sex matched controls. Steady state alpha-synuclein protein levels will be evaluated through Western Blots while alpha-synuclein’s halflife in fibroblasts will be determined through either autoradiography or the use of Actinomycin and the subsequent successive measurements of its levels with Western Blots. Results: Preliminary results show that endogenous alpha-synuclein migrating at 16 kDa can be readily detected in lysates derived from red blood cells. There is heterogeneity in the levels, even among the same group, and no significant differences between groups have been detected up to this point. Interestingly, a prominent band migrating as a dimer is recognized in all samples using a variety of alpha-synuclein antibodies. Conclusion: Although preliminary data in Red Blood Cells do not show a correlation between alpha-synuclein levels and Gaucher Disease, further experiments are under way in white blood cells and fibroblasts, tissues that are affected by glucocerebrosidase mutations to a greater degree than red blood cells, and rely more on lysosomal degradation for protein clearance. These studies will help to elucidate the possible influence of glucocerebrosidase mutations on alpha-synuclein levels and conformation and thus provide a molecular link between Parkinson’s and Gaucher’s Disease.

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Oral session 24 Clinical neurophysiology O163 Changes in cerebral metabolism in patients emerging from the minimally conscious state C. Schnakers, M. Moonen, R. Hustinx, A. Vanhaudenhuyse, C. Bernard, M. Kirsch, M. Boly, G. Moonen, S. Laureys Coma Science Group (Liège, BE); Cyclotron Research Centre (Liège, BE); CHU Nuclear Medicine (Liège, BE); CHU Neurology (Liège, BE) Introduction: Recently, the Aspen Workgroup (2002) published behavioral criteria for the minimally conscious state (MCS) and defined the criteria for emergence from MCS (EMCS). MCS patients show more than the automatic motor behavior observed in vegetative patients (eg eye tracking or inconsistent movement to command) but remain unable to communicate their thoughts or feelings. EMCS is characterized by the recovery of functional communication. We here used fluorodeoxyglucose PET to identify differences in regional cerebral metabolic rates for glucose (rCMRGlu) in MCS as compared to EMCS patients. Methods: We prospectively studied 12 MCS patients (8 men; mean age 45 years ±17 SD; mean time since brain insult 18 months; 8 non-traumatic cases) and 5 EMCS patients (3 men; aged 49±22 years; mean time since brain insult 6 months; 3 non-traumatic cases). PET data were spatially normalized, smoothed and analyzed using Statistical Parametric Mapping (SPM2). Results were thresholded for significance at false discovery rate corrected p < 0.05. Results: Compared to MCS, EMCS patients showed significantly higher rCMRGlu in the anterior cingulate (ACC) and mesiofrontal cortices (areas 32 and 9; peak voxel x y z stereotaxic coordinates –10 40 18 mm; T value = 4.35). Other areas identified were bilateral fronto-insular cortices/claustrum, Broca and Wernicke language areas, and pre-supplementary motor cortex. Conclusion: Our study, for the first time, identifies functional recovery in anterior midline, insular/claustrum and perisylvian language areas in patients emerging from the MCS as compared to patients remaining MCS. This finding is in line with the proposed critical role ACC and mesiofrontal areas in consciousness and cognition. Interestingly, the ACC (and frontoinsular cortex) contains spindle neurons, only to be found in the ACC of humans and other hominids, and hypothesized to be important for higher-order processing and consciousness. Longitudinal within-subject comparisons are needed to further disentangle the neural correlate underlying emergence from the devastating medical entity that is MCS. Supported by Belgian Fonds de la Recherche Scientifique – FNRS O164 Changes of short latency reflexes during gait in hemispastic patients after injection of botulinum toxin A in the triceps surae muscle M. Faist, H. Hefter, J. Mueller, W. Nickels, D. Messerschmidt, M. Hodapp, W. Berger, J. Wissel University hospital (Freiburg, DE); University hospital (Dusseldorf, DE); University hospital (Innsbruck, AT); Department of Neurological Rehabilitation (Beelitz-Heilstätten/Berlin, DE) Objective: In healthy subjects short latency leg muscle reflexes have been shown to be profoundly modulated throughout the step cycle in a functionally meaningful way and might contribute to EMG pattern observed during gait. In hemispastic gait this reflex modulation is partly preserved and might contribute to the force neccessary to hold the body with the paretic limb. Local injection of Botulinumtoxin A (BtxA) reduces these reflexes at least in the resting muscle. The aim of the present study was to assess short latency reflexes during gait in the M. soleus before and after injection of BtxA in hemispastic patients. Methods: Soleus Hoffmann (H-) and tendon jerk (T-) reflexes were investigated during walking on a treadmill in 10 hemispastic patients after unilateral cerebral lesion. All patients were functional walkers. Measurements were performed before and after injection of BtxA (800mU Dysport™) in the triceps surae muscle. Reflex amplitudes were normalized with respect to the maximum motor response (Mmax). Reflexes were obtained during 8 different phases of the step cycle and in a control condition with similar voluntary muscle activity during standing. Results: Similar to healthy subjects short latency reflexes showed a rhythmic modulation during the step cycle with a maximum in the second half of the stance phase. After BtxA injection Mmax and the maximum H(Hmax) and T- reflexes slightly decreased during standing but the

Hmax/Mmax ratio remained constant. In contrast, during gait H-reflexes increased in the second half of the stance phase and T-reflexes remained unchanged. The rhythmic modulation pattern throughout the step cycle was unchanged. Conclusions: A decrease in reflexes after BtxA injection during functional movements was not observed. The observation that the T-reflex is unchanged whereas the H-reflex, which is bypassing the muscle spindles, is increased could reflect an up-regulation of the central part of the reflex arc.As BtxA acts in the periphery a possible explanation is a decrease in afferent inhibitory input after the injection. This may be interpreted as a BtxA induced change in sensory-motor-integration of Ia afferent signals. O165 Perception of verticality in cerebellar lesions mediated by the dentate nucleus? B. Baier, S. Bense, M. Dieterich Neurology University Hospital (Mainz, DE) Objectives: Sensitive clinical sign of a vestibular tone imbalance in the roll plane is the ocular tilt reaction (OTR), consisting of the characteristic triad with ocular torsion (OT), skew deviation (SD), and tilt of the perceived subjective visual vertical (SVV). While a complete or incomplete OTR is regularly seen in patients with acute unilateral brainstem lesions affecting central vestibular pathways, only a few case studies are available on its occurrence in patients with cerebellar lesions [1, 2]. Thus, the question arises if contra- and/or ipsiversive tilts of SVV can be found in cerebellar lesions and if so, which cerebellar structures may be involved. Methods: We used lesion mapping technique in MRI and CT in a total of 39 patients with acute circumscribed cerebellar strokes all showing a significant SVV-tilt (> 2.5°). Twenty-nine patients had a contraversive tilt of the SVV [mean ±SD: 7.4°±3.7°] and were compared to 10 patients with ipsiversive tilts of the SVV [mean ±SD: 5.9°±5.9°]. Both groups were comparable with respect to age, acuity of lesion, size of lesion, and the occurrence of additional central ocular motor symptoms such as OT and SD. Results: MRI/CT lesion mapping revealed that lesions in cerebellar stroke patients showing contraversive SVV tilts included the middle cerebellar peduncle, the dentate nucleus, the tonsil, and the uvula. The dentate nucleus was the commonly damaged structure in contraversive tilts but not in ipsiversive tilts. Ipsiversive tilts of SVV were rather associated with lesions of the biventer lobule apart from the middle cerebellar peduncle, the tonsil, and the inferior semilunar lobule. Conclusion: These data suggest that the dentate nucleus is a critical anatomical structure within the cerebellum involved in perception of verticality, a lesion of which causes tilts of the SVV in the contraversive direction. Our findings correspond to old data in single patients in whom coagulation of the dentate nucleus led to a contraversive head tilt [3]. The study was supported by the DFG (DI 749/4–5). References 1. Mossman S, Halmagyi GM (1997) Neurology 49:491–493 2. Lee H et al. (2005) J Neurol Neurosurg Psychiatry 76:1742–1743 3. Nashold BS et al. (1969) Arch Ophthal 81:538–543 O166 The somatosensory blink reflex in Miller-Fisher syndrome and Bickerstaff brainstem encephalitis L. León, J. Casanova-Molla, J. Valls-Sole Hospital Dos de Maig (Barcelona, ES); Hospital Clinic (Barcelona, ES) Background: There are clear clinical and electrophysiological differences between Miller-Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE), even if they are considered to be part of a wide spectrum of autoimmune disorders related to anti-GQ1B antibodies. Only a few neurophysiological studies have been reported on patients with MFS and BBE. In MFS, Miwa et al. (J Neurol Neurosurg Psychiatry 1995;58:95–99) reported enhancement of the somatosensory blink reflex responses (SBR) to electrical stimulation of the median nerve. In this study we examined the SBR in 4 MFS and 4 BBE patients to determine possible differences between the two groups of patients. Methods: The diagnosis was established on clinical criteria: MFS patients had ophthalmoparesis and ataxia with loss of tendon reflexes. BBE patients had ophthalmoparesis and diminished conscience. Patients were all seen within the first 72 hours after onset of symptoms and the exams were repeated at 1 month and 3 months in most of them.The SBR was recorded from the orbicularis oculi muscles of both sides with surface electrodes. The median nerve was stimulated at the wrist using an intensity able to induce a

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supramaximal compound action potential in the thenar muscles. We also performed conventional blink reflexes to supraorbital nerve stimulation. Results: All MFS patients had responses present at a mean latency of 72.1 ms (SD = 9.7 ms). The area of the responses (amplitude times duration) was 17.3 mV·ms (SD = 5.9 mV·ms). On the contrary, responses in BBE patients were inconsistent and small in 2 patients and absent in the other 2 patients. The R1 responses to supraorbital nerve stimulation were normal in 2 and delayed in 2 MFS patients. They were delayed in 1 and absent in 3 BBE patients. Discussion: There were clear cut differences between MFS and BBE in regard to the consistency of the SBR. Our results suggest that intra-axial disorders of the brainstem may present with an abnormal sensorimotor integration of inputs from the median nerve while this is not the case with extra-axial lesions. The SBR is a neurophysiological tool with clinical applicability in disorders of the brainstem. O167 Cerebral resting state fluctuations predict somatosensory perception M. Boly, E. Balteau, C. Schnakers, C. Degueldre, G. Moonen, A. Luxen, C. Phillips, P. Peigneux, P. Maquet, S Laureys Coma Science Group (Liège, BE); Cyclotron Research Centre (Liège, BE); CHU Neurology (Liège, BE); Université Libre de Bruxelles (Brussels, BE) Introduction: At present, the functional significance of spontaneous blood oxygen level dependent (BOLD) fluctuations observed using fMRI in the human brain remains enigmatic. Methods: By means of thulium-YAG laser and event-related fMRI, we tested whether variability in perception of identical stimuli relates to differences in pre-stimulus, baseline brain activity in 26 healthy volunteers. Results: We observed a positive relationship between conscious perception of low-intensity somatosensory stimuli and immediately preceding high baseline activity in medial thalamus and lateral fronto-parietal network, respectively thought to relate to vigilance and ‘external monitoring’. Conversely, there was a negative correlation between subsequent reporting of conscious perception and baseline activity in a set of regions encompassing posterior cingulate/precuneus and temporo-parietal cortices, possibly relating to introspection and self-oriented processes.At nociceptive levels of stimulation, pain-intensity ratings positively correlated with baseline fluctuations in midcingulate cortex, an area known to be involved in the affective dimension of pain. Conclusion: Our data suggest that spontaneous brain activity fluctuations profoundly modify conscious perception of the external world. Supported by Belgian Fonds de la Recherche Scientifique – FNRS O168 Long-term cortical plasticity to extensive training: a transcranial magnetic stimulation study in piano-players L. Straffi, R. Chieffo, F. Cerri, A. Inuggi, M. Cursi, G. Comi, L. Leocani H. San Raffaele (Milan, IT) Objectives: The aim of our study was to characterize the influence of bimanual practice in cortical representation of upper limb muscles using transcranial magnetic stimulation (TMS). Methods: Eight right-handed pianists (3F; age 25±2.7 years) and seven right-handed controls (3M,4F; age27±4.5) underwent focal TMS mapping of both hemispheres with simultaneous recording of four upper limb muscles (abductor pollicis brevis-APB; abductor digiti minimi-ADM; extensor carpi radialis-ECR; biceps). The intensity of stimulation was 15 % above the lowest motor threshold for evoking motor evoked potentials (MEPs) in any of the tested muscles. The number of responsive sites was determined for each muscle tested. Upper limb dexterity was measured using NineHolePegTest (NHPT). Mirror movements during maximal unilateral voluntary isometric contraction were searched with electromyographic recordings. Results: MEPs were only evoked in the distal muscles (ADM,APB,ECR) at threshold and stimulation intensities. In the control-group, map area was significantly larger on the dominant side (p = 0.0001; Paired T Test), while a similar representation in the two hemispheres was present in piano players, being their dominant hemisphere less represented than in controls (p = 0.027; ANOVA). The dominant hand performed significantly better than the non-dominant one in control-group (p = 0.004;Paired T Test) but not in musicians. Mirrors occurred in 5 control subjects only to voluntary movement of the non-dominant hand, with significantly higher frequency (p = 0.004;Sign Test) compared to the pianists group (1 subject). The interhemispheric difference of map area was correlated to the inter-limb difference of NHPT performance (r = 0.553, p = 0.05; Pearson Correlation). Conclusions: Our finding of reduced inter-hemispheric asymmetries in motor cortical representation in musicians, by reducing representation of the dominant hemisphere, is consistent with functional imaging studies. In

our findings, the asymmetry in motor representation was related to asymmetry in motor performance. The reduced occurrence of mirror-movements in piano players compared to naive subjects suggest a more efficient and symmetrical inter-hemispheric inhibition. One possible explanation for our findings is that long-term bimanual practice may reshape motor cortical representation by re-balancing interhemispheric inhibition, which in naive subjects would tend to be stronger from the dominant to the non-dominant hemisphere.

Oral session 25 Dementia 2 O169 Dementia in Belgium: prevalence in aged patients consulting in a memory clinic J. Pepin, A. Maertens de Noordhout CHR Citadelle (Liège, BE) Objectives: Early detection of dementia is an important element for the efficacy of therapies currently proposed to slow down the disease. This detection relies on general practitioners and specialists in memory clinics. The data of the Belgian NAtional Dementia Economic Study (NADES) have showed the prevalence rate of dementia in patients aged ≥ 65 years living at home and consulting in general practice. This prevalence is thought to be higher in specialized memory clinics but local data are unavailable up to now. This study is aimed to assess the prevalence rate of dementia in our memory clinic and the differences in diagnosis and severity of dementia. Methods: The study population was based on the sampling of 674 (aged ≥ 65 years) new consecutive patients consulting the memory clinic of CHR Citadelle – Liège from 2003 to 2006. The diagnosis of dementia was based on the neuropsychological and neurological evaluation. The demented patients were classified on clinical subtypes according to the international criteria. The stage of the dementia was assessed using the Reisberg’s Global Deterioration Scale. Results: The observed prevalence of dementia in the patient over 65 years-old at the memory clinic was 5-fold higher (65 % versus 13 %) than the prevalence found in general practice. There were differences in prevalence between age-groups with an increased percentage of positive diagnosis of dementia in older. In terms of differential diagnosis,Alzheimer’s disease was the most frequent and counts for 50 % of the dementia; interestingly, this percentage is not evolving with age while diffuse Lewy Body dementia is more frequent with age and frontal lobe dementia is less frequent. In terms of severity, the stage of dementia at the time of diagnosis is higher in older patients. Conclusion: While expected, the difference in the prevalence of dementia among patients consulting in a memory clinic compared to the patients in the general medical practice is very high. The question arises of the accuracy of the screening tests for dementia used by general practicioners. The different clinical subtypes of dementia are influenced by age-group except for Alzheimer’s disease. The diagnosis of dementia is easier and its severity is greater in older patients. This could indicate a relative banalization of memory complaints in the old people leading to delay in the diagnosis. Early detection of dementia needs to be improved. O170 Presenile dementia: the experience of a tertiary referral centre S. Papageorgiou, T. Kontaxis, A. Bonakis, G. Karahalios, M. Nikaki, N. Kalfakis, D. Vassilopoulos Medical School, Athens University (Athens, GR) Background: Data from the literature about the relative frequency of diseases presenting with dementia with an early onset(< 65 yrs) are few and controversial. The purpose of the present study was to determine the relative frequency of early onset dementing diseases, on a hospital based series of a tertiary referral centre. Methods: The patients included in this study were referred to the Cognitive Neurology-Extrapyrimidal Disorders Unit, University Neurology Clinic, Eginition Hospital, Athens, during a 3 years period (from 1/01/2004 until 31/12/2006) for dementia diagnosis. The criteria for referral to this tertiary

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centre were predefined and included the following: a) any dementia with rapid progression, b) any dementia of undetermined diagnosis c) any presenile dementia (with symptoms starting before the age of 65 years). Results: Of a total of 279 patients fulfilling criteria for dementia, 107 patients had a presenile onset. The frequency of the underlying diseases is reported below (M±SD = mean age of onset ± SD, ma = lower age) 1. Alzheimer Disease (AD): n = 38 (35.5 %). M±SD: 58.8±5.5; ma: 48. 2. Frontotemporal dementia (FTD): n = 27 (25.2 %). M±SD:53.3±10.0; ma:32 3. Dementia secondary to systemic diseases – metabolic deficits: n = 15 (13.9 %). M±SD: 50.4±8.1 ma: 36 (SLE = 2, B12-folic acid deficiency = 2, neurosyphilis = 2, sarcoidosis = 1, scleroderma = 1, druginduced dementia = 2, multiple sclerosis = 1, CNS vasculitis = 1, CNS lymphoma = 1, CNS metastases = 2). 4. Other neurodegenerative diseases: n = 12 (11.2 %). M±SD: 61.0±3.0; ma:57 (PSP = 5, MSA = 5, CBD = .2) 5. Vascular dementia: n = 8 (7.4 %). M±SD: 54.3±12.0 ma:50. 6. Creutzfeld-Jacob disease (CJD): n = 5 (4.6 %). M±SD: 56.9±5.5; ma49.5 7. Dementia in the context of a psychiatric disease: n = 5 (4.6 %). M±SD:37.8±2.7; ma:35.7 8. Dementia with Lewy bodies: n = 3 (2.8 %). M±SD: 55.1±6.0; ma:50.6 9. Normal pressure hydrocephalus: n = 1 (0.9 %). Age of onset: 64.0 10. Limbic encephalitis: n = 1 (0.9 %). Age of onset: 52.0 Conclusion: The above data, suggest that AD and FTD have approximately the same frequency in demented patients aged < 65 years, accounting for a ~60 % of all cases. In a significant proportion of patients (13.9 %), dementia was due to secondary-potentially reversible causes. CJD was a non-negligible cause in our series (5 %). VaD and DLB (common in elderly patients) were relatively rarely found in our patients (7.4 % and 2.8 % respectively). O171 CSF biomarkers and APOE4 in MCI, AD and related disorders: usefulness for diagnosis and correlation with clinical phenotypes I. Guidi, D. Galimberti, C. Fenoglio, E. Venturelli, L. Perego, N. Bresolin, E. Scarpini University of Milan, IRCCS Ospedale Maggiore Policlinico (Milan, IT) Background: Use of CSF biomarkers has improved diagnostic accuracy of Alzheimer disease (AD), whereas is uncertain their usefulness in differentiating among different clinical phenotypes of AD and related disorders. A role in cytoskeletal stability and metabolism has been suggested for APOE, while is controversial the influence of APOE genotype on CSF biomarkers. Moreover, neuropathological series had shown AD pathology in 30 % of idiopathic normal pressure hydrocephalus (iNPH) patients. Objectives: To evaluate if CSF levels of Ab1–42, t-tau and p-tau181 are able to differentiate among different dementias and among different clinical, neuropsychological and neuroradiological phenotypes in order to give prognostic indications. To analyze a possible APOE e4 allele influence on CSF biomarkers. Methods: CSF biomarkers levels were measured in 10 subjects with mild cognitive impairment (MCI), 50 AD, including 18 with disease onset before age of 65 (early onset AD, EOAD), 23 fronto-temporal lobar degeneration (FTLD), 7 iNPH and 14 age-matched controls. Correlations with the presence of ApoE e4 allele, disease severity and different clinical, neuropsychological and neuroradiological phenotypes were evaluated. Results: Ab1–42 was decreased in AD versus controls and FTLD (P < 0.001), in MCI versus controls (P = 0.04) and in iNPH versus controls, FTLD (P < 0.001) and AD (P < 0.02). t-tau was higher in MCI, AD and FTLD than in controls and iNPH (P < 0.01). In AD p-tau181 was higher (P < 0.01) and Ab1–42/ p-tau181 ratio lower than in other groups (P < 0.01). Controls with e4 had higher levels of t-tau, and EOAD with e4 allele had higher levels of p-tau181 (P = 0.018). Positive correlation between t-tau and age was found in controls and FTD, while inverse correlation was present in AD patients (P = 0.01), with significantly higher levels in EOAD versus LOAD (P = 0.01). No correlation between biomarkers and clinical, neuropsychological or neuroradiological variables was found. Conclusions: This study confirms the usefulness of CSF biomarkers in AD and MCI diagnosis but not in phenotypical differentiation, except for age, suggesting an higher neurodegeneration rate in younger patients.An interaction between e4 allele and p-tau181 has been found in EOAD. e4 correlate with higher levels of t-tau in controls, suggesting that this allele could have a role in neurodegeneration also in healthy elderly. A specific CSF pattern (low Ab1–42, normal t-tau and p-tau181) can be hypothesized in iNPH patients.

O172 The effects of memantine in Alzheimer’s disease patients: a randomised, double-blind, placebo-controlled pilot study exploring the contribution of multimodal neuroimaging F. Fazekas, S. Ropele, B. Ebenbauer, M. Windisch, A. Stöffler, R. Schmidt Medical University Graz (Graz, AT); JSW Research (Graz, AT); Merz Pharma (Frankfurt, DE) Objective: The neuroprotective effect of memantine is well established in preclinical studies. We therefore aimed to evaluate the potential benefits of memantine on brain morphology and metabolism in patients with moderate to severe Alzheimer’s disease (AD) over one year using multimodal neuroimaging. Methods: In a double-blind, placebo-controlled, monocentric pilot study we randomized 37 patients to receive either memantine 20mg/day (baseline MMSE 18.7 ± 3.1) or placebo (baseline MMSE 19.3 ± 2.7). 32 patients completed the imaging evaluation after six months and 24 after twelve months. Outcome variables consisted of changes in whole brain and hippocampal volume, of changes in N-acetyl-aspartate and myoinositol as determined by magnetic resonance spectroscopy (MRS) and of changes in glucose metabolism shown by FDG-PET. Clinical outcome measures were ADAS-cog, ADCS-ADL and CDR. Results: All differences remained non-significant due to the small sample size of this pilot study. However, after one year, the memantine group showed less hippocampal volume loss than the placebo group (–2.35 % vs. –3.96 %). No such difference was detected for total brain volume (–2.31 % vs. –1.97 %). PET demonstrated less decrease of cerebral glucose metabolism in all investigated brain areas of the memantine group (total reduction –1.8 % vs. –3 %). MRS findings were inconsistent and showed neither a decline nor a trend for between group differences. Regarding clinical outcome variables memantine treated patients showed a numerical advantage over those on placebo treatment. Conclusions: This study shows the feasibility and potential contribution of multimodal neuroimaging in the investigation of possible morphologic and functional effects of AD drugs. Clinical effects of the study were consistent with previous results. Smaller loss of hippocampal volume in patients treated with memantine is in line with the suggested neuroprotective effect of memantine. A reduced decrease in glucose metabolism may also support beneficial functional effects. The study was sponsored by Dr. Kolassa and Merz pharmaceuticals O173 Progranulin gene mutation scanning in Italian Alzheimer’s disease population C. Fenoglio, D. Galimberti, F. Cortini, E. Venturelli, D. Scalabrini, I. Guidi, C. Villa, R. Del Bo, C. Lovati, C. Mariani, N. Bresolin, E. Scarpini University of Milan IRCCS Ospedale Maggiore Policlinico (Milan, IT); University of Milan Ospedale L. Sacco (Milan, IT) Objective: To perform a genetic screening of the Progranulin (PGRN) gene in Alzheimer’s disease (AD) patients in order to detect new pathogenetic variations. Subsequently, to carry out a case-control study for the known Single Nucleotide Polymorphisms (SNPs) with a frequency higher than 10 % to determine whether the presence of these variants influences the susceptibility to AD. Background: PGRN is 593 aminoacid secreted glycoprotein which is expressed in many tissues, including the Central Nervous System. Although its physiological function is not completely understood, it probably acts as a secreted growth factor involved in the regulation of multiple processes including tumorigenesis and inflammation. Furthermore, recent findings show that PGRN constitutes a major locus for Frontotemporal Lobar Degeneration with ubiquitin inclusions mapping to chromosome 17q21, close to the MAPT gene. Despite some evidence suggests that PGRN might be implicated in the susceptibility of a wider spectrum of neurodegenerative diseases including AD, so far genetic studies in AD are still lacking. Methods: Coding region for PGRN gene was screened by direct sequence in 40 AD patients. Preliminary case-control study was performed in 80 AD patients and 130 controls for rs 9897526, rs 850 713 and rs 5848 SNPs by allelic discrimination using an ABI PRISM 7000 instrument (ABI).Association was tested by using the Fisher’s exact test. Results: Two novel SNPs were detected by direct sequence in AD patients. Both of them are located in the flanking regions of exons 2 (IVS2+7G/A) and 7 (IVS7+7G/A) and involve a G to A change. One hundred and thirty controls were then screened for the same regions to confirm the results, thus leading to a frequency for these novel SNPs of 1 % and 3 % respectively in the Italian population.A slight tendency towards an increase of the frequency of rs 9 897 526 SNP was found in AD patients compared with controls (P> 0.05).

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Conclusion: PGRN is growth factor possibly involved in neuronal survival. It was shown that PGRN expression is increased in activated microglia in several neurodegenerative diseases including AD. This is the first attempt to investigate PGRN genetic variations in AD patients. Direct screening for sequence variation in the coding regions led to the identification of two novel variants which can possibly influence the protein splicing. However these results need to be confirmed in a wider population to draw definitive conclusions. O174 Frequency of memory impairment as an initial symptom in frontotemporal dementia S. Papageorgiou, T. Kontaxis, A. Bonakis, G. Karahalios, M. Nikaki, N. Kalfakis, D. Vassilopoulos Medical School, Athen’s University (Athens, GR) Background: Memory impairment is not included among the diagnostic criteria of Frontotemporal Dementia (FTD) (Neary, 1998), where FTD is defined as a behavioural dementia. However, some recent reports suggest that memory impairment can be one of the first symptoms of FTD. The aim of this study was to determine how often memory impairment occurs in the initial stage of FTD. Methods: From a total of 279 patients who were hospitalized for dementia diagnosis, in the Cognitive Neurology-Movement Disorders Unit, of our University Department, from 1/01/2004 until 31/12/2006, 29 patients (18 males and 11 females) were fulfilling the existing criteria of FTD.All patients had a comprehensive evaluation comprising blood and CSF studies, detailed assessment of cognitive functions and behavioural disturbances MRI and SPECT imaging studies. Information about the establishment of the symptoms prior to referral was systematically gathered from caregivers. Memory was considered as impaired according to the caregiver’s report, regardless of the suspected underlying nature of memory impairment (concentration deficit, forgetfulness, episodic memory or semantic memory deficit). Full data were documented for 27 patients, who were then subdivided in 2 groups, according to whether memory deficit was one of the first symptoms during the 1st year of the disease course (group M+) or not (group M-). Results: In 13 patients, memory impairment was found to be one of the initial symptoms, whereas in 14 patients memory disorders appeared after one year of the disease onset, (or not even until the patient’s referral in 8 patients). Statistical analysis with Student’s t-test revealed no differences between the 2 groups in terms of: gender, age at onset of the disease, MMSE scores, Neuropsychiatric Inventory scores, Frontal Behavioral Inventory scores and Clinical Dementia Rating Scale grade. The 2 groups differed significantly in terms of disease duration (p < 0.02). Patients in group M+ were referred after 2.0 years ± 1.16 of disease onset, whereas patients in group M- were referred after 3.6 years ±1.9 (mean ± SD) of disease onset. Conclusion: A memory deficit was one of the initial symptoms in 13 of our 27 patients (48.1 %) with FTD. These patients were referred for neurological evaluation earlier than patients without memory disturbances. Our results suggest that contrary to what is generally believed, memory disturbances are quite often encountered at the initial stages of FTD. O175 Frontotemporal dementia: patterns of clinical progression and predictive tools in a two-year follow-up study G. Tosto, G. Talarico, T. Sassun, I. Nofroni, E. Piacentini, F. Buttari, M. Canevelli, G. L. Lenzi, G. Bruno La Sapienza University (Rome, IT) Objective: Frontotemporal dementia (FTD) is a clinical syndrome characterised by profound changes in personality and social conduct, associated with prevalent degeneration of the prefrontal and anterior temporal cortex. There are conflicting results about the clinical progression of this dementia: Pasquier et al. (2004) reported a slower (half) mean annual MMSE score decline in FTD than in AD, while Rascovsky (2005), Chow (2006) reported a significantly more rapid decline (double) than AD. The present work consists in a historical cohort-study of FTD in order to assess if different pattern of clinical progression and predictive tools for FTD patients can be distinguished. Methods: 32 patients (13 men, 19 women) met the criteria for probable FDT (mild-moderate stage: MMSE > 18 points) according to the new consensus criteria.All patients were recruited at the “Memory Clinic” Unit – Department of Neurological Sciences and all underwent a neurological examination, multidimensional evaluation (MMSE, ADL, IADL), full neuropsychological assessment and MRI. Behavioural disturbances were

recorded through caregiver reports using NPI assessment. Patients had been followed at the “Memory Clinic” for a minimum period of two years and evaluated each 6 months. Mean annual MMSE points loss in FTD as reported by Pasquier (2004) was used to identify two patterns of progression: slow (≤ 2 points loss in 2 years) vs. rapid progression of cognitive decline (> 2 points loss). Results: We divided our population in two patterns of progression: slow (≤ 2 points loss in 2 years, n = 15) vs. rapid progression of cognitive decline (> 2 points loss, n = 17).Age of diagnosis and first symptoms, sex, education, NPI score were not correlated to the pattern of clinical progression through the observation time. Instead, a positive correlation between MMSE points’ loss in the first 6 months and in the first 12 months and MMSE points’ loss at the end of the follow-up period (24 months) (p < 0.01) was reported. Discussion: MMSE’s points loss throuout years in FTD can widely vary and this could explain the conflicting results of the literature. Slow or rapid progression of cognitive decline cannot be predicted by clinical features such sex, age, NPI, etc. Instead, MMSE points’ loss in the first period of clinical observation appear strongly associated with cognitive decline at twoyears follow-up. This results could be an useful tool for the clinicians when a diagnosis of FTD is made.

Oral session 26 Multiple sclerosis 4 O176 Correlation of subjective disturbances, clinical findings and “TremorAn” – computerised analysis of movement disorders in multiple sclerosis J. Koehler, J. Denzer, M. Dieterich, A. Faldum Asklepios Klinik Nord (Hamburg, DE); Johannes Gutenberg University (Mainz, DE) Objectives: Previously normative data were presented for “TremorAn”,a new computerized bedside test to analyse quantitatively movement disorders of the upper extremity. The aim of this study was to proof these findings in a large cohort of patients with definite multiple sclerosis in different stages of the disease by correlation of the test findings and subjective disturbances reported by the patients. Methods: Based on a tablet pc (Compaq Tablet PC TC1000) a individual software was used to analyse quantitatively movement of the upper extremities in 102 MS-patients (age 19–77, mean 43.5 y). The findings were categorized in three levels and correlated with four levels of severity reported by the patients. In addition clinical examination using EDSS and nine-hole-peg test were documented. For statistical analysis based on SPSS 11.0 chi-squareand Kruskal-Wallis test were used. Results: Correlation of computerized analysis of movement disorders and subjective disturbances were found (p = 0.005) as well as correlation of “TremorAn” findings and EDSS (p = 0.001) or nine-hole-peg test results (p = 0.003). Influence of other functional disturbances, i. e. weakness (p = 0.306) or sensory disturbances (p = 0.410) could not be found. Conclusions: The new computerized bedside test “TremorAn” with easy handling correlates with subjective functional disturbances of movement of the upper extremities in multiple sclerosis as well as EDSS and nine-holepeg test. Furthermore patients with abnormal “TremorAn” findings but without symptoms of the movement of the upper extremities point to non clinical signs detecting by “TremorAn”. This could be a tool for analysing prognostic factors in a early stage of disease. This study was supported by Schering Deutschland GmbH O177 Cognitive dysfunction is associated with “occult” structural brain damage in benign multiple sclerosis A. Pulizzi, M. Rovaris, E. Judica, G. Riccitelli, E. Perego, D. Caputo, A. Ghezzi, R. Capra, V. Martinelli, K. Kacar, G. Comi, M. Filippi Scientific Institute Ospedale San Raffaele (Milan, IT); Scientific Institute Fondazione Don Gnocchi (Milan, IT); Ospedale di Gallarate (Gallarate, IT); Spedali Civili (Brescia, IT) Objectives: To investigate magnetic resonance imaging (MRI) patterns underlying cognitive dysfunction in benign multiple sclerosis (BMS), as potential markers to identify those patients with a more severe “occult” disease burden.

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Methods: Conventional and diffusion tensor (DT) MRI scans of the brain were acquired from 38 BMS patients. Thirty-six secondary progressive multiple sclerosis (SPMS) patients and 15 healthy subjects (HS) served as controls. In BMS patients, neuropsychological tests exploring memory, attention and frontal lobe cognitive domains were administered. Normalized brain volume (NBV) was computed. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) were produced for the normal-appearing white matter (NAWM) and histograms of MD for the grey matter (GM). Results: Thirteen BMS patients (34 %) had cognitive impairment (CI). BMS patients without CI had significantly higher NBV and average NAWM FA than both BMS patients with CI and SPMS patients, but lower average NAWM FA than HS. BMS patients with CI had significantly lower NBV and average NAWM FA and significantly higher average NAWM/GM MD than HS. BMS patients with CI did not differ from SPMS patients for any MRI-derived quantity. Conclusions: In BMS, cognitive dysfunction is associated with an increased severity of conventional MRI-occult NAWM/GM damage, whose patterns may resemble those of more disabling disease phenotypes. The absence of locomotor impairment in BMS might be, at least partially, explained by more efficient compensatory mechanisms than in SPMS. O178 Age at onset in familial multiple sclerosis L. Romero-Pinel, L. Gubieras, S. Martínez-Yélamos, V. Casado, O. Carmona, E. Moral, L. Alonso-Magdalena, T. Arbizu Bellvitge University Hospital (Hospitalet de Llobregat, ES) Background: A familial aggregation in MS patients has long been accepted and a genetic implication in MS is nowadays well-known mainly due to the epidemiological studies performed. There are just a few studies of prevalence and clinical data of familial MS in our area. Objective: The first objective of this study is to describe the prevalence of familial MS in an MS unit. The second objective is to describe clinical factors of familial MS comparing with sporadic MS. Methods: We use the European database for MS (EDMUS) to register and prospectively follow-up our patients. This is an observational study in which we studied 1110 patients diagnosed of MS and followed in our MS Unit. The basal characteristics of this cohort showed a mean age at onset of the disease of 30.6 years (± 10.44) and a mean time from the onset to the moment of the study of 9.7 years (± 8.49). The rate of women was 60.5 %. The percentage of defined MS is 80.2 % considering Poser criteria. From this cohort we considered as familial MS those patients who have in their family at least one relative of first or second degree diagnosed of MS. Otherwise patients were considered sporadic MS. Results: Our results showed 87 of those 1110 patients with one or more relatives diagnosed of MS. Therefore the prevalence of familial MS in our cohort is 7.83 %. Those 87 patients belonged to 65 families with more than one familial member diagnosed of MS. From those 65 families, 8 had more than 2 members affected, 2 families had more than 3 members affected, one family had eight members affected from two different generations. Thirty-nine families had relatives of first degree affected, 31 families of second degree and 5 families of first and second degree simultaneously. Our study showed a significant lower age at onset of the disease in the familial MS comparing with the sporadic MS (28.4 years versus 30.8 years, p = 0.038). There were no differences in other clinical factors studied. Conclusions: The age at onset is lower in patients with familial MS comparing with sporadic MS. O179 Neutralising antibodies against interferon beta: persistence is titre dependent A. Sominanda, J. Hillert, A. Fogdell-Hahn Karolinska University Hospital Huddinge (Stockholm, SE) Objective: To assess fluctuations of neutralizing antibodies (NAbs) to interferon beta (IFN-b) over 12–36 months. The development of NAbs is a common phenomenon in treatment with IFN-b. At the group level, there is a clear correlation with efficacy measures such as relapse rate and new MRI lesions. However, NAb levels may vary over time, likely both due to factual variation and variability of methods used. Methods: Among 3,000 patients referred to a IFN-b NAb testing service, the titer levels of first and last samples were compared in all 501 patients who had been tested at least twice. NAb titres were assessed with the in vitro MxA induction test. In the initial sample 191 patients were NAb negative, 74 had low titres (10–49 TRU/ml), 39 medium (50–149), 50 high (150–599) and 121 very high titres (600-). Results: Mean time between first and last sample was 15.5 months. If the

first sample was negative or low, only 4 and 7 % respectively, had increased to the high and very high categories, i. e. to a level where in vivo response to IFN beta can be expected to be abolished, according to our previous findings. Patients whose initial sample was very high, 5 % reverted to titres low enough to expect a return of bioactivity. Patients, whose first sample was close to the functionally critical level (around 150 TRUs/ml) showed a higher tendency of migration across this level. Thus, when first samples were of medium titres, 16 % showed increased titres, whereas 22 % of patients with high titres reverted to a lower level. Conclusion: In spite of variability in biology and methodology, NAb titres are relatively stable over 12–36 months. Only patients close to the functionally critical NAb levels, have a substantial chance of losing or regaining bioactivity. O180 Diagnostic certainty in patients referred for a possible MS diagnosis: results after 7 years of follow-up J. M. Nielsen, B. M. J. Uitdehaag, C. H. Polman VU University Medical Centre (Amsterdam, NL) Introduction: From existing diagnostic guidelines for MS there is limited long term information on patients initially referred for a potential MS diagnosis, but not diagnosed as such. Patients used to evaluate these guidelines exist in selected populations where CIS patients with an atypical presentation and patients in whom another diagnosis is made are excluded from analysis. We report on a group of patients from a larger cohort in whom no certain diagnosis could be made in a tertiary referral centre for MS. These patients were referred by a certified neurologist and can be considered “diagnostically difficult cases”. In this group we retrieved information to find diagnoses that had not been made initially and aimed to find red flags in order to improve the diagnostic process in future cases. Patients and methods: From 1998 to 2001 754 patients were referred to our MS centre for a second opinion. 377 patients were referred concerning an MS diagnosis. In 87 cases no certain other diagnosis could be made. These patients were contacted by phone and if necessary and the patient consented additional information was requested from the general practitioner or consultant concerning their diagnosis. Results: 75 (86 %) patients consented, 5 patients were lost to follow up and 7 patients did not want to cooperate. The mean follow up duration of these 75 patients was 6.9 years. In 60 (80 %) patients no other diagnosis had been made in the meantime, although the cause of their complaints was thought to be neurological in 16 (21 %). In 8 out of 75 (11 %) patients another diagnosis was made. In 7 out of 75 (9 %) cases a demyelinating disease (in 6 cases MS) was diagnosed. Conclusion: After 7 years of follow up, in the vast majority of initially undiagnosed patients still no other definite diagnosis was made. In the remaining cases eventually a definite diagnosis was made. This was either a demyelinating disease or another neurological diagnosis. The MS Centre at the VUmc is funded by a program grant of the Dutch MS Research Foundation. O181 Severity of spinal cord atrophy is moderately related to severity of brain MRI measures in patients with multiple sclerosis R. Zivadinov, V. Yella, J. L. Cox, N. Abdelrahman, S. Hussein, M. G. Dwyer Buffalo Neuroimaging Analysis Center (Buffalo, US) Background: Spinal cord atrophy may contribute significantly to physical disability in subjects with multiple sclerosis (MS), and this contribution may be independent of the severity of brain MRI metrics. Objectives: To explore the relationship between spinal cord atrophy and multiple brain MRI measures of inflammation and neurodegeneration in patients with MS. Methods: We studied 55 MS patients (age 45.9 years, disease duration 13.7 years, EDSS 3.3) and 11 patients with clinically isolated syndrome (CIS). Disease course was relapsing-remitting (RR) = 34, secondary-progressive (SP) = 14 and primary-progressive (PP) = 7. Spinal cord volume (SCV) was measured on 3D-T1-weighted cervical spinal images obtained via 1.5T MRI. The following brain measures were calculated: T2- and T1-lesion volume (LV), number of Gadolinium lesions, normalized volumes of whole brain, gray and white matter, magnetization transfer ratio (MTR) of whole brain, normal appearing white and gray matter and brain tissue, and whole brain mean diffusivity and entropy. Correlation and regression analyses, adjusted for age, were used to explore the interaction between SCV and brain MRI measures. Results: In MS patients, lower SCV correlated with lower normalized brain volume (r = 0.31, p = 0.021) and higher DWI entropy (r = –0.29,

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p = 0.045) and T1-LV (r = –0.27, p = 0.47). CIS patients did not show any correlation between SCV and brain MRI measures. In both groups, correlation and regression analyses showed an inverse relationship between a higher number of Gd lesions and increased SCV (p < 0.001). In PP patients, decreased SCV showed strong a relationship with decline in cortical volume (R2 = 0.79. p < 0.0001). Conclusions: Patients who presented more acute inflammatory disease (as evidenced by a higher number of Gd lesions) had less spinal cord atrophy. In RR or SP MS, there is only moderate correlation between a decrease in SCV and severity of brain non-conventional MRI measures. In PP MS, neurodegeneration probably occurs simultaneously in the spinal cord and brain.

Oral session 27 General neurology 2 O182 Lambert-Eaton myasthenic syndrome: differential reactivity of tumour versus non-tumour patients to subunits of the voltage gated calcium channel H. L. Pellkofer, L. Armbruster, M. Krumbholz, J. J. Verschuuren, F. Schumm, R. Voltz Institute of Clinical Neuroimmunology (Munich, DE); Leiden University Medical Center (Leiden, NL); Clinic for Neurology and Neurophysiology Christophsbad (Goppingen, DE); University of Cologne (Cologne, DE) Objectives: Lambert-Eaton myasthenic Syndrome (LEMS) is an autoimmune disease in which the transmission across the neuromuscular junction is disturbed by autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels (VGCC). LEMS is paraneoplastic (T-LEMS) in about 60 % of patients mostly associated with a small cellular lung carcinoma (SCLC), but occurs spontaneously without a tumor in 40 % (NTLEMS). In most cases neurologic symptoms appear before tumor diagnosis, but there is as yet no specific serologic marker to distinguish between NTand T-LEMS. To see whether antibodies from patients with NT- and T-LEMS differentially recognize antigenic sites of the alpha 1A subunit of P/Q-type VGCC, we studied serum samples from T-LEMS and NT-LEMS patients assuming that the extracellular localisation of these regions have a potential accessibility to circulating antibodies. Methods: To search for immunodominant sites in the molecular structure of VGCC, we recombinantly expressed the extracellular S5-S6 linker segments in three of the four domains forming the alpha 1 subunit of P/Q-type VGCC. Sera reactivity of 22 T-LEMS patients, 24 NT-LEMS patients, and 9 healthy control donors were tested on these proteins by western blot analysis. Results: Sera from 9/24 (37.5 %) NT-LEMS patients, but only 1/22 (4.55 %) T-LEMS patients and 1/9 (11 %) healthy donors recognized domain IV by western blot. There was a significant difference between NT- and T-LEMS patients (p = 0.011) determined by Chi-square test and Fisher’s exact test. Seroreactivity to domain I and III was similar for NT-LEMS and TLEMS patients (domain I: 8 % / 14 %; domain III: 46 % / 41 %), but was absent in healthy control donors. Conclusion: We demonstrated that serum antibodies in LEMS usually targeting the alpha1 subunit of PQ-type VGCC are differentially directed against the S5-S6 linker of the domains I, III and IV of the alpha1 subunit. These data suggest that an antibody response to domain IV is more common in LEMS without tumor than in paraneoplastic LEMS. This may have implications for diagnostic workup in LEMS patients without previously established diagnosis of a tumor.

O183 Better use a mirror to evaluate eye tracking in post-comatose states A. Vanhaudenhuyse, C. Schnakers, S. Brédart, S. Majerus, G. Moonen, S. Laureys for the Coma Science Group Objectives: Following severe acute brain damage, some patients evolve from their coma to a vegetative state (VS; ie wakefulness without awareness). The VS can be a transient condition on the route to further recovery or it can become an irreversible condition.VS patients who recover, classically transit in a minimally conscious state (MCS). One of the first clinical signs observed in patients evolving from VS to MCS is eye tracking. We here studied 3 validated means to assess eye tracking by employing a moving mirror, a moving person or a moving brightly coloured object. Method: We tested 31 MCS patients who showed eye tracking of their own mirror-image (21 were men; mean age was 63 years; range 21–84 years). Aetiology was traumatic in 15 and non-traumatic in 16 patients (ischemic or hemorrhagic stroke (n = 8), anoxic (n = 6), metabolic encephalopathy (1 patient), and intoxication (1 patient)). Twenty patients were studied in the acute setting (ie, within 4 weeks following brain insult; mean 16 days; range 3–24 days), and 11 were studied in a chronic setting (ie, more than 4 weeks after the insult; mean 5 months; range 28 days to 3 years). All patients were assessed free of sedative drugs or neuromuscular function blockers. Mirror tracking was assessed in 3 standardized ways: (1) using a moving mirror as described in the Coma Recovery Scale-Revised (CRS-R; Giacino & Kalmar, 2004); (2) using a moving person as described in the Wessex Head Injury Matrix (WHIM; Shiel, Horn et al., 2000); or (3) using a moving object as also described in the WHIM. Results: In MCS patients who showed visual pursuit using a moving mirror, 10/31 (32 %) failed to show eye tracking using a moving person (4 traumatic and 6 non-traumatic; 7 acute and 3 chronic patients); 13/31 (42 %) failed to show eye tracking using a moving object (8 traumatic and 5 nontraumatic; 7 acute and 6 chronic patients). Conclusion: Our data emphasize the importance to employ auto-referential stimuli (ie the patient’s own mirror reflection) when assessing eyetracking in severely brain-damaged coma survivors. Funded by University of Liège Concerted Research Action – Neuroscience, cognitive psychology and psychopathology of self-processing and EU Marie Curie Training Networks Disorders and Coherence of the Embodied Self (DISCOS).

O184 Multipotent mesenchymal stromal/stem cells in experimental neurology: safety considerations P. Connick, D. P. J. Hunt, S. Chandran, D. A. S. Compston University of Cambridge Centre for Brain Repair (Cambridge, UK); University of Cambridge Department of Clinical Neurosciences (Cambridge, UK) Introduction: Neurology is now embarking on clinical trials using systemically delivered ex vivo expanded multipotent mesenchymal stromal cells (MSCs) in a variety of settings. Clearly, careful and rigorously conducted experimental medicine in this context is to be welcomed, but due caution is required. We review the relevant clinical experiences of safety from other disciplines and make the case for a coordinated approach to maximise the benefit from these early studies. Objective: To summarise the existing safety experiences across disciplines of systemically delivered MSC applications. Methods: A systematic review of published literature. Searches of Medline and Pubmed from 1966 until January 2007 were performed for the terms “human mesenchymal/marrow stem cell transplantation”, “human mesenchymal precursor cell transplantation” or “multipotent mesenchymal/ marrow stromal cell transplantation”. Studies reported in abstract form were not included. Results: Twelve studies have been published since 1995. Of 136 patients receiving systemic MSC treatment 100(73 %) had underlying neoplastic disease, 5(4 %) had neurological disease (stroke) and 31(23 %) had other conditions. Median age of recipients was 33 years (Range 2–72 years), 56 % were female. Of 151 administrations given, 65(43 %) were autologous and 86(57 %) allogeneic. Failure of cell expansion occurred in around 5 % of samples. Immediate clinical adverse events suggestive of type I hypersensitivity were seen in approximately 5 % – likely reflecting a response to animal constituents of growth media. No long-term adverse events have been recognised however the severity of underlying disease and toxicity of concomitant treatment make it impossible to discern MSC attributable adverse events, and longest reported follow up is limited to 2 years. Conclusions: Systemic MSC transplantation is feasible and relatively safe in the short term, however the long-term risks are undefined. Patients with neurological disease to be considered for MSC therapy will have a longer life

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expectancy and fewer comorbidities than the cohort of patients who have been treated to date. A coordinated approach to research activity will yield improved safety data on which more accurate future risk/benefit analyses can be based. We propose the centralised collection and publication of adverse events and safety data for patients with neurological disease who undergo treatment with MSCs. O185 A large cohort study of age-related damage to white matter fibre bundles F. Agosta, E. Pagani, M. Filippi Scientific Institute Ospedale San Raffaele (Milan, IT) Objectives: To investigate the influence of normal aging on white matter (WM) fiber bundles. Methods: We used an adaptive bases algorithm for FA-based non rigid deformation and a voxel-based approach to investigate the WM diffusivity alterations from 84 healthy subjects, spanning seven decades of life (mean age = 44 years, range = 13–70 years). The healthy subjects were grouped as follows: 11–20 year group (10 subjects), 21–40 year group (24 subjects), 41–60 year group (34 subjects), 61–70 year group (16 subjects). An analysis of variance was used to perform the between-group comparisons, with a significance threshold set at p < 0.05 (corrected for multiple comparisons). Age was entered into the SPM design matrix to assess the correlation with diffusivity abnormalities, using basic models and linear regression analysis. Results: Compared with 11–20 year group, 21–40 year group did not show significant cluster of locally decreased fractional anisotropy (FA), while 41–60 year group had a significant decreased FA in the left (L) corticospinal tract. Compared with 21–40 year group, 41–60 year group had a significant cluster of locally decreased FA values in the body of fornix. Compared with 11–20 and 21–40 year groups, 61–70 year group showed significant clusters of decreased FA in the following tracts bilaterally: corticospinal tract, fronto-parietal callosal fibers, cingulum, body and posterior columns of fornix, optic radiation, fronto-occipital connections, uncinate fasciculus. In 61–70 year group contrasted to 41–60 year group, we found significant clusters of decreased FA in the L frontal callosal fibers, in the frontal fibers of the L cingulum, in the right (R) posterior column of fornix, and in the R fronto-occipital connections. The between-group comparisons showed a concomitant significant increase of mean diffusivity (MD) values in all the same regions shown by FA contrasts. Age strongly correlated with MD and FA of all the considered WM fiber bundles (r values ranged from –0.51 to –0.79). Conclusions: This study, performed on a large cohort of healthy subjects, provide direct evidence that a widespread WM tract damage occurs with normal aging. The impairment of the neural networks seems to start early and involve WM fiber bundles subserving either cognitive and motor performance. Age-related structural changes of the WM integrity might underlie decline in function. O186 Transitory vegetative state at the intensive care unit: does it exist? D. Ledoux, S. Piret, P. Damas, G. Moonen, S. Laureys CHU ULg Sart Tilman (Liège, BE) Introduction: Vegetative state (VS) is often considered as a chronic condition. However VS is a disorder of consciousness that can be acute and reversible. The aim of the present study was to provide a description of VS at the acute stage and to examine the outcome of these patients. Methods: We analysed data collected prospectively on all consecutive admissions over a 5 years period in a 26 beds intensive care units (ICU) at the Liege university hospital. During that period of time the best Glasgow Coma Score (GCS) was recorded daily. Patients with a GCS < 15 during the first 24hour of ICU stay were included for further analysis. Among these patients VS was defined as: eye opening (spontaneously or induced by intense auditory or noxious stimulation), no verbal response or incomprehensible sounds or groaning or not assessable/ventilated and no motor response or stereotyped response or normal flexion.We looked at ICU outcome and hospital survival separating traumatic from non-traumatic aetiologies. Results: Over the 5 years period, 5908 patients were admitted to the ICU. Among them, 631 (11 %) suffered from impaired consciousness on admission. During their ICU stay, 56 % (n = 356) of ICU patients with impaired consciousness were diagnosed VS. Of the 356 VS patients 99 (28 %) patients died in the ICU, 55 (15 %) remained VS on discharge and 200 (56 %) patients left the ICU having recovered consciousness or minimal consciousness. Among these 200 patients, 118 were oriented and could obey command (59 % of good outcome), 68 (34 %) patients were confused or had inappropriate words and 14 (7 %) only localised pain. Of the 356 VS patients, 129

(36 %) were due to traumatic (TBI) and 227 (64 %) non-traumatic (NTBI) brain injuries. On ICU discharge 90 (70 %) of the TBI patients as compared to 82 (36 %) of the NTBI patients recovered some level of consciousness (p < 0.001). Hospital mortality was 19 (15 %) in TBI and 110 (48 %) in NTBI (p < 0.0001). Conclusion: Acute VS is far from being a rare clinical entity in the ICU. The prognosis of patients who are or transit through an acute VS depends greatly on the nature of the brain damage. However even in non-traumatic brain injury, an important proportion of patients showed some degree of recovery. End of life limitation in the acute setting in these patients should be considered with caution. The challenge is to identify para-clinical prognostic markers for these devastating neurological conditions. Fonds National de la Recherche Scientifique. O187 Colony stimulating factors stabilize the permeability barrier in a human blood-brain barrier in vitro model – implications for treatment of neurological diseases J. Kraus, M. Hoppen, K. S. Kim, M. Schilling, P. Oschmann, W. R. Schäbitz Paracelsus Private Medical University (Salzburg, AT); University Hospital of Munster (Munster, DE); Johns Hopkins University School of Medicine (Baltimore, US); University Hospital of Giessen and Marburg (Giessen, DE) Objective: To investigate whether granulocyte-colony stimulating factor (GCSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) exert direct effecst in a human in vitro blood-brain barrier (BBB) model. Background: BBB breakdown is an important event in the pathogenesis of several diseases of the central nervous system (CNS) such as multiple sclerosis (MS), brain tumours but also stroke. G-CSF and GM-CSF have been approved for the treatment of leukocytopenia. Moreover, G-CSF was shown to be effective in a murine model for cerebral ischemia. The positive outcome was attributed to anti-neurodegenerative and neuroprotective effects. It was also suggested that G-CSF additionally has a stabilizing effect on the BBB. Methods: In order to investigate whether G-CSF and GM-CSF exert direct effects on the BBB, we applied an in vitro BBB model where immortalized human brain microvascular endothelial cells (HBMEC) in co-culture with rat astrocytes form a tight permeability barrier for 3H-inulin and 14Csucrose. Results: Addition of both G-CSF and GM-CSF to the co-culture system led to a further reduction of the permeability for 3H-inulin and 14C-sucrose across the HBMEC monolayers in a dose dependent manner. Moreover, with our in vitro model we mimicked a pathophysiological condition which has been suggested to contribute to the breakdown of the BBB in CNS diseases: Withdrawal of the astrocytes from the co-culture (to mimic changes in the microenvironment) led to an increase in the paracellular permeability across HBMEC monolayers. Pretreatment with G-CSF and also GM-CSF prevented the modulation of the BBB after withdrawal of astrocytes from the co-culture. Conclusion: Our data demonstrate that G-CSF and GM-CSF exert direct effects on human cerebral endothelial cells leading to a direct stabilization of the barrier function in vitro including a prevention of BBB modulation by a possible pathophysiological condition. Moreover, G-CSF and GM-CSF revealed to have almost the same effects in our in vitro model as we found for IFN-beta. This direct effect on the BBB in combination with its anti-neurodegenerative and neuroprotective effects could be a hint that G-CSF or GM-CSF are possible candidates for conditions with BBB disruption such as MS, brain tumours or ischemic stroke. The study was supported by a project grant from the Innovative Medizinische Forschung (IMF) Program Munster.

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Oral session 28 Headache O188 Selective damage of the visual pathways in patients with migraine: a magnetic resonance tractography study at 3 T M. Rocca, E. Pagani, P. Tortorella, B. Colombo, A. Falini, G. Scotti, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, IT); IRCCS San Raffaele (Milan, IT); CERMAC (Milan, IT) Background: Using diffusion tensor (DT) magnetic resonance imaging (MRI), subtle abnormalities have been disclosed in the normal-appearing brain tissue of patients with migraine. At present, however, the exact location of these abnormalities in specific brain pathways has not been investigated, yet. Objectives: We used a 3T MRI scanner and MR tractography to quantify the involvement of selected brain pathways in patients with migraine and their relation with patients’ demographic characteristics, clinical manifestations of the disease, and extent of T2-visible lesions. Methods: Using a 3 Tesla scanner, dual-echo (DE) and diffusion tensor (DT) MRI (with diffusion gradients applied in 32 non-collinear directions) were acquired from 16 patients with migraine and 15 matched controls. Using DT MRI tractography, probability maps for the corticospinal tract, the corpus callosum and the optic radiation (OR) were constructed from healthy volunteers data and then applied to DT-derived maps of patients.Then mean diffusivity (MD) and fractional anisotropy (FA) histograms of these tracts were derived. Results: Compared with healthy controls, migraine patients had significantly reduced average FA (p = 0.01) and FA histogram peak location (p = 0.02) and increased MD histogram peak location (p = 0.04) of the OR. No abnormalities were found in the remaining pathways. Patients with aura had significantly lower average FA of the OR than both controls (p = 0.01) and patients without aura (p = 0.05). Compared with controls, they also had increased MD histogram peak location (p = 0.04) of the OR. In migraine patients, no correlation was found between OR abnormalities, age and T2-visible lesions load. Conclusions: DT MRI abnormalities in patients with migraine are likely to have a regional rather than a diffuse distribution. The demonstration that these abnormalities are more pronounced in patients with aura supports cortical spreading depression as their possible cause. O189 Blood pressure changes in migraine patients before,during and after the attack Y. Secil, C. Unde, Y. Yetimalar, Y. T. Bozkaya, F. Ozerkan, M. Basoglu Ataturk Education and Research Hospital (Izmir, TR); Ege University Medical School Hospital (Izmir, TR) Objectives: Autonomic dysfunction is observed in migrane patients and it is reported in many fMRG and PET studies that during migrane attacks autonomic disfunction is accoimpanied by activation of contralateral locus cereleus,dorsal pontine area,dorsal raphe nucleus.These cerebral areas have significant roles in formation and calibration of blood pressure and cerebral perfusion. Considering coexistence of migrane and autonomic dysfunction, in this study we investigated blood pressure changes of migrane patients during the migraine attacks. We focused on blood pressure change during, before and after six migrane attacks of migrane patients with and without aura who do not suffer from hypertension to figure if there is a blood pressure change triggered by the attack. Methods: Out of sixty-two patients included in the study, 23 have aura and 39 do not have aura (57 female, 5 male-mean age 32.9). Blood pressure values of patients who are not treated for migraine prophylaxis, without any known hypertension and no hypertensive values recorded in 24 hours blood pressure Holter monitoring, without any other health problems were recorded during six subsequent attacks. Blood pressure values right before, during and 1 hour after the attack for 6 attacks are collected. Results: We could not find any statistically significant hypertensive values. It is observed that presence of aura or sex difference did not have an impact on blood pressure values. Even though it was not statistically significant, we interestingly observed hypotensive changes of blood pressure before, during and after the atatcks (6.63 %). Conclusion: To our best knowledge, there is no other study that considering blood pressure changes during the attack in the literature. This study

displays the possibility of systemic autonomic changes during migrane attacks as well as better visibility of hypotensive values compared to hypertensive ones. Causes of this might be vasodilatatory effect of serotonin released during attack, vasodilatatory effect of calcitonine gene related peptide or low level of norepinephrine during attack.. Further reserch on this matter would contribute to the literature O190 S218L CACNA1A mutation in hemiplegic migraine: a cerebral vulnerability? S. Debiais, I. Bonnaud, C. Hommet, A. Autret CHRU Bretonneau (Tours, FR) Background: Hemiplegic migraine is usually familial (FHM) and inherited as an autosomal dominant trait, and more rarely sporadic (SHM). So far, mutations of 3 genes, associated with different phenotypes, have been reported in FHM, in half cases concerning the CACNA1A gene. Objectives: To describe a severe sporadic HM related to a S218 L mutation of the CACNA1A gene, constituting a new genotype-phenotype correlation. Patient: A 21-year-old pregnant woman with a medical background of migraine with aura and epilepsia, developed a severe and prolonged HM attack and was admitted in the intensive care unit with headache, left motor deficit, coma and fever. Methods: Electroencephalography (EEG), magnetic resonance imaging, analysis of the CSF and blood examinations, genetic screening for genes involved in FHM. Results: The EEG showed prolonged delta waves in the right hemisphere, the MRI with diffusion weighted sequences were normal, as the blood and CSF examinations. Genetic screening demonstrated a S218L mutation in CACNA1A gene. Conclusion: We reported the first case of S218 L mutation associated with a severe form of SHM with childhood manifestations and prolonged auras. The phenotype may result from a low threshold of cortical spreading depression due to functional disorders in the neuronal calcium channel. O191 Migraine and atrial septal abnormalities in young patients with cryptogenic stroke P. Martinez-Sanchez, L. Idrovo, L. Gabaldon, J. Fernandez, M. Ortega-Casarrubios, B. Fuentes, E. Diez-Tejedor Hospital Universitario La Paz (Madrid, ES) Introduction: Patent foramen ovale (PFO) is more frequent in migraine patients and is a cause of brain infarct among patients under 55 years old. Our goal is to study the association between PFO and migraine in ischemic stroke patients under 55 years old. Methods: Observational study with inclusion of consecutive stroke patients admitted to a Stroke Unit (1995–2005). We selected patients under 55 years of age with first-ever acute cerebral infarction of cryptogenic origin. Demographic data, vascular risk factors, stroke vascular territory, stroke severity, the presence of PFO and/or atrial septal aneurysm (ASA) in echocardiography and functional status at discharge by the modified Rankin Scale score [mRS]) were analysed according to previous migraine. Results: From a total of 396 patients under 55 years old with a first-ever acute stroke, 130 had a cryptogenic cerebral infarct. Of them, 76 were males. The 13.8 % had previous migraine, the 3.9 % among male and the 27.8 % among female (P < 0.001). Migraine patients were younger than non migraine ones (P = 0.041) and had a higher frequency of vascular risk factors (not significant, NS). Stroke severity and functional status at discharge were similar in both groups. Previous history of migraine was associated to FOP plus ASA (Odds Ratio = 5, 95 % CI, 1.422 to 17.580) and this association was higher in female (33.3 % vs. 0 %, NS). Conclusions: Previous migraine is more frequently associated to double interatrial septal abnormality -PFO plus ASA- in cerebral infarct patients under 55 years old. This association could be higher in women. O192 Spontaneous intracranial hypotension with deep brain swelling L. Chiapparini, L. Farina, L. Minati, T. De Simone, D. Aquino, E. Mea, G. Bussone, M. Savoiardo Fondazione Istituto Neurologico C. Besta (Milan, IT) Objectives: To report MRI findings and mean diffusivity measurements in 5 cases of severe spontaneous intracranial hypotension (SIH) with swelling of deep brain structures. In SIH, MRI is mainly characterized by brain sagging,

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post-contrast pachymeningeal enhancement, and subdural collections. In a few cases, very severe brain sagging through the tentorial notch leads to deformity and swelling of diencephalon and midbrain, with absent or scarce subdural fluid collections and dural enhancement. In these cases, obtundation or coma due to dysfunction of diencephalo-mesencephalic structures may occur. Methods: In a review of our 90 cases of SIH we identified 11 patients with these peculiar features (SIH with brain swelling = SIH + BS), for which we suggest a particular pathogenetic mechanism.We studied 5 of these patients with MRI and DWI. The brain appeared slightly swollen with very thin third ventricle, displaced caudally. The midbrain was deformed, as if squeezed under the tentorium, and elongated. Slight T2 hyperintensity was present.ADC values were compared with those measured in 7 other patients with SIH without BS and in 10 controls. In the hypothesis that central herniation might be responsible for venous stagnation because of impaired blood flow at the angle between the vein of Galen (vG) and the straight sinus (SS), this angle was measured in 11 patients with BS, 12 with SIH without BS, and 10 controls. Results: In areas draining into the deep venous system, collected by vG and SS, ADC values were slightly elevated in SIH + BS cases in midbrain, thalami and basal ganglia (ANCOVA, p < 0.05). The values were higher in patients with BS compared to those without BS only in the midbrain (p < 0.04). The angle was grossly decreased in patients with SIH + BS (41°, versus 68° and 73°, respectively; p < 0.001). Conclusion: The swollen aspect of diencephalo-mesencephalic structures observed in SIH with severe brain sagging, might be due to a slight degree of vasogenic edema probably related to venous congestion resulting from functional stenosis at the vG/SS junction caused by downward stretching of the vG. The occurrence of deep brain swelling shows that the invariability of brain volume, as generally accepted in the application of the Monro-Kellie doctrine to SIH, may have some exceptions: small increases in brain volume may occur, with the effect of compensating for the loss of volume of CSF. O193 Headache attributed to spontaneous intracranial hypotension in a large population E. Mea, L. Chiapparini, M. Savoiardo, G. Bussone, M. Leone Istituto Carlo Besta (Milan, IT) Objective: Early recognition of spontaneous intracranial hypotension (SIH) may avoid dangerous worsening due to delayed diagnosis. Orthostatic headache is the main symptom in SIH and may be of great help in the early diagnoses of the syndrome. Our aim was to report on headache characteristics in 90 consecutive patients referred at our centre and diagnosed as SIH. Methods: Patients ere referred to our Institution between 1993 and 2006: 55 (61 %) women, mean age 45 years (range 15–71). The International Headache Society (IHS) criteria for headache attributed to SIH were applied. Brain enhanced MRI confirmed the SIH diagnosis in all patients. Headache characteristics were obtained by direct semistructured interview; in a minority of cases detailed information on headache characteristics was retrospectively obtained through phone call. Results: All SIH patients suffered from headache. In 57 (63 %) patients the headache worsened within 15 minutes and in 12 (13 %) worsened 15 minutes after standing position. In 20 (22 %) patients, the headache was not related to position. Nine (32 %) out of the twenty-eight patients who underwent blood patch (BP) improved. Only 3 patients (3 %) fulfilled the IHS criteria for headache attributed to SIH. Conclusions: This study shows that the IHS criteria did not allow to properly diagnose many of our SIH patients. This seems mainly due to the fact that many patients did not receive nor improve after BP. A revision of these criteria may be necessary. O194 Prevalence of tension-type headache and migraine among employees of a Swiss University hospital, impact on disability, headache management and economic impact for the employer E. Sokolovic, R. Agosti MPH (Zurich, CH); Hirslanden (Zurich, CH) Objectives of this cross-sectional, observational study were to measure the prevalence of tension–type headache (TTH) and migraine among the employees of the large Swiss University hospital, to assess the migraine management (particularly the exposure to triptans), to measure the headacheand migraine-related disability by measuring the quality of life, and to make an estimation of economic implications by measuring the indirect costs of the disease.

Methods: A self-completed questionnaire was sent to 2000 randomly chosen employees of the University hospital. Results: 1210 employees (60.5 %) responded, but only 397 men and 795 women provided information on age and gender. Of the 1192 employees who provided sufficiently complete information, 723 (61 %) reported having had at least one headache in the three months before completing the questionnaire. The classification of the main type of headaches, using the IHS criteria, showed that 217 (18 %) of the 1192 respondents had a migraine headache, 438 (37 %) had TTH, and 68 (6 %) other type. Regarding the occupational groups, the health care-staff suffered more headache (p = 0.031) than other employees, irrespective of the type of headache and gender. Of the 690 who suffered from any type of headache, 221 (32 %) did not take any, 305 (44 %) consumed over-the-counter (OTC) preparations and 164 (24 %) prescription dugs. The economic consequences of productivity loss may equal approximately 1.3 million CHF, representing 0.3 % of the overall annual personnel expenditure of the hospital. Conclusion: TTH and migraine are highly prevalent conditions among University hospital employees, with significant impact on the society. The study was supported by a grant from GSK.

Oral session 29 Epilepsy and sleep disorders O195 Risk factors for seizure-related traffic accidents in drivers with epilepsy. Preliminary results V. Houliara, P. Polychronopoulos, A. Zisis, A. Argyriou, E. Chroni University of Patras (Patras, GR) Objectives: In order to identify possible risk factors for traffic accidents (TA) due to seizures, we compared patients who had TA during seizures to patients with epilepsy who drive but did not have TA. Methods: Thirty-five patients (29 men, 6 women, mean age 37) with nonrefractory epilepsy, who continued to drive after the diagnosis of epilepsy, despite the driving restrictions being valid in Greece for people with epilepsy, were enrolled. They were identified prospectively from the epilepsy outpatient clinic of our Institution.Seizure etiologies and types were defined according to ILAE classification schemes. The following data were collected from the patients’ and relatives’ reports and cross-checked with the medical files of our epilepsy monitoring unit.: Patient data: age, sex, presence of comorbidity, socioeconomic status, education. Epilepsy variables: seizure types, age of onset, etiology, frequency, time from last seizure, presence and reliability of auras, anti-epileptic drug compliance. Driving practice: driving purpose, road types, hours per week and years of experience. TA variables: number of crashes due to seizures, provoking factors (sleep deprivation, alcohol), presence of aura, number of cars, passengers involved and injuries, severity of vehicle damage. Results: Fourteen patients (40 %) had TA or last-moment avoiding accidents during seizures. The group of these patients, as compared to the remaining 21 patients did not differ in mean age, sex, socioeconomic status or education,drug compliance,hours per week and years of driving experience. Eleven patients who actually had a crashed caused a total of 19 non-fatal car accidents during seizures. The driver, but not the passengers, was injured in 4. Seizure type was the only factor that was significantly different between the two groups (x2 test, p = 0.05). In the group of 14 patients with TA, 5 had complex partial (vs. 2 in the group of 21 patients without TA), 6 secondary generalized (vs. 10), 2 simple partial (vs. 1) and 1 idiopathic generalized seizures (vs. 8). Having reliable auras and long seizure-free interval did not reduce patient’s possibility of crashing. Idiopathic generalized epilepsy was not contributed to TA. Conclusion: Our preliminary results suggested that seizure type, especially complex partial or secondary generalized tonic-clonic seizures should be considered when consulting patients with epilepsy on driving risks.

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O196 Efficacy and tolerability of levetiracetam during one-year follow-up as addon therapy in patients with treatment-resistant generalised epilepsy E. Kkolou, A. Flourentzou, A. Malikkidou, G. Stylianidou, S. Papacostas The Cyprus Institute of Neurology (Nicosia, CY); Nicosia General Hospital (Nicosia, CY); Limassol General Hospital (Limassol, CY); Archbishop Makarios III Hospital (Nicosia, CY) Objective: We investigated the efficacy and tolerability of Levetiracetam (LEV) as add-on therapy in Cypriot patients with treatment- resistant generalized epilepsy. Methods: We retrospectively identified twelve patients ranging in age from 14 to 41 years old. Eight patients had symptomatic generalized epilepsy (SGE) and four patients had primary generalized epilepsy (PGE). The patients were studied for a 12-month period. Patients received LEV as add-on therapy to 2–6 (mean 2.4) anticonvulsants. We compared mean seizure frequency for a 3-month period prior to and 12 months after introduction of LEV. Maximum doses ranged from 1000 to 3000 mg daily. All subjects had physical and neurological examinations, routine baseline hematological, biochemical, and urinary investigations at entry. Results: Two patients (16.71 %) became seizure free. Four patients (33.3 %) had seizure reduction of by 75 % or greater. Two patients (16.7 %) had seizure reduction by 50 % or greater. Three patients (25 %) became worse and two of them discontinued the study. More than 50 % reduction in the number of their seizures was seen in 62.5 % of the patients suffering from SGE and in 75 % of the patients suffering from PGE. Efficacy was clinically apparent from the first trimester of treatment. Both seizure free patients required 1000 mg of LEV as daily adjunctive therapy. There was a decreased chance of the patients becoming seizure-free as the number of previously used AED’s increased. Reasons for discontinuation of LEV were either lack of efficacy (1 patient), adverse events (1 patient) or both (1 patient). The withdrawal range was 25 %. Side effects reported were: Sedation (2 patients), headaches (1 patient), dizziness (1 patient), weakness (1 patient), weight increase (1 patient) and behavioral discontrol (1 patient). No patient showed significant changes from baseline hematological, biochemical and urinary parameters. Conclusion: Our results show that LEV has efficacy in both symptomatic as well as in primary generalized epilepsy as seen by a significant reduction of seizures. 66.7 % of our patients with refractory epilepsy experienced a reduction of 50 % or more on their seizure frequency with the addition of LEV in their antiepileptic drug regimen during the twelve months of their evaluation. Levetiracetam was also well tolerated by the majority of our patients. O197 A hypothesis how non-REM sleep might promote seizures in partial epilepsies: a transcranial magnetic stimulation study F. Salih, R. Khatami, S. Steinheimer, R. Kretz, B. Schmitz, P. Grosse Charité-Universitätsmedizin Berlin (Berlin, DE); Universitätsspital Zurich (Zurich, CH) Objective: To investigate alterations of inhibitory and excitatory cortical circuits during NREM sleep in drug-naïve patients with partial epilepsies and sleep-bound seizures only. Methods: Paired-pulse TMS-paradigm was performed to test intracortical inhibition (ICI) and facilitation (ICF) in the hemisphere of the epileptic focus in three untreated patients with non-lesional, non-genetic frontal lobe epilepsy in NREM2 (n = 3 patients), NREM3/4 (n = 1), and wakefulness (n = 3). Results: All three patients exhibited major decrease of ICI in NREM sleep as opposed to the physiological enhancement of ICI with the progression of NREM sleep. Conclusion: Decreased ICI might reflect a substrate for the association of epileptic processes with thalamo-cortical networks that propagate sleep. Thus, our findings contribute to a hypothesis how NREM sleep could promote seizures. Ramin Khatami was partly supported by a GlaxoSmithKline-Scholarship O198 Active brain processes during human quiescent sleep: an EEG / fMRI study of non-REM slow oscillations T. Dang-Vu, M. Schabus, M. Desseilles, E. Balteau, C. Degueldre, S. Gais, C. Phillips, P. Maquet University of Liège (Liège, BE) Introduction and Objectives: Functional neuroimaging studies in humans have characterized non-REM sleep (NREM) as a stage of brain deactivation (1). However, NREM is dominated by slow oscillations, with alternating hy-

perpolarization and depolarization phases at the cellular level in animals. The depolarization (“up”) phases correspond to periods of intense neuronal firing. This implies that, at the macroscopic level in humans, NREM may not be a pure quiescent state but might show increased brain activations in the up state of slow oscillations. Using simultaneous electroencephalography (EEG) / functional magnetic resonance imaging (fMRI), we aimed at characterizing the regional cerebral activities during NREM and specific to slow oscillations. Methods: 26 non-sleep deprived, healthy, young subjects were scanned during the first half of the night in a 3Tesla fMRI scanner (echo-planar imaging sequence, 32 slices, repetition time = 2.46 s, echo time = 40 ms, voxel size = 3.4 x 3.4 x 3 mm3), with a continuous 64-channels EEG recording. After scanner and pulse artifact removal, NREM (stages 2–4) epochs and corresponding fMRI time series were selected. Slow waves were automatically detected on EEG epochs as in (2). The maximum negativity, chosen as the up state onset, was taken as event of interest for each detected slow oscillation. The analysis (conducted with the software Statistical Parametric Mapping 5 [SPM5]) looked for the brain areas in which responses were significantly correlated with the occurrence of slow oscillations (up states) across subjects. Results: 14 subjects slept and were used for analyses. Positive brain responses correlated to slow oscillations were found in the thalamus, medial prefrontal cortex, auditory cortex, hippocampus, brainstem and cerebellum. We found no significant negative brain responses. Conclusion: In keeping with our hypothesis, we show that the brain remains active during NREM, in phase with the slow oscillations, in a set of brain areas potentially involved in sleep oscillations mechanisms. Activations were also located in brain areas involved in the processing of declarative memories during wakefulness, further supporting the hypothesis that slow waves participate in the consolidation of memory traces during NREM. References 1. Maquet P. et al.: Functional neuroanatomy of human slow wave sleep. J Neurosci 1997; 17(8):2807–12 2. Massimini M. et al.: The sleep slow oscillation as a traveling wave. J Neurosci 2004; 24(31):6862–70 O199 Daytime REM sleep under high and low sleep pressure in narcolepsy patients and healthy controls E. Werth, R. Poryazova, R. Khatami, C. L. Bassetti University Hospital (Zurich, CH) Objective: The interaction between a circadian and a homeostatic sleepwake dependant process determines the occurrence of sleep and wakefulness as well as the sleep structure. REM propensity is high in the early morning hours. In the present study duration of REM sleep, REM latency and number of interventions to prevent REM sleep are used to explore REM regulation in narcolepsy patients and healthy controls under varying sleep pressure (SP). Methods: Ten HLA DQB1*0602 positive and hypocretin deficient patients (7/7) with narcolepsy-cataplexy (NC) and ten age, gender and body mass index matched controls (C) underwent a four session crossover sleepstudy protocol. There were two sessions with a night of sleep deprivation to increase the SP and 2 sessions with a 4 h night time sleep episode (23:00–3:00 h) to reduce SP, followed by daytime sleep (DS, 7:00–15:00). In two sessions (one with high and one with low sleep pressure) the subjects were repeatedly awakened during the first four hours of the DS episode to prevent REM. DS was undisturbed in the other 2 sessions. Group comparisons were based on t-tests. Results: The number of interventions (NOI) to prevent REM was higher in NC compared to C in both conditions (high SP, 26.5±12.8, resp. 10±4.4, p = 0.003; low SP, 26.2±10.1, resp. 12.9±5.5, p = 0.003). Different SP did not change significantly the NOI in NC, whereas in C a trend towards higher NOI under low SP was observed. The amount of REM in C (within the first four hours of undisturbed DS) was significantly higher under the condition of low SP compared to high SP (p < 0.001). In NC no significant differences were observed. Low SP shortened significantly REM latency in controls (p = 0.013). Nine NC and four C showed sleep onset REM (SOREM) under low SP. Under high SP again nine NC showed SOREM (the patients entering sleep in NREM being different for the two conditions) but only one C (same patient had also SOREM under low SP). Conclusion: We suggest that markers of REM sleep behave differently in NC and C, obeying the interaction between the circadian and the homeostatic regulating processes in C but not in NC. Suported by a Swiss National Foundation Grant

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O200 Observational study of 37 patients with restless legs syndrome L. Gabaldón, J. Fernández, M. J. Aguilar-Amat Prior, F. Vivancos, F. J. Arpa Gutiérrez La Paz Hospital (Madrid, ES)

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Objectives: Restless legs syndrome (RLS) is a sleep disorder that has a negative influence on sleep quality. We describe the clinical spectrum of patients’ series with RLS. Methods: We studied 37 patients (21 men and 16 women; mean age: 57.64±12.38) with diagnosis of RLS acording To IRLSSG/NIH criteria. We analyse clinical features, polysimnogram (PSM), theraphy and outcome. Results: Family history: 3. Idiopathic RLS: 62.2 %; mean age: 57.16±12.05. Secondary RLS: 38.8 % (mean age: 58.5±13.59): 6 iron-deficiency anemia, 2 other anemias, 2 polineuropathy and 1 Parkinson disease. Insomnia (64.8 %: 15 conciliation and 16 support) is more frequent than hypersomnia (48.6 %). We didn’t find significant differences between both groups in relationship to insomnia’s prevalence (secundary RLS:80 %; no secundary RLS:59.26 %; p < 0.21). PSG: 56.7 % with periodic limb movement disorder (PLMD), 59.4 % with roncopathy and 21.6 % obstructive sleep apnea syndrome. Treatments: dopaminergic drugs with “augmentation”phenomenon in 4 patients; hypnotics and anticonvulsivants. Outcome: favourable 18.9 %, disfavourable 27 % and steady 54 %. Conclusions: In our serie iron-deficiency anemia is more frequent cause of secondary RLS. Factors solely associated with RLS were PLMD and other sleep disorders. Outcome is variable with an acceptable response to dopaminergic drugs. This condition is associated with decrease of sleep efficiency. Better recognition of these sleep disorders is needed.

O202 Prospective validation of the Essen Stroke Risk Score in the Systemic Risk Score Evaluation in Ischaemic Stroke Patients (SCALA) study in 85 German stroke units C. Weimar, M. Goertler, J. Röther, E. B. Ringelstein, H. Darius, D. G. Nabavi, I. H. Kim, K. Theobald, H. C. Diener University of Duisburg-Essen (Essen, DE); University of Magdeburg (Magdeburg, DE); Hospital Minden (Minden, DE); University of Munster (Munster, DE); Vivantes Hospital Neukölln (Berlin, DE); Sanofi-Aventis (Paris, FR); Sanofi-Aventis (Berlin, DE)

O201 Interhemispherical transfer and functional asymmetry between the basal ganglia during natural human sleep F. Salih, A. Sharott, A. Kupsch, P. Brown, P. Grosse Charité-Universitätsmedizin Berlin (Berlin, DE); Universitätsklinik Eppendorf (Hamburg, DE); Institute of Neurology, University College London (London, UK) Objective: To investigate interhemispheric connectivity and functional asymmetry between basal ganglia across the sleep-wake cycle. Methods: Local field potentials (LFP) from the globus pallidus internus (GPi) and cortical surface EEG were recorded in patients (n = 8) receiving deep brain stimulation (DBS) for generalized dystonia. Directed transfer functions (DTF) and basic frequency analysis techniques were assessed across different states of vigilance. Results: GPi-LFPs are involved in sleep specific coherence peaks during human slow-wave sleep. Interhemispheric coupling of delta waves and sleep spindle oscillations shows asymmetric flow between left and right motor cortex. Asymmetric DTF persists between GPi-LFPs in the delta range but is almost abolished in the sleep spindle range. Conclusion:. Our data confirm that interhemispherical directional coupling during sleep can be represented by the DTF. Distinct sleep-specific oscillations seem to modify interhemispherical transfer independently from each other. Whereas functional asymmetry of these oscillations might differ between cortical and subcortical sites. F. Salih was sponsored by a ENS Fellowship 2006

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Background: Patients with transient ischaemic attack (TIA) or ischaemic stroke (IS) carry a high risk of stroke recurrence and major cardiovascular events. Stratification of patients according to their individual risk profile, e. g. with the Essen Stroke Risk Score (ESRS) can contribute to optimised secondary prevention in such patients. Because this score so far has been developed and validated in randomized controlled trials only, we aimed to perform a prospective validation of the ESRS in the Systemic Risk Score Evaluation in Ischaemic Stroke Patients (SCALA) study. Methods: In this prospective cohort study, 85 neurological stroke units throughout Germany documented each 10 consecutive TIA/IS patients on standardised questionnaires. Risk factors and comorbid conditions were prospectively assessed in 852 patients for stratification into low versus high risk groups according to the ESRS. In addition, screening for peripheral arterial disease was done with Doppler ultrasonography to calculate the ankle brachial index (ABI). 715 patients gave informed consent for follow-up which is currently performed by central telephone interview after 18 months. Predictive ability of the ESRS will be assessed by receiver-operator curves (c statistics). Results: At baseline, a total of 852 patients (57 % men) with a mean age of 67 ± 12.4 years were included of whom 82.9 % had IS. The median National Institutes of Health stroke sum score was 4 (sum score for TIA: 1). Arterial hypertension was reported in 71 %, diabetes mellitus in 26 %, clinical PAD in 10 %, and an ABI equal to or below 0.9 in 51 %. An ESRS equal to or greater 3 was observed in 69 %, corresponding to a recurrent stroke risk of > 4 %/year in previous randomised secondary prevention trials. Actual rates of recurrent stroke and major vascular events in SCALA at follow-up after 18 months will be presented at the conference. Conclusions: While most documented patients had TIA or IS of low severity, a high proportion had a considerable risk of recurrent stroke or major cardiovascular events according to the ESRS or ABI category. Concurrent risk factors, particularly those related to atherothrombosis, should therefore be considered in the choice of antiplatelet agents.Whether the predictive accuracy of the ESRS is sufficient for treatment decisions will be discussed at the conference. This study was funded by Sanofi-Aventis, Berlin, Germany O203 Atrial fibrillation characteristics in patients with cerebral ischaemic stroke J. Staszewski, J. Kotowicz, A. Stepien Military Medical Institute (Warsaw, PL) Background and aim: Atrial fibrillation (AF) is one of the most common arrhythmia and an important risk factor for ischemic stroke (IS). The exact frequency, natural course and prognosis of AF including paroxysmal (pxAF), persistent (psAF) and permanent AF (pmAF) in patients with acute IS is however unclear. Methods: To assess this issue a prospective, non interventional study of consecutive patients with AF admitted due to IS with 6-month follow-up has been performed. Patients with AF of unknown duration were included to psAF group. Favorable stroke outcome was regarded as the patient was non dependent at 6-month follow-up visit. Results: Within 24 months of recruitment 838 patients were hospitalized due to IS or TIA. Concomitant AF was diagnosed among 200 (24.4 %) of these patients. Permanent AF was observed in 108 (54 %), pxAF in 70 (35 %), psAF in 9 (4.5 %), AF of unknown duration in 13 (6.5 %) patients. Mean age, demographics did not differ significantly among groups. Comparing with pxAF patients with pmAF and psAF were more often dependent on admission (respectively, 81 % and 91 % vs. 50 %, p < 0.001) and discharge (55 % and 31 % vs. 19 %, p < 0.001). In-hospital (13 % and 9 % vs. 3 %, p < 0.001) and 6month mortality rates (35 % and 40 % vs. 14 %, p < 0.001) were also significantly higher in pmAF and psAF than in pxAF group.

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Successful pharmacological cardioversion had been performed in 20 (66 %) patients with pxAF who experienced non-terminating recurrence of AF during hospitalization, in 10 (44 %) patients sinus rhythm had not been restored. Restoration of sinus rhythm was a significant risk factor for unfavorable stroke outcome in 6-month observation period in these patients(OR 2.14; 95 % CI 1.07–4.29; p = 0.03). During the study 29 (40 %) of patients with pxAF had experienced at least one AF recurrence, 20 (29 %) evolved towards psAF. The transformation of psAF to ptAF was observed in 8 (36 %) patients. Dependence on admission was a risk factor (OR 4.5, 95 % CI 0.9–22.9, p = 0.05) for transformation of pxAF to ptAF. Conclusions: AF was present in 24.4 % of patients admitted due to cerebrovascular incidents. Paroxysmal AF was diagnosed in 35 %, pmAF in 54 % and psAF in 11 % of patients. During 6-month of follow-up 29 % of pxAF evolved towards psAF and 36 % psAF to pmAF. The course of IS in analyzed AF groups was different. In-hospital and 6-month mortality rate and number of dependent patients were significantly lower in pxAF than in pmAF and psAF patients. O204 Countable and uncountable microembolic signals in first-ever stroke patients with PFO aged over and under 45 G. Telman, E. Kouperberg, E. Sprecher, D. Yarnitsky Rambam Medical Center (Haifa, IL) Background: There are data in the literature that the number of microembolic signals (MES) in patients with patent foramen ovale (PFO) is directly related to stroke appearance and reccurrence. We hypothesised thus that amount of artificially induced microembolic signals monitored by transcranial doppler (TCD) will be greater in younger patients with PFO and stroke. Patients and Methods: Ninety six patients with PFO by Transesophageal Echocardiography and MES by TCD were included into the study. Thirty patients aged 18–45 years were defined as “younger” patients group. The rest of patients (aged 46–77 years) were defined as “older” group. MES were generated by intravenous injection of 8 ml of saline vigorously agitated with 1 ml of air during Valsalva maneuver. The pattern of microembolization was defined as “countable” when the observers were able to calculate the number of MES. In case of “shower” of MES on TCD examination the pattern of monitoring was defined as “non-countable”. Results: There was no statistically significant difference in distribution of traditional risk factors between groups. There were 22 patients with noncountable pattern of MES in the group of older patients compared with only 2 such patients in younger group (p = 0.002). There was no difference in a number of MES between groups in those patients with countable MES – 13±10.9 in older patients and 10.7±8.5 in younger group. Conclusions: Cryptogenic stroke in young PFO patients is not related directly to the amount of MES found on TCD examination. In stroke patients older than 45 years PFOs producing large amount of MES on TCD are frequent. Thus PFO has to be considered as risk factor for stroke in older patients side by side with “routine” vascular risk factors. O205 Warfarin-associated intraventricular haemorrhage A. Zubkov, D. Claassen, A. Rabinstein Mayo Clinic (Rochester, US) Objectives: In this study we have reviewed our experience with anticoagulation-associated IVH. Our goal was to determine if IVH is an independent prognosticator of fatal outcome in patients with anticoagulation-associated ICH. Methods: Retrospective analysis of medical records and computed tomographic imaging data of 88 patients with warfarin-induced intracerebral hemorrhage (ICH), including 8 patients with predominant intraventricular hemorrhage (IVH). Main outcome measure was 30-day mortality. Results: In our population of patients with warfarin-associated ICH we found a 30-day mortality rate of 45 %. Ventricular extension increased this mortality rate to 75 %, while in the absence of ventricular extension the 30day mortality was 23 %. IVH was significantly associated with 30-day mortality (P < 0.001). Patients with predominant IVH had 50 % mortality at 30 days, despite low rates of hemorrhage expansion on serial imaging. Panventricular extension was uniformly fatal in patient with ICH and carried 75 % 30-day mortality in patient with predominant IVH. On a multivariate logistic regression model including age, ICH volume, and IVH, ICH volume (P < 0.001) and IVH (P = 0.003) remained independently associated with early mortality. Conclusion: Extension of anticoagulation-induced ICH into the ventricular system causes a high mortality, especially in patients with panventricular involvement. IVH is an independent predictor of early death in these pa-

tients. In our experience, the majority of intraventricular hemorrhages do not expand over time and poor outcome appears to be related to the magnitude of the initial insult. O206 Telephone-guided intravenous thrombolysis followed by mechanical recanalisation therapy for acute basilar artery occlusion T. Pfefferkorn, T. E. Mayer, M. Dichgans Klinikum Grosshadern (Munich, DE) Objectives: The prognosis of acute basilar artery occlusion (BAO) is extremely poor if early recanalization is not achieved. Recanalization strategies include systemic (intravenous) and local (intra-arterial) thrombolysis with rt-PA or urokinase as well as mechanical manipulations (thrombosuction). These measures may be accompanied by antithrombotic treatment with heparin or glycoprotein (GP) IIb/IIIa inhibitors. If the diagnosis of BAO is made in community hospitals that lack the capacity to perform recanalization, patients have to be referred to specialized stroke centers. This leads to a substantial delay in treatment and is associated with poor outcome. Since January 2006, we have therefore instituted a new strategy for minimizing such delay. Our initial results are presented here. Methods: As a specialized academic stroke center, we treat 20 to 30 patients with confirmed BAO each year. Most of these patients have been diagnosed in near-by community hospitals, which contact us by telephone requesting treatment suggestions and discussing referral. Since January 2006, we have treated these patients strictly according to the following modified protocol. If CT has excluded intracerebral hemorrhage, if local CT-angiography has confirmed the diagnosis of BAO, if symptom onset occurred within 6 hours of presentation, and if there are no further contraindications, we recommend the immediate initiation of systemic intravenous thrombolysis.While on thrombolytic treatment, the patients are immediately referred to our center. If BAO persists after the systemic thrombolysis, immediate intra-arterial mechanical recanalization therapy is begun. Results: In 2006, nine patients were treated according to this modified protocol. All patients received systemic thrombolysis initiated in the primary hospital. In three of these patients, systemic thrombolysis alone led to recanalization of the basilar artery. The remaining six patients required subsequent local therapy, and recanalization was achieved in five of them. Six of the total nine patients are still alive. Four of them have no or minimal neurological deficits; one has a moderate and one a severe deficit. Conclusions: Although based on only a few patients,our data suggest that telephone-guided intravenous thrombolysis followed by referral to a specialized stroke center and mechanical intra-arterial therapy may be a promising approach to improve the outcome of patients with acute BAO. O207 Systemic thrombolysis in patients over 80: clinical outcome and frequency of intracranial haemorrhage B. Dimitrijeski, A. Villringer, A. Hartmann Charite (Berlin, DE) Background: Systemic thrombolysis within a 3-hour time window is effective in patients with acute ischemic stroke. However in Europe r-tPA treatment is only approved in patients younger then 80 years and patients elder then 80 years are often excluded from treatment. Consequently information on efficacy and safety of treatment with systemic thrombolysis in patients elder 80 y is scarce. Methods: 223 patients were treated in our hospital systemically with rtPA using the NINDS study protocol and additional CT exclusion criteria from ECASS-trial. During prospective follow-up, neurological status was assessed at admission, discharge, and after 3 months using the modified Rankin scale.After informed consent, patients over age 80 years were treated when their comorbidity was low and their overall functional status was considered good. Results from patients treated with r-tPA in our hospital in the same time period with age ≥ 80 years were used to compare neurologic outcome. Results: In total 30 patients with age over 80 years (mean age 84 years, range 81–90 years, mean baseline NIHSS 14, 70 % women) were treated with systemic thrombolysis. 30 % (n = 9) had a good clinical outcome defined as Rankin ≤ 2, compared to 54 % (n = 104) in patients younger 80 years (p = 0.003). Mortality was higher in the elder age group (33 %) then in the younger age group (10 %) (p = 0.001). Symptomatic intracranial haemorrhage was not more frequent in the elder group (6.6 % resp. 3.5 %, p = 0.32). Independent risk factors for unfavourable outcome (Rankin > 2) were NIH-Baseline > 13 and infarct size > 2/3 of the A. cerebri media territory. Conclusion: The risk for symptomatic intracranial hemorrhage in pa-

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tients > 80 y treated with systemic thrombolysis is not significantly increased. However compared to younger patients they have a higher risk for unfavourable outcome (Rankin> 2) and a higher mortality. Elderly patients seem not to benefit in the same degree from treatment with systemic thrombolysis compared to patients younger 80 years.

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most stable over this time (2.0 cases per 100.000 person-years; 95 percent confidence interval: 1.9, 2.2). Survival did not change during the study period (16.4 months). Demographics and clinical features of the incident and prevalent Irish ALS cohorts were markedly different: the prevalent Irish cohort had fewer bulbar-onset patients (31.3 % versus 42.3 %) and fewer patients over the age of 65 years of age (37 % versus 52.5 %) compared to the incidence cohort. Furthermore, the survival pattern of the 2003 prevalent cases differs markedly from that of the Irish incident cohort (16.4 versus 120.9 months). Conclusions: Difference in survival between “incident” and “prevalent” cohorts has not been reported previously in ALS These findings have significant implications for stratification of both clinical trials and case-controlled studies, and for initiatives in Europe and the USA relating to DNA collection

Motor neuron disease O208 Length of prediagnostic period as a predictor of rate of disease progression and survival in amyotrophic lateral sclerosis A. Czaplinski, S. H. Appel University of Basle (Basle, CH); Methodist Neurological Institute (Houston, US) Objectives: We have previously described a strong relationship between preexamination rate of disease progression in ALS and the time from symptom onset to first examination in our clinic (Haverkamp 1995). Therefore at first encounter, the length of prediagnostic period may provide a meaningful estimate of the rate of future disease progression and survival. Methods: In a large group of 1034 patients with the diagnosis of definite or probable ALS the effects of the duration of the prediagnostic period (time from symptom onset to diagnosis) and the rate of initial disease progression on subsequent disease progression and tracheostomy-free survival were assessed with the Kaplan-Meier life-table method. The prognostic value of each factor was estimated using univariate and multivariate Cox proportional hazard analyses. Results: Patients with longer time between first symptoms and diagnosis survived longer and progressed more slowly than patients with shorter prediagnostic periods (log-rank p < 0.001). Furthermore, a significant relationship was also observed between the rate of disease progression prior to the first examination and subsequent disease progression and survival: the slower the disease progression prior to first examination, the slower the subsequent disease progression and the longer the survival (p < 0.001). Most importantly, in all performed multivariate models duration of the prediagnostic period and the rate of initial disease progression remained significantly and independently associated with outcome. Conclusion: Prognosis was significantly poorer for patients with shorter duration of the prediagnostic period and faster initial disease progression. We hypothesize that, the more rapidly a patient initially deteriorates, the shorter the delay before the first symptom and first examination. It appears likely that fast progressing patients tend to seek medical care earlier, whereas those with slower disease progression are referred later or adapt to first symptoms for a longer time before they visit a tertiary medical care facility. The fact that duration of the prediagnostic period is significantly correlated with subsequent disease progression and survival in ALS may also provide clinical investigators with an additional means of reducing heterogeneity in baseline stratification in future ALS clinical trials. O209 Temporal trends in the epidemiology of amyotrophic lateral sclerosis in Ireland between 1995 and 2004 O. O’Toole, B. J. Traynor, P. N. Brennan, C. Sheehan, B. Corr, O. Hardiman Beaumont Hospital (Dublin, IE); National Institute of Health (Bethesda, US) Background: Prospective population based studies of ALS capture all incident cases. Conversely clinic-based cohorts are biased towards the collection of prevalent cases. As ALS is a rapidly progressive illness with variable phenotype, clinical characteristics and survival of these two cohorts are likely to differ. Objective: To determine trends in survival of incident and prevalent cases of amyotrophic lateral sclerosis (ALS) in the Irish population from 1995 to 2004. Methods: The Irish ALS Register was used to identify Irish residents diagnosed with suspected, possible, probable or definite ALS between the three year period from January 1st,1995 to December 31st 1997 and the three year period from January 1st, 2002 to December 31st, 2004. Results: 465 Irish residents were diagnosed with ALS during the 10 year study period. Average annual incidence rate of ALS in Ireland remained al-

O210 Alteration of RNA editing and neuronal death in motor neuron diseases T. Hideyama, Y. Nishimoto, T. Yamashita, S. Tsuji, H. Takahashi, A. Kakita, T. Suzuki, S. Kwak The University of Tokyo (Tokyo, JP); Niigata University (Niigata, JP); Kyoritsu Pharmaceutical College (Tokyo, JP) Objectives: Deficient RNA editing of GluR2 mRNA at the Q/R site has been proposed to be the cause of death in spinal motor neurons of the sporadic ALS. As the RNA editing at this site is specifically catalyzed by adenosine deaminase acting on RNA type 2 (ADAR2), we investigate the expression level of ADAR2 mRNA and the change of RNA editing of other ADAR2 substrates in ALS motor neurons as compared with control motor neurons. Methods: Autopsied spinal cords from various types of sporadic ALS including ALS-dementia and neurologically normal subjects were used. Motor neurons were dissected from frozen autopsied spinal cord with a laser microdissector and ventral gray matter tissue was dissected en bloc under a binocular from the frozen autopsied normal human and ALS spinal cords. After RT-PCR, the editing efficiency of various ADAR2 substrates including the GluR2 Q/R site was determined by the quantitative analysis of the fragments of the PCR products produced by digestion by a restriction enzyme, and mRNAs of ADAR2 and GluR2 were quantified using LightCycler system. Results: The editing efficiency at the GluR2 Q/R site was incomplete in all the ALS spinal cord. There was an apparent correlation between the editing efficiency and the relative expression level of ADAR2 mRNA. RNA editing was significantly reduced only at the GluR2 Q/R site in ALS ventral gray. Conclusions: A decrement of the ADAR2 activity is likely the cause of deficient GluR2 RNA editing. Because an increase of unedited GluR2 causes neuronal death in animal studies, reduced ADAR2 activity may be responsible for ALS etiology. O211 Neuropsychological assessment in ALS patients: longitudinal study M. R. Barulli, R. Tortelli, M. F. De Caro, V. Samarelli, C. Tortorella, D. Mezzapesa, E. D’Errico, R. Messina, P. Livrea, I. L. Simone University of Bari (Bari, IT) Objectives: The aim of this study was to perform a longitudinal neuropsychological assessment in ALS non-demented patients. Material and methods: Forty one probable or definite sporadic ALS patients (El Escorial Criteria) were examined. Thirty one of them were men. Thirty eight had spinal onset and 3 bulbar onset. At baseline mean age was 60.2 (SD 10.2) years and disease duration 42 (SD 35) months. Neurological status was evaluated by ALS Functional Rating Scale (ALSFRS) and Manual Muscle Testing (MMT). Patients with several bulbar signs were excluded from the analysis. All subjects were right-handed. Nineteen age and education-matched healthy subjects were recruited as controls. Neuropsychological battery included: 1) MMSE as a screening for global deterioration; 2) Prose Memory Test (PMT) to explore episodic memory; 3) Working Memory Test10”/30”(WMT); 4) Verbal Phonemic Test (FAS) to explore lexical access; 5) Stroop Word-Colour-Interference Task (SWCT) and oral version of Symbol Digit Modalities Test (SDMT) to explore sustained attention and executive functions. The mood was examined by Beck Depression Inventory (BDI). Twenty of 41 ALS patients had a follow-up after 12 months. Controls were tested only at baseline. Results: No patient had clinical evidence of dementia.At baseline, pathological scores of PMT were found in 4.9 %, WMT in 24.4 %, FAS in 4.9 %, SWCT in 29.3 % SDMT in 46.3 % of patients. At baseline, ALS patients showed significant impairment in PMT, WMT/30”, SDMT and SWCT in comparison to controls (p < 0.021). After 12 months ALSFRS and MMT significantly decreased (p = 0.018 vs. baseline). SWCT significantly worsened (p = 0.047) and there was a trend of changes in working memory (WMT/30”) and verbal fluency (FAS). Significant correlation was found between PMT

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and ALSFRS (p = 0.03). Cognitive functions did not correlate with disease duration, ALSFRS, MMT and BDI. Conclusion: ALS patients showed a neuropsychological pattern characterized mainly by attention and executive functions impairment and less frequently by memory function impairment, confirming previous evidences on fronto-temporal deficit. Over the time a slow worsening of cognitive impairment was found in contrast to a more rapid clinical progression.

Oral session 32 Treatment of acute stroke O212 Treatment of middle cerebral artery occlusion in acute stroke patients: comparison of intra-arterial thrombolysis and sonothrombotripsy with standard intravenous thrombolysis D. Sanak, R. Herzig, A. Bartkova, S. Burval, M. Kocher, D. Horak, I. Vlachova, J. Zapletalova, M. Cerna, M. Kral, M. Herman, P. Kanovsky University Hospital (Olomouc, CZ) Objective: Intravenous thrombolysis (IVT) is still considered to be the gold therapeutic standard for acute ischemic stroke (IS) including middle cerebral artery occlusion. The aim of our study was to compare and assess the efficacy and safety of intra-arterial thrombolysis (IAT) and sonothrombotripsy (ST) with IVT in acute IS patients with MCA (M1–2) occlusion detected on MR angiography. Methods: Twenty-nine acute IS patients fulfilling the criteria for thrombolysis and presenting with MCA occlusion on MRI were randomized into 3 therapeutic groups and subsequently treated. Neurological deficit was evaluated using NIH Stroke Scale on admission, 24 hours later, and the 90-day clinical outcome using modified Rankin Scale. The control MRI was performed 24 hours later. Fisher exact test, Chi-square and ANOVA tests were used for statistical evaluation. Results: Fifteen patients underwent IVT, 8 IAT and 6 ST. Mean baseline NIHSS was 13.5 in IVT group, 15 in IAT group and 11.5 in ST without significant difference (p = 0.354). Recanalization of MCA was achieved in significantly higher number in IAT group (87.5 %, p = 0.027) and in ST group (83 %, p = 0.012) than in IVT (33 %). The 24hour regression of neurological deficit was not significantly higher in IAT and ST (p = 0.305) than in IVT group. Patients in ST group had significantly better 90day clinical outcome (mRS 0.7, p = 0.029), whereas in IAT group did not have significantly better outcome (mRS 1.8, p = 0.209) than in the IVT group (mRS 2.9). Incidence of intracerebral hemorrhage (ICH) was 0 in ST group,3 in IVT (1 symptomatic) and 2 in IAT (1 symptomatic). Two patients died, both of ICH. Conclusion: IAT and ST seem to be more effective than IVT in recanalization of MCA occlusion. Patients treated by ST had significantly better 90day clinical outcome, whereas the difference between IAT and IVT was not significant. Study was supported by grant of IGA MH Czech Republic, NR/8579–3/2005. O213 DWI-based prediction of infarct growth: validation in 100 MCA stroke patients C. Rosso, S. Deltour, N. Hevia-Montiel, E. Bardinet, D. Dormont, S. Baillet, Y. Samson Hopital Pitié-Salpêtrière (Paris, FR) Objectives: The MRI prediction of the risk of infarct growth is of a considerable interest for decision making in acute stroke treatment. It relies so far on the perfusion-diffusion mismatch but this concept remains challenged. We recently develop a method that only requires DWI acquisition and ADC map to predict the infarct growth, taking in account the slight ADC decrease which occurs in the at-risk tissue, and we present its validation in 100 MCA stroke patients. Methods: The method is based on an original algorithm able to expend the initial DWI lesion up to the predicted final size of the infarct. At each iteration, the mean ADC value increases and the growing process is terminated when ADC reaches a predetermined threshold value. The initial infarct volume was determined on an initial MRI performed within 6 hours of stroke onset (median: 2.3 hours, IQR: 1.8, 3) and the final

volume on a control MRI (median: 1.2 days, IQR: 1, 1.8). The observed infarct growth was defined as the control minus initial DWI hypersignal volume and the predicted infarct growth as the predicted minus initial DWI hypersignal volume. Results: The observed mean volume of infarct growth was 32.7 cm3 (SD: 46.8), and the predicted infarct growth was 35.8 cm3 (SD: 43.3). Predicted and observed final infarct sizes and infarct growths were significantly correlated (r: 0.84 and 0.59, p < 0.001). We then analyze the effect of MCA recanalization (n = 70/98) on the relationship between observed vs. predicted infarct growth, assuming that recanalization should spare the at-risk tissue. In good line with this hypothesis, the slope of the regression line was significantly higher in persistent MCA occlusion than in patients with MCA recanalization (1.25 vs. 0.59, p = 0.0004). Conclusion: These results suggest the feasibility of ADC-based prediction of infarct growth with a new, automatic, and almost operator-independent algorithm. Our data show a significant correlation between observed vs. predicted infarct growth, and that the fate of ADC-DWI mismatch is affected by recanalization as expected in true penumbra. O214 Intravenous tPA treatment in acute ischaemic stroke related to internal carotid dissection. To treat or not to treat? B. Fuentes, M. Alonso de Leciñana, J. Masjuan, J. Egido, P. Simal, F. DíazOtero, A. Gil-Nuñez, E. Díez-Tejedor University Hospital La Paz (Madrid, ES); University Hospital Ramón y Cajal (Madrid, ES); University Hospital Clinico San Carlos (Madrid, ES); University Hospital Gregorio Marañón (Madrid, ES) Background: Small series reported the safety of intravenous tPA treatment in acute ischemic stroke (IS) related to extracranial internal carotid dissection (eICAD). However, no studies analysing specifically the posible benefits on outcome are available. Methods: Multicentre, prospective study conducted in 4 university hospitals. Consecutive IS patients were included. Stroke severity (NIHSS) and 3months outcome (mRS) were compared: (1) tPA-treated patients with IS related to eICAD vs. tPA-treated patients with other causes of stroke; (2) tPA-treated vs. non tPA-treated eICAD patients. Results: 265 IS patients received intravenous tPA (7 of them with eICAD). There were no diferences in baseline NIHSS between patients with or without eICAD (14.3 vs. 14.3; ns). However, NIHSS scores at 24 h and day 7 were significantly worse in eICAD patients (17 vs. 9.6 at 24 h; 15.6 vs. 7.3; p < 0.05). No eICAD patients developed a significant improvement at 24 h (decrease in NIHSS ≥ 8 points) as compared to 67 (32 %) of patients with other IS causes. When comparing tPA-treated eICAD (n = 7) with non-treated eICAD patients (n = 7), a trend to higher improvement in 24 h and day 7 was found in the non tPA-treated eICAD group (NIHSS 7.6 vs. 17 at 24 h; 6.4 vs. 15.6;p = 0.205) with no differences in baseline NIHSS. At 3 months, 80 % of tPA-treated eICAD and 20 % of non-treated eICAD patients were dependent (mRS> 2). Conclusions: Although intravenous tPA treatment in IS related to eICAD seems to be safe, the benefit on outcome is significantly minor than in IS of other causes, and possibily worse than in non tPA-treated eICAD patients. O215 Anticoagulation in clustering transient ischaemic attacks: a systematic approach T. Mestre, J. Ferro Hospital Santa Maria (Lisbon, PT) Introduction: the risk of stroke after a transient ischaemic attack (TIA) is high, with an estimated value of 10 % at one week. Clustering TIAs are one of the possible indications for anticoagulation as a primary stroke prevention strategy. The clinical evidence supporting such option is unknown. The present work aims to evaluate the efficacy of anticoagulation in clustering TIAs. Methods: a systematic review of all clinical trials included in Pubmed and Cochrane Controlled Trials Register was conducted. All randomized blinded conducted clinical trials of any anticoagulation therapy controlled with placebo or an antiplatelet agent in patients with clustering TIAs were included. The efficacy outcomes were TIA recurrency, nonfatal stroke, dependency, global mortality, mortality of vascular origin and mortality of cerebrovascular origin. The safety outcomes were minor intracranial or extracranial hemorrhage, severe hemorrhage and fatal hemorrhage. Results: 12 clinical trials were identified of which 10 were excluded due to lack of information regarding the number of TIAs (n = 5), inadequate control (n = 1), open trial design (n = 1), lack of result analysis for the cohort of

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patients with clustering TIAs (n = 3). The 2 selected clinical trials have discordant results. Conclusions: there is no clinical evidence confirming or denying the use of anticoagulation for clustering TIAs. A clinical trial with a randomised, controlled design is needed.

Oral session 33 Management of the MS patient O216 Efficacy of alemtuzumab in relapsing-remitting multiple sclerosis is independent of baseline status A. J. Coles on behalf of the CAMMS223 International Study Group Background: Preliminary studies suggest that alemtuzumab, a humanized monoclonal antibody against the CD52 antigen expressed on lymphocytes, markedly suppresses disease activity when administered during the early stages of relapsing-remitting multiple sclerosis (RRMS). Here we present 2year interim results from CAMMS223, a rater-blinded trial comparing 2 doses of alemtuzumab with Interferon beta-1 a (IFNB-1 a) in RRMS patients. Methods: Participating patients were treatment naïve with onset of symptoms within 3 years of screening, Expanded Disability Status Scale (EDSS) scores of 0 to 3 inclusive, at least 2 attacks in the previous 2 years, and at least 1 enhancing lesion on a screening cranial MRI scan.334 patients were randomized 1:1:1 to receive thrice weekly SC injections of 44 mcg of IFNB1 a or annual cycles of low- (12 mg/day) or high-dose (24 mg/day) alemtuzumab, given IV x5 days at Month 0 and x3 days at Month 12. Co-primary efficacy endpoints were time to 6-month sustained accumulation of disability (SAD) and relapse rate. An independent Data Safety Monitoring Board reviewed these pre-specified interim analyses. Results: Compared to patients treated with IFNB-1 a, both groups of alemtuzumab-treated patients had > 75 % reduction in the risk for relapse and > 65 % reduction in the risk for SAD after 2 years of treatment. These findings were highly statistically significant. Subgroup analysis of the coprimary endpoints showed that the treatment effect of alemtuzumab is generally independent of disease duration, baseline functional status (as indicated by EDSS scores), degree of cerebral atrophy measured on MRI T1, and MRI T2 lesion volume. Adverse effects of alemtuzumab included infusionassociated events and infections. Autoimmune thyroid disorders, and immune thrombocytopenic purpura may occur late after treatment and these potential complications require additional monitoring. Conclusions/Relevance: Alemtuzumab is substantially more effective at suppressing relapses and SAD than interferon beta-1 a in treatment-naïve RRMS patients through 2 years of follow-up, regardless of disease duration, baseline functional status, degree of cerebral atrophy, or lesion load.Adverse effects have been treatable and manageable. Overall benefit/risk will be further evaluated in Phase III trials. This trial was sponsored by Genzyme Corporation. O217 Clinical and neuroradiological response to mitoxantrone in a large group of multiple sclerosis patients M. Rodegher, F. Esposito, M. Radaelli, L. Moiola, M. Rocca, L. Straffi, F. Martinelli Boneschi, V. Martinelli, M. Filippi, G. Comi San Raffaele Institute (Milan, IT) Objective: To assess the efficacy and safety of treatment with Mitoxantrone (MX) in delaying the disease progression and reducing magnetic resonance (MR) detectable activity in multiple sclerosis (MS) patients with “active”disease. Materials and methods: Following an open label protocol, 410 MS patients (262 females and 148 males) were treated with different doses of MX according to the severity of clinical worsening during the previous year and/or to the degree of Magnetic Resonance Imaging (MRI) activity. The dose regimens ranged from 10 to 20 mg given in a single dose, administered monthly or every two-three months. The object of this analysis is a subgroup of 211 patients (136 females and 75 males, mean age = 44 years, range = 24–72 years), who received at least 5 cycles and with a basal Expanded Disability Status Scale (EDSS) score ≥ 3.0. The median duration of treatment was 1.4 years and the median number of cycles was 6.0. Forty-two

(20 %) patients had a relapsing remitting (RR) course, 142 patients (67 %) had a secondary progressive (SP) MS and the remaining 27 patients (13 %) had a progressive relapsing (PR) MS. The patients were classified as non-responders if the EDSS increased of at least 1.0 point during the treatment period and responders in all the other cases. One-hundred and thirty-two patients (85 females and 47 males,33 RRMS,88 SPMS and 11 PRMS) underwent MRI before and after treatment. Patients who switched from at least one enhancing lesion at the beginning of the treatment to no enhancing lesions at the end were considered as MRI responders. Results: Clinically responder patients were 178 (84 %): 37 patients (88 %) had RRMS, 119 (84 %) SPMS and 22 (82 %) PRMS. The total number of MRI responders was 57 (43 %): 14 patients (42 %) had RRMS, while 39 patients (44 %) and 4 patients (36 %) had SPMS and PRMS, respectively. The most common side effects were amenorrhea (13 %), nausea and vomiting (38 %), transient leukopenia (18 %), urinary disturbances (17 %), and other minor side effects (7 %). One patient developed therapy-related leukaemia. Conclusion: MX treatment is effective both in delaying the progression of clinical disability and in reducing the MRI inflammatory activity. O218 How effective are disease-modifying drugs in delaying disability progression in relapsing-onset multiple sclerosis? M. G. Brown, S. Kirby, C. Skedgel, J. D. Fisk, T. J. Murray, V. Bhan, I. S. Sketris Capital Health Nova Scotia (Halifax, CA) Objective: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under ‘real world’ conditions. Methods: Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history. A basic fixed effects model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment. An expanded model estimated annual EDSS change in pre-treatment-years, treatment-years on first drug, treatment-years after drugs were switched, and in years after treatment stopped. Models were populated with 1980–2004 clinical data, including 1988–2004 data for all Nova Scotia residents treated with DMDs. Estimates were made for relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and R-onset MS groups with up to 20 years since onset of symptoms and EDSS less than 7. The RRMS group included 390 persons (2.156 visits), the SPMS group included 200 persons (1,451 visits) and the R-onset group included 590 persons (3.607 visits). Pre-DMD-treatment ’self-control’ visit data represented 36 %, 47 % and 41 % of all visit data. Results: Estimated pre-treatment annual EDSS increases were about 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment-year on the first drug were significant for the RRMS group (–0.103, 0.000), the SPMS group (–0.065, 0.011) and the R-onset group (–0.162, 0.000); relative effect size estimates were 112 %, 21 % and 105 %. Estimated EDSS progression was much faster in years following drug switches and treatment stops. Conclusions: DMDs, as a class, are effective in delaying disability progression in patients with R-onset definite MS (90 %), although effectiveness is much better for RRMS than SPMS groups. Our estimates of DMD absolute treatment effect size are statistically significant. Our estimates of treatment effect size relative to pre-treatment annual EDSS increases, in the context of “real world’ clinical practice, are similar to comparable DMD treatment efficacy estimates relative to placebo in pivotal trials, which showed only a tendency toward significance. Research funding was received from Health Canada, MSSC, Nova Scotia Research Foundation O219 The impact of immediate versus deferred treatment with IFNB-1 b on sustained neurological impairment: 3-year results of the BENEFIT Study L. Kappos, C. H. Polman, G. Edan, M. S. Freedman, H-P. Hartung, D. Miller, X. Montalban, F. Barkhof, L. Bauer, S. Dahms, C. Pohl, R. Sandbrink for the BENEFIT Study Group Objectives: There is ample evidence that early treatment with IFNB delays the conversion to clinically definite MS (CDMS) but it is not known if delaying treatment has implications on the development of sustained neurological impairment. In the prospectively planned 3-year analysis of the BENEFIT study we address this question. Methods: In this double-blind study, 468 patients received either IFNB1 b 250 μg (n = 292) or placebo (n = 176) subcutaneously every other day for two years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up study offering IFNB-1 b for up to five years after the initial ran-

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domization. All patients have recently completed a total three-year observation period and a pre-planned integrated intention to treat analysis was performed. Patients initially randomized to receive IFNB-1 b were compared to those who had been randomized to placebo and were eligible to start IFNB1 b treatment after CDMS or after completion of 2 years on study. Results: 418 of 437 eligible patients (96 %) were enrolled. Immediate IFNB-1 b treatment was associated with a statistically significant delay of EDSS progression sustained for 6 months. Additional clinical and paraclinical outcomes support this favorable effect of early versus deferred treatment on development of sustained neurological impairment after 3 years. Conclusion: These findings have important implications for early treatment decisions. Study supported by: Bayer Schering Pharma AG, Berlin, Germany.

POSTER SESSIONS Poster session 1 Cerebrovascular disorders P220 Results of stroke treatment with recombinant tissue plasminogen activator – analysis of first 50 patients A. Stepien, J. Staszewski, J. Kotowicz, B. Brodacki, J. Swistak, K. Macek Military Medical Institute (Warsaw, PL) Recombinant tissue plasminogen activator (rtPA, Actylise) has been applied for the treatment of the acute phase of an ischemic stroke for ten years. The beneficial effect of this medication is observed in patients treated in the first three hours after the appearance of the stroke. As it is a relatively new method of treatment we decided to share our experience in administration of rtPA to the first 50 patients (group A), as well as to compare our results with those of the standardized stroke treatment (aspirin 150–350 mg; n = 50, group B)conducted according to EUSI recommendations. Results of rtPA treatment in our group of patients indicate that it is an effective and relatively safe method of the ischemic stroke management and contributes to a more rapid improvement of the patients’ neurological status. Patients treated with tissue plasminogen activator showed statistically lower disability on discharge estimated in the mRS and NIHSS scales. RtPA reatment performed up to 6 hours from the onset did not lead to an increase of haemorrhagic complications in comparison to the group of patients treated within 3 hours.The observed complications of the secondary haemorrhage in the ischemic focus were rare and did not result in the deterioration of the patients’ state. P221 Recurrent ischaemic stroke: aetiological factors S. Demirci, Z. B. Yalciner, G. Bakac, H. Kucukoglu, C. Dayan, S. Baybas Anadolu Saglik Merkezi (Kocaeli, TR) Between June 2002 and February 2003, 631 stroke cases who were admitted to neurology department of Bakirkoy State Hospital of Psychiatric and Neurological Disorders were registered in the stroke database. 330 of these patients were female (52.3 %) and 301 (47.7 %) were male. The nature of the stroke was ischeamic in 537 cases (85.1 %) and 94 were haemorrhagic(14.9 %). Mean age was 67.6 for the females and 54.9 for the male patients. 461 (73.1 %) of the cases had had a stroke for the first time and 170 (26.9 %) has had recurrent strokes. In 119 of the 147(80.9 %) ischeamic recurrent strokes, the previous incident was ischeamic, and in 10 (43.4 %) of the recurrent haemorrhagic strokes, the previous incident was haemorrhagic. The results were significant and they suggested that stroke recurs in a similar nature (p < 0.0001). In ischeamic incidents, the most commonly affected vascular territory was the middle cerebral artery. When TOAST classification was used for ischeamic strokes, undetermined stroke was found to be the leading incident (38.5 %) and there was no significant difference between first or recurrent cases. As a result, we conclude that major risk factors for stroke, such as hypertension, DM or AF should be followed closely, however these risk factors and etiological causes lack the power to accurately predict the recurrence of stroke.

P222 Natural progression of carotid artery intima-media thickness in healthy men F. Weber German Air Force Institute of Aviation M (Furstenfeldbruck, DE) Objective: Ultrasound measurement of carotid artery intima-media thickness is generally considered as a valid index of atherosclerosis. Objective of this paper was to study the natural course of the progression of carotid artery intima-media thickness (IMT) in healthy men. Special emphasis was paid to the comparison between IMT at the bulb of the carotid artery and at the common carotid artery (CCA). Methods: A cohort of 802 military aviators, officially considered as fit for flying and therefore normotensive and free of infection, was included in the study. For a six years period (2000 until 2005) common carotid artery IMT was measured annually in these healthy volunteers. All attended annual examinations with measurement of cardiovascular risk factors (body mass index, blood pressure, physical working capacity, cholesterol, high-density lipoprotein cholesterol, triglycerides, gamma glutamyl transferase, cigarette smoking). The repeated measures across time were compared with the use of a linear mixed effects model fit by REML using the nlme-package of R with a random effect for the patient and for age. The above mentioned cardiovascular risk factors were taken as fixed effects. Results: Baseline IMT level at the bulb was higher than at the CCA, and the annual IMT progression in the bulb was twice as large as in the ACC.Age, BMI, smoking status, ESR and blood pressure were signficant determinants of IMT progression at the CCA, whereas in the bulb only age, BMI, blood pressure and PWC 170 significantly determined IMT progression. Conclusion: IMT progression in the CCA is different from IMT progression in the carotid bulb. In healthy men, physical fitness determines subclinical atherosclerosis only at the carotid bulb. In addition to traditional risk factors, IMT progression in the CCA is determined by erythrocyte sedimentation rate in subjects apparently free of infection. P223 Accuracy of the PWI/DWI mismatch for infarct growth prediction C. Rosso, I. Meresse, J. Labreuche, Y. Samson Hopital Pitié-Salpêtrière (Paris, FR); Hôpital Bichat (Paris, FR) Objectives: It is often suggested that the PWI/DWI mismatch is important for thrombolysis decision making. If this is true, the PWI/DWI should not only predict outcome and infarct growth in group of patients, but should also have a high predictive value in individual patients. This has recently been challenged by some authors. To investigate this issue, we performed a meta-analysis based on individual data. Methods: We search studies with individual data, in which initial MRI (with perfusion and diffusion weighted imaging) was performed in the first six hours showing MCA territory stroke and in which final volume was known. We identified 180 patients in 17 studies (median age: 68 years, median initial NIHSS: 13 for n = 100). In each study, we select the hemodynamic parameter for the PWI/DWI mismatch volume which was considered as the best predictor by the authors. Results: The median PWI volume was 68 cm3 (IQR: 20.6, 146.9) whereas the median initial DWI volume was 19 cm3 (7, 40.2).The median PWI/DWI mismatch volume (Initial PWI volume minus initial DWI volume) was 30.6 cm3 (IQR: 2.3–95.8) whereas the infarct growth volume was 10.1 cm3 (0.4–49.5). As expected, PWI volume and PWI/DWI mismatch correlated significatively with final volume (r = 0.72, p < 0.0001) and infarct growth (r = 0.498, p < 0.0001) respectively. To test the accuracy of PWI/DWI mismatch in infarct growth prediction, we classified patients into 2 groups: (a) patients with infarct growth > 10 cm3 (n = 91, 51 %) and (b) patients without (n = 89, 49 %).The ROC curve only shows a moderate accuracy of PWI/DWI mismatch to predict infarct growth (AUC = 0.675). The best compromise between sensitivity and specificity (59 % and 72 % respectively) was obtained when PWI/DWI mismatch was defined as exceeding 43 cm3. With this threshold, 66 % of patients were well classified. Using a more conservative definition of infarct growth (> 5 cm3), 106 patients were sorted in group (a) (59 %) and 74 in group (b) (41 %). The accuracy of the prediction was similar: AUC = 0.645, Sensitivity = 56 % and Specificity = 68 % for the best compromise, Patients well predicted = 61 %). Conclusion: These results confirm that the PWI/DWI mismatch is a highly statistically significant predictor of infarct growth in groups of patients but has a low sensitivity and moderate specificity for individual prediction of infarct growth. This should be considered before implementation of PWI/DWI-based therapeutic strategies in clinical routine.

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P224 Atherosclerosis risk factors in children of Iranian patients with young stroke S. Mousavi, A. Chitsaz Isfahan University of Medical Sciences (Isfahan, IR) Introduction: Strokes in young adult (under 45 years) account for up to 3 % of all strokes.Given that atherosclerotic thrombotic factors are the most common etiology of stroke second to cardioembolic causes, and that children of families with premature atherosclerosis are considered to be at risk, we assessed atherosclerosis risks in children of patients with young stroke. Methods:This cross- sectional study was conducted on 27 children of patients with young stroke due to non cardiac causes and 2 control group, one with 52 children of patients with stroke after age 50, and another with 55 children without history of stroke in their parents.Findings were analyzed with spss using ANOVA. Results: The mean values of systolic and diastolic BP, LDL-C and ApoB100 in the case group were significantly higher and mean HDL-C and ApoA1 were significantly lower in the case grroup.The number of APL-Abpositive cases was larger in case group. The other evaluated variables were not different between the two control groups. Conclusions: Atherosclerotic risk factors were more prevalent in children of Iranian patients with young stroke. P225 Multidrug resistance-associated protein-1: a gateway for drugs to the stroke brain A. Spudich, E. Kilic, Z. Y. Guo, M. Bacigaluppi, H. Wunderli-Allenspach, C. L. Bassetti, J. M. Fritschy, D. M. Hermann University Hospital Zurich (Zurich, CH); ETH Zurich (Zurich, CH); University of Zurich (Zurich, CH) Purpose: ATP-binding cassette (ABC) transporters are ATP-dependent flippases located at the blood brain barrier (BBB) that are involved in the elimination of drugs from the brain. While the majority of transporters are expressed on the luminal surface of the endothelium, carrying drugs from the brain back into the blood against concentration gradients1, some transporters, including multidrug resistance-associated protein (Mrp)-1 (also termed ABCC1), predominantly exhibit abluminal localization on vascular endothelium. Until now, the function of these abluminal transporters remained largely unclear. Methods and results: To elucidate the implication of Mrp-1 for the pharmacotherapy of ischemic stroke, we submitted adult C57bl/6 mice to 30 and 90 min of middle cerebral artery (MCA) occlusion1. Immunohistochemical studies and Western blots using enriched capillary fractions showed that Mrp-1 expression was decreased in ischemic brain at 3–12 h after reperfusion onset. Delivery of the Mrp-1 substrates 17betaEG and GSNO immediately after MCA occlusion resulted in a dose-dependent decrease (17betaEG) or increase (GSNO) in brain injury, compared to vehicle-treated control mice. Deactivation of Mrp-1 both by pharmacological inhibition with MK571 or genetic knockout completely blocked the injury effects of 17betaEG and GSNO, indicating that Mrp-1 was required for the brain entry of both pharmacological compounds. Conclusions: Our data suggest that Mrp-1 serves as gateway for drugs into the stroke brain. We predict that the selection of drugs acting as substrates of abluminal, but not luminal ABC transporters may greatly facilitate pharmacological therapies in brain diseases. Reference 1. A. Spudich, E. Kilic, H. Xing, Ü. Kilic, KM. Rentsch, H. Wunderli-Allenspach, CL. Bassetti, DM. Hermann. Nat Neurosci 2006; 9:487–488. P226 Clinical features and outcome in acute stroke patients with unrecognised diabetes mellitus B. Fuentes, E. Díez Tejedor, J. Castillo, J. Serena, A. Dávalos, A. Gil-Nuñez, J. Vivancos, J. Egido on behalf of the Stroke Project, Cerebrovascular Diseases Study Group, Spanish Society of Neurology Background: Up to 20 % of patients with acute stroke have unrecognized diabetes mellitus (DM). No prospective studies have addressed the clinical features and outcome of these patients. Methods: Secondary analysis of GLIAS (Glycaemia in Acute Stroke) Study: multicenter, prospective, observational study. Acute ischemic stroke (IS) patients (< 24 h from stroke onset) were included. Patients with no previous diagnosis of DM with A1cHb> 6.2 % were considered as unrecognized DM. Outcome was evaluated at 3 months follow-up. Results: 344 acute IS patients, 65 (18 %) of them have unrecognized DM.

They have lower rates of prior diagnosis of other risk factors: hypertension (42.6 vs. 69.5; p < 0.05) or dyslipemia (12.2 vs. 42.9 %; p < 0.05) and more frequent cardioembolic strokes (47.7 vs. 23.7 %; p < 0.05) than known DM. No differences in glucose levels or blood pressure evolution within the first 48 h or in outcome at 3 months (death 20.3 vs. 18.1 %; ns / death or dependence 55.9 vs. 47.6 %; ns) were found when comparing known and unrecognized diabetic patients. But they had higher infarct volume (median 60.8; IQR 17.3–122.4 vs. 49.2; IQR 2–110.6) and a non-significant trend to more frequent early neurological deterioration (40.7 % vs. 27.9 %; ns) than known diabetic patients Conclusions: Up to 18 % of acute IS patients are unknown DM. Although they have a possible underdiagnosis of other vascular risk factors, a trend to develop more frecuently early neurological deterioration and higher infarct size, in-hospital evolution and clinical outcome at 3 months of these patients is similar to that of known diabetics. P227 Late onset multiple sclerosis in Isfahan, Iran M. Saadatnia, M. Etemadifar, A. H. Maghzi, A. Ebrahimi, V. Shaygannejad, K. Basiri Isfahan University of Medical Science (Isfahan, IR) Objectives: The onset of Multiple Sclerosis (MS) after the age 50 is regarded as Late-onset MS (LOMS). There are few reports about the demographical and clinical characteristics of multiple sclerosis in Middle East. This study was designed to highlight the clinical and demographical features of patients with LOMS in Isfahan (a large province of Iran). Methods: Our survey examined 1606 clinically definite MS patients, diagnosed according to McDonald’s criteria, who were registered with the Isfahan MS Society till 31, December 2005. This association is the only one in Isfahan Province and nearly all MS patients in this region are registered. Results: 19 (1.1 %) were diagnosed as LOMS. The mean age of onset was 53.94 ± 3.59. The mean age of onset in males and females was not significantly different (54.3 ± 4.3 versus 53.55 ± 2.6, p> 0.5). The female to male ratio was 0.9:1. Disease course in 11 patients (57.9 %) was Relapsing-Remitting (RR), in 4 (21.1 %) was Secondary Progressive (SP) and in the remaining 4 cases (21.1 %) it was Primary Progressive (PP). The mean age of onset in patients with PP, RR, SP course was 53.5 ± 2.5, 54 ± 4.6, 53.5 ± 2.3, respectively. The most frequent first clinical presentations were brainstem symptom (42.8 %), sensory (31.6 %) and optic neuritis (21.4 %). The mean EDSS was 2.55 ± 1.45. Positive family history was observed in 10.5 %. Conclusion: LOMS was less common in our population and some of the rates observed among these patients differed from those reported in other regions, these differences maybe due to different ethnicity of Persian patients or to geographical differences. P228 Increased level of C-reactive protein at onset of acute ischaemic stroke correlates with elevation of leukocyte anti-sedimentation rate and S100 b and predicts outcome T. Molnar, A. Peterfalvi, L. Szereday, L. Szapary, S. Komoly, L. Bogar, Z. Illes University of Pecs (Pecs, HU) Objectives: Patients with stroke are more susceptible to bacterial infections, which is the leading cause of death in stroke. The innate immune system, especially leukocytes, provides an acute defense against infections. Leukocyte anti-sedimentation rate (LAR) is a specific test to detect early activation of leukocytes. Here, we examined LAR, C-reactive protein (CRP) and S100 b in patients within hours after onset of acute ischemic stroke (AIS) to characterize the innate immune response and its relation to the outcome. Methods: Venous blood samples were taken serially for measurement of LAR, S100 b, C-reactive protein (CRP) and procalcitonin (PCT) within 6 hours after onset of first symptoms (T0), at 24 (T24) and 72 hours (T72). After 24 hours, the enrolled patients were cathegorized into a definitive ischemic stroke based on the clinical and neuroimaging data. For statistical analysis Wilcoxon test, Spearman correlation and Mann-Whitney U test were used. Results: Twenty-two patients with AIS were examined. Median S100 b was significantly higher at T24 and T72 compared to values at T0 (p < 0.01, respectively,). We also observed a positive correlation between S100 b and LAR at 72 hours (p < 0.05). The initial CRP values correlated positively with S100 b and LAR at 72 hours (p < 0.05), while there was no change in PCT. Serum CRP levels at T0 were significantly higher in patients with poor outcome measured by Glasgow Outcome Scale (median: 7.5, IQR (3.25–171.5) vs. 4.75, (3.0–8.3), p < 0.05). Conclusion: Our results indicate a very early and rapid activation of innate immune responses in stroke (CRP, LAR) correlating with the size of in-

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farct, which might be important to combat infections. In addition, the initial elevation of the acute phase protein CRP predicts stronger leukocyte activation in 72 hours. However, initially high CRP also predicts an elevated S100 b at 72 hours indicating a bigger size of infarct resulting in a significantly poor outcome of stroke.

P231 Intravenous phosphocreatine improves neurological outcome in focal cerebral ischaemia and reperfusion T. Pfefferkorn, A. Trinkl, A. Bender, N. Wunderlich, G. F. Hamann, M. Dichgans, T. Klopstock Klinikum Grosshadern (Munich, DE); HSK Wiesbaden (Wiesbaden, DE)

P229 Six-month and five-year survival after acute ischaemic stroke in a hospitalbased population M. Reggiani on behalf of SINPAC Group (Società INter-regionale Piemonte e Valle d’Aosta per le Cerebrovasculopatie)

Objectives: Since intracellular phosphocreatine (PCr) acts as an anaerobe energy source that converts ADP to ATP, it may be of potential benefit in ischemic stroke. We investigated the effect of intravenous PCr on clinical outcome and infarct size in rats subjected to transient focal cerebral ischemia. Methods: Male Wistar rats weighing 280 to 320 g underwent 90 minutes of middle cerebral artery occlusion (MCA-O) by trans-carotid filament placement. During ischemia, animals received normal saline (n = 10) or PCr (n = 10; 100 mg/ml in normal saline) via the femoral vein.A bolus of 1 ml was given over 15 minutes followed by a continuous infusion of 1 ml/h. Treatment with PCr started 30 minutes prior to MCA-O and ended 15 minutes after reperfusion began with the retraction of the thread. After 24 hours of reperfusion a blinded neurological score (Garcia score) was obtained. The rats were killed and infarct volumes were quantified using stained cryosections and a morphometric imaging system. Results: Animals treated with PCr had a higher Garcia score, which reflects better neurological outcome, than controls (saline: 13.8±1.8; PCr: 16.1±1.1, p < 0.01). There was a strong but non-significant trend toward a smaller infarct volume in the treated animals (saline: 86.4±55.7 mm2; PCr: 50.7±44.4 mm2, p = 0.07). Conclusions: These results show that PCr improves neurological outcome in focal cerebral ischemia. PCr may therefore be of potential benefit in acute stroke treatment.

Objectives: To calculate the six month- and five year- survival rate of 443 patients consecutively admitted to eighteen Neurological wards in NW Italy from May to July 1999 for ischaemic stroke (first ever or recurrent) and to evaluate the role of major prognostic factors. Methods: We developed an hospital based data-base collecting information about pre-stroke conditions, risk factors, in-hospital course and follow up of stroke patients. Ischaemic stroke subtypes were topographically classified according to Bamford’s criteria and etiologically according to the TOAST criteria. Stroke severity was determined applying Glasgow Coma Scale (GCS) and Modified Rankin Scale (MRS). Survival rate was evaluated at six months and five years. Results: 40.5 % of patients were males and the mean age was 71 ± 12 years. Strokes subtypes were: large-artery atherosclerosis (33 %), smallartery occlusion (30 %), cardioembolism (17 %), other causes (3 %) and undetermined (17 %). 37 % were PACI, 28 % LACI, 20 % TACI, and 15 % POCI. Thirteen patients were lost at the end of follow up, for a total rate of 3 %. Overall survival was 84 % at six months and 60 % at the end of the 5th year of the follow up. Survival probability at 6 months and 5 years showed significant statistical differences for age, institutionalization before stroke and a history of previous vascular disease. Higher GCS and lower MRS scores at admission were predictive of higher survival probability both at 6 months and 5 years, while medical or neurological complications correlated with higher mortality. Stroke etiology was significantly predictive only at short term, while topography was also a late predictive factor (6-month and 5-year survival rate: TACI 52.4–29.2 %; PACI 89.2–66.2 %; POCI 86.2–67.3 %; LACI 96.8–70.3 %). Lower MRS score at discharge and being discharged home or to a rehabilitation unit were significantly predictive for both the endpoints. Treatment with ASA, oral anticoagulants and antihypertensive drugs at discharge and at six months were significantly associated with higher survival after 5 years of follow up. The six-month MRS score was the main predictive factor for 5-year survival at multivariate analysis. Conclusion: We found that stroke prognosis at five years is determined either by pre-stroke risk factors, stroke characteristics, in-hospital variables, prophylactic treatments and functional recovery in the first months after the event. P230 Matrix metalloproteinase-2 –1306 C/T polymorphism and risk for aneurysmal subarachnoid haemorrhage A. Borratynska, A. Slowik, T. Dziedzic, J. Pera, A. Klimkowicz-Mrowiec, D. Wloch, R. Czepko, A. Szczudlik Jagiellonian University (Krakow, PL) Epidemiological studies evidenced that genetic factors affect the risk of aneurysmal subarachnoid hemorrhage (SAH). The aim of the study was to determine whether the –1306 C/T polymorphism of matrix metalloproteinase-2 (MMP-2) gene influences the risk for aneurysmal SAH. A total of 240 patients with aneurysmal SAH and 239 subjects, matched by age and sex from the general population were studied. Aneurysmal SAH was diagnosed by cranial computed tomography, and/or lumbar puncture and digital subtraction angiography. Data concerning demographics and risk factors for SAH were collected. MMP-2 genotypes were determined by PCR and RFLP methods. The MMP-2 genotype distribution in patients with aneurysmal SAH (CC-60 %, CT–36.7 %, TT–3.3 %) differed significantly from the controls (CC-55.2 %, CT–36.8 %, TT-8 %) (p < 0.001). A logistic regression model showed that the TT genotype of MMP-2 gene was independent from cigarette smoking, excessive alcohol consumption, hypertension, and hypercholesterolemia as a risk factor for aneurysmal SAH (OR = 0.69, 95 % CI: 0.49–0.97). The study shows for the first time that TT genotype of MMP-2 –1306 C/T polymorphism is associated with the reduced risk of aneurysmal SAH in a Polish population.

P232 Acute stroke due to MCA occlusion: intra-arterial thrombolysis A. Calado, I. Henriques, R. Roque, A Bandeira, I. Fragata, C. Ribeiro, J. Cândido, J. Reis Centro Hospitalar Lisbon – Zona Centro (Lisbon, PT) Background: Standard treatment for acute ischemic stroke in eligible patients is intravenous (ev) thrombolysis, but efficacy is limited by low rates of recanalization. Intra-arterial (IA) thrombolysis, combined transcranial ultrasound, or clot retrieval devices are being evaluated to improve thrombolysis efficacy. We prospectively studied consecutive patients with acute MCA occlusion submitted to IA rt-PA thrombolysis in the first 6 hours after symptoms onset. Methods: We included patients not eligible for ev thrombolysis according to ECASS criteria. We excluded patients with vertebrobasilar stroke and with previous concomitant ev thrombolysis. Symptomatic cerebral hemorrhage was considered if associated with clinical deterioration. Major neurological improvement was defined as a reduction of more than 7 points in NIHSS after procedure. Excellent or good outcome was considered if modified Rankin scale was 2 or less. We studied 15 consecutive patients referred to our stroke unit (5 male) with median age of 72 (43– 78) years. Results: Median NIHSS at admission was 19 (15–25), and 12 at discharge (2–25). MCA recanalization was total in 33 % (TIMI grade 3) and partial (TIMI grade2) in 67 %. In five patients, recanalization was achieved together with a mechanical thrombectomy device. Hemorrhagic transformation was present in 7 patients (46 %), and symptomatic in 5 (33 %). Three patients died (20 %) in the first 72 h and none after. At discharge, excellent or good outcome was observed in 27 % of the patients. Discussion: n this group of large MCA infarcts not eligible for ev thrombolysis, total recanalization was achieved in 33 % and partial in 67 %. Mechanical thrombectomy device was used together with IA rt-PA thrombolysis in 33 % of our patients. Independency was achieved in 27 % at discharge. Since patients not eligible for ev thrombolysis with large MCA infarcts have a very high rate of disability and mortality, IA thrombolysis alone or together with mechanical device can be an alternative to current treatment. Randomized trials may confirm safety and efficacy in larger series. P233 Statins reduce neurofibrillary-tangles burden in a transgenic mouse model for tauopathy and Alzheimer’s disease M. Boimel, N. Grigoriadis, A. Lourbopoulos, L. Rozenstein, O. Touloumi, O. Abramsky, H. Rosenmann Hadassah University Hospital (Jerusalem, IL); AHEPA University Hospital (Thessaloniki, GR) Background: Statin treatment is associated with a reduced risk of developing Alzheimer’s disease (AD) and reduces amyloid deposition in AD mouse-

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models. No data are available regarding the effect on neurofibrillary-tangles burden (NFT), the aggregates of hyperphosphorylated-tau-protein which are the best correlate of dementia. Objective: To study the effect of statins on NFT pathology in our tgmouse-model for NFT (mutant P301S/K257T tau-protein). Methods: 1. Aged normocholesterolemic-mice (standard-diet fed) were treated with or without simvastatin [Blood-Brain-Barrier (BBB) permeable] for 1 month. 2. Young hypercholesterolemic-mice (western-diet fed) were treated with or without atorvastatin (BBB impermeable) for 5 months. Brains were examined for NFT burden with Gallyas-staining, and with antiphospho202/205- and anti-phospho231-tau immunohistochemistry, aswell-as for glia. 3. To elucidate whether the statin effect is cholesterol dependent we examined the effect of ezetimibe, a non-statin cholesterollowering-agent, and of a fat-lowering diet – on the NFT burden. Results: 1. One-month treatment of the normocholesterolemic-mice with simvastatin reduced the NFT burden by 25–31 % (phospho202/205and phospho231-tau immunoreactivity) relative to non-treated-controls (p = 0.005), with a 26 % decrease in microglia (p < 0.001). 2. Five-month treatment of the hypercholesterolemic-mice with atorvastatin reduced the NFT burden by 53–59 %, with 20 % decrease in microglia (p < 0.001). 3. Interestingly, the ezetimibe treatment in hypercholesterolemic-mice showed a 0–33 % decrease in phospho202/205- and phospho231-tau immunoreactivity (smaller decrease relative to atorvastatin, p < 0.001), with no effect on glia. Low fat diet showed even a smaller NFT-decrease (12–13 %). Conclusion: Statins significantly reduced NFT burden. This effect was irrespective of BBB permeability, or of onset and duration of treatment. The statin effect was evident both in normo- and hypercholesterolemic-mice, and was greater than with ezetimibe, or low-fat diet. This, and the statin-induced decrease in microglial- activation (considered to be involved in tauhyperphosphorylation), suggests that the anti-NFT effect of statins may-be related to their anti-inflammatory properties and not only to cholesterollowering.

Neuro-ophthalmology P234 How the “sinister” Tolosa-Hunt syndrome is related to the dural arteriovenous fistula in painful ophthalmoplegia: a case report S. Doitsini, E. Tsirka, I. Papadopoulos, V. Tsirka, N. Ververis, C. Chrisopoulos, K. Michailidis 2nd Hospital I. K.A “Panagia” (Thessaloniki, GR) Objective: While the diagnosis of Tolosa-Hunt syndrome (THS) is based on the presence of a unilateral painful ophthalmoplegia (PO) with palsies of defined cranial nerves, normal neuroimaging and a dramatic response to steroid therapy, numerous publications and case reports showed that other causative lesions especially of the region of the cavernus sinus such as dural arteriovenous fistula (dAVFs) have a close relation to THS. Methods: We report here a 62 years old female patient presenting with PO, exophthalmus, oculomotor nerve paresis, periorbital pain, diplopia, chemosis of the conjuctiva. There were no subjective and objectine bruits. The magnetic resonance image of brain showed dilatation of vein vessels in left hemisphere. She was treated with steroids in high doses and after 3 days there was an important improvement. The further investigation with Digital Seldiger Angiography (DSA) showed dAVFs in the right cavernus sinus which is supplied by branches of right external carotid artery (RECA). Due to dAVFs, RECA is drained through the cavernus sinus to the veins of left hemisphere.Embolism was taken place with success. The follow up is normal and she is free of symptoms three years after. Discussion: Although it is believed that the response to the steroid therapy and the exclusion of other causative lesion by neuroimaging are the diagnostic criteria for THS, steroid-responsive PO has been observed also in numerous pathological cases such as aneurysms, pachymeningitis, parasellar tumors and dAVFs. As dAVFs is concerned, the etiology is still controversial. While sinus thrombosis, trauma, venous hypertention and congenital origin have been proposed as probable causes, the inflammatory process which leads to several reactions such as the production of vascular connections between the dura mater and the patent portion of the sinus is considered to be the most plausible.Therefore THS that is attributed to nonspecific granulomatous inflammation in the cavernous sinus, is considered to be a candidate for the development of dAVFs. Furthermore the complete efficacy of steroid therapy suggests that inflammation was a key factor in dAVFs. On the other hand it is not sure that there wouldn’t have been a remission without embolism. Conclusion: It is clear that further study is necessary to clarify dAVFs treatment and its etiology. Also necessary is the revision of the criteria for

THS because firstly it can no longer be considered as being exclusive of neuroimaging abnormality and secondarily its “steroid responsiveness” must be reconsidered. P235 Opsoclonus as a first sign of breast cancer – a case report I. Marjanovic, D. Lavrnic, I. Basta, A. Nikolic, S. Apostolski Clinical Centre of Serbia (Belgrade, RS) Objective: To emphasize the importance of extensive investigation for underlying malignancy in every patient with opsoclonus. Case report: We report a 65-year-old female patient with 8-months long history of intensive dizziness, nausea, vomiting, blurred vision and walking instability. Her neurological examination revealed bilateral reduction of visual acuity and opsoclonus. Muscle reflexes were increased, more pronounced on the left side, and plantar response was bilaterally absent. She was not able to stand or walk independently. Blood tests revealed only increased ESR (42/74mm). CSF analysis showed pleocytosis (51 cell/mm3), with normal protein and glucose content. IEF showed oligoclonal bands in CSF and normal serum finding. EEG showed global mild encephalopathic pattern. Thyroid function was normal. MRI of endocranium showed multiple subcortical focal lesions and periventricular encephalopathic changes indicating subcortical encephalopathy. General physical examination descovered tumor in the upper lateral quadrant of the right breast with one enlarged lymph node in the same axillar region. The diagnosis was confirmed by ultrasonography and mammography. Chest X-rays and the abdomen ultrasound were normal. Tumor was completely removed and pathohystological finding confirmed lobular invasive breast carcinoma (gradus III; T2 N1, M0; NG III), with metastasis in limph nodes and infiltration of capsular and perinodal tissue. The patient was treated with Nolvadex and with corticosteroids for paraneoplastic opsloclonus. On control neurological examination six months later patient was in much better condition, with improved independent walking ability. The opsoclonic movements of the eyes were significantly reduced, while the rest of neurological examination as well as MRI of endocranium was not changed. Conclusion: Opsoclonus may be the first symptom of breast cancer, and it may respond to removal of the tumor tissue, antineoplastic and corticosteroid therapy. P236 Visual search strategies in homonymous hemianopia B. Machner, A. Sprenger, D. Kömpf, H. Kimmig, C. Helmchen, W. Heide Universitätsklinikum Schleswig-Holstein (Lubeck, DE); General Hospital Celle (Celle, DE) Objectives: Task-related visual search strategies in hemianopic patients are largely unknown. Previous studies explored scanning paths of hemianopic patients using either complex images without single feature-related tasks or indiscriminable targets. We asked whether parallel (bottom-up) and serial (top-down) search mechanisms remain intact with occipital lesions presenting with severe visual field loss? Does homonymous hemianopia affect visual search just as a pure sensory deficit? Methods: We recorded eye movements during visual search in 9 patients and 10 age-matched control subjects by using the search-coil technique. All patients were examined within the first few weeks following the acute stroke (mean 13 days, range: 8–30 days). Goldmann perimeter revealed homonymous hemianopia in all of them (5 left sided, 4 right-sided). Targets for visual search differed by their colour and form, among which targets, defined by colour and shape, had to be detected and marked by a mouse click. Results: Patients showed longer search durations due to a higher number of saccades, which were overall smaller than in control subjects. Although they repeatedly looked to previously fixated locations (re-fixations) spatial working memory appeared normal as they did not misjudge old targets as new (no re-clicks). Strategic search (top-down) was mainly intact in patients, however patients failed to use easy parallel search suggesting they did not benefit from pop-out stimuli. Hemifield analyses did not show any differences concerning number of fixations, however the amplitude of saccades towards the blind hemifield was significantly smaller in patients. Conclusion: Visual search in patients with homonymous hemianopia due to an acute occipital stroke is largely affected by the acute visual sensory loss which causes the higher number of saccades with smaller amplitudes. In contrast higher cortical functions like strategic planning or working memory are intact.

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P237 Abnormal back up saccadic eye movements (“quiver”) during smooth pursuit eye movements: sensitive and specific signs of myasthenia gravis T. Sander, A. Sprenger, B. Machner, D. Kompf, H. Rambold, C. Helmchen University of Lubeck (Lubeck, DE) Objective: Apart from exercise-induced gaze limitation, dysmetria and slowing of saccades, so-called “quiver” eye movements are indicative of ocular myasthenia gravis (MG). “Quivers” are small amplitude saccades that often overshoot the target on attempted saccades (Cogan et al. 1976). They are usually associated with hypermetric saccades, increased initial saccade velocities and may occur in cogwheel (saccadic) pursuit eye movements with catch-up saccades. Here we show that quiver-like movements can clinically be found in MG patients with normal pursuit gain and we propose that they are highly specific for MG. Methods: We examined a 60 years old patient with an acquired ocular MG with ACHR auto-antibodies. She suffered from progressive exercise-induced diplopia. On examination she had small amplitude conjugate back-up saccades during smooth pursuit eye movements. Results: Binocular magnetic search coil recordings revealed a binocular saccade hypermetria for small and large amplitudes. Saccade velocities for small amplitudes were higher than in normal controls. Smooth pursuit gain was normal but pursuit was intercepted by a small back up saccade which was then followed by a catch up saccade after a short intersaccadic interval. These quiver-like eye movements were conjugate. Conclusions: The following conclusions emerge from this clinical study: 1) “Quiver” eye movements are very sensitive and highly specific saccadic disorders in myasthenia gravis, which can be observed not only with attempted saccades but also during normal smooth pursuit at the bed-side. 2)They probably reflect sparing of specific extraocular muscle fibers, i. e. fast-twitch fibers in MG. 3)Their conjugacy argues for a central gain up-regulation rather than for an interaction of the extraocular “fast twitch” fibers with the mechanical forces of the orbita. P238 Peripheral vestibular lesion which impairs the low but not high frequency function of the vestibulo-ocular reflex B. Machner, S. Gottschalk, T. Sander, H. Rambold, C. Helmchen Universitätsklinikum Schleswig-Holstein (Lubeck, DE) Objectives: Peripheral vestibular hypofunction can be identified by asymmetric vestibular responses to caloric irrigation of the horizontal semicircular canal or by the head impulse test (Halmagyi-Curthoys test). Whereas the former test investigates the low frequency function of the vestibulo-ocular reflex (VOR) the latter assesses the high-frequency function. The biologically more relevant high-frequency VOR function is usually more persistently impaired in unilateral vestibular lesions (e. g. vestibular neuritis) than the low-frequency function and thus the more sensitive parameter to detect chronic peripheral vestibular deficits. Methods: We present a case history of a 47 year old patient with an intralabyrinthine schwannoma who presented with a 3 year history of repetitive episodes of short-lasting (minutes) vertigo and lateropulsion to his right side. Prior to the onset of vestibular symptoms, he reported of an acute hearing loss on the right side with still persisting tinnitus. Results: Neurological examination was normal, including head impulse testing. Serial caloric irrigation tests revealed a caloric hyporesponsiveness of the right side (43–61 % canal paresis). Scleral search coil recordings during head impulse testing showed normal VOR gain to both sides. Audiometry revealed a right-sided sensorineural pancochlear hearing loss of about 60 dB NHL. Click-evoked myogenic potentials and subjective visual vertical were normal. High resolution MRI showed a contrast enhanced structure in the right labyrinthine vestibule with a diameter of 3 mm (T1 weighted image). On T2 – weighted images this lesion revealed decreased signal intensity suggesting intralabyrinthine schwannoma. The lesion involved the right vestibule, parts of the horizontal semicircular canal and possibly proximal aspects of the cochlea. High resolution CT (slice thickness 1 mm) showed a normal bony labyrinth on both sides. Conclusion: The data indicate a selective impairment of the VOR in the low-frequency range with sparing of the high frequency VOR. Implications are twofold: First, normal high-frequency VOR testing (usually taken as the gold standard in detecting peripheral vestibular deficits) does not exclude a peripheral vestibular lesion. Second, vestibular afferents conveying the high and low frequency VOR from the horizontal semicircular canal (ampulla) may be anatomically different and functionally dissociated.

P239 Head-bending nystagmus in benign paroxysmal positional vertigo involving the horizontal canal J. S. Kim, S. Lee, S. H. Park, K. D. Choi, S. Y. Oh, S. H. Jeong, Y. M. Oh, H. J. Kim, J. W. Koo Seoul National University (Seongnam-si, KR); Chonnam National University (Kwangju, KR); Pusan National University (Pusan, KR); Chonbuk National University (Jeonju, KR) Objective: In benign paroxysmal positional vertigo involving the horizontal canal (HC-BPPV), nystagmus may be induced by head-bending while sitting.To determine the characteristics and lateralizing value of head-bending nystagmus in HC-BPPV. Methods: Using video-oculography, head-bending nystagmus was recorded in 54 patients with HC-BPPV (32 canalolithiasis and 22 cupulolithiasis). Lesion side was determined by comparing intensity of the nystagmus induced by lateral head turning (head-turning nystagmus) in supine. Results: Head-bending nystagmus was observed in 39 patients (72.2 %) and lying-down nystagmus in 41 (75.9 %). Thirty three patients (61.1 %) showed both types of nystagmus while six (11.1 %) had only head-bending and another eight (14.8 %) showed only lying-down nystagmus. In 45 patients with asymmetrical head-turning nystagmus, the direction of headbending nystagmus was mostly toward the affected ear in canalolithasis (88.9 %) and toward the intact ear in cupulolithasis (80 %). In 9 (16.7 %) patients whose affected ear could not be determined due to symmetrical headturning nystagmus, the particle repositioning maneuver based on the direction of head-bending or lying-down nystagmus resulted in the resolution of symptom. Two patients showed a transition from canalo- to cupulolithiasis during head-bending posture. Conclusion: In HC-BPPV, head-bending may generate nystagmus by inducing ampullopetal migration of the otolithic debris in the horizontal canal or by ampullofugal deflection of the cupula by the attached otolithic debris. Head-bending nystagmus may be a valuable sign for lateralizing the involved canal in HC-BPPV, especially when patients show symmetrical headturning nystagmus. Conversion of canalo- into cupulolithiasis by headbending supports the current explanation of the mechanisms of HC-BPPV. P240 Cyclosporine A treatment for ocular involvement of Behçet’s disease: is it associated with an increased risk of neurological involvement? G. Akman-Demir, G. Demir, O. Ayranci, E. N. Vanli, M. Mutlu, M. Kurtuncu, I. Tugal-Tutkun Istanbul University (Istanbul, TR) Background and objective: Cyclosporine A is a kinase/phosphatase inhibitor which has been widely used in ocular involvement of Behcet’s disease (BD). Recently it has been debated that cyclosporine A may be increasing the risk of neurological involvement in BD. The aim of this study is to determine whether such a risk exists. Patients and methods: All the files between January 2000 and January 2005 in the Ophthalmology Department of Istanbul Medical Faculty were screened retrospectively. Those patients who were sent to the neurology department for neurological complaints were evaluated. The patients with and without neurological involvement were compared regarding their baseline treatment modalities. Results: There were a total of 404 patients (118 Females and 286 Males) with BD seen at the ophthalmology department within this period. Among these patients 24 had been initialy seen at the neurology department and were subsequently sent to the ophthalmology department; 47 had been sent for routine uveal evaluation, but not found to have ocular involvement; and 64 had inadequate follow-up. Therefore these 135 patients were excluded from the analysis. The remaining 269 patients were either receiving cyclosporine (Group I: 92 patients; 19 F, 73 M), azathioprine and /or other immunosuppresant medication (Group II: 132 patients; 32 F, 100M), or they were not receiving any long-term treatment (Group III: 45; 16F, 29M). In Group I, 21 patients were sent to the neurology department.Among these 10 had headache, one had depression, one had sinus thrombosis, and 8 had parenchymal neurological involvement. On the other hand, 13 patients from Group II were sent to the neurology department, and among these patients, 10 had headache, one had premorbid epilepsy, one had sinus thrombosis, and one had parenchymal neurological involvement. In Group III all 5 patients sent to the neurology department had headache. Parenchymal neurological involvement was significantly higher among patients treated with cyclosporine A, and it included atypical findings such as epileptic seizures, and atypical MRI lesions besides typical brainstem involvement. Eye involvement also tended to be more severe in Group I. Conclusion: Although the reason for this is unknown yet, cyclosporine A

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treatment seems to be associated with an increased risk of developing parenchymal neurological involvement in Behçet’s disease. P241 Follow-up of vestibular function in bilateral vestibulopathy V. C. Zingler, E. Weintz, K. Jahn, A. Mike, D. Huppert, N. Rettinger, T. Brandt, M. Strupp University of Munich (Munich, DE); University of Pécs (Pécs, HU) Objectives: Bilateral vestibulopathy (BV) is an often overlooked vestibular disease with various etiologies. Until now, only small case series have reported on the course of the disease. Our main goal was to determine the frequency and extent of recovery or worsening of vestibular function and their dependence on the etiology of BV. Methods: 82 patients (59 males, 23 females; mean age 56.3±17.6 years) diagnosed with BV in our dizziness unit between 1993 and 2005 were examined in a follow-up study. All underwent a neuro-ophthalmological and neuro-otological examination and electronystagmography with caloric irrigation and measurement of the mean peak slow phase velocity (SPV) at the initial and follow-up investigation. All patients subjectively evaluated at the time of follow-up (1) the course of their diseases by comparing any changes in imbalance and gait unsteadiness and (2) the changes in their health-related quality of life with a self-classification system. Cranial MRIs were performed in 78 patients. Results: The average follow-up time was 51±36 months. Overall, the statistical analysis of mean peak SPV of caloric-induced nystagmus revealed no significant change over time (initial SPV 3.0±3.5 degrees/sec (deg/sec) or at follow-up 2.1±2.8 deg/sec).As regards the etiological subgroups, only caloric responses of patients with BV due to meningitis slightly increased at followup (initially 1.0±1.4 deg/sec and at follow-up 1.9±1.6 deg/sec); however, this was not significant.Vestibular outcome was independent of age, gender, time course of manifestation of BV (slowly progressively or sequentially with preceding attacks of vertigo), and severity of BV. Single analysis of each patient showed that caloric responses substantially improved by ≥ 5 deg/sec in only two patients on both sides (idiopathic BV n = 1, Sjögren’s syndrome n = 1) and in eight patients on one side (idiopathic n = 6, meningitis n = 1, Menière’s disease n = 1). Forty-three percent of the patients graded the course of their diseases as stable, 28 % as worsened and 29 % as improved. Eighty-four percent of the patients stated that BV impaired their health-related quality of life (42 % slightly, 24 % moderately, 18 % severely). Conclusions: Our data support the view that the prognosis of BV is less favorable than assumed.Vestibular function remains impaired or lost in the majority of these patients regardless of the etiology. P242 Pseudoxanthoma elasticum and cerebral small vessel disease: a case report K. Papadopoulos, M. Paschalidou, E. Zotta, N. Taskos, I. Milonas Ahepa University Hospital (Thessaloniki, GR) Objectives: Pseudoxanthoma Elasticum (PE) is a hereditary connective tissue disorder with characteristic skin lesions (soft ivory coloured papules in a reticular pattern that predominantly affect the neck), lesions in the posterior segment of the eye and cardiovascular manifestations such as, peripheral arterial occlusive disease, coronary occlusion and gastrointestinal bleeding.Cerebral small vessel disease is rarely described in association with PE. This autosomally inherited disease has attributed to mutations in the ABCC6 gene located on 16p13.1. Recent studies suggest that PE is inherited almost exclusively as an autosomal recessive trait. We report a patient with characteristic eye lesions, arterial hypertension, who was admitted to our clinic due to episodes of relapsing right hemiparesis. Methods: The patient, a 56 years old woman, was admitted to our clinic for two episodes of right hemiparesis lasting for 25 minutes each one. The patient has a medical history of light coronary disease due to arterial hypertension. The patient didn’t exert any other symptoms in the past and she did not have any familial known medical vascular history. Results: Her clinical examination revealed right pyramidal signs, with babinski and Hoffman signs to be positive, marked tendon reflexes of the right extremities, without muscle weakness ipsilaterally. Her visual acuity was 4/10 to her left eye and 8/10 to the right eye. Her skin did not have any lesions. The ophthalmological examination revealed exudative maculopathy, choroidal haemorrhage, due to angioid streaks. The latter are pathognomic for PE. The arterial blood pressure was normal. Brain magnetic tomography showed small vessel cerebral disease. The fluorangiography was positive for hyperfluorescence due to retinal pigmented epithelium and detection of choroidal neovascularization.Ultrasonography of the extra-intra cranial major arteries was normal. The cardiac examination as well as her paraclinical testing (echocardiography) was unremarkable for the present time.

Conclusions: PE is rarely manifested with small vessel cerebral disease. However in some cases it may be part of the disease, as the disease itself may include cardiovascular manifestations. For the opthalmological lesions, experimental therapy is proposed with intraocular injections of vascular endothelial growth factor. Antiplatelet therapy for the cerebral microangiopathy is also proposed. P243 Vertical “one and a half syndrome” in a patient with unilateral thalamomesencephalic infarct I. Markakis, M. Dimitraka, M. Xifaras, G. Gekas General Hospital of Nikea (Piraeus, GR) Objectives: Vertical “one and a half syndrome” is a rare oculomotor disorder, consisting in conjugate upgaze palsy with concomitant monocular downward paralysis. It occurs as a result of lesions in structures involved in the supranuclear control of vertical eye movements, like the interstitial nucleus of Cajal, and the rostral interstitial nucleus of the medial longitudinal fasciculus. We present a patient with vertical “one and a half syndrome”, complicating an ischaemic stroke in the left thalamo-mesencephalic junction. Case-history: A 47 year old man with a history of diabetes mellitus presented with sudden vertical diplopia. Neurological examination revealed a conjugate upgaze palsy, unilateral paralysis of left ocular infraversion and impaired convergence of the left eye. Horizontal gaze movements and oculocephalic reflexes were normal. Extracranial Doppler ultrasonography and digital cerebral angiography were negative. MR imaging of the brain demonstrated an acute ischaemic infarct in the paramedian region of the left thalamus, extending to the ipsilatareal portion of the rostral midbrain. Over the next days, vertical eye movements and diplopia showed a significant improvement, with almost complete remission at 2 weeks. Conclusion: The vertical “one and a half syndrome” is highly suggestive of lesions involving the medial rostral mesencephalon. These lesions produce a conjugate palsy of upward gaze, since the supranuclear pathways for upgaze control are crossed in the posterior comissure. However, the impairment in downward gaze is unilateral, because the supranuclear fibers that control downgaze remain uncrossed. Further studies are needed in order to clarify the precise functional neuroanatomy of vertical eye movements. P244 Differentiation of internuclear ophthalmoplegia and myasthenic pseudointernuclear ophthalmoplegia by subjective visual vertical A. Zwergal, H. Neugebauer, T. Brandt, M. Strupp University of Munich (Munich, DE) Objectives: Internuclear ophthalmoplegia (INO) is characterized by an adduction deficit on lateral gaze and a dissociated nystagmus of the abducting eye. In the majority of cases INO occurs with lesions of the medial longitudinal fascicle (MLF) caused by multiple sclerosis or ischemia. However, extraocular muscle weakness in myasthenia gravis (MG) can mimic this ocular motor pattern and has been referred to as pseudo-internuclear-ophthalmoplegia (pseudo-INO). Differentiation between these entities can be difficult but is crucial for choosing specific therapeutic strategies.We here report that measurement of the subjective visual vertical (SVV) reliably differentiates INO from pseudo-INO. Methods: In a retrospective study 10 patients with a unilateral pseudoINO due to MG were compared with a control group of 15 patients with unilateral INO due to CNS disease.All patients underwent a detailed neuro-ophthalmological examination and thin-slice magnetic resonance imaging (MRI) of the brainstem. Acetylcholine-receptor (AChR) antibody titer testing and the Tensilon test were done, if a myasthenic origin of INO was suspected. Results: Only 50 % of patients with the initial presentation of myasthenic pseudo-INO showed positive AChR antibodies and 60 % a positive Tensilon test. Brainstem lesions could not be excluded definitely in 20 % in MRI. Taken together initially more than 30 % of myasthenic pseudo-INO cases remained with diagnostical uncertainty. In these patients the diagnosis of MG was established later in the course of the disease. In the control group of INO, only 70 % showed characteristic unilateral MLF lesions on MRI. The others could be diagnosed only on the basis of subtle additional central oculomotor findings (vertical nystagmus of small amplitude in the scanning laser ophthalmoscopy, low-grade skew deviation). Thus, none of the common diagnostic tests had satisfactory selectivity that allowed reliable differentiation of pseudo-INO from INO. However, as the major result of this study, it could be shown that all patients with INO had pathological deviations of the SVV (from true verticality) to the contralateral side (mean: 5.3; range: 2.5–13) whereas none of the patients with pseudo-INO had SVV values out of the normal range (mean: 1.1, range: -1.8–2.3).

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Conclusions: Measurement of SVV has a discriminatory power of 100 % for the separation of pseudo-INO and INO and therefore provides a new reliable clinical tool for differential diagnosis. P245 High correlation between ocular tilt reaction and contralateral internuclear ophthalmoplegia in paramedian posterior brainstem lesions A. Zwergal, H. Neugebauer, M. Glaser, T. Brandt, M. Strupp University of Munich (Munich, DE) Objectives: The ocular tilt reaction (OTR) is characterized by displacement of the subjective visual vertical (SVV), ocular torsion (OT), and skew deviation (SD); it is most likely caused by lesions of graviceptive pathways (GP). Their anatomical localization within the brainstem is not precisely known, but evidence points to the paramedian posterior tegmental region, next to or within the medial longitudinal fascicle (MLF). Patients with lesions of the MLF regularly present with ipsilateral internuclear ophthalmoplegia (INO). Thus, the aim of the present study was to clarify GP localization by analyzing the correlation of INO, OTR, and brainstem lesions. Methods: In a retrospective study we analysed 120 patients with INO (87 unilateral, 33 bilateral) for signs of OTR and localization of lesions in magnetic resonance imaging (MRI). All patients underwent a neuro-ophthalmological examination including measurement of SVV (psycho-physical), OT (scanning laser ophthalmoscopy), and SD (cover test, prisms). Lesion localization was drawn from thin-slice MRI. Results: Unilateral INO was accompanied by at least one component of OTR in 98 % of the patients; all tilt effects were contraversive. SVV tilt was contralateral to the INO in 96 % (mean: 6.1 range: 2.6–36.1), corresponding OT in 80 % (54 % monocular, 26 % binocular), and SD in 50 % (contralateral eye undermost). MRI detected brainstem lesions in only 68 % of all patients with unilateral INO. Most lesions (96 %) were in the paramedian posterior pontomesencephalic region on the side contralateral to the OTR, involving the area of the MLF (from levels between the nucleus VI and III). Interestingly, examination of 33 patients with bilateral INO for components of OTR revealed that only three had a pathologic tilt of the SVV, and one, OT and SD. Conclusions: The high correlation between the side of a unilateral INO and contraversive components of OTR suggests that the GP run in the posterior paramedian tegmentum within or near the MLF. In agreement with this hypothesis, patients with bilateral lesions of this region do not present with OTR due to functional counterbalancing defects in GP of both sides. MRI data confirm that unilateral INO with contraversive OTR is caused by a lesion in the paramedian posterior pontomesencephalic brainstem. Furthermore, our data show that clinical findings (especially SVV deviation) are far more sensitive for monitoring lesions near the MLF than MRI. P246 Downbeat nystagmus after epidural administration of morphine R. Gordo Mañas, A. Villarejo Galende, L. Ballesteros Plaza, C. Domínguez González, A. Sánchez Ferro Hospital Doce de Octubre (Madrid, ES) Objective: Downbeat nystagmus is a spontaneous downward-beating jerk nystagmus present in primary position that increases in downgaze. This uncommon type of nystagmus can result from cerebellar disorders, craniocervical junction abnormalities, focal brainstem lesions, hydrocephalus or toxic-metabolic disorders.We present a rare case of drug-induced downbeat nystagmus. Methods: A case description Results: We present a 74 year old man who underwent radical cystoprostectomy during treatment of infiltrating tumour of the urinary bladder, and subsequently developed typical downbeat nystagmus after epidural administration of morphine for pain relief. No other neurological symptoms or signs were reported or found on physical examination. Neuro-ophthalmological findings disappeared 24 hours after morphine infusion withdrawal. A magnetic resonance imaging scan only showed periventricular small vessel disease. We also review similar cases reported in literature and experimental models approaching pathophysiology of downbeat nystagmus. Conclusion: Although classically related to craniocervical junction pathology, drugs are a well recognised cause of downbeat nystagmus. Diagnosis is made on clinical grounds. Presentation of this ophthalmological movement disorder as an adverse effect of epidural morphine administration must be kept in mind as these procedures become more widely used.

Extrapyramidal disorders P247 Huntington’s disease: experiences with diagnostic and predictive testing in Czech Republic J. Roth, J. Klempir, J. Zidovska Charles University (Prague, CZ) Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by increased number of CAG triplets in the IT15 gene on the 4th chromosome, resulting in polyglutamine expansion in the huntingtin protein. Clinically, HD is manifested by choreatic dyskinesias, personality changes, behavioral disturbances and progressive cognitive deterioration. The IT15 gene was discovered in 1993. From 1994 we performed 701 genetical tests (630 diagnostic, 70 presymptomatic and 1 prenatal). Diagnostic test confirmed the clinical diagnosis of HD in 72.5 % of all patients. New mutation was found in 2 cases. In cases with positive family history we confirmed HD in 95 %, in cases with negative family history in 18 % and in case with unknown family history in 60 % of patients. Presymptomatic testing was finally accepted by 33 % of applicants. The mutation was found in 41 % of these cases. The acceptance of presymptomatic testing was only 4 % of estimated risk population. DNA analysis is the reliable diagnostic tool for HD in patients with clinical symptoms. Low acceptance of predictive testing in people at risk is caused most probably by the lack of effective HD treatment. Supported by MSM 0021620849. P248 Ataxia as a main manifestation of celiac disease J. I. Castro-Macias, A. A. Lugo-Pon, G. A. Cárdenas Hernandez National Institute of Neurology of Mexico (Mexico City, MX) Background: Celiac sprue, also known as celiac disease or gluten-sensitive enteropathy, is a chronic disease of the digestive tract that interferes with the digestion and absorption of food nutrients. People with celiac sprue cannot tolerate gluten, a protein commonly found in wheat, rye, and barley. Most patients with celiac disease tolerate oats, but they should be monitored closely. When people with celiac sprue ingest gluten, the mucosa of their intestines is damaged by an immunological mediated inflammatory response, resulting in maldigestion and malabsorption. Patients can present with failure to thrive and diarrhea. However, some patients have only subtle symptoms or are asymptomatic. The neurological manifestations are infrequent but it calculates that they occur in 10 % of the cases of confirmed celiac disease. Case report: a 68 year old woman, right-handed. She presented a 5 year history of ataxia of gait, dysarthria, and slowly progressive, Neurological examination revealed hipotonía, dysartria, dysmetria, dysdiadochokinesia, and impaired check response, kinetic and static tremors. The magnetic resonance showed cerebellar atrophy. Complementary studies were normal (general laboratory test, CSF examination, hormonal profile and serological tests for HIV and syphilis, antibody paraneoplastic, and levels of Vitamin E, B1, B6, B12). Genetic tests for spinocerebellar ataxia 2, 10, 17, Frataxin was negative. Electrophysiological studies was normal, Antibody again antigliadin, de 17.9UI/ml (0–10 UI/ml). antiendomisium, tissue transglutaminase positive. The patient improves with treatment without gluten three months after the diagnosis. Conclusions: Our patient has evident features of ataxia. The most frequent neurological alteration described is cerebellar ataxia, associated with signs of atrophy in the magnetic resonance. Recently the antigliadin antibodies have been systematically used in patients with idiopathic cerebellar ataxia, a 68 % were positive, as opposed to a 12 % in the general population. Immunoglobulin A (IgA) antibodies to smooth muscle endomysium, gliadin,and tissue transglutaminase (the most commonly used test) are used for serological diagnosis. However, 3–5 % of all patients with celiac disease are Ig A deficient. A diet free of gluten is the base of the treatment of the disease. This diagnosis must be considered when we evaluated a patient with ataxia symptoms because it can be potentially treatable and reversible P249 Evaluation of evoked potentials in patients with neurodegenerative disorders: an electrophysiological comparative study M. Nevrly, P. Otruba, J. Dufek, I. Nestrasil, H. Vranova, P. Kanovsky Palacky University (Olomouc, CZ) Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder caused by deficit of dopamine in the basal ganglia. However, other morphological

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and biochemical changes were also found not only in the basal ganglia, but also in the brain structures related to primary tracts. These changes are reflecting progression of PD. Multimodal evoked potential (EP) examinations do not provide specific findings for any neurodegenerative disease. However, some abnormalities in evoked potentials examinations were recently found. The aim of our study was to compare findings in PD patients and other neurodegenerative diseases. Methods: Motor (MEP), somatosensory (SEP), visual (VEP), brainstem auditory EP (BAEP) and also cognitive event-related potentials (P300) were examined in 33 patients (14 females, 19 males). 19 patients (aged 30–78, mean 60.7 ± 12.6) suffered from PD, 14 patients (aged 34–79, mean 56.2 ± 14.5) suffered from other neurodegenerative diseases (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, spinocerebellar ataxia, Huntington disease and frontotemporal dementia). The latency, amplitude and areas of potentials were mutually compared. Results: Although some abnormalities (prolongation of P300 latency) were found, no statistically significant differences between PD patients and patients with other neurodegenerative disease were detected. Conclusions: Results of our pilot study show that a predominantly subcortical lesion, typical for PD, does not affect primary tracts (motor, somatosensory, visual and auditory). These tracts are probably spared also in other neurodegenerative diseases.

P250 Postanoxic dystonia treated by nucleus ventralis oralis deep brain stimulation J. Ellul, E. Markaki, C. Assimakopoulos, S. Marousi, C. Constantoyannis Patras University Hospital (Patras, GR) Objective: Structural lesions on the globus pallidus is a well-known entity in dystonic patients. The presence of focal brain abnormalities in the globus pallidus internus may raise difficulties for the position of a deep brain stimulation electrode in a dystonic patient. Targeting the thalamus was abandoned after the publications from several groups, suggesting that the GPi is the first choice for stereotaxy in patients with dystonia. Could thalamic nuclei, especially the Voa/Vop nucleus, be used as an alternative target for deep brain stimulation in cases of dystonia? Methods: A 37-year-old lady with a long history of severe postanoxic hemidystonia was wheelchair bound for the last nine years. She required assistance in dressing and hygiene. The preoperative Magnetic Resonance Imaging showed bilateral postanoxic lesions in the globus pallidus internus. The patient underwent a left thalamic (ventralis oralis nucleus) deep brain stimulation surgery. Results: The functional status and the daily life activities were markedly improved after 6 months, having the best results on the 12 months follow up. The BFM dystonia scale improved by 76 % (baseline: disability scale 13/30, movement scale 20/120 and at 1 year: disability scale 6/30, movement scale 2/120). Conclusion: Our case illustrates a potential re-approach of the Voa/Vop nucleus as an alternative target in dystonic patients, when the positioning of DBS electrodes in GPi is restricted by the presence of structural abnormalities.

P251 Is there a morphological substrate of parkinsonian rest tremor? A voxelbased morphometry study D. Benninger, S. Thees, C. L. Bassetti, S. Kollias, D. Waldvogel University Hospital of Zurich (Zurich, CH) Objectives: To investigate morphological substrates of rest tremor in patients with Parkinson’s disease (PD). Rest tremor is a hallmark of PD. Its pathogenesis remains incompletely understood. Nigrostriatal dopaminergic deficiency correlates with bradykinesia, but not with rest tremor. It is hypothesized that an interaction of basal ganglia- and cerebello-thalamo-cortical circuits may cause rest tremor. Methods: We investigated 24 men (median, range [years], age 62, 55–70, at onset 55, 42- 67, disease duration 7, 3–20) with mild to moderate PD (Hoehn Yahr [HY] 2 and 3). Exclusion criteria were advanced PD (HY 4 and 5), dementia and other significant brain pathology. Patients with (n = 14) and without rest tremor (n = 10) were compared. Demographical and clinical profile, including detailed neuropsychological and psychiatric evaluation, were similar, except for higher prevalence of motor fluctuations (90 % vs. 14 %, p < 0.01) and impaired balance (100 % vs. 50 %, p < 0.01) in those without tremor. Voxel-based morphometry of a high-resolution 3 Tesla T1weighted MRI image, pre-processed according to an optimized protocol using SPM2, was performed. The resulting normalized grey matter volume dis-

tributions of the two groups were tested for local differences by a voxel-wise ANCOVA. Results: Grey matter density is decreased in the quadrangular lobe and declive of the cerebellum in PD with tremor compared to those without (PFDR < 0.05). Conclusion: These results demonstrate for the first time morphological changes in the cerebellum in PD-patients with rest tremor and underscore the involvement of the cerebellum and cerebello-thalamo-cortical circuit in the pathogenesis of Parkinsonian rest tremor. P252 Different cortical activation in writer’s cramp in homozygote twins during a simple, non-affected motor task D. Benninger, D. Waldvogel, C. L. Bassetti, S. Thees, S. Kollias, V. Candia University Hospital of Zurich (Zurich, CH); Collegium Helveticum (Zurich, CH) Objective: To compare motor induced BOLD-signals with fMRI in a patient with late-onset writer’s cramp (WC) and cervical dystonia and in his non-affected monozygote, twin brother. Anomalies during non-affected motor behaviours have been sparsely reported. In case of heredity, we expected comparable disturbed BOLD-responses during dystonia-free task performance, assuming sub-clinical motor abnormalities in both brothers. Methods: Brain imaging was performed with a 3T MR Philips scanner in a standard block design during performance of a tonic power grip of the left or right hand. Results: The non-affected twin showed normal activation patterns in sensory and motor areas including contralateral M1, SI and SMA during task performance. In the affected twin, no such activation was observed while using the right or left hand, except for contralateral supramarginal gyrus activity during task performance with the left, subsequently affected hand. Conclusion: The lack of significant activity during performance of a simple motor task agrees with previous reports and also supports the assumption that motor abnormalities in WC can be observed sub-clinically. The lack of cortical activation during performance with the left hand in the affected twin points to a behavioral component in the pathogenesis of hand dystonia as opposed to a genetic predilection. P253 Essential tremor responding to low-dose topiramate: a report of three familial cases in Korea J. M. Chung, S. J. Kwon Inje University (Seoul, KR) Background: Essential tremor is the most prevalent and the most disabling disorder in older patients. Beta-blocker and benzodiazepine usually have been used. However, additional therapies are required for patients with an inadequate response or intolerable side effects with these medication. A few studies have reported about effectiveness of topiramate, an antiepileptic drug in essential tremor, of which results were inconsistent. Here we report three Korean familial cases with essential tremor which is responsive to low dose topiramate. Case: Three family members (father and his two children: son and daughter) visited complaining with tremulous movement of both hand. This movement started since their childhood. Pastmedical history was unremarkable and there was no drug history. The movement was rhythmic and fine. It occured during postural maintenance and when they were using hands, interfered with some activities of daily living such as writing, using the utensil and pouring water into a cup. This movement temporarily improved after small digestion of alcohols. Neurological examination showed no abnormality except for this movement. This tremulous movement was similar in all of the three family members and the most severe in daughter. Laboratory tests including thyroid function test, serum copper and ceruloplasmin were all normal. Propranolol and clonazepam were first prescribed, which gave them no benefit. Low dose of topiramate (50mg/day) started and the tremor showed dramatic responsiveness to this drug. They came to have much less discomfort in doing such activities. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking. No side effect was observed and this improvement lasted during six months follow-up. Conclusions: Topiramate may be considered especially in the patients with essential tremor which is unresponsive to preexisting medications.

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P254 Motor unit firing properties and rhythmical correlations in parkinsonian postural tremor S. Erimaki, E. Anagnostou, D. Anastasopoulos, C. N. Christakos Medical School, University of Crete (Heraklion, GR); School of Nursing, University of Athens (Athens, GR); Institute of Applied and Computational Mathematics, FORTH (Heraklion, GR) Objective: We examined the discharge patterns and the rhythmical synchrony of motor units (MUs) during steady muscle contractions of parkinsonian subjects, as these features determine the properties of the muscle force signal, including tremor. Methods: 8 parkinsonian subjects (69 ±8 years) and 8 age-matched control subjects participated. Participants exerted constant force at different low levels with their extended index finger against a transducer by contracting the first dorsal interosseus muscle. First- and higher-order analyses of MU interspike intervals (ISIs) were used to study MU firing patterns. Unitto-aggregate (MU/force) coherence and cross-correlation analyses (1, 2) were used for estimation of the parameters of the MU tremor synchrony, namely, the extent, strength and MU phase relations. Results: (I) In parkinsonian tremor (PT, observed range 4–8 Hz), the large MUs fired once per tremor cycle. However, medium-sized and small MUs, which fired above the tremor frequency, often exhibited per tremor cycle a spike doublet (i. e., one short ISI, between 35 and 65 ms, followed by a longer ISI), or triplet (two successive short ISIs followed by a longer ISI). This effect also appeared as high incidence of second- or third-order ISIs around the tremor period. Such patterns were very uncommon among control subjects (tremor range 6–10 Hz). (II) In PT, single spikes, doublets and triplets for all recorded MUs occurred at or near local tremor minima. The rhythmical tremor synchrony was thus widespread and in-phase. Its strength varied widely among contractions and subjects (MU/force coherence from 0.11 to 0.84). These properties of the tremor synchrony also existed in our control subjects, as they do in younger healthy subjects (3). (III) The amplitude of both PT and normal tremor increased with the strength of synchrony, but overall the PT amplitude was much larger (p < 0.01). Conclusions: MU synchrony does not differ between PT and normal tremor. However, PT is characterized by the occurrence of rhythmical spike doublets or triplets (also see 4). This can account for the large PT amplitude, since even linear superposition of MU twitches per doublet, or triplet, produces MU force pulses which can be twice, or three times, as large as the single MU twitch. Supported by the European Social Fund and National Resources (PYTHAGORAS Project 2090). References 1. 2. 3. 4.

Christakos CN (1994) Neuroscience 58:43 Christakos CN (1997) J Neurophysiol 78:3453 Christakos CN et al. (2006) J Neurophysiol 95:53 Dengler et al. (1989) Electromyogr Clin Neurophysiol 29:113

P255 Management of comorbidity in Parkinson’s disease K. S. Paulus, G. P. Sechi, P. Galistu, G. A. Cocco, V. Agnetti Università di Sassari (Sassari, IT) Introduction: The advanced phase of Parkinson’s disease (PD) is characterized by motor and non-motor complications, due to both disease progression and dopaminergic treatment. Further difficulties in the management of PD patients may derive from the presence of comorbidities related to the complex neurological pathology, but often represented by different diseases. In patients with long PD duration anxiety, depression, sleep disorders, and psychiatric disorders are frequently observed. But also other pathologies such as cardio-circulatory, bronco-pulmonary, enteric, endocrinal, and genital-urinary diseases could increase patient’s discomfort and suffering, so worsening patient’s quality of life. Furthermore, the pharmacological treatment of these pathologies could interfere with the extrapyramidal syndrome and its therapy. Finally, some of these pathologies could represent risk factors for secondary parkinsonisms,such as the ischemic,hypertensive and arrhythmic cardiopathy, diabetes mellitus, hypercholesterolemia, and the thyreopathy. Objectives and Methods: The aim of this retrospective study is to observe the frequency of other pathologies in PD patients by means of the Cumulative Illness Rating Scale (Linn et al., 1968; Miller et al., 1992). Results: In the last four years, 281 (146 females, 135 males) of 605 consecutive patients admitted to our Movement Disorders Centre were on dopaminergic therapy for possible or probable idiopathic PD, secondary PD, or atypical parkinsonisms. These 281 patients resulted affected by: hyper-

tension (135; 48.1 %), respiratory pathology (56; 19.6 %), diabetes mellitus (51; 18.1 %), ischemic and/or arrhythmic cardiopathy (47; 16;7 %), enterologic pathology (40;13.9 %), thyreopathy (30;10.8 %), orthopaedic pathology (28; 9.9 %), genital-urinary disease (27; 9.6 %), hypercholesterolemia (22; 7.8 %), haematological disease (16; 5.8 %), neurological (other than PD) or psychiatric disorder (18; 6.5 %), no comorbidity (49; 17 %). Conclusion: The comorbidities and their therapies could make the pharmacological treatment of PD difficult and could worsen the neurological disease. For this reason, it is necessary to create multidisciplinary teams for an optimal management of PD patients.

P256 Different types of hand tremor in hemifacial spasm patients M. Wójcik, M. Rudzinska, A. Szczudlik University Hospital (Cracow, PL) Objective: To assess the occurrence and characteristic of hand tremor in hemifacial spasm (HFS) patients. Background: Tremor commonly accompanies focal dystonia and may occur in other involuntary movements. There is no report describing tremor in HFS patients. Methods: 31 HFS patients and 51 age and sex matched healthy controls were included to the study. Patients with other possible causes of tremor (hyperthyreosis,calcium blockers and other tremorogenic drugs,alcohol abuse, etc.) were excluded. Rest, postural and kinetic tremor was assessed after half-hour repose clinically and objectively using four different methods: three-axial accelerometry, EMG, three-dimensional system of digital cameras and quantitative computerized tremor analysis on the graphic digitizing tablet. To identify enhanced physiological tremor the mass loading test (MLT) was performed. Results: In both, clinical and objective examinations postural and kinetic tremor in both hands was found in 15 (48.3 %) patients. The mean frequency of postural and kinetic tremor in accelerometric assessment was 8.6 2.2 Hz (range: 5.0–12.6 Hz) and 7.4 1.9 Hz (range:4.1–11.7 Hz), respectively. Enhanced physiological tremor was diagnosed in 3 (20 %) patients (mean frequency: 9.9 2.6 Hz; mean reduce of frequency in MLT: 3.9 1.7 Hz), ET-like type of tremor in 4 (26.6 %) patients (mean frequency: 8.9 2.2 Hz), and mixed tremor (ET-like type of tremor in one hand and enhanced physiologic type of tremor in the other) in 6 (40 %) patients. One patient fulfilled criteria of ET. One patient revealed features of psychogenic tremor. No tremor in the control group was detected. The occurrence of tremor was related to severity of HFS (2 = 9.4, p = 0.02) but not to age and HFS duration. Hypertension was found in 87 % of HFS patients with tremor as compared to 44 % of HFS patients without tremor (2 = 4.5, p = 0.03). Conclusions/Relevance: Hand tremor, mostly diagnosed as enhanced physiological or ET-like tremor, occurs in nearly 50 % of HFS patients.

P257 Effect of L-dopa on gastric motility in Parkinson’s disease G. Albani, N. El Assawy, S. Cataldo, A. Mauro Istituto Auxologico Italiano (Piancavallo, IT) Objectives: In Parkinson’s disease (PD) are well known various clinical gastrointestinal disfunctions, supported also by anatomopathological evidences since first studies of Lewy. It has also been hypothesized a crucial role of these dysfunctions on the absorption of L-dopa(LD), and thus on LD plasma levels and thus in the genesis of motor fluctuations. Aim of this study was to evaluate the mioelectrical gastrointestinal activity in patients with PD by means of an electromyographic (EMG)surface evaluation. Methods: We studied three groups of patients (total 18): a) de novo b) with motor fluctuations c) without motor fluctuations. The protocol of study was: 1) stopping L-dopa therapy and have an empty stomach in the last 12 hours before EMG evaluation 2) two sessions of EMG registration, each one lasting 45 minutes, before and after LD intake. For the EMG study we placed on the abdominal skin two active recording electrodes, one reference electrode and one ground electrode. The electrogastrographyc (EGC) signal was registered, sampled, filtered by a dedicated system. In the same patients we evaluated in three different days the LD plasma levels. Results: The EGC frequency at rest and after LD intake was normal and does not change in the three clinical groups. The LD plasma levels showed a marked intraindividual and interindividual variability in all three groups. Conclusion: In PD the gastric motility at rest is normal and is not influ-

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enced by LD intake. L-dopa plasma levels seem to be not correlated with severity of disease.

Rehabilitation P258 Therapy control study in neurological rehabilitation: mental deficits A. Büttner, H. Bennefeld Klinik Ambrock (Hagen, DE); Heinrich-Mann-Klinik (Bad Liebenstein, DE) Introduction: Apart from a multitude of physical complaints, neurological disorders (strokes, cerbrovascular diseases, brain traumas, brain tumors etc.) can also lead to various kinds of cognitive changes and even a reduction in quality of life (QoL). The objective of this study was to investigate the degree of vigilance and of quality of life achieved in neurologic patients. Methods: The study was carried out involving two groups of randomly selected persons, neurologic patients and healthy persons. All patients were selected according to their clinical diagnosis (ICD-10). 1.) Vigilance: So far, data have been gathered for 51 healthies (42 m; 9 f) and 148 neurologic patients (101 m; 47 f). This persons using the vigilance test Carda, which was developed and standardized at Clinic Ambrock. Measurement of vigilance was invariably carried out in the afternoon and took place in a quiet, sound-proofed room. Datas (1.Health.: N = 51, age: 24.0±8.6; 2.Neuro: N = 148, age: 57.2±15.8, BI = 79.6±27.3) The study design intends to compare this group of neurologic patients and healthy persons. 2.) Quality of Life QoL: For 40 healthies (25 m; 15 f) and 132 neurology patients (76 m; 56 f) datas have been gathered. The participants of the study using a sample of questionnaires, consisting of 4 questionnaires, e. g. the Münchner Lebensqualitäts-Dimensionen-Liste MLDL-Z. Datas (1.Health.: N = 40, age: 42.1±12.1; 2.Neuro: N = 132, age: 65.2±13.3, BI = 81.3±22.6) The study design intends to compare this group of neurologic patients and healthy persons. Further, the influence of the degree of disease severity on quality of life Findings: 1.) Vigilance: Testing of vigilance achievements revealed a highly significant difference between healthy persons and neurology patients (p <.001). After 3 weeks of neurological rehabilitation, the neurologic patients’ quality of life improve to a significant degree (p <.001). 2.) Quality of Life QoL: Testing of quality of life revealed a highly significant difference between healthy persons neurology patients (p <.001). Examination of specific domains of quality of life, 4 (of 4) subscales (p <.05) of the MLDL-Z showed significant to highly significant differences in patients with neurologic disorders. Discussion: The study revealed that neurologic patients show problems and deficits concerning their vigilance achievements and their QoL. In contrast, the degree of severity of the disorders is not relevant in vigilance, but in the QoL. In summary, based on our results, it is to be said that although continuous therapy improves the neurological symptoms; vigilance and attention achievements and quality of life require longer-term regeneration. P259 Changes of cortical excitability following combined visual attention and finger movement H. Y. Jung, T. H. Kim Inha University (Incheon, KR) Objectives: We want to know whether the amounts of cortical excitability following voluntary finger movement combined with or without visual attention are different. Subjects and methods: Eight normal healthy right-handed volunteers were enrolled to compare the effects of voluntary finger movement with and without visual attention. The changes of cortical excitability were obtained with transcranial magnetic stimulation (TMS) while subjects performed one of two tasks that required a voluntary repetitive pinch movement, with attending to the video film recorded finger movement or with attending the dark screen, simultaneously. All subjects were required to perform regular

repetitive finger movements for light touch between tip of thumb and index finger guided with a Metronome sound at 0.5Hz frequency, for a duration of 30 minutes. Changing on cortical excitability was assessed with transcranial magnetic stimulation (TMS) and electromyography(EMG), including resting motor threshold, paired pulse tests, recruitment curves, and compound muscle action potentials, F waves recorded at right first dorsal interosseous (FDI) muscles. These protocols were done pre- and post-finger movement with visual attention or without attention. Results: In all two groups, there were no changes in the resting motor threshold, paired pulse tests, CMAPs, and F waves as compared to pre- and post-interventions. However, at TMS with 120 %, 140 % and 160 % of the resting motor threshold, recruitment curves recorded at the FDI muscles were only increased in voluntary finger movement group with visual attention. Conclusion: The findings suggest that visual attention for guiding finger movement has some effects on cortical excitability via the recruitment of additional cortical neurons near the cortical representation for the target hand muscles. P260 Enhancing language performance with transcranial direct current stimulation in healthy humans: implications for rehabilitation and recovery of function after stroke R. Sparing, M. Dafotakis, M. D. Hesse, G. R. Fink Institute of Neuroscience and Biophysics (Julich, DE); University Hospital (Cologne, DE) In humans, cognitive brain functions might be modulated effectively by a recently revived neuromodulatory technique: transcranial direct current stimulation (tDCS) (Paulus, 2004; Hummel & Cohen, 2006; Talelli & Rothwell, 2006). TDCS can be used to induce, depending on polarity, increases or decreases of cortical excitability by polarization of the underlying brain tissue. Cognitive enhancement as a result of tDCS has been reported for motor, visual and frontal brain areas. The purpose of this study was to test if weak tDCS (57 μA/cm2) modifies language processing. 15 healthy subjects performed a visual picture naming task before, during and after tDCS applied over the posterior perisylvian region, i. e., Wernicke’s area (WA, BA 22). Four different sessions were carried out: (1) anodal and (2) cathodal stimulation of the left WA and, for control, (3) anodal stimulation of the homologous region of the right hemisphere, and (4) sham stimulation. We found that subjects responded significantly faster following anodal tDCS to the left posterior perisylvian region (p < 0.01). Decreases in performance were not detected. The data show that non-invasive tDCS applied over left WA can be used to enhance linguistic processing in healthy subjects.Whether tDCS can also be used to ameliorate deficits of picture naming in aphasics needs further investigation. Together with previous studies which have investigated the modulation of picture naming latencies by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS), our findings suggest that the posterior perisylvian region, including Wernicke’s area (BA 22), could be a paramount target for the non-invasive, non-pharmacological enhancement of recovery from aphasia through neuromodulation. P261 Effect of passive gait training on brain activity in patients with impaired consciousness due to severe traumatic brain injury N. Lapitskaya, J. F. Nielsen, A. Fuglsang-Frederiksen, J. Jakobsen Hammel Neurorehabilitation and Research Centre (Hammel, DK); Aarhus University Hospital (Aarhus, DK) Objectives: Early mobilization is required in rehabilitation of severely braindamaged patients. Passive gait training on a tilt table with an integrated stepping system was performed in order to increase afferent cortical input. The aim of this pilot study was to determine whether passive gait training induces changes in electrical brain activity in patients with severe traumatic brain injury. Methods: Three patients with severe traumatic brain injury (Glasgow Coma Scale 3 on admission to hospital) and three healthy persons were prospectively investigated. All patients had a functional level 2 score according to Rancho Los Amigos Scale 74±5 days after injury,indicating an ongoing severe impaired state of consciousness. An electroencephalogram (EEG) was recorded (16 channels) before and immediately after a single training session (20 minutes) of passive gait training on a tilt table with an integrated stepping system. Power (amplitude squared) spectrum analysis (the total power and the absolute power in the frequency bands delta, theta, alpha and beta) of each EEG was done. Results: Power spectrum analysis of EEG revealed higher power in the delta band and lower power in the alpha band in patients compared with

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controls. After passive gait training the decrease of the power was observed in both patients and healthy subjects. The most prominent EEG change was the decrease of delta activity power in both groups. Conclusion: Our data indicate that power spectrum analysis of EEG appears to be a useful non-invasive method for measuring changes in electrical brain activity as a result of training. A prospective controlled study with larger sample size is ongoing to evaluate effects of training on tilt table with integrated stepping system in patients with severe brain injury. P262 Neurological recovery severe post-cerebral hypoxic patients: which exams? S. Marino, C. Rifici, D. Floridia, A. Todaro, G. D’Aleo, E. Sessa, P. Di Bella, P. Bramanti IRCCS Centro Neurolesi Bonino-Pulejo (Messina, IT) Objective: To assess neurological recovery in severe post-cerebral hypoxic patients using clinical, neuropsychological, neurophysiological and neuroradiological examinations. Background: As a result of the improvement in intensive care medicine, an increasing number of patients enter in coma state, that can lead to an independent state or to a persistent vegetative state (VS).A reliable assessment after global cerebral hypoxia is very important. Evented related evoked potentials (EREP) have a potential role in predicting the outcome of hypoxic patients. Conventional imaging (CT scan or MRI) is highly sensitive in detecting lesions and provides crucial information for the management of hypoxic patient care, especially in the acute stage. However, abnormalities detected by CT scan or conventional MRI have limited importance in the classification of the degree of clinical severity and in predicting patients’ outcome. Materials/Methods: We studied 20 patients with severe post-cerebral hypoxia (8 females, 12 males), after prolonged comatose state and after they had been discharged from the neurological intensive care unit.We used clinical scores (GCS and LCF scores), neurophysiological test (evoked potentials, EEG), EREP (P300) and neuroradiological findings (MRI). Results: Of our 20 patients 30 % died due to internistic problems (pneumonia, heart failure), 40 % entered a VS and the other 30 % showed a partial neurological recovery. All survivor patients had a resolution of respiratory and swallowing problems and had altered EEG and P300. Patients entered in VS had altered somatosensory evoked potentials (SSEP). Conventional MRI revealed hyperintense areas in basal ganglia in 70 % of the patients while 30 % showed no abnormalities. Discussion/Conclusions: Post-anoxic state is a well-known condition with a large impact on care for all the people involved. Thus, a reliable tool for predicting clinical outcome is necessary. To date, bilateral absence of SSEP is the most important predicting index for a negative clinical outcome. Thus, we used a pool of techniques to try to predict recovery in hypoxic patients, based on clinical, neuropsychological and neurophysiological exams. The use of non conventional MRI, such as MR spectroscopic and functional MR imaging, is beginning and increase the knowledge about the assess of clinical severity and the predicting of disease outcome. P263 Study on influencing factors of functional recovery of stroke patients Y. Zhang, N. Wei, K. Dong, C. Wang, X. Zhao, Y. Wang Beijing Tiantan Hospital (Beijing, CN) Background and purposes: Rehabilitation treatment can markedly reduce the disability level of stroke patients and relieve burdens of society and family. In clinical, we also found that the functional of some patients recovery well after stroke while some patients recovery poor, it is necessary to take several factors influencing functional advancement into account when formulating a reasonable and feasible rehabilitative treatment. In this study, we tried to collect the factors related with stroke patients outcome and observed the influence of these factors on functional recovery. Methods: We selected stroke inpatients at Neurology department of Beijing Tiantan hospital from May 2004 to July 2005, all patients were applied rehabilitation technique, such as Bobath and Rood technique. All trainings were conducted for 1–2 hours per day, and 6 times per week. We evaluated the rehabilitation effects of stroke patients using functional independence measure (FIM) at admission and discharge, and studied the influence of gender, age, motor and cognitive function at admission, time interval from stroke onset to arrival at, laterality of lesion on the functional recovery of stroke patients. We used SPSS 11.5 to analyze the relationship of these factors and functional recovery. Results: 350 patients were involved into the results analysis. The FIM total score of patients was significantly higher at discharge than that of at admission (p < 0.005), motor and cognitive function also increased at dis-

charge compared with that at admission (p < 0.001). The analysis showed that scores of motor and cognitive status at admission, age, time interval from stroke onset to arrival at hospital admission affected the FIM total scores. There were no association between gender, laterality lesion of damaged and functional recovery (P> 0.005). The most influential factors of functional recovery were orderly motor score, cognitive score, age, time interval from stroke onset to arrival at hospital admission. Conclusions: Motor and cognitive function at admission, age and time interval from stroke onset to arrival at hospital admission associated with functional recovery of stroke patients. We should think about these factors when we treat stroke patients, and provide patients with suitable rehabilitative treatment as soon as possible and reduce the disability occurrence. P264 Approaching robotic rehabilitation in post-stroke hemiplegic children: three case reports G. Di Rosa, F. Frascarelli, M. Petrarca, L. Masia, P. Cappa, E. Castelli Childrens Hospital Bambino Gesù (Rome, IT); University of Rome “La Sapienza” (Rome, IT) Objectives: Robotics and related technologies have begun to realize their promise to improve the delivery of rehabilitation therapy. Our work is a preliminary investigation to verify the effects of robot-assisted movement therapy on upper limb performance in three children with motor impairment following ischemic stroke. Methods: Using an InMotion2 planar robot with two degrees of freedom and force feedback control, a pilot study on three hemiplegic subjects has been performed. Robotic therapy for the paretic upper limb consisted of either sensorimotor active-assistive exercise or progressive-resistive training during repetitive, planar reaching tasks. A computer recorded the position, velocity, force exerted at the robot handle and five measures of smoothness were applied to the kinematics data collected during point-to-point movements. All patients underwent to complete clinical evaluation including the following standardised scales: Modified Ashworth Scale, Melbourne Assessment of Unilateral Upper Limb Function and Reaching Performance Scale to assess trunk displacement during reaching tasks. Patients received robot therapy three times per week for 6 weeks, each session lasted about 1 hour. Results: Recording patients’ hands’ paths during the robot assisted exercises from the beginning to the end of the therapy, showed an improvement of motor performances. In particular the subjects’ peack speed tended to increase and the movement duration tended to decrease. Patients movements tended to get smoother over the course of therapy. The movement pattern at the end of the therapy seems to indicate an increased interaction of the arm of the patient with the robot in performing tasks. Over the course of therapy, the number of submovements required to reach a single target decreased. These aspects are important for functional tasks requiring interaction with objects and in order to try new sensorimotor experiences by using hands. Discussion: The results indicate that the most appropriate focus for robotic therapy may be movement coordination and head and trunk postural control. This preliminary study suggests that robotic rehabilitation could play a new important role between rehabilitative techniques. P265 Stabilometric study of conscious voluntary control influence on posture in patients with post-stroke hemiparesis O. Pascal, E. Agapii, L. Perjesco Institute of Neurology & Neurosurgery (Chisinau, MD) Objectives: To study an influence of conscious voluntary control on posture in patients with post-stroke hemiparesis. In accordance to this purpose we investigated stabilographic characteristics of static and dynamic balance in patients with post-stroke hemiparesis before and while performing a cognitive task. Methods: Quantitative assessment of static and dynamic balance was performed by computerized stabilography. Basic stabilographic indices as a length of sway path, stabilogram area, dispersion of centre of pressure coordinates on the lateral and sagittal axes and others were analyzed before and while performing the cognitive task. Patients were asked to calculate white circles appearing on monitor screen together with circles of different colour. This test was aimed to concentrate patient’s visual attention and distract him from voluntary conscious control of posture. A total of 98 patients with unilateral post-stroke hemiparesis who were able to maintain independent unsupported stance for 3 minutes and 20 age-matched healthy subjects were evaluated. Results: The examined patients exhibited different changes of static and dynamic stability recorded before and while performing the cognitive task. Twenty-six patients showed significant stabilometric changes characteristic

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for improvement of static and dynamic stability while performing the cognitive task in comparison with initial data (p < 0.05). Thirty-three persons showed no significant changes of stabilometric parameters. Thirty-nine subjects exhibited significant changes of stabilometric indices specific for worsening of static and dynamic stability during performing the cognitive task (p < 0.001). Two tendencies of stabilometric changes were observed in normal subjects. Thirteen persons showed no significant changes during the test performing. Seven subjects exhibited changes of worsening of static and dynamic balance. Conclusion: The results of this study showed that weakening of conscious voluntary component of postural control by performing a cognitive task had a positive influence on static and dynamic stability in some stroke patients. The improvement of postural control by weakening of conscious control of posture in these subjects could suggest that this group of patients modulate inadequate strategies for voluntary postural control. This should be taken into account in planning of appropriate physiotherapy strategies in postural retraining programs.

2. BMD cortical-20 % (mg/ccm): 1094.02±35.57 (normal side) and 1075.08±51.47 (paretic side) (P > 0.05). 3. SSI trabecular-4 %: 440.9±115.4 (normal side) and 410.1±82.9 (paretic side) (P > 0.05). 4. SSI cortical-20 %: 314.1±142.3 (normal side) and 261.5±177.4 (paretic side) (P > 0.05).

P266 Body composition by DXA in stroke: paretic vs. normal lower limb O. Lazoura, S. Stathopoulou, M. Vlychou, E. Antoniadou, E. Drakonaki, K. Kalokerinou, P. Papadaki, N. Groumas National Rehabilitation Centre (Athens, GR); Medical School, University of Thessaly (Larissa, GR)

Background and Purpose: Poststroke depression is associated with impaired functional recovery. We examined the differences on functional recovery among poststroke depressed patients (DP) with remission of their depression compared with poststroke nondepressed patients (NDP) over the 6 months after stroke. Methods: On the basis of a semistructured psychiatric examination, DSM-IV diagnostic criteria and Hamilthon Depression scores, a consecutive series of ischemic or hemorhagic stroke patients who did not have depression during the first 15 days of stroke were included in this study. They had first-time stroke and did not have depression diagnosis previously. During follow-up, treatment with citalopram 20 mg/day p. o. has been started whenever we diagnosed depression. Their functional recoveries were assessed by the National Institutes of Health stroke scale, the modified Rankin scale and the Barthel index during acute hospitalization, time of depression diagnosis, 3rd and 6th months. Results: Forty patients met the diagnostic criteria and 11 patients had depression at follow-up. There were no differences in demographic variables, lesion characteristics, and neurological symptoms between the two groups. Impairments in functional recovery in DP were seen in comparison to the NDP (p < 0.05).All DP whose mood improved after administration of citalopram had significantly greater recovery in daily living functions at followup and catched the NDP. Conclusions: Our findings suggest that remission of poststroke depression over the first few months after stroke is associated with improvement in functional recovery. Early diagnosis and effective treatment of depression help the rehabilitation outcome of stroke patients.

Aim: To compare bone mineral density, fat and lean mass of the affected and unaffected lower limbs in hemiparetic patients. Materials and Methods: Twenty-eight Greek male patients with a sixmonth history of hemiparesis due to stroke were included in the study. Fat mass (FM) and lean mass (LM) were measured at both paretic and normal limb using dual X-ray absorptiometry (DXA) in all twenty-eight patients. Eighteen of them also had a DXA measurement of bone mineral density (BMD) at the femoral neck, trochanter and Ward’s triangle at both paretic and normal limb. Patients were evaluated for the degree of spasticity and the phases of motor improvement. Results: Stroke patients assessed for fat and lean mass had a mean age of 63.06±9.58 (range 44–74) years, mean height of 170.8±6.58 (range 155–182) cm and mean weight of 71.68±10.77 (range 54–102) kg. Fat mass of the affected leg (3151.68±1273.3 gr) was not significantly different (P > 0.05) from the normal leg (2901.27 ±1221.7 gr). However, the affected leg’s lean mass (5354.18+/-990.7 gr) was significantly lower (P = 0.04) compared with the normal side (5917.9±1038,1 gr). Stroke patients assessed for bone mineral density had a mean age of 62.9±10.4 (range 44–74) years. BMD at the femoral neck and trochanter of the affected side was not significantly different from BMD of the normal side (P> 0.05). However, affected side’s BMD of Ward’s region (0.68±0.14 gr/cm2) was significantly higher (P = 0.035) compared to the normal side (0.58±0.1 gr/cm2). All the patients relearned to walk within the first three months after stroke. Seven patients had spasticity (25 %). Conclusion: Lower lean mass of the paretic leg six months following stroke, reflects diminished physical activity compared to the normal leg. Higher BMD of the affected side Ward’s region in hemiparetic patients may be related to spasticity and changes in walking pattern, which increase the mechanical stress loading of the Ward’s region. P267 Alpha pQCT study of the forearm after stroke O. Lazoura, S. Stathopoulou, M. Vlychou, E. Antoniadou, E. Drakonaki, K. Kalokerinou, P. Papadaki, N. Groumas National Rehabilitation Centre (Athens, GR); Medical School, University of Thessaly (Larissa, GR) Aim: To compare bone mineral density of the forearm between paretic and normal arm in hemiparetic men six months after stroke. Materials-Methods: Twenty Greek male patients with a six-month history of hemiparesis due to stroke participated in the study. Cortical and trabecular bone density were measured at the distal radial epiphysis (4 % and 20 % respectively of the length of the radius) of both the paretic and normal limbs. Peripheral quantitative computed tomography (pQCT) was the method used for measurements. Patients were evaluated for the degree of spasticity and the phases of motor improvement. Results: Stroke patients had a mean age of 63.3±9.9 (range 44–75) years. Trabecular and cortical BMD as well as SSI at the 4 % and 20 % of the length of the radius were as follows: 1. BMD trabecular-4 % (mg/ccm): 194.3±43.22 (normal side) and 183.34±49.41 (paretic side) (P > 0.05).

All the patients regained part of upper limb mobility within the first three months. Five patients had spasticity (25 %). Conclusion: In men with a six-month history of hemiparesis BMD and SSI of the affected side’s radius were not significantly different from BMD and SSI of the normal side. P268 Improved functional recovery associated with treatment of depression C. Bilge, E. Koçer, A. Koçer, Ü. Türk Börü Kartal Teaching Hospital (Istanbul, TR); Düzce University (Düzce, TR)

P269 Misdiagnosis of the vegetative and minimally conscious state C. Schnakers, A. Vanhaudenhuyse, M. Ventura, S. Majerus, L. Pirnay, V. Bartsch, S. Pirnay, A. Dioh, D. Ledoux, P. Damas, F. Damas, G. Moonen, S. Laureys Coma Science Group (Liège, BE); CTR ULB (Brussels, BE); Department of Cognitive Sciences (Liège, BE); Rehabilitation Fraiture (Liège, BE); CHU (Liège, BE); IPAL Peri (Liège, BE); CHR Citadelle (Liège, BE) Introduction: Previous studies have shown a high rate of misdiagnosis of the vegetative state (VS; Childs et al, 1993 and Andrews, 1993). Since the time these studies were performed there have been a series of diagnostic guidelines published clarifying the criteria for the VS (Multi-Society Task Force on PVS, 1994; Royal College of Physicians 1996, 2003). In 2002, Giacino et al. published the criteria for the minimally conscious state (MCS). We here assessed the rate of misdiagnosis of VS and MCS. Methods: We prospectively studied patients with a consensus-based diagnosis of VS, MCS or “unsure if VS or MCS” concluded upon by the multidisciplinary team of care-givers and compared this to a careful standardized behavioral assessment performed by two skilled examinators using the Coma Recovery Scale-Revised (CRS-R; Giacino et al, 2004). Results: We included 103 patients aged 55±19 years (mean±SD). Etiology was traumatic in 36 patients; 45 were studied in the acute setting (< 28 days) and 58 in chronic setting (> 28 days). In 45 patients with a clinical consensus diagnosis of VS, CRS-R assessment showed that 18 actually were MCS (ie 40 % misdiagnosis; 10 were of traumatic aetiology; 14 were chronic patients). The diagnosis of MCS (as defined by Giacino et al, Neurology 2002) was based on: response to verbal command (4), eye fixation or tracking (n = 8), oriented response to noxious stimulation (1), automatic motor response (1) or several of the above (4). In the 41 patients with a clinical consensus diagnosis of MCS, CRS-R assessment showed that 4 patients actually were communicating functionally (and hence no longer were MCS; ie 10 %

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misdiagnosis; 3 traumatic; 4 chronic patients). In 18 patients with an inconclusive clinical consensus diagnosis (ie unsure if VS or MCS), CRS-R assessment showed that 16 were MCS (ie 89 %; 7 traumatic and 8 chronic patients) and 2 were VS. Conclusion: Our data show that despite the publication of medical guidelines and increased awareness of VS, the previously reported diagnostic error rate has not decreased over the last 15 years. Remarkably, the rate if misdiagnosis is much lower for the recently defined medical entity of MCS. Finally, it seems that when clinical caregivers aren’t sure if the diagnosis if VS or MCS, the vast majority of these uncertain cases actually are MCS. Diagnostic error of VS and MCS is more frequent in chronic patients and for MCS cases traumatic cases more often lead to misdiagnosis or diagnostic uncertainty. Supported by Belgian Fonds de la Recherche Scientifique – FNRS.

Genetics P270 Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 gene polymorphisms in multiple sclerosis Y. Benesˇová, M. Beránek, M. Hladíková, J. Vácha, Z. Kadanka, A. Vasˇku University Hospital Brno (Brno, CZ); Masaryk University (Brno, CZ) Objectives: Multiple sclerosis (MS) is a multifactorial, polygenic disease. Matrix metalloproteinases (MMPs) play an important role in the immunopathogenesis and progression of MS. The activity of MMPs is regulated by different levels: gene expression level, pro-enzyme activation, and the activity of the tissue inhibitors of MMPs. The aim of this study was to examine possible association among polymorphisms in gene promotor region for MMP-2 (–168G/T, –735C/T, –790T/G, –1306C/T) and TIMP-2 (–853G/A, –418G/C) with multiple sclerosis. Methods: A sample of 211 patients (aged 40 years in average) with multiple sclerosis was compared to 118 healthy subjects (aged 39 years in average).The DNA genotyping was performed using PCR methods with restriction analyses. Results: No statistical differences were found between MS patients and controls in MMP-2 and TIMP-2 gene polymorphisms genotypes distribution.When the patients had been divided according to disease form to relapsing-remitting, secondary progressive and primary progressive, significant differences in genotype distribution s(Pg = 0.013) between the relapsing-remitting form and control group of patients was found in –853 G/A TIMP-2 polymorphism. Homozygote GG genotype was found to be more frequent in patients with relapsing-remitting form (odds ratio- OR –2.68, 95 % CI 1.26–5.69). Significant differences in allelic frequencies (P = 0.021) was found as well. Significant differences in allelic freqencies (P = 0.044) between the relapsing-remitting and control group was found in–735 C/T MMP-2 polymorphism. Hetero CT and homozygote TT genotype was found to be more frequent in patients with relapsing-remitting form of MS (odds ratio- OR-1.79, 95 % CI 0.99–3.24). When the patients with relapsing-remitting form of the disease had been divided according to immunomodulatory treatment with interferons, similarly, significant differences had been observed in allelic frequencies G(Pa = 0.029) between MS subgroup withouth interferon treatment and control group in -853 G/A TIMP-2 polymorphism. Now, allele G was found to be more frequent in subgroup not treated with interferon (odds ratio –OR-5.19, 95 % CI 1.14–23.56). The differences between genotyping and allelic frequencis these polymorphismus in other groups was not statistically significant. Conclusions: According to our results, distribution of polymorphisms in MMP-2(-735C/T) and TIMP-2(-853)G/A gene is associated with higher risk for relapsing-remitting multiple sclerosis clinical manifestation. The study was supported by grant NR /8832–4 IGA from the Ministry of Health of the Czech Republic P271 Fragile X-associated tremor/ataxia syndrome: a rare case without tremor A. Chaussenot, M. Borg, C. Bayreuther, C. Lebrun Pasteur Hôspital (Nice, FR) Objective: Carriers of the X fragile premutation can present the clinical FXTA Syndrome. It was described for the first time by Hagerman et al. in 2001 and is mostly revealed by ataxia and tremor. We report a rare case of FXTAS without tremor. Methods: We report a case of a 50 years-old right-handed man without personal or familial history. He presented since 2002 progressive gait ataxia

associated with paresthesia in the lower limbs. At the clinical examination, static and kinetic cerebellar ataxia with dysarthria were observed. A biological exhaustive screening (inflammatory, immunological, metabolic, infectious and neoplasic) was normal, but detects a folates deficiency. The common homozygous mutation C677T of the methylenetetrahydrofolate reductase was found. The cerebrospinal fluid analysis was normal. Brain MRI showed on the T2-weighted sequences, diffuse hypersignal in both cerebellar white matter and middle peduncles suggestive of FXTAS. Functional explorations (evoked somesthesic and visual potentials, electromyogram, and cerebral scintigraphy) confirmed the isolated cerebellar involvement. The FXTAS was supposed and genotype was explored. Southern Blot revealed an expansion of trinucleotide CGG with 107 repetitions, allowing posing the diagnosis of FXTAS (premutation defined by a number of repetitions ranging between 55 and 200). Results: The FXTAS (prevalence 1/3000) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS are an intention tremor and/or a cerebellar ataxia, with or without a parkinson’s syndrome and cognitive disorders. The MRI shows symmetrical signal abnormalities in the middle cerebellar peduncles and deep cerebellar white matter, typically sparing dentate nucleus, associated with generalized atrophy. Neuropathologic examination reveals eosinophilic intranuclear inclusions in neurons and astrocytes throughout the cortex, subcortical regions, and brain stem. Conclusion: The FXTAS must be suspected with unexplained late cerebellar ataxia. Typical presentation includes 50 years-old man with progressive ataxia and tremor. Brain MRI with symmetrical cerebellar hypersignals is very suggestive of this diagnosis. Genetic screening and advice for the patient and his family must be proposed in order to detect the fragile X syndrome. P272 New point mutation at nucleotide 3244 of tRNA-Leu in a case of MELAS A. Radtke, A. Brinckmann, L. Harms, S. Spuler, M. Schülke Charité (Berlin, DE) Objective: MELAS, a heredetary mitochondrial disorder, is a rare cause of stroke in young adults. In about 80 % of cases, one of several point mutations of mt-DNA can be identified, the most prevalent being an A-to-G mutation at nucleotide 3243 of the tRNA-Leu-(URR). A G-to-A mutation of the adjacent nucleotide 3244 has similarly reported to be associated with MELAS. We present a case of a 24 year old male with cerebral stroke of cortical/ subcortical location with clinical clinical evidence of MELAS-syndrome in whom a new point mutation of mt-RNA at nucleotide 3244 of tRNA-Leu was identified. Patient and methods: A 24 year old male with a history of migraine without aura, arterial hypertension and hypercholesterinemia developed sudden onset non-fluent aphasia with cortical dysarthria. Cerebral MRI showed an atypically located ischemic cortical/subcortical lesion of the frontal cortex in the left middle cerebral artery territory with high intensity signal in diffusion-weighted imaging and reduced apparent diffusion coefficient. Angiography of cerebral vessels was normal. There was no evidence of cardial embolism. Baseline lactate and pyruvate were elevated and increased by 100 % on exercise. Muscle biopsy revealed red-ragged-fibers of the left medial vastus muscle. For mutation analysis, the entire mitochondrial genome of blood cells encoding for leucin-1, lysine, asparagine and serin-1 were sequenced. Results: Sequential analysis of mt-RNA of blood cells showed a mutation of G-to-G/C at nucleotide 3244 of tRN-Leu-(URR). Semiquantitative analysis showed a heteroplasmy of C in 30 % and of G in 70 % of mt-DNA copies. Conclusion: A G-to-G/C mutation of tRNA-Leu located next to the classic MELAS mutation seems to be associated with MELAS. P273 Clinical and genetic characterisation in a cohort of 80 Italian patients affected by spinocerebellar ataxia M. Masciullo, A. Modoni, M. G. Pomponi, G. Neri, P. A. Tonali, G. Silvestri Catholic University (Rome, IT) Objective: To assess the relative prevalence of the various genetic forms in 80 Italian SCA patients and characterize the predominant features in each subgroup of patients Methods: We studied 39 familial (53 % autosomal recessive (AR), 47 % autosomal dominant (AD) and 41 sporadic SCAs. The diagnostic work-up included brain and spine MRI, laboratory tests to rule out other etiologies and identify specific markers of genetic SCAs (i.e, alpha-fetum protein for ataxia-teleangectasia-AT) and molecular testing for SCA1, 2, 3, 6, 7, 8, 10, 12,

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17, FMR1 premutation, mutations A467T e W 748S in the polimerase gamma (POLG) gene and MERRF 8344, 8356, NARP 8993, MELAS 3243, G > A nt 5540 in the miotchondrial DNA. RESULTS: We obtained a genetic characterization in 45 % AD, 18 % AR and 32 % sporadic SCAs. SCA1 e 2 were the most frequent forms among ADSCAs, followed by SCA 7. None was positive for other AD loci. The Friedreich ataxia (FRDA) expansion was detected in 21 % AR-SCAs, which also included primary vit E deficiency and ATM. FRDA expansion was the most frequent (8 %) also among sporadic SCAs, followed by SCA1, 2 and FMR1 premutation.Non of the patients was positive for known mtDNA mutations in the mtDNA or nuclear DNA (POLG), mean age of onset was significantly lower in AR vs. AD SCA (p < 0.001), and in sporadic vs. AD SCA (p> 0.05). A significant prevalence of dysarthria e neuropathy was present in genetic vs. sporadic SCAs. Conclusions: SCAs are genetically heterogeneous, and often similar clinical manifestations occur in different genetic forms. Their genetic characterization, which requires an extensive laboratory diagnostic screening, may be optimized estimating the prevalence of the various forms in different ethnic backgrounds and their clinical and diagnostic features. Based on our results and literature data we propose a diagnostic flowchart for Italian SCA patients: the first line screening includes SCA1, 2 in AD, FRDA in AR and FRDA, SCA1, 2 and FMR1 premutations in sporadic SCAs. Specific features are helpful to identify some genetic forms, i.e retinal pigmentary degeneration for SCA7 and increased alpha-fetum protein in AT,and to address the correct genetic diagnosis in patients with an atypical clinical phenotype.

P274 APOE/APOC1 and APOA1/APOC3 polymorphisms in Greek patients with multiple sclerosis: evidence of an interactive effect of the APOC1 and APOC3 loci on susceptibility G. Koutsis, G. Karadima, D. Mandellos, M. Karouli, G. Karachalios, C. Sfagos, D. Vassilopoulos, M. Panas University of Athens (Athens, GR) Objectives: Apolipoproteins APOE,APOC1,APOA1 and APOC3 are interesting candidate genes for multiple sclerosis (MS) susceptibility as a result of both positional information from full-genome linkage and association screens and functional evidence regarding their role in myelination, nerve regeneration and immunomodulation. Moreover, evidence of their convergence on a clearly defined metabolic pathway (the glia/neuron cholesterol shuttle) adds further interest to the investigation of their interaction. The present study investigated the effect of the HhaI, HpaI, MspI and SstI polymorphisms of APOE, APOC1, APOA1 and APOC3 respectively, and their interaction, on MS susceptibility in the Greek population. Methods: A case-control methodology was used including a total of 278 unrelated patients with MS (174 females, 104 males) satisfying the McDonald criteria and 214 ethnicity and age matched controls (77 females, 137 males; randomly selected blood donors). DNA was isolated from peripheral blood and genotyped for APOE, APOC1, APOA1 and APOC3 polymorphisms using previously described techniques. Genotype, minor allele carrier and haplotype frequencies as well as minor allele carrier combination frequencies were investigated to detect differences between patients and controls. Results: All polymorphisms were in Hardy-Weinberg equilibrium in patients and controls. Carriers of the h allele of APOC1 had 1.59-fold increase in the relative risk of developing MS (95 % CI 1.06–2.38, p 0.026). This association was substantially increased in terms of risk and significance when combined with carriership of the minor allele of APOC3. Carriers of both minor alleles of APOC1 and APOC3 had a 4.50-fold increase in relative risk (95 % CI 1.70–11.88, p 0.001). No other individual polymorphisms, bilocus haplotypes or minor allele combinations showed significant association with MS. Conclusion: We found evidence of a strong association of MS with a combination of APOC1 and APOC3 gene polymorphisms. A weaker association was found with the APOC1 gene polymorphism on its own. Given the currently available biological evidence on apolipoprotein function, we hypothesized a possible epistatic interaction of the 2 loci as one of several plausible explanations of the present findings.

P275 A novel mutation in CACNA1A associated with familial hemiplegic migraine – clinical and genetic data from a German family T. Freilinger, M. Dichgans Ludwig-Maximilians University (Munich, DE) Background: Familial hemiplegic migraine (FHM) is a rare monogenic variant of migraine with aura characterized by some degree of hemiparesis during the aura. Mutations in three genes have been identified in affected pedigrees: CACNA1A, ATP1A2 and SCN1A. More than 50 % of pedigrees are linked to the CACNA1A locus, making CACNA1A the most frequent FHM gene. Objectives: To present clinical and genetic data on a German FHM family in which a novel mutation in CACNA1A was detected. Methods: All individuals were phenotyped with a detailed semi-structured telephone interview. Diagnosis was based on the criteria of the International Headache Society. Blood samples were obtained from all available family members, and DNA was extracted from leukocytes according to standard procedures. All 47 exons of CACNA1A were analysed by direct sequencing. DNA samples of 100 healthy control subjects were tested for the identified sequence variant in exon 7 by analysis of a restriction fragment length polymorphism. Results: Sequencing analysis of the entire coding region of CACNA1A revealed a heterozygous G-to-A substitution at position 1069 (c.G1069A) which causes a glycine-to-serine change at amino-acid position 357. The G357S allele showed complete cosegregation with the FHM phenotype in the family and was absent from a panel of 200 control chromosomes. G357S affects the S6-transmembrane segment of protein domain I, which like the other S6 segments is known to control the channel’s inactivation properties. Gly357 is evolutionarily completely conserved among alpha1A-subunits from several other species. The novel mutation was associated with a particularly severe phenotype in the index patient: attacks were accompanied by elevated temperature and coma of several hours duration. Several phenotypic features in the affected son deserve particular attention: first, motor and cognitive development was slightly delayed. Secondly, a diagnosis of attention-deficit-hyperactivity-disorder (ADHD) was established at age 4 years. Conclusion: Several lines of evidence qualify the G357S variant as a true mutation; however, electrophysiological data are necessary to clarify its functional relevance. G357S is the first FHM-mutation affecting the S6-segment of domain I. Given the known intra-familial variability of FHM, it is possible that the association with delayed mental/motor development and ADHD in one affected is not merely due to chance, but indicates a true genotype-phenotype correlation. P276 A new opa1 gene mutation associated with neuropathy M. Spinazzi, L. Vergani, G. Cenacchi, B. Wissinger, C. Angelini University of Padua (Padua, IT); University of Bologna (Bologna, IT); University of Tubingen (Tubingen, IT) Objective: to describe the clinical, histological and molecular features of a new family of patients affected by dominant optic atrophy of Kjer type (ADOA). Hereditary mitochondrial fusion disorders like ADOA, due to OPA1 gene mutations, and CMT2, due to MFN2 gene mutations, are recognized causes of optic atrophy, due to optic nerve fibers degeneration. CMT2 additional distinguishing feature includes axonal polyneuropathy. Methods: clinical, laboratory, electrophysiological data and muscle biospy were obtained in two sisters affected by ADOA. DNA was screened for mutations in the OPA1 gene by DHPLC and direct sequencing. Results: there was a different degree of visual loss between the 2 female patients, 46 (index patient) and 45 years old. Neither complained of muscle weakness and sensory loss but both complained of muscle exertional fatigability and one had pes cavus. EMG showed a severe motor-sensory axonal neuropathy in the index patient, while a mild demyelinating polyneuropathy in her sister. Muscle biopsy showed neurogenic atrophy and mitochondrial granular reactions by oxidative stains within fibres. DNA analysis showed a new 38 base pair deletion in the junction between exon and intron 14 predicting a frame shift. Conclusions: the association between ADOA and polyneuropathy has never been described previously. This observation warrants further electrophysiological studies even in asymptomatic ADOA patients to elucidate if the polineuropathy is a unique feature due to the new mutation detected in this family, or a frequent, subclinical feature of ADOA whose functional and histopathological substrate could be overlapping with CMT2.

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P277 Whole genome association study in primary progressive multiple sclerosis F. Esposito, F. Martinelli Boneschi, M. Rodegher, P. Rossi, A. Ghezzi, R. Capra, G. Coniglio, L. Collimedaglia, D. Toniolo, H. Abderrahim, G. Comi Scientific Institute San Raffaele (Milan, IT); Ospedale di Gallarate (Milan, IT); Fondazione Moro Girelli Don Gnocchi (Brescia, IT); Ospedale San Carlo (Potenza, IT); Ospedale Maggiore della Carità (Novara, IT); Serono Pharmaceutical Research Institute (Geneva, CH) Multiple Sclerosis (MS) is a complex disease, depending on a combination of genetic and environmental factors and characterized by clinical and genetic heterogeneity. It is believed to result from the action of allelic variants in several genes, each with small individual effects. Genetic association studies are an effective approach for detecting the effects of such common variants with modest effect Our aim is to identify the susceptibility genes or markers associated to a particular course of MS, the Primary Progressive MS, which is clinically very different from the more common courses (Relapsing Remitting and Secondary Progressive MS). We enrolled 197 Italian patients with PP MS and 234 healthy controls matched for age and sex. The 72 % of patients were pure Primary Progressive MS with no relapses, 20 % were Primary Progressive MS with relapses and 8 % were transitional MS. We performed a whole genome association study comparing the Single Nucleotide Polymorphism allele frequencies at polymorphic loci in the cases and in the healthy matched controls using the Affymetrix GeneChip® Human Mapping 500K Array Set genotyping assay. A range of statistical tests was performed to identify the genes associated with the disease, either as causative or in linkage disequilibrium with the markers used. The validation of these results is currently ongoing, and includes also a comparison with the results obtained from a whole genome scan on 230 Relapsing Remitting patients, performed with the same technique. P278 Heterozygous Tim 23 knockout mice: an animal model of mitochondrial protein import T. Klopstock, T. Floss, I. Schneider, L. Becker, H. Prokisch, W. Wurst, T. Meitinger, U. Ahting LMU (Munich, DE); GSF (Neuherberg, DE) Objectives: Tim23 protein (Tim23 p) is a key component of the mitochondrial import machinery. It is part of the Tim23 complex which is responsible for translocation of matrix-located protein precursors across the inner membrane. Its own import is dependent on the DDP1p/Tim13 p complex. Mutations in DDP1 (deafness/dystonia peptide) cause the Mohr-Tranebjaerg syndrome (OMIM #304700), one of the two so far only known human diseases caused by impaired mitochondrial protein import. In the context of a systematic approach to generate mitochondrial animal models, we created a Tim23 knockout mouse. Methods: The pT1betageo gene trap vector, which contains betageo, a fusion of the genes for beta-galactosidase and neomycin resistance, was electroporated into mouse embryonic stem cells. Gene-trap expressing cell clones were selected, manually picked, expanded and sequenced. Blastocysts were harvested by uterine flushing 3.5 days after a vaginal plug was observed and separated individually into tubes. The blastocysts were used directly as template for the genotyping PCR reactions. After breeding, mice were phenotyped at the age of 12 weeks including SHIRPA protocol, grip strength and RotaRod measurements. Results: Homozygous Tim23-/- mice were not viable. Heterozygous Tim23+/- mice showed ubiquitous expression of a LacZ fusion protein as shown by lacZ histochemistry and a 50 % reduction of TIM23 as determined by immunoblotting. Phenotypic characterization revealed impairment of motor coordination, balance and grip strength. The reduced Tim23 p levels correlated with a markedly reduced lifespan of Tim23+/- mice. Some heterozygous mice showed signs of premature aging such as alopecia and kyphosis. Conclusion: Here we show that the homozygous knockout of Tim23, that is essential in yeast, is embryolethal in mice. Interestingly, the heterozygous Tim23+/- mice showed a severe phenotype of premature aging and markedly reduced life span. These data emphasize the utmost importance of the mitochondrial protein import machinery. No human deficiency of Tim23 p has been described so far. However, the Tim23+/- mice may be considered as an indirect model of the rare human Mohr-Tranebjaerg syndrome since Tim23 p interacts closely with the DDP1p/Tim13 p complex. Moreover, the data provide new evidence for the pivotal role of mitochondria in aging.

P279 Clinical and pathological aspects of an Italian patient with inclusion body myopathy and frontotemporal dementia carrying a novel mutation in valosin-containing protein gene A. Bersano, R. Del Bo, C. Lamperti, S. Ghezzi, N. Bresolin, L. Napoli, E. Ballabio, M. Moggio, L. Candelise, G. P. Comi, S. Corti Fondazione Ospedale Maggiore Policlinico (Milan, IT) Objective: To describe clinical and pathological features of a patient affected by inclusion body miopathy (IBM) and frontotemporal dementia (FTD). Hereditary IBM associated with Paget disease of the bone (PDB) and FTD (IBMPFD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene, mapped on chromosome 9p13–p12. VCP is an ubiquitously expressed member of ATPase family, involved in different cellular pathways including ubiquitin-proteasome–dependent protein degradation, apoptosis and cell-cycle control. All the pathogenic mutations of VCP gene described so far are located within the region coding of N-terminal domain, which is the binding region for partner proteins suggesting that genetic variants could interfere in protein interaction with components of ubiquitin proteasome and endoplasmic reticulum associated degradation. Methods: A 69-year-old Italian male patient presented by the age of 50 years a progressive weakness distally in arms and proximally in legs and developed frontotemporal dementia at the age of 66 years. Family history was negative A CT scan disclosed a selective fronto-temporal atrophy. Muscle biopsies were analysed by standard histological, histochemical and ultrastructural methods. VCP, ubiquitin, desmin and myotilin immunoreactivities were investigated by immunohistochemistry.VCP gene was analysed by sequence analysis. Results: Two muscle biopsies disclosed pathological features consistent with IBM characterized by progressive degenerative changes and rimmed vacuoles in association with the presence of VCP- and ubiquitin-positive cytoplasmic and nuclear muscle protein aggregates. These deposits were present, although in a lower quantity, also in patients with sporadic inclusion body myositis.A novel heterozygous mutation C687T was found within exon 5 (R159C) of the VCP gene. The C687T mutation was absent in 200 agematched control individuals. It is located only four amino acids away from the mutational hotspot previously described in IBMPFD and represents the same type of mutation (R>H). Conclusions: A novel VCP gene mutation was found in an apparently sporadic IBM with later appearance of frontotemporal dementia. The histopathologic features, such as VCP sarcoplasmic over-expression and nuclear inclusion, may suggest this molecular aetiology. However only the combined clinical features of IBM and FTD seems to be helpful to address the correct genetic investigation. P280 Alpha-synuclein gene promoter variability in peripheral blood mononuclear cells from patients with Parkinson’s disease: association with increased oxidative stress but not with soluble alpha-synuclein overexpression A. Prigione, A. Galbussera, B. Begni, L. Brighina, S. Andreoni, R. Piolti, C. Ferrarese University of Milan-Bicocca (Monza, IT) Objectives: We recently participated in a collaborative analysis (GEO-PD) that demonstrated the association of a 263 base-pair (bp) repeat sequence (REP1) in the alpha-synuclein (SNCA) gene promoter with Parkinson’s disease (PD) susceptibility. Since we previously identified higher levels of oxidative stress in peripheral blood mononuclear cells (PBMCs) from treated PD patients compared to controls, we aimed herein to determine whether REP1 variability influences SNCA protein concentration and oxidative stress parameters in these cells. Methods: 27 treated PD patients and 32 age-matched healthy subjects were selected for the present study. The distribution of REP1 genotypes was representative of the global population provided for the GEO-PD analysis. REP1 allele length variants were assayed by real-time PCR and allelic sizes assessed by GeneScanner software. Ex-vivo PBMCs were used as peripheral dopaminergic cell models, as they can synthesize endogenous dopamine and they express dopamine transporters and receptors. Reactive oxygen species (ROS) production was measured with DCF, glutathione reductase activity (GR) was assayed by spectrophotometer, and soluble SNCA protein levels were quantified by ELISA. Results: Soluble SNCA protein concentration in PBMCs did not vary between PD patients and control subjects, and it was not influenced by REP1 variants. Increased ROS production (two-tailed unpaired Student’s t test, p < 0.05) associated with unaltered GR activity was detected in PBMCs from PD patients compared to controls, confirming our published results. In the

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studied population, 263 bp REP1 genotypes were significantly associated with higher PBMC ROS production (ANOVA analysis, p = 0.0038; Tukey’s Multiple Comparison post-test: 259 vs. 261, p> 0.05; 259 vs. 263, p < 0.05; 261 vs. 263, p < 0.01). Conclusion: REP1 variants did not show any correlation with soluble SNCA protein levels in peripheral dopaminergic cells from PD patients and control subjects. However, increased free radical production in PBMCs appeared to be linked with genotypes defined by the 263 bp length allele, although the responsible mechanism is still undefined. If our data could be reproduced in a larger population, we might hypothesize that 263 bp REP1 variant could be associated not only with a generic risk of PD susceptibility, but also with a specific biochemical dysfunction causing an increase in cellular oxidative stress, even in the absence of SNCA protein overexpression. P281 α (-308) gene polymorphism and primary intraTumour necrosis factor-α cerebral haemorrhage E. Dardiotis, M. Dardioti, K. Aggelakis, A. Komnos, A. Tasiou, K. Paterakis, S. Ralli, I. Gabranis, G. Xiromerisiou, A. Papadimitriou, G. Hadjigeorgiou University Hospital of Larissa (Larissa, GR); General Hospital of Larissa (Larissa, GR) Objectives: There is accumulating evidence that genetic elements contribute to the pathogenesis of ICH. It is also known that lobar and non-lobar ICH is generated by different pathogenetic mechanisms. Apolipoprotein E polymorphism was implicated in lobar ICH while angiotensin converting enzyme I/D genetic variants were linked to deep brain structure ICH. Tumor necrosis factor-a (TNF-a), a proinflammatory cytokine, was found to participate in vascular damage and coagulation processes. Recently, it was shown that TNF-a promoter was implicated in the pathogenesis of subarachnoid hemorrhage. We conducted a prospective study to test possible association of TNF-a (-308) gene polymorphism with ICH. Methods: 147 prospectively recruited patients (mean age ± SD = 63.5 ± 14.2; females 31.1 %) with ICH and 287 age- and gendermatched control subjects were genotyped for the TNF-a (-308) gene polymorphism. The following data were collected: age, gender and other epidemiological factors, location and volume of ICH, Glasgow Coma Scale (GCS) at admission and 6-month modified Rankin Scale (mRS). H-W equilibrium was tested with exact test. Odd ratios (ORs) and corresponding 95 % coefficient intervals (CI) were calculated using logistic regression. Possible association was examined using the Fisher’s exact test. Results: The population was in H-W equilibrium. The distribution of the TNF-a genotypes in the whole group of ICH patients (GG = 85.7, GA = 12.2, AA = 2.1), in patients with lobar ICH (GG = 79.6, GA = 16.3, AA = 4.1) and non-lobar ICH (GG = 88.7, GA = 10.2,AA = 1.1) did not differ from that of the controls (GG = 80.1, GA = 19.2, AA = 0.7) (p = non-significant). Conclusion: Our study did not provide evidence of an implication of TNF-a (-308) gene polymorphism in the development of ICH. P282 Interleukin 6 (-174) gene polymorphism and traumatic brain injury E. Dardiotis, M. Dardioti, A. Komnos, K. Paterakis, G. Noulas, G. Xiromerisiou, K. Aggelakis, A. Tasiou, I. Gabranis, S. Ralli, A. Karantanas, A. Papadimitriou, G. Hadjigeorgiou University Hospital of Larissa (Larissa, GR); General Hospital of Larissa (Larissa, GR); University Hospital of Crete (Heraklion, GR) Objectives: Genetic variants in susceptibility genes were reported to influence the pathophysiology of traumatic brain injury (TBI). TBI triggers inflammatory processes the extent of which determines the degree of acute and chronic neuronal death and patients’ clinical outcome. Interleukin-6 (IL-6), a proinflammatory cytokine, is induced shortly after TBI. Elevated IL6 levels were associated with more severe acute brain injury and unfavorable outcome. Allele G carriers of IL-6 (-174) gene polymorphism were found to have higher levels of IL-6. We conducted a prospective clinical study to test possible influence of IL-6 (-174) gene polymorphism on patients’ clinical presentation and 6 month outcome after TBI. Methods: 216 patients with TBI [mean age±SD = 39.8±21.1, females = 35 (16.2 %)] successively admitted to the neurosurgical unit were evaluated.Initial neurological status was assessed by means of the Glasgow Coma Score (GCS), while we defined patients’ six-month outcome using the Glasgow Outcome Scale (GOS). We genotype for IL-6 (-174) polymorphism from blood samples using standard PCR/RFLP method. Possible associations were examined using the t-test, the Fisher’s exact test and the x2 test. Odds ratios with the corresponding 95 % confidence intervals were also calculated using logistic regression analysis. Results: The population was in H-W equilibrium. Distribution of IL-6

genotypes and alleles were similar in TBI patients with favorable (CC = 60.8 %, CG = 34.9 %, GG = 4.3 %, C = 78.2, G = 21.8) and unfavorable (CC = 63.4 %, CG = 33.4 %, GG = 3.2 %, C = 80 %, G = 20 %) outcome. (p = non-significant). There was also no significant influence of IL-6 polymorphism on patients’ GCS at admission (p = non-significant). Conclusion: Our study fail to provide evidence of an implication of interleukin 6 (–174) gene polymorphism in the patients’ clinical presentation at admission and 6 month outcome after TBI.

Multiple sclerosis P283 Differential patterns of interferon-beta usage in secondary progressive multiple sclerosis J. Sellner, A. Gebhardt, R. Bühler, O. Findling, S. Humpert, V. Blatter-Arifi, C. Lienert, H.-P. Mattle Inselspital, University Hospital Berne (Berne, CH) Background: Interferon beta (IFN-b) has an effect on disease activity in secondary progressive multiple sclerosis (SPMS) when relapses are present but may not slow progression in patients without relapses or once patients with relapsing remitting MS (RRMS) have reached a secondary progressive phase. The ideal time point for the beginning, if at all, and discontiunation of IFN-b remains yet to be determined in patients with SPMS. Objective: To evaluate the frequency and spectrum of Interferon-beta (IFN-b) usage in SPMS by assessing patterns and duration of treatment in our Outpatient Clinic cohort. Methods: In our records we identified 106 patients with SPMS (male/female ratio 1:1.65). Their mean age (SD, range) was 51.1 years (y) (9.3, 29.1–67.8) and the median EDSS was 6 (1.4, 2–8.5) at the most recent visit. The age at symptom onset was 34.1 y (11.4, 14.9–63.0). The diagnosis of SPMS was based on physician’s judgement, and the mean follow-up after reaching the secondary progressive phase was 6.7 y (5.3, 0.1–23.9). 54.7 % SPMS patients had at least one superimposed relapse. Results: 75.5 % of the SPMS patients had received IFN-b treatment. Therapy had already been discontinued in 19.8 %. We identified three patterns of IFN-b usage: i) patients already on IFN-b during RRMS and continuation of treatment after transition to SPMS (32.5 %, mean treatment duration 9.9 y (4.8,2.2–17.8)),ii) start of IFN-b 1 y preceding or 1 y post conversion to SPMS due to increasing relapsing activity and residual symptoms (30 %, 3.8 y (3.4, 0.1–11.5), and iii) start of IFN-b > 1 year after conversion to SPMS in order to slow ongoing progression (37.5 %, 5.6 y (4.5, 1.0–22.0)). In group i) treatment with IFN-b was initiated 3.9 y (2.8, 1.0–10.9) prior to the transition to the chronic progressive course and was then continued for 6.0 y (2.9, 1.1–10.9). The initiation of INF-b treatment in group iii) was 5.6 y (4.5, 1.1–22.2) after conversion to SPMS. Conclusion: This study underlines the increasing use of IFN-b treatment in SPMS over the recent years. The majority of the patients in our SPMS cohort was initially treated with IFN-b when there were still relapses. In a minority, however, treatment was started when there were no relapses any longer and randomized trials do not support the use of IFN-b any more. Furthermore, IFN-b treatment is continued in many SPMS patients, though relapses do not occur any longer and though a continuing effect may not be present any more. P284 Depression: relationship to disease-modifying therapy S. Kirzinger, A. Siegwald, A. Crush University of Louisville School of Medicine (Louisville, US) Objectives: Depression is a common symptom for Multiple Sclerosis (MS) patients and more than 40 % of MS patients suffer with this symptom.At the University of Louisville MS Care Center Program site at Baptist Hospital East, patients are evaluated for depression using the Beck Inventory at each visit in addition to assessments for changes in response to their Disease Modifying Therapy (DMT).These assessments include the Expanded Disability Status Scale (EDSS), Timed 25 ft. Walk, Box and Blocks, 9-Hole Peg test, Modified Fatigue Impact Scale, and the CogniStat to assess cognitive impairment. The present study conducted an analysis to determine the relationship, if any, between DMT and depressive symptoms. The analysis included 142 MS patients who had been exclusively on either Glatiramer Acetate (GA) or Interferon-beta for up to 48 months. Methods: The assessments were obtained at baseline within six weeks of initiating a DMT. A mean difference between the baseline BI score and the

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last assessment was used. This eliminated the difference in baseline scores between the two treatment groups. The assessments occurred up to a 4 year period. Results: There was no difference in the change in the BI scores between the two groups either if treated or not treated with anti-depressants. No statistically significant difference was found although the Interferon-beta group showed a greater decrease in the depression score over time compared to the GA group. Conclusion: The common perception is that there is an increased tendency for Interferon-Beta treated MS patients to experience an increased incidence of depression. This retrospective analysis did not confirm this perception and showed no difference in the DMT treatment groups with regard to the Beck Inventory. P285 A case of fulminant malignant demyelination along total central nervous system axis. ADEM or MS? Diagnostic speculation and therapeutic efforts A. Galanopoulos, K. Belis, E. Alexiou, G. Gekas General Hospital of Nikea (Piraeus, GR) Introduction: Fulminant malignant demyelination is rare and may lead to death or serious disability in a period of days to weeks. Few cases are reported in literature, which are classified either as the fulminant form of multiple sclerosis (Marburg disease, MD) or acute disseminated encephalomyelitis (ADEM), provided that infectious and other demyelinating causes have been excluded. Clinical presentation, precedent infection or vaccination, dissemination in time and final outcome are indicative for diagnosis. Certain diagnostic criteria, discerning clearly ADEM from MD, however, have not yet been established. Case report: We describe the case of a young woman with massive fulminant demyelination along total CNS axis. The disease started with legs’ numbness and weakness 15 days before patient’s transport to our Department. Her history was free of recent vaccination or infection. On admission, she presented paraplegia, upper limbs’ weakness and sphincter dysfunction, whereas on 20th day of hospitalization, she was already quadriplegic and her life was seriously threatened of respiratory deficiency. Sequential MRI of CNS revealed unrestrained massive demyelination, expanding from cerebral hemispheres to lower spinal cord, including conus medullaris Most of lesions were Gd-enhanced. CSF analysis showed 40 leucocytes/mm3, total protein: 450 mg/dl, myelin basic protein: > 95 ng/ml). No oligoclonal bands were detected. Blood and CSF tests were negative for recent infection, vasculitis or other systemic disease. Immediate and intensive treatment was applied, including all recommended therapeutic agents (corticosteroids, mitoxantrone, plasmapheresis, g-globulin), one by another, as the course of the disease seemed unaffected. Therapeutic efforts managed finally to save patient’s life, even though serious neurological disability remained. Thus, one year after the onset, patient presents little only motor activity of upper limbs, whereas remains paraplegic. Conclusion: Fulminant malignant demyelination is an acute and urgent disorder of CNS, often resulting in early death or serious neurological deficits. Its classification as MD or ADEM is frequently uncertain, due to the lack of clear diagnostic criteria. We conclude that, beyond the obvious diagnostic dilemma, early, intensive treatment with all available immunosuppressive medication is substantial for preventing a potential fatal outcome of the disease and achieving the optimum therapeutic effect for patients. P286 Post marketing survey by a year/patient model for disease-modifying therapies in multiple sclerosis: 10th year data G. Iuliano, R. Napoletano, A. Esposito OO.RR. Salerno (Salerno, IT) Background: Italian Multiple Sclerosis (MS) centers deal with many and changing disease modifying therapies; their patients (pt), are observed for different times. The so-called “Year-patient” (y-p) method fits best for longitudinal study of such groups. In 1998 we built a registry for y-p; this paper is the update to dec.2006. PTS and methods: Only pts with complete anamnesis are included, to avoid biases as regression to the mean. Interferons (IFN) or copolimer (COP) can be prescribed in “relapsing-remitting” (RR) type, EDSS up to 5.5; IFN1 b also in “secondary-progressive” (SP), up to EDSS 6.5. For Intention to treat, the first therapy is accounted for each year. Statistics are made by KruskallWallis test and post hoc LSD for relapse-rates and EDSS; chi squared and Odds-Ratios for RM data; multiple regression for longitudinal data. Results: 143 pts are included (38M, 105F, age at onset 11–59, m29.25) from which 1505 years are collected (without therapy = 837; IFN1b = 128, IFN1 a 1/w = 189, IFN1 a 3/w = 172,AZA = 107, COP = 45; other = 27). In RR type, be-

fore therapy, relapse rate mean was 0.68(SD0.72); for IFN1 b is 0.67(0.81), for IFNIa1/w, 0.54(0.80); for IFNIa22mg, 0.86(0.83); for IFNIa44mg, 0.44 (0.77); for AZA, 0.40(0.69) for COP 0.42 (0.83); for Mitoxantrone 0.14 (0.37). Overall p is < 0.0001; post hoc LSD is significant vs. no therapy for all drugs but IFN1 b and IFN1a22mg; The only frequent side effect is fever. COP and IFN1a44mg show lower switching rate. All drugs reduce RM lesions, new or enhanced, vs. no therapy. New lesions: IFN1 b: OR = 0.15 (0.06–0.35); IFN1a1/w: OR = 0.19 (0.12–0.31); IFN1a22 OR = 0.22 (0.06–0.67); IFN1a44 OR = 0.23 (0.14–0.40); AZA OR = 0.19 (0.08–0.42); COP OR = 0.17 (0.07–0.41). Enhanced lesions: IFN1 b OR = 0.28 (0.10–0.68); IFN1a1/w OR = 0.37 (0.22–0.62); IFN1a22 OR = 0.47 (0.12–1.60); IFN1a44 OR = 0.27 (0.16–0.46) AZA OR = 0.16 (0.05–0.46); COP OR = 0.24 (0.08–0.63). Longitudinal data are evaluable up to 11 years for IFN, 14 for AZA, and 32 pre-therapy. Relapse rate decays progressively before therapy (regression to the mean, p = 0.023), with IFN1 b (p = 0.0040) IFN1a44 (p = 0.0046), and association IFN-AZA (p = 0.0015). Discussion: Longitudinal observation can be the main contribute of postmarketing studies on SM therapy. Nevertheless, the most prolonged studies are the extensions of the original trials. Our data are comparable to the literature, for “year-patient” method, though some limits, is simple and reliable, cheaper, and allows more powerful data with smaller casuistics.

P287 Dysarthria and phonatory instability in multiple sclerosis K. Konstantopoulos, M. Vikelis, K. Xifara, D. Mitsikostas Athens Navy Hospital (Athens, GR) Dysarthria is present in 23–51 % of multiple sclerosis (MS) patients, and the perceived characteristics of dysarthria have been shown to predict quality of life in these individuals.While objective measures of voice function in MS have been made, the small sample size has prohibited using voice as a predictor of function. Similarly, there is a paucity of data relating the degree of phonatory impairment in MS with neurological evidence, such as the severity of neurological involvement and disability. Objectives: This study provides objective measures of phonatory function and relates speech acoustics with neurological variables such as disease duration, number of T1 and T2 lesions, and disability involvement. Methods: The speech of 64 MS patients and 64 matched pair controls (age, gender and smoking habits) was recorded digitally using electroglottography (EGG). EGG is a physiological method to measure vocal fold contact in otolaryngology. Digital audio tapes were analysed by means of the Speech Studio software. All MS patients were seen in the Neurology clinic of Navy hospital of Athens between March 2004 and March 2006. Results: 45.3 % of the MS patients (n = 29/64) and 0 % of the matched pair controls (n = 0/64) reported communication difficulties affecting speech and voice.Vocal jitter (a measure of vocal fold stability during production of the sustained vowel “ee”) was significantly different between groups (U = 1620.50, N = 128, p = 0.041). The standard deviation of the average fundamental frequency during the “ee” production was also significantly different between the groups (U = 1552.50, N = 128, p = 0.018). Finally, the mean fundamental frequency of the vibrating vocal folds during reading (F (1.124) = 5.120, p = 0.025) differentiated the MS from the control group. Multiple regression using the enter method revealed that these voice variables accounted for 32.3 % of the variation in the number of T1 neurological lesions (p = 0.003). Conclusions: The association of voice symptomatology due to dysarthria with neurological factors reveals the impact of phonation on the disease and signals the timing for voice assessment and therapy. Multiple regression reveals that the phonatory measures can be useful tools to predict degree of lesion activity in a non-invasive manner, perhaps in conjunction with other acoustic and non-acoustic data.

P288 Xerophthalmia, xerostomia and primary Sjögren’s syndrome in multiple sclerosis patients treated with immunomodulating drugs: an Italian multicentre study P. Annunziata, L. De Santi, S. Di Rezze, E. Millefiorini, E. Capello, G. Mancardi, M. De Riz, E. Scarpini, R. Vecchio, F. Patti University of Siena (Siena, IT); University La Sapienza (Rome, IT); University of Genoa (Genoa, IT); University of Milan (Milan, IT); University of Catania (Catania, IT) Objectives: Primary Sjogren’s syndrome (PSS) may coexist with multiple sclerosis (MS). We previously reported a case of a woman with MS treated with interferon-beta (IFN-beta) developing PSS after a long time from MS onset, and other cases of autoimmune connective disease under IFN-beta

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therapy have been reported. The aim of this exploratory study was to assess the frequency of xerophthalmia, xerostomia and PSS in relapsing-remitting (RR) and secondary (SP) MS patients treated with disease modifying drugs (DMDs+) compared to naive-to-treatment (DMDs-) MS patients. Methods: Two hundred fifteen consecutive patients (148 females, 67 males) with definite MS from five centres of northern, central and southern Italy were included in the study; 124 patients (58 %) were on DMDs+ (26 % IFN-beta 1 a i. m., 29 % IFN-beta 1 a s.c, 35 % IFN-beta 1 b, 10 % glatiramer acetate) and 91 (42 %) DMDs-. For each patient clinical history and neurological examination were recorded. The presence of ocular and/or oral symptoms both at the time of MS onset and examination was assessed by a structured questionnaire. In patients complaining of dry eyes or dry mouth, laboratory, instrumental and histological tests were performed and PSS was diagnosed according to the classification criteria established by the American-European Consensus Group for Sjogren’s syndrome. All patients included in the study did not fulfill exclusion criteria for PSS. Results: Nineteen of 215 (8.8 %) MS patients (11.7 % of DMDs+ and 5.7 % of DMDs- patients, p = 0.15) complained of either ocular (4.8 %) or oral symptoms (2.4 %) or both (1.4 %) not present at disease onset. Two patients (1 RR DMDs+ and 1 SP DMDs-) fulfilled diagnostic criteria for PSS. No differences were observed for clinical course of MS (RR, SP), EDSS, therapy and disease duration of patients presenting or not ocular and/or oral symptoms and also for duration of therapy of patients presenting ocular and/or oral symptoms or not in the DMDs+ group. There was a trend for a higher frequency of sensory (p = 0.057) and visual (p = 0.055) signs in patients with xerophthalmia and/or xerostomia compared to those without. No differences were observed for other functional systems. Conclusion: In this cohort, Sjögren-like symptoms may occur during the course of MS, independently from immunomodulating therapies. However, this preliminary data encourages a larger multicentre study to definitively assess a hypothetical role of immunomodulating drugs in triggering PSS. P289 Neuropsychological factors of fatigue syndrome in patients with multiple sclerosis: paradox fatigue? R. Hibbeln, M. Himmelmann, S. Kunze, O. Merse, H.-D. Oelmann St. Barbara Hospital (Gladbeck, DE) Objectives: 70 % of MS patients complain of tiredness (fatigue) as a daily symptom. For 33 % of them this is the most burdening syndrome.A valid definition of the term fatigue is still lacking.The pathophysiology of the fatigue syndrome (FS) in MS patients is not known. The FS is generally assessed with the self-questionnaire (SQ). Moderate correlation with depression and low correlation with the EDSS (Extended Disability Status Scale) score are known. The aim of this study is to evaluate the factors influencing FS and tiredness before and after a cognitive strain. Methods: We investigated N = 103 persons, n = 55 relapse remitting and secondary progressive MS outpatients (McDonald criteria) with existing prophylaxis of interferon beta (Rebif 22 mcg sc tiw and Betaferon 8 miu sc eod) and n = 48 neurologically healthy persons in the control group (CG) in a double blinded completely balanced randomised design. We matched age, education, time of day, gender in the CG. We investigated EDSS score, visus, date of first ms-symptoms and diagnosis, former prophylaxis, additional drugs, quality of life, fatigue before and after NPT (strain) with visual analogue scale (VAS) and fatigue in the last 4 weeks with an SQ (MFIS, Modified Fatigue Impact Scale). The strain consisted of a neuropsychological test battery (NPT) of about 1.75 hours, including MFIS. Results: 1) MS pat. vs. CG are significantly (sign.) more tired after NPT measured with VAS (rank sums, MS = 2661, CG = 1995, U-test, 2-tailed, p = 0.0147). 2) MFIS correlates sign. from moderate to high (r = 0.58 / 0.62, p = 0.01) with anxiety and depression (Mental Health Inventory, MHI). There is only a low correlation with tiredness measured by the VAS (r = 0.35, p = 0.05 / r = 0.39, p = 0.01). 3) The assessment of neuropsychological disorders in an SQ (Perceived Deficits Questionnaire) does not show a sign. correlation with the validly and objectively measured abilities of the MS patients, but does partially so in the CG. 4) 22.9 % (CG 37.5 %) of the MS patients claim to be less tired or at least not more after NPT than before NPT (= paradox fatigue). Conclusion: 1) MFIS is more associated with depression and anxiety than tiredness. 2) Assessment of subjective complaints about neuropsychological disorders with an SQ is not sufficient, standardised neuropsychological tests are necessary. 3) Cognitive demanding task does not necessarily increase fatigue.

Unrestricted grant by Schering Germany GmbH and Serono GmbH Germany. P290 Human antigen specific T cell lines express neurturin, a member of the GDNF family ligands V. Vargas-Leal, M. Knop, J. Hornung, F. Weber Max Planck Institute of Psychiatry (Munich, DE) Objectives: Glial cell line-Derived Neurotrophic Factor (GDNF) family ligands (GFLs) are potent trophic and survival factors for central and peripheral neurons. Neurturin (NTN), a member of the GFLs, is constitutively expressed by human immune cells and modulates TNF-alpha turnover at the post-transcriptional level in activated mononuclear cells. NTN and its receptors may mediate a communication between the immune and the nervous system, playing a protective role in chronic inflammatory CNS disorders, such as multiple sclerosis (MS). According to current hypothesis activated antigen (Ag) reactive T cells enter the CNS, release several cytokines and neurotrophins, which inhibit the action of other encephalitogenic T cells, thus contributing to the neuroprotective immunity. Therefore we investigated NTN expression in activated and resting Ag specific T cell lines from healthy donors and from a MS-patient. Methods: Using the “split well technique” we generated six myelin basic protein (MBP) and six glatiramer acetate (GA) specific T cell lines from two controls and a MS patient, before and after six months of GA therapy. We established a direct intracellular NTN staining and flow cytometry analysis to quantify the amount of NTN produced by activated (5 days after Ag specific restimulation) and resting (9 and 14 days after Ag restimulation) T cells. U936 and THP-1 human cell lines were used as positive and negative control, respectively. Results: Both, MBP and GA specific T cell lines from a MS patient (before and during GA therapy) and healthy donors express significantly higher amounts of NTN in activated state compared to resting state. No differences were found in the percentage of NTN expression in MBP or GA specific T cell lines from controls and the MS patient generated before and during GA therapy. Conclusion: Our results demonstrate that human Ag specific T cell lines produce Neurturin, a member of the GFLs. NTN production depends only on the activation state of T cells. Inflammatory reactions in the CNS – usually considered as detrimental – may also be beneficial due to the delivery of NTN and other neurotrophins by infiltrating activated immune cells. NTN may be protective by modulating the inflammatory process or by promoting regeneration. P291 Reduced immunogenic potential of a new IFN beta-1 a formulation: comparative studies in the BALB/c mouse model F. Bellomi, A. Muto, G. Palmieri, C. Focaccetti, C. Dianzani, M. Mattei, A. ALSabbagh, G. Antonelli University La Sapienza (Rome, IT); University Tor Vergata (Rome, IT); University Campus Biomedico (Rome, IT); EMD-Serono (Rockland, US) Objectives: To compare the relative in vivo immunogenicities of Rebif® New Formulation (RNF), Rebif® and Avonex® using the BALB/c mouse model. Methods: RNF, Rebif®, Avonex® or a control (phosphate-buffered saline) were administered subcutaneously at a dose of 0.1mcg/mL three times weekly to female BALB/c mice, in two studies. Serum samples were collected on Days 7, 21 and 35 (study 1), or Days 28, 42, 49 and 60 (study 2), 72 hours after the third weekly administration of study treatment. Samples were assayed for neutralizing antibodies (NAbs) to interferon (IFN) beta-1 a using the virus-induced cytopathic effect assay. Titres were determined using the Kawade method and expressed as t1/10, the reciprocal of the serum dilution that reduces the potency of IFN from 10 to 1 laboratory units/mL. Titres are presented as log10 and represent the mean (standard deviation) of two independent determinations. A t-test was used to compare mean values. Results: A total of 24 mice was used in each study (RNF, n = 6; Rebif®, n = 6; Avonex®, n = 6; control, n = 6). Study 1: NAbs were not detected at Day 7; however, by Day 21, 1 mouse in the RNF group had developed NAbs compared with 3 and 4 mice in the Rebif® and Avonex® groups, respectively. Study 2: at Day 28, NAbs were detected in 3 mice receiving RNF compared with 4 mice in the Rebif® and 3 mice in the Avonex® groups (serum quantity was not sufficient for titration in 2 mice from both the Rebif® and the Avonex® groups). All mice in the active treatment groups had developed NAbs by Days 35 or 42 (studies 1 and 2, respectively). NAb titres were the lowest in the RNF group and highest in the Avonex® group throughout study 1. At day 35, NAb titres were significantly lower in the RNF group (1.91 t1/10

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[0.55]) than the Rebif® group (2.55 t1/10 [0.35]; p = 0.037), which had a significantly lower NAb titre than the Avonex® group (3.10 t1/10 [0.38]; p = 0.026).In study 2,NAb titres were lowest in mice receiving RNF at all time points except Day 60; there were no statistically significant between-group differences. Conclusion: RNF appears to have a lower immunogenic potential, on a gram-for-gram basis, than previous formulations of IFN beta-1a. Time to development of NAbs was longer and NAb titres were lower with RNF compared with Rebif® or Avonex®, despite identical dose, route and frequency of administration. This study was supported by Merck Serono. P292 Brainstem lesions associated with pendular nystagmus in patients with multiple sclerosis F. Zellini, C. R. Tench, T. Patel, I. Gottlob, C. Constantinescu University of Nottingham (Nottingham, UK); University of Leicester (Leicester, UK) Objective: Pendular nystamgus (PN) can be a disabling symptom of multiple sclerosis (MS). The precise location of MRI detectable pathology causing PN is still not well understood. Lopez et al found brainstem involvement in PN, in particular in inferior olivary complex, central tegmental tract and red nucleus. However a major limitation of that study was the absence of a control group. Our proposal is to accurately localize MS lesion in specific brain structures and to look for differences between nystagmus patients and mached control group. Methods: T2 weighted MRI was performed in 10 MS patients with PN and in 14 control subjects (MS patients without nystagmus) mached for age, Expanded Disability Status Scale, disease duration and sub-type, and T2 total lesion load.A semiautomated contouring algorithm was used to asses the lesion volumes in major brainstem structures and in cerebellum. Regions of Interest (ROIs) were identified to delineate T2-visible MS lesions by an operator blinded to the study group, generating lesion maps. Group comparison of lesion volumes in specific structures was performed using MannWhitney U-Test. The presence of pathological hyperintensity in olivary complex, central tegmental tract and red nucleus was evaluated comparing with a digital atlas in both groups. Results: The preliminary results confirm the high frequency of MS lesions in the localization characteristic for MS. Lesion volumes in medulla, pons, midbrain and cerebellum did not differ significantly between the two groups. Higher percentage of lesions in inferior olivary complex and central tegmental tract was found in the PN group compared to the control group. Further analysis is required to confirm these results. Conclusion: While brainstem and cerebellum are regions with high frequency of lesions in MS, and conventional MRI lacks in pathological specificity, in MRI studies focused on localizing lesion relating to specific symptoms, there is an absolute need for a control group. This could improve the real association between MRI abnormalities in selected areas and specific MS symptoms. P293 Clinical factors influencing health-related quality of life in Polish subjects with multiple sclerosis E. Papuc, H. Bartosik-Psujek, Z. Stelmasiak Medical University of Lublin (Lublin, PL) Aim: The aim of this study was an assessment of clinical factors which can influence quality of life in polish subjects with multiple sclerosis. Factors taken into consideration in the analysis were: level of disability measured in EDSS, disease duration, clinical course of the disease, disease activity measured by relapse rate, depression and fatigue. Methods: 173 patients with a diagnosis of MS according to McDonald criteria participated in the study (M/F = 52/121; mean age:36.9± 8.9; mean disease duration: 8.9± 6.6 years; mean EDSS: 4.34±1.84). 101 subjects had a relapsing-remitting course of the disease (RR-Ms), 32 patients had primary progressive MS (PP-MS), 36 secondary progressive (SP-MS), and 4 progressive relapsing multiple sclerosis (PR-MS). All subjects were assessed with Mini Mental Status Examination(MMSE), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), World Health Organisation Quality of Life Instrument (WHOQOL-100) and underwent a standard clinical evaluation (including EDSS). Results: Analysis of correlations between clinical parameters and quality of life revealed better quality of life in relapsing-remitting compared to primary and secondary progressive course of the disease. No correlations were observed between disease duration, disease activity and quality of life. Results of this study also confirmed that higher level of depression and fatigue

in multiple sclerosis patients correlated with worse overall quality of life and worse quality of life in physical and psychological health domains, lower level of independence, worse social relations and lower satisfaction with the surrounding environment. Higher level of disability measured in EDSS correlated with worse overall quality of life and worse quality of life in the physical and psychological health domains, worse social relations, lower level of satisfaction with the surrounding environment they live in (p < 0.05). Conclusions: 1. Subjects with RR course of the disease have better quality of life compared to patients with PP or SP multiple sclerosis. 2. Higher level of depression and fatigue is correlated with lower quality of life of multiple sclerosis patients. 3. No correlations were found between disease duration, disease activity and quality of life of multiple sclerosis patients. 4. Functional disability measured by EDSS and especially pyramidal and cerebellar dysfunction, bowel and bladder dysfunction, gait impairment are correlated with worse quality of life. P294 Early predictors of poor response to interferon beta therapy in a cohort of relapsing-remitting multiple sclerosis L. Prosperini, L. Ausili Cefaro, G. Borriello, L. De Giglio, F. Fubelli, C. Pozzilli MS Center, S. Andrea Hospital (Rome, IT) Objectives: To define clinical and paraclinical variables related to a poor response to Interferon beta (IFN-b) therapy in a cohort of Multiple Sclerosis (MS) patients regularly attending the MS Outpatient Clinic of S. Andrea Hospital in Rome. Methods: Patients with clinically definite relapsing remitting MS receiving one of the three formulation of IFN-b as a first treatment with disease modifying drugs were considered in this retrospective post-marketing study. We considered as potential predictive variables clinical data and MRI parameters at baseline and after one year of IFN-b treatment. Disease activity on MRI was based on the presence of enhancing lesions in post-contrast T1-weighted scans and the accumulation of hyperintense lesions on T2weighted images. For the subjects who discontinued IFN-b therapy, the final EDSS was calculated at the last neurological assessment during the IFN-b treatment. We considered as definition of poor clinical response an increase of at least 1 point on the EDSS score confirmed in two consecutive visits separated by a 6-month interval. Results: We analysed data of 345 patients (244 females, 101 males) with a mean (±SD) IFN-b treatment exposure of 4.5±2.2 years (median 4, range 2–13). At baseline, mean age of study population was 32.9±9.1 years, mean disease duration 5.5±4.9 years and median EDSS score 1.5 (range 0–4.5).One hundred and seven patients (31 %) satisfied the criterion of “poor response” to IFN-b therapy as previously defined. They had a longer disease duration at the beginning of IFN-b treatment and a higher baseline EDSS than those with a stable level of disability (p = 0.04 and p < 0.001, respectively). The occurrence of a relapse within the first year of IFN-b therapy was associated to an increase of disability over the study period (OR 2, C. I. 95 % 1.3–3.4; p = 0.003). MRI data considered after one year of IFN-b treatment resulted stronger predictors of poor response: both the presence of at least one Gdenhancing lesion at 1-year MRI scan (OR 3.4, C. I. 95 % 2–5.7; p < 0.001) and an increasing in T2 lesion burden (OR 8.6, C. I. 95 % 5–14.5; p < 0.001) was related to a poor outcome. Conclusions: The present study supports the routine use of MRI to monitor disease activity during IFN-b treatment in order to identify those patients with poor response to IFN-b treatment who could possibly benefit from a different therapeutic approach. P295 Phase I/II Trial of a myelin basic protein-encoding DNA plasmid (BHT3009) alone or combined with atorvastatin in patients with multiple sclerosis F. Valone, T. Vollmer, A. Bar-Or, J. Antel, L. Weiner, J. Oger, Y. Lapierre, D. Arnold, N. Kachuck, J. Gianettoni, L. Steinman, W. Robinson, H. Garren Bayhill Therapeutics Inc (Palo Alto, US); Barrow Neurologic Inst. (Phoenix, US); Mcgill University (Montreal, CA); University of Southern California (Los Angeles, US); University of British Columbia (Vancouver, CA); Stanford University (Palo Alto, US) Objective: To assess safety, immune modulation and MRI changes by BHT3009 in MS patients Methods: This is a double-blind, randomized placebo-controlled, dose escalation trial with an open-label cross over for placebo-treated patients. Patients with either relapsing MS or secondary progressive MS without relapses who had failed at least one approved disease modifying agent were

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randomized to double placebo, BHT-3009 + atorva-placebo or BHT-3009 + atorvastatin. BHT-3009 was administered intramuscularly in weeks 1, 3, 5, and 9. Three dose levels were tested: 0.5 mg, 1.5 mg and 3.0 mg. Atorvastatin (80 mg) was taken daily. In addition to standard clinical, laboratory and MRI assessments blood was collected for assessment of T cell responses to myelin antigens and (optionally) spinal fluid was collected for assessment of antimyelin antibodies. Result: Thirty patients with relapsing (17) or secondary progressive (13) MS were enrolled. BHT-3009 had an excellent safety profile. There were more treatment-related adverse events on the placebo arm. Adverse events were generally mild and transient in nature. There were no significant clinical laboratory abnormalities. Treatment with BHT-3009 was associated with a selective decrease in peripheral blood Th1 cells reactive to myelin antigens in all five of five evaluable patients. Decreased anti-myelin T cells persisted for at least 41 weeks after the last dose of BHT-3009. Treatment with BHT-3009 was also associated with decreased anti-myelin antibody levels in all three patients who underwent lumbar punctures before and after treatment. Follow-up MRIs showed improvement after BHT-3009 treatment compared to placebo treatment. Gadolinium-enhancing lesions increased in the placebo group and decreased in the BHT-3009 groups. Similarly, mean T2 lesion volume increased in the placebo group and decreased in the BHT-3009 groups. The mean T2 volume decrease after BHT-3009 was comparable to that reported for interferon. Decreased T2 lesion volume persisted for at least 16 weeks after the last dose of BHT-3009. Atorvastatin had no effect on either immune response changes or MRI improvements. Conclusion: These data suggest that BHT-3009 is safe, decreases antimyelin immune responses selectively and may decrease CNS inflammation. Based on these data, a phase 2 b trial of 289 patients with relapsing-remitting MS was launched. Results from that trial will be available later this year.

P296 Quality of life and patients’ characteristics in the Berlin MS-Society I. Nippert, P. Scherer Berlin Multiple Sclerosis Society (Berlin, DE) This survey had the aim to describe the satisfaction of Berlin Multiple Sclerosis Society (BMSS) members with the BMSS, with familiy and peer group, with medical and political institutions in comparison with the data from 1996. Methods: In 2006, the BMSS mailed questionnaires to 1985 BMSS members (people with diagnosis multiple sclerosis, MS). BMSS members were asked on their medical history, their personal and socio-demographic characteristics and on the satisfaction with institutions and social domains and with services and activities of the BMSS and on their quality of life. This paper presents the satisfaction data. Satisfaction scores (SaS) ranged from very high (SaS1) to very low (SaS6). Results: (1) Responses: 1015 questionnaires were returned (51 %) and could be analysed. (2) Satisfaction with sources of information: While BMSS members were not very satisfied with newspapers, television and radio (SaS 3.8 to 4.0), the satisfaction was high with the BMSS, the neurologists and internet (SaS 1.9 to 2.3). About 69 % of the BMSS members used the internet. (3) Importance of BMSS offers: ‘information’, ‘personal contact when needed’, ‘lectures’, and ‘seminars, workshops’, ‘support in authorities concern’ were reported as the most important services. Most of the BMSS members did not need regular personal BMSS contacts. (4) Satisfaction was rather high (SaS 2.2 to 2.4) with ‘office neurologist’, ‘BMSS’, ‘family’, and ‘friends’. Satisfaction was rather low (SaS 4.4 to 4.5) with regional and national political institutions (government). Satisfaction was lower as compared to the 1996 data with ‘general practicioner’,‘personal financial status’, ‘contacts to friends’, and ‘contacts to people not affected by MS’. Satisfaction was higher in 2006 as compared to 1996 with ‘neurologist’, ‘university/research institutes’,‘health insureance’ and ‘family’. Conclusion: In times of monetary tightness, the importance of self-helporganizations, e. g. the BMSS, seemed to increase. Social participation might be reduced by financial restrictions. Satisfying contacts focus on neurologists, self-help-organizations, and family.

P297 Cytokine treatment of central nervous system glial cultures regulates expression of genes associated with ischaemia/preconditioning R. P. Lisak, J. A. Benjamins, B. Bealmear, L. Nedelkoska, B. Yao, S. Land Wayne State University (Detroit, US) Objectives: Some multiple sclerosis (MS) lesions have features characteristic of ischemic or hypoxic injury to oligodendrocytes. Our objective was to determine if mixtures of different types of cytokines (Cyt) regulate genes for

proteins associated with ischemia/hypoxia and ischemic preconditioning in glial cells. Methods: We incubated mixed rat central nervous system (CNS) glial cell cultures with Cyt mixtures typical of Th1, Th2 lymphocytes and monocyte/macrophages (M/M) and examined gene expression at 6 hours using Affymetrix microarray gene chips. In these screening experiments increases or decreases of > 2 fold compared to control cultures were considered significant. Results: In addition to changes in genes for proteins associated with apoptosis and mitochondria, Th1 Cyt upregulated other genes associated with CNS ischemia including adhesion molecules (intercellular adhesion molecule-1/ICAM-1 and vascular cell adhesion molecule/VCAM), Cyt/chemokines (Chm) and receptors (interleukin-1 beta/IL-1beta and CCL2), death/survival proteins (Bcl-X), proteases (matrix metalloproteinase-9/MMP-9) and growth factors (fibroblast growth factor 1/FGF-1; nerve growth factor receptor p75/NGFRp75 and vascular endothelial growth factor/VEGF). Th1 Cyt did not affect the gene for e-selectin but upregulated the gene for its ligand. Conversely, Th1 Cyt downregulated genes for neurotrophins and their receptors (brain derived neurotrophic factor/BDNF; neurotrophin 3/NT3 and serine kinase linked receptor/trkB) and Cyt/Chm and their receptors (several related to transforming growth factor-beta/TGF-beta). M/M Cyt upregulated genes for cell adhesion molecules (ICAM-1,VCAM), heat shock protein (HSP)70, Cyt/Chm and receptors (IL-1 beta, IL-R type 1, IL-6, CCL2), FGF 5 and 10, VEGF, and MMP9 and inhibitors (tissue inhibitor of MMP-1), but downregulated genes of interest for response to ischemia, including TGF-beta 3, NT3, and FGF2. Th2 Cyt upregulated ischemia related genes for growth factors (BDNF, FGF 10 and 14, FGFR 1), Cyt/Chm and receptors (IL-6, IL-1R type I and TGF-betaR2) and downregulated genes for IL-1R type 1, and NT3. Differential expression of many of these genes were reported in NAWM of some patients with MS [Graumann, et al., 2003]. Conclusion: Cyt have the capacity to regulate early gene expression for proteins associated with ischemia and preconditioning, raising the possibility that such findings in MS lesions may represent the effects of cytokines. This research was supported in part by a grant from Teva Neuroscience.

General neurology P298 Psychiatric manifestation as first sign of vitamin B12 deficiency R. L. Gheorghe-Dane, C. A. Sirbu, T. D. Lupescu, D. Constantin, O. Rizea, I. Chirca Central Clinical Emergency Military Hospital (Bucharest, RO); Agrippa Ionescu Emergency Hospital (Bucharest, RO); Central Clinical Emergency Military Hosp (Bucharest, RO) Background: Vitamin B12 deficiency is characterised by lesions in the posterior and lateral columns, leading to sensory and motor deficits. The consequences are neuropathy, myelopathy, ataxia and less frequent psychiatric manifestations including depression, mania, psychosis, dementia, but never as a first sign. Case report: A 79-year old man developed irritability, apathy, suspiciousness and emotional instability, claustrophobia leading to short moments of losing conscience, intellectual deterioration, one year before. The treatment for anxious disorder was without any result. In time, he developed progressive paresthesias involving the hands and feet. At the time of neurological admission he presented the loss of vibration sense and thermo-algic dissociation more pronounced in the feet and legs, impaired position sense, mild symmetrical loss of strength in proximal limb muscles.The patellar and Achilles reflexes was found to be diminished. The serum B12 level was less 30 pg/ml. CSF was normal. The EMG shows slowing of sensory conduction. Somatosensory evoked potentials reveal delayed conduction. The MRI (T2 sequences) shows lesions in the posterior columns from C3 to C7 level (funicular myelosis). The EDS show atrophic gastritis and a gastric polypus which was resecated.After 6 months of vitamin B12 therapy neurologic, psychiatric symptoms and signs including MRI lesion was improved. Discussion: By reporting this case of vitamin B12 deficiency with psychiatric onset to a 79-year-old man, the authors emphasise the necessity to evocate this etiological hypothesis in the diagnosis algorithm of psychiatric disturbances in aged people.

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P299 A prospective study on the relationship between the severity of concussion and post-traumatic symptoms D. Mickeviciene, H. Schrader, L. J. Stovner, D. Surkiene, D. Obelieniene, T. Sand Kaunas University of Medicine (Kaunas, LT); Trondheim University Hospital (Trondheim, NO) Objectives: A prospective cohort study to investigate the influence of duration of unconsciousness and amnesia on the severity of post-traumatic symptoms including those most commonly attributed to the so-called postconcussion syndrome. Methods: The study was performed in Lithuania, a country in which there is little expectation of chronic symptoms after concussion and minimal possibilities for secondary gain. The patients were consecutively recruited from emergency wards of hospitals in Kaunas and consisted of 300 patients aged 18–60 years who had been admitted for the evaluation and treatment of a head trauma involving loss of consciousness that lasted no more than 15 minutes. The responding subjects (n = 221) answered questionnaires about post-traumatic symptoms shortly after their injury. Of these, 200 answered questionnaires after 3 months and 215 after 1 year. For the evaluation of the influence of duration of unconsciousness and amnesia on the severity of symptoms, linear regression calculations were performed with visual analogue scale (VAS) scores of post-traumatic symptoms at different times after the accident as dependent variables. Results: At no time after the concussion was there a significant positive correlation between duration of unconsciousness or amnesia and any of the post-traumatic symptoms. On the contrary, headache, dizziness, fatigue, tiredness, tinnitus, nausea, tendency to cry and alcohol intolerance shortly after the accident and/or after 3 months, but not after one year, seemed to be less severe when duration of unconsciousness and/or amnesia was longer. Conclusion: There was no positive dose-response relationship between severity of concussion and post-concussive symptoms. Consequently, the results of the study do not lend support for a causal relationship between concussion and persisting post-traumatic complaints. P300 Cerebral oedema and pseudotumour cerebri in an adult with maple syrup urine disease R. Sutter, H. W. Ott, S. Bilz, H. E. Killer, C. Stützle, A. J. Steck, S. Renaud University Hospital of Basel (Basel, CH) Introduction: Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder with a dysfunction of the branched-chain alpha-keto acid dehydrogenase complex, which leads to an accumulation of branched chain amino acids and their a-keto acids in plasma and organs. Cerebral edema (CE) and pseudotumor cerebri (PTC) are frequent complications of MSUD in newborns and may result from impaired function of the blood-brain barrier secondary to altered amino acid metabolism. Here we report on an adult MSUD-patient with a CE and a PTC with a favourable clinical course. Case report: A 23-year-old male with MSUD and inadequate metabolic control secondary to malcompliance with the dietary regimen, presented with headache and double vision. He had a reduced the visual acuity, double vision and a bilateral papilledema. Brain MRI demonstrated a partial empty sella, an excavation of both nervi optici and an edema in the brainstem and the basal ganglia. CSF analysis revealed a high pressure (over 50 cm H20). The plasma leucine concentrations were increased to 18 mg/dl [normal range < 6]. Dietary leucine intake and a branched-chain amino acid free formula was established. Caloric intake was adjusted to 35 kcal/kg body weight to prevent protein catabolism. The plasma leucine levels decreased. Despite metabolic control, repeated drainage of CSF and therapy with acetazolamide, visual acuity decreased and subretinal haemorrhages appeared. The patient was referred for a fenestration of the optic nerve sheaths. After the procedure the visual acuity improved. Discussion: We present a MSUD-patient with an inadequate metabolic control and a CE and a PTC. Histilogically proven optic nerve atrophy, which is thought to be related to a disturbance of the myelinic lipid synthesis, has been previously described. Rapid institution of metabolic control, repeated CSF drainage and acetazolamide failed to improve the patient’s condition. The finding of rapid improvement of the visual acuity after optic nerve sheath fenestration, demonstrates increased intracerebral pressure lead to significant vision impairment. It remains to be discussed if recurrent intracerebral pressure alterations may be an additional mechanism leading to optic nerve atrophy.

P301 Metronidazole-induced encephalopathy in patients with liver dysfunction B. C. Suh, D. S. Shim, B. S. Ye, Y. B. Kim, K. Heo, I. N. Sunwoo, S. M. Kim Kangbuk Samsung Hospital (Seoul, KR); Yonsei University College of Medicine (Seoul, KR) Objectives: Metronidazole is a commonly used antibiotics prescribed for the treatment of anaerobic and protozoal infections. Peripheral neurotoxicity is well known and there are some reports about characteristic MRI findings of encephalopathy with metronidazole treatment. Because metronidazole is mainly metabolized in the liver, it is possible that metronidazole treatment in patient with liver disease amplify neurotoxicity. So, we wanted to characterize metronidazole-induced encephalopathy with liver disease. Methods: We studied retrospective manner and identified 4 cases. Diagnosis of metronidazole-induced encephalopathy is based on temporal relationship between metronidazole treatment and encephalopathy and helped by brain MRI findings. We analyzed clinical findings, dose of metronidazole and brain MRI. Results: The range of patients age was 54 to 69 and female to male ratio was 2:2. The underlying liver diseases were various two cases of liver cirrhosis, hepatoma and common bile duct cancer. Metronidazole was used for intraabdominal infection or liver abscess. The cumulative dose of metronidazole was 22.5 g, 33.7 g, 36 g, 234 g and the interval from start of metronidazole to onset of encephalopathy was 30, 30, 24, 156 days respectively. Confusion or attention deficit was main symptoms and gait disturbance, deficit of eye movement, nystagmus, hearing impair or auditory hallucination, dysarthria, athetosis were observed. Symptoms and sign of peripheral polyneuropathy which confirmed by nerve conduction study were observed in all. Lesions in brain MRI were symmetric and they involved red nucleus (4), dentate nucleus (3), dorsal medullar (2) and splenium of corpus callosum (1). After discontinuation of metronidazole treatment, the symptoms began to improve within 15 days. Follow up brain MRIs were done in 2 cases and the lesions were improved or disappeared. Conclusion: Metronidazole may induce encephalopathy and neuropathy with lower dose than usual dose of toxic neuropathy in patient with liver dysfunction. Red nucleus and dentate nucleus is most common involving site and discontinuation of drug may improve neurologic deficit and lesions in brain MRI.

P302 Two cases of atopic myelitis J. H. Cho, S. H. Kim, G. S. Kim, S. A. Choi, J. H. Lee National Health Insurance Corporation Ilsan Hospital (Goyang-si, Gyeonggi-do, KR); Yonsei University Wonju College of Medicine (Wonju-si, Gangwon-do, KR) Myelitis is caused by various infectious organisms or an autoimmune mechanism. We report two cases of myelitis with increased serum total IgE and mite antigen specific IgE. The patients had paresthesia and Lhermitte’s sign without weakness nor bladder dysfunction. Spine MRI revealed T2-high signal lesion with focal enhancement in the upper cervical cord. They showed favorable response to steroid treatment. We should consider atopic myelitis as a form of myelitis. This is the first report of typical atopic myelitis outside Japan.

P303 Pineal gland lesions evaluated with transcranial sonography M. Budisic, A. Lovrencic-Huzjan, V. Vargek-Solter, T. Breitenfeld, K. Jergovic, V. Demarin University Hospital Sestre Milosrdnice (Zagreb, HR) Objectives: Transcranial sonography (TCS) of brain parenchyma is a low cost, noninvasive, easy-to-perform neuroimaging technique based on highresolution ultrasound systems and phase array sector transducers. None of the studies have yet shown usability of TCS in the evaluation of morphology of pineal gland. We initiated this study to evaluate the possibility of TCS to detect normal and cystic morphology of the pineal gland, find its correlation with MRI scan and to seek out if TCS may serve as an alternative follow-up neuroimaging method in the evaluation of pineal gland cysts. Also we seek out to determine interobserver reliability for this method. Methods: The study included 17 patients with incidental pineal gland cyst detected by MRI scan and 36 controls with no previously documented data of the disease or signal abnormalities related to pineal gland on the MRI scan. Two independent physicians performed TCS blindly on results of MRI scan, freehandedly with Aloka ProSound SSD-5500. Pineal cyst was detected

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as every hypoechogenic area within hyperechogenic gland matrix or hypoechoic lession with or without septum surrounded by a thin echoic wall. Maximal width in latero-lateral and antero-posterior line was measured two times and matched with MRI scans. Results: Control scans revealed a pea-like uniformly hyperechogenic structure superior to mesencephalic line. The average size of gland in laterolateral and antero-posterior line was 4.7 and 6.5mm which significantly corresponded to the results of MRI scan (p < 0.05), and the gland was occasionally dislocated slightly sidewise. Cysts size on TCS scan varied from 3.5x5 mm to 17x10 mm in diameter what also significantly corresponded to the results of MRI scan (Pearson’s coefficient 0.96, p < 0.01). Also, interobserver reliability of this method was significant (r = 0.99 p < 0.05). Conclusion: In conclusion, our results suggest that TCS is a suitable method of neuroimaging in the evaluation of pineal gland lesions, especially in adult age.Although its resolution cannot match the MRI resolution, its repeatability and accuracy might add to its practical value.We suggest that the repeating MRI scanning of such lesions might be replaced by clinical and TCS exam follow-up. P304 Purkinje cell mitochondrial oxidative defect in the animal model of spinocerebellar ataxia type 1 V. Lucchini, G. Fagiolari, C. Lamperti, F. Fortunato, D. Ponzi, V. Crugnola, M. Sciacco, N. Bresolin, M. Moggio, G. P. Comi, S. Bonato IRCCS Fondazione Ospedale Policlinico (Milan, IT); Istituto La Nostra Famiglia, Bosisio Parini (Lecco, IT)

requirements. Medical devices and items that can be exposed to an MR environment must be basically tested on magnetically induced forces, torques, RF heating, induction of voltages and safe functioning as well as MR image artifacts. Subjects and Methods: Magnetically induced forces can be measured via the deflection angle test to determine the forces and risk magnitude. Magnetically induced torque aligns a device to the magnetic field and is measured at the magnet isocenter.ASTM F2052 and F2213 provide standard testing methods (e. g. for aneurysm clips, coils, stents). Radio frequency (RF) induced heating is an important MR safety issue. RF pulses are in the area of MHz and apply the main amount of heating energy. This topic is complex and multi-parameter dependent. Not only device properties like electric conductivity, dimension, etc. have to be considered, but also geometric arrangement (e. g. the configuration and orientation of neurostimulator leads, reinforced drainages, pressure sensors, etc.) relative to the specific MR environment. ASTM F2182 provides a basic test method. Computer simulation of electromagnetic fields, SAR and temperature distribution assist in heating testing. RF pulses and switched gradients can induce voltages in conductive structures. No appropriate standardized test method is available, but is under development. The safe functioning is a concern for the MR system and the device respectively. A device must undergo an individual test procedure. MR imaging artifacts can lead to significant lack of information and thus shall be included in device labeling with results from ASTM F2119 standard test method. Results: Comprehensive investigation of all interactions and worst-case scenarios is necessary. MR test methods for magnetic force, torque, RF heating and MR artifacts are established. Continuous redefining is required. Further issues have to be examined for standardization. Conclusion: Standardized MR testing of neurologic medical devices and items is compulsory for minimizing patient risk, providing the MR user with a comprehensive safety labeling and guide manufacturers in device development. Gregor Schaefers is shareholder and managing director of MR:comp GmbH, Germany

Objective: Spinocerebellar ataxia type 1 (SCA 1) is an autosomal dominant inherited disorder due to the expansion of an unstable CAG trinucleotide repeat. Mutant SCA 1 transgenic mice present some pathological cerebellar signs with concomitant progressive Purkinje neuron atrophy, but relatively little cell loss. Therefore, the SCA 1 phenotype is not the result of cell death per se, but the result of cellular dysfunction and pathological alterations that occur before neuronal demise. The aim of our project is to get inside the pathogenesis of this disease studying the earliest histopathological changes in transgenic mice. Methods: We studied the morphological CNS alterations and the mitochondrial histochemical and biochemical enzymatic activity of both heterozygous and homozygous SCA 1 transgenic mice 2 and 6 months old. Morphological evidence for apoptosis was also looked for (terminal deoxinucleotidyl transferase-mediated uUTP nick and labelling -TUNEL-, Fas, Bcl-2, Casp3). Ultrastructural examination was also performed. Results: In 2 months old mice, homozygous animals show significant loss of the Purkinje cell population at haematoxylin-eosin (EE) sections. In addition, numerous ectopic Purkinje cells are found in the molecular layer and, occasionally, in the granular layer. Heterozygous mice show a milder cerebellar damage. There are occasional ectopic Purkinje cells in both molecular and granular layers, with less evidence of Purkinje cell loss. Interestingly, almost all Purkinje cells show severe cytocrome c oxidase (COX) deficiency in the homozigous mice. This enzymatic defect is present in fewer Purkinje cells in the heterozygous mice. Ultrastructural enzymatic COX examination confirmed these data. These pathological findings are more severe in 6 months old mice. We also found apoptosis in some Purkinje cells in 2 months old mice, this finding being more evident in homozygous than in heterozygous mice. Enzymatic assay of respiratory chain activities performed on cerebellar tissue homogenate did not show generalized defects. Conclusion: Our results suggest that mitochondrial oxidative defects may represent the earliest pathogenetic step of the Purkinje cells’ suffering, being already present in 2 months old asymptomatic mice. Oxidative stress may trigger the mitochondrial apoptotic pathway leading to specific Purkinje cells’ degeneration.

Neuro-oncology

P305 Neurological implants: current standards and testing methods for magnetic resonance safety and compatibility of medical devices G. Schaefers MR:comp GmbH (Gelsenkirchen, DE)

P307 Brain and kidney tumours are differentially infiltrated by subsets of mucosal-associated invariant T cells A. Peterfalvi, E. Gomori, T. Magyarlaki, J. Pal, L. Szereday, Z. Illes University of Pecs (Pecs, HU)

Objective: MR safety and image compatibility are internationally recognized as important issues especially for neurological implants. The American Society of Testing and Materials (ASTM) standard F2503 provides comprehensive marking requirements. FDA guidelines, first European and International standards contain MR safety and imaging compatibility

Objectives: A novel innate T cell population, mucosal-associated invariant T (MAIT) cells, expressing an invariant Va7.2-Ja33 T cell receptor (TCR) and possessing similar regulatory properties to NKT cells in autoimmune models, has recently been described. The role of human MAIT cells in tumor immunity is unknown. Here we investigated previously published invariant

P306 Neurogenic stunned myocardium following haemorrhagic cerebral contusion D. Deleu, M. Kettern, Y. Hanssens, S. Kumar, K. Salim, F. Ruiz Miyares HMC (Doha, QA) Background: Neurogenic stunned myocardium (NSM) is a well-known complication of subarachnoidal hemorrhage, but has rarely been reported in association with other central nervous system disorders. Objective: To report the occurrence of NSM in a patient with hemorrhagic brain contusion associated with cerebral edema. Design: Case report. Setting: Trauma intensive critical care unit of university teaching hospital. Patient: An 18-year-old man was admitted with severe cranial trauma following a car roll-over. Six days after admission he developed findings suggestive for NSM. Results: The troponin T and creatine kinase-MB level were elevated and echocardiogram showed apical and inferoposterior hypokinesis and diffuse left ventricular akinesis with severely reduced ejection fraction (18 %). Invasive measurements confirmed low cardiac output. His cardiac function resolved completely within six days after decompressive craniotomy. Conclusion: NSM may occur in patients with hemorrhagic contusion associated with cerebral edema. This case supports the presumed unifying role of the increased intracranial pressure, probably triggering a vigorous sympathetic outflow hyperactivity leading to NSM.

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TCRs including that of MAIT and NKT, and the immunological environment in CNS and kidney tumors. Methods: All tumors were examined for the expression of CD3 and CD56 either by immunohistochemistry or by FACS analysis of tumor infiltrating lymphocytes (TILs). CD56+ and CD56- subsets were sorted by MACS from peripheral blood. Messenger RNA was isolated from 19 tumor tissues (8 primary or secondary brain tumors and 11 primary kidney cancers). Invariant TCRs were examined by RT-PCR single-strand conformation polymorphism (SSCP) clonotypic analysis using Calpha- or invariant alphaCDR3specific probes. Expression of IL-4, IL-10, IFN-g, TNF-a, IL-12, IL-17 and the antigen presenting molecules of MAIT and NKT cells, MR1 and CD1 d, were examined by RT-PCR. Results: All tumors were infiltrated by CD3+ T cells. Invariant Va7.2-Ja33 receptor of MAIT cells was found in 75 % of brain and 73 % of kidney tumors. The MAIT- and NKT-specific invariant TCRs co-existed in 50 % of brain and 64 % of kidney tumors, all positive for MR1 and CD1d. No invariant Va4 and Va19 TCRs have been identified, and Va4 and Va19 T cells did not infiltrate brain tumors at all. The majority of tumors expressed TNF-a and IL-12. All four brain and kidney tumors expressing only pro-inflammatory cytokines were positive for MAIT invariant TCR. While both peripheral CD56+ and CD56- subsets contained invariant Va7.2-Ja33 TCR of MAIT cells, TILs in all kidney tumors but in none of the brain tumors expressed CD56. Conclusion: The majority of both kidney and CNS tumors were positive for the invariant TCR of MAIT cells indicating their role in tumor immunity for the first time. CD56+ and CD56- subsets of MAIT cells differentially infiltrated kidney and CNS tumors. In addition, invariant TCR of MAIT cells could be detected in pro-inflammatory environments indicating that MAIT cells should have a pro-inflammatory/Th1 subset similar to NKT cells. Finally, the presence of the invariant Va24-JaQ TCR in CNS tumors indicates that the previously reported selective absence of NKT cells in multiple sclerosis plaques is specific to the disease and not related to the CNS immune environment. P308 Bortezomib-associated autonomic neurotoxicity and prophylactic strategies S. Ferrari, R. Crocchiolo, J. Peccatori, S. Amadio, U. Del Carro, V. Calbi, M. Marcatti, F. Ciceri, G. Comi, M. G. Natali Sora San Raffaele Hospital (Milan, IT) Bortezomib, a selective proteasome inhibitor, has been approved for the treatment of relapsed and refractory multiple myeloma after one line therapy. Among neurological adverse events peripheral neuropathy is one of the most frequent but there are no studies addressed to a detailed evaluation of bortezomib-associated autonomic neurotoxicity and prophylactic strategies. 12 consecutive patients were prospectively investigated for neurological adverse events between February 05 and July 06.All patients were affected by relapsed or refractory multiple myeloma after first or more lines of therapy, or they received bortezomib as a part of first-line high-dose melphalanbased chemotherapy; they received bortezomib, at the dose of 1.3 mg/mq on day 1, 4, 8 and 11 every 21 days, unless dose-reductions due to hematological and/or non hematological toxicities. Assessment included neurological examination, INCAT Disability scale, INCAT sensory sum score, MRC sum score, nerve conduction studies, and standard cardiovascular autonomic tests including lying to standing, deep breathing and postural hypotension. These tests were conducted baseline and after each Bortezomib 21-days cycle up to 3 consecutive cycles. Two pts showed symptomatic postural hypotension; in these 2 patients the cardiovascular tests changed from normal to pathological values in 2 out of 3 tests. Both patients showed the reversibility of autonomic signs after drug discontinuation. Four pts presented only 1 pathological test (without any clinical sign or symptom of postural hypotension) and 6 patient had normal results. There was no evident correlation between autonomic impairment and disease response to therapy or patients baseline characteristics (disease stage, Ig class, previous anti-myeloma therapies, concomitant thalidomide or anti-hypertensive treatment); furthermore none had evidence of previous autonomic dysfunction. Our prospective study confirms that bortezomib neurotoxicity involves not only somatic nerve fibers, but also autonomic nervous system. For the cardiovascular system the use of non invasive testing may reveal subclinical involvement and avoid severe autonomic dysfunction. Further studies in larger cohorts of patients are needed to clarify the interactions between proteasome inhibitor activity and autonomic nervous system, in order to assess the frequency, to confirm the possibility of a sub-

clinical diagnosis and the reversibility of autonomic involvement after drug discontinuation. P309 Increased risk of neoplasia among relatives of glioma patients A. González Aguilar, A. Rasmussen, E. Briceño, M. E. Alonso, D. Rembao, P. Gutierrez National Institute of Neurology and Neurosurgery (Mexico City, MX); University of Oklahoma Health Sciences Center (Oklahoma City, US); National Institute of Pediatrics (Mexico City, MX) Some previous studies have suggested familial aggregation of gliomas, although the results have not always been replicated. In the present study of a Mexican population, we compared 100 cases of glioma with 124 healthy unrelated controls, as well as their 1st, 2nd and 3rd degree relatives (n = 3575 and 4520 respectively). The relatives of the cases had a significantly higher risk of developing brain tumors than the relatives of controls (OR = 5.3, p < 0.05, 95 % IC 1.10–25.7), and their risk of developing any cancer was also increased (OR = 2.0, p < 0.05, 95 % IC 1.16–3.51), this risk was twofold for men when compared to females (OR = 2.0, p < 0.05, 95 % IC, 1.15–3.37). The present study supports familial aggregation of brain tumors and warrants further research into their genetic etiology. P310 Dexamethasone decreases gap junctional communication in F98 and U87 glioma cell lines D. Hinkerohe, D. Wolfkühler, A. Haghikia, U. Schlegel, R. Dermietzel, C. Meier, P. M. Faustmann Ruhr-University (Bochum, DE) Objectives: Glucocorticoids are the most efficient therapeutics in cerebal edema associated with brain tumors like glioblastoma but can also reduce cytotoxicity and growth inhibition induced by chemotherapeutics. Like astrocytes in the CNS, different astroglioma cells form a well coupled syncytium via gap junctional intercellular communication. Astroglial gap junctional communication serves for a number of physiological properties related to CNS homeostasis like buffering of potassium and transmitter uptake and dissipation. The major gap junction protein in astrocytic and astroglioma cells is connexin43. Purpose: To test the effects of dexamethasone on astroglial intercellular coupling and astroglial membrane resting potential (MRP) in a F98 rat glial cell line and a human U87 glial cell line and to prevent in a second experiment the effects of dexamethasone by addition of mifepristone, a glucocorticoid receptor-specific antagonist. Methods: We evaluated the influence of dexamethasone (0.1, 1, 10 micromol) and mifepristone (1, 10 micromol) on intercellular functional coupling and MRP in U87 and F98 glial cell lines. MRP was measured by patch clamp technique (whole cell), functional coupling was tested by Lucifer Yellow dye-application and presence of connexin43 was analysed by Western blotting and immuno-cytochemistry. Results: Dexamethasone causes a dose dependent significant reduction of intercellular functional coupling and connexin43-expression in both glial cell lines accompanied by an astroglial depolarisation. Furthermore, preincubation with mifepristone could prevent dexamethasone induced astroglial uncoupling in a dose dependent manner. Conclusion: Our results indicate that dexamethasone reduces astroglial intercellular functional coupling and astroglial Cx43 expression through activation of glucocorticoid receptors. This reduced GJC could be one possible mechanism by which glucocorticoids attenuate the efficacy of several chemotherapeutic drugs used in the therapy of human malignant gliomas. P311 Immunosuppressive properties of transforming growth factor-beta-1 in a glioma cell-culture model in vitro D. Wolfkühler, D. Hinkerohe, A. Haghikia, U. Schlegel, R. Dermietzel, C. Meier, P. M. Faustmann Ruhr-University (Bochum, DE) Objectives: The most prominent glioma-associated cytokine, transforming growth factor (TGF)-beta1 is known to stimulate migration, invasion, and angiogenesis during neoplasia. Its levels are increased in the plasma of glioblastoma patients. Production of this potent immunosuppressive cytokine has also been detected in glioma cell lines in vitro. Like astrocytoma cells, astrocytes in the CNS form a well coupled syncytium via gap junctions, which is responsible for a number of physiological properties related to CNS homeostasis. Microglia is the main inflammatory effector in the CNS and its

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activation is enhanced in the circumference of human gliomas. In healthy brains, microglia is found in a resting ramified form and comprises 5–20 % of the glial cell population, whereas under pathological conditions, like neoplasia, its is increased. The aim of the study is to investigate the effect of TGF-beta1 on functional intercellular coupling using rat primary wild type astrocytes and a rat F98 glioma cell line. Methods: Primary rat glial cocultures containing 30 % microglia (M30) as well as the F98 glioma cell line were incubated with TGF-beta1 (5ng/ml, 10ng/ml) for 24h. The astroglial membrane resting potential (MRP) was measured by patch clamp technique, functional intercellular coupling was tested by Lucifer Yellow dye-application, and presence of Connexin 43 was analysed immunohistochemically. Microglial activation was detected using a monoclonal anti-ED1 antibody. Results: In contrast to untreated M30 cocultures, TGF-beta1 treated cocultures showed a significant reduction of astroglial MRP (p ≤ 0.0001) and increased astroglial functional coupling (p ≤ 0.0001). In contrast, TGF-beta1 treatment on F98 rat glioma cells resulted in depolarisation of the MRP and a significant reduction of functional intercellular coupling. Furthermore, TGF-beta1 reduced the amount of activated microglia in M30 cocultures (p ≤ 0.0041). Conclusion: TGF-beta1 was able to enhance functional coupling in glial cocultures (M30) but decreased functional coupling in the rat glioma cell line. Reduction of activated microglia in M30 cocultures may be one mechanism of the immunosuppressive effect of TGF-beta1. Together with the increase of functional coupling of glial cocultures (M30) in response to TGFbeta1 these in vitro changes might provide an explanation for the well known TGF-beta1 effects like decreasing immune recognition and supporting migration, invasion and proliferation of gliomas. P312 Anti-Hu and anti-Yo-associated paraneoplastic cerebellar degeneration treated with rituximab: two case reports P. Penza, M. Esposito, G. Orefice, E. Parente, A. Abbadessa, V. Bonavita Federico II University (Naples, IT); AORN-S. Sebastiano (Caserta, IT) Objectives: We describe two cases of paraneoplastic cerebellar syndrome occurred after a cancer diagnosis and treated with rituximab. Patients and methods: The first case is about a 48-year-old woman with a small cell lung cancer diagnosis in 2000. In June 2004, after a long period of well-being and no evidence of tumour relapse, she subacutely experienced an anti-Hu-associated ataxic syndrome (ICARS score: 40). Paraneoplastic antibodies were determined with a semiquantitative method on primate cerebellar sections by immunofluorescence and by immunoblotting using purified recombinant Hu, Yo, Ri and amphiphisyn antigens. The second case is about a 54-year-old woman with an ovarian cancer diagnosis in 2003 successfully treated with surgery and chemotherapy. In August 2006, she experienced an anti-Yo-associated ataxic syndrome, and she gradually deteriorated albeit several courses of immunoglobulins and corticosteroids. There was no evidence of tumour relapse. She was admitted to our hospital in December 2006 with severe gait and stance ataxia(ICARS score: 43). Both patients received a two-month weekly intravenous administration of Rituximab (375 mg/m2).The first one had another course of Rituximab. Results: the first patient experienced a dramatic clinical improvement (ICARS of 11 in June 2006).The second patient started her treatment in December 2006 with the same scheme. Two months later, her clinical conditions were no more deteriorating. Conclusion: With very few exceptions, paraneoplastic neurological syndromes do not remit spontaneously. They are considered to be autoimmune diseases, but immunotherapy seems to be ineffective in most of the cases. Critical analysis of the role of immunosuppressive therapy is hampered by the rarity of the syndrome and by reports in which patients received concomitant tumour therapy and immunosuppressive treatment. On the contrary, our cases do not have tumour treatment bias. Rituximab is a humanized chimeric anti-CD20 monoclonal antibody successfully used in other autoimmune conditions,too. To the best of our knowledge, cases of successful outcome of paraneoplastic cerebellar degeneration without any concomitant tumour treatment are very few. Our reports seem to suggest a possible role for Rituximab in the treatment of paraneoplastic neurological disorders and a major role for B cells in their pathogenesis.

P313 Acute onset of symptomatology in neurofibromatosis type 2 with polymyositis K. Papadopoulos, O. Koutoula, N. Taskos, I. Milonas Ahepa University Hospital (Thessaloniki, GR) Objectives: Neurofibromatosis type 2 (NF2) is an autosomal dominant neurocutaneous disorder with widely variable presentations and degrees of severity. The genetic locus for NF2 is the 22q12.2. NF2 has very high rates of spontaneous mutation, resulting in 50 % of cases arising de novo. NF2 has essentially 100 % penetrance but wide phenotypic variability. The factors modulating phenotypic variability in NF2 are not well understood but likely represent both genetic and environmental factors. The NF2 gene encodes for merlin, which may act as a regulator of growth, motility, and cellular remodeling by inhibiting the transduction of extracellular mitogenic signals. The clinical features of NF2 are restricted almost entirely to tumors of the central and peripheral nervous system (particularly schwannomas) with few cutaneous or non–nervous-system-related abnormalities. NF2 can be diagnosed based entirely on clinical manifestations (age onset at 20, bilateral acoustic neurinoma, glioma meningioma, schwannoma, neurofibroma and juvenile posterior subcapsular lenticular opacity). Methods: We report a case of NF2, in which the major symptoms had acute onset and the patient, suffered from polymyositis and pneumonic fibrosis. The patient, a 57 years old woman, whose medical history started abruptly with bilateral hypacousia, numbness of the right face, asymmetrical elevation of the left corner of the mouth, dysphagia and dysphonia. Her clinical profile revealed in ten days. Results: Her clinical examination revealed bilateral hypacousia (otological tests were concomitant with the clinical examination), right trigeminal sensory loss, right Bell’s palsy, nasal quality of speech, pharyngeal weakened muscles, marked dysphagia (ninth and tenth nerve lesion), left cord paresis, and gastric paresis. Pyramidal tracts were intact. Palpation of the left and right brachium revealed numerous nodules subdermally, in which the biopsy showed peripheral schwannoma. Brain magnetic resonance showed bilateral acoustic neurinomas in the cerebello-pontine angle. Muscle strength was normal. Laboratory tests were normal. The patient could not be treated surgically, due to the pneumonic fibrosis. Her clinical coarse is progressive. Conclusions: Age onset is not obligatory to be the second decade.A thorough understanding of this complex disorder is essential for proper medical management, anticipatory care, and requires coordinated multidisciplinary care. P314 Bone marrow stromal cells are attracted by malignant gliomas through angiogenic pathways T. Birnbaum, J. Roider, C. Schichor, R. Goldbrunner, A. Straube LMU (Munich, DE) Objectives: The transplantation of progenitor cells is a promising new approach for the treatment of gliomas. Bone marrow stromal cells (MSC) are possible candidates for such a cell-based therapy, since they are readily and autologously available and show an extensive tropism to gliomas in vitro and in vivo. However, the signals that guide the MSC and the interactions between glioma cells and MSC are still poorly understood. Aim of this study was to identify the cytokines, which are responsible for the glioma-directed tropism of human MSC. Methods: Human MSC were isolated from bone marrow biopsies and characterized by flow cytometry (FACS). In vitro migration assays were performed using a chemotaxis chamber. MSC were challenged with 1) a panel of cytokines, which are known to be secreted by gliomas, and to exhibit a chemotactic effect on mesenchymal cells, and 2) different glioma-conditioned media before and after neutralization of specific cytokines, respectively. The respective cytokine concentrations in the glioma-conditioned media were analyzed by enzyme-linked immunosorbent assays (ELISA). The respective cytokine receptors on MSC were visualized by immunofluorescence staining. Results: In the migration assays all glioma-conditioned media proved to be potent chemoattractants to human MSC. We found evidence that interleukin-8 (IL-8), transforming growth factor-beta 1 (TGF-b1), neurotrophin3 (NT-3), and vascular endothelial growth factor (VEGF) mediate the MSC recruitment by glioma, whereas several other candidates (epidermal growth factor, platelet-derived growth factor, glial cell-derived neurotrophic factor, brain-derived neurotrophic factor, and ciliary neurotrophic factor) do not seem to be involved in this process. Conclusion: We demonstrate in this study that the migration of MSC toward glioma represents an active recruitment of mesenchymal progenitors by the glioma cells. It is caused by the secretion of several cytokines, among

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them VEGF, IL-8, TGF-b1, and NT-3. These results might be useful for improvement of the effectiveness of cell engraftment in future in vivo studies. Since these cytokines are key mediators in tumor angiogenesis, we hypothesize that MSC participate in this process. Future in vivo studies must address this question. This work was supported by grants of the Förderprogramm für Forschung und Lehre, LMU Munich, Germany, and by grants of the Friedrich-Baur-Stiftung, Munich, Germany. P315 Intravascular lymphomatosis, a cause of recurrent confusional state K. Kinugawa, J. Adam, V. Denys, S. Demeret, F. Bolgert, D. Seilhean Pitié-Salpêtrière Hospital (Paris, FR) Objective: To describe a patient with autopsy-proved intravascular lymphomatosis (IVL) with detailed neuropathological examination and unusual presentation. Case report: A 71-year-old male patient presented with a subacute confusional state and recurrent falls. He had an history of left frontoparietal haemorragic stroke 2 years previously with full recovery. Examination showed disorientation in space and time, urinary incontinence, left hemiparesis with bilateral Babinski sign. EEG showed diffuse slowing and brain MRI showed bilateral rounded areas of hyperintensity in the corona radiata on FLAIR sequences. He made a full recovery within a week. Three weeks later, he had a similar subacute episode and was readmitted. CSF examination revealed high protein level (1.87g/L) without hyperglycorachia and elevated cell count (12 lymphocytes/mm3). Brain MRI remained unchanged. He made a progressive recovery within a month. Four months after the initial episode, he presented with subacute confusional state, paraparesis and drowsiness. He also had bilateral interstitial pneumonia. MRI of the spinal cord showed an abnormal signal involving the thoracic region and cranial MRI showed diffuse white matter hyperintensities on FLAIR sequences. Routine laboratory examination found pancytopenia and bone marrow aspiration disclosed an haemophagocytic syndrome. A new CSF examination found high protein level (1.42g/L) and normoglycorachia with 3 cells/mm3. and high protein concentration in the CSF. A comprehensive work-up failed to identify a clear etiology. A diagnosis of possible post-infectious encephalomyelitis was made and he received intravenous corticosteroid treatment for 10 days. Despite this treatment his condition gradually deteriorated to coma and he died suddenly from an acute respiratory distress. Post mortem examination showed that blood vessels were filled with large neoplastic CD20+ lymphoid cells in the CNS and all other examined organs. The final diagnosis was intravascular lymphomatosis. Conclusion: Various neurological manifestations can occur in the course of IVL including multifocal stroke like episodes, dementia, progressive encephalopathy, seizures, myeloradiculopathy, peripheral neuropathy and myopathy. Our case expand the clinical spectrum of IVL and emphasises the need to consider the diagnosis of IVL in patients with unexplained recurrent confusional state. P316 Lymphatoid granulomatosis presenting with painful ophthalmoplegia and footdrop A. Jha, R. Pugh, R. Lee, A. Jafari, D. Mckee Hope Hospital (Manchester, UK); Manchester Royal Infirmary (Manchester, UK); Manchester University (Manchester, UK) Case report: A 53 year old man presented with a several day history of retroorbital pain and diplopia, with simultaneous evolution of low back pain radiating posteriorly down the left leg and paraesthesia of the foot. On examination there was a pupil-sparing left oculomotor nerve palsy and a moderately severe left footdrop, with an absent ankle reflex and sensory impairment in the first sacral dermatome. Gadolinium-enhanced magnetic resonance imaging of the brain and spine was normal, as was computerised tomographic (CT) angiography of the cerebral vessels. Cerebrospinal fluid (CSF) analysis demonstrated raised protein and low glucose concentrations but normal cellularity. No malignant cells were identified. Serum and CSF angiotensin converting enzyme levels were normal as were serological investigations for vasculitic conditions. Neurophysiological examination provided evidence of a left distal sciatic lesion. CT thorax demonstrated multiple small nodules in both lungs, with mediastinal lymphadenopathy. The patient’s clinical condition deteriorated steadily. He developed complete left ophthalmoplegia and increasing weakness of the left leg with severe neuropathic pain. He lost weight rapidly and developed a normochromic normocytic anaemia. The most likely clinical diagnosis was thought to be lymphoma, or possibly an aggressive form of sarcoidosis. A mediastinoscopic lymph node biopsy was unhelpful but a subsequent open

lung biopsy provided a tissue diagnosis of lymphomatoid granulomatosis. In spite of treatment with rituximab his condition continued to deteriorate and he died approximately six months after presentation. Discussion: Lymphomatoid granulomatosis is a rare atypical lymphoproliferative disorder related to Epstein Barr virus B lymphocyte infection, and can present a considerable diagnostic challenge. It involves the neuraxis in at least 20 % of cases although rarely from the outset, and may cause a range of central and peripheral nervous system lesions. Multiple parenchymal lung lesions are typical. If early diagnosis is made, some cases respond to anti-CD20 monoclonal antibodies such as rituximab and sometimes to chemotherapeutic regimens but overall the prognosis is poor.Although rare, this condition is important in the differential diagnosis of multifocal neurological disease, particularly with concurrent lung involvement. Extensive imaging of the nervous system may be normal, and tissue biopsy is almost invariably required for diagnosis. P317 Limbic encephalitis with voltage gated potassium channel antibodies associated with small cell lung carcinoma R. Pugh, S. Irani, R. Lee, P. Bannister, D. McKee Manchester Royal Infirmary (Manchester, UK); Manchester University (Manchester, UK); Greater Manchester Centre for Clinical Neurosciences (Salford, UK) Case report: A 57 year old man presented with a clinical picture of limbic encephalitis, having developed a subacute encephalopathy characterised most prominently by loss of short term memory, progressing over several months and associated with several seizures. On bedside neuropsychological examination there was evidence of a severe amnesic syndrome, and mini-mental test score was 17/30. The lower limbs were areflexic, there was mild ataxia of tandem gait and both plantar responses were extensor. The rest of the neurological and general physical examination was normal. Magnetic resonance imaging of the brain demonstrated subtle high signal change in both temporal lobes. Cerebrospinal fluid analysis revealed a raised protein concentration and the presence of oligoclonal bands, but was otherwise normal. There was no hyponatraemia. Antibodies to voltagegated potassium channels (VGKC abs) were isolated in the serum at a very high titre, other paraneoplastic antibodies being negative. Computerised tomography of the thorax revealed a suspicious lung parenchymal lesion associated with mediastinal lymphadenopathy. A mediastinoscopic lymph node biopsy led to a histological diagnosis of small cell lung carcinoma. Discussion: Limbic encephalitis is an inflammatory syndrome with a predilection for the temporal lobes and other limbic structures, typically presenting with a subacute encephalopathy characterised by an amnesic syndrome, associated with seizures and often hyponatraemia. It has been reported as a primary autoimmune condition, most often accompanied by serum VGKC abs, and also as a paraneoplastic syndrome, in association with a range of malignancies and a spectrum of other antineuronal antibodies. It has been suggested that treatment of an underlying malignancy may improve the neurological outcome, which may also be modified by steroid and immunoglobulin therapy.The combination of limbic encephalitis with small cell carcinoma and VGKC abs as described above is extremely unusual. This case illustrates the point that when investigating a patient with the syndrome of limbic encephalitis, it is important to be aware that the presence of VGKC abs does not exclude a paraneoplastic aetiology, as the discovery of a potentially treatable malignancy may positively influence the clinical outcome. P318 Ping-pong peripheral facial palsy as presenting sign in primary CNS lymphoma D. Ulbricht, M. Kruger, B. Thill, P. T. Dang, G. Dooms Centre Hospitalier Emile Mayrisch (Esch-sur-Alzette, LU); Centre Hospitalier de Luxembourg (Luxembourg, LU) Introduction: primary CNS lymphoma (PCNSL) is an enigmatic and devastating disease, and presentations are usually with signs of brain tumour. We present on a case, which presented alternating peripheral palsy as initial sign. Case report: a 78 year-old man had right-sided peripheral facial palsy, which resolved spontaneously. Three weeks later, a left-sided peripheral palsy occurred. When ambulatory work-up was about to start, he presented to our emergency department with left-sided facial palsy, right abducens palsy, retropulsion, and severe amnesia profoundly affecting the verbal domain, and relatively sparing episodic and recognition memory. MRI disclosed a large tumoural infiltration encompassing the left mesial temporal lobe, both columns of the fornix, and around the fourth ventricle. The course

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of the affected cranial nerves seemed to be spared. Stereotactic biopsy was not performed due to the lesion location in eloquent brain areas, but cerebrospinal fluid cytology was in line with PCNSL. The patient was put on cortisone, whole-brain radiation was instored, but he died during the first treatment cycle. Discussion: PCNSL presented with resolving facial palsy, which was misleading. The subsequent extent to other cranial nerves raised the suspicion of basal meningitis, and the central nature of the process was confirmed by the appearance of typical fornix amnesia. P319 CNS lymphoma masquarading as haemorrhagic stroke L. Streletz, T. Burgut, D. Deleu, K. Salem, A. Raza, C. E. Connolly, D. Terzic Weill Cornell Medical College (Doha, QA); Hamad Medical Corporation (Doha, QA) Primary CNS Lymphoma may present in protean ways, which may mislead even the savviest clinician. We report such a case that was encountered in a large Middle Eastern general hospital, including CT scan and MRI of the brain, CSF analysis and brain biopsy. The clinical neurological presentation revealed an acutely ill 41 year old Indonesian engineer who experienced abrupt onset of a R partial 3rd cranial nerve palsy and L hemiplegia (Weber’s Syndrome) associated with a severe headache. At onset he became poorly responsive with evidence of a diffuse encephalopathy without fever or meningeal signs. A snout reflex was found and a forced grasp response was present on the R side. Deep tendon reflexes were overactive throughout. Sensory examination was unreliable. Babinski’s sign was present bilaterally. Upon admission neuroimaging with CT revealed a large R midbrain haemorrhage, diagnostic of a brainstem stroke. MRI revealed an unusual picture consisting of mutifocal areas of high signal involving the subcortical structures in frontal lobes, basal ganglia and thalamus on T2 and Flair and many contrast enhancing lesions scattered in the white matter. A large intensely dark signal was seen in the R midbrain as well as several smaller abnormalities in the posterior R internal capsule and thalamic areas on the susceptability weighted images indicative of recent haemorrhages. The CSF revealed mild pleocytosis and slight elevation of the IgG without oligoclonal bands. The patient had no evidence of a congenital or acquired immunocompromised state and systemic work-up which included chest, abdomen and pelvis CT’s were normal. Based on clinical suspicion of a vasculopathy and MRI findings, the patient was referred for stereotactic biopsy of meninges and several subcortical lesions. These gave histopathologic evidence of a poorly differentiated neoplasm consistent with a malignant lymphoma of the diffuse large B cell type. The patient has improved on high dose corticosteroids and whole brain radiotherapy. We conclude that this represents a rare stroke–related complication of primary CNS Lymphoma. Though the prognosis is uniformly poor, we recommend prompt identification and treatment of this condition. Stereotactic brain biopsy plays an important role in this regard. P320 Myopathy after bone marrow transplantation: graft-versus-host disease or steroid myopathy? L. Bataller, N. Muelas, M. Garcés, F. Mayordomo, M. J. Chumillas, L. Algarra, G. Sanz, J. J. Vilchez Hospital La Fe (Valencia, ES) Objectives: To report the clinical, electrophysiological, magnetic resonance imaging (MRI) and pathological findings in two patients who developed myopathy after bone marrow transplantation for hematological malignancy. Methods: The two patients reported here underwent clinical evaluation, nerve conduction and electromyographic studies, muscular MRI and deltoid muscle biopsy. Results: Patient 1: A 44 year old woman received allogenic bone marrow transplantation from a HLA-matched related donor in September 2006 for relapsing non-Hodgkin follicular lymphoma. One month after the transplant she developed acute graft versus host disease (GVHD) with skin rash, gastroenteritis and jaundice. She received high dose intravenous methylprednisolone during three days. Several days later she acutely noticed limb girdle weakness, more severe in pelvic and femoral groups. Serum CK levels were normal. EMG showed low amplitude, short duration action potentials. MRI demonstrated atrophy of affected muscles, without edema. Muscle biopsy disclosed atrophic muscle fibers with myosin loss on ATP-ase stain. Steroid dose was cautiously reduced, and the weakness slightly improved. On January 2007 she developed massive fungal pneumonia and died. Patient 2: A 60 year old man was treated with allogenic bone marrow

transplantation from HLA-matched related donor in 2003 for multiple myeloma. Over the months he developed chronic GVHD with skin manifestations that was treated with prednisone and cyclosporine. On November 2006 he came to our attention because of a six month history of progressive weakness on neck extension and limb girdle muscles. He also had mild camptocormia. Serum CPK was within normal range. EMG demonstrated short duration polyphasic motor unit potentials with fibrillations and positive sharp waves. MRI disclosed high T2 and STIR signal in affected muscles. Muscle biopsy showed scattered necrosis and phagocytosis with inflammatory cells around blood vessels. Despite increasing steroid dose (60 mg of prednisone) the weakness steadily progressed. Currently he is under mycophenolate-mofetil and a tapering dose of prednisone, and stabilized. Conclusions: To differentiate toxic versus inflammatory myopathies on clinical grounds only is often not possible after hematopoietic cell transplantation. A careful study including muscle MRI and biopsy may help clinicians to establish the correct diagnosis and decide the best treatment strategy.

Peripheral neuropathy P321 A case of slowly progressive gait ataxia with positive antidisialosyl-antibodies S. Thomann, S. Renaud, P. Fuhr, A. Steck, A. Czaplinski University Hospital (Basle, CH) A 56-year old man was admitted because of slowly progressive distal paresthesias and ataxia of the lower extremities. Over the past 5 years he developed a progressive unsteady gait and was unable to stand or walk with closed eyes. Neurological examination revealed a severe painless symmetrical sensory impairment of the lower extremities with a profound loss of vibration sense but no weakness. Deep tendon reflexes were absent in the lower limbs and weak in the upper limbs. He presented with a broad-based, ataxic gait. Upper extremities and cranial nerve examination were normal. The sensory nerve conduction studies of the sural nerves, in particular sensory nerve action potentials (SNAPs), were normal. Somatosensory evoked potentials (SSEP) of the tibial nerve could not be recorded neither from thoracolumbal nor cortical electrodes, whereas the SNAPs in the poplitea were normal, which suggests a lesion proximal to the dorsal root ganglion, probably postganglionic sensory nerve roots and dorsal columns. The MRI of the spinal revealed no abnormalities. Cerebrospinal fluid analysis showed a slight increase of total protein (649 mg/l) with normal cell count. Anti-disialosyl-antibodies (asialo-GM1, GD1 a, GD1 b, GQ1 b) were positive. Infections (HIV, syphilis), solid tumors, paraneoplastic conditions, diabetes, Sjögren syndrome and rheumatoid diseases were excluded by specific investigations. The patient responded well to IVIg therapy showing a moderate gait improvement after one treatment course. The differential diagnosis of our case involves severe sensory ataxic neuropathies (i. e. chronic idiopathic ataxic neuropathy, CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M protein, cold agglutination and disialosyl-antibodies), paraneoplastic neuropathies, Sjögren’s syndrome- or celiac disease-associated neuropathies) and disorders of dorsal root ganglion (sensory ganglionopathies). However, sensory neuropathies and ganglionopathies are characterized by abnormalities of sensory nerve action potentials, whereas in our case the SNAPs were normal. In addition, there were no signs of tabes dorsalis or diseases primarily affecting posterior column fibers. To our knowledge, this is the first case of chronic progressive gait ataxia with positive anti-disialosyl-antibodies and good IVIg-response affecting the postganglionic sensory nerve roots and dorsal columns. P322 The clinical and neurophysiologic investigation in HTLV-1 myelopathy patients (inpatients and outpatients) in an Iranian neurology ward, 2003–2004 M. Etemadi, M. Saeidi, S. Shahami, M. Khajeh Daluee Ghaem Hospital (Mashhad, IR) Introduction: The main neurological manifestation of the Human T-cell lymphotropic virus type 1 (HTLV-1) is spastic paraparesis with progressive nature, also known as HTLV-1 Associated Myelopathy (HAM) or Tropical Spastic Paraparesis (TSP).Although various CNS complication in HAM/TSP have been described, relatively liitle known attention has been directed toward disorders of the pereipheral nervous system (PNS). In this study we

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tested comcomitant neuropathy with clinical and neurophysiological methods in HAM/TSP patients. Method: Possible concomitant of neuropathic disease by clinical and neurophysilogic methods was evaluated in 73 HAM/TSP patients. A questionnaire was completed for each patient, then median and ulnar nerves from the upper extremity and peroneal, tibial and sural nerves from the lower extremity were evaluated by electrophysiologic studies (NCV). Results: 65.8 % of patients were clinicaly suspected to neuropathy.We noticed that in 54.8 % of patients with HAM/TSP, there is concomitant peripheral nerve disease. Mononeuropathy in 15 (20.45 %), multiplex mononeuropathy in 5 (6.8 %), motor-sensory polyneuropathy in 17 (23.3 %), motor polnuropathy in 2 (2.7 %) and sensory polyneuropathy in 2 (2.7 %) of patients were present. Conclusion: We conclude that electrophysiological compromise of the peripheral nerve is frequent in patients with HTLV-1 associated myelopathy. Furthermore, electrophysiological compromisecan arise even when the patient dose not present clinical manifestatiopns denoting this kind of problem. Hence, the study of the neuroconduction has to become a routine test for patients of HAM/TSP. P323 Clinical analysis of Bell’s palsy D. K. Lee, K. J. Kim Daegu Catholic University Hospital (Daegu, KR) Objectives: Bell’s palsy (BP) is a self-limiting rapid onset facial palsy that is non-life-threatening and has a generally favorable prognosis. Facial paralysis can be caused by numerous conditions, all of which should be excluded before a diagnosis of BP is reached. The aetiopathogenesis and clinical course of BP is uncertain. So we analyzed that the epidemiology and clinical course of BP in Korean patients. Methods: The subjects include 104 cases of BP examined during a period of 17 months. Careful clinical history, neurologic examination, laboratory test, electrophysiologic study, and brain imaging was performed. Follow-up examination was done once a week during the first month and subsequently once a month until normal function was restored or for up to 3 months. Facial nerve function was assessed by House-Brackman(HB) facial nerve grading scale and electrophysiologic studies. Results: Of 104 patients, 46 (44.2 %) were men and 58 (55.8 %) were women and the average age was 51.2 (±16.1) years. Recurrent facial palsy was observed in 13 (12.5 %) patients and 3 (2.9 %) patients showed a familial tendency. The initial examination within 1 week after attack revealed 37.4 % was below HB grade 4 and 62.6 % was above grade 3. The associated symptoms are as follows; postauricular pain, increase tear flow, taste change, hyperacusis and drooling. The initial facial nerve conduction study and blink reflex within 1 week after attack showed abnormal findings in 17.4 % and 100 %, respectively. Brain MRI was performed in 64 (70.3 %) patients and showed abnormal enhancement of affected nerve in 62 (96.9 %). Followup examination showed that 75.8 % partially improved within 4 weeks and remains improved within 3 months. Finally 80.2 % of total patients obtained normal function in 3 months. Conclusion: We reports the epidemiologic, clinical, electrophysiologic and radiologic characteristics of BP in Korean patients. P324 Peripheral neuropathies associated with hypereosinophilia: two case reports T. Afrantou, A. Angelou, I. Mavromatis, M. Paschalidou, I. Milonas, N. Taskos Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Causes of hypereosinophilia usually are allergic disorders and parasitosis while haematological malignancies, Churg Strauss syndrome, connective tissue disorders, HIV and psoriasis are less frequently identified. Neurological involvement may be seen in these cases either due to direct neurotoxicity of eosinophils or due to vascular damage. Case 1: A 57year old man with a history of asthma was admitted because of numbness and weakness of his lower limbs. Neurological examination revealed distal weakness, hypoesthesia and dysesthesia and diminished tendon reflexes. CSF analysis was normal. Neurophysiological testing disclosed non-symmetrical damage of the peripheral nerves involving both the axon and myelin. There was marked eosinophilia (54 %) in repeated blood tests while the centimentation rate (CR) was elevated (47). The patient was fully investigated for possible causes of hypereosinophilia and finally he was diagnosed as having Churg Strauss syndrome. Methylprednisolone led to significant improvement. Case 2: A 49year old man presented with weakness of the lower limbs and

mild sensory disturbances. Neurological examination revealed proximal weakness of the lower extremities, hypoesthesia on the distal parts of all limbs while tendon reflexes were apparently reduced. Conduction velocities were slowed, conduction block was present on motor nerves and F-responses were absent. Biopsy did not reveal vasculitis. A marked hypereosinophilia was found in the peripheral blood (24 %) and CR was high (54). The patient had a diarrheal syndrome 3 weeks ago and high titers of abs against Salmonella typhi were detected. The immunological screening showed increased titers of ANA and IgG anticardiolipin antibodies. Cefuroxime and gamma-globulin improved his symptoms. Conclusions: In our first case multiplex mononeuritis presented in a chronic asthmatic patient. A few days later lung and heart involvement developed and administration of corticosteroids resulted in remission of his condition and normal levels of eosinophils. In the second case the patient presented with Gullain-Barré syndrome and hypereosinophilia; the full laboratory research revealed a recent infection by S.typhi and additionally a non-typical immunological disorder although there was no evidence of vasculitis in biopsy. Neurological complications of hypereosinophilia may be severe but usually respond well to treatment when the underlying cause is early identified.

P325 Vivid dreams and hallucinations in a patient with Guillain-Barré syndrome E. Santos, M. Cardoso, J. Barros Hospital Geral Santo António (Oporto, PT) Introduction: Guillain-Barré Syndrome (GBS) is an acute imuno-mediated polyradiculoneuritis that in severe cases leads to quadriplegia and respiratory insufficiency requiring artificial ventilation. Less widely appreciated is the occurrence of pronounced perceptual disturbances and hallucinatory experiences in this disorder. Case report: A 59 year-old man, began paresthesia in both feet and progressive loss of motor strength in both legs, ascending to the knees, hands and forearms in a week, with gait impairment. It was followed by speech difficulties, red eyes and tearing. On admission he presented facial diparesis, weak neck extension and flexion. Flaccid quadriparesis, with distal predominance. CSF was normal; there was no evidence of infection and blood analyses were normal. EMG revealed slowed sensitive and motor nerve conduction. GBS was diagnosed and he started i. v. immunoglobulin. At the 6th day of admission, he experienced motor worsening with reduction of the respiratory movement amplitude, without hypoxia. CSF had 2 leuc/uL and protein 1.09 g/L. In this setting, he started strange dreams (walking in the beach, bathing in the roman and greek thermal waters) with predominance in the wake/sleep transition, with frequent short naps during the day, and periods of visual hallucinations. He was transferred to the intensive care unit, but no artificial ventilation was needed. He still had periods of visual hallucinations (he saw rice, sugar and fruits in the grocery) and illusions. Brain MRI scan was normal. EEG showed paroxistic posterior activity, with occasional bilateralization. During the admission these symptoms persisted until motor weakness and autonomic dysfunction improved. He was transferred, at the 27th day after admission, to the rehabilitation ward, with discrete improvement of the motor strength and no psychotic symptoms. Discussion: It has been shown that the frequency of psychotic symptoms is dependent on severe quadriparesis, disautonomy, cranial nerve dysfunction, artificial ventilation requirement and high CSF protein levels. An association between this phenomena and sleep and dream abnormalities has been suggested. Explanations for this, beyond a sensory deafferentation and the continuous lying position, include a possible brain involvement in weaker parts of the blood-brain barrier, like third ventricle walls (sleep and autonomic related structures), that would be more vulnerable to the autoimmune attack.

P326 Carpal tunnel syndrome and obesity S. Kurt, Y. Kaplan, H. Karaer, B. Kisacik, B. Yildirim, I. Etikan Gaziosmanpasa University (Tokat, TR) Objective: Obesity is defined as a risk factor for carpal tunnel syndrome (CTS). In this study presence or absence of recovery in median nerve conductions after weight loss in obese patients was assessed in order to determine if excess weight or other factors are effective in higher prevalence of CTS in obese patients. Materials and methods: Patients with body mass indexes (BMI) equal or above 30 were included in the study. CTS symptoms, age, gender, heights, bodyweights, and concomitant diseases were interrogated. One upper extremity nerve conduction studies (NCS) were obtained.All patients were in-

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cluded in dietetic programs. Three months later NCS were repeated, and compared with the first NCS. Results: Second NCS of 92 (13 men, 79 women) of 126 (22 men, 104 women) patients were taken. The patients aged between 17–77 years (mean age: 42.74 ± 10.75 years). During second visits at 3rd months BMIs were statistically significantly lower (p = 0.0001).A statistically significant difference was not observed in second NCS of electromyographically diagnosed cases with CTS (p> 0.05). Conclusion: We expected a recovery in median nerve conduction velocities in patients with CTS after weight loss. In literature even in untreated cases with CTS, spontaneous improvements in second NCS were reported. This finding suggests that higher prevalence of CTS in obese patients, factors other than excess bodyweight might be influential. A more detailed genetic factor targeted investigation or a longer-lasting research are more benefical to clarify this issue. P327 Ascorbic acid in Charcot-Marie-Tooth 1A disease: the CMT-TRIAAL, a multicentre placebo-controlled randomised controlled trial D. Pareyson, A. Schenone, N. Rizzuto, G. Fabrizi, L. Santoro, A. Quattrone, G. Vita, L. Padua, F. Gemignani, F. Visioli, D. Calabrese, A. Solari on behalf of the CMT-TRIAAL Group Objective: There are no drug treatments for Charcot-Marie-Tooth disease type 1A (CMT1A), associated with the peripheral myelin protein 22 (PMP22) gene duplication. Ascorbic acid (AA) has been shown to be effective in transgenic mice overexpressing PMP22. We designed a randomised controlled trial of AA in CMT1A, named CMT-TRIAAL (CMT-TRial Italian with Ascorbic Acid Long term). Aims of the trial are: to assess the clinical efficacy and safety of a longterm AA treatment in CMT1A; to devise and validate an evaluation protocol suitable for future CMT trials; to prospectively assess the disease course using valid and reliable scales. Methods: The CMT-TRIAAL is a phase III randomised, double blind, placebo-controlled study, involving 222 CMT1A adults from 8 Italian centres. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of two-year oral AA (1500 mg/day) or placebo. Primary trial endpoint is a change in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal maximum voluntary isometric contraction; 10-meter timed walking; 9-hole-peg test; Overall Neuropathy Limitations Scale; pain and fatigue VAS; health-related quality of life (SF-36); electrophysiology.Assessments are performed at baseline and every six months thereafter. PMP22 expression in skin nerves will be evaluated in consenting patients from three centres. Results/Conclusion: The planned one-year enrolment started on March 2006. Between March and December 2006, a total of 265 patients had been screened (female 156 [59 %], mean age 42.6 year [SD 13.3; range 18–70]), and 194 of them (87 % of target) had been randomised to receive AA or placebo (female 117 [60 %], mean age 41.9 [SD 13.0; range 18–70]). Main reasons for exclusion were lacking or different genetic diagnosis (n = 18), other causes of neuropathy (n = 17), other major diseases (n = 6), renal stones (n = 5), recent or planned limb surgery (n = 5). In June 2007, data on the baseline assessment will be available. Supported by Telethon Italy Grants GUP04002-GUP05007, and partially by the Italian Drug Agency-AIFA. P328 Motor nerve biopsy in the diagnosis of lower motor neuron syndrome C. Casellato, M. Malaguti, A. Lazzerini, A. Quattrini, E. Nobile-Orazio IRCCS Istituto Clinico Humanitas (Milan, IT); IRCCS Ospedale San Raffaele (Milan, IT) Objective: To determine whether motor nerve biopsy may help differentiating motor neuropathy (MN) from motor neuron disease (MND) in patients with unclassifiable lower motor neuron syndrome (LMNS). Background: Morphometric studies on motor nerve biopsy have been reported to help distinguishing MN from MND (Corbo et al. 1997). No systematic prospective study has been however performed to determine whether this procedure may help in the diagnosis of patients with indefinite forms of LMNS. Methods: We performed motor nerve biopsy in 12 patients with symptoms and signs of lower motor neuron impairment with no definite sign of upper motor neuron or sensory impairment whose origin (MN versus MND) remained uncertain after extensive neurophysiological, neuroimmunological and neuroradiological studies. Biopsy of the motor branch from the anterior division of the obturator nerve to the gracilis muscle was performed under local anaesthesia after written informed consent. Nerve

specimens were examined by routine pathological studies while light microscopy morphometric analysis was performed in a double-blinded fashion using a computer-assisted Image Analyzer (Image measure, Phoenix Technology Inc., Seattle, WA). Results were correlated with clinical and electrophysiological findings and with the follow-up of the patients. Results: No consistent difference were observed among patients in the density of myelinated fibers, g-ratio and number of large myelinated fibers while there was a marked variability in the density of regenerative clusters of small myelinated fibers.In five patients the density was > 100/mm3,in four was 7–53/mm3 and in two patients there was no cluster of regeneration. Patients with high number of regenerative clusters either had a slow progression or long duration of symptoms and none developed signs of upper motor neuron impairment. Both patients with no regenerative cluster developed respiratory involvement or other signs of motor neuron disease in the months following nerve biopsy. In patients with an intermediate density of clusters the diagnosis at follow-up was quite variable. Conclusion: In this preliminary study on a small series of patients with a no better classifiable LMNS at presentation, motor nerve biopsy permitted to predict the final diagnosis in seven of the twelve patients examined (58 %) indicating that this method may be useful in the assessment of patients with lower motor neuron impairment of uncertain origin. P329 Distal hereditary motor neuropathy with HSP27 mutations – clinical, electrophysiological and neuroimaging features S-B. Kim, S-Y. Cho, S-J. Hwang, B-O. Choi Kyung Hee University (Seoul, KR); Ewha Womans University (Seoul, KR) Objectives: Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous disorders that motor neurons are selectively degenerated. Heat shock protein 27 (HSP27) plays significant roles in the cellular stress responses by defence mechanism as chaperons. Mutations in the HSP27 have been identified as causes of both axonal Charcot-Marie-Tooth disease (CMT) and dHMN type II. In this study, we investigated to find the characteristics in dHMN patients with the HSP27 (Ser135Phe) mutation. Methods: We identified 12 dHMN patients (male, 7; female, 5) with HSP27 mutation, and the range of disease duration is from 1 year to 39 years. We administered neurological examination and the nine-point functional disability scales (FDS) for evaluation of clinical disease severity. Nerve conduction studies and MRIs of lower legs were performed in all patients. Leg MRI studies included T1- and T2-weighted spin-echo sequences in coronal and axial planes, at proximal, middle and distal calf muscle locations. In all patients, both feet were simultaneous studied in coronal and axial planes. Axial images of legs were divided into 4 compartments (anterior, lateral, superficial and deep posterior), and individual muscles. Results: The onset of dHMN was between 18 and 25 years. Electrophysiological patterns of all patients with HSP27 mutations showed typical features of axonal neuropathies. However, the clinical and neuroimaging findings were different between short disease duration (≤ 20 years) and long disease duration (> 20 years) groups. FDS scores of females (4.0 ± 1.9) had more higher than those of males (1.6 ± 1.1; p < 0.05). Patients with short duration showed selective involvements of superficial posterior, and lateral compartments with relative sparing of other compartments.We found a tendency toward the orderly involvement of lower leg muscles from lateral and superficial posterior compartments to deep posterior and anterior compartments with disease progress. Proximal-distal gradient of leg muscular degeneration and involvement of intrinsic foot muscles are characteristics, and those are suggestive of a length-dependent motor neuropathy as the mechanism of muscle denervation of dHMN. Conclusion: We found that female patients with HSP27 mutations showed more severe phenotypes than male patients. Prominent involvement of superficial posterior and lateral compartments but anterior compartment is distinct from what has been found in CMT1A and CMT2A. P330 Churg Strauss syndrome: clinical presentation and follow-up of 5 patients P. Dacci, M. Scarlato, R. Fazio, A. Quattrini, S. Previtali, L. De Toni Franceschini, D. De Feo, G. Comi San Raffaele Hospital (Milan, IT) We describe 5 patients presenting with a subacute multineuropathy associated with fever and elevation of inflammation blood index. Anamnesis discovered an history of asthma and allergic reactions while blood laboratory data showed a hypereosinophilia. A sural nerve biopsy was made in 4 of them and it showed direct or indirect signs of vasculitis in most cases. This data together made a final diagnosis of Churg Strauss vasculitis possible. The Churg Strauss syndrome is a rare, small sized necrotizing vasculitis

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that develops in patients who have usually asthma, fever and hypereosinophilia. PNS involvement occurs in about 80 % of patients and it often represents the clinical onset of the disease. Three of our patients responded to steroid therapy but with relapses and severe side effects. In these cases association with an immunosuppressive therapy was necessary with often a good outcome. Only one patient had a very sever presentation with pericarditis and intestinal infarct with very poor response to immunomodulating therapies. In conclusion, we observed that a patient presenting with a severe subacute asymmetric neuropathy could have a vasculitic peripheral neuropathy. Among systemic vasculitis, Churg Strauss syndrome is the more frequently associated with peripheral neuropathy. It often requires immunosuppressive therapy but with good long term outcomes in most cases. P331 Efficacy of oxcarbazepine against chronic oxaliplatin-induced peripheral neuropathy: a randomised controlled trial A. Argyriou, P. Polychronopoulos, G. Iconomou, A. Koutras, P. Gourzis, K. Assimakopoulos, H. Kalofonos, E. Chroni University Hospital of Patras (Rion-Patras, GR) Purpose: A randomized, controlled trial was performed to assess the efficacy and safety of oxcarbazepine for prophylaxis against chronic oxaliplatin-induced peripheral neuropathy (OxIPN). Patients and methods: Thirty two patients with colon cancer scheduled to receive 12 courses of cumulative oxaliplatin-based regimens were randomly assigned to receive either chemotherapy with oxcarbazepine (600 mg, bi.d, group I) or chemotherapy without oxcarbazepine (OXC) (group II). A detailed clinical neurologic examination and electrophysiologic study was performed at baseline, during and at the last course of chemotherapy. The severity of OxIPN was summarized by means of a modified Total Neuropathy Score (TNS). Results: The incidence of neurotoxicity differed significantly between groups, occurring in 5/16 (31.2 %) of patients assigned to the OXC supplementation group and in 12/16 (75 %) of controls (P = 0.033). The relative risk (R.R) of developing OxIPN was significantly higher in controls, than in OXC group,RR = 0.42,95 % C. I. = 0.19–0.91.Mean TNS values were 4.1±6.5 (range 0–17) for patients of group I and 11.2±9.05 (range 0–28) for controls, (P = 0.016). Electrophysiological findings favored OXC administration in two of the three sensory nerves tested.OXC supplementation was well tolerated and showed a very good safety profile. Conclusion: Our results showed that OXC may have an important neuroprotective effect against chronic, cumulative OxIPN in patients with advanced colon cancer. Further larger placebo-controlled multi-institutional trials are warranted to address this important issue. P332 Peripheral neuropathy and cold agglutinin disease: case report suggesting pathogenetic mechanism N. Riva, G. Bezzi, M. Ponzoni, R. Epis, S. Previtali, F. Cerri, G. Comi, A. Quattrini San Raffaele Scientific Institute (Milan, IT); E. Monelli Hospital (Sondrio, IT) Objective: Peripheral Neuropathy (PN) is a rare complication of Cold Agglutinin Disease (CAD), with isolated cases reported. Pathogenetic mechanisms are still uncertain; suggested mechanisms are ischaemic factors related to agglutination of erythrocytes in vasa nervorum, an associated vasculitis, or immunologically mediated damage. Here we describe a patient affected by CAD and mononeuritis multiplex providing novel insights into pathogenetic mechanism of PN in patients with CAD. Methods: we describe a 58-year-old man affected by multifocal neuropathy. Three years before admission CAD had been diagnosed; at that time two bone marrow biopsies showed no evidence of lymphoma.On admission, laboratory investigations showed mild anemia, elevated Erythrocyte Sedimentation Rate (80 mm/h), an IgMk M protein (2 g/L); CA titer was 1:512 at 4°C, 1:64 at 25°C. CSF examination was within normal range, anti nerve autoantibodies and HCV RNA were negative. EMG revealed a sensory-motor multifocal neuropathy associated with denervation pattern in all muscles tested. Sural nerve biopsy and bone marrow aspirate were performed. Results: Sural semithin sections revealed asymmetrically axonal degeneration and B cell lymphoid infiltration of peripheral nerve. Electron microscopy confirmed the axonal damage. Immunocythochemical studies did not reveal IgM deposition on myelin sheaths and showed almost all lymphocytes to be of B-cell lineage (CD20 positive, CD68 negative) with immunoglobulin K light chain restriction.At this time, a bone marrow aspirate showed a moderate (40–50 %) infiltration of a monotypic IgM-kappa positive lymphocytes.

Chemotherapy was started in combination with plasmapheresis; however, after an initial, transitory improvement, fever, generalized rash and pancytopenia appeared and the patient died after three months from the first neurological consultation. Conclusions: Lymphoid infiltration of peripheral nerves suggests a novel, additional pathogenetic mechanism for PN in CAD and must be considered as one of the possible causes of PN in patients with CAD. P333 Non-dystonic writing disorders S. Llufriu, J. Casanova-Molla, J. Valls-Solé Hospital Clinic Barcelona (Barcelona, ES) Background: Fine tasks carried out by human fingers and hands, such as writing, require a careful control of activity in antagonistic muscles. The median, and specially, the ulnar nerves are in charge of innervating hand muscles that should be used selectively or in different combinations to perform fine tasks. Our hypothesis is that such control of muscle activation is impaired if an abnormal (aberrant) reinnervation occurs after a peripheral nerve lesion. Objectives: To describe the characteristics of the dysfunction of hand muscles in patients with antecedents of peripheral nerve lesions who reported movement disorders or cramps when writing. Patients/Methods: We revised the history and neurophysiological recording of patients who were sent for electromyographic examination to our Neurology Department with the diagnosis of motor deficit, cramps or abnormal control of hand muscles associated with median or ulnar nerve lesions during the last 10 years. We selected 8 patients who complained of difficulties with writing. They were video-taped and had a thorough EMG and nerve conduction study. Results: Patients were 4 men and 4 women aged from 27 to 76 years old. Seven had ulnar lesion and one had a median neuropathy. The duration of their lesion ranged from 6 to 30 months. Clinical inspection revealed small involuntary movements of the 5th, 4th or 3rd fingers, and an abnormal posture in adduction of individual fingers. Spasms were precipitated by writing in such a way that most patients dropped the pen and squeezed their hand. EMG recordings and nerve conduction studies showed evidence for various degrees of motor and sensory deficits in the affected nerve. Reinnervation motor unit action potentials were recorded from hand muscles in all patients, and were observed to fire synchronously in antagonistic muscles. Aberrant responses of interossei or hypothenar muscles were recorded to stimuli to the 5th finger in 6 patients. Conclusions: Peripheral nerve lesions may cause abnormal movements and cramps while writing in hand muscles in association with aberrant nerve regeneration. The pathophysiological mechanism underlying this movement disorder is likely to be abnormal branching of growing axons and should be clearly distinguished from that of central dysfunctions causing dystonia.

Poster session 2 Cerebrovascular disorders P334 Comparison of two hospital scores with computerised tomography in ascertaining stroke type (Bangkok and London) F. Salawu, A. Danburam, H. Mshelia, L. Ahmed, J. Agbo, D. Balami, I. Umar Federal Medical Centre (Yola, NG); State Specialist Hospital (Maiduguri, NG); University of Maiduguri Teaching Hospital (Maiduguri, NG) Routine computerised tomography (CT) for all patients with stroke is not available to most doctors in Nigeria, and this poses management problems. There are about 30 neurologists in a country with a population of over 130 million people. Approximately two-thirds of stroke patients are cared for by physicians, medical officers, and health personnel, often without the involvement of a neurologist. Objective: compare two available clinical scores with brain CT for the differential diagnosis of cerebral ischaemia and haemorrhage in first-ever acute stroke patients. Methods: Three centres in north east Nigeria were involved in the study: the University of Maiduguri Teaching Hospital (24 hour access to comput-

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erized tomography), the State Specialist Hospital (no CT in the hospital; patients sent by ambulance 5–8 km for CT) and Federal Medical Centre, Yola (no CT in hospital, patients referred by ambulance 50–60 km for CT). Ninety-five consecutive patients fulfilling the inclusion criteria presenting with first-ever-stroke were included. Patients with transient ischaemic attacks and those on anticoagulants were excluded. They were all evaluated with the Siriraj score on presentation and the guy’s Hospital score 24 hours after admission. These 2 scores were compared with the results of CT and sensitivity, specificity, positive predictive value and negative predictive values were calculated. Results: Applying the recommended optimum cut-off points for the 2 clinical scores, diagnoses were classified by the Guy’s Hospital and Siriraj stroke scores as probable haemorrhage strokes (49 % and 25 % respectively) and probable ischaemic (40 % and 65 % respectively). The remainder were classified as “uncertain.” The prevalence of haemorrhage (diagnosed with CT) was 33.7 %, while the prevalence of ischaemia (diagnosed with CT) was 57.9 %. The CT brain was normal in 8.4 %. Sensitivity, specificity, positive predictive value and negative predictive value for haemorrhage was 0.64, 0.48,0.4,and 0.71 for Guy’s Hospital score; and 0.35,0.73,0.4 and 0.68 for Siriraj score. Conclusion: It is evident from this study that these clinical scoring systems alone are not sufficient and one has to employ the use of CT scan in establishing stroke type. We are wary about their use as diagnostic screening procedure for decision about treatment in our ordinary clinical practise, as they did not diagnose the same case as certain infarction or certain haemorrhage. P335 Predictors of mortality in intracerebral haemorrhage: analysis of a cohort of Nigerian patients F. Salawu, A. Danburam, S. Bwala, H. Mshelia, U. Umar Federal Medical Centre (Yola, NG); University of Maiduguri (Maiduguri, NG); State Specialist Hospital (Maiduguri, NG) Intracerebral haemorrhage (ICH) can have devastating effects, with a mortality of over 30 % to 40 %. Spontaneous (non traumatic) ICH makes up approximately 20 % of our stroke patients, with an unfortunately considerably worse outcome than ischaemic stroke, and the majority of survivors are left with significant disability. Objective: To analyse clinical characteristics and neuroimaging findings that worsen mortality in Nigerians with ICH. Method: A ten year retrospective review of medical records of all firstever stroke patients with computerized tomography proven ICH admitted at the University of Maiduguri Teaching Hospital, a tertiary referral centre and main University Hospital in North east Nigeria were analysed. Comparison of parameters was made between survivors and dead patients. Results: Non-traumatic ICH constituted 128 of 552 (23 %) stroke patients admitted between January 1995 and December 2004. Complete information was available in 118 patients, who formed the cohort for data analysis. Mean age at onset of ICH was 57.0±11 (range, 43 to 78 years). The male to female ratio was 2.3:1. Twenty-four hours after the event 15 (13 %) had died in the hospital, 29 % at 7 days, 36 % at 30 days. The most important risk factor for ICH was poorly controlled chronic hypertension in 92 (78 %), others included amyloid angiopathy in 9 (8 %) and vascular malformations in 6 (5 %). Clinical factors predictive of early mortality were increased age, low Glasgow Coma Scale less than 7, blood glucose level on admission ≥ 8.5mmol/l, renal impairment and blood pressure. Radiological variables included volume of haematoma, midline shift and the presence of intraventricular haemorrhage or hydrocephalus on CT brain scan.A number of the patients (10 %) were on antiplatelets or anticoagulants before the event (two on warfarin, one on heparin, eight on aspirin and one on combination of heparin and low dose aspirin because of myocardial infarction. None of the patients had neurosurgical intervention. The administration of mannitol infusion and frusemide intravenously was associated with improved clinical outcome in a number of patients. Conclusion: Our experience has been that although mortality seems high in patients with ICH, empirical treatment with a combination of mannitol and frusemide in the first week may be effective and alter outcome. Further multicentre studies should be conducted on a larger population to confirm this.

P336 Atherosclerosis is a risk factor for cerebral white matter ischaemic changes in patients with stroke M. Mijajlovic, E. Ben-Assayag, I. Bova, L. Shopin, S. Shenhar, S. Berliner, T. Nissel, I. Shapira, N. Bornstein Institute of Neurology, Clinical Center of Serbia (Belgrade, RS); Tel Aviv Sourasky Medical Center (Tel-Aviv, IL) Objectives: Previous studies have shown that white matter lesions are associated with increasing age, hypertension, diabetes and history of stroke. Although several lines of evidence suggest a role of atherosclerotic processes in atherothrombotic vascular events, their involvement in leukoaraiosis remains to be determine. Our study examines the association between atherosclerosis, reflected as intima-media thickness (IMT) and carotid plaques, lipid profile and leukoaraiosis in a group of ischemic stroke patients. Methods: One houndred sixty four consecutive ischemic stroke patients were included (mean age 66.7±3.4 years, 61 % males).All patients underwent brain computed tomography (CT), carotid dupplex with measurements of IMT in the common carotid artery and lipid profile. Results: Seventy two patients (44 %) were found to have 1 or more white matter lesions on CT images located in frontal, parietal or occipital region. The majority of the patients (62.5 %) had leukoaraiosis located in at least two brain regions, and 13.8 % had leukoaraoisis in all regions. Mean IMT was significantly higher in stroke patients with leukoaraiosis (p = 0.004) compared to those without it. Also, leukoaraiosis was associated with carotid plaque occurrence (ö2 = 6.154, p = 0.013). High density lipoprotein (HDL)-cholesterol was found to be significantly lower in the leukoaraiosis patients (p = 0.041). In logistic regression analysis, including age, gender, body mass index, and all vascular risk factors, leukoaraiosis was found to be associated with age and IMT (O. R. 1.04, 95 % CI 1.01–1.071, p = 0.009; O. R. 13.058, 95 % CI 1.509–113.014, p = 0.02; respectively). Conclusions: In our acute ischemic stroke patient cohort, the incidence of leukoaraiosis is relatively high. Advanced atherosclerotic process (expressed by significantly increased IMT) is associated with more widespread atherosclerotic lesions, comprising large, as well as small cerebral arteries. P337 Cerebral haemodynamic impairment and cardiac sequelae of subarachnoid haemorrhage: time for active management M. Aidaros Zagazig University (Zagazig, EG) Objective: We studied the incidence of myocardial injury in aneurysmal subarachnoid hemorrhage (SAH) by assaying creatine kinase MB fraction (CKMB), and the more sensitive cardiac troponin T, as well as by repeated electrocardiography (ECG) and echocardiography. Transcranial Doppler Scanning (TCD) was done to assess the participation of cardiac dysfunction in the aggravation of cerebral vasospasm. We examined serum epinephrine level as it was claimed to be the cause for both myocardial dysfunction and cerebral vasospasm. Methods: We studied 42 patients admitted to Intensive care unit for aneurysmal subarachnoid hemorrhage over a period of 2.5 years. All patients underwent the following investigation within 3 days of onset (1) CT scan examination and, Digital subtraction angiography (2) transcranial Doppler ultrasonography, (3) electocardiagram and echocardiogram, and (4) CK-MB levels, troponin and epinephrine. All of our patients had no history of preexisting cardiac disease. Results: Patients with subarachnoid hemorrhage exhibited increased level of plasma epinephrine ›and this level was statistically higher in patients with wall motion abnormality. Again, patients who experienced cerebral vasospasm had higher epinephrine level than others but the difference was statistically insignificant, left ventricular wall motion abnormalities were identified in four (9.52 %) of 42 patients. One of these patients experienced hypotension, and pulmonary edema compared to none of the 38 patients with normal wall motion.Cerebral vasospasm, on TCD, was found to occur more commonly in patients with high blood pressure, poor neurological grade (Hunt and Hess grade HI to V), high Fisher grade(IH and IV), peak CK-MB levels less than 2 %, and wall motion abnormality. These variables were positively correlated to poor outcome. Conclusion: These results demonstrate an association between wall motion abnormalities with impaired left ventricular performance and both mild creatine kinase MB elevation and positive troponin in acute SAH. Symmetrical T wave inversion could be a useful marker to identify patients at risk for myocardial dysfunction and may serve as a useful criterion for echocardiographic screening following SAH. In severely affected patients, reduction of cardiac output may increase the risk of cerebral ischemia related to vasospasm, and may consequently contribute to poor outcome.

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P338 Premorbid treatment: some risk factors and early outcome of stroke D. Salihovic, D. Smajlovic, O. Sinanovic University Clinical Centre (Tuzla, BA) Objectives: The aim of this study was to analyze the frequency of stroke risk factors and effects of their treatment in premorbid period for early outcome of stroke. Methods: From January 1st to June 30th 2006 at the Department of Neurology, University Clinical Centre Tuzla, Bosnia and Herzegovina, 527 patients with acute stroke were hospitalized. For the analysis in this study we excluded patients with recurrent stroke (n = 73) and subarachnoid hemorrhage (n = 17). We analyzed following risk factors: hypertension, hearth diseases, atrial fibrillation and diabetes mellitus. Results: Out of total (n = 437), 230 (52.5 %) patients were women. Hypertension, atrial fibrillation and diabetes mellitus were more frequent in women (86 % vs. 73 %, p = 0.0004; 18 % vs. 12 %, p = 0.1; 38 % vs. 27 %, p = 0.01, respectively). At least one stroke risk factor was registered among 399 patients (91 %) but on previously recommended therapy were 139 patients (35 %). Women used therapy more regularly then men (42 % vs. 26 %, p = 0.0007). Patients with diabetes mellitus (60.4 %) most regularly used recommended therapy, then hypertension (50 %), while just 7.5 % of patients with atrial fibrillation took prescribed anticoagulant therapy. Patients who did not take therapy for hypertension regularly had higher incidence of intracerebral hemorrhage (18.5 % vs. 12 %, p = 0.09). Hospital mortality was higher in patients who did not used prescribed therapy before stroke onset (28 % vs. 24 %, p = 0.3). Premorbid treatment of the analyzed stroke risk factors did not have influence on severity and disability in acute phase of stroke (p> 0.1). Conclusion: Before stroke onset only 35 % of patients regularly use previously recommended therapy for the risk factors treatment. Premorbid treatment of stroke risk factors has influence on hospital mortality but does not have influence on severity and disability in acute phase of stroke.

P339 Cerebral venous thrombosis and dural fistula development P. Cardona, L. Bau, M. Cos, A. Escrig, C. Majós, F. Rubio Bellvitge Hospital (Barcelona, ES)

thrombotic crisis states as well as to evaluate the role of some laboratory and genetic parameters as predisposing factors for development of stroke. Methods: The study included 20 children with SCA diagnosed clinically, hematologically and confirmed by hemoglobin electrophoresis. They were divided into two groups, group I; included 10 children with SCA in steady state and group II; included 10 SCA children in thrombotic crisis. Another 10 healthy children with matched age and sex were taken as a control group. All the studied groups were subjected to full clinical examination, measurements of: FPA, TAT, D-dimer and PECAM-1 as well as molecular genetic study of the ACE gene polymorphism. Brain computed axial tomography (CT) scan and / or magnetic resonance imaging (MRI) as well as electro-encephalographic studies (EEG) were done only for patient groups. Results: Showed that silent ischemic brain infarction evidenced only by CT scan and/or MRI was present in one patient in group I (10 %) and one patient in group II (10 %). On the other hand, two patients in group II (20 %) were presented by clinically overt strokes. Thus, according to the presence or absence of stroke either silent or clinically overt there were stroke group (4 children) and non-stroke group (16 children). Laboratory results showed that the levels of FPA, TAT, D-dimer and PECAM-1 were significantly elevated in SCA patients both in the steady and crisis states as compared to control, with more evident significant elevation in group II (thrombotic crisis) as compared to group I (steady state). Stroke group showed significant elevation in all the studied parameters; FPA, TAT, D-dimer and PECAM-1 as compared with non-stroke group. The molecular study results showed that the frequencies of both DD genotype and D allele of ACE gene in the thrombotic crisis were significantly higher than in the control group and that all stroke group children are of DD genotype. Conclusion: Significant increase in FPA, TAT, D-dimer and PECAM-1 levels as well as the presence of D allele of the ACE gene are significant predisposing factors for stroke in children with SCA either in the steady or in the crisis states.

P341 Antiplatelet therapy for aneurysmal subarachnoid haemorrhage: a systematic review S. M. Dorhout Mees, W. M. van den Bergh, A. Algra, G. J. E. Rinkel University Medical Center Utrecht (Utrecht, NL)

Introduction: Dural arteriovenous fistulas (DAVF) rarely are associated with cerebral venous thrombosis (CVT). We report five cases of symptomatic intracranial dural arteriovenous fistulas during follow-up of CVT. Methods: We retrospectively review forty patients with intracranial venous thrombosis between 1996–2006. In five cases DAVFs were developed during follow-up period 1 year after anticoagulation stopping (after 6–9 months of period treatment); leptomeningeal drainage were present in all the cases. Results: Symptoms as pulsatile tinnitus or headache appeared 3–12 months interval after anticoagulation cessation. All five patients where the initial angiogram studies had showed abnormalities of the venous transverse or sigmoid sinuses, persistent abnormalities were seen on the later angio-MR previous to stopping oral anticoagulant (6–12 months period) as occluded or filiforme sinus. Two of five patients had factor V Leiden previously unknowned. Embolization of DAVF was performed in three cases with good outcome. Discussion: DAVF appeared over previous ocluded or filiforme transverse sinus demonstrated in angio-MR. All fistulaes were on the transverse or sigmoid sinuses.It was hypothesized that factor V Leiden and other inhereted deficiencies of coagulation factors, might be involved in the pathogenesis of DAVFS secondary to venous thrombosis predisposition over damaged venous wall. Also the anticoagulation cessation may predispose to DAVF formation. Conclusion: The longterm anticoagulant therapy in occluded or partial thrombosed sinus might be important for prevention of thrombosis and DAVF formation although patients were asymptomatic. Due to a potential risk of intracranial hemorrages, embolisation previous to prompt anticoagulation may be developed in these cases.

Objectives: Secondary ischaemia is a frequent cause of poor outcome in patients with aneurysmal subarachnoid haemorrhage (SAH). There is evidence that, besides vasospasm, platelet aggregation plays a role in the pathogenesis of secondary ischaemia. Experimental studies have suggested that antiplatelet agents can prevent secondary ischaemia. We performed a systematic review to determine whether antiplatelet therapy improves outcome in patients with aneurysmal SAH. Methods: We searched Medline, EMBASE and the Cochrane Library until August 2006 to identify all randomised controlled trials of antiplatelet agents versus control. Relative risks (RR) with corresponding 95 % confidence intervals (CI) were calculated with regard to poor outcome, case fatality, secondary ischaemia, haemorrhagic intracranial complications and rebleeding according to the intention-to-treat principle. Results: Seven trials were included in the review totalling 1385 patients. The RR for poor outcome for any antiplatelet drug was 0.79 (95 % CI 0.62–1.01). There was no effect in case fatality for all agents (RR 1.01 (95 % CI 0.74–1.37), a trend was shown towards less occurrence of secondary ischaemia (RR 0.79, 95 % CI 0.56–1.22). There was a trend towards more intracranial hemorrhagic complications (RR 1.36, 95 % CI 0.59–3.12) but not towards rebleeding (RR0.98, 95 % CI 0.70–1.38). Conclusions: This review shows a trend towards better outcome in patients treated with antiplatelet agents, probably due to a reduction in secondary ischaemia. However, results were not statistically significant and no definite conclusion can be drawn. Also, antiplatelet agents may increase the risk of haemorrhagic complications. On the basis of the current evidence treatment with antiplatelet agents in order to prevent secondary ischaemia or poor outcome can not be recommended. S. M. Dorhout Mees was sponsored by the Netherlands Heart Foundation, grant number 2005BO16.

P340 Haemostatic and genetic predisposing factors for stroke in children with sickle cell anaemia W. Fadel, H. Mourad, M. Batch, M. Rewisha Tanta University Hospital (Tanta, EG)

P342 Can aspirin resistance be clinically predicted in stroke patients? I. S. Joo, J. H. Yoon, P. H. Lee, K. Huh, J. I. Seok, O. Y. Bang Ajou University Hospital (Suwon, KR); Catholic University Hospital (Daegu, KR); Sungkyunkwan University Hospital (Seoul, KR)

Objective: This study was done to detect cases of silent and clinically overt strokes in children with sickle cell anemia (SCA) either in the steady or

Objectives: Aspirin resistance is one of several possible explanations for limited efficacy or treatment failure of aspirin. However, the predictors of as-

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pirin resistance are not known.We therefore conducted a study of aspirin resistance in Korean patients with ischemic stroke and considered a wide range of factors as possible predictors. Methods: In total, 88 patients taking aspirin daily for the secondary prevention of stroke were included in the study. Platelet function was assessed using the Rapid Platelet Function Assay-Aspirin (RPFA-ASA) system and the level of urinary thromboxane B2 (TX-B2). The result of the RPFA-ASA system was expressed as an aspirin reaction unit (ARU). We analyzed a wide range of factors including demographic data, stroke risk factors, and laboratory findings to identify the clinical predictors of aspirin resistance. Results: Eleven (12 %) patients were identified as aspirin resistant by the ARU criteria. Univariate analysis showed that an older age, lower LDL cholesterol level, and concurrent medication with angiotensin converting enzyme inhibitors or receptor blockers were related to aspirin resistance by ARU criteria. Aspirin resistance by urinary TX-B2 criteria was associated with an older age, metabolic syndrome, diabetes, cigarette smoking, and the use of angiotensin-converting enzyme inhibitors or receptor blockers. However, this association lost significance in multivariate testing, and the correlation between the two criteria was poor (r = –0.115, p = 0.34). Conclusion: Despite the comprehensive analysis of this study, we failed to identify independent predictors for aspirin resistance. Additionally, little overlap was found between the two criteria with which to assess aspirin resistance. We thank Yuyu Inc. for providing the RPFA-ASA system (VerifyNow Aspirin Assay). P343 Prevalence and clinical significance of cerebral microembolism in acute ischaemic stroke J. Lee, J. P. Yoon, S. J. Lee Yeungnam University (Daegu, KR) Introduction: Microembolic signals(MES) detected by transcranial Doppler(TCD) have been considered as an independent predictor of recurrent ischemic stroke. However, the association between the presence of MES and the risk of stroke has predominantly been studied on small and selected patients. To evaluate the clinical significance of MES in patients with acute ischemic stroke, we investigated the prevalence of MES and analyzed the relationship between MES and stroke subtype. Methods: We intended to perform TCD monitoring for 30 minutes to detect MES from the bilateral middle cerebral arteries in patients within 15 days of stroke onset. The strokes were subtyped using the TOAST classification criteria. Results: Between September 2005 and December 2006, a total of 884 consecutive transient ischemic attack or stroke patients admitted to our stroke unit within 7 days of stroke onset. TCD study performed 590 patients and we excluded 65 patients because there was a long interval between onset of symptoms and examination, an artificial heart valve, and inadequate temporal bone window. MES were detected in 23(4.2 %) of the remaining 525 patients despite the fact that all patients were receiving an antiplatelet or an anticoagulant treatment. Among patients with positive MES detection, 7(31.8 %) had recurrent MES during follow-up TCD monitoring within 3 days after the first examination. MES were detected in 3.1 % of patients with large-artery atherosclerosis stroke, 4.1 % of patients with cardioembolic stroke, 2.1 % of patients with lacunar stroke, 9.1 % of patients with cryptogenic stroke, and 4.1 % of undetermined stroke(p = 0.241). The patients who were assumed lacunar infarction showed index lesions in the posterior circulation. In 6 of the 8 patients(75 %) with lesions in the anterior circulation, MES were observed ipsilateral to the affected territories. Conclusions: During antithrombotic treatment in patients with acute ischemic stroke, the prevalence of MES is low and TCD-detected microembolism dose not contribute to classify the ischemic stroke subtype. However the MES are frequent in the territories of symptomatic arteries in the anterior circulation stroke and recurrent MES are common during a short follow-up. P344 Effect of a volume therapy with gelatin solution in comparison with HES 200/0.5 in patients with acute stroke: a randomised, double-blind study of possible side effects R. Woessner, S. B. Hoock, M. Herber, R. M. Loreth, F. W. Albert, M. T. Grauer, J. Treib Westpfalz-Klinikum GmbH (Kaiserslautern, DE); Bezirksklinikum (Haar, DE) Introduction: In patients with acute stroke who suffer from hypotension, the use of colloid solutions is a possible therapeutic option. So far, gelatin solu-

tions have not been studied for this indication, although they are widely used as a colloidal volume replacement. Materials and Methods: In a randomized, double-blind study, 40 patients suffering from acute ischemic stroke were treated with either 6 % hydroxyethyl starch 200/0.5 (Hemohes 6 %) or a gelatin solution (Gelatine 4 %) for 4 days. Treatment was started with a loading dose of 500 ml over 4 hours, subsequently 1000 ml were administered continuously over 24 hours. Routine laboratory values, coagulation parameters and rotation thrombelastometry (roTEM) were analyzed. Results: In both groups, no relevant adverse events were observed. Pruritus occured in the gelatin group in one patient, in the HES group in 3 patients. Activated partial thromboplastin time (aPTT) increased 11.6 % between day 1 and day 5 in the HES group and 4.4 % in the gelatine group (p = 0.024). No significant effects on thrombin time, fibrinogen, factor VIII, vWF:Ag, thromboplastin time, INR, hematocrit, hemoglobin, MCV, MCH, MHCH, platelets, leukocytes and erythrocytes were observed. Regarding rotation thrombelastometry, only small, non-significant differences between the two groups were observed. Discussion: Both substances were shown to be safe. The studied parameters of the coagulation system were hardly affected. The question of clinical efficacy can only be answered in large, multi-center study. From the side effect profile, both volume substitutes would be suitable. The study was supported by B. Braun-Melsungen AG Germany. The research fund is controlled by our administration so that no personal advantages for the researchers result. The sponsor did not influence the data analysis. P345 Is renal failure a predicting factor of poor evolution in acute stroke? L. Gabaldon, B. Fuentes, J. Fernández, L. Idrovo, P. Martinez-Sanchez, E. Diez Tejedor University Hospital La Paz. UAM (Madrid, ES) Background: Previous studies have pointed out that renal failure is an independent factor of poor outcome in patients with cardiac failure, myocardial infarction and coronary surgery. However, no studies analysing its possible influence on stroke outcome are available. Methods: Observational study including consecutive first-ever acute stroke in-patients with a two-years recruitment period. Renal failure was defined as creatinine level ≥ 1.2 mg/dl on admission or previous diagnosis of it. In-hospital mortality and outcome at discharge (modified Rankin Scale) were the main outcome measures. Results: 445 patients were included, mean age 69.7±13.2. In the univariate analysis creatinine > 1.2 mg/dl was associated to more in-hospital mortality (31.7 vs. 20.7 %; p = 0.04) but not to poor outcome at discharge. In multivariate logistic regression analysis the predictive factors independently associated to in-hospital mortality were: stroke severity on admission (OR 0.49; 95 % IC 0.39–0.63) and the development of systemic (OR 17.97; 95 % IC 5.47–59) or neurologic complications (OR 23.49; 95 %IC 7.25–76.01) without any influence of renal failure. Conclusions: Renal failure measured by creatinine serum level does not significantly influence in-hospital mortality or outcome at discharge in acute stroke patients. However, new studies analysing other parametres of renal function such as creatinine clearance are need to get definite conclusions. P346 Neurological syndromes in 24 consecutive patients with spontaneous cervical artery dissection D. Ulbricht, R. J. Metz, N. J. Diederich Centre Hospitalier Emile Mayrisch (Esch-sur-Alzette, LU); Centre Hospitalier de Luxembourg (Luxembourg, LU) Introduction: MRI contributes to the diagnosis of spontaneous cervical artery dissection (SCAD) by showing wall-hematoma non-invasively. It has been postulated that it also demonstrates acute multiple brain infarction (AMBI) as the main mechanism of neurological deficits. We sought to verify this hypothesis. Patients and methods: 24 consecutive patients, 15 men and 9 women, mean age of 44.5 years with a total of 28 SCAD were prospectively studied. Multimodal MRI included at least cerebral diffusion weighted imaging and fat-saturated sequences of the neck. Cervical MRI and conventional angiography were performed as needed. Lesions were assessed according to standard vascular topography. AMBI was diagnosed when the parenchymal lesion was distant from SCAD, local symptoms when best explained by direct effect of wall hematoma either by distention or local occlusion of an arterial ostium (e. g. Horner’s syndrome, posterior spinal artery stroke).

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Results: In 12 patients the territory of the internal cerebral artery (ICA) and in the remainder the territory of the vertebral artery (VA) was affected. There was no SCAD in both territories, and four had bilateral SCAD (2 ICA, 2 VA). Lesions were directly visualized in 17/24 patients. Seven had SCAD and corresponding clinical symptoms without lesion of parenchyma. All demonstrated lesions were situated in the corresponding arterial territory (ICA: distant = 5, distant + local = 3, local = 4), (VA: distant = 6, local = 4). The cause of neurological deficits was AMBI in 13 patients, local compression in 8, and combined in 3. Discussion: The present series confirms the concept of AMBI as the principal cause of neurological syndromes in SCAD. However, in situ compression by wall hematoma accounts for further deficits in about a third of the patients or is the only cause. P347 Thalamic infarcts S. Ari, T. Aydin, N. Isik, F. Candan, I. Aydin Goztepe Training Hospital (Istanbul, TR) Objective: The data of patients with an CT or MRI-confirmed diagnosis of thalamic stroke were analyzed to identify risk factors, clinical, etiological and neuroradiological patterns according to the thalamic arterial territory involved. Material and methods: We reviewed the records of all patients with a diagnosis of pure thalamic stroke confirmed by CT or MRI who attended to our registory from 2000 to 2006. A database containing risk factors, clinical course, mechanism of stroke and vasvular territory was analized. Results: Twenty-eight patients (15 men and 13 women; mean age, 59.7) had CT or MRI confirmed thalamic stroke. Regarding the affected vascular territory, the patients divided into the following subgroups: paramedian infarctions (thalamoperforating arteries, 12 patients, 3 left, 2 right, 7 bilateral), inferolateral infarcts (thalamogeniculate arteries, 12 patients, 6 left, 6 right) and polar infarcts (tuberothalamic arteries, 4 patients, 3 left, 1 bilateral). We did not observe any infarction in the territory of posterior choroidal artery. The leading symptoms of paramedian thalamic infarcts were disorders of consciousness, different types of oculumotor involvement disorientation, apathy and hypophonia. The patients with inferolateral thalamic infraction were presented with focal sensory-motor defisits and ataxia, whereas those with tuberothalamic infarcts were presented with acute confusional statement, disorientation and diplopia. The main cause of thalamic infarction were small artery disease, followed by cardioembolism. We found no risk factor in three patiens. Clinic course was severe in paramedian infarcts, 3 patients died in observation period in the hospital. Conclusions: Thalamic infarcts are often associated with specific neurologic-neuropschological patterns, and the main cause is usually cardioembolism. In our study, small artery diseases were found as the main cause of the infarcts. Evaluation of cognitive and behavioral functions with neurologic-neuropsychological tests will be illustrative in planning prospective examinations for acute thalamic infarcts prognosis. P348 The role of hypercoagulation in young ischaemic stroke patients A. Bartkova, D. Sanak, I. Vlachova, R. Herzig, V. Krcova, M. Kral, P. Kanovsky University Hospital Olomouc (Olomouc, CZ) Objectives: Ischemic stroke (IS) is less frequent and caused by different etiological factors in young adults than in elderly patients. The aim of our study was to evaluate the frequency, etiology and subtypes of IS in patients aged ≤ 50 years and to assess the occurrence and the type of hypercoagulopathy as a cause of IS. Methods: 853 consecutive acute IS patients admitted to our stroke unit from January 2004 to December 2006 were analyzed. Stroke subtype was assessed using the TOAST criteria. Standard examination protocol including magnetic resonance imaging, ultrasound examination and transesophageal echocardiography was used in all patients ≤ 50 years. In the same patients, coagulation examination (including plasma levels of antithrombin III, proteins C and S, activated protein C resistance, factor V-Leiden mutation, lupus anticoagulans and anticardiolipin IgG and IgM antibodies) was performed at admission and 6–12 weeks later. In the case of suspicion of antiphospholipid syndrome (APS), serological laboratory screening for systemic lupus erythemathodes was completed. Results: Eighty-four (9.8 %) IS patients ≤ 50 years were found. The following IS types were diagnosed: cardioembolic in 33 (39.3 %), atherosclerotic in 14 (16.7 %), undetermined in 29 (34.5 %) and others in 8 (9.5 %) of the patients. Coagulopathy was found in 28 (32.8 %) of the patients, out of whom 16 (57.2 %) were classified as undetermined IS. Within this subgroup, primary APS occurred in 10 (35.7 %), secondary APS in 5 (17.8 %), APC re-

sistance associated with Leiden mutation was present in 8 (28.6 %) and nonspecific coagulation abnormalities were found in 5 (17.8 %) of the patients. Conclusions: IS of undetermined and cardioembolic etiology was associated with a higher frequency of coagulopathy in our cohort. It seems to be useful to perform complete coagulation examination in the case of unclear cause of IS in young patients.

P349 The impact of cerebrovascular risk factors on brain tissue changes with normal ageing: a magnetisation transfer imaging study S. Ropele, F. Gorani, C. Enzinger, R. Schmidt, F. Fazekas Medical University Graz (Graz, AT) Objective: In addition to the continuous loss of brain volume and the frequent occurrence of white matter hyperintensities (WMH) with ageing, studies using magnetization transfer imaging (MTI) have provided evidence for tissue changes which go undetected by conventional MRI. The causes for the observed decrease of the magnetization transfer ratio (MTR), a measure derived from MTI, with advancing age are still unknown but likely to result from a diffuse impact or mechanism. We therefore wanted to explore if specific cerebrovascular risk factors may have an impact on changes of the cerebral tissue matrix as assessed by the MTR. Methods: MTI was performed in 328 neurologically asymptomatic participants of the Austrian Stroke Prevention Study (mean age 70, age range 52–87 years) using a spoiled 3D gradient echo sequence on a 1.5T scanner. Fluid attenuated inversion recovery MRI was used to delineate WMH and to define normal appearing brain tissue (NABT).After brain extraction and lesion masking a MTR analysis was done in NABT and WMH using histogram analysis. A large battery of possible risk factors was assed including age, sex, arterial hypertension, diabetes, smoking, cardiac disease, body mass index, total cholesterol, and glycated hemoglobin. A multivariate regression model was used to study the impact of these factors on the global and lesional MTR. Results: Age, sex, arterial hypertension, and diabetes mellitus were the only factors, that showed a significant effect (p < 0.05) on the global MTR by the multivariate analysis. Age was the strongest predicator for global MTR reductions where males did show a stronger reduction with increasing age than females. Regarding WMH subjects with arterial hypertension had a significantly lower lesional MTR (p < 0.05) than those with normal tension after correction for age. Apart from age and hypertension no other factor had an effect on the lesional MTR. Conclusion: Changes of NABT as detectable with MTI are related predominantly to the ageing process per se, while diabetes mellitus and hypertension may exert some additional minor effects. The observation that lesional MTR was related to arterial hypertension underlines the impact of micro-angiopathy as an important source of WMH in the elderly.

P350 The comparison of carotid plaque measurements according to the ischaemic stroke subtypes S. H. Kim, J. H. Cho, S. H. Park, J-M. Chon, J-Y. Lee, S-S. Lee Yonsei University Wonju College of Medicine (Wonju, KR); National Health Insurance Coporation Ilsan Hospital (Goyang, KR) Objectives: Although carotid plaques may be associated with development of an ischemic stroke, a few studies examined carotid plaques in the aspect of etiologic classification. The present study was aimed at investigating the ultrasound utility for etiologic grouping by comparing various plaque measurements of the carotid artery among ischemic stroke subtypes. Methods: We retrospectively analyzed medical and sonographic records of acute stroke patients who admitted to neurology department between July, 2004 and June, 2006. Plaque score, the sum of all plaque thickness, and maximal plaque thickness (MPT) of the carotid artery was compared among the subgroups classified by Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification. Results: 531 patients with acute ischemic stroke, evaluated by cerebral angiography and carotid sonography, were enrolled and grouped into following categories: large artery atherosclerosis (LAA; n = 190), cardioembolism (CE; n = 59), small artery disease (SA; n = 95), more than 2 causes (2MC; n = 20), or negative evaluation (NEG; n = 167). Plaque score and MPT of the carotid artery were significantly increased in LAA and 2MC compared with others (p < 0.01). The median values of plaque score were 5.8mm in LAA, 2.4mm in CE, 2.7mm in SA, 9.0mm in 2MC, 3.3mm in NEG. The median values of MPT were 2.8mm in LAA, 1.7mm in CE, 2.0mm in SA, 4.1mm in 2MC, 2.0mm in NEG. Conclusion: Acute stroke patients with large artery atherosclerosis had severer atherosclerotic plaques in carotid artery. In patients with acute cere-

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bral infarction, carotid plaque evaluation by ultrasound may be helpful for etiologic classification. P351 The impact of alpha2-adrenergic receptor subtypes on stroke outcome after transient middle cerebral artery occlusion in mice S. Braeuninger, M. Brede, L. Hein, C. Kleinschnitz, G. Stoll Julius-Maximilians-Universitaet (Wurzburg, DE); Albert-Ludwigs-Universitaet (Freiburg, DE) Objectives: Alpha2-adrenergic receptors have been reported to mediate neuroprotective effects, but the role of receptor subtypes has not yet been addressed.We studied the role of the different alpha2-adrenergic receptor subtypes in experimental stroke using transgenic mice and assessed the effects of the alpha2-adrenergic receptor agonist clonidine. Methods: Transgenic mice with deletions of the alpha2-adrenergic receptor subtypes alpha2A, alpha2B, alpha2C and alpha2A/C, and wild-type (wt) animals were subjected to transient focal cerebral ischemia with or without clonidine pre-treatment. The right middle cerebral artery (MCA) was transiently occluded using an intraluminal monofilament. After 1 hour, the occluding monofilament was removed to allow reperfusion. Brains were harvested, brain slices stained with triphenyl-tetrazolium chloride, and the infarct volume was determined as percentage of the contralateral hemispheric volume. Moreover, the mean arterial blood pressure was measured in the right common carotid artery by a miniature pressure catheter. Data were statistically analyzed using 2-way ANOVA with post-hoc Bonferroni’s test (infarct volumes) and Kruskal-Wallis tests with post-hoc Dunn’s test (haemodynamic parameters). Results: Surprisingly, infarct volumes in wt mice with as compared to without clonidine pre-treatment did not differ. Without clonidine pre-treatment, infarct volumes in alpha2A-knock-out (ko), alpha2B-ko, alpha2C-ko and alpha2A/C-ko were similar to wt mice. After clonidine pre-treatment, however, the infarct volumes of the alpha2A/C-ko mice (mean, 30.2 %) were significantly smaller than the infarct volumes of alpha2B-ko mice (mean, 50.3 %),alpha2C-ko mice (mean,55.8 %) and wt mice (mean,53.7 %); the difference to alpha2A-ko mice (mean, 46 %) did not reach statistical significance. Clonidine pre-treatment caused a significant decrease of the mean arterial blood pressure in all groups except alpha2A/C-ko mice. Conclusion: After transient MCA occlusion, no neuroprotective effect of clonidine could be demonstrated, which is in contrast to reports in the literature. This is corroborated by the fact that infarct volumes did not increase in any of the different ko mice compared to wt animals. The smaller infarct volumes in alpha2A/C-ko mice after clonidine pre-treatment may well be explained by lack of blood pressure decrease. Thus, it is mandatory to monitor haemodynamic parameters in parallel to stroke assessment. P352 Degradation of extracellular RNA by intravenous RNase reduces brain oedema and provides neuroprotective effects in ischaemic stroke T. Gerriets, M. Walberer, S. Fischer, C. Friedrich, G. Bachmann, C. Mueller, E. Stolz, F. Blaes, M. Tschernatsch, K. T. Preissner University Giessen (Giessen, DE); Kerckhoff-Clinic (Bad Nauheim, DE) Objective: Recent studies indicate that release of intracellular RNA during ischemic cell necrosis exerts deleterious effects within the surrounding tissue. This novel and hitherto unrecognized mechanism leads to VEGF-mediated blood-brain barrier (BBB) damage and thus contributes to ischemic brain damage in acute stroke (S. Fischer et al. Manuscript submitted). Extracellular RNA can be degraded by RNase. The present study aimed to determine potential neuro-protective and oedema-protective effects of intravenous RNase application in vivo. Methods: 46 Wistar-rats were randomly assigned to 2 groups (placebo or 42μg/kg RNAse). Middle cerebral artery occlusion (MCAO) was performed 10 minutes after i. v.-drug injection. MRI (Bruker PharmaScan 7.0 T) was carried out 4 h and 24 h after MCAO. Infarct volume was determined on T2and diffusion weighted images. T2-relaxation time (T2RT) was calculated in regions of interest to quantify vasogenic oedema-formation. Oedema was furthermore determined by measuring the absolute brain water content using the wet-dry method. Results: Intravenous application of RNase was well tolerated. Mean infarct volume was significantly reduced 4 h and 24 h after ischemia (4 h: 11.7 % ± 5.5; 24 h: 24.8 % ±8.7) compared to placebo (4 h: 21.6 % ±11.5; 24 h: 36.8 % ±11.5). T2-RT was slightly reduced after 4 h (p> 0.05) and significantly reduced after 24 h (p < 0.05) as compared to placebo. Absolute brain water content was highly significantly reduced by RNase (p < 0.0005). Conclusion: The present study corroborates the recently discovered mechanism of RNA-mediated blood-brain-barrier (BBB) damage. RNase-

treatment, however, did not only reduce vasogenic brain oedema but also significantly reduced infarct volume. Further research should explore the therapeutic potential of RNase in stroke and other diseases leading to BBBdamage, such as brain trauma or tumour. P353 Testing procedure for lumen quantification of in-stent restenosis using magnetic resonance imaging G. Schoenwald, A. Melzer, G. Schaefers University of Applied Sciences FH Gelsenkirchen (Gelsenkirchen, DE); Universities Dundee & St Andrews & Ninewells (Dundee, UK); MR:comp GmbH (Gelsenkirchen, DE) Objectives: This study evaluated a test procedure for quantification of instent restenosis under MRI. Methods: 3 carotid stents (30–34 x 8mm) have been investigated consisting of different materials and stent designs (Strecker Tantalum (open cell), Boston Scientific; Nitinol Precise RX and 316L Palmaz Genesis, both (closed cell), Cordis).An appropriate material (non-disclosed due to confidentiality) for simulating the artificial in-stent restenosis has been pre-selected by comparison of different materials T1 parameter with vascular tissue of a pig’s aorta at 1 and 1.5 Tesla. The stents were placed in silicone tubes. Artificial stenosis of 50 %, 75 % and 90 % of the diameter were built into the stents. Reference tubes without stents were used. The tubes were positioned in a static phantom. All were filled with 0.9 % NaCl solution. Stents were placed with axes parallel to the static magnetic field into the head coil of the 1 Tesla MR system (Intera, Philips Medical Systems). We ran gradientecho, T1- & T2weighted spinecho (SE) and 3D balanced Fast Field Echo (b3DFFE) pulse sequences. Signal intensities in- and outside the stents were measured in the MR image using DICOM tools.Artifacts were rated qualitatively. In a second test with same sequences, the NaCl solution inside the tubes was doped with a clinical dose (0.2 mmol/kg) of contrast medium (Gadovist, Schering, Berlin, Germany). Results: According to each stent type different results appeared. The rest lumen was covered by artifacts within the 316L stainless steel stent. The Nitinol stent reduced the signal of the rest lumen, thus no evaluation was possible. In spite of signal reduction the artificial restenosis were visible in the T2SE only. 50 % artificial stenosis resulted in 43 %; 75 % stenosis owned a degree of 69 %; 90 % stenosis was depicted with 81 % of the diameter. The Tantalum stent produced the lowest artifacts, thus measurements of the different stenosis were possible. Using the b3DFFE, the Tantalum stent was depicted with actual value at 50 % and 75 % degrees of stenosis. Merely with 90 % there was a divergence of 2.5 % resulting in 87.5 % depicted stenosis. Conclusion: This test procedure allows a quantitative determination of in-stent restenosis by analysis with MRI. It is obvious, that the stent material has great influences on the visibility of an in-stent restenosis. With the choice of a low-artifact stent material and a design with low RF shielding, a quantification of an in-stent restenosis is possible. Gregor Schaefers is shareholder and managing director of MR:comp GmbH; Gerrit Schoenwald is student of University of Applied Sciences FH Gelsenkirchen and employee of MR:comp GmbH P354 Thiamine deficiency: a frequent misdiagnosis of central nervous system complications of gastroplasty. Two case reports E. Soulaeva, V. Sansone, L. Morricone, B. Ambrosi, G. Meola IRCCS Policlinico San Donato (Milan, IT) Objectives: Vitamin deficiency disorders may complicate medium- and long-term outcome of surgical procedures due to morbid obesity. Neurological disorders due to vitamin deficiency are not infrequent but may be subtle and underestimated. We describe 2 patients in whom the diagnosis was delayed. Methods: Patient 1: 62-year-old obese female subjected to gastrostomy 5 months prior, complicated by persistent vomiting, was referred for neurological evaluation because of fatigue and proximal muscle weakness. Neurological examination showed proximal atrophy and grade 4+ MRC shouldergirdle and grade 3+ limb-girdle weakness. Tendon reflexes were absent. Reduced sensation in the feet was observed. Laboratory tests showed: normocytic normochromic anaemia, hypokalemia; EKG: tachycardia, premature atrial complexes, left bundle branch block, left ventricle hypertrophy; Muscle biopsy: type II fibers atrophy; EMG at onset showed membrane instability. The diagnosis of muscle channelopathy was made. Patient 2: 39-year-old obese type II diabetic female subjected to gastrostomy 3 months prior, with persistent vomiting, was referred for neurological evaluation because of psychomotor delay. Initial neurological examination was unremarkable except for slowed thinking and apathy. The diagnosis of

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depression was made. The clinical picture deteriorated within 20–24 hours: the patient became unresponsive; there was ocular rowing, ophthalmoplegia and grade I nystagmus. Respiratory insufficiency, significant decrease in blood pressure and high temperature were observed. Iv thiamine supplementation was started because of the comatose state of unclear origin. Laboratory tests showed: normocytic normochromic anaemia, alkalosis, hypokalemia, hyperglycaemia; EKG: left bundle branch block. The diagnosis of possible encephalitis was made. Results: Patient 1: Repeat EMG showed axonal sensory motor polyneuropathy. She was treated with thiamine supplementation and presented a slow but steady improvement of proximal weakness and reduced sensation. Patient 2: CSF was normal. Two days after thiamine iv supplementation the patient regained consciousness and neurological examination improved significantly. Brain MRI showed findings consistent with Wernicke encephalopathy. Conclusion: We suggest that B1 vitamine replacement shoud be included in a screening protocol after gastroplasty. The surveillance is important because thiamine deficiency is a potentially reversible medical emergency if readily recognized.

Clinical neurophysiology P355 Effect of hemispheric dominance on motor cortical representation of upper limb muscles: a study using transcranial magnetic stimulation R. Chieffo, L. Straffi, F. Cerri, A. Inuggi, M. Cursi, G. Comi, L. Leocani IRCCS S. Raffaele (Milan, IT) Objectives: Focal transcranial magnetic stimulation (TMS) allows to map non invasively the muscle representation over the motor cortex. The aim of our study was to investigate the effect of hemispheric dominance on the cortical representation of several upper limb muscles. Methods: Motor cortical mapping of the two hemispheres using focal TMS, with simultaneous recording of four upper limb muscles (abductor pollicis brevis–APB; abductor digiti minimi–ADM; extensor carpi radialis–ECR; biceps) was performed in 14 healthy volunteers subdivided in two groups: 7 right-handers (RH) (4 males, age 27 ± 4.5 yrs) and 7 left-handers (LH) (3 males, age 25±1.2 years). The intensity of stimulation was 15 % above the lowest motor threshold (MT) for obtaining motor evoked potentials (MEPs) in any of the four muscles tested. MEPs amplitude and number of responsive sites were determined for each muscle. Hand performance was measured with finger tapping (FT). Mirrors to maximal voluntary isometric contraction were searched with electromyographic recordings. Results: MEPs were obtained only in the 3 more distal muscles (ADM, APB, ECR). The dominant hemisphere had a higher representation compared to the non-dominant in both groups concerning map area (RH:p = 0.0001; LH:p = 0.001; Paired T Test), and only in RH group concerning MEPs amplitudes (p < 0.0001; Paired T Test). A significant group effect was present on the inter-hemispheric difference of map area (p = 0.02; ANOVA), which was higher in RH, but not on MEPs amplitude. Mirror movements were observed to movement of the non-dominant hand in 6 RH and in 1 LH, and to movement of both sides in 5 LH. FT and NHPT were faster in the dominant compared to the non dominant hand in both groups (p < 0.04; ANOVA) and the FT inter-side difference was significantly greater in RH compared to LH (p = 0.006; ANOVA). Conclusions: our finding of higher motor cortical representation in the dominant compared with the non-dominant hemisphere, consistent with previous neuroimaging and TMS mapping studies, may be determined by plastic changes related to a preferred use of the dominant hand, or may develop early during ontogenesis. Our finding of a greater asymmetry in cortical representation, motor performance and tendency to mirror, all in favour of the dominant hemisphere, in right-handers compared to left-handers, may be related to a greater inter-hemispheric inhibition of the dominant over the non dominant hemisphere

Methods: Twenty-four patients, who met the clinical criteria for MCI, 20 patients with AD and 17 elderly controls were included. They all underwent power analysis of resting 64-channel EEG, using LORETA, and event-related potentials to odd-ball paradigm. MCI underwent subsequent neuropsychological evaluation every 6 months for 24 months. On the basis of the evolution, the whole MCI group was divided into converters (n = 14) and nonconverters (n = 10). Results: Oddball task: MCI converters showed, compared to normal subjects, increased latency (p = 0.018) and decreased amplitude (p = 0.008) of N200 and P300 (p = 0016) and, compared to MCI nonconverters, decreased N200 amplitude (p = 0.027). Compared to controls, AD patients had increased latency of N200 (p = 0.025) and P300 (p = 0.020), and decreased amplitude of P300 (p = 0.027). MCI nonconverters did not show significant differences compared to controls. EEG power: Compared to normal controls, alpha power (8–12 Hz) was significantly decreased in MCI converters in the left inferior temporal gyrus (BA 20) and in AD in the left parahippocampal gyrus (BA36) bilaterally. MCI nonconverters had decreased beta3 (22–30 Hz) in the precuneus (BA7) bilaterally. MCI converters, compared to nonconverters, had increased theta (4–7Hz) in the left middle occipital gyrus (BA19). Conclusions: MCI patients who will convert to AD have some neurophysiological abnormalities resembling those of AD which, if validated, may have a predictive value in the prognosis of MCI concerning the future conversion to AD. P357 Reaction time changes induced by transcranial magnetic stimulation: differential effect of single pulse versus paired pulse protocols O. Soto, H. Kumru, J. Valls-Solé Teknon Medical Center (Barcelona, ES); Hospital Clínic (Barcelona, ES) Introduction: In movements in response to external stimuli, the application of single pulse transcranial magnetic stimulation (TMS) to the contralateral motor cortex during the preparatory phases of movement is known to modify the latency of the response. Stimuli applied during early time-points of the reaction time interval produce a shortening of the reaction time (RT) whilst stimuli given during late time-points result in RT prolongation. The first is usually attributed to inter-sensory facilitation while the second is attributed to delayed execution of the motor program. Little is known regarding the effect on RT of paired pulse stimulation protocols that produce short-interval intracortical inhibition (SICI). Objectives/aims: To examine whether there exists a differential effect of single or paired pulse TMS protocols on RT. Material and methods: In 9 healthy adult subjects (4 women/5 men),aged 23–55 we applied single pulse TMS (spTMS) and paired pulse TMS (ppTMS) during the RT interval in simple and choice RT paradigms (SRT and CRT, respectively). In spTMS the intensity used was 1.2*resting motor threshold. In ppTMS the same stimulus was preceded 2.5 ms earlier by a stimulus of an intensity of 0.8*active motor threshold. The time points of TMS where at stimulus presentation and at 125 ms, 100 ms, 75 ms, 50 ms, and 25 ms preceding the expected onset of electromyographic activity. We computed the cumulative response probability (CRP) curves at each time point and in each curve computed the RT50 as the 10 ms interval in which the response probability reached 0.5. All CRP curves were normalized to the non-stimulated condition. Results: In both SRT and CRT conditions we observed that the application of TMS resulted in a shift of CRP curves, though there was no difference in the RT50 between the SRT and CRT conditions (t-test, p> 0.05). As expected, stimuli during early time points of the RT interval produced a shortening of RT latency, while those applied later produced a prolongation. Significantly, the use of ppTMS resulted in an attenuation of RT prolongation (mean RT50 difference at spTMS versus ppTMS, t-test, p < 0.01). Discussion: The application of stimuli that activate inhibitory cortical networks counteract the delaying effect of TMS on RT. This effect may be in part related to the different size of the induced descending volleys and/or to quicker resetting of the motor cortex to allow the execution of motor programs.

P356 Neurophysiological findings in mild cognitive impairment prior to conversion to Alzheimer’s disease S. Velikova, G. Magnani, N. Amato, M. Falautano, A. Barbieri, R. Mossini, C. Vismara, G. Comi, L. Leocani IRCCS San Raffaele (Milan, IT)

P358 Voluntary head motor control: on-line vestibular feedback via the cerebellum N. Lehnen, U. Büttner, S. Glasauer Ludwig-Maximilian-University (Munich, DE)

Objective: Mild cognitive impairment (MCI) is considered as a frequent prodromal phase of Alzheimer disease (AD). The aim of our study was to assess neurophysiological markers predictive of MCI evolution.

Objectives: We have recently shown that vestibular feedback is crucial for the on-line guidance of voluntary head movements. Patients with bilateral loss of vestibular function are unable to compensate for an increase in the head

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moment of inertia; their heads start to oscillate. Here, we investigate whether the vestibular feedback loop involves the cerebellum. Methods: We increased the head moment of inertia by means of a helmet with eccentrically attached masses in five patients with cerebellar atrophy of unknown etiology (cerebellar patients).All cerebellar patients had intact peripheral vestibular function. Their head movements were compared to those of age-matched patients who have undergone complete bilateral vestibulectomy for acoustic neuroma (vestibular patients) as well as to those of healthy control subjects. Eye and head movements in space were recorded with the search-coil-in-magnetic-field technique while patients and subjects performed horizontal gaze shifts towards shortly flashed targets in darkness. Target step amplitude was ±75 and ±80 degrees. Results: Normally, head movements oscillate neither in cerebellar or vestibular patients nor in control subjects. Increasing the head moment of inertia leads to significantly more head oscillations in cerebellar and vestibular patients than in healthy control subjects. The amount of head oscillations in cerebellar patients is comparable to that of vestibular patients. Conclusion: Increasing the head moment of inertia leads to similar deficits in voluntary head motor control in patients with cerebellar atrophy and in patients after complete bilateral vestibulectomy. This indicates that vestibular information that guides voluntary head movements on-line is processed by the cerebellum. Supported by the BMBF (BCCN Munich) P359 Evaluation of central silent period evoked by transcranial magnetic stimulation in patients with spinocerebellar ataxia types 1 and 2 R. Rola, M. Rakowicz, E. Zdzienicka, M. Derejko, A. Sulek, R. Poniatowska, E. Inglot, M. Wieclawska, M. Niewiadomska The Institute of Psychiatry and Neurology (Warsaw, PL) Objectives: Spinocerebellar ataxias type 1 (SCA1) and type 2 (SCA2) are neurodegenerative disorders caused by expansion of CAG repeats. Cerebellar atrophy in SCAs is the most prominent lesion leading to balance dysfunction and limb and gait ataxia. The cerebellar degeneration also affects the cerebellocortical pathways, which may influence motor cortex excitability and intracortical inhibitory and excitatory circuits. Aim: To assess alterations in excitatory and inhibitory components of motor cortex and corticospinal projections in genetically confirmed SCA1 and SCA2 patients. Methods: Transcranial magnetic stimulation was performed on 28 patients with SCA1, 24 with SCA2 and 16 healthy volunteers matched for age, sex and height. Cortical excitability threshold (MT) at rest, central silent period (SP) during voluntary contractions, central motor conduction time (CMCT) and amplitude of motor evoked potentials (MEPs) from abductor digiti minimi (ADM) and extensor digitorum brevis (EDB) muscles were evaluated. Severity of ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS). MRI was performed to confirm cerebellar atrophy. Results: Age of disease onset in SCA1 and SCA2 groups, 33.0 ±10.5 and 30.3 ±13.1 respectively, was not statistically different, while disease duration, 7.0 ±3.9 and 12.4 ±8.0 respectively, clinical signs and ICARS revealed significant differences. MT was significantly higher in SCA1 as compared to SCA2 and the controls (p = 0.01), revealing a statistical relation to CAG. The silent period was significantly prolonged (p = 0.01) in SCA1 and SCA2 from ADM 261 ±73 msec and 175 ±47 respectively, compared to 113 in the case of the controls. A comparable SP prolongation was found from EDB in SCA1 (229 ±46) and SCA2 (225 ±46) versus the controls (134 ±76). SP lengthening did not correlate with the CAG repeats number, disease duration and ICARS. MEP amplitudes were diminished in SCA1 only from ADM. CMCT was significantly prolonged in all SCA1 patients and 30 % of SCA2 cases. More pronounced alterations in electrophysiological parameters were observed in the SCA1 patients, probably due to involvement of the pyramidal pathways. Conclusion: Our study indicates that cerebellar atrophy may modify the cortical excitability and cortical inhibitory circuits of the motor areas, which can influence motor performance in SCA patients. The research was supported by Polish Ministry of Science Grant No 3PO5B 019 24.

P360 An in vivo mouse preparation for estimation of spinal cord conduction velocity S. K. Polyzoidis, E. K. Kosmidis, N. Grigoriadis, N. Tascos, G. Theophilidis Aristotle University (Thessaloniki, GR) Objectives: Spinal pathways electrophysiological study is of extreme importance for the evaluation of relevant pathological conditions. An in vivo mouse preparation for the estimation of spinal cord conduction velocity is described here. Methods: Mice are anesthetized and fixed on a customized frame and their body temperature is maintained at 37˘C. All surgery is performed under a binocular dissecting microscope. First, the sciatic nerve of the left hind limb is exposed. Secondary, a midsagittal incision of the dorsal skin is made and the superficial muscle layers are exposed,then gently dissected away and the para-vertebral musculature is removed to expose the vertebral column. Double laminectomy is performed, caudally and rostrally along the vertical column. The animal is then transferred to a Faraday cage for electrophysiological recordings. Recording pipettes are fabricated from glass capillaries using a micropipette puller and filled with 150mM NaCl solution. The recording electrodes are lowered into the caudal and rostral openings. A “hook” electrode is used to supramaximally stimulate the sciatic nerve. The evoked compound action potential (CAP) is then recorded in two places on the spinal cord (caudally and rostrally) enabling the calculation of its conduction velocity. Results: In control experiments, the CAP velocity was estimated at 16.4±5.4 m/sec (n = 6). The CAP shape reflects the summation of the external currents generated by each activated nerve fiber and contains additional information concerning the fiber number, conduction velocities and diameter distribution as in control cases velocity is directly proportional to fiber diameter. To explore the full range of information in our signal, we apply linear algebra techniques to estimate the Conduction Velocity Distribution (CVD) from the recorded CAP. The comparative evaluation of control and non-control CVDs may quantify loss of specific diameter-group fibers, myelin defects or action potential propagation failure. Conclusion: The preparation described here offers advantages over the in vitro ones in that the nervous system remains intact, the body temperature is maintained and the stimulation is not imposed directly on the spinal cord. P361 3D kinematic analysis of upper limbs in ataxic subjects E. Milano, F. Menegoni, M. Bigoni, C. Trotti, M. Galli, A. Mauro IRCCS Italian Auxologico Institute (Piancavallo, IT); Polytechnic of Milan (Milan, IT) Objective: The aim of this study was to define a protocol for the quantification of upper limb movements in normal subjects and cerebellar ataxic patients, simple enough to be suitable for clinical application. The protocol was designed in order to characterize functional disorder and to become a quantitative evaluation tool of potential treatments. Methods: 26 normal subjects (NS, age: 43 ± 12 years) without musculoskeletal or neurological problems and 12 cerebellar ataxic patients (AP, age: 45 ± 8 years, 7 multiple sclerosis, 5 spinocerebellar ataxia) were recruited. Patients with upper limb rigidity, motor neuron signs, or peripheral neuropathy were excluded. The study was approved by the local ethic committee. Movement analysis was conducted using an optoelectronic system (VICON 460, UK) with 21 passive markers to measure the kinematics of movement. The functional task was a frontal reaching movement: each subject was seated in front of a monitor displaying the circular target (25 mm diameter); the patient-monitor distance was the 80 % of the subject arm length. Each movement was repeated 18 times (3 trials consisting of 6 movements) for each arm at self selected speed. Kinematics of upper limbs were studied and a clinical report was developed (Smart Analyzer, BTS, IT). We computed parameters about movement precision (minimum distance from target, 3D path length of the final reaching phase), movement smoothness (index of curvature, Jerk), movement velocity (number of velocity peaks, maximum velocity) and angular kinematics at shoulder and elbow. Statistical analysis was conducted using parametric and non parametric tests (P < 0.05). Results: In the following only statistically significant results are reported. Precision parameters showed that AP performed higher adjustment movements in the final reaching phase (AP: 16 ± 13 mm, NS: 8 ± 3 mm). The index of curvature was higher in AP then in NS (AP: 1.19 ± 0.19; NS: 1.07 ± 0.05) and the same was found in terms of the number of velocity peaks (AP: 3.03 ± 2.45; NS: 1.21 ± 0.34). Conclusion: The considered ataxic population show less smooth movement in terms of both index of curvature and number of velocity peaks, as-

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sociated with inaccurate movement in the final reaching phase. The proposed protocol and the associated clinical report allow the quantitative characterization the motion pattern of ataxic subjects in a non-invasive way, even if the heterogeneous considered pathologies. P362 Impairment of autonomic reflex function in phobic postural vertigo T. Nedelka, R. Mazanec, R. Cerny, R. Pourova, J. Jerabek Charles University (Prague, CZ) Objectives: The aim of our study was to assess the autonomic reflex function in patients with diagnosis of phobic postural vertigo /PPV/, a syndrome of subjective unsteadiness and illusory perturbation of posture with no signs of identifiable objective vestibular symptomatology, which is frequently associated with different forms of autonomic arousal. Methods: Short term, time and frequency domain heart rate variability /HRV/ power spectrum analysis was used to investigate the autonomic reflex function in 36 patients suffering from relapsing PPV. The group contained 9 male and 27 female patients. Results were compared to findings at 20 healthy controls. Continuous HRV measurement contained 5 minutes long recording at supine rest, followed by orthostatic test /5 minutes/ in active stand position. For the 3rd phase of the test, the patient was instructed to lie down for 5 minutes. BDI-II and Beck’s Anxiety Score questionnaires were used to evaluate the intensity of depression and anxiety in PPV patients and healthy controls. Results: The neurological findings were normal in patients and controls, without any present sign of neurootological impairment. In patients suffering from PPV, we found decreased absolute values of total spectrum power /TSP/, power spectrum density/PSD/ and both low-frequency/LF/ and high frequency/HF/ spectrum power during supine rest and orthostatic test in comparison to group of healthy controls. In group of patients, marker of sympathovagal balance /LF/HF ratio/ was elevated during supine rest, comparable when standing, baroreceptor activity /dif%LF/ response was suppressed in orthostatic test. Depression and anxiety score was normal in healthy subjects. In patients, mild to moderate depression and anxiety was observed. Conclusion: A complex dysregulation of autonomic cardiovascular reflex function was observed in a group of patients during supine rest position and orthostatic tests. Elevated values of sympathovagal balance during supine position points to the sympathetic hyperreactivity and vagal hypofunction. The cause for those findings still remains unclear, in some patients it may outcome from prolonged stress and anxiety associated with chronic dizziness. Moreover, due to impaired baroreceptor activity during stand up phase and overall decrease of cardiovascular reflex function, primary autonomic failure is most likely to be responsible for various dysautonomic symptoms associated with PPV. Results in details will be discussed. The study was supported by grant IGA MZd nr.8439–3/2005 and Ministry of Education grant VZ 00064203/6506 P363 Delayed blink reflex in Lewy bodies dementia L. Bonanni, F. Anzellotti, S. Varanese, A. Thomas, L. Manzoli, M. Onofrj University G.D’Annunzio (Pescara, IT) Blink reflexes (BR) to electric stimuli of the supraorbital nerve were recorded in 26 patients with Lewy Bodies Dementia (LBD), 26 patients with Multiple System Atrophy (MSA), 26 patients with Parkinson’s Disease (PD), with or without REM Sleep Behaviour Disorder (RBD), and in 20 patients with Alzheimer’s Disease (AD) and 20 with Progressive Supranuclear Palsy (PSP) without RBD, and compared with recordings in 30 healthy controls. BR were significantly delayed (p < 0.001) only in LBD patients in comparison with controls and with the other groups of patients. 14 (53.8 %) patients had BR latency above 2 SD of the control mean, ranging from 36.1 to 46.3 ms. BR latency was not related with the presence of RBD, while a Spearman correlation rho of 0.68 was found with scores assessing the presence of cognitive fluctuations. R2 delay was prominently (71.5 %) bilateral.

Extrapyramidal disorders P364 Pulmonary function test abnormalities in Parkinson’s disease H. Mikaeili, M. Yazdchi University of Medical Sciences (Azadi, IR); Emam Khomeini Hospital (Tabriz, IR) Background: In patients with Parkinson’s disease and – other extrapyramidal disorders, respiratory problems commonly contribute to morbidity and mortality. Aim: In order to investigate the characteristics of respiratory function tests (PFT) abnormalities in patients with parkinson’s disease. Methods: We studied PFT performed in 25 patients (male: 69 % Female: 24 %) with no history of respiratory, cardio – vascular disease and smoking and 25 non respiratory disease subjects as age matched control. We obtained Body plethysmographic measurements of lung volumes and respiratory determinations of pulmonary function test. Parkinson disease severity was evaluated by Hoehn and Yahr staging. Results: The mean age of PD onset was 58.8 ± 11.6 years. 44 % (n = 4) of patients in H-Y Group 1, and 75 % (n = 6) in group 2 and 3 and 75 % (n = 6) in group 4 and 5 had abnormal PFT values. The residual volume (RV > 120 % of normal value); Forced Vital capacity (FVC < 80 % of normal value), FEV1 / FVC < 75 % were significantly higher (P value < 0/05) in patients with PD compared with the controls. Conclusions: obstructive pattern of ventilatory abnormalities is the most common cause of PFT impairment in PD patients.The evaluation and rehabilitation of respiratory disorders should be routinely included in the management of patients. P365 Endogenous expression of erythropoietin ligand and receptor in animal model of Parkinson’s disease M. T. Yang, W. M. Fu, M. L. Chen, S. Y. Hung Taipei Tzu-Chi General Hospital (Xindian City, TW); National Taiwan University (Taipei, TW) Objectives: Erythropoietin (Epo) has been proved as a neuroprotective peptide in recent years, predominantly in hypoxic-ischemic encephalopathy model. While in Parkinson disease (PD), its role still needs to be clarified. 1methyl-4-phenylpyridinium (MPP+) has been used to induce animal model of PD. Here we will investigate the role of Epo in MPP+-induced neurotoxicity both in vitro and in vivo. Methods: For in vitro dose-dependent study, different concentrations of MPP+ were applied to the C6 cells, plated on 6-well plates. For time-dependent experiment, different durations of MPP+ treatment were applied. Then they were subjected to RT-PCR or Western blotting. For in vivo study, adult male Wistar rats (300–350 g) received stereotaxic intra-substantial nigral injection of MPP+.After 3 days, their locomotion and rotational behavior were observed, and then the rats were sacrificed by decapitation. Bilateral substantia nigra and striatum were quickly dissected out and frozen in liquid nitrogen. The samples were also subjected to RT-PCR or Western blotting. Results: The expression of Epo but not EpoR increased, both in mRNA and protein levels, in C6 astroglia cells following treatment with MPP+. Intra-substantia nigral injection of MPP+ also showed the similar results in substantia nigral region. Conclusion: MPP+ does induce the endogenous expression of Epo ligand and receptor in animal model of PD. We are doing more experiments to clarify the signaling pathway and the role of Epo in MPP+-induced neurotoxicity. P366 Myoclonus dystonia and Silver-Russell syndrome in a patient with a supernumerary ring chromosome 7 E. Guettard, M-F. Portnoi, B. Keren, S. Rossignol, S. Leu, I. El Kamel, E. Apartis, M. Vidailhet, E. Roze Saint Antoine Hospital (Paris, FR); Salpêtrière Hospital (Paris, FR); Trousseau Hospital (Paris, FR) Objective: To describe a patient myoclonus-dystonia associated with a Silver-Russell syndrome in a patient with a supernumerary ring chromosome 7. Case report: A 36-year-old man had movement disorders since the age of 17 years with progressive worsening. There was no familial history of neurological or genetic disease. On examination, he had shock-like myoclonic jerks of the upper limbs, trunk and face. In addition he had mild cervicofa-

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cial dystonia with retrocollis and increased blinking. The jerks could occur in all body position, were attenuated by voluntary movements, were not suppressed by volition and could occasionally be elicited by cutaneous stimuli. Stress, fatigue, emotion and competitive tasks increased the severity of the movement disorders. In particular, he had no mental retardation. In addition, he had features consistent with Silver Russell syndrome (SRS), including severe intrauterine and postnatal growth retardation with normal OFC, feeding difficulties in infancy, triangular face, prominent forehead, prominent low-set posteriorly rotated ears, micrognathia and brachydactily. Brain MRI was normal. Neurophysiological study showed sub-cortical myoclonus. Electromyography recording showed spontaneous bursts lasting 85–140 ms. C reflex was absent and EEG back-averaging detected no short-latency cortical potential. Mutation screening of the 12 exons and flanking introns of the epsilon-scarcoglycan gene was negative. Caryotype analysis disclosed the presence of a supernumerary ring chromosome 7. Conclusion: A maternal uniparental disomy for the chromosome 7 occurs in up to 10 % of SRS patients. Coexistence of uniparental disomy with supernumerary marker chromosomes can be related to various mechanisms: functional trisomy rescue, postzygotic reduplication, postfertilisation error or complementation. Despite a genetic heterogeneity, the genomic imprinting is likely to underlie the SRS condition in some patients with, at least, one maternally imprinted gene on chromosome 7 that controls intrauterine and post-natal growth. Dominant mutations in the maternally imprinted epsilon sarcoglycan gene, located on 7q21, are responsible for myoclonus dystonia syndrome. We propose that differential maternal imprinting can account for both myoclonus dystonia and Silver Russell syndrome in our patient due to maternal uniparental disomy of the chromosome 7. Validation of this hypothesis is under process.

P367 Subacute dopa responsive parkinsonism and hypersomnia after successful surgical treatment of aqueductal stenosis K. Kinugawa, E. Roze, I. Mari, J. F. Lepeintre, S. Leu, F. Heran, M. Vidailhet Saint Antoine Hospital (Paris, FR); Foch Hospital (Paris, FR); Fondation Rothschild Hospital (Paris, FR) Objective: To describe a patient who developed levodopa responsive parkinsonism and recurrent episodes of hypersomnia 3 months after treatment of aqueductal stenosis with ventriculoperitoneal shunt (VPS). Case report: A 48 year-old man, developed a progressive hydrocephalus due to idiopathic aqueductal stenosis. He was treated with a ventriculoperitoneal shunt.His medical history was otherwise unremarkable.After surgery he remained free of symptoms for 3 months. Within the 2 following months, he developed swallowing difficulties and dysarthria. He also complained of general slowness. In addition he had 3 episodes of unexplained hypersomnia (20 hours). On waking he complained of transient headaches, blurred vision and horizontal diplopia, lasting few hours. On examination, he had bilateral akinetorigid syndrome with predominant cervico–facial involvement, intermittent resting tremor of the left upper limb and partial Parinaud’s syndrome. The revision of VP shunt was done and brain MRI showed no reappearance of hydrocephalus.A treatment with L-dopa 300mg/day and trihexyphenidyl 6mg/day was started. He had a dramatic improvement within 2 weeks. Similar clinical features reappeared few days after the treatment was incidentally discontinued. He recovered when he took the medication again. Conclusion: There is few report of patients who developed dopa responsive parkinsonism following VP shunt for hydrocephalus due to aqueductal stenosis despite the normalization of ventricular size. The pathogenic mechanisms seems to be related to physical factors, such as increased local pressure at the midbrain and diencephalon level, with shear, torsion, or ischaemia of the nigrostriatal projection fibers. In our patient, associated Parinaud’s syndrome may be related to the pressure on medial longitudinal fasciculus. Episodes of hypersomnia may have resulted from dysfunction of posterior hypothalamus and subsequent decreased hypocretin secretion. Nowadays, in the aqueductal stenosis, the gold standard surgical option is the neuroendoscopic third ventricle cysternostomia, to avoid shunt dysfunction, and to reach a more physiological approach of the CSF circulation.

P368 Unified Huntington’s Disease Rating Scale: clinical practice and a critical approach J. Klempir, O. Klempirova, N. Spackova, J. Zidovska, J. Roth Charles University (Prague, CZ) The purpose of this study was to test the usefulness of the Unified Huntington’s Disease Rating Scale (UHDRS) in clinical practice.

The UHDRS was used to examine 45 persons with genetically diagnosed Huntington’s disease (HD) in various stages. The rate of motor involvement, cognitive deficit and reliance on nursing care rose in linear proportion to HD duration. The severity of motor involvement correlated significantly with all UHDRS subscales except for that of behavioral disorders, the rate of these disorders being unrelated to any of the parameters under study. The number of CAG triplets was inversely correlated with the age at onset of HD. Being considerably time consuming, administration of the whole UHDRS calls for interdisciplinary co-operation. For valid data acquisition, the participation of caregivers is also essential. In clinical practice it is advisable regularly to monitor the patient’s conditions and the efficacy of treatment using the UHDRS motor, functional and behavioral subscales. Cognitive tests present difficulties but, in view of the progressive cognitive deterioration in HD, they are very useful in the early stage of the disease. The UHDRS does not assess impaired voluntary motor activity, or furnish information relating to therapy, dysphagia, weight loss, sexual problems or drug abuse. Supported by a grant from Czech Ministry of Health, reg. No IGA MZ CR NR8937–4 and from Czech Ministry of Education, Research Program MSM0021620849. P369 Abnormalities of contrast sensitivity, visual fields and visual evoked potentials in Parkinson’s disease and effect of dopaminergic treatment S. Ture, I. Inci, M. Gedizlioglu Izmir Training and Research Hospital (Izmir, TR) Objective: To evaluate the effect of dopaminergic treatment on visual parameters in Parkinson’s disease (PD). Method: Twenty new diagnosed Parkinson’s patients (Group 1 = G-1) were recruited. The inclusion criteria were: absence of any neurological disease other than PD; normal ophtalmologic examination besides refractive errors. Controls were twenty healthy subjects of similar age and gender (Group 2 = G-2) in addition to 20 PD patients of at least 5 years’ duration under levodopa (LD) treatment (Group 3 = G-3). Pattern visual evoked potentials (VEP), visual fields (automated perimetry), and contrast sensitivity (Cambridge Low Contrast Gratings Scale) determinations were applied to the both eyes of all subjects. New diagnosed PD patients were put on LD treatment and the visual tests were repeated 6 months later. The results of visual tests in G-1, prior and after treatment were compared to the results of G-2 and G-3 in addition to comparison of G-2 to G-3 using Student’s t and Schafeer tests, variant analysis, SPSS 13.0. Results: VEP: Of the values prior the treatment, the difference between 32 size VEP latencies of right eyes, and 64 size VEP latencies of left eyes of G1 and G-2 were statistically meaningful. Visual field: The MD values of all eyes of G-1 were different from G-2 in the first evaluation. Contrast sensitivity (CS): The mean values of CS scales in G-1 prior to treatment were meaningfully different from G-2. CS scores had increased after treatment. After 6 months’ treatment the differences in all vysual tests from both G1 prior to the treatment and G-2 had dissappeared. The results of all of the tests were markedly abnormal in G-3 and statistically different from both G-1 and G-2. Conclusion: The most prevalent of chemical transmitters of the human retina is dopamine. Some abnormalities of vision in PD increasing with the duration of the disease has been long recognized. We have found that both newly diagnosed and old PD patients exhibited abnormalities. CS and visual field determinations were the most sensitive parameters of visual involvement. However VEP was not consistently abnormal, and somewhat insensitive. Early vysual abnormalities could be reversed with LD treatment in early PD patients, but not in late ones. LD treatment might have a clearcut, but transitory effect probably early in the disease on visual parameters. These objective visual abnormalities may explain the vague visual complaints of PD patients which are usually overlooked. P370 Deep brain stimulation for movement disorders in a university hospital, Greece J. Ellul, E. Markaki, G. Klironomos, S. Marousi, C. Assimakopoulos, C. Constantoyannis Patras University Hospital (Patras, GR) Objective: We describe our initial experience using Deep Brain Stimulation (DBS) for patients(pts) with Parkinson’s disease(PD), dystonia and Essential tremor(ET).

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Methods: Twenty three patients (18 PD pts, 3 dystonia pts and 2 ET pts) underwent DBS surgery between 2004 and 2006. The Parkinson’s disease patients presented with on-off fluctuations, severe rigidity and tremor. The symptoms were resistant to any medical treatment. The patients affected from PD underwent bilateral subthalamic nucleus DBS (STN DBS) in 17 cases and unilateral Ventral Intermediate Nucleus DBS (Vim DBS) in 1 case. The patients affected from dystonia (2 secondary hemidystonias and 1 generalized dystonia) were treated by Internal Globus Pallidus DBS (GPi DBS) in 2 cases and by thalamic nucleus Ventrooralis (Voa DBS) in 1 case. The ET patients presented with bilateral upper limp tremor, resistant to any medical treatment. The stereotactic implantation of electrodes was performed using preoperative MRI for target identification, intraoperative Microelectrode recordings (MER) and Stealth Station neuronavigation for planning. Results: All patients with PD in this series experienced improvement in their symptoms. The clinical improvement of UPDRS III with DBS ranged from 42 to 79 %. The mean L-dopa administration decreased postoperatively by 55 %. There was a 82 % decrease in the duration of the –off- state after surgery. The tremor of the patients in the ET group was totally abolished. On the other hand only one of the patients with secondary dystonia experienced clinical improvement (the BFM dystonia scale improved by 76 %). There were no complications or side effects intraoperatively. One patient experienced an infection of the pulse generator which required treatment with antibiotics and finally revision surgery. Conclusion: DBS surgery is an effective treatment in Parkinson’s disease and Essential tremor patients. It improves the quality of life of patients and their caregivers. In the secondary dystonia group the results were less impressive. P371 Bilateral striopallidal calcinosis and parkinsonism in a case of Gorlin syndrome B. Habermeyer, K. Weier, A. Gass, P. Fuhr, I. Lotz-Bläuer, F. Müller-Spahn University Hospital Basel (Basel, CH) Objectives: Gorlin-Syndrome (GS) is an autosomal dominant inherited phacomatosis but nearly 50 % of all cases are new mutations. Typical findings in GS include basal cell carcinomas, odontogenic keratocysts, palmar and plantar pits and calcification of the falx cerebri. Intracranial calcification of the cerebellar tentorium, petroclinoid ligaments, dura, pia, choroids plexus and basal ganglia have been described, however these cases did not show associated clinical symptoms. We report a case of Gorlin-Syndrome with bilateral striopallidal calcinosis and progressive parkinsonism. Case description: A 70 year old woman with Gorlin syndrome was treated with Chlorpromazine and Fluphenazine for delusion and depression since the age of 30. While during more than 35 years of antipsychotic treatment no features of extrapyramidal disease were seen, she developed a hypokinetic rigid syndrome with tremor in 2004, which responded to L-Dopa for 9 months. In 2004 brain MRI (T1, T2, Flair) showed no abnormality of the basal ganglia. During disease progression she developed vivid dreams as a side effect on L-Dopa while the treatment response to L-Dopa decreased. Follow up brain MRI (T1, T2, Flair and T2*) in 2006 showed symmetrical striopallidal calcinosis of 2x1,5 cm size and lateral to the putamen a thin hyperintense lining medially and laterally suggesting local atrophy in this region. After change of medication to 50mg Quetiapine parkinsonian features remained unchanged (UPDRS III score 44). Discussion/Conclusion: We present a patient with GS who in parallel to the development of a Parkinson’s syndrome also developed quite extensive striopallidal calcifications over 2 years. An influence of long term antipsychotic treatment cannot be ruled out completely. However the parallel development of calcifications and clinical symptoms is an interesting observation and both the speed of the development of calcifications and its presence in GS point to possible pathophysiology of the Parkinson syndrome. P372 Influence of psychosocial factors on cervical dystonia S. Ochudlo, L. Drzyzga, K. Drzyzga, G. Opala Silesian Medical University (Katowice, PL) Background: Spasmodic torticollis – a disease classified as a form of focal dystonia – is characterized by variable severity of symptoms and high susceptibility to the influence of various psychosocial and environmental factors that are capable of alleviating as well as aggravating the disease. Aim: To select the most modifiable factors and to classify them as 1) alleviating, 2) aggravating, and 3) neutral. Material and methods: On the basis of case histories and the literature data we selected twelve factors that were likely to affect disease severity. The

questionnaire was filled out by 33 patients with cervical dystonia. The assessed factors were: 1) relaxation, 2) sleep, 3) stress, 4) physical activity, 5) tiredness, 6) emotions, 7) social meetings, 8) high temperature, 9) low temperature, 10) alcohol, 11) cigarette smoking, 12) time of day. The possible answers for questions 1–11 were: a) alleviates, b) aggravates, or c) has no influence on the disease. Results: The obtained answers enabled us to divide the factors into 3 groups: 1) alleviating factors: relaxation, sleep, high temperature, 2) aggravating factors: stress, physical activity, tiredness, emotions, social meetings, low temperature, 3) neutral factors: cigarette smoking, alcohol. Moreover, only 12 % of patient reported greater symptoms in the morning while as many as 43 % and 45 % of subjects reported deterioration of disease in the afternoon and night hours, respectively. Conclusions: The elucidation and classification of modifiable factors influencing cervical dystonia may be helpful in the therapeutic approach to a patient in whom standard therapy (botulinum toxin) was less or not effective. Such approach could be based on the elimination of negative and the enhancement of positive factors by means of psychotherapeutic and behavioral techniques.

P373 The mtDNA A8344G MERRF mutation is not a common cause of sporadic Parkinson’s disease D. Frosini, M. Mancuso, L. Petrozzi, C. Nesti, G. Siciliano, N. Sassi, E. Unti, L. Murri University of Pisa (Pisa, IT) Objectives: Mitochondria play a central role in the bioenergetics of the cell and apoptotic cell death and mitochondrial dysfunction appears to play a role in the pathogenesis of several neurodegenerative diseases. Moreover there are evidences suggesting that mitocondrial dysfunction and oxidative stress occur in brain and peripheral tissues of Parkinson disease (PD) patients, supporting the idea that mitochondria may trigger the onset of neuronal degeneration in PD and that in selected cases mitochondrial genetic abnormalities can directly cause PD. Parkinsonism has been previously associated with mitochondrial DNA (mtDNA) mutations and very recently has been observed the association of the A8344G MERRF mutation on the tRNALys gene of the mtDNA in a 66-year-old man with dopa-responsive parkinsonism, elevated CK levels and ragged red and Cox negative fibers in muscle biopsy. Aim of the study is to evaluate the presence of the mtDNA A8344G MERRF mutation in a group of sporadic PD. Methods: We have analysed 159 Italian patients (90 men, 69 women, mean age 67.51±10.57 years, range 28–84 years) with sporadic PD diagnosed according to the Gelb clinical diagnostic criteria. The mean age at onset was 56.94±10.75 years (range 19–72 years). Blood samples were drawn for DNA extraction from all patients after informed consent and the restriction fragment length polymorphism-RFLP-analysis for the A8344G point mutations was performed by standard method. Results: None of the patients carried the A8344 mutation in peripheral blood lymphocytes DNA. Conclusions: Our observation doesn’t support the view that the mtDNA A8344G MERRF mutation might be a frequent cause of PD, indicating that this is a rare cause of parkinsonism in general PD population and that a screening of this mutation should be limited to patients with parkinsonism and others symptoms or signs suggestive of mitochondrial disease.

P374 Sympathetic activity during cold pressure test in patients with multiple system atrophy B. Meglic, A. Grad, A. Mesec University Medical Center (Ljubljana, SI) Objectives: Profound autonomic failure with orthostatic hypotension (OH) is predominant and distinctive feature of multiple system atrophy (MSA) and in patients with Parkinson’s disease and autonomic dysfunction (PD). Results of standard cardiovascular tests indicate autonomic failure in both groups of patients and the testing is not sufficient to distinguish between both diseases. However, patients with MSA exhibit supine hypertension, which is driven by residual sympathetic activity. Among tests for peripheral sympathetic function, reduced increase of blood pressure during cold pressure test (CPT) was reported as typical in patients with autonomic failure. We describe a group of MSA patients with orthostatic hypotension, who had normal/enhanched systolic blood pressure (SBP) response during CPT. Methods: 46 patients with MSA and 54 patients with PD and OH were tested in Autonomic laboratory in our institution in the period from 2002 to

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2006. The battery of cardiovascular autonomic tests was performed and results were compared to normal, age corrected references. Results: We identified a group of six patients with MSA (45 to 68 years, mean 56,1 years; 3 males), who had increase of SBP during CPT that corresponded to normal references (from 15 to 35 mm Hg, mean 22 mm Hg). The patients had symptomatic OH (mean drop of systolic blood pressure during orthostatic test was 66 mm of Hg), profound decrease in SBP during phase II of the Valsalva maneuver, the absence of blood pressure overshoot during phase IV, the reduced response handgrip and severely decreased respiratory sinus arrhythmia and the Valsalva heart rate ratios. Three patients had supine hypertension. All patients with PD and OH had abnormal SBP response during CPT. When compared ratio of abnormal and normal SBP response during CPT in both groups of patients, the difference reached p < 0.01 (chi square test). Conclusion: Some patients with MSA have normal or even enhanced response of SBP during cold pressure test. Residual sympathetic activity is the most probable cause of such response, which is not present in patients with PD and OH. P375 “Hot cross bun” sign is a valuable MRI finding in multiple system atrophy A. Fallah, H. Pakdaman, Y. Kholghi, R. Pakdaman, M. Ilkhani, K. Gharaeghouzli Beheshti University of Medical Sciences (Tehran, IR) Multiple system atrophy (MSA) is a degenerative disorder of central nervous system. A definite diagnosis is only possible at necropsy when cell loss and gliosis as well as glial cytoplasmic inclusions are found in pathologic examination. Clinically, diagnosis of MSA especially in early stages is often difficult and differentiation from idiopathic Parkinson’s disease may results a high rate of misdiagnosis. Here we report two cases of multiple system atrophy in which we found a valuable neuroimaging sign,“hot cross bun” which is apparently due to loss of pontine neurons and myelinated transverse pontocerebellar fibres with preservation of the corticospinal tracts. Our patients presented with a severe parkinsonian syndrome associated with cerebellar and urinary incontinence with orthostatic hypotension.According diagnostic criteria both patients are probable cases of multiple system atrophy and both had typical “hot cross bun” sign in their MRI imaging. P376 Oculomotor apraxia and corticobasal degeneration L. Correia Guedes, M. Coelho, S. Madureira, M. Guerreiro, J. Ferreira, M. M. Rosa Hospital de Santa Maria (Lisbon, PT) Corticobasal degeneration (CBD) usually presents with apraxia, mostly in the form of ideomotor and limb-kinetic apraxia. CBD is the parkinsonian syndrome most frequently associated with this phenomenon, but others, and mostly progressive supranuclear palsy (PSP), can also present the same clinical manifestation. Eye movement apraxia is less frequently observed in CBD and typically manifests as an impaired latency of saccades equally affecting horizontal and vertical movements. Eye involvement in PSP more commonly involves vertical movements and affects velocity rather than latency of saccades. We report the case of a 66 year-old male with a clinical diagnosis of corticobasal degeneration, presenting with a symmetric akinetic-rigid syndrome and right limb dystonia that started insidiously 4 years ago, and later developing a frontotemporal dementia. Physical examination also revealed asymmetric pyramidal signs, kinetic –limb apraxia on the distonic arm, constructional apraxia and eye movement apraxia mostly involving vertical gaze, manifesting as impaired latency and velocity of saccades. Magnetic resonance imaging showed bilateral frontoparietal atrophy, more predominant on the left hemisphere. Eye movement abnormalities have been used for distinguishing between CBD and PSP. Predominant vertical gaze apraxia and the slowness of saccades in our patient example the possible clinical overlap that make the differential diagnosis between these two tauopathies harder. Our report may suggest that between these two entities it is probably the distribution of lesions and not the origin of the diseases that explains the phenotypes.

Child neurology P377 Posterior reversible encephalopathy syndrome in the paediatric population: a Montreal children’s hospital experience M. G. Ziller, B. Rosenblatt, C. Poulin University of Sherbrooke (Sherbrooke, CA); McGill University (Montreal, CA) Objective: Posterior Reversible Encephalopathy Syndrome (PRES) has been described recently in adult patients. Typical features are headache, seizures and visual disturbances. We aim to describe the characteristics of patients with PRES in a large urban paediatric centre. Methods: We searched hospital and departmental records between 1995 and 2006 for patients compatible with PRES and analysed clinical, electrophysiological and radiological features. Results: We identified 7 patients with age ranging from 6–18 years. All patients presented with arterial hypertension (range 135–200 mmHg systolic, 65–120 diastolic). Clinical manifestations included seizures (n = 5), headache (n = 4), confusion (n = 2), hemianopsia (n = 1), visual hallucinations (n = 1) and expressive aphasia (n = 1). Underlying conditions were renal (focal glomerulosclerosis, lupus nephritis, vasculitis and immediate post-transplant period) and treatment of Acute Lymphocytic Leukemia (n = 2). Patients were receiving calcineurin-inhibitors (n = 2), cyclophosphamide (n = 1) or intrathecal methotrexate (n = 2). On MRI, all patients displayed abnormal T2/FLAIR hyperintensity in the posterior areas, but also in the frontal and temporal lobes, complicated by an intraparenchymal bleed and secondary ischemia in one patient. Symptoms resolved within 3 days to 2 months, but one patient died of multi-organ failure and one requires continued anticonvulsive treatment. Conclusion: Paediatric patients with PRES have severe underlying systemic conditions complicating diagnosis and treatment. MRI abnormalities can be found in the parieto-occipital regions, but also in frontal and temporal lobes. Intraparenchymal bleeding can complicate the clinical course. Treatment is antihypertensive and anticonvulsive. The clinical prognosis is generally favorable, but outcome may be affected by the underlying conditions.

P378 Hot water reflex seizures M. Gandea, O. Tarta-Arsene, I. Minciu, S. Magureanu Clinical Hospital Al.Obregia-Bucharest (Bucharest, RO) Purpose: Hot water reflex seizures are determined by complex tactile stimulation through pouring hot water over the head during bathing. This kind of seizures could be part of reflex epilepsy or not. The aim of this study is to analyze the characteristics and evolution of these seizures. Methods: This presentation is a parallel of clinical and paraclinical features of those patients with reflex seizures to hot water, evolution for a period of 2 years, outlines the common characteristics and comparisons with the results from the anterior studies. Results: Hot water epilepsy was diagnosed in 3 boys with ages varying from 4 to 9 years old. They had partial complex seizures during pouring hot water over their head, and one patient was diagnosed as reflex epilepsy. All patients showed modified intercritical EEGs, but cerebral imaging exams were normal. It was used practical measures of avoiding pouring the hot water directly on the head for all patients, but the seizures persisted even this way, and it was used the antiepileptic treatment – carbamazepine. Only the patient with reflex epilepsy had a favorable evolution. Conclusions: Hot water reflex seizures are not very frequent epileptic seizures, with a benign evolution only for the patient with reflex epilepsy and a “malignant” evolution for the rest of epilepsy. So, having reflex seizures to hot water is a poor prognostic factor to cryptogenic epilepsy. Further comparative studies with more patients are necessary to confirm this hypothesis.

P379 A retrospective and prospective study of tuberous sclerosis in childhood D. Plesca, F. Buruiana, R. Teleanu, A. Davitoiu, I. Stancea, L. Cretu, M. Moiceanu University of Medicine Carol Davila (Bucharest, RO); Dr. Victor Gomoiu Children’s Hospital (Bucharest, RO) Background: Tuberous sclerosis, a genetic disease inherited in an autosomal dominant manner, is part of the neurocutaneous syndromes. The disease is

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often underdiagnosed in general population and the diagnosis is established late and with difficulty, during childhood. Objectives: The present study aims to describe the clinical and imagistic characteristics in the evolution of tuberous sclerosis. For that, a statistical retrospective and prospective study involving this disease was designed. Materials and methods: From a total number of 16 986 patients with neurological problems admitted in clinic from 1996 to 2005, the authors selected a group of 25 children with tuberous sclerosis. All cases were evaluated by clinical and neurological examination, EEG, imagistic assessments and psychometric evaluation. Selected and presented cases were of particular medical interest, due to the atypical onset, the unexpected response to medication or even to their evolution and prognosis. Results: Establishing the diagnosis of tuberous sclerosis is a difficult task, confirmed at various ages (range from 5 month to 16 years). The authors compare the age at the onset of the first clinical manifestations and the age when the diagnosis was established. They quantify the main clinical aspects (cutaneous and visceral lesions, neurological impairments). Cutaneous lesions were present in 96 % of the patients, while visceral lesions were present in 64 % of the patients (cardiac involvement – rhabdomyoma in 36 %, renal involvement – renal cysts in 24 %, ocular involvement – retinal hamartomas in 8 % and optic nerve hamartomas in 4 %). There was no diagnosis of lymphoangioleiomyoma, a specific pulmonary lesion. 96 % of the patients had neurological problems (various types of seizures, severe mental retardation, behavior anomalies, sleep disturbances). Neuroimagistic assessments identified cerebral calcifications in 96 % of the patients. Seizures response to treatment was also evaluated. Conclusions: Establishing the diagnosis of tuberous sclerosis is a difficult task. The authors underline the various modalities of clinical presentation at the onset of the disease that could allow an early diagnosis and institution of the proper therapy. Tuberous sclerosis patient develop, in time, severe mental retardation, severe behavior anomalies, motor deficits, organic seizures, visceral complications. P380 Infantile spasms: aetiological and neuroimagistic aspects F. Buruiana, D. Plesca, R. Teleanu, A. Davitoiu, I. Stancea, M. Moiceanu, L. Cretu, M. Stefanescu, D. Dragomir University of Medicine Carol Davila (Bucharest, RO); Dr. Victor Gomoiu Children’s Hospital (Bucharest, RO) Objectives: Establishing the etiology and the correlation between etiological factors and neuroimagistic aspects. Material and Methods: a total of 77 infants and small children were diagnosed with infantile spasms (IS) on the basis of the three clinical and electrical criteria. Results: From a total of 77 cases, 10 (12 %) had idiopathic IS, the remaining 67 cases (88 %) beeing symptomatic.Among the cases with symptomatic IS, a great majority was associated with tuberous scerosis (15 cases-22 %), followed by the IS secundary to perinatal hypoxic-ischemic encephalopathy (14 cases-20 %), 9 cases (13 %) had anomalies of neuronal migration, of which 6 cases with lisencephaly and 3 cases with Aicardi syndrome. Other congenital CNS malformations were found in 3 cases. IS secundary to an acute CNS infection (bacterian meningoencephalitis) where found in 3 cases (4 %). Two patients had chromosomal anomalies (Down syndrome and 4p15.1 deletion) and other two had phenotipic features suggestive of chromosomal anomalies. In 25 cases (37 %) no etiological factor could be established. The analysis of the CT/RMN images revealed: periventricular calcifications (15 cases), as well as other lesions suggesting tuberous sclerosis; anomalies of neuronal migration were found in 9 patients; patients sequelae after PHIE had various lesions: porencephalitic cyst, cortico-subcortical atrophies with or without cerebral calcifications, multicystic encephalomalacy. This type of lesion was also found in patients with CNS infections and as a sequelae after a fronto-temporal hematoma. The most often encountered neuroimagistic aspect was diffuse cortico-subcortical atrophy. Conclusion: There is a great variety of etiological factors which are responsible for IS. The most frequent etiological factors found in the studied patients were cerebral malformations (including especially tuberous sclerosis) and perinatal hypoxic-ischemic encephalopathy.

P381 Malformations of corpus callosum: clinical and imaging aspects D. Patrichi, F. Buruiana, D. Plesca, I. Stancea, L. Cretu, R. Teleanu, M. Moiceanu, V. Popescu, D. Dragomir Dr. V. Gomoiu Pediatric Hospital (Bucharest, RO); Carol Davila University of Medicine and Pharmacy (Bucharest, RO) The corpus callosum (CC) is the major connection between the two cerebral hemispheres. Hypoplasis or agenesis of corpus callosum can be an isolated malformation of the central nervous system (CNS), may be associated with other CNS malformations or abnormalities of other organs. Method: From a total of 187 children diagnosed with cerebral malformations, hospitalized between 1998–2005. There were selected 37 patients with malformations of corpus callosum (MCC). The diagnosis was documented on clinical and neuroimagistic basis. Results: The analysis of the total of 37 cases with MCC demonstrated that 5 cases had different genetic syndromes that associated MCC (3 casesAicardi syndrome, 1 case-Miller Dieker syndrome, 1 case-Cornelia de Lange syndrome, 1 case-trisomy 13), 2 cases had congenital infection (toxoplasmosis). Clinical examination identified other anomalies, as follows: microcephaly (22 %), epicantus (16 %), ophtalmological defects (16 %), hypertelorism (11 %), auditory deficits (5 %), genitourinary anomalies (5 %) and macrocrania (3 %). The most frequent neurological manifestations associated with MCC were: mental retardation of different degrees of severity (68 %), epilepsy (54 %), hypotonia (16 %), language deficits (8 %). With the help of neuroimagistic investigations (CT and/or IRM), different aspects of MCC were identified: 25 cases had agenesis of CC (67,56 %) and 12 cases had hypogenesis of CC (32.43 %). In 35 % of cases MCC was isolated and in 65 % of cases it was associated with other CNS malformations. Conclusions: MCC may be associated with mental retardation, epilepsy, motor deficit, facial dysmorphism. Any child with suggestive clinical manifestations must have neuroimagistic investigations. CC agenesis associates an extremely severe clinical picture. P382 Brain magnetic resonance spectroscopy is a useful tool for the diagnosis and follow-up of argininosuccinic aciduria C. Azuar, E. Roze, C. Menuel, S. Chokron, A. Chabli, J. Häberle, R. Guillevin Saint Antoine Hospital (Paris, FR); Pitié-Salpêtrière Hospital (Paris, FR); Adolphe de Rotschild Foundation (Paris, FR); Necker-Enfants-Malades Hospital (Paris, FR); Munster University Hospital (Paris, FR) Objective: Argininosuccinic aciduria (ASA) is an urea cycle disorder characterized by hyperammonemia, elevated argininosuccinic acid in brain fluids, low argininemia and high citrullinemia. The clinical spectrum of the disease is wide from severe neonatal encephalopathy to slow progressive disorder including psychomotor retardation, epilepsy, liver dysfunction and hair abnormalities. Episodic life-threatening acute hyperammonemic encephalopathy is a hallmark of the disease and can occur unexpectedly throughout the course. Progressive form can be difficult to diagnose due to the absence of specific features and therapy may be difficult to optimize. We describe the case of an adult patient, in whom brain magnetic resonance spectroscopy (MRS) was performed before treatment and three months after the treatment was started. Case report: A 30-year-old patient presented with psychomotor retardation, epilepsy, disturbed visual perception and integration and scarce brittle dry hair. The diagnosis of ASA was confirmed by biochemical and genetic analysis. MRS showed a decreased creatine resonance peak, with an anteroposterior gradient of deficiency, consistent with the cortical visual dysfunction. Serum creatine concentration was in the low normal range suggesting a secondary selective creatine defect in the CNS. She was treated with low protein diet, arginine supplementation and benzoic acid.After 3 months, the creatine peak went back to normal, and cognitive functions were markedly improved. Conclusion: We hypothesized that ASA patients have a functional impairment of the creatine synthetic pathways secondary to arginine depletion and/or hyperammonemia. Primary creatine deficiency results in progressive encephalopathy, and creatine was found to be neuroprotective in rodents. We thought that a selective brain creatine deficiency may play a role in CNS impairment observed in ASA and may be reversible under treatment. This report suggests that brain MRS analysis is a useful tool for the diagnosis and follow-up of patients with ASA.

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P383 Chediak Higashi syndrome, a study of one case I. Ben Hamouda, N. Ben Ali, M. Fredj, A. Mrabet Charles Nicolle Hospital (Tunis, TN) Introduction: Chediak Higashi syndrome (CHS) is a rare recessive autosomic disease due to lysosomial membrane fusion abnormality encoded by LYST gene 1q42.1q42.2. It includes ocular, cutaneous, neurological, haematologic disturbances and increased infectious susceptibility. Observation: We report the case of a 6 years old girl who presents an encephalopathy with generalized epilepsy, psychomotor delay, instability; partial oculocutaneous albinism; splenomegaly; cervical adenopathy; torpid cheek infection. Clinical history reveals recurrent cutaneous and bronchopulmonar infections. Cerebral magnetic resonance imagery shows periventricular T2 hyper signal white matter. On biology we note anaemia, thrombopenia, function platelet and immunity disturbances. Polarized light hair analysis and molecular study confirm the diagnosis of CHS. Discussion: The association neurological signs, partial albinism with immunodeficiency are evocative of CHS, which must be confirmed by ophthalmologic examination and hair microscopic analysis, haematological and molecular study. Neurological features of CHS could be peripheral (polyneuropathie, cranial nerve palsy) or central (epilepsy, mental delay, ataxia, dementia, parkinsonism . . .). They results from lymphocytes and histiocytes accumulation in nervous tissues. CHS evolves to death after a phase of acceleration in 85 % of cases. This phase is announced by polynuclear giant intracytoplasmic inclusion accumulation, evidenced on blood smear and myelogram, concomitant to clinic aggravation with lymphoproliferative syndrome, pancytopenia and haemorrhages. Conclusion: Chediak Higashi syndrome is a rare but severe multisystemic pathology. An early diagnosis permits the possibility of precocious treatment by a bone-marrow graft, actually sole mean able to ameliorate vital and functional prognosis. P384 Cerebellar activation during syllable repetition and reading tasks – a comparative fMRI-study in adults and children C. F. Schorn, M. Frings, A. Dimitrova, H. G. Elles, C. Hein-Kropp, E. R. Gizewski, D. Timmann Universitätsklinikum Essen (Essen, DE) Dysarthria following cerebellar tumor surgery in childhood is a rare sign (Richter et al. Brain Lang 2005; 92: 153–167). Probably this is due to the fact that most tumors affect the medial and inferior parts of the cerebellum leaving areas of the superior paravermal cerebellum unaffected which are known to be important in motor speech control in adults. The aim of this study was to evaluate whether the same cerebellar areas are employed in adults and children in speech motor control using functional magnetic resonance imaging (fMRI). Healthy right-handed adults (7 female, 6 male) and children (age between 9–12 years, 4 female and 2 male) were included in this study. The study included five condititions. A block design was employed. The first condition was loud (overt) repetition of the syllables “Ba, Da and Ga” synchronized to auditory stimuli with a frequency of 1 Hz each. In contrast the second task was silent (covert) repetition of the syllables without using tongue or lips. The reading task consisted also of an overt and a covert condition. In brief subjects were asked to read loudly or silently substantives presented via a beamer. The last condition was passive listening to the tone. FMRI analysis revealed activation particularly of the superior paravermal parts of the cerebellum (lobules H VI and Crus I) for the syllable repetition and reading tasks in both adults and children. Activation was bilateral with no clear lateralisation. The pattern of activation for mostly automatised tasks (syllable repetition) was not different in comparison to higher speech motor control functions (reading). The activation was higher for overt speech in comparison to covert (inner) speech for both conditions. In sum, speech motor control related areas were the same in children and adults involving predominantly superior paravermal areas. Dysarthria is likely a rare sign following tumor resection in childhood because tumors affect most frequently the medial-inferior cerebellum and spare the superior cerebellum. Acknowledgments: Supported by DFG Ti 239/5-2.

P385 Acute transverse myelitis in children R. I. Teleanu, D. M. Teleanu, D. Bosoncea, D. Plesca, D. Dragomir Dr. V Gomoiu Children’s Hospital (Bucharest, RO); Emergency University Hospital (Bucharest, RO) Introduction: Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, in which an immune-mediated process causes neural injury to the spinal cord resulting in motor, sensory, and autonomic dysfunction. ATM may exist as part of a multifocal cerebral nervous system disease, a multisystemic disease, or as an isolated, idiopathic entity. Patients and methods: We present two cases of acute transverse myelitis in children. First case, a 6 years and 8 month old boy who developed flaccid paraplegia, 48 hours after an acute infectious respiratory disease. Second case, a 15 years old girl, presented urinary incontinence and lower limb paralysis, 14 days after rubella vaccination. Results and discussions: Both children, accomplished inclusion criteria for idiopathic acute transverse myelitis and magnetic resonance image revealed a transverse myelitis aspect. Acute myelopahies are rare in children and because of this, often the diagnosis is delayed. Using a diagnostic algorithm will likely lead to improve care and initiate a precocious and effective treatment. P386 Relationship between oral imitation and primitive reflexes in patients with severe brain damage T. Go, Y. Konishi Tokyo Women’s Medical University, JST-CREST (Tokyo, JP) Objectives: Babies have been shown to reproduce mouth opening and closing in response to an adult model without visual feedback of their own behavior as early as a few hours after birth. This oral imitation disappears at about 2- to 3-months of age possibly due to the development of cortical control and reappears in patients with severe brain damage (Go T. et al. Neonatal oral imitation in patients with severe motor dysfunction. European Academy of Pediatrics 2006 Book of Abstracts p.34). In this way, it is considered to be something similar to primitive reflexes. This time, the relationship between primitive reflexes and oral imitation was studied in patients with severe brain damage. In addition, brain computed tomography (CT) and electroencephalogram (EEG) were investigated to evaluate residual cortical function in some patients. Methods: Nine patients with cerebral palsy, from 4 years to 39 years, were included in this study. Three were male and six were female. They were able to vocalize but did not speak a single word. Their physical ability was limited depend on the severity of their disease. Sucking and rooting reflexes were chosen as representatives of primitive reflexes because the mouth was their effector organ similarly in oral imitation. Sucking and rooting reflexes and oral imitation were examined in each patient. Oral imitation was examined after slowly singing their favorite songs while making eye contact with them. Patients were evaluated as being able to perform oral imitation when they opened their mouth repeatedly. Results: In seven patients, both oral imitation and primitive reflexes were positive or negative at the same time. In two patients, only one of them was seen separately. Severe cortical atrophy in brain CT and low voltage in EEG was shown in two patients with positive oral imitation and primitive reflexes together. Conclusion: Oral imitation reappears in the same brain-damaged patients with primitive reflexes and is considered to be something similar to primitive reflexes. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency P387 Clinical aspects of L-2-HGA disease in 13 Turkish children Z. Yapici, K. Alpay, D. Yalcin, H. Hanagasi, M. Eraksoy Istanbul University (Istanbul, TR) Objective: L-2-Hydroxyglutaric aciduria (L-2-HGA) is an organic aciduria with autosomal recessive inheritance, which is quite rare. Method: We present 13 Turkish patients with L-2-HGA disease. Our purpose was to assess the main clinical features of the disease, and the long-term follow-up. The diagnosis was made according to metabolic tests and MRI characteristics. The follow-up period was between 5–9 years, during which time systemic and neurological evaluations were made regularly. Developmental milestones, age at onset of first presenting symptoms, seizure types, outcome of epilepsy, and the severity of the cerebellar/ extrapyramidal findings, and cognitive levels were studied in all of the cases.

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Results: There were 7 girls and 5 boys and current age of the cases ranged from 10 to 27 years (13±5.6). The first symptom was seizures in 8 (febrile in 4), unstable walking in 2, cognitive problems in 2, and dysarthria in 1 patient. The onset age of seizures was between 7 months and 11 years. Various seizures were identified; generalized convulsions (7), complex partial (4), absance (1), and atonic (1) seizures. Mental and/or motor developmental delay were detected in all but one patient. The extrapyramidal findings were mild in 6, moderate in 1, and severe in 2 patients. The cerebellar findings were mild in 5, moderate in 5, and severe in 1 patient. Clinical course was static in 6, slowly progressive in 5, and rapidly progressive in 2 patients. Their MRIs revealed an identical abnormal pattern with subcortical leukoencephalopathy, signal changes in the basal ganglia in particular the putamina, and dentate nuclei in all of them. Conclusions: Although the clinical heterogeneity can be seen even in the same family, the clinical pattern of most of the patients with L-2-HGA seems to be consistent with moderate mental retardation, mild ataxia, and mildmoderate dystonia/bradikinesia.Pyramidal signs may be additional finding. Seizures can ocur early in the course of the disease, however most probably may not be intractable. The clinical course tends to be slowly proggresive. P388 The development of personal deictic lexemes and morphems in children with developmental dysphasia B. Covic, S. Golubovic Institute for Experimental Phonetic & Speech Pathology (Belgrade, RS); University of Belgrade (Belgrade, RS) Developmental dysphasia is a developmental language disorder with symptoms witch can vary according to extent and difficulties. With the long-time usage of gests and mimics in communication child with developmental dysphasia misses the critical periods for the development whay impacts on neurobiological and psychosocial development of a child. In our clinical experiences we saw that the special problem of dysphasic child is to develop lexemes whose “out of language” content is “empty” and which are changeable in every new communicative situation in a relation with time, place and participants in communication. The inability of knowing rules and relations between elements in language system is one of the characteristics of children with developmental dysphasia. These children very rigidly string lexemes in sentences. They do not have the ability of language economics and creativity. That is the reason why they stereotypically repeat developed elements and make conclusions according to analogy. The aim of this research is to examine the development of usage personal deictic lexemes and stringed morphems in children with developmental dysphasia. The sample consisted of 45 children with developmental dysphasia (Egroup). The children are divided into two subgroups: younger children (from 3 to 5 years old) and older children (from 5 to 7 years old). The data were collected with the usage of language corpus for evaluation of deictic lexemes and morphemes usage (author Covic, B., 2006). Research results are shown in tables and in charts from which we can see that the average scores in usage of personal deictic elements of order children are statisically significantly higher than usage of these elements by younger children. Older dysphasic children showed better ability of understanding and usage of personal deictic lexemes and stringed morphemes. P389 Development of space deictic elements in children with developmental dysphasia B. Covic, S. Golubovic Institute for Experimental Phonetic & Speech Pathology (Belgrade, RS); University of Belgrade (Belgrade, RS) One of the major problems in children with developmental dysphasia in the process of language development is deficit in understanding relation between language units. The aim of this research is to examine the development of space deictic elements in children with developmental dysphasia.The sample consisted of children with developmental dysphasia(Egroup).The data were collected with the usage of language corpus for evaluation of deictic lexemes and morphemes usage (author Covic, B. 2006). Research results showed that space deictic lexemes are special problem for dysphasic children.We tested the development of understanding and usage of these lexemes in the range of 6 months. We concluded that is the optimal period for advancement in speech and language development. Children 3 and 4 years old with diagnosis of developmental dysphasia showed severe difficulties in understanding and in production of space deictic elements. Older dysphasic children 6 and 7 years old

from our sample showed better understanding of the lexemes, but they used space deictic lexemes very rarely.

Infection P390 Mollaret’s meningitis may be caused by cerebral toxoplasmosis J. Prandota University Medical School (Wroclaw, PL) Objective: Mollaret’s meningitis (MM) is a condition occurring mainly in females and characterized by recurrent episodes of headache, transient neurologic abnormalities, and the cerebrospinal fluid containing mononuclear cells. Recently, we found that recurrent headaches in non-HIV-infected subjects were due to reactivation of latent cerebral toxoplasmosis (CT). The aim of this study was therefore to focus on the pathomechanisms that may lead to simultaneous reactivation of both latent herpes simplex virus (HV) and acquired/inborn CT. Methods: Literature data cited in this work were selected to illustrate that various factors may affect latent CNS T. gondii and HV infection intensity and/or host defense mechanisms, such as the production of NO, cytokines, tryptophan degradation by indoleamine 2,3-dioxygenase, mechanisms mediated by an IFN-g responsive gene family, etc., and finally manifest as choroid plexitis. Results: Examples of various triggers revealing MM with accompanying disturbances of IFN-g-mediated immune responses that control T. gondii and possibly HV in both phagocytic and non-phagocytic cells, are the following: female predominance: female mice are more susceptible to T. gondii infection than males by showing clear differences in the kinetics and magnitude of T-cell responses and the production of TNF-a, IFN-g, and IL-10; HV infection: increased IL-12, INF-g, TNF-a, IL-4, IL-6 (types 1 and 2); Ibuprofen: increased TNF-a, INF-g, IL-1, IL-2 and IL-6 levels; systemic lupus erythematosus: increased NO, TNF-a, INF-g, IL-1, IL-2, IL-6, IL-8 levels; decreased IL-10 Conclusion: Subjects with MM should have tests for T. gondii infection obligatorily performed. P391 Cerebellar ischaemic stroke as first manifestation of HIV infection T. Afrantou, A. Angelou, S. Tsounis, N. Artemis, D. Valagouti, P. Kollaras, M. Paschalidou, N. Taskos, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: In a previous study of HIV-patients 40 % of them developed a variety of neurological complications but only 1.3 % presented with ischaemic stroke. In a series of autopsy cases the frequency of cerebral infarction ranges between 19 % and 34 % while in one other study of 13 HIV patients with stroke 68 % of the lesions were localized to the anterior circulation territory. Case report: A 39 year old woman was admitted to our department with fever, dysarthria, swallowing difficulty, hiccup and gait disorder of acute onset. Neurological examination revealed cerebellar ataxia of her left upper and lower limb, nystagmus, and impairment of the lower cranial nerves. The brain MRI showed an infarct of the posterior circulation involving the territory of the posterior inferior cerebellar artery. Routine blood and biochemical tests were normal as well as the full testing of the coagulation mechanism, immunological screening, B12, folic acid and homocysteine. Among a variety of serological tests that was given in order to investigate for possible causes of stroke in young adults we found an extremely increased titer of antibodies against HIV. The patient was referred to Special Infections Unit. The populations of CD4(197 cells/uL) and CD8(681 cells/uL), CD4/CD8 = 0.3 % were counted for determination of the activity of the disease(stage C3). CSF analysis revealed 0 cells/mm3, while PCR for CMV, HSV, EBV, HZV, Candida, Aspergillus, Cryptococcus and Toxoplasma were negative. Finally she received antiplatelet, antiretroviral therapy and a combined treatment consisting of pyrimethamine, clindamycin because an underlying CNS infection was clinically suspected. Her neurological symptoms were partially improved and the number of CD4 was gradually increased during the next months of follow up. Conclusions: There are only few case reports describing stroke as the presenting manifestation of HIV infection.In our case there were no risk factors for stroke so we tend to believe that an HIV-induced vasculopathy could be a possible cause. Biopsy is necessary for a definite diagnosis but usually it is not performed. The aetiology of stroke in HIV patients may be multifactorial; in clinical

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and autopsy studies vascular abnormalities, opportunistic infections, coagulation disorders and cardioembolic disease were identified as the main causes. P392 Isolated intracerebral cystic echinococcosis and cisticercosis: report of three cases A. Bochynska, W. Lojkowska, J. Malicka, M. Derejko, R. Poniatowska, D. Ryglewicz Institute of Psychiatry and Neurology (Warsaw, PL) Introduction: Echinococcosis is rare parasitic disease and for only 2 % of patients which affect the central nervous system. Cisticercosis is the most frequent parasitic disease and about 70 %are cerebral symptoms. Diagnostic difficulties occure if in neuroimaging studies are atipical prestentations and serogical tests may be negative over a long period within the clinical course of these diseases. Clinical course and treatment: We report three cases: two patients with echinococcosis (53 years old male, with isolated cerebral forrn, the atipical brain MRI, demonstrated disseminated cerebral focal lesions in brain and cervical spinal cord as well as two atypical large foci with specific construction of hydatid cyst in brain; 18 years old female with meningo-ophthalmic form) and one patient with cisticercosis (65 years old male, with cerebral miliary). Excluded localisation in the lung and hepatic. Diagnosis was based on CT, MRI findings, cerebrospinal fluid analysis and serological testes. All patients were treatment oral therapy: Albendazole and corticosteroides. Now clinical and neurological state patients are stabile. Conclusion: Both disease still became in Poland. Isolated intracerebral manifestaision of these disease is very rare.Diagnosis should be based on the neuroimaging findings, serological test and cerebrospinal fluid analysis. The present cases demonstrated that oral treatment seems to be effective. P393 Extensive white matter disease associated to herpesvirus 6 G. A. Cárdenas-Hernández National Institute of Neurology (Mexico City, MX) Introduction: Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the Humanes-herpesvirus subfamily. Like other herpesviruses, it establishes latency after primary infection. There are two subtypes: HHV 6A and HHV 6B, the first one is found in the majority of documented primary infections by herpesvirus 6 and the second is potentially more neurotropic. Objective: We report the case of a woman with extensive white matter disease, with few clinical symptoms. Methods: case report. A 41 year-old female without any important antecedent, began her illness 4 months ago with paresthesias in index and middle fingers of the right hand that in a short time involved right leg, she only took aspirine without any improvement. She arrived at our hospital because she developed severe headache, clinically we found slight right hemicorporal motor deficit and ipsilateral hemicorporal sensitive deficit, and her laboratories showed HIV testing negative, lumbar punction was normal. Magnetic resonance imaging showed extensive hypodensity in the white matter, sparing U-fibers. Nerve conduction study showed slight axonal neuropathy, evoked potentials were normal. Conclusions: Primary infection of central nervous system (CNS) by HHV-6 can cause seizures meningitis and encephalitis/encephalopathy. HHV-6 is acquired primarily in approximately 70 % of infants by 24 months of age. Primary HHV-6 infections are usually symptomatically associated with nonspecific febrile illness, although some infants present with clinical manifestation of roseola infantum but there had been a pediatric case of unusual cortical liquefaction in encephalopathy by this virus. After primary infection, HHV-6 remains latent not only in saliva, but also in the CNS. HHV-6 DNA can be detected by polymerase chain reaction during and after primary infection, and in adult brain tissue of patients who died from other causes not associated with HHV-6 infection. Both primary infection and virus reactivation in the CNS have recently been shown to cause various neurological complications. Patients with primary HHV-6 infection can develop acute encephalopathy associated with CNS hypoperfusion. In Addition, HHV-6 associated acute necrotizing encephalopathy had been reported in a patient with status epilepticus, quadriplegia and abducens nerve palsies. Our case is very interesting because is related to CNS infections by HHV-6 in an adult besides the majority of reports are in pediatric population.

P394 A patient with zoster myelitis, paraneoplastic severe combined immunodeficiency and paraneoplastic nephrotic syndrome due to malignant invasive thymoma M. Kurtuncu, Y. Ozpeynirci, N. Keles, M. Mutlu, G. Akman-Demir, M. Eraksoy Istanbul Faculty of Medicine (Istanbul, TR) Objective: We present a 48 year old male patient with a past medical history of malignant invasive thymoma, superior vena cava syndrome, subclavian graft, and paraneoplastic nephrotic syndrome who had complaints of fever, episodic confusion and transient left hemiparesis during his treatment with corticosteroids for his nephrotic syndrome. After a normal brain MRI, the patient was put on cephtriaxone empirically without a CSF (cerebrospinal fluid) examination since he was on warfarin treatment for his subclavian graft. Two days later he developed papulopustuler eruption on his left T4 dermatome region consistent with zona zoster and acyclovir was added to his treatment regimen. Five days later, the patient developed acute renal failure on acyclovir and his treatment was discontinued. His neurological examination revealed a fully oriented male, without any signs of meningeal irritation, and paresis. He was complaining of blurred vision with his left eye. He had hypoesthesia on his legs under his knee bilaterally and a diminished vibration sense, more striking in his lower extremities. His deep tendon reflexes were normoactive and he did not have any pathological reflexes.Without any signs of appendicular ataxia, he had moderate gait ataxia. He was also complaining of urinary retention and constipation. His MRI showed a remarkable T2/Flair hyperintense lesion in his C4–6 cervical spinal cord with contrast enhancement. His ophthalmologic exam was consistent with acute retinal necrosis due to herpes zoster retinitis. The patient was put on gancyclovir and methylprednisolone. Further investigation for his lymphopenia revealed hypogammaglobulinemia, and reduced absolute counts of CD45, CD3, CD4, CD19, and NKT positive cells disclosing a paraneoplastic severe combined immunodeficiency syndrome and prophylactic trimethoprim-sulfomethoxazole and intravenous immunoglobulin treatment was started. After a course of antiviral therapy for 3 weeks, patient’s neurological complaints regressed. Conclusion: The patient is peculiar because of comorbidity of paraneoplastic severe combined immunodeficiency and paraneoplastic nephrotic syndrome associated with malignant thymoma which led to myelitis due to herpes zoster. The patient died of complications of his nephrotic syndrome 2 years after diagnosis of malignant thymoma. P395 Toxocara infection as a cause of relapsing atopic myelitis J. H. Kim, C. H. Kim, M. S. Kim, D.J Yun, M. Kim, B. J. Kim Samsung Medical Center (Seoul, KR); National Cancer Center (Ilsan, KR); Seoul Medical Center (Seoul, KR) Objectives: Myelitis in patients with atopic diathesis or mite-specific hyperIgEaemia was named atopic myelitis. The causal relationship between atopic diasthesis and myelitis is obscure. Toxocariasis is a zoonotic infection caused by toxocara canis, and a rare cause of central nervous system infection manifesting meningitis, encephalitis, or myelitis. This study is to investigate if toxocariasis may be a cause of atopic myelitis. Methods: We retrospectively examined ELISA study for Toxocara canis in patients with myelitis and hyperIgEaemia. Clinical, laboratory and MRI findings were analysed.Results: Four patients with atopic diasthesis were enrolled to have atopic myelitis. All the patients were men, aged from 28 to 58 years old, presented subacute progression of sensory disturbance, mild to moderate paraparesis, and gait disturbance, indicating spinal cord involvement. Spine MRI revealed enhancing lesions in thoracic cord extending 1~ 8 vertebral segments. Blood tests showed eosinophilia (24~43 %) and hyperIgEaemia (541~10427). They showed d2 mite-specific hypersensitivity in skin test. Cerebrospinal fluid protein and IgG index was elevated (0.71) in a patient. ELISA study for toxocara canis in serum was repeatedly high. Clinical course was step wise progression. The responses to intravenous high dose methylprednisolone at the time of progression were not good. Conclusion: We report 4 cases of myelitis of unknown cause, in which the infection of toxocara canis was highly suspected as a cause of myelitis. Screening of toxocara canis infection in “atopic myelitis” should be considered.

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P396 Cerebral and oropharyngeal actinomycosis: a case report M. Zouari, D. Essafi, M. Araar, F. Hentati National Institute of Neurology (Tunis, TN) Objectives: We studied a 42 years old man, who complain since four months from headache and right six nerve palsy due a nasopharyngeal and cerebral actinomycosis. Actinomycosis is a bacterial infectious disease. It can touch several localizations. Cerebral infection is rare (1–15 %) and often severe. Nasopharyngeal actinomycosis is extremely rare, and to our knowledge, only seven cases have previously been reported. Diagnosis of actinomycosis is made by clinical finding, observation of the bacteria and histopathological examination. Methods: A 42 years old man, complains since four months, from headache and right retro-orbital pain. One month later, he develops an horizontal diplopia. A brain MRI is done, with different sequences; T1 weighted images with and without gadolinium injection, T2 weighted images, and FLAIR. A histological study of a pharyngeal lesion was done. Results: Neurological examination reveals an isolated right six nerve palsy, with normal visual acuity, and normal ocular fundus. No other cranial nerve are involved. There is no sensory-motor weakness, the tendon reflexes are normal. No feaver or meningeal syndrome are noted.Brain MRI shows a sellar and supra-sellar pseudotumoral lesion afecting the right cavernous sinus, and continuing through the sphenoidal bone bilaterally. After gadolinium injection, there is enhancement of the lesion and of the meningea. This aspect is suggestive of a granulomatous process. The CSF is normal. The biological data are normal (calcemia, phosphoremia,VIH, and immunological data). The chest CT-scan and bronchic endoscopy are normal.The pharyngeal endoscopy reveals a pharyngeal lesion. The histological exam concludes to an actinomycosis. The diagnosis of a cerebral and oropharyngeal actinomycosis is made. The patient is treated by IV-penicillin, then by oral penicillin for several weeks, with disappearance of headache,and slight improvement of diplopia.The second brain MRI, made after treatment, shows disappearance of the primary lesion. Conclusion: Cerebral actinomycosis should be considered in the differential diagnosis of any chronic inflammatory mass of the head and neck, and biopsy should be performed easily since it is a curable cause. P397 Limbic encephalitis-like syndrome with pronounced inflammatory cerebrospinal fluid changes only responding to high-dose steroids C. Böhm, S. Lamprecht, R. Niesser, S. Troll, B. Borcherding, F. Erbguth, I. Bär Klinikum Nürnberg Süd (Nuremberg, DE) In November 2006 a 58 year old male patient was admitted to our neurological emergency department with a two weeks history of occipital headache, recurrent shivers, fever and periods of confusion. The neurological examination revealed meningism, otherwise no focal sensomotoric deficit but disorientation. CSF analysis initially showed a pleocytosis of 257 mononuclear cells/μl, slightly elevated protein level, while lactate and glucose being within normal range. The patient was first treated by aciclovir and cefotaxim. Cerebral MRI showed symmetric hippocampal enhancement (T2). So limbic encephalitis was suspected, however, due to the unusual clinical appearance including CRP elevation, viral or bacterial encephalitis could not be excluded. Additionally an increasing CSF cell count of now up to 700 neutrophilic cells/μl was not at all conformable to “pure” limbic encephalitis. Nevertheless all applied antibiotic, antiviral and antimycotic treatment as well as tuberculostatics showed no benefit. No potential inflammatory focus or any pathogen could be detected in a wide diagnostic range of laboratory and imaging methods (cultures of blood, urine and cerebrospinal fluid, polymerase chain reaction, thoracical and abdominal CT scan, transesophageal echocardiography, MRI of the spinal cord, leucocyte scintigraphy). Assuming an autoimmune or paraneoplastic process causing the “limbic encephalitis like syndrome“, all corresponding markers showed no pathology, voltage-gated potassium channel antibodies could not be detected. Interestingly, recurring application of high-dose methylprednisone (500 mg/d) repetitively improved the patient’s clinical condition and correlated with a decrease in CSF cell count, whereas every trial of reducing the corticoid dose rate immediately worsened his state seriously. After a period of three months, the patient is still hospitalized, current treatments by immunoglobulines and chemotherapeutics have not obtained any resounding benefits up to now. The definite diagnosis still remains unclear, we are, however, discussing a paraneoplastic process, lymphoma or an autoimmune disorder.

P398 Syphilitic chorioretinitis as initial manifestation of neurosyphilis in HIV patient M. Rodriguez, J. Flores Rivera, P. Morfin, J. Soto National Institute Neurology (Mexico, MX); APEC (Mexico, MX) Objective: To describe an infrequent clinical presentation of neurosyphilis in HIV patient without inflammatory findings in the anterior eye segment. Methods: Case report: A 42 years old male patient diagnosed with HIV infection three years ago, without antiretroviral treatment. He remained asymptomatic until eight weeks before admission, when he developed diminished visual acuity on his right eye with ocular pain, red eye and photophobia. At that time he had not received any treatment, but showed a partial improvement on the following next weeks. Twenty one days prior to admission the left eye underwent the same clinical course. The neurological examination was normal. CSF analysis revealed pleocytosis 8 cells/field, proteins 58mg/dL and 79mg/dL of glucose. CT cranial scan and Chest X ray film were normal; CSF VDRL and FTA ABS reached 1:32 and a positive reaction respectively. The ophthalmological examination showed cellular traces at the anterior segment on both eyes and bilateral uveitis. On admission, visual acuity of 20/60 on the right eye and 20/200 on the left eye were recorded.An ocular ultrasonogram showed multiple vitreal condensations. Serum VDRL had positive titre ranges (1:2). There was a viral load of 156.000 copies per ml (PCR mRNA amplification) and a total count of CD4 + Lymphocites of 208 cells/Litre. We used steroids (systemic, retro-ocular) and Cephtriaxone (2g/24 hours IV for 14 days). His visual acuity improved. Conclusion: In HIV patients syphilis is an important cause of ocular affection and chorioretinitis. It can be the initial manifestation of neurosyphilis. P399 Irreversible papillitis and ophthalmoparesis as a presenting manifestation of neurobrucellosis D. Deleu, F. Ruiz Miyares, S. ElShafie, F. Equia, B. Mesraoua, H. Al Hail, K. Salim HMC (Doha, QA) Background: Cases of meningitis due to neurobrucellosis with bilateral optic nerve and eye movement involvement are rare, most of them with favorable outcome. Objective: To report a case of neurobrucellosis presenting with meningitis, irreversible ophthalmoparesis and papillitis resulting in optic atrophy with blindness. Design: Case report. Setting: University teaching hospital. Patient: A 35year-old man presented with a meningeal syndrome and acute onset of visual blurring. Results: Clinical investigations revealed bacterial meningitis with bilateral papillitis and ophthalmoparesis. Serum and cerebrospinal fluid serology confirmed the diagnosis of chronic active neurobrucellosis. Following therapy there was no improvement and he developed optic atrophy. Extensive literature review revealed, one case of bilateral irreversible papillitis resulting from neurobrucellosis. However no cases of neurobrucellosis have been reported with meningitis, irreversible papillitis and ophthalmoparesis. Conclusion: This case demonstrates that in endemic areas, acute meningitis is a potential manifestation of neurobrucellosis and that bilateral irreversible papillitis with ophthalmoparesis can be a potential serious complication.

Multiple sclerosis P400 Magnetic resonance spectroscopy in the assessment of Egyptian multiple sclerosis patients A. Abdelalim, S. Hamdy, D. Salem, M. Zaki Cairo University (Cairo, EG) Objectives: The aim of this study is to evaluate the clinical aspects of multiple sclerosis (MS) in correlation to quantitative & qualitative results of the magnetic resonance spectroscopy (MRS). Methods: Fifty patients (28 females, 22 males) with definite MS and 20 healthy controls were included in a Case-Control study. Patients were subjected to: Clinical assessment, routine laboratory investigation, rating scales: Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), Hamilton Depression Rating Scale (HDRS) & Minimental State Examination

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(MMSE), cerebrospinal fluid examination for oligoclonal bands (30 patients), Both patients and controls were subjected to conventional magnetic resonance imaging (MRI) including measurement of intercaudate ratio and single voxel proton MRS using a PRESS pulse sequence (TR = 2000, TE = 35); peaks for N-acetylaspartate (NAA), Creatine (Cr), Choline (Cho) & myoinositol (mI) were processed and analyzed using jMRUI software. Results: Patients had significantly lower NAA/Cr (P < 0.01) and higher mI/Cr (P < 0.01) ratios compared to controls. Cho/Cr ratio was higher (P < 0.01) and NAA/Cho (P = 0.029) ratio was lower in patients with evidence of activity (n = 15). The NAA/Cr ratio was negatively correlated with EDSS (P = 0.002). Patients with mild disability (EDSS< 3) show higher NAA/Cr (P = 0.002) & Cho/Cr (P = 0.005) compared to those with moderate to severe disability. Patients with EDSS ≥ 5 showed a significantly larger number of lesions in all sites but no significant spectroscopic differences compared to those with EDSS< 5 (P = 0.007). No significant spectroscopic differences were found between relapsing remitting and secondary progressive MS patients. Conclusion: Single voxel proton MRS could be a valuable tool in the assessment of patients with multiple sclerosis. NAA/Cr ratio could be used as a reliable tool in the quantitative assessment of axonal damage; Cho/Cr could serve as a helpful marker of disease activity even in absence of clinical or conventional neuroradiological evidence for activity. P401 Genetic polymorphisms in the promoter of osteopontin are associated with disease course in multiple sclerosis C. Cárcamo, A. Kroner, P. Viviani, P. Rieckmann Bayerische Julius Maximilians Universität (Wurzburg, DE); Pontificia Universidad Católica de Chile (Santiago, CL) Objective: Osteopontin (OPN) has been implicated in TH1 mediated autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). There is some evidence that OPN has a role in clinical activity and progression of these diseases. OPN intron polymorphisms have been described in MS patients but whether they have functional and clinical consequences remains conflictive. We analyzed whether there is a correlation between promoter polymorphism at nt–443 and nt–66 of the OPN gene (which affect its transcriptional activity) and the clinical course of MS in German patients. Methods: We studied the single nucleotide polymorphisms (SNP) at nt–443 and nt–66 of the OPN gene by allele specific polymerase chain reaction (PCR) of genomic DNA from 498 German MS patients with clinically definite MS according to the criteria of Poser followed in the MS outpatient clinic at the University of Würzburg. Disability was assessed by Kurtzke’s Expanded Disability Status Scale (EDSS). The rate of accumulation of neurological disability was expressed by the progression index (PI = EDSS/duration (years)). As control group for the allelic frequency analysis we used 106 age- and sex-matched healthy individuals. The results were confirmed by automatic DNA sequencing. Results: From 498 patients (68 % female and 32 % male), 39 (7.8 %) had primary progressive course (PPMS), 292 (58.6 %) had relapsing-remitting course (RRMS) and 167 (33.5 %) showed a secondary progressive disease course (SPMS). We didn’t find any difference between controls and patients but genotyping of SNP at -66 in the promoter region of OPN showed a significantly (P-Value = 0.005) association with the different course of MS in our patients. In PPMS G/G homozygote was found in 12.8 %, G/T heterozygote in 28.2 % and T/T homozygote in 58.9 %. In RRMS G/G homozygote was found in 5.1 %, G/T heterozygote in 46.2 % and T/T homozygote in 48.6 %. In SPMS G/G homozygote was found in 4.1 %, G/T heterozygote in 32.9 % and T/T homozygote in 62.8 %. The frequency of T-allele significantly increased in patients with progressive courses of the disease. Conclusion: SNP of the OPN gene at –66 could be helpful to predict the different courses of MS and it is consistent with the finding that the promoter sequence from –94 to –62 is essential for the human OPN transcriptional activity. Further functional studies of the promotor activity in association with genotype differences are underway in our laboratory.

P402 Influence of repeated intrathecal triamcinolone acetonid application on cerebrospinal fluid biomarkers of axonal damage and glial activity in multiple sclerosis patients M. Abu-Mugheisib, H. Tumani, F. Kamin, A. Apel, W. Koehler, F. Hoffmann, R. Benecke, U. K. Zettl University of Rostock (Rostock, DE); University of Ulm (Ulm, DE); Saechsisches Krankenhaus Hubertusburg (Wermsdorf, DE); Staedt. Krankenhaus Martha-Maria Halle-Doelau (Halle, DE) Objective: This pilot study wanted to characterize the effects on cerebrospinal fluid (CSF) Tau protein and S-100 induced by repeated intrathecal triamcinolone acetonid (TCA) applications in multiple sclerosis patients. Methods: 10 patients suffering from MS (4 relapsing remitting [RR], 6 secondary or primary progressive [SP/PP]) were included in this prospective pilot study that is still continuing. Three TCA applications were performed as part of an ongoing trial every second day to reduce spasticity. Tau protein and S-100 were measured using standard ELISA techniques at baseline and at each TCA application. Results: The median EDSS was 5.5 (range 1–8) at baseline and 4.5 (1–8) at follow up (p = 0.49). The mean CSF Tau protein levels were 196.1 pg/ml at baseline (age dependent normal range 75–274 pg/ml), 243.9 pg/ml at visit 2 and 272.3 pg/ml at visit 3. We observed a significant increase of Tau protein levels over the observation period for all patients from baseline to visit 3. The mean CSF S-100 levels were 1.24 ng/ml at baseline, 1.13 ng/ml at visit 2 and 1.06 ng/ml at visit 3. No significant differences of CSF S-100 levels either over the time of the observation period nor among the MS subtypes could be detected. Conclusion: This pilot study demonstrated that an increase of CSF-Tau protein occurs consistently in MS patients with intrathecal TCA applications. The degree of alteration may be influenced by the MS subtype. Our ongoing treatment trial or further studies on larger cohorts of patients have to evaluate whether these markers may serve as surrogate marker for treatment response and/or disease activity.

P403 Tau protein in cerebrospinal fluid and cognitive function in patients with a first clinical demyelinating event suggestive of multiple sclerosis M. Valisˇ, R. Taláb, C. Andrys, J. Krejsek, J. Masopust Faculty Hospital Hradec Králové (Hradec Králové, CZ) Introduction: Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system and the non-traumatic cause of the neurological dysfunction in young adults. Axonal damage is now being recognized as a common finding in multiple sclerosis (MS) lesions and a cause of irreversible neurological damage. Attempts to identify markers of early axonal damage are of great significance. Cognitive dysfunction, as with other symptoms of MS, has highly variable-estimates of its frequency range from 43 % to 72 %. Severe dementia is observed in 20–30 % of MS patients with cognitive impairment. Cognitive dysfunction can have a dramatic impact on several aspects of the quality of live independently on degree of physical disability. Method: We aimed to investigate associations between tau protein in CSF and two tests for MS cognitive impairment – Mini Mental State Examination (MMSE) and the Paced Auditory Serial Addition Test (PASAT). We examined the microtubule-associated protein tau in the cerebrospinal fluid (CSF) of patients with MS vs. controls. We included 7 patients with the first clinical demyelinating event with MRI scan abnormalities suggestive of MS within the last 60 days. Patients were compared to controls (n = 10). Cognitive functions were used for testing PASAT and MMSE. The PASAT were alternated forms A and B. CSF tau protein was measured by double antibody sandwich ELISA (Innogenetics, Ghent, Belgium). The results were evaluated using the t-student test and Mann Whitney Probability. Results: The CSF tau concentrations of patients with first clinical demyelinating event were significantly increased from the control group. There were no difference in results the MMSE and PASAT tests among patients with first clinical demyelinating event and the control group. Discussion: Axonal damage is now being recognized as a common finding in MS lesions and a cause of ireversible neurological damage. In this preliminary paper tau protein in cerebrospinal fluid in patients with a first clinical demyelinating event suggestive of multiple sclerosis was increased from the control group. There were no difference results in MMSE and PASAT compared to the control group. Using tests weren’t specific, effective and reliable for MS cognitive im-

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pairment. Tau protein should be the possibly predictable factor of cognitive impairment to select “at risk” patients for early treatment. P404 Glucocorticoid treatment reduces T-bet and pSTAT1 expression in mononuclear cells from relapsing-remitting multiple sclerosis patients G. Frisullo, V. Nociti, R. Iorio, A. K. Patanella, A. Bianco, M. Caggiula, C. Sancricca, P. A. Tonali, M. Mirabella, A. P. Batocchi Catholic University (Rome, IT); Don Gnocchi (Rome, IT) Objective: The aim of this study was to evaluate both in vivo and in vitro effects of high dose Glucocorticoid (GC) treatment on pSTAT1, T-bet and pSTAT3 expression and annexinV (A-V) binding on peripheral blood subpopulations of CD4+, CD8+ T cells and monocytes from relapsing multiple sclerosis (MS) patients. Moreover, we correlated modification of transcription factors expression with peripheral blood mononuclear cell (PBMC) production of IFNgamma, IL6 and IL10 and with the patient’s clinical outcome. Methods: For in vivo study PBMCs were collected from 15 patients in acute phase of disease before GC treatment (intravenous methylprednisolone 1g/day for 5 days), on day 3 and the day after the end of treatment (day 5); for in vitro study PBMCs from 5 untreated patients in relapse, 5 in remission and 5 controls were cultured with medium alone or methylprednisolone 0.1 mcg/ml for 24 or 48 hours. Detection of A-V binding and transcription factor expression (pSTAT1, T-bet and pSTAT3) in CD4+, CD8+ T cells and monocytes were performed by flow cytometry. CD4-PC5, CD8PC5, CD14-PC5, anti-pSTAT1 (A-2)-PE, anti-pSTAT3 (B-7)-PE, anti-T-bet (4B10)-PE antibodies and Annexin V Apoptosis Kit were used for cytometric analysis. Cytokine production by PBMCs were measured by ELISA. Results: Both in vivo and in vitro studies showed that high dose GC treatment in relapsing MS patients induces a reduction of pSTAT1 and T-bet expression in circulating CD4+, CD8+ T cells and monocytes. Furthermore we observed a reduction of IFNgamma production by PBMCs after GC treatment. A significant increase of AV-positive CD4+ and CD8+ T cells was detectable after GC treatment without any variation in the percentage of AVpositive monocytes. By in vitro analysis, patients during relapse, either before or after GC treatment, exhibited a lower proportion of apoptotic lymphocytes than remitting patients and controls. Conclusions: Our study suggests that GCs can modulate IFNgamma signalling by regulating T-bet and STAT1 expression and that IFNgamma signalling inhibition contributes to anti-inflammatory action of GCs in the treatment of relapses of RRMS patients. In addition T lymphocytes from MS patients in acute phase of disease seem more resistant to GC-induced apoptosis as shown by annexin V staining. P405 Distribution of plaques in Iranian multiple sclerosis patients using magnetic resonance imaging E. Rahimian, R. Abolfazli, H. Pakdaman, J. Lotfi, S. Vazerian, M. Tahsini Athari Neuroimaging Center (Tehran, IR); Tehran University of Medical Science (Tehran, IR); Shahid Beheshti University of Medical Science (Tehran, IR) Background: The traditional notion that MS is a primary demyelinating disease has led to a plaque-centered view of both etiology and pathogenesis of disease progression. Previous studies have found a 10 % involvement of infratentorial region.The aim of this study was to study the anatomic and morphologic distribution pattern along with the size of plaques in Iranian patients with additional statistic comparison to distribution pattern of lesions according to previous studies. Material and methods: A cohort of 125 MS patients (97 female and 28 males range 15–60 years) referred to an imaging centre were enrolled in this study. MR images were obtained on a 1.5 Tesla GE SIGNA system.T2 Fast spin echo and T1 spin Echo sequences covering the entire brain was gathered in the axial plane, 5mm thickness contiguously with 256x256 acquisition matrix. The images were transferred automatically to PACS and were observed by the radiologist. Results: Highest rate of MS was found in the range of 35–40 years in females and in the range of 30–35 years in male patients. Infratentorial region was the most affected area (82 %) as compared to international statistics of 10 % worldwide. Occurrence of lesions was highest in Pons (58 %) in females while 70 % in the cerebellar peduncles in males and occurrence in medulla was 50 %. 100 % occurrence of lesions was seen in callososeptal area and the body of corpus callosum.In the population under study 79 % had involvement of the sub cortical area, 48 % had lesions in cortex and gray matter while 4 % of the patients had occurrence of lesions in the Basal Ganglia. The most affected lobes in females was the temporal lobe followed by frontal,

parietal and occipital lobes and the most affected lobe in males was temporal lobe followed by parietal, frontal and occipital lobes. The size of MS plaques was between 5–15mm in 98 % of the cases while it was less than 5mm in 84 % of the cases. Morphologically 97 % of the plaques were spherical and oblong in shape while the typical Dawson’s finger and Target shape had the lowest rates of occurrence (36 % and 18 %) respectively. Conclusions: There was high involvement of the infratentorial region (82 %) including the posterior fossa and medulla in Iranian patients as compared to 10 % worldwide. Moreover, the high rate of involvement in the sub cortical area and its relation to neurocognitive disability highlights prompt attention to the neurocognitive function of multiple sclerosis patients. P406 Cost-impact assessment of treating multiple sclerosis with natalizumab in an Irish context G. O’ Connor, J. Roche, O. Hardiman, A. Dee Beaumont Hospital (Dublin, IE); HSE-South (Cork, IE) Background: The development of disease modifying drugs (DMD) for multiple sclerosis (MS) led to a series of pharmacoeconomic studies aimed at cost-benefit analysis. In most European states, the entry of natalizumab into the market in 2006 has prompted a detailed cost analysis, taking into account the costs of identifying and managing the potential risks of this new project. Objective: To estimate the potential overall cost of natalizumab therapy in Ireland, thus giving a basis for future cost-effectiveness analysis. Methods: The population of MS patients in Ireland was estimated, based on national disease surveillance data, and an estimate made of those patients who would meet the criteria for treatment with natalizumab. The strategy used was a micro-costing approach to include costs for bed occupancy, routine laboratory tests, medical and clinical professional staff and nursing staff pay. Costs for imaging and cerebro-spinal fluid analyis (to investigate for possible cases of progressive multifocal leukoencephalopathy [PML]) were included. Figures for rates of discontinuation of therapy were presumed to be at the same rate as those given in the AFFIRM study. Follow-up for each patient was presumed to be on the basis of the TOUCH protocol. Results: The population of those in Ireland with MS who may benefit from natalizumab was estimated at between 243 and 486 people – for the purposes of calculation, a figure of 425 people was presumed. Total cost per 12 month period for treatment with natalizumab was estimated at Euro 35,410 per patient, of which the drug cost Euro 27,747. Allowing for a discontinuation rate from adverse effects of 4 %, and assuming a 10–15 % rate for investigating for PML, the total cost per year was estimated at Euro 14,601,095. Estimated cost for DMD therapy with older agents for the same patient group was Euro 9,350,000. Conclusion: Natalizumab has the potential to be an extremely effective therapy for a group of patients who have not benefited from avaliable treatments. However, the cost of the drug represents a significant investment. Although an increase in current levels of expenditure, decreased costs from relapses and reduced need for support services may reduce this difference in cost. Detailed clinical surveillance of patients will be required to determine the overall cost-benefit ratio for natalizumab. P407 A Phase IIb safety, tolerability and efficacy study of oral cladribine add-on therapy with interferon beta-1 a in multiple sclerosis X. Montalban, B. Cohen, D. Jeffery, T. Leist, H. Moses, B. Musch on behalf of the ONWARD Study Group Objectives: Interferon (IFN) beta-1 a is an effective first-line therapy for multiple sclerosis (MS). However, clinical relapses and inflammatory lesions detected by magnetic resonance imaging (MRI) persist in some patients (pts) despite treatment and may contribute to disease progression. While treatment efficacy may be augmented by an additional disease-modifying therapy, safety of combination therapies is less well understood and additional controlled studies are required. Oral cladribine, a preferential lymphocytedepleting therapy, offers a potential future option for both monotherapy and combination therapy. Manageable side-effect profiles have been established in approved indications and in early studies in pts with MS, where significant suppression of CNS inflammation was shown. This 96-week, Phase IIb study (26593) investigates the safety, tolerability and efficacy of oral cladribine plus IFN beta-1 a (Rebif® New Formulation) in pts with active MS. Methods: Pts will be 18–55 years old, have relapsing MS (≥ 1 relapse in prior 48 weeks), an Expanded Disability Status Score of 1.0–5.5, and be receiving subcutaneous IFN beta-1 a, 44mcg 3 times weekly (n = 260). All pts will continue to receive IFN beta-1 a and be randomized 2:2:1 to concomitant once-daily intermittent dosing with 1 of 2 oral cladribine regimens (n = 104 each) or matching placebo (n = 52). Oral cladribine is administered

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in cycles, once daily for 4–5 consecutive days. Year 1: 4 cycles of study drug will be administered; 4 of active drug for level 1 cohort, 2 of active drug and 2 of placebo for level 2 cohort and 4 of placebo for the control group. Year 2: both active groups receive 2 cycles of oral cladribine. Results: Key primary safety endpoints are: proportion of pts developing grade 3–4 toxicity, median time to first grade 3–4 toxicity on selected haematology and liver function parameters and incidence of infections (including opportunistic infections). The primary efficacy endpoint is the mean change in the number of new T1 gadolinium-enhancing lesions from baseline to Week 96. Secondary endpoints include MRI measures, relapse rate, proportion of pts relapse-free and mean time to disability progression. Conclusions: The differing mechanisms of action of IFN beta-1 a and oral cladribine may be complementary in the future treatment of MS. While safety is paramount, the convenience of the oral, short, intermittent dosing regimen of cladribine facilitates its potential use as add-on therapy. Study supported by Merck Serono P408 Phase I safety, tolerability and pharmacokinetic/pharmacodynamic results for a new formulation of subcutaneously administered interferon beta-1 a B. Stubinski, M. Bertolino, A. Priestley, M. Seiberling Merck Serono (Geneva, CH); Merck Serono, RBM (Ivrea, IT); LCG Bioscience (Cambridge, UK); Swiss Pharma Contract Ltd (Allschwil, CH) Objectives: Patient adherence to treatment is an important factor for achieving maximal benefits from interferon (IFN) beta therapy in multiple sclerosis (MS). Injection-site reactions are a frequent treatment-emergent adverse event (TEAE) with subcutaneous (sc) injections and, although generally mild in patients receiving IFN beta-1 a sc three-times-weekly (tiw) (Rebif®; R), they may affect adherence in some patients. The objective of this Phase I study (25394) was to compare the safety, tolerability, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of two new formulations of R (RNF1 and RNF2) with the current formulation and placebo. Methods: In this double-blind, placebo-controlled, parallel-group study 48 healthy volunteers were randomized (1:1:1:1) to receive one of three active treatments (44mcg IFN beta-1 a sc) or placebo (normal saline) as single 0.5mL doses using a 29 gauge 5-bevel needle. Evaluations of pain intensity on injection were based on the McGill short-form questionnaire and a 100mm visual analog scale (VAS: > 5 mm = pain). Safety, tolerability and PK/PD effects were monitored for 24-hours post-dose, and further evaluations (except PK/PD effects) were made until 10–14 days after dosing. Results: Although TEAEs occurred in equal numbers of subjects (10) in the RNF1, RNF2 and R groups, overall incidence was lower with RNF2 (21 events) than RNF1 or R (31 and 33 events,respectively).The mean worst pain intensity was lower with RNF1 or RNF2 than with R or placebo (mean VAS score [SD]: 1.4 [2.61], 1.0 [1.04], 10.7 [17.08], and 3.9 [8.01]mm, respectively). Combined VAS pain scores for all subjects were also lower in the RNF1, RNF2 and placebo groups than in the R group at the time of dosing (4, 12, 22 and 114mm, respectively) and up to an hour post-dose. The RNF2 group had fewer subjects with local injection pain than the RNF1, R or placebo groups (1 versus 4, 6 and 3, respectively). Furthermore, fewer subjects receiving RNF2 experienced injection-site redness than those receiving RNF1 or R, 3 versus 7 and 4, respectively. The PK/PD profile of RNF2 was similar to that of R. Conclusion: These results suggest that, compared with the current formulation of R, RNF2 may offer tolerability advantages, which could improve patient adherence. An ongoing Phase IIIb study (25632) is investigating the safety and immunogenicity of this formulation in patients with MS. This study was supported by Merck Serono. P409 REFLEX: a phase III trial to assess the effect of dosing frequency of interferon beta-1 a (Rebif®) in delaying conversion of patients with a clinically isolated syndrome to clinically definite multiple sclerosis L. Kappos, M. Freedman, N. De Stefano, P. Labauge, G. Comi, B. Stubinski on behalf of the REFLEX Study Group Objectives: Evidence shows that interferon (IFN) beta delays progression to clinically definite multiple sclerosis (CDMS) in patients with a single demyelinating event (CIS), and that in established relapsing–remitting MS, IFN beta dose and frequency have an impact on efficacy. Rebif® New Formulation (RNF) has been developed to improve injection tolerability and decrease immunogenicity. This study assesses the effect of once-weekly (qw) and three-times-weekly (tiw) dosing of RNF vs. placebo on time to conversion to CDMS. Methods: This is a double-blind, placebo-controlled, multicentre study (protocol 27025; NCT00404352). A total of 480 patients will be randomized

1:1:1 to RNF 44mcg subcutaneously (sc) tiw, RNF 44mcg sc qw (plus twiceweekly placebo for blinding) or placebo tiw. Patients must be 18–50 years, have experienced a demyelinating event within 60 days of study entry and have ≥ 2 clinically silent lesions on T2-weighted brain magnetic resonance imaging (MRI). Patients will receive 24 months of study treatment and undergo clinical assessments every 3 months (+ Month 1 safety assessment). MRI will be performed every 3 months until study end or conversion to CDMS, then every 6 months. Patients reaching CDMS will be retitrated to open-label RNF 44mcg sc tiw. Those who do not convert within 24 months will be offered open-label RNF 44mcg sc tiw for an extra 12 months. Results: The primary endpoint will be time to conversion to MS using revised McDonald criteria (2005). Comparisons of time to conversion will be made for RNF 44mcg sc tiw vs. placebo. If there is a significant difference (p ≤ 0.05), comparison of RNF 44mcg sc qw vs. placebo will be performed. The two doses of RNF (44mcg sc tiw vs. 44mcg sc qw) will be compared only if both previous comparisons are significant. Secondary endpoints include safety measures and cognitive assessments such as Paced Auditory Serial Addition Test scores. A sub-study will assess the thickness of the retinal nerve fibre layer by means of optical coherence tomography. Exploratory assessments will be made of pharmacogenomic markers associated with development of CDMS and treatment outcomes. Conclusions: Early treatment with RNF is expected to delay disease progression to CDMS and improve treatment outcomes. The study will also determine the respective therapeutic benefit of two different RNF dosage regimens for patients with CIS. This study was supported by Merck Serono. P410 Neuropsychological profile and personality traits in multiple sclerosis E. Reich, E. Arias, M. Kerzberg Hospital Julio Mendez (Buenos Aires, AR); Buenos Aires University (Buenos Aires, AR) Background: Several predisposing factors (immunological, genetical, environmental) are recognized among the Multiple Sclerosis(MS) patients, and its role and influence in the pathogenic process is widely discussed, but there is sparse information related to the previous personality traits and psychological profiles in this population. Objective: Our aim is to investigate and asses the presence of common personality traits among this group of patients, that, acting as a previous personality and psychological profile could be considered as predisposing factors or common neuropsychological pattern for such disease. Methods: We evaluated a group of 41 patients(26 females and 15 males) with clinically definite MS (according Poser Criteria) with a mean age of 31 years (SD 6.5). The clinical picture was Relapsing Remiting in 24 patients and Secondary Progressive in the remaining 17 cases. The mean time of evolution was 5.2 years (SD 3.4), and the mean EDSS was 3.0 (SD 2.0). The formal education period was 9.6 years (SD 5.3) All the patients were evaluated utilizing a computerized version of the Minessota Multiphasic Personality Inventory 2 (MMPI 2), a test that is oriented to caracterize different personality profiles, according to thirteen different subscales, scoring 567 questions. Results: Considering the analysis of the different subscales of MMPI 2, we observed some personality traits that were present in a high percentage of the studied subjects and that could be considered as common factors among this group of patients. The most common findings consisted in operatory and concrete thinking, trend to social isolation and introversion, with severe limitations in expressing emotions and difficulties in separate inner-outer spaces. Other common personality traits that were usually present among this group of patients were marked anhedonia, alexithymia, difficulties to insight about symptoms and its causes, and high cultural level. Also appeared with significant frecuency introversion and inflexibility, immaturity and infantile behavior, and low ability to discriminate fantasy and reality. Conclusion: As was observed in other diseases (for example type “A” personality in cardiovascular diseases) a lot of personality traits and a repeated psychological profile are commonly found among patients that develop MS, suggesting a possible relationship between previous personality and such disease, with potential clinical usefulness related to prevention and treatment.

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P411 Cardiac function monitoring in relation to mitoxantrone infusion in patients with multiple sclerosis: a surveillance study R. Bennett, J. Hillier, D. Funch, H. Norman, J. Seeger, A. AL-Sabbagh EMD Serono, Inc. (Rockland, US); I3 Drug Safety (Auburndale, US)

P413 The importance of an early initiation in the immunomodulatory therapy for multiple sclerosis O. C. Chebut, R. Balasa, M. Dan Mures County Emergency Clinical Hospital (Targu-Mures, RO)

Objective: To assess compliance with PI monitoring guidelines among patients who receive mitoxantrone for MS. Mitoxantrone is indicated for patients with worsening multiple sclerosis (MS). To maintain its risk-benefit profile, adherence to recommended monitoring guidelines in the product insert (PI) is needed. In April 2005, the guidelines for cardiac function were updated to recommend cardiac testing prior to each infusion. Methods: Insurance claims were queried from a large health insurance plan between October 2000 and June 2005, with additional data for cardiac testing from July 2005 to December 2005. Medical records were collected for a portion of the patient cohort, providing supplemental data on dosing regimen, cumulative dose, and test results. Results: Insurance claims identified 1525 infusions from 463 MS patients, and medical records were obtained for 825 infusions from 201 MS patients. Claims data for cardiac function testing were made available for 143 additional infusions occurring between July 2005 and December 2005 following the PI change. Between October 2000 and June 2005, there were claims for cardiac function (by Left Ventricular Ejection fraction [LVEF]) testing in the month prior to initial infusions in 34 % of patients. There were 44 infusions at doses ≥ 100 mg/m2 but only 10 of LVEF tests were documented (23 %). From July 2005 to December 2005, compliance with LVEF testing prior to initial infusions increased to 41 % with medical records showing similar compliance. LVEF testing increased at cumulative doses of 12–100 mg/m2 from an average of 7 % between October 2000 and June 2005 to 34 % between July 2005 and December 2005. There were too few observed infusions at cumulative doses above 100 mg/m2 to reliably assess LVEF testing compliance. Conclusion: Compliance with recommended cardiac monitoring is incomplete, but increased substantially following a change in the labeled recommendations for LVEF testing. Study supported by EMD Serono, Inc.

Objectives: We investigated the efficiency of IFN-beta-1 b regarding the moment of initiation of this immunomodulatory therapy for the relapsing-remitting multiple sclerosis (MS) patients. An early treatment is imposed by the following statements: the irreversible axonal lesions appear precocious in the disease’s evolution, the efficacy of the repairing mechanisms in the white matter is reducing constantly during the progression of the disease, the therapeutical effect of IFN-beta-1 b is stronger in patients with lower Expanded Disability Status Scale (EDSS), IFN-beta-1 b prevents the appearance of further lesions, IFN-beta-1 b is better tolerated in younger patients. Methods: In the Neurology Department from Mures County Emergency Clinical Hospital were treated with IFN-beta-1 b (8 MIU subcutaneous injection every second day) for 5 years a number of 67 MS patients. The inclusion criterions were: a) a diagnosis of relapsing-remitting MS b) age over 18 c) EDSS ≤ 3.5. We divided them into 2 groups: 1) 19 patients began treatment in the first year after the diagnosis was established, 2) 48 patients began the therapy after a mean period of 9,5 years. We followed: a) the initial symptomatology, b) the change of EDSS, c) the number of relapses during a period of 5 years before and after the initiation of treatment, d) the MS clinical pattern and the quality of patients’ life after 5 years of treatment, e) the side effects of IFN beta-1 b, f) magnetic resonance imaging (MRI) at the beginning and after 5 years of treatment. Results: 67.2 % of patients were women. The mean age of patients was similar for the 2 groups. The initial symptomatology was with pyramidal disfunction in 26.8 % patients and optic disfunction in 23.9 % patients. The initial/final EDSS for the first group was 2.3/3.5 and for the second 2.8/4.1. The relapsing-remitting pattern was maintained in disease evolution at 49.3 % patients. MRI emphasized a more intense imagistic activity than a clinic one. The side effects of the therapy were modest consisting mainly of flu-like symptoms and erythema at the injection site. Conclusion: The patients who began the immunomodulatory treatment earlier have a lower EDSS, frequency and severity of relapses and number of “black holes” in T1–weighted images after 5 years of therapy and a superior quality of life. IFN-beta-1 b was good tolerated and the side effects were minimum.

P412 Immunocytochemical localisation of components of GEMSP in the rat CNS after treatment with GEMSP in a chronic EAE model A. Mangas, R. Coveñas, D. Bodet, M. de Leòn, S. Duleu, M. P. Dabadie, M. Geffard Gemacbio, SA (Cenon, FR); INCYL (Salamanca, ES); IDRPHT (Talence, FR); ENSCPB-EPHE (Pessac, FR) The effects of GEMSP in an Experimental Autoimmune Encephalomyelitis (EAE) model have been previously studied and it has been appointed the beneficial effect of the GEMSP treatment on brain leukocyte infiltration (Mangas et al., Lett. Drug Des. Discovery 2006, 3: 138–148). In order to evaluate if this new potential therapy for Multiple Sclerosis (GEMSP) crosses or not the blood brain barrier (BBB), we have induced a chronic (EAE) model administering a mixture containing myelin oligodendrocyte protein and Mycobacterium tuberculosis to 10–11 weeks old Lewis 1A female rats. Daily,clinical score was measured and GEMSP (fatty acids,anti-oxidants, amino acids and scavengers linked to poly-L. lysine (PL)) was administered (since day nine and until the end of the experiment) with a single subcutaneous injection (0.5 ml = 7.5 mg). At the end of experiment (sixty days after induction of the model), animals were deeply anaestethized and perfused, brains and spinal cords were dissected out, crioprotected and processed. After application of immunocytochemical techniques, one of the components of GEMSP (methionine-PL) was localized in the spinal cord using antibodies directed against conjugated methionine. After immunocytochemical controls (first antibody elimination and preabsorption), the absence of immunoreactivity in negative and positive control groups indicated that methionine immunoreactivity was specific for methionine-PL. Moreover, no presence of clinical signs was observed in animals treated with GEMSP, meaning that GEMSP abolished the EAE crisis. Histological data confirm that, in general, animals did not present leukocyte infiltration in the zones of the CNS studied. In summary, our results after using immunocytochemical techniques confirm that this new drug candidate crosses the BBB. Moreover, the action of GEMSP abolishing EAE crisis and decreasing leukocyte infiltration confirm previous data found in the acute EAE model. This work has been supported by INCYL-Federación de Cajas de Ahorro de Castilla y León (Spain); Gemacbio (Cenon, France) and Institut pour le Developpement de la Recherche en Pathologie Humaine et Therapeutique (IDRPHT) (Talence, France).

P414 Glatiramer acetate and minocycline effects on blood monocyte-derived dendritic cells in multiple sclerosis patients M. Ruggieri, C. Pica, A. Lia, G. B. Zimatore, P. Livrea, M. Trojano, C. Avolio University of Bari (Bari, IT); University of Foggia (Foggia, IT) Objectives: Multiple Sclerosis is an inflammatory disease of the central nervous system in which dendritic cells (DCs),the most potent antigen-presenting cells, contribute to initiate and orchestrate immune responses. Approved treatments for MS ›interferon-beta and glatiramer acetate (GA) ›fails to provide a solution because their effects are limited. Both therapies affect several immune variables like cytokine levels and surface molecules expression. Minocycline(min), a semisintetic tetracycline derivative antibiotic, has been proved to EAE and in combination with GA it showed a more significant reduction of EAE severity and disease burden. Aim: To study the effects in vivo and in vitro of GA treatment alone and in combination with min in RR MS patients and healthy controls on the HLA-DR, CD1 a (a cell surface molecule) with capacity to present glycolipids to T cell), CD11 c (a specific markers for myeloid DCs), CD83 (a costimulatory molecule that activate Th1 and Th2 responses) expression in blood monocyte-derived DCs both immature (iDCs) and mature (mDCs). Methods: Eleven RR MS patients and 11 HCs were studied. Four out of the MS patient group were re-tested after 2 months GA treatment period. iDCs were induced from blood monocytes with GM-CSF and IL-4 and their maturation obtained with LPS. Flow cytometric analysis was used to evaluate CD3, CD19, CD14, HLA-DR,CD1 a, CD11 c and CD83 marker expression in iDCs and mDCs. This expression was studied in untreated MS and HCs without and with in vitro addition of GA and GA+min; and in GA treated patients without and with in vitro addition of min. Results: Lineage markers were negative in HCs and MS induced DCs. No significant differences were observed between HCs and MS in HLADR, CD1 a, CD11 c and CD83 expression. The in vitro GA+min treatment showed in both untreated MS and HCs to downregulate (p < 0.05) HLA-DR expression or a trend to downregulate (p> 0.05) CD83 expression in both iDCs and mDCs. After 2 months of treat-

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ment, HLA-DR in both iDCs and mDCs was reduced and in vitro addition of minocycline did not further modify such expression. GA treatment instead did not change CD83,CD11 c and CD1 a that trended (p> 0.05) to be reduced after in vitro addition of minocycline. Conclusion: These results seem to show both GA and GA+min effects on Ag presentation (HLA-DR) capability by DCs whereas GA in combination with minocycline acts also on lipidic Ag presentation, costimulation and myeloid phenotype acquisition by DCs. P415 BDNF in the acute phase of non-treated patients with multiple sclerosis and other neurological disorders M. Paschalidou, R. Lagoudaki, A. Aggelou, T. Afrantou, M. Krommyda, N. Taskos Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Brain-derived neurotrophic factor belongs to the neurotrophin family and its expression is regulated by neuronal activity or peripheral hormones. It is involved several functions from early development up to adulthood. BDNF in the CNS may be modified by stress, ischaemia, seizure activity, hypoglycemia and epilepsy,Alzheimer’s disease and Parkinson’s disease. In adult rat brain BDNF mRNA is expressed in the hippocampus, septum, hypothalamus, cortex and in the adrenergic brainstem nuclei. BDNF was found to be present in immune cells and astrocytes of MS lesions. Immune cells such as those that infiltrate the demyelinating plaques produce BDNF. In fact, neurotrophins prevent neural death, favor neural regeneration and remyelination and also act as immunomodulators by interacting with local microglia, by regulating the migration of monocytes across the blood-brain barrier and the balance between the release of pro- and antiinflammatory cytokines, thereby helping to suppress the formation of new lesions. Objectives: To determinate the levels of BDNF in the serum of patients with MS in the early stage of their disease at the time of diagnosis. The results are compared o those of other autoimmune neurological disorders during the acute phase. Methods and patients: We included 10 patients (male:6, female:4, mean age: 2.7yrs) with definite MS in relapse that were no treated with immunomodulating factors and 10 patients (male: 6, female: 4) with autoimmune neurological disorders of undetermined aetiology. The quantification of BDNF in the patients’ sera was performed by using a sandwich enzyme immunoassay technique commercially available (Quantikine,R&D systems). The BDNF immunoassay has a minimum sensitivity of 20pg/ml. Absorbance was measured at 450nm and BDNF concentrations were normalized using the recombinant protein as recommended by the manufacturer. Results: The levels of BDNF observed in MS patients were decreased (mean value: 62.3ng/ml) compared to other autoimmune neurological disorders (meanvalue:90.2ng/ml), in a statistically significant manner. Conclusions: The preliminary data of this study indicate a decrease in the expression of the neurotrophic factor BDNF in the acute phase of MS patients, suggesting an inability of the CNS to regenerate and therefore to lead to lesion repair. It is suggested that the BDNF levels can be used as a marker of the regeneration of the lesion as well as a marker of the value of the therapeutic schemes. P416 Cerebral cortical metabolic rate of glucose correlate with magnetic resonance spectroscopy in early multiple sclerosis M. Blinkenberg, T. Tscherning, H. Mathiesen, A. Jønsson, E. Rostrup, H. Larsson, O. Paulson, P. Soelberg Sørensen Danish MS Research Center (Copenhagen, DK); Danish Research Center for MR (Copenhagen, DK); Department of MRI (Trondheim, NO); Neurobiological Research Unit (Copenhagen, DK) Objectives: Positron emission tomography (PET) studies have shown that cortical cerebral metabolic rate of glucose (CMRglc) is reduced in multiple sclerosis (MS) as a consequence of the ongoing disease. MR spectroscopy (MRs) measurements of NAA illustrate the ongoing neuronal deterioration, which also seem to be related to cognitive dysfunction in MS. We wish to determine if there is a relationship between PET and MRs measurements in early MS, and furthermore look for cognitive changes in this group of patients. Methods: Twenty-one newly diagnosed, clinically definite, MS patients with a mean age of 35.6 [range 22–48] years old and with a mean EDSS score of 1.8 [range 0–4] were neuro-psychologically tested and a general cognitive index was calculated. Global and cortical CMRglc was estimated using PET and 18-F-deoxyglucose and NAA/Cr ratio was estimated using multisliceecho-planar spectroscopic imaging. A group of 75 normal individuals,

matched for age, sex and educational level, served as controls with regard to neuropsychological test results. Results: Cognitive testing showed that 11 MS patients were within normal range (< 1.5 SD below controls), 6 had mild cognitive dysfunction, and 4 had moderate to severe cognitive dysfunction. There was no correlation between PET measurements and cognitive dysfunction. Average measures of cortical CMRglc correlated with whole brain MRs (r = 0.52; p = 0.015) and NAWM MRs (r = 0.49; p = 0.04), but the strongest correlation was found between cortical CMRglc and cortical MRs (r = 0.67; p = 0.003). Conclusions: The study shows that cognitive dysfunction was present in a considerable part of newly diagnosed MS patients, although we found no correlation between cerebral metabolism and cognitive measurements. PET measurements were significantly correlated to MRs data, suggesting that these two techniques both measure the neurodegenerative process in early MS. The strongest correlation was found between cortical PET and MRs measurements, which may reflect that the most significant neural loss is observed in the cerebral gray matter of MS patients. P417 Glatiramer acetate reduces toll-like receptor 9 expression and augments expression of neurotrophic factors in EAE induced mice S. Haque, A. Sharma, I. Kasper, A. Haque, L. Kasper Dartmouth Medical School (Lebanon, US) Objective: To evaluate the effect of glatiramer acetate (GA) on the induction of Toll-like receptors (TLR) gene and expression of neurotrophic factors in EAE. Background: Neurotrophins (NTs) such as BDNF, NT-3 and NT-4 are important modulators of neuronal function and survival. TLR recognition of pathogen-associated molecular patterns is critical to the induction of innate immunity.In EAE, studies (Prinz M. JCI 2006 116:456) demonstrated that the bacterial CpG receptor TLR9 is critical for the effector state of EAE. GA is an approved drug for RRMS that can induce Th2 polarization.We have recently demonstrated in vivo that GA induces a population of CD4+CD25+FoxP3 T cells that are functionally suppressive to plate bound anti CD3 stimulated effector cells, express IL-10 and downregulate IFNg production. In the present study, we investigated whether the effect of GA, applied at clinical stages of experimental autoimmune encephalomyelitis, affect the expression of NTs, particularly BDNF, in the brain. Design/Methods: Lymph nodes and brain were obtained from EAE induced, CD25 depleted EAE mice, GA treated EAE mice on either a TLR2KO or TLR9KO background and radio-resistant chimeric mice with restricted TLR9/TLR2 or Myd88 expression in the CNS. Expression of specific cytokine including IL-4, IL-6, IL-10, IL-12, IL-17, IFNg and BDNF were evaluated by immunochemistry, multiplex and RT-PCR. Results: Increased expression of TRL9 and STAT4 genes were observed in the CNS of EAE induced mice. Both TLR9 and STAT4 expression were reduced (p < 0.0001), and BDNF expression was augmented following treatment with GA. Of importance, in GA-treated mice, intense BDNF expression was manifested by CD4+CD25+Foxp3+ Treg that migrated into EAE brain. Depletion of the CD25+ T cell subset increased both TLR9 and BDNF expression in EAE mice to above non-depleted EAE control mice. Gene expression of BDNF, TLR9, TLR2 and STAT4 was organ specific with a greater GA effect within the CNS. Conclusions: These observations demonstrate that GA has a significant downregulatory effect on TLR9 expression within the CNS that may be responsible for mediating the anti-inflammatory effect in EAE induced mice. Our results further indicate that the therapeutic drug GA exerts not only an anti-inflammatory effect, but also enhances neurotrophic release that may lead to neuroprotection and regeneration of neural elements in the diseased brain. Study supported by: NIH AI061 938 and Teva Neuroscience.

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Neuro-biology P418 A ferritin tracer study of compensatory spinal CSF outflow pathways in kaolin-induced hydrocephalus D. Kondziella, K. Voeltz, B. von Rautenfeld, T. Brinker, W. Lüdemann University Hospital Sahlgrenska (Gothenburg, SE); Hannover Medical School (Hannover, DE); International Neuroscience Institute (Hannover, DE) Objectives: Spinal drainage of cerebrospinal fluid (CSF) into the lymphatic system is important in physiological and pathological conditions in both humans and rodents. However, in hydrocephalus and syringomyelia the exact CSF pathway from the central canal into the lymphatic tissue around the spinal nerves remains obscure. We sought to identify this pathway using light and electron microscopy. Methods: Syringomyelia and hydrocephalus were induced in 36 Lewis rats by injection of 0.1ml kaolin into the cisterna magna. Two, four and six weeks later cationized ferritin was stereotactically infused into the cisterna magna of controls and into the lateral ventricles of hydrocephalic animals followed by dissection of brain, spinal cord and spinal nerves. CSF pathway and tracer flow were studied by light and electron microscopy. Results: It could be shown that CSF in rats with kaolin-induced CSF outflow obstruction passes from central canal syringes through ruptured ependyma and dorsal columns into the spinal subarachnoidal space, from where it is absorbed along spinal nerves into extradural lymphatic vessels. Moreover, evidence was found for a valvular function of the spinal nerve root sleeves and meningeal funnels. Conclusions: Taken into account that spinal hydrostatic pressure in humans differs significantly from pressure in animals due to the upright gait, spinal compensatory CSF outflow pathways might be of even greater importance in human hydrocephalus. P419 Restoration of msk-1: a new therapeutic target in Huntington’s disease E. Roze, S. Betuing, E. Marcon, C. Deyts, K. Brami-cherrier, C. Pages, K. Merienne, S. Humbert, J. Caboche Saint Antoine Hospital (Paris, FR); Pierre et Marie Curie University (Paris, FR); Institut de Génétique et Biologie Moléculaire et Cellulaire (Strasbourg, FR); Institut Curie (Orsay, FR) Objective: Huntington’s disease (HD) is an inherited neurodegenerative disorder due to an abnormal polyglutamine extension in the N-terminal region of huntingtin protein (Exp-Htt). This mutation causes protein aggregation and neuronal dysfunction, and leads to neuronal death. Transcriptional dysregulation initiated by direct binding of Exp-Htt or cleaved products is thought to participate in neuronal death in HD. The aim of this work was to identify abnormalities in the intracellular signaling cascade that could account for this transcriptional dysregulation and subsequent neuronal death. Methods: we used the R6/2 transgenic mouse model of HD, post mortem brain of HD patient, and, as in vitro model, primary culture of striatal neurons transiently transfected with a cDNA encoding the first exon of human Htt with 103 continuous CAA or CAG repeat (ExpHtt). Protein expression levels were analyzed using immunocytochemistry or western blotting. Neuronal death was analyzed using Hoechst DNA labeling. Results: we identified a new molecular alteration that could account for gene dysregulation in R6/2 mice. We observed a significant activation of the MAP kinase/ERK pathway in the striatum of R6/2 mice at 12 weeks, along with hyperphosphorylation of the transcription factors Elk-1 and CREB. Histone H3 acetylation levels were strongly increased in the striatum and cortex. By contrast, we observed no hyperphosphorylation of histone H3, which would be expected after nuclear ERK activation. We also found that expression of mitogen and stress-activated kinase-1 (MSK-1), a kinase downstream ERK, was strongly reduced in the striatum of R6/2 mice at this stage as well as in post mortem brain of HD patient. In vitro studies of primary striatal neurons from MSK-1 knock-out mice showed that MSK-1 was critically involved in histone H3 phosphorylation and in c-Fos induction by glutamate. Striatal death induced by transient expression of mutated Htt was significantly increased in cultures of MSK-1 knock-out mice whereas overexpression of MSK-1 in neurons transfected with exp-Htt dramatically reduced neuronal death. Conclusion: Taken together, these findings suggest that dysregulation of gene expression in HD may be related to MSK-1 deficiency in striatal neurons, resulting in defective histone H3 phosphorylation and nucleosomal responsiveness that is necessary for expression of pro-survival genes. Restoration of MSK-1 activity may be a new therapeutic target in HD.

P420 A study of late pituitary dysfunction and its relation with global outcome in patients with traumatic brain injury E. Yollin, O. Kozlowski, C. Cortet-Rudelli, P. Fontaine, M. Rousseaux CHRU de Lille (Lille, FR) Objective: The aims of this study were to determine the prevalence of pituitary dysfunction in patients keeping with cognitive disorders at least 1 year after traumatic brain injury (TBI), and to analyse the relations of endocrine abnormalities with TBI severity, late autonomy and quality of life (QoL). Methods: We studied 50 patients (42 men, mean age 36, range 20–59 years, mean BMI 25, range 17–42 kg/m2) who survived severe (n = 38), moderate (n = 2) or mild TBI (n = 10) at a mean of 59 months (range 13–247) post-event; 52 % had moderate, 32 % had severe disability (GOS score: 2 or 3 respectively), 30 % had anosognosia. Each patient underwent a complete assessment of initial Glasgow Coma Scale (GCS) and CT scan lesions, late Glasgow Outcome Scale (GOS), autonomy (EBIS questionnaire), QoL (AGHDA), and pituitary functions. Results: No patient showed posterior pituitary dysfunction, hyperprolactinemia or gonadotropin deficiency. Six patients (12 %) showed TSH deficiency. Ten patients (20 %) had partial ACTH deficiency (diagnosed by ITT or metyrapone test). Severe GH deficiency (GHD) was diagnosed in 44.5 % (glucagon stimulation test confirmed by ITT or arginine+GHRH test) and was isolated in 40 % of cases. GHD patients had significantly higher BMI, triglycerid, fasting and postprandial insulin plasma levels than no-GHD patients. Totally 46 % of the patients showed at least one anterior pituitary deficiency requiring substitutive treatment (multiple and isolated hormone deficiency in 24 % and 22 % respectively). Hypopituitarism was not related to GCS score, initial CT scan lesions, GOS score, QoL, autonomy and resumption of work. Conclusions: In TBI patients with persistent cognitive disorders, the high risk of anterior pituitary deficiency, especially of GH secretion, justifies systematic assessment with reference tests. In this population, the endocrine disorders seem to be relatively independent from the global outcome, autonomy and QoL. P421 Influence of anti-MOG CD4+ T cells on MPTP mediated injury of dopaminergic neurons in mice model of Parkinson’s disease I. Kurkowska-Jastrzebska, J. C. Moller, E. Balkowiec-Iskra, M. M. Zaremba, I. Joniec, A. Czlonkowski, A. Czlonkowska Medical University of Warsaw (Warsaw, PL); Philipps-University (Marburg, DE) Inflammation has recently been shown to play an essential role in the pathogenesis of neurodegenerative diseases. In the recent years a protective role of inflammation that accompanies neurodegeneration had been studied. It has been suggested, that a clue role in processes of protective inflammation may be played by myelin-specific autoreactive T lymphocytes gathering in the area of injury. In the present study influence of CD4+ anti-MOG T cells on degeneration of dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration has been studied. C57BL male mice, 2 months old, received 10 millions of T cells 6 days prior, and 1 day after MPTP injection (40mg/kg). The injection of T cells caused typical EAE with clinical signs of tail and hind limb paresis. In mice receiving CD4+ anti-MOG T cells, MPTP caused less dopaminergic system damage than in only MPTP injected mice.Administration of T cells 6 days before the MPTP insult resulted in 1,2 times higher dopamine level in striatum on the 14th day after injury (p < 0.02), compared to MPTP mice. Respectively, T cells given 1 day after MPTP increased dopamine level on the 7th day (1,5 times higher compared to MPTP mice). However, the protective effect has not been visible on 14th day after injury. RT-PCR studies showed altered mRNA level of IL-1,6, TNFalpha, TGF and GDNF.We presume, that the observed neuroprotective effect may be mediated by augmented production of trophic factors in the injured areas of the CNS. P422 Survival of bone marrow stromal cells in the presense of pro- and anti- inflammatory cytokines, in vitro K. Kotta, R. Lagoudaki, O. Touloumi, C. Simeonidou, E. Spandou, N. Taskos, I. Milonas, N. Grigoriadis Aristotle University of Thessaloniki (Thessaloniki, GR) Objectives: Bone marrow stromal cells (BMSCs) are non-haematopoietic multipotent stem cells which are able to differentiate into several cell types including those of the central nervous system (CNS). Cell therapy using BM-

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SCs for autoimmune demyelinating diseases such as Multiple Sclerosis (MS) is a very promising therapeutic method. It remains to be answered though whether BMSCs are capable to survive in an inflammatory environment, such as the one present in MS. The evaluation of BMSCs survival, apoptotic gene and protein expression in the presence of pro- (IFNg, TNFa and IL4) and anti- inflammatory (TGFb) cytokines, was studied here. Methods: BMSCs were extracted and cultured from C57Black/6 mice. The in vitro proliferation assay MTT was used to measure cell proliferation in the presence of the cytokines, in concentrations ranging from 30 to 2000 units/ml. Immunocytochemistry for the apoptotic proteins Bax, Bcl-2, Fas and Caspase 3 and western blotting were performed in order to detect whether the reduction in cell proliferation was due to apoptosis. Real-time PCR was used to confirm the gene expression of the apoptotic proteins Bid, Bax, Apaf-1, and Bad. Results: In vitro proliferation results indicate a significant reduction of BMSCs survival in the presence of pro-inflammatory cytokines through apoptosis and increased survival in the presence of anti-inflammatory TGFb. The presence of IFNg reduced the proliferation of BMSCs (22.38 %–51.35 %) and so did IL-4 (9.5 % – 15.2 % reduction) and TNFa (18.1 %–55.4 %). However, TGFb increased the proliferation ability of the cells (9.5 %–31.3 %). Increased expression of caspase-3 was observed in the presence of pro-inflammatory cytokines, such as INFg. The apoptotic genes Bid, Bad, Bax and Apaf-1 were up-regulated in the cytokine-treated cells compared to control cells, especially in the presence of TNFa. However, the gene LICE that leads to irreversible apoptotic death was not increased, supporting the survival of BMSCs under inflammatory conditions during the 48-hour incubation. Conclusion: Our results are very encouraging with regard to the survival of BMSCs in an inflamed CNS environment and therefore could be tested as a potential cell-based therapy for MS. The study was supported by the Pythagoras research grant from the General Secretary for research and techonology of the Greek Ministry for Development

P423 Volumetric measurement of human red nucleus with 3D fast spin echo T2weighted sequence magnetic resonance imaging E. Rahimian, M. Tahsini, A. Vossough, B. Ohadi Dr.Athari Center (Tehran, IR); Massachusetts General Hospital (Boston, US) Objectives: The human red nuclei are a pair of globular, iron-containing structures located in the mid brain. Our purpose was to assess the feasibility and reliability of red nucleus volume measurements in healthy volunteers, and also to establish a normative baseline in order to assess its volume changes during the aging process and neurodegenerative disorders. Structures with high iron content such as red nucleus are easily identifiable in T2weighted images, and therefore a three-dimensional fast spin-echo (3D FSE) magnetic resonance imaging (MRI) sequence was performed in this study to measure the volume of the normal human red nucleus in-vivo. Methods: 20 healthy volunteers, 20 to 40 years old (10 men, age 27 ± 3.27 years (mean ± standard deviation) and 10 women, age 28.1 ± 4.7 years) were examined with a 3D FSE T2-weighted MR sequence using a 1.5-Tesla magnet. The scanning parameters were 2800/80/1 (repetition time/echo time/number of excitations), acquisition matrix size of 192 x 256, and a slice thickness of 1.5 mm. The 3D acquired images were transferred to an offline dedicated workstation for volumetric analysis and red nucleus volumes were manually quantified on axial slices. Results: The volume of the red nuclei were 265.28 ± 45.07 mm3/ 259.87 ± 48.68 mm3 (right/left) in men and 238.24 ± 36.96 mm3/ 242.59 ± 32.01 mm3 (right/left) in women. There was no statistically significant difference between volume of right and left nuclei in either gender (P> 0.05). Also, the measured red nucleus volumes showed no statistically significant difference between men and women (P> 0.05). The volume of the red nuclei was relatively constant between the ages of 20 to 40 years in both genders. Conclusion: To our knowledge, no study to date has measured red nucleus volumes for providing normative data. We attempted to define a feasible quantitative method for red nucleus volumetric measurements.

P424 Genetic tracing to visualise noradrenergic neuronal circuitry change after permanent focal cerebral ischaemia in mice B. I. Lee, Y. J. Cho, H. J. Kim, K. Heo, G. W. Kim, Y. B. Huh Severance Hospital Yonsei University College of Medicine (Seoul, KR); Kyunghee University College of Medicine (Seoul, KR) Objectives: The exact location or extent of noradrenergic circuitry damage, and its functional implication in stroke remains to be elucidated. We attempted to visualize the evolving features of noradrenergic neuronal circuitry after permanent focal cerebral ischemia (pFCI) in mice through a novel genetic tracing method using cDNA of wheat germ agglutinin (WGA) under the control of specific promoter element. Methods: Adult male C57BL/6 mice were subjected to pFCI by intraluminal suture occlusion of middle cerebral artery. The recombinant adenoviral vector introducing WGA and GFP cDNA under the control of noradrenergic neuron-specific PRS promoter was injected in the ipsilateral locus coeruleus (LC) of mice brain. Through the immunohistochemistry and in situ hybridization, the expression of WGA protein and mRNA were examined. 5-bromo-2’-deoxyuridine (BrdU) labeling was also performed. The measurement of blood pressure, body temperature, body weight, and neurobehavioral tests were also performed. Results: Double immunohistochemistry for WGA and tyrosine hydroxylase showed successful WGA expression in LC. In situ hybridization revealed that WGA mRNA was expressed exclusively in noradrenergic cell in LC. WGA protein was detected in various brain regions including pontine reticular nucleus, thalamus, lateral hypothalamic area, amygdala, and olfactory bulb. After pFCI, physiological and behavioral dysfunctions resulting from structural damages involving thalamic and hypothalamic regions were recovered by subsequent reorganization of noradrenergic circuitry over eight months of recovery phase. Conclusion: Here, we visualized the mice noradrenergic circuitry, using a novel genetic noradrenergic neuron-specific WGA expressing adenoviral vector system, and its change after ischemia. This suggests structural neural plasticity is responsible for functional recovery of noradrenergic system after cerebral ischemia.

P425 Attenuation of pro-inflammatory and apoptotic gene expression with NNZ2566 following experimental penetrating ballistic-like brain injury H. Wei, A. Williams, A. Pulcifur, A. Lim, K. De Souza, K. Phillips, Z. Liao, R. Chen, C. Yao, M. Lu, F. Tortella, J. Dave Walter Reed Army Institute of Research (Silver Spring, US) NNZ-2566 is a novel analogue of Glypromate® (Neuren Pharmaceuticals) recently shown to promote functional recovery following experimental penetrating ballistic-like brain injury (PBBI) in rats. The goal of the current study was to evaluate the effects of a neuroprotective dose of NNZ-2566 on both pro-inflammatory and apoptotic gene expression associated with PBBI. NNZ-2566 (10mg/kg) or vehicle (saline) was administered as an i. v. bolus injection at 30 min post-PBBI, immediately followed by a continuous infusion of NNZ-2566, 3mg/kg/h, or equal volume of saline (400ul/min for up to 12 h). Brain tissue was collected at 1 h, 4 h, 12 h, 24 h, 72 h, and 7 days post-injury for gene expression analysis (n = 3–6 per group). Initial studies using pathway focused low-density oligo-DNA microarrays (pooled tissue, n = 6 per group) indicated that NNZ-2566 reduced the increase in expression of genes related to both inflammation (7/11 genes) and apoptosis (3/5 genes) (> 2 fold difference between groups) as evaluated 4 h post-PBBI. Quantitative real time PCR was used to verify and extend the observed microarray results for several target genes. NNZ-2566 treatment significantly reduced the up-regulation of IL-6 (88 %), IL-1beta (70 %),TNF-alpha (42 %), E-selectin (66 %), ICAM (50 %), Casp-8 (99 %), Fadd (71 %), and Bax (99 %) in the acute phase of the injury (maximal response between 1–24 h) followed by a significant increase in the anti-apoptotic Bcl-2 gene (2 fold) at later time points (3–7days) as compared to matched vehicle control groups. These results indicate that the neuroprotective effects of NNZ-2256 are directly related to an attenuation of both inflammatory and apoptotic mechanisms of brain injury. The views of the authors do not purport to reflect the position Neuren Pharmaceuticals, the Department of the Army or the Department of Defense.

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P426 Lactadherin, a novel factor of A-beta peptide phagocytosis in Alzheimer’s disease J. Boddaert, K. Kinugawa, J-C. Lambert, F. Boukhtouche, J. Zoll, O. Blancbrude, D. Mann, C. Berr, J. Vilar, B. Garabedian, N. Journiac, D. Charue, JS. Silvestre, C. Duyckaerts, P. Amouyel, J. Mariani, A. Tedgui, Z. Mallat Inserm U689 (Paris, FR); Inserm U508 (Lille, FR); University of Manchester (Salford, UK); Inserm E361 (Montpellier, FR); Laboratoire développement et viellissement du système nerveux (Paris, FR); Pitié-Salpêtrière Hospital (Paris, FR) Objectives: Excess deposition of Abeta peptide is a hallmark of Alzheimer disease (AD). The most consistent genetic variability associated with the sporadic form of AD is at the ApoE locus. ApoE has been involved in A-beta clearance and phagocytosis of apoptotic cells. Interestingly, lactadherin is a secreted glycoprotein expressed by phagocytes that contributes to the phagocytosis of apoptotic cells. We therefore hypothesized that lactadherin may also contribute to phagocytosis of A-beta. Methods: Using western blot analysis, we examined the expression of lactadherin in various cultured cells including glial cells, neuronal cells and smooth muscle cells. Using immunohistochemistry and real time semiquantitative PCR analysis,we studied the expression and transrcription level of lactadherin in post mortem brain sections of AD patients and matched control. Surface plasmon resonance was used to detect an interaction between lactadherin and Abeta1–42 peptide. We then studied the role of lactadherin in phagocytosis of the Abeta peptide in vitro and in vivo using lactadherin knocked out mice and neutralizing specific antibodies. Results: vascular smooth muscle cells and astrocytes, showed a time-related increase in lactadherin production in culture. Lactadherin expression was found to be lower in the post mortem brain of AD patients in areas enriched in senile plaques. Quantitative analysis of the level of lactadherin showed 35 % reduction in lactadherin mRNA expression in AD brains (n = 52) as compared with age-matched controls (n = 5; p = 0.003). We found a direct protein-protein interaction between recombinant lactadherin and Abeta1–42 peptide. Lactadherin deficiency or neutralization using specific antibodies significantly inhibited Abeta1–42 phagocytosis by murine macrophages. Conclusion: Lactadherin plays key role in the phagocytosis of Abeta1–42 peptide and its expression is reduced in AD. Alterations in lactadherin production/function may contribute to the initiation/progression of AD. Fondation pour la recherche médicale, contrat d’interface AP-HP P427 Targeted gene expression analysis in Parkinson’s disease and ageing M. Elstner, C. Morris, H. Prokisch, M. Mader, T. Klopstock, D. Turnbull Ludwig-Maximilians University Munich (Munich, DE); School of Neurology, Neurobiology and Psychiatry (Newcastle upon Tyne, DE); National Research Center (Munich, DE) Microarray gene expression studies in neurodegenerative disease are a novel and promising approach for identification of genes and key regulatory pathways involved in disease pathology. Unlike other techniques current microarray platforms give a overview of the whole genome expression and allow detection of gene expression changes in an unprejudiced manner. This knowledge will amend currently available techniques in an effort to identify new diagnostic and therapeutic target genes. The necessary conditions for this approach are careful selection and processing of samples, targeted analysis of affected cell populations, and objective analysis and interpretation of microarray data.We analyzed whole genome expression in dopaminergic cells of the substantia nigra pars compacta (SNc) using laser microdissection, in-vitro transcription and microarray analysis. We compared gene expression data of SNc from post-mortem samples with Lewy-body pathology to age matched controls. Furthermore, we determined gene expression changes in ‘normal’ ageing. In all the samples investigated dopaminergic neuronal populations were distinct in vulnerability to cell death, i. e. ventral and dorsal tier of SNc.A large number of differentially regulated genes were detected, where the highest numbers of genes and most significant changes were seen with age and tier. Additionally we found previously unreported candidate genes in the disease including inflammatory and stress markers as well as neurotrophic factor response.

P428 Generation of neuronal and glial cells from adult skin by targeted microdissection of the human hair follicle D. P. J. Hunt, J. Anderson, D. A. S. Compston, S. Chandran University of Cambridge (Cambridge, UK) Objectives: Skin-derived precursor cells (SKPs) are neurogenic multipotent cells which reside in developing skin. SKPs can generate myelinating glial cells as well as neurons, and these cells have shown promise as cell based therapies for central and peripheral demyelinating disorders. However efficiency of isolation and propagation of SKPs from adult skin is poor, posing a significant barrier to further clinical translation.We approached this problem by identifying and targeting a highly enriched niche of SKPs in the dermal papilla of the adult hair follicle. Methods: Adult patients undergoing plastic surgery procedures donated facial skin samples for analysis. The dermal papilla of hair follicles was microdissected to quantify the enrichment of the dermal papilla for SKP-like cells. Spheres were characterised by immunocytochemistry and RT-PCR analysis. The generation of neural cells in response to a variety of external cues was studied. Results: We describe a highly enriched niche of adult SKPs in the dermal papilla of the hair follicle. The sphere-forming efficiency of isolated adult dermal papilla cells is 1000-fold higher than whole skin. Single dermal papilla cells generate multipotent “papillaspheres” which generate neuronal cells and Schwann cells following exposure to neurotrophic factors and neuregulin respectively. We demonstrate that papillaspheres can be generated in significant numbers by targeted microdissection of a single human facial hair follicle Conclusions: We describe a highly enriched niche of neurogenic skin-derived precursor /stem cells in the dermal papilla of the hair follicle. Targeted microdissection of this niche in adult human facial skin allows the efficient generation of neuronal and glial cells from a minimally invasive procedure. P429 Neosynthesized ganglioside GD3 induced by amyloid beta peptide targets to mitochondria in neural cell apoptosis J. K. Kim, H. R. Bae, S. U. Ha, M. J. Kim, B. G. Yoo, K. S. Kim Kosin University College of Medicine (Busan City, KR); Dong-A University College of Medicine (Busan City, KR) Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the extracellular deposition of amyloid beta peptide (A-b) in the brain. Neuronal apoptosis induced by A-b plays an important role in the pathophysiology of AD. However, the precise molecular mechanisms of its neurotoxicity are not fully understood. Gangliosides, sialic acid-containing glycosphingolipids, constitute a signaling system involved in the modulation of neuronal cell death as well as proliferation and differentiation. The disialoganglioside, GD3 has attracted attention due to its emerging role as an effector of apoptosis.We performed this study for evaluating the role and significance of ganglioside GD3 in A-b induced neuronal apoptosis. Methods: Human brain-derived TE671, T98G and U-87 MG cells were used. Apoptosis was induced by incubating cells with culture medium containing GD3, synthetic A-b fragment (25–35), Brefeldin A, H2O2, high potassium solution and Etoposide. Apoptosis was assayed by flow cytometry and western cleavage blots. Mitochondrial damage was assessed by JC-1 and cytochorome c release. Intracellular GD3 level was measured by thin layer chromatography (TLC) immunostaining. Expression of GD3 synthase mRNA was assayed with real-time RT-PCR. Cell surface GD3 trafficking was measured by flow cytometry and mitochondrial targeting was examined by confocal microscopy. Results: A-b or extracellular GD3 induced apoptosis of both neuronal cells and glial cells with higher susceptibility of neuronal cells. A-b stimulation induced the collapse of mitochondrial membrane potential, cytochrome c release from mitochondria, and activation of caspase-3 and PARP, indicating that A-b-induced apoptosis is linked to mitochondrial damage. TLC immunostaining showed a large increase in intracellular GD3 level after addition of A-b. The expression of GD3 synthase mRNA was also increased by A-b. Cell surface GD3 was increased 12 h after A-b treatment, and then decreased. Colocalization study using confocal microscopy revealed that GD3 was redistributed to mitochondria by its virtual disappearance from the plasma membrane in response to A-b stimuli. Membrane cholesterol disruption by MbetaCD prevented A-b-induced apoptosis. Conclusions: These results suggest that GD3 synthesis and its targeting to mitochondria with consequent mitochondrial dysfunction contributes to A-b-induced neurotoxicity.

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P430 Rosiglitazone increases hippocampal neurogenesis in type 2 diabetes animal model S. W. Jeong, E. Choi, J. H. Noh, D. W. Kim Dongguk University College of Medicine (Goyang City, KR); Ilsan Paik hospital (Goyang City, KR) Objective: Recent evidence has shown an association between diabetes mellitus and deficits in learning and memory. However, the mechanism by which cognitive abilities are impaired in diabetes has not been identified. The dentate gyrus of the hippocampus plays an important role in spatial learning and memory. It is known that hippocampal neurogenesis is decreased in type 1 diabetes animal model. To investigate whether peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone treatment affect hippocampal neurogenesis in type 2 diabetes animal model, we studied the proliferation rate of neural precursor cells in the dentate gyrus using bromodeoxyuridine (BrdU). Methods: We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of human type 2 diabetes (n = 20). From 31 weeks, we fed ordinary diet or rosiglitazone-contained diet (3 mg/kg/day) for 4 weeks. Afterwards, BrdU (50 mg/kg_) was subsequently administered once a day for 7 consecutive days. Animals were sacrificed 48 hrs after the last injection of BrdU. The numbers of BrdU-positive cells in the hippocampus were counted in every seventh section in a series of 30 μm coronal sections. Results: Blood glucose level in rosiglitazone-fed rats showed significant reduction after 4 weeks compared with ordinary diet group (119.11 ± 27.42 mg/dl vs. 244.40 ± 83.87 mg/dl, n = 10, respectively, p < 0.001). Rosiglitazonetreated rats showed significant large number of BrdU positive cells in hippocampus (58.45 ± 19.27 vs. 46.93 ± 17.16, p < 0.01). Conclusion: Our results showed that augmented cell proliferation in diabetes animal model treated with rosiglitazone. Appropriate glucose control may increases hippocampal neurogenesis in type 2 diabetes rats, which might be related to improved cognitive function.

Peripheral neuropathy P431 Peripheral neuropathy caused by chronic graft-versus-host disease after allogeneic bone marrow transplantation S. Thomann, S. Rüegg, J. Halter, M. Tolnay, P. Fuhr, A. Steck, S. Renaud University Hospital (Basel, CH) Objective: To present a patient with initially symmetric, cytostatic drug-induced sensorimotor polyneuropathy (PNP) and – after transplantation – asymmetric vasculitic PNP resulting most probably from graft-versus-host disease (GvHD). Case report: A 48-year old patient was diagnosed with common B-cell ALL with an aberrant myeloic marker. After complete remission following induction chemotherapy (including vincristine (VCR) and cytarabine (ARA-C)) he received high-dose consolidation therapy (including VCR and ARA-C). Two months later, he developed progressive sensorimotor PNP with acral numbness and weakness in all extremities. Nerve conduction studies showed severe sensorimotor axonal neuropathy. Chemotherapy was stopped and allogeneic bone marrow transplantation (ABMT) performed 4 months later. After initial improvement, the patient complained of painful, burning acral sensations two weeks after ABMT and clinically showed asymmetrical sensory impairment of all extremities and distal weakness of the lower extremities. Repetition of motor nerve conduction studies yielded a progression of the axonal peripheral nerve damage. Muscle/nerve biopsy revealed signs of small vessel vasculitis suggestive for chronic GvHD of the peripheral nervous system (PNS). Discussion: While PNS toxicity of VCR is well known, ARA-C rarely, and the other cytostatic drugs used in this patient almost never cause PNS complications. Most interestingly, our patient experienced a second worsening after ABMT and developed an asymmetrical sensorimotor PNP implicating a vasculitic, immune-mediated process. Nerve-muscle biopsy was consistent with the hypothesis of a chronic GvHD. So far, only a few cases have been reported with isolated chronic GvHD of the PNS after ABMT. The exact mechanism is poorly understood. Direct allograft T-or NK-cell-mediated cytotoxic effects on the PNS combined with neurotoxic and indirectly immune-mediated effects after exposure to cytostatic drugs may have contributed to this process. Immunosuppression with steroids and azathioprine led to improvement of the symptoms. Conclusion: Graft-versus-host disease of the PNS is a rare complication of ABMT. Differentiation from the more prevalent post-transplantation GBS/CIDP and neurotoxic effects of pre-transplantation cytostatic drug

therapy may be difficult. Nerve-/muscle biopsy together with asymmetric clinical presentation and axonal neuropathy upon electrodiagnostic testing may allow for the proper diagnosis. P432 Hereditary motor and sensory neuropathy type Lom in Serbian Romany family M. Keckarevic-Markovic, V. Milic-Rasic, V. Dobricic, M. Kecmanovic, R. Dimitrijevic, M. Saric, D. Savic-Pavicevic, D. Keckarevic, S. Todorovic, S. Romac Faculty of Biology (Belgrade, RS); School of Medicine (Belgrade, RS) Objectives: Hereditary motor and sensory neuropathy type Lom (HMSNL) is a severe autosomal recessive demyelinating neuropathy with onset before 10 years of age. The most distinctive symptom of HMSNL is deafness, beginning in 2nd or 3rd decade of life. HMSNL is caused by mutations in Nmyc downstream regulated gene 1 (NDRG1), which encodes for tumor suppressor and heavy metal response protein. The most common mutation in NDGR1 is C564T transition, resulting in the replacement of arginine by a stop codon at position 148 (R148X mutation). So far, R148X mutation has been identified in patients of Romani ethnicity in Bulgaria, Slovenia, Italy and Spain, implying HMSNL as the most common peripheral neuropathy among the Roma. The aim of this study was to analyze patients from Serbia with severe demyelinating HMSN for R148X mutation in NDRG1. All analyzed patients were negative for duplication and deletion of peripheral myelin protein 22 (PMP22) gene, of which PMP22 duplication is the most frequent mutation associated with demyelinating neuropathies. Methods:.DNA isolated from blood samples was used to PCR amplify exon 7 of NDRG1. 176 bp long PCR products were digested using TaqI restriction endonuclease, and restriction products were separated in 3 % agarose gels stained with ethidium bromide.C564T transition abolishes TaqI restriction site in exon 7 of NDRG1, so analysis of HMSNL patients on agarose gel show one band of 176 bp instead of two bands of 104 and 72 bp. Results: The analysis of 56 patients from 55 HMSN families revealed two patients from a single family with R148X mutation in NDGR1, thus identified them as HMSNL. Our HMSNL patients belong to a Romani family, 1 of 4 known Romani families analyzed in this study. Conclusion: HMSNL should be considered in the differential diagnosis of any patient with severe, early onset, demyelinating neuropathy, especially for patients with Romani ethnic background. Also, the most striking symptom of HMSNL, deafness, appears late in the course of the disease, so molecular genetic analysis of NDRG1 gene should be used as diagnostic tool even in cases where all symptoms are not present. P433 Guillain-Barré syndrome in the elderly S-H. Hwang, S-B. Kwon, S. Jung, S-S. Hong, K-H. Kwon Hallym University College of Medicine (Seoul, KR); Soon Chun Hyang University College of Medicine (Seoul, KR) Objectives: Guillain-Barre Syndrome (GBS) is now the most frequent etiology of acute flaccid paralysis and still an important cause of severe disability, particulary among aged patients. GBS has received little attention as a cause of peripheral neuropathy in elderly people. There are few papers specially addressing clinical, electrophysiologic and outcome profiles among elderly patients. Most available data do not take into account peculiarities of the geriatric group. We undertook this study to evaluate the clinical, neurophysiological and functional outcome profiles of GBS in older patients. Methods: We retrospectively reviewed clinical data and all neurophysiologic studies performed on patients at the Hallym Medical Center from 1996 to March 2006, who fulfilled published clinical criteria for GBS. Clinical and electrophysiologic findings in patients aged ≥ 60 years were compared with those aged 15–59 years. Results: Sixteen patients were over the age of 60 years and 46 between 15 and 60 years of age. Old patients more frequently had other diagnoses accompanying GBS. The duration of hospital stay was significantly longer in the elderly, though the overall functional outcome was similar in both age groups. There were no significant differences between old and young in: preceding illness; subtype of GBS; severity of maximal neurological impairment; requirement for artificial ventilation; CSF and serologic studies; electrophysiologic findings. Axonal GBS seems to be somewhat frequent in the elderly but the difference was not significant. Conclusion: The variety and severity of clinical and electrophysiologic features of GBS are similar in old and young adults. Although it may present with equal severity in both old and young, it carries a similar prognosis in the elderly. Old patients must be as vigorously managed as younger patients.

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P434 Oculomotor palsy and acute viral sinusitis R. Santos Silva, M. Arantes, M. Costa Hospital Pedro Hispano (Matosinhos, PT) Objectives: To display the clinical characteristics and establish a possible relationship between oculomotor palsy and viral sinusitis. Sinusitis refers to inflammation of paranasal sinus mucosa, despite aetiology. In the majority of cases there’s always involvement of more than one paranasal sinus, usually maxilar and ethmoidal. Ethmoidal and sphenoidal sinusitis are most likely to result in orbital complications namely regional cellulitis and orbital abscess. To our knowledge there is no report of oculomotor palsy related to ethmoidal sinus infection in so far. Methods: Correlation of imaging and clinical findings Results: 48 year-old woman presented with diplopia and non painful right eye ptosis following a previous nasosinusal infection. Her medical history included several episodes of rhinosinusitis and she was a heavy smoker. She had no history of migraine or thyroid pathology. Neurological examination was consistent with a right oculomotor palsy. Laboratory evaluation disclosed no abnormality. Brain computed tomography (CT) scan and Magnetic resonance imaging (MRI) revealed bilateral ethmoidal sinusitis. She started treatment with nimesulide and had full recovery in about one week. 54 year-old man admitted to our hospital with left eye ptosis preceded by a eight day evolution of a flue-like syndrome. His past medical history was unremarkable. Neurological examination revealed left oculomotor palsy. Laboratory evaluation was unrevealing. Brain and orbital CT scan showed bilateral ethmoidal and right maxilar sinusitis. He began treatment with nimesulide and clinical features subsided entirely in a five day period. Conclusions: Ethmoidal sinusitis may cause oculomotor neuropathy in result of direct extension of nasosinusal infection to the orbit through the natural dehiscence of papyraceous lamina. We hipothized that reversible oculomotor palsy was due to inflammatory neuropathy related to viral sinusitis. P435 Risk factors for cardiovascular autonomic neuropathy in type 2 diabetes mellitus patients E. Semyatichko, V. Nemtsova, I. Feclina Kharkov Medical University (Kharkov, UA) Objective: Risk factors for diabetic cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes were analyzed to establish a regression model for evaluating the diagnosis of CAN. Methods: 116 patients with type 2 diabetes were divided into four groups according to the results of four standard function tests. Every patient was required to offer detailed disease history and accept physical examination, serum and urine tests and examinations including ECG, nerve conduction velocity, retinoscope and Doppler of carotid and lower limb arteries. Results: 63.7 % of the patients had abnormal autonomic function and 29.8 % definite CAN. There was significant difference among groups about age, average glycosylated forms of hemoglobin (HbA1 c), systolic blood pressure, corrected 24 h albumin excretion and heart rate at rest (P < 0.001). The incidence of diabetic complications and accompanying diseases increased with deterioration of CAN (P < 0.05). The regression model showed that age, average HbA1 c, hypertension, peripheral neuropathy, retinopathy, tachycardia at rest and duration of peripheral neuropathy were significant related factors for CAN. With these factors, a mathematic formula was established which could be used for evaluating the diagnosis of CAN. Conclusion: All risk factors, except age and hypertension, were induced by hyperglycemia. It is suggested that control of hyperglycemia is of primary importance in preventing diabetic complications. P436 Contralateral reinnervation of orbicularis oris after peripheral facial palsy J. Casanova-Molla, J. Fortea, J. Valls-Solé Hospital Clínic (Barcelona, ES) Introduction: Reinnervation motor unit action potentials can be seen in the orbicularis oris (OOr) of most patients with unilateral facial paralysis a few weeks after onset. This is impossible to be due to ipsilateral nerve growth in cases with complete denervation and the possibility of reinnervation by the contralateral nerve has been suggested through two pathophysiological mechanisms: sprouting of axons crossing the midline or preserved activity in circular muscle fibers which motor endplate lies in the contralateral side.

Objective: To characterize the timing and electrophysiological features of contralateral reinnervation of the OOr in patients with complete denervation due to peripheral facial palsy. Methods: We studied the responses induced in the OOr of the paralyzed side by stimuli applied to the contralateral healthy facial nerve. Patients were 11 women and 14 men, aged 27–74 years, with complete peripheral facial palsy of different causes: idiophatic (15), postoperative (6), postinfection (2) and posttraumatic (2). The study was performed 10 days after onset, and up to the presence of ipsilateral reinnervation. The EMG activity was recorded with a concentric needle electrode implanted about 1 cm lateral to the oral comisure. We used conventional surface electrodes for stimulation of the non-paralyzed side at different points along a line between the tragus to midline lower lip. We measured the latency of the responses and their variability. We calculated conduction velocity in several segments. Results: We found responses of paralyzed OOr by contralateral non-paralyzed electrical stimuli in all patients at 20 days after onset. Mean conduction velocity in the segment tragus-oral comisure was 45.5 m/s (SD = 5.85) and the latency variability was of 0.23 ms. Mean conduction velocity in the segment oral comisure-midline lip was 4.62 m/s (SD = 1.5) and the latency variability was 0.01 ms. The characteristics of the individual responses remained unchanged in subsequent examinations. Conclusion: Our results confirm that contralateral facial nerve reinnervation takes place in patients with complete denervation, starting at a time compatible with collateral sprouting. This phenomenom occurs at OOr where denervated muscle fibers run from side to side, parallel to normally innervated muscle fibers. Our conclusion is that the responses of the OOr to contralateral nerve stimulation are recorded after propagation of impulses through muscle fibers across the midline. P437 Painful polyneuropathy in patients presenting hepatitis C and autonomic dysfunction O. J. M. Nascimento, B. Coutinho, M. R. G. de Freitas, G. Quintanilha, R. R. Silveira, M. Maroco Universidade Federal Fluminense (Rio de Janeiro, BR) Objective: Painful neuropathies are related to peripheral neuropathies of small myelinated and demyelinated fibers. There are many related causes for these neuropathies but most of them are still not understood. Our goal is to report the occurance of neuropathic pain in Hepatitis C infected patients, associated or not to autonomic dysfunction. Methods: we analyzed the prevalence of neuropathic pain in a group of twelve patients presenting Hepatitis C and sensory small fiber polyneuropathy.Anamnesis, and pain evaluation tools as visual analogue scale (VAS) and SF questionnaire were used to evaluate this prevalence. We applied four cardiovascular and autonomic tests: respiratory sinus arrhythmia, passive head-up tilt-table test, isometric exercises and Valsalva maneuver. Results: five patients (41 %) complained about burning pain in distal lower limbs. It was more frequent during the night. Other modalities of pain were not referred by the patients. Four out of these five patients presented abnormal cardiovascular and autonomic tests. Conclusion: Our results point to the importance of a neuropathic pain questionnaire during the anamnesis of patients with Hepatitis C. The neuropathic pain in these patients seems to be due to an ischemic (microvasculitis) process. Patients with Hepatitis C and neuropathic pain seems to present autonomic dysfunction related to efferent sympathetic denervation. Evaluation P438 Risk factors for diabetic distal symmetric sensorimotor polyneuropathy in Korea J. Y. Oh, D. L. Kim, H. J. Kim, H. Y. Kim, I. K. Lee, S. H. Han, K. D. Park Konkuk University School of Medicine (Seoul, KR); Ewha Womans University School of Medicine (Seoul, KR) Objectives: Distal symmetric sensorimotor polyneuropathy (DMPN) is one of the most common complications of diabetes mellitus. There is no proven method for quit or delay the neuropathy other than strict control of serum blood glucose level. If there are some modifiable factors associated with DMPN,it would be a great therapeutic challenge to reduce the morbidity and to improve the quality of life of the patients with diabetes mellitus. Methods: We examined type 2 diabetic patients, aged from third to seventh decades, from Konkuk University Hospital diabetic clinic. To differentiate the patients with polyneuropathy from the patients without polyneuropathy, we performed brief questionnaire and neurological examinations using Michigan Neuropathic Diabetic Scoring (MNDS). DMPN was confirmed by nerve conduction study (one upper extremity and two lower ex-

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tremities). 47 patients with DMPN and 53 patients without DMPN were selected. The relation between the presence of neuropathy and multiple factors including age, sex, disease duration, height, body weight, body mass index (BMI), presence of hypertension or retinopathy, smoking, and biological markers were analyzed with logistic regression model. Results: After adjustment for two major risk factors, disease duration and level of glycated hemoglobin, microalbuminuria has strong relationship with diabetic polyneuropathy. There was no statistical evidence of relationship between neuropathy and other cardiovascular risk factors, such as serum lipid level, BMI, smoking, and gender. Conclusion: Our results imply that DMPN share common pathophysiologic mechanism of microalbuminuria exclusive of vascular ischemia. Further studies observing the efficacy of clinical strategies for nephroprotection on neuropathy would be meaningful to find methods retarding progression of neuropathy aside from aggressive glycemic control. P439 Features of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer A. Argyriou, P. Polychronopoulos, G. Iconomou, A. Koutras, P. Gourzis, K. Assimakopoulos, H. Kalofonos, E. Chroni University Hospital of Patras (Rion-Patras, GR) Aim: The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern. Patients and methods: Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients, were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS). Results: Evidence of OXLIPN was disclosed in 16 of the 25 patients (64 %). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9 ± 5.8 (range 7–28). All longitudinal comparisons concerning the motor conduction velocities parameters failed to reach significance. By contrast, comparisons of the mean changes at baseline and each of the follow-up studies revealed significant decrease in the amplitudes of all sensory action potentials examined. Conclusion: Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity. P440 Evidence for minimal abnormalities of motor axonal excitability in restless leg syndrome R. Dilena, L. Ferini-Strambi, S. Marceglia, F. Cogiamanian, S. Mrakic-Sposta, A. Leone, M. Vergari, S. Barbieri, A. Priori University of Milan Fondaz. IRCCS – Osp.Policlinico (Milan, IT); University Vita-Salute – S. Raffaele (Milan, IT) Objective: Though standard neurophysiological techniques (nerve conduction studies, electromiography, H and F reflex responses, somatosensory evoked potentials) failed to disclose consistent abnormalities in Restless Leg Syndrome (RLS), these methods cannot detect subtle abnormalities of nerve fibres excitability.Yet, several disorders affecting the peripheral nervous system can give rise to symptoms resembling RLS. We therefore aimed to assess whether subtle abnormalities of motor axonal excitability are present in RLS (Iannaccone et al. 1995) Methods: Twelve tibial motor nerves from 6 RLS patients most under dopaminergic treatment and 18 tibial motor nerves of healthy subjects were studied. We estimated motor compound action potential (CMAP) amplitude, motor threshold, strength-duration curve and recovery cycle (Priori et al. 2002). Results: Group statistic showed that CMAP threshold and amplitude, strength-duration properties (time constant and reobase), supernormal and subnormal period did not significantly differ between RLS patients and controls. Though not significantly, subnormality was slightly decreased and motor threshold slightly increased in patients. But, composite indexes of axonal excitability revealed significant differences between patients and controls (motor threshold divided for CMAP amplitude – mT/A- and subnormality divided for CMAP amplitude – SbN/A- p < 0.05). Conclusions: Though our findings rule out abnormalities of the elementary variables of axonal excitability, the analysis of composite indexes of axonal excitability (mT/A and SbN/A) would suggest very subtle abnormalities of motor axonal excitability in RLS.

P441 Rituximab therapy in IgM paraproteinemia related neuropathies C. Kilidireas, A. Anagnostopoulos, N. Karadreas, E. Kastritis, D. Vassilopoulos, M. Dimopoulos University of Athens (Athens, GR) Objective: Treatment of IgM paraproteinemia related neuropathy with antiCD20 chimeric monoclonal antibody (Rituximab). Methods: Eleven patients with Demyelinative neuropathy and IgM monoclonal gammopathy (one of them biclonal IgMI IgA) were treated with Rituximab. The underlying disease was 1-MALT lymphoma, two Waldenstrom and 8 MGUS). Western Blot analysis (pure MAG), TLC overlay (Glycolipid extracts of Bovine Cauda Equine) and ELISA (Gangliosides) were used for target antigent identification. Neurophysiological testing and clinical scales including MRC in six groups, Hand Grip, 9 hole peg test, sensory sum score, Vibration threshold and 10 m walk were assessed, before therapy, one month after and every six months. Results: Clinical syndromes include five anti-MAG neuropathies, four CIDP and two IgM related neuropathies without identified target Ag. Four out of five anti-MAG neuropathy patients showed improvement (three slight and one significant 10–20 % in almost all scales lasting for 6–9 months). One out of five was stable and deteriorated two months later finally cured with cytostatics. The CIDP patients showed significant improvement. Two out of four had complete remission lasting for seven and four years respectively and the two others (one with biclonal IgM, IgA with SGPG but not MAG as IgM target antigen) showed significant improvement. The remaining two patients improved also. In conclusion Rituximab therapy is effective, particularly in CIDP-IgM paraproteinemia related neuropathy, but more studies are needed to determine the specific clinical, immunological and neurophysiological determinants of a favourable therapeutic response. P442 Bilateral isolated phrenic neuropathy and myasthenia gravis: case report A. F. Valadas, A. C. Fonseca, A. R. Peralta, F. Morgado, M. Carvalho, L. Albuquerque Hospital Santa Maria (Lisbon, PT) Background: Bilateral phrenic neuropathy associated with arm weakness and neck or shoulder pain, is usually included in the spectrum of immune brachial plexus neuropathy. We present a patient with Myasthenia Gravis (MG) and Bilateral Isolated Phrenic Neuropathy (BIPN) as a rare association of immune-mediated conditions. Clinical Case: A 56-year-old woman was admitted into the intensive care unit for respiratory failure. In the week before admission she has progressively developed dyspnea, exercise intolerance and orthopnea. The patient has MG for twelve years, (clinical, EMG and acetylcholine receptor antibodies based diagnosis) but she has been asymptomatic for the last ten years on pyridostigmine (120 mg/day) treatment. The clinical examination was normal except for the presence of orthopnea and paradoxal respiration on supine position associated with arterial desaturation. Results: No motor responses were obtained bilaterally by phrenic nerve stimulation in neck. Needle EMG of right diaphragm disclose fibrillation sharp waves, no motor units (MU) during inspiration on the right side, but on the left side four remaining MU were observed. Repetitive stimulation was normal in trapezius, anconeus and abductor pollicis brevis. Needle EMG of sternocleidomastoid and intercostals muscles were normal, and sternocleidomastoid was activated during inspiration. Chest X-rays demonstrated bilateral elevation of the diaphragm. The cervical and thoracic CT scans and cervical spine and plexus MRI showed no abnormalities. CSF examination including culture and serologic screening tests for Lyme disease, Syphilis and herpevirus were negative. The screening for vasculitis was negative and seric angiotensin converting enzyme was normal. Treatment with intravenous immunoglobulin was not effective and non-invasive ventilation was applied for patient respiratory support. Respiratory improvement has been observed. Conclusions: This case represents one very rare association of two autoimmune disorders and suggests that phrenic conduction should be performed in MG patients with respiratory impairment disproportionate.

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P443 Leg and foot magnetic resonance imaging features in axonal and demyelinating Charcot-Marie-Tooth diseases H. S. Song, J. H. Lee, K. D. Park, K. G. Choi, I. N. Sunwoo, S. M. Kim, B. O. Choi Ewha Womans University College of Medicine (Seoul, KR); Yonsei University College of Medicine (Seoul, KR) Objectives: Charcot-Marie-Tooth disease (CMT) is a heterogeneous motor and sensory neuropathy, all most marked in the distal part of the legs. CMT1A with PMP22 duplication is the most frequent cause of demyelinating CMT, and CMT2A with MFN2 mutations is the most common cause of axonal CMT. CMT2A patients cluster in two subgroups; a severe early-onset (EO; < 10years) and a milder late-onset (LO; ≥ 10years) groups. MRI is an ideal method for identifying areas of muscle atrophy and fatty infiltration that occur secondary to denervation in demyelinating or axonal neuropathies. Methods: A total of 39 CMT1A patients with PMP22 duplication and 21 CMT2A patients with MFN2 mutations (EO, 10 and LO, 11) were evaluated. In all 60 patients, leg MRI studies included T1- and T2-weighted spinecho sequences in coronal and axial planes. In 57 patients, both feet were simultaneously studied in coronal and axial planes.Axial images were divided into 4 compartments and individual muscles. Results: Frequency of patients who had toe gate defect was significantly higher in LO than in CMT1A (p < 0.001). Cross-sectional areas in leg MRI strongly correlated the disability as measured by CMTNS and FDS scores in CMT2A patients (p < 0.001), but not in CMT1A patients. MRI of EO cases showed marked fatty infiltration in all four compartments, whereas LO cases showed selective fatty infiltration with a preference for the soleus muscle, and CMT1A patients showed a preference for the TA and peronei muscles. These results were well correlated with clinical findings. In LO, we found a tendency toward the orderly involvement of lower leg muscles from soleus to TA, and TP muscles with ages. Involvement of intrinsic foot muscles is a characteristic of both demyelinating and axonal CMT with minimal disease signs, and those are compatible with a length-dependent neuropathy. Conclusion: MRI findings of CMT1A patients are classified as the “P type” showing preferential peroneal nerve innervated muscle involvement and CMT2A classified as the “T type” preferential tibial nerve innervated muscle. In LO, prominent involvement of soleus muscle but not TA or peronei muscles is distinct from what has been found in CMT1A and may be related to type 1 fiber type predominance and/or mitochondrial axonal transport dysfunction. Therefore, MRI imaging provides a sensitive, potentially quantifiable method of evaluating CMT.

P445 Reliability of quantitative sensory analysis in the diagnosis of early small fibre neuropathy P. Lozeron, D. Adams, C. Lacroix, G. Said, V. Planté Bordeneuve CHU de Bicêtre (Kremlin Bicêtre, FR) Objective: Evaluate the diagnostic role of quantitative sensory testing (QST) in the detection of early small fibre neuropathy, such as TTR familial amyloid polyneuropathy (FAP). To this end, the data of QST were compared to the clinical findings and the morphological aspects of the sensory nerve in a prospective pilot study. Methods: Eleven carriers (6 women / 5men) of pathogenic TTR mutations were included in the study.All of them presented with recent mild neuropathic symptoms and on examination by 2 independent examiners, temperature and pain sensation were decreased in a stocking distribution. QST (Case IV, WR Testworks) and near nerve sensory potential recording were performed in the lower limbs in all cases and completed by a sural nerve biopsy to corroborate the diagnosis of TTR-FAP. A quantitative analysis of the small myelinated fibres (MF) and unmyelinated fibres (UF) was performed on cross sections in optic and electronic microscopy. QST is considered as impaired when results are above 2 standard deviations (2 SD). QST thermal and heat pain sensations data were compared to the clinical findings and to the density of small MF (≥ 8μ) and UF of the nerve specimen. Results: QST thermal sensation was quoted as abnormal (> 2 SD) in 2 cases with no evidence of small MF loss on nerve biopsy. Conversely, it was rated as normal (< 2 SD) in 2 patients who presented significant loss of small MF and an active axonal degeneration on the sampled nerve. Likewise, QST heat-pain sensation was quoted as normal (< 2SD) in 6 patients with decreased UF density, whereas it was quoted abnormal (> 2 SD) in one case with normal UF density. Overall, discrepancies were observed between QST thermal and /or heat pain sensations and nerve biopsy findings in 8 of the 11 cases.Furthermore,in five of these 8 patients QST was misleading because it contradict relevant clinical findings. Finally, sensory potential was normal in all but 3 patients who had additional decreased of large fibre density. Conclusion: QST findings showed some discrepancy with the other tests. This underlines the difficulty to detect early sensory defects in small-fibre neuropathies. Misleading results may delay liver transplantation in TTRFAP.

P444 Efficacy of intravenous immunoglobulin treatment in demyelinating neuropathy associated with monoclonal gammopathy of unknown significance M. Théaudin, P. Lozeron, C. Lacroix, D. Adams, V. Planté-Bordeneuve, G. Said, CHU Bicêtre (Kremlin-Bicêtre, FR)

Poster session 3

Objectives: To study restrospectively the efficacy of IVIg, considered as an efficient treatment in CIDP, in patients with demyelinating neuropathy associated with MGUS. Material and methods: the data of 21 patients (10 females/11males), seen in our center between 2003 and 2007 were reviewed. The diagnostic of the neuropathy relied on clinical examination, electrodiagnostic tests. A nerve biopsy was performed in 13 cases. IgM monoclonal gammopathy was diagnosed in 16 cases with anti-MAG activity in 7 patients, IgA or IgG in 5. The course of the neuropathy was progressive in 11 cases, whereas relapses occurred in 10. All patients were evaluated before the first infusion, then 1 to 3 months after, and at an average follow up of 1.9 years [0.2–5.5]. In addition to a neurological examination, assessment included a standardized evaluation of the walk and a functional grading score (modified Norris score). IVIg was prescribed at the dose 1 to 2 g/kg body-weight. Seven patients also received specific chemotherapy for their gammopathy. Results: At first evaluation, 5 patients had improved, (4 had a relapsing course), 15 were stable and one deteriorated further. On the long term follow up, 3 patients remained improved, 8 were stable and 10 deteriorated. Presently, 10 patients continue to receive IVIg infusions regularly. Serious side effect (generalized seizure) occurred in 1 patient. In the present study, the majority of patients (20/21) with demyelinating neuropathy and MGUS seem to improve or stabilize shortly after IVIg infusion. After 1.9 years of treatment, approximately half of them have a sustained stabilization. In our experience, these results are not as good as in CIDP patients without MGUS in which one third of the CIDP patients have a sustained improvement after 2.5 years of IVIg treatment (Fagniez et al, P606, ENS 2005). Conclusion: IVIg treatment can be useful in the management of demyelinating neuropathy with MGUS.

P446 General perception of stroke in North East Nigeria: a preliminary report F. Salawu, A. Danburam, D. Balami, J. Agbo, K. Onye-eri Federal Medical Centre (Yola, NG); State Specialist Hospital (Maiduguri, NG)

Cerebrovascular disorders

The number of patients with stroke continues to increase in Nigeria because of demographic changes and the inadequate control of major risk factors for stroke. Combating this huge problem depends largely on increased awareness among the general public on the prevention strategies. Objectives: To assess the knowledge of stroke and potential risk factors among the general public in north east Nigeria. Methods: A cross-sectional community based survey was carried out at primary health centres in urban and semi-urban areas of two large states in north east Nigeria. Four hundred and fifty randomly selected adults were interviewed face-to-face by trained health-care workers using a structured, pre-tested questionnaire. No attempts were made to prompt the subjects by suggesting answers directly. Results: Ninety-five (21 %) respondents had heard of the term stroke but their concepts of it varied widely, 18 % knew that stroke occurred in the brain, and 22 % considered age group 40 to 50 at highest risk for stroke. The commonest risk factors identified were hypertension (15 %) and old age (18 %). None of the subjects knew eating at least 5 servings of fruits and vegetables a day, and limiting one’s salt intake to less than one teaspoon a day, could help to prevent strokes. Almost half of the patients thought stroke resulted from mystical powers and witch-craft. The blockage of blood vessels was recognised as the commonest cause of stroke (16 %) followed by tension and worrying (36 %). The most frequently identified stroke symptoms were weakness of one-half of the body (20 %) and difficulty speaking (18 %). People who did not recognize the term stroke had lower educational attainment,

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and level of stroke knowledge was poorest among housewives, artisans and traders. In univariate comparison, younger age (p < 0.001), male gender (p < 0.05), higher level of educational attainment (p < 0.0001) and family history of stroke (p < 0.001) predicted better stroke knowledge. Surprisingly only 10 % of subjects had received information about stroke from health professionals (doctors 6 %, and nurses 4 %). Conclusion: The knowledge about stroke prevention and early stroke recognition is poor in the general population. The participants viewed stroke as a supernatural phenomenon and as a significant cause of death and morbidity and were aware of the sudden impact on family life, but unfortunately they were ignorant that it is preventable. P447 An audit of stroke care in a Nigerian tertiary care hospital F. Salawu, A. Danburam, S. Bwala, H. Mshelia, I. Abdullahi Federal Medical Centre (Yola, NG); University of Maiduguri (Maiduguri, NG); State Specialist Hospital (Maiduguri, NG); Federal Medical Centre (Azare, NG) Most neurological problems in Nigeria are first dealt with by general practitioners and hospital physicians, not by neurologists. Its burden is enormous and a major cause of death and disability in developing countries. Objective: We carried out a descriptive audit of stroke care in a tertiary care hospital in 2006 and compared with a 2001 audit to assess changes in stroke management vis-à-vis modern management of patients with acute stroke. Methods: The records of patients admitted with a diagnosis of stroke into the University of Maiduguri Teaching Hospital were reviewed. The timing of the audit (May to October) and the method of identification were the same as those used in 2001. Details of health-care team responsible for management of these patients were reviewed. Results: There were 43 stroke patients (29 men and 14 women) with age range of 42–79 years, unlike 36 stroke patients in 2001. Twenty-five percent of patients with stroke were treated under general medicine by non-neurologists and 75 % in general neurology units by 2 neurologist and 3 neurological residents in 2006, while 8 % were treated under general medicine by 1 neurologist and 3 neurological residents in 2001. There were no stroke units. There has been an increase in the proportion of patients taking aspirin or warfarin at the time of admission with stroke. Most patients arrive at the hospital after 24 hours, with less than 10 % arriving within 3 hours of symptom onset. An accurate time of stroke was identified in 70 % of patients. The frequency of diagnostic tests was low. Computerized tomography (CT) scans were performed in 45 % of stroke patients in 2001, compared to 70 % in 2006. However; no CT scan was performed within 3 hours. Magnetic Resonance Imaging became available in 2006. Doppler studies were underutilized. Inpatient rehabilitation has increased by 50 %. Almost all surviving ischaemic stroke patients were discharged on antiplatelet or anticoagulant therapy. At discharge in 2006, lipid lowering medications had been prescribed to 30 % of surviving patients. Conclusion: This audit has enabled an examination of changes in stroke management and demonstrating a partially sub-optimal level of care in our practice. Stroke units are non-existent, and local standards for stroke care and prevention are in use, not in line with European and United States guidelines. Because of this, there is need to periodic audit in order to improve the outcome of management of our stroke patients. P448 Splenic atrophy in experimental stroke is accompanied by increased Treg cells and circulating macrophages H. Offner, P. Hurn Oregon Health & Science University (Portland, US) Objectives: The objective of this study was to evaluate effects on spleen and blood four days after experimental stroke induction in the mouse. Induction of stroke not only produces local ischemia and brain damage, but also has profound effects on peripheral immune responses. Methods: Age-matched male mice were used in all experiments. Focal cerebral ischemia was induced by 90 min of reversible MCAO under halothane anesthesia. At end-ischemia, the animal was briefly reanesthetized and reperfusion was initiated by filament withdrawal. Sham-operated mice were treated identically with the exception of insertion of the filament to produce occlusion. Four days after stroke induction, terminal histopathology, cytokine determination by CBA, proliferation assay, analysis of cell populations by FACS, RNA isolation and RT-PCR, and TUNEL were performed. Results: In the current study, we evaluated effects on spleen and blood cells four days after stroke induction. Surprisingly, there was a less inflam-

matory cytokine profile in the MCAO-affected right brain hemisphere at 96 h compared to earlier time points. Moreover, our results demonstrate that stroke leads to splenic atrophy characterized by a reduction in organ size, a drastic loss of splenocyte numbers, and induction of Annexin V+ and TUNEL+ cells within the spleen that are in the late stages of apoptosis. The consequence of this process was to reduce T cell proliferation responses and secretion of inflammatory cytokines, resulting in a state of profound immunosuppression. These changes produced a drastic reduction in B cell numbers in spleen and blood, and a novel increase in CD4+FoxP3+ regulatory T cells. Moreover, we detected a striking increase in the percentage of non-apoptotic CD11b+ VLA-4 negative macrophages/monocytes in blood. Conclusions: Immunosuppression in response to brain injury may account for the reduction of inflammatory factors in the stroke affected brain, but also potentially could curtail protective immune responses in the periphery. These findings provide new evidence to support the contention that damage to the brain caused by cerebral ischemia provides a powerful negative signal to the peripheral immune system that ultimately induces a drastic state of immunosuppression caused by cell death as well as an increased presence of CD4+FoxP3+ Treg cells.

P449 MMP-2, MMP-9 and their inhibitors in ischaemic stroke. Gender differences and time course D. Mirowska-Guzel, G. Gromadzka, V. Vargas-Leal, A. Kobayashi, R. Poniatowska, A. Czlonkowski, A. Czlonkowska, F. Weber Medical University of Warsaw (Warsaw, PL); Institute of Psychiatry and Neurology (Warsaw, PL); Max-Planck Institute for Psychiatry (Munich, DE) Objectives: Matrix metalloproteinases (MMPs) are involved in remodelling of extracellular matrix of different tissues, including central nervous system (CNS). Tissue inhibitors of metalloproteinases (TIMPs) inhibit MMPs activity, with TIMP-1 inhibiting activity of MMP-9, and TIMP-2 of MMP-2. In experimental and clinical studies, increased MMPs synthesis during the course of ischemic stroke (IS) was detected. In animal models of brain ischaemia, MMP-9 expression was related to blood-brain-barrier disruption, oedema formation, and hemorrhagic transformation. Experimental studies suggest that MMPs synthesis may be gender dependent. The aim of the present study was to analyze the time course of synthesis of MMPs and TIMPs in male and female patients after IS. Methods: One hundred fifteen patients (58 men, 57 women) admitted to our hospital within 12 hours after the onset of IS were included to the study. Peripheral blood was collected from each patient at the study entry, after 24, 48 hours, 3 and 7 days. Serum levels of MMP-9, TIMP-1, MMP-2 and TIMP-2 were determined by ELISA. Results: Among IS patients (analyzed without and with stratification by gender) the MMP-2 and TIMP-2 levels at 24 h, 48 h, 3 and 7 days after onset were significantly lower compared to baseline. No significant changes in serum concentration of MMP-9 were noticed during the observation period. TIMP-1 was lowest at study entry, and increased significantly to reach a peak at day 7. MMP-2 level was lower in males than in females within the first 3 days, but comparable at day 7. Serum MMP-9 was significantly lower in women than in men at all time points of the study. No gender difference was seen in TIMP-1 and TIMP-2. Conclusion: Our results show that MMP-2 synthesis is both time and gender dependent, whereas MMP-9 level was only gender dependent. TIMPs levels are not affected by gender, but their levels change significantly after the onset of acute stroke. Given the results of animal experiments, increase of TIMP-1 after the onset of stroke could be of importance concerning its inhibitory potential on MMP-9 activity. The study was supported by ENS grant for 2005 and State Committee for Scientific Research grant No 2P05B 01827.

P450 Edaravone diminishes reactive oxygen species of circulating neutrophils in patients with ischaemic brain attack H. Aizawa, Y. Makita, K. Sumitomo, Y. Aburakawa, T. Katayama, S. Enomoto, Y. Suzuki, M. Nakamura, K. Fujiwara, H. Enomoto, K. Kuroda, T. Kimura, O. Yahara, S. Koyama, J. Maruyama, N. Hasebe, K. Kikuchi Asahikawa Medical College (Asahikawa, JP); National Dohoku Hospital (Asahikawa, JP); Asahikawa Rehabilitation Hospital (Asahikawa, JP) Objective: Accumulating evidence implicates free radicals in the damage of ischemic brain attack, and free radical scavengers have been proposed as a new clinical strategy.We examined the alteration of oxidative stress markers

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due to edaravone, a novel free radical scavenger, in human ischemic brain attack. Methods: Twenty-one patients with ischemic brain attack and 19 controls were enrolled in this study. Edaravone treatment was started for the patients within 24 hours after the onset of ischemic brain attack. Blood samples were obtained just before and soon after the first administration of edaravone (30mg) or ozagrel (40mg), a thromboxane A2 synthase inhibitor. Intracellular reactive oxygen species (ROS) of neutrophils was measured using 6-carboxy-2’, 7’-dichlorodihydrofluorescin diacetate and a fluorescenceactivated cell sorter. Superoxide from neutrophils, induced by phorbol myristate acetate (PMA), was determined by luminol-amplified chemiluminescence assay. Results: Treatment with 30 mg of edaravone significantly decreased intracellular ROS of neutrophils (Wilcoxon test, p = 0.0001) and PMA-induced superoxide produced by neutrophils (Wilcoxon test, p = 0.001). Ozagrel did not alter the intracellular ROS or superoxide production of neutrophils. Conclusion: Edaravone diminished free radicals in circulating neutrophils in patients with ischemic brain attack, which could at least partially explain the clinical efficacy of edaravone on ischemic brain attack. P451 Thrombolysis: more time, less speed A. H. C. M.L. Schreuder, C. L. Franke Atrium Medical Centre (Heerlen, NL) Objectives: The time window for thrombolysis in acute ischemic stroke is three hours. This time window consists of two parts: onset of stroke till arriving at hospital, the onset-to-door time, and from arriving at hospital till the start of the thrombolysis, the door-to-needle time. According to the NINDS-criteria the door-to-needle time may not exceed one hour. We investigated the door-to-needle time in relation to the onset-to-door time. Methods: We registered data on onset-to-door and door-to-needle time prospectively as part of our thrombolysis registration in order to evaluate the quality of this therapy. From June 2001 until January 2007, more than 250 patients were treated. The analysis centers on the door-to-needle time needed for thrombolytic therapy in the first 200 patients. Results: 200 patients (107 men) with a mean age of 73 years (21–96) received treatment between June 2001 (the start of thrombolysis) and April 2006. The mean NIHSS-score at admittance was 11 (1–22), the mean onsetto-door time 61 minutes (10–130) and the mean door-to-needle time 74 (20–155). The mean onset-to-door time reduced from 69 minutes in 2001 to 54 in 2004 but did rise up to 64 minutes in 2005. The mean door-to-needle time shortened from 101 in 2001 to 65 minutes in 2005. A short onset-todoor time led to an evidently longer door-to-needle time: of all patients the 25 % with the shortest onset-to-door time (mean 30 minutes (10–40)) had a door-to-needle time of 83 minutes versus 63 minutes for the 25 % with the longest onset-to-door time (mean 102 minutes (82–135)), a difference of 20 minutes. Conclusion: The results of the study show that we did not comply with the NINDS-criteria for door-to-needle time. Our mean door-to-needle time in 2005 was 5 minutes more than what was permitted by the NINDS-criteria. Furthermore there was an inverse relation between the onset-to-door time and the door-to-needle time. The shorter the onset-to-door time, the longer the door-to-needle time. We should speed up pre-thrombolysis workup, not only for patients arriving late after stroke onset with less time left for thrombolysis, but especially for patients arriving early. P452 Is heart disease a prognostic factor for acute stroke outcome? A prospective study I. Ybot, M. J. Abenza Abildúa, B. Fuentes, B. San José, M. A. Ortega, P. Martinez-Sanchez, E. Díez-Tejedor University Hospital La Paz. UAM (Madrid, ES) Background: Heart disease in ischemic stroke (IS) may be the cause of stroke, a coexistent illness, or even a consequence of stroke, but its presence means a higher risk for vascular death. Objective: To analyse the presence of cardiopathy in patients with acute IS and its impact on stroke outcome. Methods: Prospective study with inclusion of consecutive IS patients in a 4-month recruitment period. Previous or current cardiopathy, vascular risk factors, stroke severity on admission, in-hospital complications and modified Rankin Scale (mRS) at discharge were analysed. Results: 91 patients included, 33 % with known heart disease. Most frequent entities were arrhythmia, including atrial fibrillation (AF) (53.3 %) and ischemic cardiopathy (36.7 %). They they were older (72 vs. 63 years old; p < 0.05), had greater frequency of hypertension (80 % vs. 42 %; p < 0.05), hypercholesterolemia (60 % vs. 19 %; p < 0.05) and peripheral artery disease

(20 % vs. 4.9 %; p < 0.05), had more severe strokes on admission and worse outcome at discharge (mRS> 2: 48.1 % vs. 18.2 %) than patients without previous history of heart disease. It was diagnosed cardiopathy in 11 among 61 patients without known heart disease (18 %), being the AF most frecuently diagnosis (6 patients). In the logistic regression analysis, the only independent factor of poor outcome was the stroke severity on admission, without significant influence of heart disease. Discussion: Although previous cardiopathy seems to be associated to higher stroke severity on admission and worse recovery at discharge, when adjusting for other prognostic factors it was not independently associated to poor outcome. P453 Fractional anisotropy in acute ischaemic stroke with progression Y. S. Shim, D. W. Yang, S. W. Chung, S. J. Han, J. H. Kwon, K. S. Lee The Catholic University of Korea (Gyunggi-do, KR); The Catholic University of Korea (Seoul, KR); The Catholic University of Korea (Incheon, KR); The Ulsan University (Ulsan, KR) Background & Objectives: Early stroke progression (SP) is variable even with lesions of the same size and severity, and is frequently observed in lacunar infarction. We investigated fractional anisotropy (FA), mean diffusivity (MD) and infarct volume using diffusion tensor imaging (DTI) during the acute phase of ischemic stroke to determine whether these parameters are useful in characterizing and predicting SP. Subjects & Methods: We studied 41 consecutive patients admitted within 12 hours of ischemic stroke onset by using DTI with FA, MD and infarct volume. The National Institutes of Health Stroke Scale (NIHSS) and the Canadian Neurological Scale (CNS) were performed, and SP was defined as an increase ± two points in NIHSS and a drop ± one point in CNS from admission to day three. The distribution of clinical characteristics and imaging parameters was compared between two groups, with and without SP, and multiple logistic regression analysis was performed. Results: FA ratio in 11 patients with SP was lower than that in patients without SP (p = 0.003). The infarct volume was also different between the two groups (p = 0.010). The stroke severity, determine by NIHSS, was more severe in patients with SP. However, the MD ratio as well as age, gender, and stroke etiology were not different. After the multiple logistic regression analysis, only the FA ratio remained as an independent predictor of SP (odds ratio, 1.083; 95 % CI, 1.001 to 1.151; p = 0.010). Conclusion: Patients with SP showed lower FA values, which accounts for rapid and severe vasogenic edema involving the disruption of cell membrane and axonal fibers. Moreover, FA may be a predictor of SP. P454 High prevalence of asymptomatic coronary artery disease in patients with cerebral atherosclerosis and associated factors B. R. Lee, S. J. Lee, J. U. Chun, T. H. Kim, S. J. Yoon, B. H. Lee, S. Lee, Y. J. Choi, G. S. Oh Eulji University Hospital (Daejeon, KR) Objectives: Coronary artery disease (CAD) is a frequent cause of death among stroke survivors. But, there is no consensus on the appropriate evaluation and treatment of asymptomatic CAD in these patients. Several studies suggest that 25 % to 60 % of patients with carotid disease and no symptoms of CAD have abnormal provocative test results for myocardial ischemia. But, provocative tests do not identify non-flow-limiting coronary plaque that is at risk for acute myocardial ischemia or sudden death from rupture of the plaque. We assessed the hypothesis that the true frequency of asymptomatic CAD in patients with cerebral atherosclerosis may be substantially higher. Also we identified factors associated with its presence. Methods: From symptomatic or asymptomatic patients with extracranial or intracranial stenosis on MR angiography and absence of known CAD, 94 patients revealed conventional angiographic confirmation of severe atherosclerosis.All patients underwent coronary angiography at the same time. The traditional and novel risk factors (such as age, sex, hypertension, smoking, diabetes, level of HbA1 c, cholesterol, triglyceride, LDL, HDL, lipoprotein(a), homocysteine, and C-reactive protein) for atherosclerosis were determined before angiography. Results: Coronary angiography detected severe coronary atherosclerosis (> 50 %) in 66 of 94 patients (70.21 %); 20 patients (30.3 %) had 3-vessel disease, 20 patients (30.3 %) had 2-vessel disease, and 26 patients (39.39 %) had 1-vessel disease. Forty four of 66 patients (66.67 %) had need of coronary angioplasty and 36 patients had undergone a coronary artery stenting. Associated risk factors of CAD in patients with cerebral atherosclerosis were hypertension and multiple extra- and intracranial stenoses. Conclusions: Our study show 70.21 % of the patients with cerebral ath-

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erosclerosis and not overt CAD has severe coronary atherosclerosis on coronary angiography. The prevalence of occult CAD in our study was higher than previous study that had used myocardial perfusion imaging or provocative tests, because provocative tests do not identify non-flow-limiting coronary plaques. Hypertension and multiple extra- & intracranial stenoses were significantly and independently associated with a overt CAD. In conclusion, One-step coronary angiography during conventional cerebral angiography is useful method for evaluation of occult CAD in patients with severe cerebral atherosclerosis and high risk factors. P455 Orbital ultrasound in diagnosis of dural carotid-cavernous fistula S. Tuta, B. Dumitriu, C. Popa Institute of Cerebrovascular Diseases (Bucharest, RO) Objective: To demonstrate the usefulness of ultrasound as adjunctive and screening method of diagnosis in dural carotid-cavernous fistula. Methods: A 51 years-old men was admitted for right abducens nerve palsy with slight ocular movement limitation. Two month before the patient accused isolated diplopia in right side gaze, without strabismus or limitation of eye movement and an ambulatory cerebral MRI was considered to be normal. Because the absence of myotatic tendon reflexes studies of nerve conduction were done and prove to be in normal limit, also inflammatory CSF tests. The in hospital ultrasound examination of cervical arteries with colour duplex probe (Philips Envisor C HD) was also in normal limits, but orbital ultrasound examination showed a right superior ophthalmic vein with much higher than expected velocities and enlarged diameter. The cerebral MRI was repeated in hospital (0.5 T Philips Aura) provided the same results like the ultrasound – a large right superior ophthalmic vein, without any other lesions in orbital, skull base or brain stem regions. A digital subtraction angiography was indicated. Results: The six vessels (including external carotid artery) DSA confirm a right sided dural carotid-cavernous fistula type I Cognard, fed by branches of ipsilateral external carotid artery (especially internal maxillary and middle meningeal artery) and venous drainage through dilated ipsilateral superior ophthalmic vein, continuing in the facial vein. The superior and inferior petrosal sinuses were not injected on the right side. Because the evolution of the symptoms during the last two month since onset, the patient was advised for an endovascular treatment of fistula, but for the moment he refused this approach. Conclusion: Orbital ultrasound examination could be an useful adjunctive ambulatory evaluation tool for patients with neuro-ophtalmic signs – in this case of dural carotid-cavernous fistula provided the same information as MRI – and could avoided the delay in diagnosis. P456 Characteristics of moribund stroke patients in a hospital-based study in Targu Mures, Romania K. Orban-Kis, Z. Zima, I. Szocs, Z. Bajko, K. Fekete, S. Szatmari University of Medicine and Pharmacy (Targu Mures, RO); Debrecen Hospital (Debrecen, HU) Stroke, one of the leading causes of death and disability in adults, has a growing incidence in certain Eastern-European countries. Even more alarming is the high number of young patients with severe stroke, which raises serious questions about the control of risk factors and early management of stroke patients. The objective of this study was to assess the profile of patients with severe stroke who died early after onset of stroke, in order to establish the potential pitfalls of management of severe stroke patients. Methods: In the framework of a larger study data were prospectively collected for each patient admitted to Targu Mures County Hospital with diagnose of acute stroke, over a period of one year. In the present study we selected only the patients who deceased in hospital early after onset of stroke or were released from hospital in moribund state at family’s request. Results: In the above mentioned time period 1514 patients were admitted with acute stroke diagnosis; out of these 189 patients died in the acute – subacute stage. Male/female ratio was 1.14; average age was 68 ± 10 years for men and 70 ± 12 years for women. An important number of patients (26 %) were still active (i. e. young) at the stroke onset. Only 7.9 % of these patients had no evident risk factors; 60.3 % had at least two known risk factors. Cardiopathy (coronary heart disease, atrial fibrillation, etc) was the second most frequent risk factor after hypertension. The type of stroke was evenly balanced within this group of patients, 54 % had intraparenchimal or subarachnoideal hemorrhage. Loss of consciousness, the grade of hypertension as well as hyperglycemia, present in 78.8 % of cases, were negative prognostic factors. In case of in-hospital death the length of hospitalization in-

creased when compared to all patients. After clinical and CT examination 16 % of moribund patients were discharged at the family’s request after signing an informed consent; 86 % of them had severe intracerebral hemorrhage on CT scan. Conclusions: The assistance of stroke patients with severe prognosis is an important issue with ethical, psychological and none the least financial implications that regards all levels of health system (first aid, paramedics, emergency unit, hospital physician). The high number of active patients is worrisome as their death represents a significant burden both on society and family and emphasizes the failure of the primary prevention system in this group. This work was supported by Ro-19/2005 Bilateral Intergovernamental S&T Cooperation.

P457 Delirium in stroke patients: epidemiology and risk factors M. Kostalova, J. Bednarik, A. Haluzova, R. Badurova, S. Vohanka, I. Urbanek, R. Jura Masaryk University (Brno, CZ) Objective: Delirium is an acute, transient disorder of cognition and consciousness with fluctuating intensity that is considered underdiagnosed especially in an intensive care unit (ICU) setting. Previous study gave conflicting data regarding the frequency of delirium in stroke (13- 48 %) and its precipitating and risk factors. The aim of this study was to investigate the frequency and type of delirium and risk factors for delirium (including the extend and localisation of the stroke) in the acute stage of stroke using specific tool for delirium assessment. Methods: A cohort prospective observational study was performed in stroke patients admitted to the ICU or stroke unit of a University Hospital within 24 hours after the stroke onset. Patients with the NIHSS score > 5 at onset were evaluated with a specific tool for delirium assessment – the Czech version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) – for 7 consecutive days compared with assessments by delirium experts using the DSM- IV-TR criteria. A large list of variables including demographic data, pre-stroke conditions (dementia evaluated by the Blessed Dementia Scale), chronic alcohol abuse (quantified with the AUDIT scale), type, location and extend of stroke, presence, duration and severity of sepsis and multiple organ failure, metabolic, pharmacological, iatrogenic and nutritional parameters were evaluated daily on the daily basis and analysed. Results: Preliminary data were available from the analysis of first 30 consecutive stroke patients (mean age 68, range 35–86 years). An episode of delirium lasting at least two days was observed in 12 patients (40 %). Five patients displayed purely hypoactive form of delirium. The CAM-ICU showed a sensitivity of 100 %. However, in some aphatic patients with impaired comprehension, the evaluation of inattention and disorganised thinking gave falsely positive results. Delirium patients were significantly older with a trend toward more frequent pre-existing dementia and non-dominant hemispheric lesion. Conclusion: Delirium is a frequent condition in stroke patients. The assessment of delirium with a validated delirium instrument is recommended. The CAM-ICU is a reliable method in the ICU setting, but the criteria for delirium in patients with aphasia should be modified. Higher age, pre-existing dementia and right hemispheric stroke are probably the most important risk factors for delirium in stroke patients. Supported by the Research Plan of the Czech Ministry of Education No. MSM0021622404.

P458 External validity of anticoagulation versus aspirin trials for oldest patients with atrial fibrillation A. Corvol, D. Somme, H. Lahjibi-Paulet, C. Bauer, C. Lazarovici, O. Saint Jean European Hospital Georges Pompidou (Paris, FR) Objectives: Guidelines recommend long-term anticoagulation to prevent stroke in patients with atrial fibrillation. Nevertheless, several authors have pointed out an underuse of anticoagulant therapy in old person with atrial fibrillation, especially the oldest ones. Thus, we aimed to assess the external validity of clinical trials for the oldest patients. Methods: A systematic review of randomized controlled trials comparing aspirin versus anticoagulation in patients with atrial fibrillation was performed. Inclusion and exclusion criteria in these trials were collected. These criteria were compared to the characteristics of patients with atrial fibrillation hospitalized in an acute geriatric department during six months.

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We investigated how many of them would have been included in at least one trial. Results: We identified 9 relevant trials. None of them were doubleblinded. Four reported significant differences in favour of anticoagulation: three were addressed to high risk for stroke patients; the fourth one has a weak methodological design. Five trials found no significant differences. In seven trials, age was not an explicit exclusion criteria. In seven trials, the general practitioner could refuse any patient inclusion if he estimated that it was too risky. In our geriatric department, 95 patients with current or passed atrial fibrillation were retrospectively identified in six month, 83 of whom were alive at discharge. 30 % were discharged on anticoagulant, 45 % on antiplatelet. Their mean age was 89 (as compared to 71 in trials). 69 % had cognitive dysfunction, 41 % repeated falls, 20 % severe chronic renal failure. They had a high risk of stroke (mean CHADS2 score = 2.7), and a high risk of bleeding (mean HEMORRH2AGE score = 3). 16 % of the surviving patients fulfilled inclusion criteria without any explicit exclusion criteria of at least one trial. 77 % of them were actually treated by anticoagulant. Conclusion: For 84 % of the patients hospitalized in a geriatric department, the external validity of randomized controlled trial in favour of anticoagulation is poor. Most of the oldest old would have been excluded from trials because of their comorbidities. It could be hazardous to apply them without caution results of trials from which they were excluded because of their high risk of bleeding. 77 % of the patients concerned by the trials are actually treated by anticoagulant in a geriatric department. P459 Unilateral asterixis in acute ischaemic cortical stroke: report of two cases G. Georgakoudas, C. Mavrommatis, A. Avramidou, M. Bagkeri Florina Hospital (Florina, GR) Objective: To report two cases of acute rolandic infarct with contralateral asterixis at clinical presentation. Background: Asterixis is defined as arrhythmic lapses of sustained posture. Bilateral asterixis is a common clinical sign of metabolic and toxic encephalopathies, whereas unilateral asterixis may indicate the presence of focal brain damage. In a large series of 2500 acute stroke cases, contralateral asterixis was found in two cases (0.08 %). Thalamus is the most frequent localization (54–63 %), followed by anterior cerebral artery territory, upper midbrain, and cerebellum. Contralateral asterixis in lesions of primary motor and sensory cortex has been very rarely reported. Case 1: A 73-year-old man, with history of recent acute myocardial infarction, presented with right hand clumsiness and slight right hemisensory deficit. Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) of the brain revealed an acute ischemic rolandic lesion in the left hemisphere. Asterixis was observed contralateral to the infarct, most prominent in the right upper limb. Echocardiography showed a left ventricular aneurysm with intracavitary thrombus. Case 2: An 80-year-old man, with history of arterial hypertension, developed slight right hemiparesis, and right hand asterixis was found on clinical examination. DW-MRI of the brain showed an acute ischemic infarct in the left precentral gyrus. Magnetic resonance angiography of the brain and carotid and heart ultrasonography were normal. In both cases, any metabolic cause was ruled out and the intensity of asterixis declined as patients improved. Conclusion: Unilateral asterixis can be a clinical sign of cortical infarcts and should prompt a thorough investigation for a possible embolic source. P460 Enoxaparin versus unfractionated heparin in acute ischaemic stroke in evolution-differential effects of enoxaparin on von Willebrand factor release and a possible relation to improved clinical outcomes A. Saleh, A. El Fily, S. Ashour, A. Abdel Moneim, N. Sabri, A. Morad, M. Zaki, H. Awadalla Ain Shams University (Cairo, EG) Background: The significance of low-molecular-weight heparins (LMWHs) in the management of acute stroke remains controversial. Patients and Methods: 100 patients with acute ischemic stroke in evolution were enrolled (with symptoms of stroke within eight hours of randomization). Patients were randomized to receive Unfractionated Heparin (UFH) at a dose of 5000 IU by IV bolus, followed by a continuous IV infusion; or to Enoxaparin (ENOX) at a dose of 0.5 mg per kg body weight. Therapy was continued for 10 days. The plasma concentrations of von Willebrand factor (vWF) antigen were measured with a sandwich ELISA technique, on ad-

mission and 48 hours after initiation of theerapy. National Institutes of Health Stroke Scale (NIHSS) and a computed tomography (CT) scan of the brain were performed on all patients at the time of admission, and after forty eight hours of randomization. A composite clinical endpoint of (death, stroke, hemorrhagic complications, and deterioration in the NIHSS) was used for the purpose of assessing response to either UFH or Enoxaparin. Results: The mean baseline NIHSS was 9.14 ± 0.62 among patients randomized to UFH, vs. 7.86 ± 0.54 among patients randomized to ENOX (p = 0.2).At discharge, the mean NIHSS showed a statistically significant difference in favor of the ENOX group (7.9 ± 0.82 for the UFH arm vs.4.96 ± 0.54 for the ENOX arm; p = 0.002). 60 % of patients in the UFH arm demonstrated NIHSS improvement, as opposed to 80 % of patients in the Enoxaparin arm (p = 0.012). The mean NIHSS after therapy in patients who demonstrated neurological improvement was 5.6 ± 0.46 in the UFH arm, as opposed to 3.65 ± 0.39 in the ENOX arm (p = 0.001). The incidence of composite clinical endpoint was 34 % in the UFH group vs. 14 % in the ENOX group (p = 0.003). No statistically significant differences were observed for recurrent strokes, or death. The mean baseline percentage value for von Willebrand factor antigen in the UFH group was 119 ± 3.9, as opposed to 124 ± 3.54 in the ENOX group (p = 0.32). The mean percentage value for vWF antigen after 48 hours of initiation of the study drug was 273 ± 1 in the UFH group, as opposed to 184 ± 0.7 in the ENOX group (p = 0.0001). Conclusion: Enoxaparin [+ aspirin] was superior to UFH [+ aspirin] in reducing neurological disability after acute ischemic stroke in evolution. This superiority was not associated with reductions in mortality, and could be explained by blunting of von Willebrand factor release by Enoxaparin. P461 Proportion of t-PA treatment for acute ischaemic stroke patients admitted to emergency departments within 3 hours after symptom onset S. S. Yoon, K. C. Park Kyung Hee University (Seoul, KR) Backgound: The treatment of t-PA is restricted to patients who arrived in hospitals within 3 hours after the onset of symptoms. This study was designed to evaluate the time interval between symptom onset and hospital arrival, and to investigate its relation with the adoption of t-PA treatment strategy for patients with acute ischaemic stroke. Methods: Eligible 256 patients with signs or symptoms of acute ischemic stroke, admitted to Kyung Hee Medical Center through the emergency room, were prospectively assessed from September 2003 to December 2004. The time intervals between symptom onset and hospital arrival were recorded and was analyzed with patients’ clinical characteristics and medication procedures. Results: The average interval between symptom onset and hospital arrival was 28 hours, and 56 (22 %) patients were shown in the interval of 0 to 3 hours after symptom onset corresponding to the eligibility of thrombolytic therapy. Intravenous t-PA was medicated in 26 (46.4 %) out of those 56 patients. This proportion was compared with those of previous studies. Conclusion: The proportion of patients within 3 hours after symptom onset was 22 %, which is similar to those of North America. And the overall proportion of t-PA treatment was 10 %, which is a little higher than those of other countries. P462 Epidemiology of acute ischaemic stroke in France: a DRG-based analysis D. Saragoussi, A. A. Epis de Fleurian, T. Dispot, J. Rüthemann, C. Guilhaume H.Lundbeck A/S (Paris, FR); Medcost (Paris, FR); Paion GmbH (Aachen, DE) Objectives: Since 2004, the collection of longitudinal data useful for studying disease evolution and epidemiology has been implemented in the French Diagnosis Related Group (DRG) system. The objective of this study is to describe acute ischemic stroke (AIS) epidemiology and management in France using the national DRG database. Methods: The DRG database encloses the description of all hospital stays in public and private hospitals. We evaluated stays for AIS (ICD-10 code: I630-I636; I638-I639) and strokes of undetermined origin (SUO; ICD-10 code I64) during the year 2004. Outcomes of interest were incidence, mortality and recurrence rates. Recurrence rates and associated pathologies during the first year post-stroke were studied on patients who had a hospitalization for AIS during the first quarter of 2004. Results: 70 579 patients (47 % men), aged 74.2 in average were hospitalized for acute stroke in 2004. This corresponds to a crude incidence rate of 100 per 100,000 person-years. 71 % had an AIS and 29 % had a SUO. Mortality rate during hospitalization was 11 %. 50 % of AIS patients were hospitalized at least once in the year poststroke, with 3 stays per patient in average. AIS recurrence rate and coronary

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artery disease rate in the first year post-stroke were 13 % and 5 % respectively. AIS recurrence was the first cause of acute re-hospitalization in AIS patients after hemodialysis and radiotherapy/chemotherapy sessions. Conclusions: Besides its known value for providing information on resource consumption and costs, French DRG data can offer reliable epidemiological data at a nationwide level. These results confirm findings from French stroke registries. Future database updates will provide further information on long-term characteristics of AIS patients. H. Lundbeck A/S provided funding for this study.

P463 Deep cerebral vein thrombosis: retrospective analysis of nine cases T. Pfefferkorn, J. Linn, T. E. Mayer, A. Bender, A. Straube, H. W. Pfister, M. Dichgans Klinikum Grosshadern (Munich, DE) Objectives: Deep cerebral vein thrombosis (DCVT) is a rare form of cerebral vein and sinus thrombosis (CVST) characterized by a variable clinical presentation and course, a difficult and often delayed diagnosis, and a high risk of poor outcome. Due to the infrequency of DCVT, larger patient series have hardly been reported. In this retrospective monocentric study, we evaluated symptoms, neuroradiological findings, course and outcome in patients with DCVT. Methods: Clinical charts of all identified patients with the unequivocal diagnosis of DCVT admitted between 1993 and 2006 were analyzed. Survivors were contacted for long-term follow-up. Results: A total of nine patients were identified. In six patients, thrombosis was restricted to the deep venous system. The clinical presentation was highly variable with no single symptom present in all patients. Non-contrast CT and/or MRI demonstrated bi- or unilateral thalamic edema in seven patients but was negative in two. D-Dimer levels were elevated in six but normal in two patients. In seven patients the correct diagnosis was only established after considerable delay (five to 76 days). Six patients had a stable clinical course under intravenous heparin therapy followed by oral anticoagulation and a good long-term outcome (modified Rankin score 0–2). Three patients had a deteriorating course progressing to coma despite heparin therapy. They underwent local endovascular therapy, which was successful in one patient. Two patients died. Conclusions: The diagnosis of DCVT is difficult and relies on the correct interpretation of symptoms and findings. With intravenous heparin followed by oral anticoagulation, the majority of patients with DCVT have a stable clinical course and a surprisingly good long-term outcome. Progressing coma is seen in a subset of patients. Endovascular treatment should be considered very reluctantly and may only be an option in cases with an impending fatal course despite heparin treatment.

P464 White blood cell count as prognostic factor in acute stroke patients R. M. Psaras, K. Tsatsou, G. Nasis, C. Bairaktaris, D. Panoutsopoulou, I. Papanastasiou 417 N. I. M. T.S. Army Share Fund Hospital (Athens, GR) Objectives: To determine the influence of high White Blood Cell (WBC) count on survival after acute stroke. Methods: We studied 200 patients diagnosed with stroke, hospitalized in our department between August 2003 and August 2005, categorizing them according to WBC count on admission and 2nd day of hospitalization and analyzing them according to survival at 7 days, 28 days, and 3 months after stroke. There was no clinical or paraclinical evidence of infection at the time of blood count in these patients. Results: On admission, WBC mean count was 9154/microlitre (4420–28030, SD: 3467) while 69 patients were admitted with WBC > 10 000 (34.5 %). The mean age of these patients was 76.24 (SD:11.8), while of those with low WBC count was 76.95 (SD:10.1). Case fatality 7 days after stroke was 17.39 % in patients with high WBC count and 8.4 % in those with low WBC count (OR:2.29). 28 days after stroke, case fatality was 37.68 % in patients with high WBC count and 16.79 % in those with low count (OR:2.99). 3 month case fatality was 46.38 % in those with high WBC count and 26.72 % in low WBC count patients (OR:2.37). 31.8 % of men had > 10 000 WBC. 28 day case fatality was 37.14 % in these patients and 9.33 % in those with low WBC count (OR:5.74).37.8 % of women had > 10 000 WBC. 28 day case fatality was 38.2 % in high WBC count patients and 26.8 % in the low WBC count ones (OR:1.69). There were 163 patients with ischemic strokes, 29.45 % of them having a high WBC count. These patients had a 43.75 % 28 day case fatality, while those with low WBC count, 13.91 %. 37 patients suffered hemorrhagic

strokes, with the 54.05 % of them having a high WBC count. These patients had a 30 % 28 day case fatality, while those with low WBC count, 29.4 %. On the 2nd day of hospitalization,39.2 % of the patients had a WBC count of > 10 000 and 60.8 % had a count of < 10000. 7 day case fatality was 26.76 % in patients with high WBC count, and 0.91 % in those with low count (OR:39.83). 28 day mortality was 52.11 % in high WBC count patients and 5.45 % in low count patients (OR:18.86). 3 month case fatality was 57.75 % in patients with high WBC count and 10.91 % in those with low count (OR:11.16). Conclusion: Patients with admission WBC count > 10 000 had a higher case fatality, especially men and ischemic stroke patients, and patients with 2nd day WBC count > 10 000 had an extremely higher case fatality, allowing us to say that a high WBC count, especially on the 2nd day, is a negative prognostic factor after stroke.

P465 Outcomes of ischaemic stroke in patients who were already on aspirin compared to patients who were aspirin naïve S. Wallis, P. Shibu, A. Gupta, S. H. Guptha, P. Owusu-Agyei Peterborough & Stamford NHS Hospitals Trust (Peterborough, UK) Introduction: We tested the null hypothesis that patients admitted with ischemic stroke who are already taking aspirin are likely to have lower mortality and shorter length of stay than patients who are aspirin naïve. We also assessed the incidence of cerebral haemorrhage in patients with stroke who are already taking aspirin. Methods: We conducted a retrospective analysis of data collected on all patients admitted with stroke to our hospital in the years 1998, 2003 and 2005. Results: 1049 patients were admitted with stroke over the three years of study. 690/1049 patients had an ischemic stroke confirmed on brain imaging. 60/308 patients with ischemic stroke who were already on aspirin died following their admission and 84/382 patients who were aspirin naïve died following their admission (p = 0.45). The mean length of stay in patients who were already on aspirin was 38.2 days (range 1–245) and in patients who were aspirin naïve was 36.8 days(range 1–239). The incidence of intracranial haemorrhage in patients who were already on aspirin was 41/303 and in patients who were aspirin naïve was 108/398 (p = 0.0003). Brain imaging was not performed in 100/444 patients already on aspirin and in 97/603 patients who were aspirin naïve(p = 0.01). The status of aspirin prescriptions was unknown in 2 patients. Conclusions: Patients admitted with ischemic stroke who are already on aspirin at the time of their stroke do not have either reduced mortality or length of stay following their admission compared to patients who are aspirin naïve. The risk of a haemorrhagic stroke in patients who were already on aspirin at the time of their stroke is unlikely to be higher than in patients who are aspirin naïve although a significantly greater number of patients in aspirin naïve group had brain imaging.

P466 Blood glucose levels after ischaemic stroke in patients with and without sleep apnoea M. Siccoli, C. L. Bassetti University Hospital of Zurich (Zurich, CH) Background/aims: Sleep apnea (SA) is well recognized as risk factor for cardiovascular morbidity and mortality, and is present in 50–70 % of patients with acute ischemic stroke. Elevated blood glucose after stroke is associated with a worse outcome. The aim of our study is to investigate changes in blood glucose in patients with acute ischemic stroke and their relationship to SA severity and type. Patients/methods: We included 29 consecutive patients with acute ischemic stroke admitted within 96 hours after stroke onset, in which fasting blood glucose level was repeatedly assessed at day 1, 2, 3, 4, 7, and 15 after admission in the same period of time (between 6 and 10 a. m.). Stroke severity on admission (NIH Stroke Scale, NIHSS) and stroke outcome at discharge (modified Rankin Disability Scale, mRS) were recorded. Respirography was performed in the first night and scored according to standard criteria. Results: The mean age was 62±12 [25–83], 75 (66 %) were male. NIHSS on admission was 7±5 [0–21], mRS at discharge (11±6 days after admission) was 1.7±1.4 [0–5]. Blood glucose on admission was 7.4±2.9 [4.1–19.9], and 6.4±2.0 [4.6–11.1] at day seven. We found a significant correlation between glucose at day seven and apnea-hypopnea-index (p = 0.002, r = 0.622), central apnea-index (p = 0.009, r = 0.556), and oxygen desaturation-index (p < 0.0001, r = 0.751) independent of cardiovascular risk factors, age, and body-mass-index. Glucose at day seven correlated with stroke severity on

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admission (p = 0.004, r = 0.607) and with functional disability at discharge (p = 0.017, r = 0.528). Conclusions: Glucose level at day seven after ischemic stroke is an independent predictor of stroke severity and outcome, and is associated with severity of SA, central apneas, and oxygen desaturations. Further studies are needed to test the hypothesis that these findings may reflect an increased sympathetic activity possibly related to sleep apnea. P467 Reduced neuro-functional reserve and connectivity in patients with subcortical vascular encephalopathy M. Griebe, M. Amann, K. Szabo, R. Kern, A. Bongers, J. Hirsch, L. Achtnichts, M. Hennerici, A. Gass Universitaetsklinikum Mannheim (Mannheim, DE); Universitaetsspital Basel (Basel, CH) Objectives: Progressive subcortical white matter changes are found as characteristic patterns in patients with subcortical vascular encephalopathy (SVE). Important symptoms even early in the course of SVE are cognitive dysfunction, particularly affecting processing speed, attention and working memory. We asked whether altered functional interactions between regions normally recruited are present in patients with subcortical vascular lesions. Methods: Ten patients with clinically mild SVE and ARWMC (age-related white matter changes) Rating Scale grades 2 and 3 and ten healthy controls (grades 0 and 1) were recruited. On a 1.5T scanner they performed 3 different fMRI tasks in block designs: an alertness task (reaction time), an attention task (0-back) and a working memory task (2-back). After pre-processing, the statistical maps underwent a three factor analysis of variance (ANOVA). The resulting t-maps were thresholded at a level of p < 0.01. To test for functional connectivity, physiophysiological interaction (PPI) analyses were performed for the areas activated in all fMRI tasks. In the PPI, experimental design, signal-time course of the specific area and interaction between both were used as regressors. Results: Patients and controls performed equally well. Task specific activation was found in both groups in bilateral posterior parietal areas, in dorsolateral prefrontal cortices and in medial frontal areas (MFA). Patients, however, showed a significantly smaller increase in activation in the specific brain regions than controls with increasing task difficulty (p < 0.01). PPI revealed further differences: both superior parietal areas were significantly stronger (p < 0.001) correlated with the left MFA in controls, also the right MFA with the left medial temporal lobe and the supplementary motor area with the right inferior parietal area (p < 0.05). In patients only the right anterior insula and the right primary motor area were stronger correlated compared to controls (p < 0.05). Conclusion: Though utilizing similar brain regions in cognitive task processing SVE patients showed reduced increase in functional response with increasing difficulty of the presented tasks, possibly indicating a reduced functional reserve. The PPI suggests altered intra- and interhemispheric interactions, mainly a reduced connectivity. The observed phenomena thus might be the correlates of sub-clinical early changes most likely due to the disruption of subcortical fiber tracts in SVE patients. P468 Chronic progressive myelopathy due to spinal dural arteriovenous fistula: clinical and radiological findings in two cases. A devastating and rare condition, with effective treatment J. Romero-Imbroda, J. Tamayo, L. Garcia, O. Fernandez Hospital Carlos Haya (Malaga, ES) Objectives: Spinal dural arteriovenous fistulas are uncommon with a calculated incidence of 5 cases million/year in the general population. The diagnostic delay of this entity behaves a special risk of causing an irreversible damage in the spinal cord. We present two cases of recent diagnosis. Methods: Case 1: 70-year-old man with past medical history of ischemic cardiopathy and hypertension. Sudden onset of progressive leg weakness and abnormal gait associated with mild lumbar pain and global hypoesthesias in both feet. Magnetic Resonance Imaging (MRI) of spinal cord showed an extensive dorsolumbar intraxial lesion with paraspinal image compatible with enlarged vessels. Angio-MRI demonstrated intrinsic and extramedullary dilated vessels concluding spinal fistula with draining veins. Case 2: 60-year-old woman with no interesting medical history. Subacute paraparesia and sensory disturbance in legs. Lumbar pain in the onset. Spine MRI study detected dorsolumbar spinal cord lesion suggested of edema with abnormal spinal blood vessels. Catheter angiography showed arterial supply and draining veins. Results: Patient 1 will recieve endovascular treatment. The result will be shown.

Patient 2 was treated with endovascular embolization with clinical improvement after the procedure. Conclusion: Spinal dural arteriovenous fistula have to be included in the differential diagnosis of progressive myeolpathy of unclear origin. P469 Dissection of the extracranial vertebral artery E. Bartels University of Gottingen (Gottingen, DE) Dissection of cervical arteries causes ischemic stroke in young adults. This reports the clinical, ultrasonographic and neuroradiological findings in 24 patients with 28 vertebral artery dissections in the neck (4 occurring bilaterally). In 20 patients (83 %), the dissection was temporally related to trauma. No patients had an underlying vascular disease, e. g. atherosclerosis or fibromuscular dysplasia. In all, the major initial manifestation was pain in the occipital or neck region. The next most common symptoms were vertigo and nausea (in 17 patients). Clinical manifestations were vertebrobasilar TIA (n = 5), cerebellar infarction (n = 10), brainstem infarction (n = 5), posterior cerebral artery territory infarction (n = 1), and multiple vertebrobasilar ischemic lesions (n = 3). Typical angiographic findings were irregular narrowing of the vessel lumen or a tapering stenosis with distal occlusion. Magnetic resonance imaging showed a thickened vessel wall with hematoma signal at the site of a dissection. Ultrasonographic abnormalities in the extracranial course of the vertebral artery were observed in all patients. The findings varied depending on mechanism and on site of a dissection: The distal V1- and the proximal V2-segment (at the level of C6 vertebra) was the most frequent localization of dissections (in 43 %). Intramural hematoma, irregularities of the vessel wall, dissecting membrane, tapering stenosis, true and false lumen, intravascular echoes, localized arterial dilation with decreased pulsatility and pseudoaneurysm formation could be visualized in this region. The outcome was favorable except for two patients with basilar artery occlusion. Embolism to the basilar artery may be avoided by early administration of anticoagulants. P470 Stroke volume, clinical severity and functional outcome in stroke are related to CSF levels of glial and axonal biomarkers A. Petzold, P. Michel, M. Schluep Institute of Neurology (London, UK); CHUV (Lausanne, CH) Background: Body fluid biomarkers have great potential for improving prognostic accuracy, monitoring development of secondary brain injury and as a secondary outcome measure for treatment trials. Brain-specific proteins are most accurately measured in the cerebrospinal fluid (CSF), which provides a basis for their interpretation in serum. This study is set against the backdrop of a number of studies on serum biomarkers and a lack of data on CSF biomarkers in stroke. Method: We performed a study on 34 patients with a well characterised stroke. All patients underwent acute and subacute brain imaging. Stroke severity and outcome was rated using the NIHSS and modified Ranking Scale (mRS). CSF levels of S100B, ferritin and the neurofilament heavy chain (NfH-SMI35) were measured using standard ELISAs. Results: CSF S100B and CSF ferritin levels were elevated in a significant proportion of patients with stroke when compared to previously published upper reference limits (p < 0.0001 for both comparisons). Median CSF S100B levels were higher in patients with a cardio-embolic stroke (2.88 ng/mL) than in those with small vessel disease (0.89 ng/mL, p < 0.05). CSF S100B level correlated with the NIHSS on admission (R = 0.46, p < 0.01) and the stroke volume (R = 0.42, p = 0.01). CSF NfH-SMI35 levels were weakly correlated with the mRS on discharge (R = 0.37, p < 0.05). CSF ferritin levels were highest in one patient with a haemorrhagic transformation (150 ng/mL). Discussion: CSF S100B levels were related to stroke severity and infarct size consistent with previous studies on serum S100B levels. CSF ferritin and NfH-SMI35 levels may be of future relevance for identification of patients with haemorrhagic transformation and may improve prognostic accuracy. P471 Fibrinogen and high-sensitive C-reactive protein as predictor for cerebral microembolism after carotid endarterectomy L. Esposito, H. Poppert, O. Wolf, H. Eckstein, P. Heider Technical University (Munich, DE) Background: Cerebral embolism can occur during or directly after carotid endarterectomy (CEA). Postoperative magnetic resonance imaging (MRI)

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including diffusion-weigthed-imaging (DWI) reveals cerebral ischemic lesions in about 25 % of patients after TEA, but most patients do not show neurological symptoms. Inflammatory processes may be one cause for the occurrence of cerebral lesions during or after CEA. Fibrinogen and high-sensitive C-reactive protein (hsCRP), as inflammatory markers, are known to play an important role in atherosclerotic disease. The aim of our study was to investigate if microembolism detected by DWI lesions is associated to elevated fibrinogen and hsCRP-levels. Methods: 183 patients (58 females) presenting with severe carotid artery stenosis > 70 % underwent CEA. 92 patients presented with a recently symptomatic stenosis, 91 patients were asymptomatic. For each patient, measurement of fibrinogen and hsCRP-levels was performed before sugery; hs-CRPlevels were analysed using enzyme linked immuno assay (ELISA). One day before and one day after TEA each patient underwent MRI including DWI. Correlation between Fibrinogen, hsCRP and DWI lesions was performed using Chi-square-test. Results: In 41 patients postoperative DWI-lesions were found, 8 of these patients presented with neurological symptoms. Fibrinogen and hsCRP were elevated in patients presenting with postoperative DWI lesions as compared to patients without DWI-lesions (397.6 mg/dl vs. 324.7 mg/dl; p < 0.0001 and 7.9 mg/dl vs.2.8 mg/dl; p = 0.004).Regression analysis showed increased risk for the occurrence of postoperative DWI lesions in patients with elevated fibrinogen and hsCRP-levels. Conclusion: Elevated fibrinogen and hsCRP-levels are associated to a higher risk for postoperative cerebral ischemia caused by microembolism in patients undergoing CEA. Our results indicate fibrinogen and hsCRP to represent additional markers for unstable atherosclerotic plaques.

Clinical neurophysiology P472 Assessment of correlation between carpal tunnel syndrome with body mass index and anthropometric indices of hand M. Yazdchi Marandi, M. Sharifi Emam Khomeini Hospital (Tabriz, IR) Carpal tunnel syndrome (CTS), an entrapment of the median nerve at the wrist, is the most commonly encountered neuropathy causing disability. There has been much debate over the last few decades as to whether it is an occupationally caused or personally attributed syndrome that plays a major role in the development of CTS and in the prevention of the condition. Despite some contradicting data, obesity and squarer wrists have been identified as individual risk factors associated with an increased risk of CTS in the last two decades; however the role of hand anthropometrics in the development of CTS has been given less attention. This study aimed at evaluating this role. Methods & Materials: One hundred thirty one patents with CTS were compared with 131 people without CTS in a 14-month period. The diagnosis of CTS and determining its severity subtypes were based on electrodiagnostic criteria.Wrist, shape and digital indices, hand length/height ratio and body mass index (BMI) were compared between the two groups and different severity subtypes. The mentioned anthropometric indices were compared between the upper extremities with and without CTS. Results: There were 121 (92.4 %) females and 10 (7.6 %) males in each group. Shape (p < 0.001), wrist (p < 0.001) and body mass indices were higher in the case patients based on univariate analysis; and wrist (p < 0.001) and body mass (p = 0.028) indices in multivariate test. Shape (p < 0.001) and digital (p < 0.001) indices were higher in upper extremities with CTS based on univariate analysis; but only shape index (p < 0.001) in multivariate test. The wrist index was lower in the mild form of CTS (p < 0.05). Conclusion: our results are in conformity with reports in the literature; however more studies with larger sample sizes, especially about the upper extremity and male patients are recommended to be carried out. P473 Neurogenic potentials using auditory stimuli originating from the vestibular system: evidence from a case of unilateral acoustic neuroma E. Papathanasiou, C. Thodi, M. Pantzaris, S. Papacostas Cyprus Institute of Neurology & Genetics (Nicosia, CY); Cyprus Audiology Center (Nicosia, CY) Objectives: Neurogenic electrophysiological evoked responses from vestibular nerve stimulation in humans have been attempted in the past using rotational and head drop techniques. The diversity of responses has been attributed to the use of low intensity stimulation, slow rise time and poor

replicability.Vestibular evoked myogenic potentials (VEMPs), using high intensity auditory clicks and recording mainly from the tonically activated sternocleidomastoid muscles, have recently been developed. It is possible to us an auditory stimulus to test a vestibular pathway, as it has been shown that saccular afferents are sensitive to sound. Using the same stimulus, our group has demonstrated the presence of a consistent waveform from the parietal area, a vestibular evoked neurogenic potential (VENP). We present a case of unilateral acoustic neuroma that provides evidence that the VENP originates from the vestibular system, and not from the cochlear system. Methods: Brainstem auditory evoked potentials (BAEP), threshold latency series (TLS), pure tone audiometry and electronystagmography (ENG) were performed in the standard manner. For VENP, silver surface EEG electrodes were used. One channel recording was performed with the parietal electrode (P3 or P4) ipsilateral to the ear tested referred to Fpz. Filter settings were 100 Hz- 3 kHz, with a sweep of 2msec/division and a sensitivity of 0.2 uV/division. The rate of stimulation was 10.1 Hz delivered via headphones. A tone-pip auditory rarefaction stimulus was used with a frequency of 1 kHz with two cycles. Stimulus intensity was 90 dB nHL. The first major negative peak occurring around 5 msec after stimulus onset was labeled N5. Results: The VENP was within normal limits and symmetrical bilaterally. The BAEP was unobtainable on the left, and normal on the right. The TLS was also normal on the right. Pure tone audiometry revealed a sloping mild to profound hearing loss on the left and normal hearing on the right. ENG showed normal saccadic and gaze responses, negative Dix-Hallpike response and symmetric caloric responses. Conclusion: This case has demonstrated that the VENP response is within normal limits, against a background of severe hearing loss in relation to the left ear, and normal vestibular responses using a second independent test of vestibular function. This suggests that the VENP response is independent of cochlear function, and originates from the vestibular system. P474 Analysis of mean blood flow velocities in posterior cerebral arteries by transcranial Doppler M. Lisak, Z. Trkanjec, I. Mikula, M. Budisic, A. Aleksic Shibabi, V. Sulentic, V. Demarin Sestre Milosrdnice University Hospital (Zagreb, HR) Changes of mean blood flow velocities (MBFV) in the posterior cerebral arteries (PCA) during visual stimulation were recorded in a group of 51 healthy, right-handed volunteers. There were 27 (52.9 %) males and 24 (47.1 %) females aged from 20 to 59 years (mean age 36.98 years). Measurements were performed with hand-held 2 MHz transcranial Doppler (’I’CD) probe through temporal window, while the subjects had eyes opened, when subjects had eyes closed and when looking at white light. In half of the subjects, first right PCA was insonated and then left PCA, while in the other half a reverse procedure was used. Statistical analysis was made using Wilcoxon’s matched-pair signed-rank test. Mean BFV value in the left PCA was 41.2±8.6 cm/s (mean ± SD) with eyes opened, 27.8±8.5 cm/s with eyes closed, and 42.3±9.1 cm/s while looking at white light. Mean BFV value in the right PCA was 41.7±8.9 cm/s with eyes opened, 28.2±9.1 cm/s with eyes closed, and 42.4±8.8 cm/s while looking at white light. Differences between eyes opened and closed, between eyes opened and white light in the left PCA were statistically significant (p < 0.001, z = –6.2146, and p < 0.001, z = –3.4836, respectively). In the right PCA, a difference between eyes opened and closed and between eyes opened was statistically significant (p < 0.001, z = –6.2146 and p < 0.001, z = –3.6928), but there was no significance between eyes opened and white light (p = 0.03, z = -2.1693). The results demonstrated that straightforward visual stimulation had an effect on blood flow velocities in PCA and that it could be measured with TCD. P475 Cortico-spinal excitability changes after robotic gait training in healthy subjects J. U. Blicher, J. F. Nielsen Hammel Neurocenter (Hammel, DK) Introduction: Transcranial magnetic stimulation has been used to demonstrate short-term excitability changes in the motor cortex. It has been argued that these changes are relevant for motor learning. Most studies have focused on relative simple movements, whereas excitability changes related to more functional training has been far less studied. The purpose of the current study was to investigate changes in cortico-spinal excitability in healthy subjects after active and passive robotic gait training in a driven gait orthosis (DGO) (Lokomat). Methods: 13 healthy subjects participated in two experiments. In exper-

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iment 1, each subject performed 20 minutes of active gait training in a DGO. Experiment 2 was identical, except the training was completely passive. Motor evoked potentials (MEP), short-interval intracortical inhibition (SICI), intracortical fascilitation (ICF), F wave frequency, and M max amplitude were measured in the right tibialis anterior muscle before and after training in both experiments. Results: Active training led to a decline in MEP amplitude and F wave frequency. The MEP decline was associated with subjective muscle fatigue whereas the change in F wave frequency was not. Passive training induced a decrease in SICI lasting for 20 minutes post training. Other measures were unchanged. Conclusions: The decline in MEP after active training is most likely due to central fatigue, whereas the decline in F wave frequency might reflect short-term plastic changes on a spinal level. The decrease in SICI after passive training probably reflects a decreased in intracortical GABA activity. GABA disinhibition might play an important role in controlling the magnitude of functional reorganisation after brain injury.

P476 Abnormalities in the responses to transcranial magnetic stimulation in patients with sporadic and hereditary spastic paraparesis T. Serranová, J. Valls-Solé, E. Muñoz, D. Genís Charles University (Prague, CZ); University of Barcelona (Barcelona, ES); Hospital Universitari de Girona Dr. Josep Trueta (Girona, ES) Objectives: Central motor conduction time (CMCT) may be prolonged in patients with sporadic (SSP) and hereditary spastic paraparesis (HSP). However, such finding does not have a direct clinical correlate. We hypothesized that, apart from the motor conduction disorder in the corticospinal tract, patients with SSP/HSP might have an abnormal modulation of segmental leg reflexes by descending motor volleys which would interfere with the normal flow of movement. In this study, we have examined the effects of transcranial magnetic stimulation (TMS) over the H reflex of the soleus muscle, as a representative of the leg monosynaptic stretch reflexes. Methods: We examined 10 healthy controls and 19 patients with SSP/HSP. All of them were examined for CMCT and characteristics of the motor evoked potencials (MEP). All controls and 10 patients were also examined for the modulation of the H reflex by TMS. For the modulation of the H reflex, we used a two stimulator electromyograph which synchronized the triggering of both the magnetic and electrical stimulators at the required intervals. The interstimuli intervals (ISI) were from 0 to 110 ms. ISI steps were 10 ms. TMS intensity was adjusted at just below threshold for elicitation of a MEP in the soleus muscle. The amplitude of the baseline H reflex was kept within the limits of 5 to 10 % of the M response by adjustments of the posterior tibial nerve electrical stimulus intensity. Results: In healthy controls, the factor interval had a significant effect on the amplitude of the H reflex (ANOVA; p = 0.04). Post-hoc comparisons demonstrated that the differences were due to two phases of facilitation: the first facilitatory peak occurred at the interval of 20 ms and had an amplitude of 247 % (SE = 9.9 %), and the second one occurred at the interval of 100 ms and had an amplitude of 242 % (SE = 11 %). In patients, there was not a significant effect of interval on H reflex amplitude (p = 0.2), and no consistent early or late facilitatory phases were observed. Conclusions: Our results indicate an abnormal effect of TMS on the excitability of propriospinal interneurons and soleus motoneurons which is not modified in tune with the arrival of descending inputs. Desynchronization of the descending volley may be responsible for both the lack of early facilitation and the presence of inconsistent late facilitatory phases. T. S. was supported by Czech Ministry of Education, Program MSM0021620849.

P477 Prepulse inhibition of facial reflex responses to painful electrical median nerve stimulus E Lladó, J. Casanova-Molla, P. Schestatsky, L. León, J. Valls-Solé Vall d’Hebrón Hospital (Barcelona, ES); Hospital Clínic (Barcelona, ES); CAPES (Brasilia, BR); Hospital Clínic Barcelona (Barcelona, ES) Introduction: Prepulse inhibition (PI) is known as the inhibitory effect induced on a response to a strong stimulus by a preceding stimulus of subthreshold intensity. It has been documented in responses such as the startle and blink reflexes. However it is not known if it occurs also in pain-induced reflexes. In normal subjects the mentalis muscle (MM) response to electrical stimulation to the median nerve, which has been considered an electrical correlate of the palmo-mental reflex, is usually elicited by electrical nociceptive stimuli. The same stimulus also induces responses in the

orbicularis oculi (OOc), known as the somatosensory blink reflex, which is probably integrated in a circuit different from that of the MM. Objectives: To examine whether PI is present in MM and OOc reflex responses to nociceptive median nerve stimulus and what is the timing and intensity of the effect in both responses. Methods: The study was carried out in 8 healthy volunteers (three women and 5 men), aged 28–55 years. We recorded electromyographic activity of MM and OOc. In control trials we applied painful electrical median nerve stimulus (20 times sensory threshold). In test trials, electrical prepulse stimuli were applied to either ipsilateral or contralateral digital nerves of the third finger at inter-stimuli intervals (ISIs) varying between 40 and 100 ms. We compared the area of the response and the perceived intensity of the shock (using a 10-mm Visual Analogue Scale) in control and test trials. Results: Mean pain sensation was 6 ± 1 in control trials and 4 ± 1 in test trials (p < 0.05). MM and OOc responses were recorded in control trials in all subjects and were significantly reduced in ISIs from 80 to 100 ms in test trials (p < 0.05). No differences were found between ipsi- and contralateral stimuli. Conclusions: Our results show that there is a common effect of ipsilateral and contralateral somatosensory prepulse stimuli on MM and OOc responses, which indicates a common polysensory system integrating both circuits. The observation that nociceptive reflexes can be inhibited by innocuous prepulse stimuli could have some clinical applicability in the modulation of pain pathways. Studying the prepulse effects of peripheral nerve afferents on MM and OOc stimulus could offer new possibilities for the assessment of brainstem reflexes.

P478 Investigation of central neuropathy by evoked potentials in diabetic patients without peripheral neuropathy H. Turker, K. Oruc, M. Onar Ondokuzmayis University (Samsun, TR) Objectives: The role and importance of the evoked potentials (EP) in diagnosing involvement of the central nervous system (CNS) in diabetic patients were reported by several studies before. However, most of these studies were practiced in patients with polyneuropathy. In this study, our aim was to reveal whether there was CNS involvement in diabetic patients who did not show the clinical and electrophysiological signs of peripheral neuropathy. Methods: We performed nerve conduction studies (NCS), needle electromyography (EMG), median somatosensory EPs (SEPs), short, middle and long latency auditory evoked potentials (BAEP, MLAEP and LLAEP respectively) in 36 diabetic patients and 37 healthy volunteers. NCS and EMG were studied in 3 extremities of all subjects. EPs were performed bilaterally. A total of 146 median SEPs, 146 BAEPs, 146 MLAEPs and 146 LLAEPs were performed. We compared all the parameters of the EPs statistically between patients and controls. We also investigated the correlation of EP parameters with duration of diabetes, age of the patient and HbA1 c concentration. Results: The results revealed a statistically prolonged onset and peak central conduction time in median SEPs of diabetic patients, while BAEP and MLAEP studies indicated prolongation of the interpeak latencies and the latencies of Na, Nb and Pb potentials, respectively. LLAEP studies confirmed that P1 latencies of the patient group were longer than the latencies of the controls. The amplitudes of P1, N1, P2 and N2 potentials were lower in the patient group when compared with the controls. There was no correlation between EP parameters and the duration of diabetes, age and HbA1 c concentrations, with the exception of P2 amplitude showing positive correlation with the concentration of HbA1c. Conclusion: The results of this study may be interpreted that the involvement of CNS in diabetes may not evolve simultaneously with polyneuropathy and may perhaps begin earlier. CNS involvement does not seem to correlate with duration of disease and age of the patient.

P479 Electrophysiological diagnosis of carpal tunnel syndrome in patients with diabetic polyneuropathy H. Turker, O. Bayrak, A. Yilmaz, M. Onar Ondokuzmayis University (Samsun, TR) Objectives: Comorbidity of carpal tunnel syndrome (CTS) and diabetic polyneuropathy (DP) is frequent in patients with diabetes mellitus (DM). However the diagnosis of CTS in diabetic polyneuropathic patients is usually clinical, because the electrodiagnostic tests to differentiate CTS findings from polyneuropathic findings are indefinite. It is controversial whether routine electrodiagnostic tests for DP without CTS are also useful for DP with CTS in DM. The aim of this study is to investigate the reliability of rou-

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tine electrodiagnostic tests in the latter group of patients and to estimate which tests may be beneficial in everyday practice. Methods: One hundred and seventy-five subjects were enrolled in this study and 350 wrists were studied electrophysiologically. Groups of patients according to the clinical diagnosis were classified as group 1 diagnosed with both DP and CTS, group 2 as DP without CTS, group 3 as diabetic patients without DP and CTS, group 4 as diabetic patients without DP, but having CTS, group 5 as patients with CTS without diabetes and group 6 as normal subjects. Every patient had a thorough physical and neurological examination and diabetic patients were also evaluated with neuropathic impairment score (NIS). Physicians performing clinical and electrophysiological examinations were blind. Electrophysiological study comprised nerve conduction tests (NCT) as median and ulnar motor and sensory NCT and median-ulnar latency difference test in 4th finger sensory NCT for all patients besides peroneal and posteriortibial motor and sural sensory NCT in all diabetic patients and in non-diabetic groups where necessary.All parameters of the upper extremity NCT were compared statistically between all groups. Results: Statistical comparison tests revealed that median-ulnar latency difference in 4th finger sensory NCT, values of distal median sensory latency, amplitude, nerve conduction velocity and distal median motor latency were reliable and showed statistically significant differences among diabetic polyneuropathic patients with and without CTS. Values of distal median motor amplitude, nerve conduction velocity and ulnar NCT did not differ statistically among them. Conclusion: This study confirms that most of the NCS used in everyday practice are reliable and valuable in electrophysiological differential diagnosis of CTS in DP. P480 Auditory event related potential in patients with mild cognitive impairment K. Slotwinski, S. Budrewicz, R. Podemski, M. Koszewicz, A. Pokryszko-Dragan Wroclaw Medical University (Wroclaw, PL) Auditory long-latency P300 potential is endogenous evoked responses, which correspond with efficiency of cognitive processes, especially with memory dysfunctions. Disturbance of these processes results in complete lack of endogenous response or in abnormal parameters of this response (prolonged latency and/or lowered amplitude). The patients with mild cognitive – amnestic subtype (AMCI) present isolated memory dysfunctions without different cognitive disturbances, which may by a prodromal phase of dementia. The aim of this study was to evaluate the latency and amplitude of auditory P300 potential in patients with mild cognitive impairment. Material and methods: The study group was comprised of 10 patients (6 men, 4 women, aged 47–56, mean age 51.6) with mild cognitive impairment (MCI). In all patients routine neurological examination and brain CT were performed. Cognitive function was evaluated by means of neuropsychological tests battery, including Auditory Verbal Learning Test, Digit Span, Rey Figure Test, Trial Making Test (part A and B). Auditory P300 potential was evoked using basic “oddball paradigm”. Superficial recording electrodes were placed in Fz, Pz, Cz (according to 10–20 system), with the reference electrode at the mastoid process. At least 30 target responses were averaged. Control group consisted of 18 healthy persons (10 men, 8 women), aged 4557, with normal CT head scan and without cognitive decline. Results: 1. In all patients marked memory decline was found in Auditory Verbal Learning Test. 2. In all patients P300 latency was significantly prolonged in comparison with control group (mean results respectively: 356 ms and 339ms) 3. There was no significant difference of mean P300 amplitude in the patients with MCI and the control group. 4. No significant correlations were found between memory decline and latency P300. Conclusion: 1. In patients with AMCI bioelectrical changes appear in the neuronal network and they could be related with cognitive function, mainly with memory. P300 latency prolongation is an electrophysiological sign of these changes. 2. Changes of P300 latency in patients with AMCI are unspecific and do not allow to quantitative analysis of memory impairment. P481 False positive in the short segment nerve conduction study by ulnar nerve dislocation at the across-elbow segment B. J. Kim, K. W. Park, D. H. Lee, D. Y. Kwon, H. J. Kim, J. M. Lee Korea University Medical Center (Seoul, KR) Objectives: The most valuable diagnostic method in patients with ulnar neuropathy at the elbow is nerve conduction study. However, possible technical

error induced by ulnar nerve dislocation when the elbow is flexed has been recently suggested. This study was performed to evaluate the effect of the ulnar nerve dislocation on the short segment nerve conduction study (S-NCS) at the across-elbow segment. Methods: Two-hundreds-thirty-four elbows from 117 healthy volunteers (mean age 30.4 years) were enrolled in this study. The ultrasonography was performed to observe whether ulnar nerve dislocate at the elbow when it is flexed and to determine the angle of elbow when the ulnar nerve dislocate. The S-NCS was performed at the across-elbow segment with two different methods: 1) conventional method, stimulation on the skin above ulnar nerve which typically course in the ulnar groove, 2) adjusted method, stimulation on the skin above ulnar nerve searched by ultrasonography. Results: Ulnar nerve dislocation occurred in 13 elbows (5.6 %). The mean angle of elbows when the ulnar nerve dislocated was 99.8 degree (range 75–135). Of 13 elbows which had dislocated ulnar nerve, all elbows had conduction block around medial epicondyle during the S-NCS with conventional method. However, the abnormal conduction block was confirmed as normal conduction by adjusted method. Conclusions: The results suggest that caution is needed during interpretation when compound muscle action potential of ulnar nerve is not evoked or has significant amplitude drop at the across-elbow segment, because possible ulnar nerve dislocation may cause significant technical error by volume conduction. P482 Cortical activation changes following botulinum toxin treatment of poststroke arm spasticity: evidence from fMRI examination P. Hlustik, P. Kanovsky, H. Vranova, Z. Senkarova, R. Herzig, P. Otruba Palacky University and University Hospital (Olomouc, CZ) Objectives: Brain hemisphere impaired by stroke is able to restore motor function of the disabled arm, probably due to mechanism of cortical plasticity. It is also supposed that botulinum toxin (BTX) treatment can relieve focal spasticity after stroke, presumably through dynamic changes at multiple levels of the motor system, including cerebral cortex. Both these processes should be reflected in changes of cortical activation during motor or mental tasks as assessed using functional MRI (fMRI). Our aim was to localize the changes in motor cortex activation induced by botulinum toxin treatment in stroke patients using fMRI. Methods: Four patients (2 males, 2 females, mean age 25. 5, SD 3.4 years) with hemiplegia and distal arm spasticity due to middle cerebral artery stroke sparing the motor cortex were studied. Brain fMRI during mental movement simulation (imagined sequential finger movements of the impaired hand) was performed in two sessions, before and 4 weeks after BTX injection into the spastic arm. Change in arm spasticity was assessed using the modified Ashworth scale (MAS). Following L-R flip of the right hemisphere-lesioned brains, whole-brain fMRI group data were processed with a general linear model, testing for treatment effects with linear contrasts. Results: BTX treatment decreased arm spasticity across the group (mean MAS change 2.1). fMRI data pre- and post-BTX treatment showed consistent activation of the contralateral motor cortex, bilateral premotor cortices and posterior cingulate/precuneus during imagined movement. The pre- > postBTX contrast revealed a significant decrease (P < 0.05) in activation of the posterior cingulate/precuneus region after BTX treatment. Conclusion: This pilot study suggests that structures outside the classical motor system may be associated with the relief of post-stroke arm spasticity. The posterior cingulate/precuneus region was implicated in functions such as global attention or complex motor learning, however, in special circumstances it probably can modulate motor processing as well. Study supported by IGA MH CR grant NS 8367–3/2005. P483 The effect of botulinum toxin type A therapy on cortical somatosensory evoked potentials in patients with upper limb spasticity R. Opavsky, P. Otruba, P. Hlustik, R. Herzig, P. Kanovsky Palacky University, Faculty of Medicine (Olomouc, CZ) Objectives: The exact mechanism of action of botulinum toxin type A (BTXA) in spasticity has not been elucidated so far. Besides well-known local effect on the neuromuscular junction of the alpha motoneuron, latest data also suggest reorganization of the central nervous system (CNS). These effects on CNS are presumably mediated through afferent pathways. Methods: Somatosensory evoked potentials (SEPs) of the median nerve were recorded in patients suffering from upper extremity spasticity following a supratentorial ischemic stroke. Parameters of cortical SEP components (precentral: P 22, N 30, postcentral: P 17, N 20, P 23) were measured in order to assess the central effects of BTX-A. Three examinations were performed:

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prior to BTX-A injection (E 1), 4 weeks (E 2) and 12 weeks (E 3) following the injection into the most affected forearm muscles. Spasticity of the affected limbs was measured with the Modified Ashworth Scale (MAS). Results: A total of 17 patients (8 with affected left arm, 9 with affected right arm) with mean age 60.8±17.4 years were studied. There was a significant decrease of MAS from 3.0±0.9 in E 1 to 2.0±0.5 in E 2 with a subsequent return to 3±0.9 in E 3 for the whole group of patients. Subgroups with right or left-sided spasticity showed similar results for MAS. In patients with leftsided spasticity significant (p < 0.05) relative prolongation of latencies on the affected limb, if compared to the unaffected side, was found for postcentral component P 17 in E 1, E 2 and precentral components P 22/N 30 in E 3. There was a trend for P 17 and P 22/N 30 latencies recorded from the unaffected arm to prolong from the normal values in E 1 to E 2 with subsequent return to normal values in E 3, whereas a gradual increase of the delay in these latencies from E 1 value over E 2 to E 3, when detected on the affected arm. There were no significant differences in amplitudes and latencies of cortical SEP components within each extremity over time. Conclusion: The results may reflect different roles of the right and left brain hemisphere in processing of afferent input, as well as a distinct cortical modulation of each hemisphere following BTX-A treatment. Supported by grant IGA MH CR NR 8367-3/2005. P484 Spontaneous course of presymptomatic spondylotic cervical cord compression and prediction of its clinical manifestation J. Bednarik, Z. Kadanka, S. Vohanka, M. Kerkovsky, I. Urbanek, O. Novotny, D. Surelova, Z. Petrakova Masaryk University (Brno, CZ) Objectives: The data available on the prediction of the outcome in surgical and conservative treatment of spondylotic cervical myelopathy are controversial. Little is known about the clinical natural history of asymptomatic magnetic resonance image-detected spondylotic cervical cord compression and/or changes of signal intensity. Objectives was to investigate whether various demographic, clinical, imaging, and electrophysiological parameters could predict progression from clinically asymptomatic (preclinical) spondylotic cervical cord compression to symptomatic myelopathy. Methods: We conducted a cohort study of clinically asymptomatic spondylotic cervical cord compression cases with the primary end point of the development of clinical signs of cervical myelopathy. A group of 158 patients (73 women, 85 men, median age 50 years, range 28–75 years) with magnetic resonance signs of spondylotic cervical cord compression but without clear clinical signs of myelopathy was followed prospectively for at least 2 years (range, 2–13 years; median 5 years).Various demographic, clinical, imaging, and electrophysiological parameters were evaluated after inclusion into the study and than annually, and correlated with clinical outcome. Results: Clinical signs of myelopathy during the follow-up period were detected in 33 patients (20.9 %). The annual risk was highest during the first year after the detection of compression and then decreased. The only variables significantly associated with the development of clinically symptomatic spondylotic cervical myelopathy (SCM) were electrophysiological abnormalities indicating cervical cord dysfunction (abnormal somatosensory and motor-evoked potentials and electromyographic signs of anterior horn lesion) and the presence of symptomatic cervical radiculopathy. A multivariate logistic regression model based on these variables correctly classified 90 % of cases into 2 subgroups: a group with development of symptomatic SCM and that without clinical manifestation of subclinical cervical cord compression. Conclusions: Electrophysiological abnormalities together with clinical signs of cervical radiculopathy could predict clinical manifestation of preclinical spondylotic cervical cord compression. Supported by the Research Plan of the Czech Ministry of Education No. MSM 0021 622 404 and by Grant project of the Internal Grant Agency of the Czech Ministry of Health No. NR 7993-5.

Extrapyramidal disorders P485 Cardiac MIBG scintigraphy abnormalities and the time course of Parkinson’s disease Y. Aburakawa, T. Kimura, K. Fujiwara, T. Katayama, Y. Makita, H. Enomoto, K. Kuroda, H. Aizawa, O. Yahara National Dohoku Hospital (Asahikawa, JP); Asahikawa Medical College (Asahikawa, JP) Objectives: A high frequency of cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy abnormalities are found in patients with Parkinson’s disease (PD). However, some patients have no such abnormalities. Since it is necessary to distinguish PD from other diseases, such as Progressive Supranuclear Palsy (PSP) or Multiple System Atrophy (MSA), the purpose of this study was: to elucidate the frequency of MIBG abnormalities in PD, examine other factors associated with MIBG, examine normal MIBG cases of PD, and examine the time course of MIBG. Methods: Cardiac 123I-MIBG scintigraphy was used to evaluate the cardiac sympathetic nervous system. After injecting patients with 111MBq of, 123I-MIBG images were taken after 15 min and 4 h as the early phase and delayed phase, respectively. The region of interest was set up and the accumulation ratio of each left ventricular area of the heart to the upper mediastinum (H/M), and the wash out ratio (WR) were calculated. A 24 h Holter ECG analysis was performed to evaluate the cardiac sympathetic and parasympathetic nervous system, and also on patients who underwent MIBG. We checked pNN 50 values and the L/H ratio, as well as each patient’s age and the Hoehn-Yahr stage of the disease. For the statistical analysis, the Fischer t-test was used. P values of < 0.05 were considered to be statistically significant. Results: The high sensitivity and incidence rate of MIBG abnormalities in PD is 94 %.With Planner images the abnormal incidence rate is 83 %. Thus used together with single photon emission computed tomography (SPECT), a higher sensitivity is obtained. MIBG abnormalities correlate with L/H and reflect cardiac sympathetic nerve abnormalities. H/M (D) correlates to the duration of the disease. In SPECT, there is a higher frequency of decrease at the inferior wall, so observing the MIBG time course provides much higher sensitivity. Conclusion: To diagnose PD, MIBG scintigraphy is extremely useful. While MIBG may be normal at first, follow up of the time course of MIBG images and clinical symptoms is essential. Our patients are being followedup to investigate the relationship between clinical symptoms and MIBG abnormalities; the relationship between cardiovascular symptoms and MIBG abnormalities; and finally to investigate any differences in the prognosis of patients whose MIBG abnormalities appear at the early stage. P486 Evaluation of substantia nigra in atypical parkinsonian syndromes and Parkinson’s disease P. Bartova, D. Skoloudik, T. Fadrna, P. Ressner, R. Herzig, P. Kanovsky FN Ostrava-Poruba (Ostrava-Poruba, CZ); NsP Novy Jicin (Novy Jicin, CZ); FN Olomouc (Olomouc, CZ) Backround: Differentiation among idiopathic Parkinson’s disease (PD), essential tremor (ET) and atypical parkinsonian syndromes (APS) using clinical criteria may be difficult, especially in early stage of disease. Transcranial sonography (TCS) is able to detect structural abnormalities of substancia nigra (SN). The aim of study was to test an ability of TCS in differentiation of PD, ET and APS patients. Methods: SN echogenicity and area were examined using TCS (Philips HDI 5000, 2–4 MHz probe). Out of the 209 examined patients 111 had PD – Hoehn and Yahr (HY) stage 2–4, 8 patients had parkinsonian variant of multiple system atrophy (MSA-P) – HY stage 3–4, 10 patients had vascular parkinsonian (VP) syndrome – HY 2–4,10 patients had ET, 8 patients had neuropathic or drug induced tremor and as control group we examined 60 patients without any extrapyramidal symptoms. Results: The enlarged (? 0.25 cm2) hyperechogenic SN was detected in 84.7 % patients with PD (p < 0.05), 50 % patients with MSA-P (p < 0.05), 27.3 % patients with VP, 20 % patients with ET, 30 % patients with other tremors and 0 % patients without extrapyramidal symptoms. Conclusions: TCS could be used in differentiation between PD, APS and other extrapyramidal symptoms. Enlarged hyperechogenic SN seems to be a marker of structural involvement of this nucleus in PD or APS.

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P487 Immune factors or depression? Fatigue correlates in Parkinson’s disease S. Bostantjopoulou, Z. Katsarou, G. Kourtesi, S. Karachristianou, O. Hatzizisi, G. Kyriazis University of Thessaloniki (Thessaloniki, GR) Objectives: Fatigue is a frequent symptom in Parkinson disease (PD), but its pathogenesis remains obscure. Fatigue may be influenced by depression and motor disability but immunological factors have been also implicated. The purpose of the study was to assess fatigue in PD patients in relation to depression and various immunological factors. Methods: Thirty PD patients and 26 normal matched controls were studied. PD patients were classified in Hoehn and Yahr stages and their motor disability was evaluated by means of the UPDRS. The Beck Depression Inventory (BDI) was employed for depression screening. Fatigue was assessed by the Fatigue Severity Scale (FSS). The following immunological factors were estimated: a) T- and B-lymphocytes, T-lymphocyte subsets (Helper/Suppressor cells) as well as Natural Killer cells (NK). b) serum levels of Interleukin IL-1beta. Results: Mean [SD] FSS score in PD patients was higher than controls (4.8 [1.5] versus 3.4 [1.6], p <.01). PD patients had fewer T-lymphocytes (p <.05) and more NK cells (p <.01). IL-1beta levels were significantly increased (p <.01). Correlation between FSS score and immunological factors was significant for NK cells only (rho: –0.372, p = 0.043).FSS score correlated also significantly with BDI(p = .001). However multiple regression analysis relating FSS to all relevant parameters revealed BDI as the only significant predictor of fatigue (beta = .486, p = .009) Conclusions: Our results indicate that fatigue is a common non specific symptom in PD. Although lower NK cells percentage showed a weak association with fatigue, depression emerged as its main predictor. P488 Diet habits as a risk factor in Parkinson’s disease B. Gulel, S. Ozkan, N. Uzuner Eskisehir Osmangazi University (Eskisehir, TR) Objective: Some recent studies suggests diet habits might be a risk factor for Parkinson’s disease. However, there are conflicting results in different epidemiological studies. In this study, we aimed to assess the relation between the diet habits and the risk of Parkinson’s disease by correlating the diet habits of idiopathic Parkinson’s disease patients and healthy age matched controls. Methods: Seventy idiopathic Parkinson’s disease patients (mean age ± SD; 65.05 ± 9.2 years) living in Eskisehir and who were being followed up at least for 2 years in our movement disorders out patient clinic were included the study. Seventy healthy subjects (63.07 ± 8.9 years) without any neurological and systemic disease were assessed in control group. Patients who were under a obligatory diet program were excluded. Diet habits were assessed with American National Cancer Institute Food Frequency Questionnaires which was modified for Turkish population (107 basic food habits). Questionnaire includes a detailed inquisitions of food intakes during a one month period. Questionnaires were answered by patients and their relatives during a face to face interview. Food intake frequencies for each basic food were statistically correlated with the control group by logistic regression analysis method. Results: There were no statistically age or gender difference between the patients and the control subjects. No significant difference was observed for each 107 basic food intake frequency between Parkinson’s disease patients and the controls. Conclusion: Although there are many studies investigating the realtion between the neurodegenerative diseases and the diet habits, results are generally conflicting. In this study, we observed no significant difference between the patients and the controls. However these results does not exclude the environment effect (heavy metals, air polution, etc) on neurodegeneration. P489 Sonographic detection of basal ganglia calcification in Fahr’s disease C. Krogias, S. Meves, M. Schoellhammer, R. Gold, J. Andrich Ruhr University Bochum (Bochum, DE) Background: Recent works report a high diagnostic yield of brain parenchyma sonography (BPS) in differentiating parkinsonian syndromes. Sporadic or familial striopallidodentate calcinosis (Fahr’s disease) is an idiopathic calcification of the basal ganglia which may be associated with movement disorders like parkinsonism and dystonia, and other neurological features such as behavioural dysfunction, psychiatric symptoms and

seizures. The aim of this case report was to examine the diagnostic value of brain parenchyma sonography in Fahr’s disease. Methods: A 65-year-old male patient presented at our department with a four year history of progressive hypokinesia with rigidity, dysarthria and cerebellar ataxia. The family history was unremarkable regarding neurological disorders. BPS was performed in different examination planes and modes using a Siemens Sonoline Elegra ultrasound system. Findings were compared to those from cranial computer tomography. Results: BPS showed a massive bilateral hyperechogenicity of pallidostriatal regions as well as of central midbrain structures, while substatia nigra showed no hyperechogenicity. Cerebral computertomography revealed an excessive symmetric striopallidodentate calcinosis as well as in midbrain structures and in cerebellum compatible to Fahr’s disease. Conclusions: To our knowledge this is the first case of sonographic visualization of bilateral basal ganglia calcification in Fahr’s disease. In view of these findings, the diagnostic potential of transcranial ultrasound in the evaluation of parkinsonian syndromes is even more augmented. P490 Possible propriospinal myoclonus in a patient with contralateral cervical disc herniation J. H. Kwon, Y. S. Shim Ulsan University (Ulsan, KR); Catholic University (Ulsan, KR) Propriospinal myoclonus is a rare manifestation of spinal myoclonus. It presents a more complex and multisegmental activity than segmental myoclonus and characterized by semirhythmic jerking movements of abdomen and trunk. In most cases the causes has remained unclear. Secondary causes are various disorders such as spinal cord injury, multiple sclerosis, syringomyelia and infectious diseases. So far, propriospinal myoclonus related with cervical disc herniation has been rarely reported. We report a 41-yearold man with possible propriospinal myoclonus and contralateral cervical disc herniation. He was initially presented with diffuse dysesthesia and allodynia in the abdomen, trunk and posterior chest area. One day after dysesthesia, myoclonic jerks affecting the abdomen and trunk spread to the neck, left perioral area and left fingers. Magnetic resonance imaging showed narrowing of neural foramen and nerve root compression at the C 5–6 level on the right side. However, there was no evidence of cervical myelopathy and brainstem lesion. Evoked potential studies of upper and lower extremities and electroencephalography showed no conduction defects and epileptiform discharges. Electromyography showed semisimultaneous activity in rectus abdominis and pectoralis major muscles. His propriospinal myoclonus was gradually disappeared after clonazepam therapy. Cervical disc herniation should be considered when clinicians encounter a patient with propriospinal myoclonus. P491 Implementation of static posturography for the measurement of postural control in patients with morbus Parkinson H. Ambach, J. Bresch, H. J. Koch, L. Rausch, G. W. Ickenstein HELIOS General Hospital Aue (Aue, DE); European Fachhochschule Fresenius (Zwickau, DE) Objectives: Postural instability is a one of the most common symptoms of Morbus Parkinson. In clinical practise the measurement of postural control depends on a neurological examination, technical methods are not established yet. The goal of our study was to identify the posturographic parameters that are influenced by Morbus Parkinson to measure postural control. Methods: In our pilot study we examined patients with Morbus Parkinson (PP, n = 12) on a static posturographic platform (GK-1000, IMM Elektronik, Mittweida, Germany) performing a standard Romberg-test (eyes open/closed) during neurological routine examination.We compared the results with an aged-matched control group (AC, n = 10) and a student control group (SC, n = 21). The measurement included: area, mean radius, mean shift, mean velocity and frequency. Uni- and multivariate analysis were performed. Results: In the platform Romberg-test the patients with Morbus Parkinson showed a significant greater area (PP: 2.46 vs.AC: 0.88 vs. SC: 0.78 [cm2], p < 0.05), greater shift (PP: 14.98 vs. AC: 8.77 vs. SC: 7.80 [mm], p < 0.05), greater radius (PP: 28.31 vs. AC: 16.36 vs. SC: 14.19 [mm], p < 0.05), and greater velocity (PP: 20.13 vs. AC: 13.01 vs. SC: 9.77 [mm/s], p < 0.05) compared with the control groups in both tests (open / closed eyes). Conclusion: The platform Romberg-test showed group dependent results reflecting a different postural stability. The neurodegenerative process in patients with Morbus Parkinson is clinically reflected by postural instability which can also be measured with an technical approach. The platform

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Romberg-test can therefore be used for diagnostic purposes but also treatment effects of postural control. P492 The evaluation of tau-protein in the CSF of patients suffering from Parkinson’s disease H. Vranová, J. Maresˇ, M. Nevrli, R. Herzig, P. Kanovsky Palacky University (Olomouc, CZ) Objectives: Sporadic Parkinson disease (PD) is a progressive degenerative illness of the nervous system manifesting itself clinically after the pathology already has reached an advanced stage. According to the Braak’s staging of brain pathology the severity of involvement of the brain is expressed in the severity of motor manifestation of the disease. Tau-protein is a component of neuronal cellular scaffold. During neurodegeneration the cells decay and tau-protein is being released into the CSF. The severity of neurodegeneration should correlate with tau-protein CSF levels. The aim of our study was to assess the tau-protein CSF levels in patients suffering from PD and to compare the tau-protein levels with both the PD duration and severity of motor manifestation of PD. Methods: The tau-protein CSF levels were assessed in 25 patients suffering from PD (18 males, 7 females, aged 37–73, mean 58.8 ± 11.52 years). The tau-protein CSF levels were correlated with PD duration and severity of motor manifestation of PD. Hoehn-Yahr scale was used for the assessment of the severity of motor manifestation. Correlation analysis and t- test were used when assessing statistical significance of the results. Results: The statistically significant moderate positive correlation between the tau-protein CSF levels and the severity of motor manifestation was found (r = 0.503, p = 0.014). No statistically significant correlation was found between the tau-protein levels and the PD duration. Conclusion: The CSF levels of tau-protein may serve as a potential marker of neurodegeneration in PD. P493 Environmental influences and toxic substance exposure and characteristics of Parkinson’s disease D. Italo, M. Budisic, T. Breitenfeld, K. Jergovic, V. Vargek-Solter, M. Crnjakovic, V. Demarin University Hospital Sestre Milosrdnice (Zagreb, HR) Objectives: Epidemiological studies support the hypothesis that Parkinson’s disease (PD) may be caused by environmental factors, but etiology of PD is still uncertain. It is also widely accepted that there is a genetic component of the disease and the earlier the age of onset, the greater the likelihood that genetic factors play a dominant role. We initiated this study to detect possible neurotoxic influence on clinical course, disease characteristics and morphology of Substantia Nigra (SN) as detected by transcranial sonography (TCS) in PD patients. Methods: Our study included 47 PD patients with PD diagnosis based on Parkinson’s disease Society Brain Research Centre clinical criteria. Severity of the disease was recorded according to Unified Parkinson’s Disease rating Scale (UPDRS) and Hoehn & Yahr rating scale.According to epidemiological screen three subgroups were made; 26 PD patients without any data about exposure to known PD related toxins, 15 PD patients occasionally exposed and 6 patients professionally daily exposed to numerous neurotoxic potent chemicals. Epidemiological screen data included exposure to pesticides, herbicides, heavy metals (manganese, mercury, lead, iron, zinc), organic solvents, head trauma, smoking, rural living and well water drinking. All patients underwent complete neurological and sonographic examination. Each patient underwent brain parenchyma sonography and hyperechogenicity of SN was measured by standardized protocol. Results: Our results showed younger age of PD onset (p < 0.05), the fastest development of late motor complications (p < 0.001), rigor as dominating symptom, and UPDRS and H&Y score showing higher motor disability (p < 0.05) in highly exposed group. However, sonographic examination revealed no statistically significant difference in SN echogenicity between groups. Conclusion: Results of this study suggest that exposure to toxins could cause younger age of onset of PD, acceleration of PD progression and higher incidence of motor disability. However, it appears like toxic influence does not have influence on SN size as detected by sonography.

P494 A two-year follow-up of depression in patients who underwent posterovental pallidotomy for Parkinson’s disease I. Laskowska, P. Andryszak, A. Stachowiak, M. Harat, E. Gorzelanczyk Regional Centre of Palliative Care – Sue Ryder Care (Bydgoszcz, PL); 10 Military Hospital (Bydgoszcz, PL) Objectives: Major depression is a common phenomenon in Parkinson’ s disease (PD). It affects nearly 20–40 % of PD patients. The mood of patients with PD who had undergone pallidotomy (PVP) was evaluated at a mean of 2 years postsurgery. Most of studies suggest an improvement or no change in mood following unilateral or bilateral PVP. Only in few of the papers aggravation of depression was reported. The aim of our study was to evaluate whether the degree of depression in PD patients changes at a longer time scale. Methods: 46 patients with PD and depression symptoms, aged between 45 and 74 years, (17 women (w) and 29 men (m)participated in the study. Patients underwent unilateral (31 patients: 10 w and 21 m) or bilateral (15 patients: 7 w and 8 m) posteroventral pallidotomy. The unilateral lesion was on the right hand side in 15 patients and on the left hand side in 16 patients. The results were compared with those obtained in two control groups: 1) 44 agematched healthy individuals, 2) 35 age-matched PD patients without surgery. In order to examine participants’ emotional status the following tests were administered: the Beck Depression Inventory (BDI) and the Montgomery Asberg Depression Rating Scale (MADRS). PD patients were assessed three times: before, after and at the mean of 2 years postsurgery. Results: The results obtained by 2 groups of PD patients, measured for the first time using BDI test, were significantly higher as compared to those in healthy controls. The second measure did not show any significant differences between groups. The scores of BDI in both groups of PD patients decreased. The third me>sure obtained at the mean of 2 years postsurgery demonstrated significantly increased scores. Similar data were obtained using MADRS. Both groups of PD patients revealed higher scores in all three assessments. However, PD patients who underwent pallidotomy had significantly lower degree of depression in the second assessment although this effect did not persist till the third assessment performed at the mean of 2 years postsurgery. Our results demonstrated also that the side of the PVP lesion affected the degree of depression measured in long term follow-up, both in BDI and MADRS tests: PD patients with left side pallidotomy obtained significantly higher scores. Conclusion: This finding confirm that ablation of globus pallidus reducing depression symptoms postsurgery. However, at the long run, PVP is not an effective therapy for depression in PD. P495 Effects of rotigotine transdermal patch on early morning motor impairment and sleep disorders in subjects with early-stage Parkinson’s disease T. Mueller, J. Kassubek, B. Boroojerdi on behalf of the SP 825 study group Objective and background: Given the continuous 24-hour drug delivery achieved with the rotigotine transdermal patch (Neupro®), control of early morning motor impairment and sleep disorders was assessed in early stage PD patients who did not receive levodopa. Methods: Subjects received rotigotine (up to 8mg/24 h) or ropinirole (up to 9mg/day). The investigators performing the assessments were blinded to the treatment. There was a Screening Period (up to 28 days), a Baseline Period including 2 overnight stays, a Titration Period (up to 4 or 6 weeks for rotigotine and ropinirole subjects, respectively), and a 4-week Maintenance Period including 2 overnight stays. Early morning motor performance was evaluated using UPDRS Part III before administration of morning medication. Improvements in sleep were assessed using the Parkinson’s Disease Sleep Scale (PDSS). In addition, patients’ treatment preference was assessed using a questionnaire. Results: A total of 51 subjects were randomized (25 to rotigotine and 26 to ropinirole). There were marked improvements in both early morning motor function and sleep disorders. UPDRS III scores were reduced by 6.3±1.3 (SEM) and 5.9±1.3 points for rotigotine and ropinirole groups, respectively (CI: –8.8/–3.7 and –8.5/–3.4, respectively). The PDSS sum score showed a slightly larger improvement for the rotigotine group (increase of 4.2±2.7 vs. 1.8±2.6 for the rotigotine and ropinirole groups, respectively, CI: –1.3/ 9.8 and –3.5/ 7.0, respectively). All rotigotine-treated subjects with previous pharmaceutical treatment for PD were “satisfied” or “very satisfied” with the treatment compared to previous treatment compared to 9 % of ropinirole subjects. More of the rotigotine-treated subjects (91 %) than ropinirole-treated subjects (60 %)

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“agreed” or “strongly agreed” that they would prefer using a patch over oral medication. A total of 56 % of rotigotine subjects and 65 % of ropinirole subjects reported adverse events (AEs). The most common AEs for rotigotine-treated subjects included nausea, application site reactions, and fatigue and for ropinirole-treated subjects nausea, fatigue, and headache. Conclusions: The rotigotine transdermal patch at doses up to 8mg/24 h led to clinically relevant improvement in early morning motor function and sleep quality in this trial. There was only a small difference between rotigotine and ropinirole treatment groups although a larger proportion of subjects on rotigotine were satisfied with their treatment. This study was supported by Schwarz Pharma.

Epilepsy P496 Epilepsy in multiple sclerosis in Dubai J. Inshasi, M. Thakre, M. Saadah Rashid Hospital (Dubai, AE) Objectives: We aimed to determine the risk of developing epilepsy in MS patients and to identify the underlying pathogenesis for epilepsy. Methods: The medical records of 200 patients with clinically definite laboratory supported multiple sclerosis that were seen in Rashid hospital, Dubai in the period between 1986 and 2005 were reviewed. Poser’s and Mc Donald’s criteria were used. Results: There were 200 clinically definite Multiple Sclerosis.10 patients had epilepsy and were on regular antiepileptic drugs (AED). 47 patients had non-epileptic events. 39 patients (out of 47) were on regular AED for the non epileptic events. Seizures presented as multiple sclerosis relapse in 1 patient. Interferon induced the seizures in 1 patient. EEGs demonstrated partial epileptic discharges in 5 patients, partial with secondary generalized discharges in 2 patients, theta delta slowing in 1 patient and generalized spikes and sharp waves in 1 patient. 31 EEGs done of 47 patients with non-epileptic paroxysmal phenomena, 26 had abnormal EEGs with epilepstic activities and focal or diffuse slowing. MRIs of the brain demonstrated old lesions in 9 patients and enhancing lesion in 1 patient. Brain atrophy was seen in 3 patients. 14 patients had tonic spasm, 13 had painful dysesthesias, Lhermitte’s sign was positive in 10 patients and 10 patients had trigeminal neuralgia. Seizures were associated with MS activity in two patients, in one was related to MS relapse and in the other was related to progressive disease ativity and severe disability. In both MRIs showed new lesions.The lesions were subcortical in 6/10 patients and cortical in 4/10 patients. Conclusion: The epileptic seizures do not seem to be related to the MS activity in majority of the patients, they are rather related to the epileptogenesis of the chronic lesions (plaques). The epileptic seizures rarely occur as the first presenting sign of MS and they may be triggered by interferon therapy.Those related to MS relapse rarely recur and they are controlled with AED monotherapy.The risk of epilepsy in MS patients is underestimated because many MS patients take AEDs to treat non-epileptic phenomena. AEDs therapy for non-epileptic events reduces and masks the chances of developing true epileptic seizures. Seizures associated with relapse rarely recur. Seizures not related to disease activity tend to be chronic. Patients with Seizures associated with progressive disability and cognitive decline, have poor prognosis. P497 Unverricht-Lundborg disease: the first report of genetically confirmed case in Serbia M. Kecmanovic, M. Ercegovac, R. Dimitrijevic, V. Dobricic, M. KeckarevicMarkovic, D. Savic-Pavicevic, D. Keckarevic, M. Saric, L. Beslac-Bumbasirevic, S. Romac Faculty of Biology (Belgrade, RS); School of Medicine (Belgrade, RS) Objectives: Progressive myoclonic epilepsies (PME) are a heterogeneous group of rare inherited disorders, associated with myoclonus, generalized epileptic seizures and progressive neurological deterioration, including dementia and ataxia. Unverricht-Lundborg disease (ULD) is the most common of these disorders and it is the most prevalent around the Baltic See and in the western Mediterranean region. The most common genetic defect (~90 %) associated with the ULD phenotype is homozygosity for an expanded dodecamer repeat in the cystain B gene (CSTB) located on chromosome 21q22.3. Minisatellite repeat unit 5’-CCCCGCCCCGCG-3’ is located 175 bp upstream from the translation initiation codon in the putative promoter region of the CSTB, which is normally polymorphic, with 2–3 copies

in healthy population. Mutant alleles contain 40 to 80 dodecamer repeats. Less percentage of ULD patients are compound heterozygotes for expansion on one, and point mutation on another chromosome. Very often ULD is underdiagnosed or misdiagnosed, and for that reason it is rarely mentioned in other European and countries around the world. We present male patient, 30 years old, who had the first symptoms of PME at the age of 15, with predominant stimulus sensitive myoclonus, slowly progressive cerebellar symptoms (dysarthria, dysmetria, ataxia), rare GTC and low concentration as the only cognitive symptom. Histological examination with light and electron microscopy showed neither pathological findings on mitochondria nor “ragged red fibers”. Methods: Genomic DNA isolated from blood samples of proband and his parents was digested with EcoRI and amplified by long range PCR. The sizes of expanded alleles were determined by Southern blot hybridization using (CCCCGCCCCGCG)2 oligonucleotide probe. Results: Southern blot hybridization revealed two expanded alleles in patient, and one normal and one expanded allele in each parent. The size of each discrete band (expanded allele) was determined according to DNA molecular weight marker using Total Lab 1.10 program. Proband had 60 repeats on the chromosome inherited from mother, and 64 repeats on the chromosome inherited from father, so with no variation in repeat size in individual transmission. Conclusion: Molecular diagnostics confirmed suspected ULD, and to our best knowledge, this is the first report of genetically confirmed case of ULD in whole Balkan region. P498 Best treatment of refractory focal epilepsy in children O. Tarta-Arsene, M. Buzatu, M. Gandea, S. Magureanu Clinical Hospital “Al. Obregia” (Bucharest, RO) Purpose: The aim of the study is to evaluate the therapeutic response of different antiepileptic drugs for refractory focal epilepsy in children. Method: It was considered refractory focal epilepsy, the partial seizures experienced by patients for more than a year, which were not controlled by two antiepileptic drugs. We retrospectively evaluated all case records of patients diagnosed in our department between 2005 and 2006. As clinical features was included personal history, age of onset, types of seizures and neurological exams at the moment of trial. The patients were evaluated through electroencephalography, imagistic exams. The efficacy of treatment was evaluated. Results: Refractory focal epilepsy was diagnosed in 55 children (34 females and 21 males) with ages between 18 months and 18 years old. Considering the etiology, 54.5 % of epilepsy was symptomatic and 45.5 % was cryptogenic. In 58 % of cases focal seizures were associated with generalized seizures. The seizure-free interval was between 1 day and 2 years 10 months. The treatment consisted in antiepileptic drugs with 3–11 different drugs during the evolution of the disease and ketogenic diet in one patient. In 67, 2 % of cases valproate in monotherapy or in association had the best control of seizures. Conclusion: According to the results, in our group with refractory focal epilepsy, valproate either in monotherapy or in association is the most frequent used and efficacious antiepileptic in children with focal seizures. To confirm this hypothesis, larger comparative studies are necessary. P499 Epilepsy and stroke T. Afrantou, A. Angelou, D. Karakostas, N. Artemis, I. Milonas, N. Taskos Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Stroke is the most common cause of epilepsy in adults.Almost 10 % of all stroke patients will experience at least one epileptic attack on the acute phase of stroke or during the next years from the onset. The development of post-stroke epilepsy is estimated around 2.5 % of the patients. Aim: The study of clinical, imaging and EEG features of patients with stroke and paroxysmal episodes(P. E.) in order to determine the risk factors predisposing to the development of epilepsy after stroke. Method-Patients: We studied retrospectively the data of 50 patients (males: 37, females: 13, mean age: 59) of our department with stroke and P. E. (type of stroke, type of P. E., EEG). The EEG study was performed either for the identification of the nature of the P. E. or for the assessment of already known epileptic seizures. Results: A) 23 patients with clinically definite, repeated epileptic seizures: type of stroke: ischaemic: 15, haemorrhagic: 8, time interval between stroke and P. E.: 0–24hrs: 10 patients while in the rest the mean time was 23 months af-

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ter the stroke. EEG findings: focal abnormality with sharp component in 8 patients, slow multiform abnormality(SMA) in 9 patients, normal EEG in 6 patients. B) 9 patients with clinically possible epileptic seizures: type of stroke: ischaemic: 7, transient ischaemic attack (TIA): 2, time interval between stroke and P. E.: 0–24hrs: 6 patients. EEG findings: focal abnormality with sharp component: 3 patients, SMA: 1 patient, normal EEG: 5 patients. C) 18 patients with clinically non typical P. E.: type of stroke: ischaemic: 13, haemorrhagic: 3, TIA: 2. Time interval: 0–24hrs in 11 patients. EEG: SMA: 4, normal EEG: 8, theta activities focally: 6. Conclusions: The risk factors for the development of epilepsy after stroke range from study to study; the late onset of seizures, cortical location, lobar haemorrhage and the severe neurological defect are considered as the most predisposing factors.Additionally focal spikes are connected with a high risk of seizures (78 %), while focal slow activities, diffuse slowing and normal EEG have a relatively lower risk (20 %, 10 % and 5 % respectively). In our study the patients with post-stroke epilepsy presented the following main characteristics: haemorrhagic stroke in 35 %, late onset seizures in 56 %, epileptiform activities in 35 %.

P500 Effectiveness of topiramate in medically complicated patients and refractory seizure D. G. Lee, D. W. Yang, B. S. Kim, Y. I. Kim, Y. M. Shon Catholic University of Korea (Seoul, KR) Objectives: As multiple cancer chemotherapy regimen develops, life expectancy of cancer patients increased. But these treatment regimens can not avoid immunosupression, bone marrow suppression, and multiple organ toxicity, inevitably. In those situation, choosing proper antiepileptic drug (AED) is crucial but very difficult, because most AED have adverse effects such as bone marrow suppression, organ toxicity and drug-drug interaction. TPM has a favorable pharmacokinetic profile with rapid absorption, good bio-availability, linear pharmacokinetics, relatively long half-life and limited drug interactions. These characteristics of TPM enable medication access to epilepsy in medically complicated patients. The goal of this study was to report the effectiveness of topiramate (TPM) in medically complicated patients (such as renal failure, hepatic failure, and bone marrow suppression) and patients in refractory seizure. Methods: We retrospectively reviewed charts of inpatients who were prescribed TPM over usual dose (more than 200mg per day) in St. Mary’s hospital of Korea between July 15th, 2004 and August 10th, 2006. Results: 32 patients were reported to neurology department in that period, of them male to female ratio was 1:1.2 and mean age was 51.8 years. Most common co-morbid disease were malignancies (n = 10, 37.5 %), and sepsis (n = 10, 37.5 %). 5 had both of them. Only 4 had history of epileptic seizure previously. In laboratory study, 22 (68.7 %) had hematologic problem and 16 had kidney problems, and 15 had liver problems. Most common seizure feature was status epilepticus (SE, n = 21), of them, 8 were in nonconvulsive SE. Mean TPM treatment dose was 519mg (range 200mg~1000mg) and treatment duration was 15.13 days. Of 32 treated with TPM, 27 (84 %) ceased seizures, 5 were uncontrolled, and 1 was lost to follow-up. Of 27 responded to TPM, mean seizure duration was 5.74 days (range 1~18days). Of 21 in SE, 16 ceased seizure after TPM add on. No patients were aggravated CBC and BC profile who was treated with TPM. Conclusion: TPM was effective in treating epileptic patients with medical complication in even SE. It should therefore be considered as an option in these situations, especially when other AEDs are too dangerous to be used.

P501 Complex partial status epilepticus in a patient with hypoparathyroidism and chronic mucocutaneous candidiasis B. Dumitriu, S. Tuta, B. Dumitriu Institute of Cerebrovascular Diseases (Bucharest, RO) Objectives: Our purpose is to stress the importance of searching the causes of the symptomatic focal epilepsies. We present a clinical case of an young patient 21 years old known with focal epilepsy (versive and aphasic seizures) with secondarily generalized seizures since he was 13 years old. He was born normally with no history of trauma, meningitis, genetic diseases, intracranial masses or stroke. Actually, he was admitted in our Department for a rise in the frequency of the seizures with the modification of the features of the crisis and for unresponsiveness to the medication. Methods: Clinical presentation revealed a patient with a prolonged twilight state with partial responsiveness, impaired speech and quasi-purpose-

ful automatism and with superimposed paroxysms with staring and total unresposiveness and speech arrest. Electroencephalogram(EEG) showed continous discharges of spike and polyspike-wave 2–2.5 Hz. Computed tomography (CT) displayed extensive bilateral calcifications of the caudat, putamen, pallidus and frontal subcortical white-matter that in conjunction with Chvostek’ sign and general spastic status strongly sugessted a hypoparathyroidism confirmed by the severe electrolytes changes: hypocalcemia, hypomagnesemia and hyperphosphatemia. Results: The endocrinological examination revealed an autoimmune polyglandular deficiency syndrome type I(hypoparathyroidism and mucocutaneous candidiasis). We proceeded to continous infusions with Calcium gluconat,magnesium supplements, thiazides and acetazolamide as far as the patient recovered and EEG showed normal alfa rythm with a few spikes. We have modified the antiepileptic medication introducing oxcarbazepine. Conclusions: Even if the epilepsy was diagnosed in childhood and apparently, could be idiopathic, the features of the seizures, the unresposiveness to the polydrug regimen, the CT aspects and the clinical signs and serum electrolytes have led to the correct diagnostic. P502 A multicentre open-label comparative evaluation of the cognitive function of topiramate versus zonisamide monotherapy S-D. Yi, J. E. Kim, S. J. Lee, J. J. Lee, S. P. Park Keimyung University (Daegu, KR); Catholic University (Daegu, KR); Yeungnam University (Daegu, KR); Fatima Hospital (Daegu, KR); Kyungpook University (Daegu, KR) Objectives: Topiramate(TPM) and Zonisamide (ZNS) have a structure of sulfa moiety, an action of carbonic anhydrase inhibition and a unique side effect of stone formation in common. We compaired the cognitive effects of TPM and ZNS as monotherapy. Methods: From Sep. 2005 to Dec. 2006 thirty patients (±13years old) with either newly diagnosed epilepsy or epilepsy that has not been treated with antiepileptic medications for more than 4 months completed open-label, randomized multi-center study incorporating 24 weeks treatment periods of TPM and ZNS titrated to a target dosage of 100mg/day and 200mg/day, respectively. Evaluation of 16 objective neuropsychological measures yielding 26 variables of cognitive function occurred at two times; pretreatment base line and after 24 weeks treatment. Groups did not differ with respect to epilepsy relevant variables and neuropsychological variables at baseline. Results: Mean scores of some neuropsychological measures declined after 24 weeks treatment from baseline pretreatment. ZNS group (15 patients) showed significant differences in the performance of forward digit span (p < 0.05), backward digit span (p < 0.01), semantic and phonemic word fluency (p <.05). TPM group (15 patients) showed significant differences in the performance of prose memory (p <.05), backward digit span (p < 0.05), semantic (p < 0.05) and phonemic word fluency (p < 0.001). There are no significant differences between TPM and ZNS group on these cognitive effects. Conclusion: This study demonstrates the comparable effects of TPM and ZNS on cognitive function. TPM and ZNS appears to be associated with negative cognitive side effects. But there are no significant differences between TPM and ZNS on these cognitive effects. P503 Clozapine related EEG changes J-M. Kim, C-G. Ha, S. H. Park, Y. H. Lee Chungnam National University Hospital (Daejeon, KR); Inha University Hospital (Incheon, KR); Bundang Seoul National University Hospital (Seongnam, KR) Background: Clozapine is an “atypical” neuroleptic drug with less acute or chronic extrapyramidal symptoms. Clozapine has low affinity at most dopamine receptors, and interact at several other classes of receptors. Although it has less adverse effects, clozapine has profound impact on EEG, and in some patients, may cause seizures. We evaluated the prevalence and risk factors of EEG abnormalities & seizures and effects of valproic acid in prevention of seizure induced by clozapine. Methods: 163 EEGs of 44 patients and the medical records including the dosage of clozapine at each EEG and history of seizures from Jan. 2000 to Jul. 2006 were reviewed. EEG was graded as follows: (0: Normal, 1: Less than 50 % of theta waves, 2: More than 50 % of theta or less than 50 % of delta waves or grade 0/1 plus epileptic discharge, 3:More than 50 % of delta waves or grade 2 plus epileptic discharge, and 4: electroclinical seizure or marked low amplitude EEGs). Results: Dosage of clozapine and EEG abnormality significantly correlated (P <.001). 23 out of 28 EEGs (82 %) with less than 100 mg of clozapine were grade 0, whereas 8 out of 83 (9.7 %) EEGs were grade 0 with more than

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400 mg of clozapine. Epileptic discharges were frequently found when clozapine dosage was 200 mg or more [27/130 EEGs (21 %)]. Valproate administration did not prevent EEG deterioration in 4/13 patients as far as clozapine was increased. Although preventive treatment with valproate was done in 11 patients, seizure occurred in 2 patients (more than 400 and 600mg each). Conclusions: Abnormal EEGs were significantly correlated with dosage of clozapine. EEG abnormality usually started around 100mg of clozapine and epileptic discharges were common in 200mg or more of clozapine. Efficacy of valproate can not be determined in the prevention of seizure induced by clozapine. P504 Rasmussen’s encephalitis G. Karlikaya, B. Citci, I. Kovanlikaya, B. Güclü, A. Hamamci, U. Türe, C. AykutBingöl Yeditepe University Hospital (Istanbul, TR) Introduction: Rasmussen’s encephalitis is a rare neurological disorder of unknown cause associated with inflammation of the brain, and progressive functional and structural destruction of a single cerebral hemisphere. It is characterized by severe epilepsy, and accompanied by intractable seizures, hemiparesis, dementia leading to severe neurologic and mental deficit. Case description: An 18 year old male patient started to have epileptic seizures at the age of 9. His neuroimaging studies displayed atrophy of the right hemisphere, sterotactic brain biopsy was suggestive of an inflammatory process and he was diagnosed with Rasmussen’s encephalitis at age 12. He was treated with IVIG and several antiepileptic medications with some stabilization. He was admitted to our hospital at age 18 due to intractable seizures, and his neurological findings included dysarthric speech, conjugate gaze paralysis to the left side, left hemiparesis and pyramidal symptoms on the left side. He was not able to function with his left hand, but he was able to walk unassisted. He had epilepsia partialis continua with regular clonic movements of the left side of the face, left hand and sometimes left foot and he was evaluated for hemispherectomy. His presurgical evaluation included EEG, Neuropsychological tests, MRI, PET, Ictal SPECT and fMRI. His EEG displayed low amplitude slow wave activity on the right side with no epileptiform activity. He had frontal lobe associated deficits and right hemisphere related deficits (attention, visuospatial construction) on neuropsychological testing, with normal left hemisphere function. His fMRI studies included language dominance and motor function studies. The fMRI demonstrated left hemisphere language dominance. He had left hemisphere activation during right hand and leg movement, but he also had left hemisphere activation during left leg movement, which was suggestive of plasticity. Although this finding helped making the desicion for the hemispherectomy; during the operation cortical and subcortical stimulation was used for protection of the motor pathways. After the operation he had no new neurological deficits and was seizure free with tapering the antiepileptic treatment. Conclusion: We conclude that hemispheric surgery is an effective therapy for Rasmussen’s encephalitis even in the late period and fMRI and direct cortical stimulation can reduce the morbidity of hemispherectomy in such patients. P505 Tolerability and efficacy of zonisamide in intractable epilepsy. A Spanish epilepsy unit experience J. Ojeda, V. Ivanez La Paz University Hospital (Madrid, ES) Objectives: Symptomatic or probably symptomatic focal or generalized epilepsy are common types of epilepsies in adults. The high rate of drug resistance in this group is well known. This drives usually to politherapy and to use new antiepileptic drugs(AED). Zonisamide (ZNS) arrived in Europe in early 2006, with extensive clinical experience in the US and Japan. Methods: Observational Study. Epilepsy Unit Databank. Consecutive adult outpatients included (2005 -2007). We studied the efficacy and tolerability of add-on ZNS, in patients with refractory symptomatic or probably symptomatic focal (RFE) or generalized epilepsy(RGE). The tolerability of ZNS was studied in terms of withdrawal due to adverse effects. We specifically studied the efficacy of ZNS used as add-on therapy with other AEDs. Patients ought to be treated with stable ZNS dosages for at least three months at the time of the evaluation. The AED efficacy was classified as: class 1: seizure free; class 2: reduction of 50–99 % in seizure frequency; class 3: reduction of 1–49 % in seizure frequency; class 4: no changes in seizure frequency. Results: 34 patients with RFE or RGE. Male: 15. Female: 19. Average age:

46.3. Epileptic Syndromes: Temporal Lobe Epilepsy (TLE) with Hippocampal Sclerosis: 15 patients (44.1 %) (one unsuccessfully operated). Frontal Lobe Epilepsy: 6. Lesional Neocortical TLE: 5. Non Lesional TLE: 4. LennoxGastaut: 4. Etiology: Hippocampal Sclerosis 15, Develomental Abnormalities: Cortical Dysplasia 5, Heterotopia 2, Tuberous Sclerosis 1, Polymicrogyria 1. Schizencephaly: 1. Dual Pathology: 2. Cryptogenic: 11. TOLERABILITY: withdrawal rate: 17.6 % (6 patients); seizure frequency increase:1; dizziness: 2; erectile dysfunction: 1; anorexia:1; weakness: 1 (3 of these patients were also on CBZ). Efficacy: Average time on ZNS: 79 days.Average Dosage: 357 mg per day. Efficacy: Class 1: two; class 2: four (two Lennox-Gastaut); class 3: eight; class 4: fourteen. Conclusion: Zonisamide was partially effective not only for refractory partial epilepsies but also for refractory generalized cryptogenic epilepsies, as well as well tolerated. P506 Effectiveness of topiramate across age groups in elderly patients with epilepsy – Results of an open-label, phase IV clinical trial H. Stefan, A. Schreiner, B. Schäuble Epilepsiezentrum Universität Erlangen-Nürnberg (Erlangen, DE); JanssenCilag (Neuss, DE) Objective: To assess effectiveness of topiramate (Topamax®, TPM) in different age groups of elderly patients (≥ 60) with epilepsy. Methods: In this prospective, open label, multicenter phase IV flexible dose clinical trial (TOP-GER-13), elderly patients (60–64, 65–74 and ≥ 75 years (yrs)) with epilepsy irrespective of seizure type were included and followed for a median of 12 months. Doses of TPM and concomitant AEDs could be adjusted individually. Seizure frequency and adverse events were assessed at each visit. Results: 107 patients (53 % male, mean age 69±7 years) were enrolled encompassing 32 patients 60–64yrs, 54 patients 65–74yrs and 21 patients ≥ 75 yrs. 102 patients had at least one seizure during the retrospective 12-week baseline. Mean duration of epilepsy was 11.8, 9.7 and 5.5 years, respectively. Most frequent seizure types at baseline were generalized tonic-clonic (58 %) and complex partial (25 %) with the highest seizure frequency in the oldest group (9.3±34.1 at baseline). Mean seizure frequency for all was 3.5 ±14.6 at baseline and decreased to 1.6±7.7 at endpoint (p < 0.0001). At endpoint, the mean TPM dose given as monotherapy was 98 mg/day and 153 mg/day if given adjunctively. Mean monotherapy dose was lowest in the oldest elderly group (86 mg/day) and the percentage of monotherapy was highest in the oldest group. The proportion of responders (seizure reduction ≥ 50 %) was highest in the youngest group (87 % responders), and overall, 78 % of patients were responders and 44 % remained seizure-free throughout the study. 46 patients (43 %) had at least one treatment-emergent adverse event (TEAE). The number of TEAEs was highest amongst the oldest elderly. TEAEs ≥ 5 % were somnolence (9.4 %), dizziness (7.5 %), paraesthesia (5.6 %), and memory difficulties 5.6 %. Main reasons for study discontinuation (40 % overall) were an TEAE (15.9 %) or loss to follow-up (12.2 %). Conclusion: In elderly patients with epilepsy, TPM was well tolerated amongst all age groups, was associated with a significant decrease in seizure frequency, and was well tolerated. Doses used were slightly lower than the recommended target doses for adults. The study was supported by Janssen-Cilag Germany. P507 Randomised dose-controlled multicentre study of topiramate as first-line therapy in adolescents with epilepsy – a post-hoc analysis (EPMN-106/INT28) B. Schäuble, S. Wang, F. Wiegand on behalf of the EPMN-106/INT-28 Investigators Objectives: Analyses of data on adolescent subjects from dose-controlled studies evaluating the efficacy and tolerability of topiramate as initial monotherapy. Methods: Subset analyses of a previously published trial (Arroyo et al., 2005) including patients between 10–15yrs with newly diagnosed epilepsy or untreated patients with epilepsy relapse and > 2 lifetime seizures and 1–2 partial or generalized tonic-clonic seizure during a 3 months retrospective baseline. The primary efficacy endpoint was time to first seizure; a secondary efficacy measure was the seizure free rate at 6 months and 1 year. The safety population was pooled with patients receiving 50mg/day in a very similar pivotal trial (Gilliam et al., 2003). Results: A total of 470 patients were included in the initial efficacy analysis, 114 patients between 10–15 years of age (50 % female) are presented in this analysis. Kaplan-Meier survival analysis for time to first seizure in the

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adolescent subset of the IIT population favored 400mg/day (n = 57) over 50mg/day (n = 57) (P = 0.001). The probability of being seizure free at 6 months was 79 % in those randomized to 50mg/day and 94 % in patients randomized to 400mg/day (P = 0.001). Average daily dose of topiramate during the double blind phase was 43mg/day (0.92mg/kg/day) in the 50mg group and 335 mg/day (7.47mg/kg/day) in the 400mg/day group. Adverse events leading to study discontinuation were anxiety, chest pain and migraine in one patient in the 50mg arm. In the 400mg arm, 7 patients overall discontinued due to cognitive problems, fatigue and mood complaints. No treatment related serious adverse events occurred. Mean weight change from baseline to final visit in the double blind phase (6 months) were a 2.5 % weight gain in the 50mg arm and a 0.7 % weight loss in the 400mg arm. Conclusion: The results of this analyses support the efficacy and safety of topiramate for initial monotherapy of partial-onset or generalized tonicclonic seizures in adolescents with epilepsy. The study was supported by Ortho McNeil Neurologics, Titusville, United States P508 Quality of life in patients with epilepsy after transition from carbamazepine or oxcarbazepine to topiramate monotherapy B. Schäuble, A. Schreiner Janssen-Cilag (Neuss, DE) Objective: To evaluate quality of life (QUOLIE-10), tolerability and weight change in patients with epilepsy after transition from carbamazepine (CBZ) or oxcarbazepine (OXC) to topiramate monotherapy (Topamax®, TPM). Methods: Multicenter open-label non-interventional trial (TOPMATEPY-405). Patients ≥ 12 years of age with epilepsy unsuccessfully treated (due to lack of efficacy and/or lack of tolerability) with CBZ (72 %) or OXC (28 %) were eligible for this study. Patients were prospectively followed for 26 weeks after initiation of, and transition to, TPM. Results: 140 patients (54 % women, mean age 47±18 years) were enrolled. Main reasons for CBZ/OXC discontinuation were side effects (80 % of patients) and/or lack of efficacy (75 %). At end point, median TPM dose was 100 mg/day. Mean seizure frequency decreased from 6/month at baseline to 1.4/month at endpoint (p < 0.0001). 81 % of patients completed the study.All QUOLIE-10 items including subscores mental health, role functioning, and severity of epilepsy improved significantly (p < 0.0001 vs. baseline for all items and subscores). Mean baseline BMI slightly improved from 26 to 25.5 kg/m2 at endpoint, mean weight decrease was –1.9±3.7 kg. TPM was well tolerated: 26 % of patients reported treatment-related adverse events (AEs). AEs? 5 % were paraesthesia (9 %), memory difficulties (5 %) and weight decrease (8 %). 12 % of patients discontinued treatment due to an AE. The only additional cognitive side effect reported was speech disorder in 4 % of patients. Tolerability of TPM was rated as ‘good’ or ‘very good’ in 80 % by physicians. Conclusion: Transition from CBZ or OXC to topiramate monotherapy was associated with a significant improvement in quality of life and was well tolerated. The study was supported by Janssen-Cilag Germany. P509 Effectiveness of topiramate in patients with epilepsy transitioning from carbamazepine or oxcarbazepine – results of an open-label, non-interventional trial B. Schäuble, H. Adam, A. Schreiner Janssen-Cilag (Neuss, DE); Private Practice (Rostock, DE) Objective: To explore seizure frequency and tolerability in patients with epilepsy treated with topiramate (TPM; Topamax®) transitioning from carbamazepine (CBZ) or oxcarbazepine (OXC). Methods: Multicenter open-label non-interventional trial (TOPMATEPY-405) prospectively following patients with epilepsy ≥ 12 years of age who were previously unsuccessfully treated with CBZ (72.1 %) or OXC (27.9 %) for 26 weeks after transitioning to TPM. A 12-week retrospective seizure frequency was used as baseline. Results: 140 patients (54 % female; mean (± SD) age 47±18 yrs) were enrolled. 72.1 % of patients had unsuccessfully been treated with CBZ and 27.9 % with OXC. Mean (± SD) duration of epilepsy was 14.3 ± 13.7 yrs and patients had had an average of 2.2 AEDs (range, 1–10) prior to observation. 84 % had seizures during the 12-week retrospective baseline. Most frequent seizure types at baseline were generalized tonic-clonic (52 %), complex partial (25 %), and simple partial (16 %). Main reasons for transition from CBZ/OXC to topiramate were insufficient efficacy (75 %) and/or side effects (80 %). Mean dose of CBZ at treatment initiation of TPM was 825mg ± 397mg/day and 1254 ± 555mg/day with OXC. At endpoint, the me-

dian TPM dose was 100mg/day. 73 % of patients received TPM monotherapy by the end of observation. Mean (± SD) seizure frequency decreased significantly from 6 ± 21/month at baseline to 1.4 ± 5/month during the observation period. The responder rate (≥ 50 % seizure reduction) during the last 3 months of observation was 91 %, and 62 % of patients remained seizure-free during this period. 19 % of patients discontinued TPM, in 12 % due to an adverse event (AE), and in 3 % due to insufficient efficacy. The only treatmentemergent adverse events reported in? 5 % were paraesthesia (9 %) and weight decrease (8 %). Conclusions: In patients previously unsuccessfully treated with CBZ or OXC, topiramate was well tolerated and associated with a substantial reduction in seizure frequency and a high seizure-free rate. The study was supported by Janssen-Cilag Germany. P510 Are there differences in patients switching from phenytoin, valproic acid, carbamazepine or oxcarbazepine to topiramate? Results from a prospective, observational study A. Owega, A. Schreiner, K. Rettig, B. Schäuble Private Practice (Cologne, DE); Janssen-Cilag (Neuss, DE); G. E. M. (Meerbusch, DE) Objective: To describe differences in effectiveness and safety profile in patients treated with the most commonly prescribed AEDs in Germany transitioning to topiramate monotherapy (Topamax®, TPM). Methods: Multicenter, open label, observational study (TOPMAT-EPY0001) examining patients ≥ 6 yrs diagnosed with epilepsy and prior insufficient treatment (lack of effectiveness and/or tolerability) with PHT, OXC, CBZ or VPA monotherapy and planned transition to TPM monotherapy. Patients were followed for 16 weeks after initiation of TPM. Results: The ITT analysis included 407 patients (53 % female, no significant difference between groups) treated with VPA, CBZ, OXC or PHT. Mean age (±SD) over all groups was 45.8±16.8 yrs. Between-group comparisons were performed by the Chi2- or the Kruskal-Wallis-H-test. Patients on VPA or PHT were younger at diagnosis than patients on CBZ or OCX (p < 0.005), but epilepsy duration was longer in the PHT treated group (p < 0.001). Overall, 75 % of patients transitioned to TPM due to lack of efficacy (no differences between groups) and 61 % due to insufficient tolerability (Chi2test: p = 0.067). TPM median dose at endpoint was 100mg/day. Overall, seizure frequency decreased from 2.35±5.4 per 4 weeks during the 12-weeks retrospective baseline to 1.14±4.05 during the prospective observational period (Wilcoxon- test: p < 0.001). All patients showed a significant seizure reduction while transitioning. 64.2 % of all patients had an at least 50 % seizure reduction and 41.8 % were seizure free during the entire documentation period. 51 AEs had at least a possible relationship to TPM treatment. Treatmentrelated AEs (≥ 3 % out of 58 AEs) were: tiredness, nausea, weight loss, dizziness, lack of concentration, restlessness, ataxia, exanthem, and development of seizures. Most common reasons (≥ 3 %) for discontinuation of TPM (15.8 % overall) were AE (3.1 %) or “unknown” (8.9 %). 87 % of physicians rated the effectiveness of TPM “very good” or “good” regardless of previous AED and 91 % considered the patient’s situation as very much or much improved. The number of seizure related physician visits or loss of workdays decreased (p < 0.001). 82 % of patients continued on TPM treatment. Conclusion: Transitioning from PHT, VPA, CBZ or OXC to TPM was associated with a substantial seizure reduction and good tolerability regardless of the AED previously used. In addition, there was a significant reduction in seizure related physician visits and loss of workdays. The study was supported by Janssen-Cilag Germany. P511 Estimation of population pharmacokinetic parameters of free-levels of anti-epileptic drugs in adult epileptic patients D. Deleu, L. Aarons HMC (Doha, QA); University of Manchester (Manchester, UK) Objective: To define the pharmacokinetic profile of anti-epileptic drugs (AEDs) in adult Omani epileptic patients and to improve dosing schedules through population pharmacokinetic analysis using the nonlinear mixed effects modeling (NONMEM) program. Method: Steady-state trough free-carbamazepine (F-CBZ) and freephenytoin (F-PHE) serum concentrations, AED dosing history, and associated information were collected prospectively. The analysis for CBZ assumed a one-compartmental open model with first order absorption and

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elimination. The F-CBZ clearance (CL) (modeled independently of dose) and volume of distribution (Vd) were estimated. For F-PHE, the maximum metabolic rate (Vm) and Michaelis-Menten constant (Km) and their interindividual variability were estimated. Results: Inclusion criteria were met by 48 CBZ (total of 149 dose/serum concentration pairs) and 29 PHE-treated patients (total of 63 dose/serum concentration pairs). Patients were taking either CBZ (200–1200 mg/day) or PHE (100–500 mg/day) in monotherapy. The population estimates for CL and Vd were 13.2 (SD 0.6 L/h) and 525 (SD 44 L), respectively. However, CL increased as a function of dosing rate and consequently was modeled as a linear function of steady state concentration. The population estimates of FPHE for Vm and Km were 9.1 mg/kg/day and 7.3 mg/L, respectively. The models were prospectively validated in two groups of additional patients. The predictions were good and unbiased. Conclusion: Based on a desired steady-state F-CBZ serum concentration of 1.8 mg/L the recommended daily dose of CBZ in monotherapy was 9.4 mg/kg/day. For a desired steady-state F-PHE concentration of 1.5 mg/L the recommended daily dose was 6.09 mg/kg/day. P512 Risk factors for poor seizure control: preliminary findings from a tertiary hospital in northeast Nigeria F. Salawu, A. Danburam, M. Wakil, I. Rabbebe, S. Pindar Federal Medical Centre (Yola, NG); Federal Neuropsychiatry Hospital (Maiduguri, NG) Epilepsy, the falling sickness recognized since ancient times, continues to terrify and mystify the lay public. The past decade has brought new antiepileptic drugs (AED) to market and despite our best efforts, many individuals with epilepsy fail to achieve adequate seizure control with medication. Very little information is available on the psychological aspect and other factors that may interfere with adequate management of individuals with epilepsy in northeast Nigeria. Objective: This study describes our preliminary findings of the study to identify risk factors for poor seizure control in patients with epilepsy. Methods: The records of consecutive patients with epilepsy on follow-up at the Federal Neuropsychiatry Hospital, Maiduguri over a 6-month period were reviewed. The duration of follow-up ranged from 6 months to 8 years. Details of biodata including demographic characteristics, frequency and pattern of seizures, AED, drug compliance, electroencephalography and computerized tomography were retrieved. Blood assays of AED were not done. Seizure control as assessed by reduction in seizure frequency was graded as excellent (> 90 %), good (75–90 %), fair (50–74 %), poor (< 50 %). The patient or caregiver was asked to grade seizure control as being acceptable or not. Results: There were 42 patients (29 males and 13 females). Mean age of onset of seizure was 19.9±5.9. Fifty percent were seizure free after the first drug and another 23 % achieved that status with a second AED. A further 12 % responded to a third AED. Longer duration of epilepsy, presence of underlying structural pathology on neuroimaging, the use of multiple AED, partial seizures with no secondary generalization and status epilepticus increased the risk for poor seizure control. The frequency of seizures that the doctors considered acceptable concurred with patients or their caregivers’ assessment. However, factors such as poor drug compliance and individual life style may be contributory. Conclusion: These findings suggest that some of the risk factors for poor seizure control are potentially treatable or preventable. We conclude that individuals who do not respond to the first two AED have a very low likelihood of responding to additional agents and should consider the possibility of epilepsy surgery or alternative treatments for epilepsy. P513 Electrophysiological evaluation of children from mothers with epilepsy using anti-epileptic drugs B. Guveli, C. Gurses, N. Bebek, B. Baykan, A. Gokyigit Istanbul University (Istanbul, TR) Objectives: The aim of this study is to evaluate children born from mothers with epilepsy who were using antiepileptic drugs during pregnancy. Method: 45 children between the ages 1 and 15 (mean 5.5), 23 of whom were female and 22 male, born from 36 mothers with epilepsy who used antiepileptic drugs during pregnancy were investigated. The epilepsy type of the mothers, names of their syndromes and the drugs used were recorded. Their EEGs were recorded with 5 minutes hyperventilation, photic stimulation and sleep activation for 20 to 60 minutes. Results: Among the 36 mothers studied, 20 had generalized epilepsy (%55.6), 12 cryptogenic partial epilepsy (%33.3), 3 symptomatic partial

epilepsy (%8.3) and 1 idiopathic partial epilepsy %2.8. Among the 45 children whose EEGs were evaluated, 19 were normal (%42.2), 3 were within normal limits (%6.7), 23 were abnormal (%51.1). Of the 23 abnormal EEGs; 8 had nonspecific paroxysmal abnormality (%17.8), 6 generalized epileptiform abnormality (%13.3), 4 focal sharp or spike waves (%8.9), 3 background activity abnormality (%6.7), 2 focal slow waves (%4.4). When the mothers of the 23 children with abnormal EEGs were evaluated, it was observed that 15 had idiopathic generalized epilepsy (%65.2), 7 cryptogenic partial epilepsy (%30.4), 1 symptomatic partial epilepsy (%4.3). 17 of these mothers used a single antiepileptic drug during pregnancy (%73.9). 3 used 2 drugs (%13), 2 used 3 drugs (%8.7), and 1used 4 drugs (%4.3). 11 of them used valproate (%47.8), 3 used phenobarbital (%13), 2 used phenytoin (%8.7) and 1 used carbamazepine; 3 used one of the combinations of phenobarbital and phenytoin, valproate and lamotrigine or valproate and phenobarbital; 2 used a combination of phenobarbital, phenytoin and carbamazepin (%8.7); and one used a combination of phenobarbital, phenytoin, carbamazepin and vigabatrin. Conclusion: In the development of electrophysiological abnormality in children, the epilepsy type and syndromes are as important as the antiepileptic drugs used during pregnancy.

Peripheral neuropathy P514 The diagnostic value of sural sparing in differential diagnosis of acute and chronic inflammatory demyelinating polyneuropathies M. Yazdchi Marandi, A. Arami, H. Ayromlou Emam Khomeini Hospital (Tabriz, IR); Milad Hospital (Tehran, IR) Background: In last decade many advances have occurred in knowledge of pathogenic, in the different types of clinic expression and in the therapy of both acute and chronic polyneuritis. In this study sensory nerve conduction (NC) studies that were performed on patients with Guillain-Barre syndrome (GBS) were reviewed. These were compared with the sensory NC findings in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Materials and methods: In our survey 25 patients with the definite diagnosis of AIDP and 20 patients with the definite diagnosis of CIDP, were examined in a cross-sectional descriptive-analytic study. In all patients, we measured the sensory nerve action potential (SNAP) amplitude and latency and, conduction velocity (CV) of three sensory nerves (Median, Ulnar and Sural) with a standard method. Intact sural nerve and involved median or ulnar nerves or both, were considered as sural sparing. Results: Of 25 AIDP cases 12 (48 %) showed sural sparing pattern in NC studies.Sural nerve NC study was normal in 3 patients (of 20 CIDP cases.The results were significant %), p = 0.02. We also obtained significant results from the comparison of the mean conduction velocity (CV) of the sural nerve of two diseases, p = 0.049, but there was no significant relation between the mean values of the amplitude or latency of these two diseases. Conclusion: In GBS, the sural sensory nerve frequently showed normal NC findings compared to the median and ulnar sensory nerves. The reverse pattern was seen in CIDP, in which the sural nerve showed more abnormalities than the median and ulnar nerves. We concluded that this pattern of sensory NC abnormalities may assist the examiner in differentiating GBS from CIDP. P515 Small nerve fibre neuropathy in systemic lupus erythematosus O. Koutoula, K. Papadopoulos, N. Taskos, I. Milonas AHEPA University Hospital (Thessaloniki, GR) Introduction: Systemic lupus erythematosus (SLE) is a chronic inflammatory multiorgan disease characterized by a variety of clinical and immunologic abnormalities. The clinical spectrum of the disease is wide, from an almost asymptomatic clinical presentation to a severe life-threatening disease affecting several internal organs. The prevalence of peripheral neuropathy (PN) in SLE varies from 5 % to 27 % and is characterized by mild sensory or sensorimotor neuropathy. Methods: Six consecutive and nonselected patients (6 women) fulfilling the revised American College of Rheumatology criteria for SLE were included in the study. Patients with other causes of polyneuropathy were excluded. All participants were subjected to a standardized general and neurologic examination, nerve conduction velocity studies (NCS), standard blood and urinary tests. Ages ranged from 42.0 to 75.0 years, with a mean ± SD age of 57.2 ± 12.5 years.

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Results: On neurologic examination, five out of 6 patients were remarkable for clinical polyneuropathy (they had a modified Neuropathy Symptom and Change Score greater than 0 for positive sensory symptoms). Quantitative sensory testing demonstrates an impairment of the sense of warmth in patients with SLE compared with healthy subjects. Neurophysiologically, large-diameter nerve fibers were examined by NCSs.Results of NCSs were normal in 4 patients (66 %),and 2 patients (34 %) had abnormal results. One of these 2 patients had PN defined by neurophysiologic criteria of abnormalities in 2 or more nerves. Findings were sensorimotor neuropathy. The second patient had unilateral carpal tunnel syndrome. Conclusion: Some patients with SLE have neuropathic symptoms and clinical signs of PN despite normal results of NCSs. Such observations therefore indicate that there may be a pathogenic process selectively affecting small-diameter nerve fibers in some patients with SLE. The considerable frequency of subclinical peripheral neuropathy in patients with SLE and the absence of associated clinical or analytical parameters makes it necessary to carry out neurophysiological studies in these patients to detect its presence and establish the precise extent of the disorder. P516 Proteome analysis of cerebrospinal fluid in Guillain-Barré syndrome H. Tumani, V. Lehmensiek, J. Brettschneider, S. Suessmuth, G. Tauscher University of Ulm (Ulm, DE) Objectives: Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy with an often severe course and poor prognosis. Cerebrospinal fluid (CSF) is a promising source of proteins which may provide important information about the pathomechanisms in GBS. The proteomic approach for identification and quantification of the entire protein content (proteome) of the CSF has been used in several neurological diseases aiming at the identification of disease-related biomarkers. So far, there is no study analysing the proteome of patients with GBS Methods: CSF samples were collected from 6 patients with GBS according to diagnostic criteria by Asbury and Cornblath and 12 control patients with tension-type headache. We used the two-dimensional difference in gel electrophoresis (2-D-DIGE) for proteome analysis of CSF. Spots showing more than 2-fold difference between GBS and controls were analysed using MALDI-TOF mass spectrometry. Results: Out of 1962 spots, we observed 1073 (54 %) to be similar in concentration in GBS and controls. In contrast, 408 spots (21 %) were decreased and 481 (25 %) were increased in GBS as compared to controls.. Analysis of only those spots with a more than 2-fold difference in concentration over three independent 2-D-DIGE gels revealed 27 unique spots in GBS corresponding to 12 distinct proteins. Proteins that were upregulated in GBS included haptoglobin, serine/threonine kinase 10, alpha-1-antitrypsin, SNC 73, alpha II spectrin, IgG kappa chain and cathepsin D preprotein, while transferrin, caldesmon, GALT, human heat shock protein 70, amyloidosis patient HL-heart-peptide and transthyretin were downregulated. Conclusion: Some of these proteins are reported in CSF of GBS for the first time. Accordingly, the 2-D-DIGE technology may be useful to identify disease-specific proteins in patients with GBS. Since the pathophysiological role of the above mentioned proteins still remains to be further elucidated, additional validation is needed. P517 Peripheral neuropathies in patients with malignant lymphoma M. Suzuki, P. Lozeron, C. Lacroix, D. Adams, G. Said CHU de Bicêtre (Le Kremlin Bicêtre, FR) Background: A variety of peripheral neuropathy occurs in patients with malignant lymphomas. Objectives and Methods In order to learn more on the subject we reviewed the clinical, electrophysiological and morphological data of the patients with malignant lymphoma with a disabling polyneuropathy referred between 2004 and 2006, excluding those whose neuropathy was obviously related to treatments (chemotherapy or radiotherapy). Results: 17 patients, 3 with Hodgkin lymphoma (HL), 14 with nonHodgkin lymphomas (NHL) (4 patients had a monoclonal gammopathy, including one with Waldenstrom disease) were included. In the NHL group, one patient had bone lymphoma, one had follicular lymphoma, the others had B-cell lymphomas; one NHL patient had been treated for HL before. As for the neuropathic pattern in this group: Chronic inflammatory demyelinating neuropathy (CIDP) was observed in 3 patients; toxic neuropathy in 2; dysglobulinemic neuropathy, mixed neuropathy by toxic and dysglobulinemia; neuropathy in the setting of a graft-versus-host

reaction; amyloid neuropathy; vasculitic neuropathy associated with HIV infection; post-radiation multifocal radiculopathy and Guillain-Barré syndrome (GBS) after bone marrow transplantation were observed each in one patient. Post mortem examination of one patient with CIDP and NHL showed a demyelinating pattern, without invasion of the nervous system by the lymphoma, in keeping with the transient improvement after plasma exchanges. Two patients had axonal nerve lesions related to mechanical compression in one, to infiltration by malignant lymphocytes in the other. Among the HL patients, a GBS, compression by lymphomatous nodules and multifocal neuropathy and leucoencephalopathy with normal biopsy findings, were observed each in one patient. Discussion: Peripheral neuropathy is more common in NHL than in HL. In 3 patients the diagnosis of drug induced neuropathy was retained after nerve biopsy. CIDP can be difficult to distinguish from radiculopathy secondary to radiotherapy. Axonal neuropathies were more common than demyelinating neuropathies. Unexpected and treatable causes of neuropathy are found in some of these patients. Conclusion: Peripheral neuropathies that complicate the course of malignant lymphomas can be due to a variety of causes including invasion by malignant cells, side effects of treatment, inflammatory-immune reaction with vasculitis and CIDP, and amyloidosis. P518 Electrophysiological and ultrasonographic parameters’ correlation in carpal tunnel syndrome A. Domanasiewicz, M. Koszewicz, J. Jablecki, S. Budrewicz, R. Podemski, K. Slotwinski Trzebnica Hospital (Trzebnica, PL); Wroclaw Medical University (Wroclaw, PL) Electroneurography is thought to be the most important diagnostic method in carpal tunnel syndrome (CTS). But now many other methods are taking into consideration in CTS diagnosis, mainly ultrasonography. Aim of the study: Evaluation of sensitivity and specificity of ultrasonography and neurography to find critical value of median nerve section area and circumference crucial for CTS diagnosis. Material and methods: The study group was comprised of 89 patients (153 hands), 17 men and 72 women, age 38 to 72 (mean 62.5 years old) with clinical and electrophysiological signs of CTS (according to AAN criteria). The control group consisted of 50 healthy persons matched for age. In all patients and in the control group motor and sensory conduction velocity test were done in median nerve according to standard methods. Ultrasonographic vertical and horizontal projection were performed. Section area and circumference of median nerve in carpal tunnel were estimated. Results: Based on Youden’s index, we revealed that median nerve section area equal 0.1cm2 was crucial for CTS diagnosis: index value – 0.625, with specificity 88 % and sensitivity 74.5 %.We did not revealed such dependence of median nerve circumference in the diagnosis of CTS. All parameters of ultrasonography and electroneurography, accept sensory potential latency, significantly differed between the patient and control group. There were also statistically significant correlations between parameters of these groups. These results indicated to Conclusions: 1.Section area of median nerve in CTS diagnosis is a more reliable parameter then circumference, mainly in case of elliptic section with different short axes (the same circumferences, different section area). 2.Very high correlation between electrophysiological and ultrasonographic results indicates to usefulness of ultrasonography in CTS diagnosis. P519 Study of Martin-Gruber anomalies in patients with carpal tunnel syndrome H. Ayromlou, M. H. Naeimi Tabiei Imam Hospital (Tabriz, IR) Objective: Median-ulnar communication in the forearm, also known as the Martin-Gruber communication (MGC); is a common anomaly with the incidence ranging from 5 % to 34 % in the normal population. MGC is traditionally diagnosed based upon changes in the amplitude of the compound muscle action potential (CMAP) in routine nerve conduction studies. Knowledge of this crossover is of crucial importance in the clinical evaluation of nerve injuries of median and ulnar nerves, as well as in accurate interpretation of the nerve conduction velocity of these nerves, especially in association with carpal tunnel syndrome (CTS). This study aimed at evaluating the frequency of MGC and its types in patients with CTS. Methods: One hundred fifty one patients with CTS were assessed through a prospective analytic-descriptive study over a 13 month-period. After definite diagnosis of CTS by electrodiagnostic studies (NCV, EMG),

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prevalence of MGC was determined in these patients. Afterwards, the types of MGC (I, II, III and the mixed types) and its gender distribution were assessed. The types of MGC were determined based on the findings of electrodiagnostic studies. The frequency of MGC and its types were determined in upper extremities, as well. Results: One hundred fifty one patients with defiantly diagnosed CTS, 123 females and 28 males with the mean age of 46.42±11.21 years (20 to 79 years) were enrolled in the study. Nineteen (12.6 %) patients (13 females, 6 males) had MGCs. In 285 upper extremities with CTS, 25(8.8 %) cases had MGCs. I, II, III and the mixed types were seen in 7(43.8 %), 14(87.5 %), 6(37.5 %) and 9(56.3 %) patients and 9(40.9 %), 17(77.3 %), 6(27.3 %) and 10(45.5 %) upper extremities, respectively. In 3 patients (6 upper extremities) the typing of the MGC was not applicable due to inaccessibility. In 22 hands, there were 3 (13.6 %) type I, 8 (36.4 %) type II, 1 (4.5 %) type III and 10 (45.5 %) mixed type cases. Conclusion: In our study the frequency of MGC in the patients with CTS was within the range in the literature, however lower than the mean reported value. More studies with larger sample sizes are recommended to be carried out. P520 Femoral nerve involvement in diabetic patients S. Kurt, Y. Kaplan, H. Karaer, U. Erkorkmaz Gaziosmanpasa University (Tokat, TR) Objective: Femoral neuropathy is not common among diabetic patients. It is characterized by weight loss, pain in back, waist and legs, pelvifemoral muscle weakness and atrophy. It is also called diabetic amyothrophy.Anomaly in femoral nerve conduction is distinct in diagnosis. In this study, femoral nerve conductions of diabetic patients who do not clinically have femoral nerve involvement were examined and compared to healthy controls. Patients and Method: 53 patients, including 15 males and 38 females, were included in the study. Patients were examined in terms of neuropathy and their neuropathy scores were calculated. In addition to femoral nerve conductions, peroneal, posterior tibial nerve motor; sural and superficial peroneal nerve sensory; median and ulnar nerve motor and sensory conductions were electromyographically examined. Findings of patients were compared to those of 17 healthy volunteers. Results: There was a statistically significant difference between diabetic patients and the control group in terms of both nerve motor latency and amplitude. Femoral latency of patients was significantly related to duration of diabetes, age of patient, neuropathy examination score and neuropathy score; femoral amplitude was significantly related to neuropathy score. Discussion: In our study, femoral nerve conduction anomalies were determined in diabetics who do not clinically have femoral nerve involvement. Polyneuropathy of the patients is getting more severe as the degree of anomalies becomes more evident. However, diabetic femoral neuropathy may clinically exist even without diabetic distal symmetric polyneuropathy. Thus, the value of femoral nerve conduction anomalies is controversial in diagnosis of diabetic amyothrophy in diabetics with clinically femoral neuropathy. P521 “Cuff sign” a new manoeuvre for decision-making in patients with carpal tunnel syndrome S. Abrishamkar, K. Basiri Kashani University Hospital (Isfahan, IR); Alzahra University Hospital (Isfahan, IR) Introduction: Carpal tunnel syndrome (CTS), the most common entrapment neuropathy consists of pain, paresthesis, numbness and burning of the first three fingers especially during the night. Although different electrodiagnostic methods have been used to show the severity of the disease, the problem that which patient profit from operation is unsolved. Material and methods: Thirty patients with mild changes in sensory nerve distal latency entered the study. Those with weakness, muscle atrophy, neuropathy or previous CTS operation were excluded. Symptom free healthy volunteers (both hands) and asymptomatic hands of the patients were tested before and after the cuff application as control values. Electerodiagnostic studies were performed before and after placement of cuff of sphygmomanometer at the arm at mean arterial pressure for three minutes. Defect in nerve conduction was graded as; mild, moderate and severe according to sensory latency. Only the patients with mild electrodiagnostic findings were included in placement of the cuff and the rate of satisfaction at first and 14th post operative day was recorded. Results: Thirty symptomatic patients with mild findings in electro diagnostic studies and 17 controls entered the study. Fifteen asymptomatic

hands of patients are also included (total = 59 asymptomatic hands). Fifteen patients reported good pain relief at first post operative day (50 %) which increased to 21 at 14th post operative day (70 %). Sensory latency changes (difference between pre and post blood pressure cuff application above diastolic pressure) were significantly higher in the pain relief group, both in the first and 14th post operative days (2.28 vs. 1.04 millisecond (p = 0.006) and 2 vs. 0.88 millisecond (p = 0.002) respectively). Conclusion: Considering the fact that cooperation of the patients is not necessary; and double effects of direct pressure and ischemia over the proximal parts of the median nerve leads to prolong latencies, this test is a useful method for decision making in patients with severe symptoms of CTS despite mild electrodiagnostic findings. P522 A comparison of sural nerve conduction studies in patients with impaired oral glucose tolerance test A. Koçer, F. Mayda Domaç, E. Boylu, T. Tanridag, Ö. Us Düzce University (Düzce, TR); Haydarpasa Numune Teaching Hospital (Istanbul, TR); Gülhane Military Medical School (Istanbul, TR); Marmara University (Istanbul, TR) Objective: Monitoring of the sural nerve is a sensitive method for detection of neuropathies. We assessed the different sural nerve conduction values of the patients with impaired glucose tolerance (IGT) in the same study. Materials and Methods: Several parameters of sural nerve were investigated in 20 patients. Firstly, sensory NCS of the sural nerve were performed on the distal-leg and the proximal-leg segments. Secondly, dorsal sural nerve studies were conducted. Thirdly, the sural / radial nerve SNAP amplitude ratios were calculated. The results were compared with those obtained from 21 healthy controls. Results: Abnormal results revealing peripheral neuropathy were found in only one patient and dorsal sural SNAP was absent in another patient (5 %). Though the results of nerve conduction studies were within normal ranges except the patient with peripheral neuropathy, the lower extremity nerves and especially sural nerves have been found more effected and the parameters revealed large differences between groups (p < 0.05). Only dorsal sural nerve latency related to fasting blood glucose level in patients (< 0.05). Discussion and Conclusions: Sural nerve conduction studies may have value to determine neuropathy in IGT patients. This study supported that IGT was a transitional state before diabetes and the importance of the dorsal sural nerve latencies for early detection of neuropathy. P523 Moebius syndrome, a study of 3 cases I. Ben Hamouda, H. Batti, M. Fredj, A. Mrabet Charles Nicolle Hospital (Tunis, TN) Introduction: Moebius syndrome is defined by the congenital and bilateral lesion of the sixth and the seventh cranial nerves, sometimes associated to other malformations. Observation: We describe three patients: two children of male sex, aged respectively six and nine years, presenting in addition to the bilateral lesion of VI and VII nerves, a dimorphic syndrome of the face, the trunk and the limbs; and a 41 years old woman presenting a facial diplegia with complete and bilateral oculomotor palsy without associated malformation. The cerebral MRI showed a right facial nerve hypoplasia and an agenesis of the left one in the first case, a bilateral agenesis of the sixth and seventh cranial nerves in the second case; cerebral CT scan was normal in the third case. The EMG of the four limbs and the face practiced in one case confirmed the absence of activity on the corrugator supercilii muscle and a neurogene lesion on the mentalis muscle. Discussion: Several etiopathological hypothesis of this syndrome are advanced is not solved: genetics, toxic or intra-uterine ischemia of the brainstem. Clinical presentation includes in addition to the VI and the VII nerves paralysis, a malformative syndrome of the limbs, the trunk and a hypogonadism. Other peripheral and central nervous lesions are reported. Conclusion: Rare congenital entity, this neuro-dismorphic syndrome profits recently, of plastic and reconstructive microsurgery progress.A morphological and functional preliminary detailed exploration is essential in order to consider therapeutic possibilities for a better quality of life.

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P524 Spinal root hypertrophy and central nervous system abnormalities in chronic inflammatory demyelinating polyneuropathy M. Deleidi, R. Fazio, P. Dacci, S. Gerevini, L. Politi, V. Martinelli, G. Comi IRCCS San Raffaele (Milan, IT) Objectives: Central Nervous System (CNS) demyelinating lesions have been reported in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). So far, it is still unclear whether sporadic reports of concurrent Multiple Sclerosis (MS) and CIDP represent coincidence or whether these two demyelinating disorders are pathogenically related. Reported, a 37-year-old man with CNS demyelinating lesions, CIDP and enlargement of the nerve roots. Methods: In June 2002 he was admitted to our hospital as he had been suffering from vertigo and gait unsteadiness since 1996. Results: Neurological examination showed nystagmus, lower extremity weakness, areflexia, bilateral Babinski, moderate impairment of sensation distally in lower extremities causing ataxia. Laboratory investigations were normal. CSF revealed high protein levels (264 mg/dl) with no oligoclonal bands. Cranial MRI showed multiple bilateral lesions involving periventricular and brain stem white matter and multiple cranial nerves enhancement. Spinal cord MRI showed hyperintense diffuse C 2 and C 3-C 7 lesions with pial enhancement extended to lumbar tract and cauda equina and enlargement of nerve roots. Electroneurography fulfilled criteria for CIDP. Moreover, both motor and somatosensory evoked potentials showed significantly longer peripheral conduction times. Visual evoked potentials were also altered. Despite his symptoms were stable, follow-up MRI revealed new enhancing lesions in the cervical spinal cord. Steroid therapy, azathioprine, intravenous immunoglobulins and cyclophosphamide were unable to induce a clinical improvement. In 2005 he had an acute impairment of his left hand strength and a right side foot drop, so he started therapy with IFNbeta 1b. Last year he had no relapse and follow-up MRI was unchanged. Conclusions: This case report supports the existence of a peripheral inflammatory demyelinating syndrome associated with central nervous system demyelinating lesions. Both immunosuppressive and immunomodulatory treatments failed to induce a significant and persistent improvement. P525 Loss of pain sense in Japanese diabetic patients: a survey using Japanese bamboo cooking stick with one end sharp and the other dull M. Baba, S. Yagihashi, T. Toyota Prefecture Medical Centre (Aomori-City, JP); Hirosaki University (Hirosaki, JP); Tohoku Rosai Hospital (Sendai, JP) Objectives: To evaluate usefulness of Japanese bamboo cooking stick as a testing tool of pinprick sense, and to determine the prevalence of loss of pain sense in Japanese diabetic patients. Methods: Pain perception of the foot skin was tested in 4.238 diabetic patients, if they could discriminate a hurting pricking sense from dull poking sense evoked by a cooking stick of bamboo with one end sharp and the other dull. The testing sites were dorsum pedis around the toe, medial side of Achilles tendon at the ankle, and the upper calf below the knee. Ankle jerks were tested by using Babinski hammer with reinforcement procedure under kneeling position. Vibratory sense was examined with C 128 tuning fork on the medial malleolus. Control subjects were 53 patients with non-sensory neurogic diseases aged 25–90. Results: All control subjects well discriminated the sharp end from the other end of the stick. Of 4.238 diabetic patients, 654 (15.4 %) showed loss of pin-prick sense; 401 (9.5 %) were bilateral, and 253 (6 %) showed unilateral loss. Among patients with bilateral loss, 222 (5.2 %) had loss in the feet. In 122 (2.9 %), analgesia was demonstrated up to the ankle; 57 (1.3 %) showed up to the knee. The extent of analgesic area showed strong statistical correlation(s) with abnormalities in ankle jerk and vibratory sense, orthostatic hypotension, and positive sensory phenomenon, duration of diabetes, insulin treatment, and presence of hypertension. In around 5 % of the diabetic patients, loss of pain sense was the only neurologic abnormalty. Comments and conclusion: Loss of pain sense in the feet is one of the most critical abnormalities in diabetic patients, since it causes foot ulcer, infections, and many other foot abnormalities. However, traditional procedures using a pin or cogwheel seem troublesome for general physicians to properly evaluate decrease in the pain sense. To overcome such situation, we introduced a Japanese cocking stick made of bamboo with one end sharp and the other dull as a test tool. The present study revealed the Japanese bamboo cooking stick is a useful and reproducible screening tool for pain sense in diabetic patients.

P526 Correlation of subclinical sensory disturbances and early stages of macroangiopathy in patients with type 1 diabetes mellitus – a preliminary report S. Szczyrba, K. Kunicka, G. Kozera, B. Wolnik, L. Bieniaszewski, W. M. Nyka Medical University of Gdansk (Gdansk, PL) Objectives: Among many complications of diabetes both neuropathy and angiopathy play crucial role in increasing of mortality and decreasing of life quality in diabetic patients. In spite of obscured beginning, therapy of their pre-clinical stage seems to be most effective. Quantitative sensory testing, including vibration and temperature perception threshold (VPT and TPT) evaluation, enables detection of pre-clinical stage of diabetic neuropathy. Measurement of Intima-Media Complex thickness (IMT) can assess early stages of macroangiopathy. Our aim was to compare the VPT and TPT with IMT and cerebral blood flow autoregulation in patients with type 1 diabetes mellitus (DM t.1). Methods: 30 patients with DM t.1, 18 females and 12 males (mean age 33.7 ± 5.8 years), with no previous symptoms of diabetic neuropathy were examined. Testing procedure consisted of: (1) personal questionnaire about diabetes history; (2) estimation of VPT and TPT [Vibratron II and NTE-2 Thermal Sensitivity Tester]; (3) measurement of IMT in the common carotid artery (CCA) [Aloka 400 Ultrasonograph using semiautomatic method]; (4) evaluation of vasomotor reactivity of middle cerebral artery (MCA) by breath-holding index and vasomotor reactivity (VMR) measurement with use of Transcranial Doppler ultrasonography (TCD) [MultiDop T 2 DWL], (5) fundoscopy and cicardian albumin secretion measurement. Results: Duration of diabetes ranged from 6 to 23 years (mean 15.4 ± 4.9 years). Retinopathy was found in 36.6 %, nephropathy in 10 % of the study group. Mean VPT in the upper and lower limb scored 0.97 ± 0.41 and 1.60 ± 0.90 vibration units (vu), and was within normal range in 93 % and 90 % of the patients, respectively. TPT in the upper and lower limb was 1.47 ± 0.18 and 3.03 ± 0.97 degrees Celsius, and within normal range in 87 % and 70 % of the studied patients, respectively. Mean IMT was 0.036 ± 0.004 cm. Values of BHI and VMR of MCA were 1.65 ± 0.46 and 0.87 ± 0.16 respectively.We found no correlation (p> 0.05) between presence of microangiopathy (retino- and nephropathy) and VPT and TPT. There was also no correlation between VPT and TPT and vasomotoric reserve of MCA. There was correlation between VPT in the lower limb and IMT in CCA (p < 0.05). Conclusions: Temperature and vibration sensation measurement revealed subclinical sensory deficits in DM t.1 patients. Correlation of impaired sensory function with IMT suggests parallel progression of neuroand macroangiopathy. P527 Infant-onset multifocal motor neuropathy with conduction blocks leading to skeletal deformities S. Gregoire, A. Marshall, D. Gow Hope Hospital (Manchester, UK) Case report: We report a 30-year-old right-handed female patient with a slowly progressive asymmetrical lower motor neurone syndrome, and multiple skeletal deformities. Motor milestones were delayed. She walked at the age of 3 and had never been able to run comfortably as a child. Scoliosis and foot deformities which required multiple operations developed throughout her childhood. There was no family history of neuromuscular disorder. Her weakness gradually progressed through her second and third decades.When she was referred to us at age 30, examination revealed asymmetrical lower motor neurone weakness of her left sternocleidomastoid muscle, of her hands and left leg, with wasting, absent tendon reflexes, and no sensory loss. A scoliosis and foot deformities were evident. Nerve conduction studies revealed multiple sites of motor conduction blocks and normal sensory nerve action potentials. These findings were strongly suggestive of multifocal motor neuropathy (MMN) with conduction blocks. Her anti GM 1 antibodies were negative. Interestingly, in the single case report of a child aged 6 affected by the disease, anti GM 1 antibodies were again absent. She was treated with intravenous immunoglobulins for 5 years without significant benefit. Results: We will discuss her neurophysiological data and provide pictures of her deformities. Conclusion: On the basis of her clinical presentation and neurophysiology, we suspect that MMN has affected her at an early age and led to her skeletal deformities. To the best of our knowledge, this is the first case report of infant onset MMN with skeletal deformities.

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Multiple sclerosis P528 Effect of mitoxantrone on suppressive function of regulatory T cells in multiple sclerosis patients N. Putzki, M. Kumar, E. Kreuzfelder, V. Limmroth University Clinic Essen (Essen, DE) Background: Multiple Sclerosis (MS) is regarded as an inflammatory demyelinating disorder including autoimmune responses to self-antigens in a genetically susceptible host. CD 4+CD 25+ regulatory T cells (Tregs) play an important role in the control of autoimmunity by suppressing autoreactive T cells.We recently demonstrated that the suppressive function of Treg is lost in MS patients. The cytotoxic immunosuppressant mitoxantrone is recommended as treatment for patients with progressing MS and ongoing disease activity. The mode of action of mitoxantrone is not fully understood. Objective: To examine if mitoxantrone restores the loss of suppressive of regulatory T cells in MS in vivo. Results: Stimulation with Myelin Basic Protein (MBP) and PWM led to significant proliferation of CD 4+CD 25- in patients (n = 34) and healthy age matched controls (n = 34). Co-culturing of Tregs with CD 4+CD 25- cells significantly (p < 0.05) reduced the MBP and PWM induced cell proliferation in controls (MBP: 37 % suppression; PMW: 41 % suppression). In MS patients, co-culturing did not lead to suppression in MBP induced stimulation (p> 0.05). In PWM, suppression is significantly less pronounced (19 % suppression in MS vs. 41 % in controls). Mitoxantrone treatment (10mg/m2 every 3 months; n = 20) did not exhibit an effect (p> 0.05) on suppressive Treg function in 3 monthly follow up examinations (before treatment, up to 12 months). The relative as well as the absolute B cell count decreased from 14.1±2.1 % (mean±standard error of the mean) to 7.5±1.8 % and 1415±394 cells/μL to 819±348 cells/μL, respectively. No effects on other cell populations were found. Conclusion: The suppressive function of Tregs is impaired in MS patients. This suggests that a failure to maintain peripheral immune tolerance may be one of the critical factors for the development of CNS autoimmunity against myelin components. Mitoxantrone does not have an impact on the impaired function of Tregs in vivo. Our study demonstrates a selective long-term effect of a standardized mitoxantrone treatment regimen on B lymphocyte subsets while the frequency of T lymphocytes is not persistently reduced. P529 α levels in cereChanges in vitamin B 12 and tumour necrosis factor-α brospinal fluid of patients with different subtypes of multiple sclerosis G. Scalabrino, D. Galimberti, D. Scalabrini, F. Bamonti, D. Veber, E. Mutti, M. Carpo, M. De Riz, R. Capra, C. Cordioli, E. Scarpini University of Milan (Milan, IT); University of Brescia (Brescia, IT) Objectives: There has long been considerable debate concerning the possible role of tumour necrosis factor (TNF)-α and vitamin B 12 (cobalamin, Cbl) in the pathogenesis of multiple sclerosis (MS). We have previously demonstrated experimentally (in Cbl-deficient rats) and clinically (in patients with pernicious anaemia or subacute combined degeneration) that Cbl deficiency induces an imbalance in the levels of TNF-α and epidermal growth factor in the central nervous system (CNS) and biological fluids (serum and cerebrospinal fluid (CSF)) by increasing the former and decreasing the latter. Furthermore, these abnormalities are normalised by Cblreplacement treatment. All of these results indicate that Cbl has new noncoenzymatic functions insofar as it seems to modulate the synthesis of some cytokines and/or growth factors in the CNS (and probably elsewhere) and their levels in some biological fluids of mammals. The aims of this ongoing study are: (a) to determine the levels of Cbl and TNF-α in the CSF of MS patients stratified on the basis of their MS subtype; and (b) to verify the correlation between them in order to clarify whether Cbl maintains its physiological regulatory role on CSF TNF-α levels. Methods: CSF samples are being collected from patients with primaryprogressive (PP), relapsing-remitting (RR), or secondary-progressive (SP) and assayed for Cbl and TNF-α levels. The Cbl levels are determined by means of a radioassay, and the TNF-α levels by means of an enzyme-linked immunosorbent assay kit. A control group consists of patients with non-immunological and non-neoplastic neurological diseases. Results: The preliminary results so far indicate that the RR-MS and SPMS patients have statistically significantly higher Cbl levels than those of the PP-MS and control patients. The RR-MS and SP-MS patients have significantly lower TNF-α levels than the PP-MS and control patients, with the levels being higher in the RR-MS than the SP-MS patients. The negative correlation between Cbl and TNF-α levels is statistically significant.

Conclusion: Given the clear-cut difference in the CSF Cbl and TNF-α levels between PP-MS patients and RR- or SP-MS patients, our results support the notion that PP-MS may be a very different disease as compared to RRMS. The pathological significance of these differences merits further investigation. P530 Gender-specific influence of the chromosome 16 gene cluster on the susceptibility to multiple sclerosis M. De Riz, D. Galimberti, D. Scalabrini, C. Fenoglio, C. Comi, E. Venturelli, F. Cortini, M. Piola, E. Brighina, U. Dianzani, S. D’alfonso, F. Monaco, N. Bresolin, E. Scarpini IRCCS Ospedale Maggiore Policlinico (Milan, IT); University Amedeo Avogadro (Novara, IT) Background: The initial step of multiple sclerosis (MS) pathogenesis is the aberrant activation of specific populations of autoreactive T lymphocytes in the periphery, followed by T cell recruitment into the brain with activation of several cytokines and chemokines, resulting in demyelination and axonal damage. Most of the chemokines bind to receptors preferentially expressed on Th1 lymphocytes, but recent evidence pointed out that chemokines binding to receptors expressed on Th2 cells are crucial as well. MDC/CCL 22, which interacts with CCR 4 receptor, preferentially expressed on Th2 lymphocytes, is likely to play a role in MS pathogenesis. Recently, the chromosome 16 chemokine gene cluster composed by MDC/CCL 22, fraktalkine/CX 3CL 1 and TARC/CCL 17 has been proposed as a susceptibility locus for inflammatory disorders, and several polymorphisms have been described in this region. Objective: a case-control association study was performed in a population of Italian multiple sclerosis patients and matched healthy subjects, in order to determine whether the presence of some other allelic variants in chromosome 16 chemokine gene cluster could influence the susceptibility or exert a protective effect towards the development of the disease. Methods: the frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL 22 as well as the C/T SNP in the promoter of CCL 17 were determined in 277 patients with diagnosis of multiple sclerosis according to the Mc Donald’s criteria and compared with 269 controls. Allelic discrimination by Taqman technology was used. Results: a decreased allelic frequency of the A allele of the CCL 22 C/A SNP as well as of the T allele of the CCL 17 C/T SNP was found in patients compared with controls (P = 0.0137 and P = 0.0025). The frequency of the AT haplotype was decreased in male (P = 0.0003; OR: 0.06) but not female patients. Conclusions: the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS. Most interestingly, the effect of this allele is likely to be gender specific, as it was found in males only, decreasing the risk to develop the disease by more than 10 fold. This is the first attempt to screen a MS population for genetic variants in a cluster including chemokines with an important role in demyelinating disorders and which has been previously considered a potential susceptibility locus to autoimmune diseases. P531 Apolipoprotein variation influence on interferon-beta treatment response in multiple sclerosis A. L. Guerrero, M. A. Tejero, F. Gutiérrez, J. Martín-Polo, F. Iglesias, E. Laherrán, O. Capilla Hospital Rio Carrion (Palencia, ES) Objectives: Interferon-beta is one of the treatments of choice for relapsingremitting (RR) multiple sclerosis (MS). It decreases relapse rate by approximately 30 % compared with placebo in therapeutic trials. Nevertheless, not all patients respond to this treatment, though there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence, as has been previously shown with IL-10 or INF gamma polymorphisms. The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to statins treatment in patients with hypercholesterolemia; this may have future implications for MS. Methods: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) followed in our Neurology Unit, all of them treated with interferon beta during at least two years. The criterion for treatment was the presence of at least two relapses in the previous three years. We collected data concerning variables as age, age of onset, clinical type or disease duration. Patients were classified as responders and non-responders based upon clinical

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criteria available in the literature, which rely on the presence of relapses, increase of disability, or both, two years after each patient started treatment. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient’s subgroups with allele E 2 or E 4 and the mentioned variables was tested. Results: 20 patients (52.6 %) received Interferon beta 1 b subcutaneously (Betaferon), 13 (34.2 %) Interferon beta 1 a intramuscularly (Avonex), and 5 (13.2 %) Interferon beta 1 a subcutaneously (Rebif). We found 2 patients (5.2 %) heterozygous for the E 2 allele and 9 (23.7 %) for the E 4 allele. No patient was homozygous for E 2 or E 4. Comparison of patients with and without E 2 or E 4 allele showed no significant differences in any of the ten therapy response variables assessed. Conclusion: Findings of a recent meta-analysis do not support a role for APOE in MS susceptibility or severity. We do not find, in our patients, influence of this gene in the Interferon beta response. Anyway, larger series should be necessary to confirm these results. P532 Clinical study of primary progressive multiple sclerosis in Isfahan, Iran A. H. Maghzi, M. Etemadifar, M. Saadatnia Isfahan University of Medical Sciences (Isfahan, IR) Objectives: There are few reports about the demographical and clinical characteristics of Multiple Sclerosis (MS) in Middle East. This study was performed to highlight the clinical and demographical characteristics of Primary Progressive MS (PPMS) patients in Isfahan, Iran as well as to shed light on any similarities or differences among our results and the results of other studies carried out in high risk regions. It also provides more information on this uncommon form of MS. Subjects and Methods: Our survey was performed cross-sectionally over 1606 definite MS patients, diagnosed according to McDonald’s criteria, who were registered in Isfahan MS Society. This association is the only one in Isfahan Province and nearly all MS patients in Isfahan province are registered. All PPMS patients were re-evaluated and all should satisfactorily meet the Thompson’s clinical criteria for definite PPMS to be included in the study. Results: 92 PPMS cases were identified according to Thompson’s criteria, so the frequency of PPMS among MS patients would be 5.7 % (95 % CI: 6.7 %, 4.7 %). Mean Expanded Disability Scale Status (EDSS) for the group was 5.09 ± 1.33.The commonest mode of presentation was motor disturbance in 54 (59.3 %), other modes of presentations were, vertigo in 15 (16.3 %), visual loss in 12 (13 %), sensory disturbances in 6 (6.5 %), and diplopia in 4 (4.3 %). The present symptoms were motor problems in all 92 (100 %), cerebellar symptoms in 46 (50 %), and cognitive impairment in only 6 (6.5 %). Interestingly two (2.2 %) were affected by poliomyelitis during childhood and presenting symptom in both was limb weakness. Conclusion:Primary progressive form of multiple sclerosis is less common in Persian population and some of the observed rates in PPMS patients differ from reported in other regions, these differences maybe due to different ethnicity of Persian patients or maybe because of geographical differences. P533 An assessment of the relation of the Multiple Sclerosis Severity Score to known clinical predictors of disease severity in a cohort of Greek patients with multiple sclerosis A. Konstantinopoulou, G. Karachalios, A. Areovimata, G. Koutsis, D. Mandellos, E. Andreadou, C. Sfagos, D. Vassilopoulos University of Athens (Athens, GR) Objectives: The Multiple Sclerosis Severity Score (MSSS) has been recently developed as a measure of multiple sclerosis (MS) disease severity based on single assessment data. The relation of the MSSS to known prognostic indicators of disease severity has not been extensively studied. However, the extent to which MSSS behaviour reflects established measures of severity (such as time to disability in prospective cohorts) is important in terms of its suitability as measure of severity in association studies. In order to assess MSSS behaviour, we investigated the effect of established clinical predictors of disease severity on the MSSS in a Greek MS cohort. Methods: We calculated the MSSS in 365 patients (235 females, 130 males) with MS (McDonald criteria) and disease duration greater than 1 year, from a total of 499 consecutive patients with MS or possible MS followed up over a period of 3 years at the MS Unit, Neurology Department of Eginition Hospital, University of Athens. The effect of gender, age at onset, first attack symptoms, disease course, time to clinically definite (CD) MS and relapse rate on the MSSS was investigated using standard statistical procedures. Results: The cohort included 39 patients with clinically isolated syn-

dromes (CIS), 227 with relapsing-remitting (RR) MS, 59 with secondary progressive (SP) MS and 40 with primary progressive (PP) MS. Mean age was 38.13±10.55 years, mean MSSS 3.72±3.02 and mean disease duration 7.79±7.17 years. One hundred thirty four patients were on disease modifying therapy. Mean MSSS was higher in men (p = 0.038), was dependent on clinical course (data from RRMS, SPMS and PPMS; p < 0.001) and first attack symptoms (data from CIS, RRMS and SPMS; p = 0.014) and showed significant correlation with age at onset (r = 0.29, p < 0.001). In RRMS patients, MSSS correlated with time to CDMS (r = –0.20, p = 0.004) and relapse rate (r = 0.23, p = 0.001). Conclusion: The MSSS behaved as expected in relation to known clinical predictors of disease severity in the present population. This would make the MSSS an appropriate measure of disease severity to be used in potential future association studies.

P534 Neuromyelitis optica antibodies in Greek patients with suspected NMO: a report of four consecutive cases M. E. Evangelopoulos, E. Anagnostou, E. Karantoni, E. Andreadou, D. Mandellos, P. Loukaidis, G. Koutsis, C. Sfagos, D. Vassilopoulos Eginition Hospital University of Athens (Athens, GR) Neuromyelitis Optica antibody (NMO-IgG) is a recently discovered biomarker for Neuromyelitis optica (NMO) and related conditions such as recurrent longitudinally extensive myelitis and recurrent optic neuritis. NMO may be easily misdiagnosed as multiple sclerosis (MS). NMO has a poor prognosis and early therapeutic initiation is necessary. NMO-IgG represents a useful tool to distinguish NMO from MS. The presence of NMO-IgG has not been investigated to date in Greek patients with suspected NMO. Objectives: We have screened 498 consecutive patients with demyelinating disorders of the central nervous system (CNS), followed at the MS Unit, Neurology Department of Eginition Hospital, University of Athens, from 2004 to 2006. We reviewed demographic data, clinical features, clinical course, magnetic resonance imaging (MRI) and cerebrospinal fluid data to identify patients suspected of NMO or NMO related syndromes. Results: We found two patients with recurrent severe myelitis and optic neuritis (patient 1 and patient 2), one with recurrent severe myelitis (patient 3) and one with recurrent severe bilateral optic neuritis (patient 4). All 4 patients had negative brain MRI at onset and negative oligoclonal bands. Patients 1–3 had extensive spinal cord lesions extending over 3 vertebral segments on MRI (patient 1 C 5-T 9, patient 2 T 2-T 9, patient 3 T 4-T 12). Serum samples were obtained with informed consent and were shipped to the Mayo Clinic, Rochester, Minnesota, USA. NMO-IgG was measured by indirect immunofluorescence method with a substrate of mouse CNS tissue. Three patients (cases 1–3) were found positive for NMO IgG. Serological and clinical markers of an autoimmune disease were found in Patient 3. Immunosuppressive treatment was initiated in all NMO-IgG positive patients. During follow up, all three patients were responsive to long-term immunosuppression and had significant clinical improvement. Conclusions: From a total of 4 patients identified with suspected NMO, NMO-IgG was present in 2 patients with clinically typical NMO and 1 out of 2 patients with NMO related syndromes. These findings are in accordance with previously published data from other populations. Early identification of NMO-IgG supported the use of early and aggressive immunosuppressive therapy contributing to an improved outcome in NMO-IgG positive patients.

P535 Outcome measures for trials of remyelinating agents in multiple sclerosis: retrospective longitudinal analysis of VEP latency A. Niklas, H. Sebraoui, F. Then Bergh Universität Leipzig (Leipzig, DE) Objectives: There are currently no accepted surrogate markers to test remyelinating agents.Visual evoked potentials (VEP) latencies are suitable, because many MS patients display prolonged latencies (subclinical demyelination), which can display both improvement or deterioration of function.VEP are known to improve after acute optic neuritis (ON), but the extent of improvement in the absence of acute ON has been insufficiently studied. We aimed to define required changes of P 100 latency as outcome measure for trials of potentially remyelinating agents in MS. Subjects and methods: 124 patients (three VEP recordings, > three months apart), analysed in MS group (71 patients with MS and no history of clinical optic neuritis), and ON group (12 patients with isolated ON, 23 patients with ON as the initial attack of eventually definite MS, 18 patients with ON as an attack of previously known MS). Latencies of P 100 were deter-

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mined for all recordings. Latencies for three recordings were analysed by multivariate analysis of variance. Results: Unaffected eyes of MS patients had a mean P 100 latency of 111.2 msec unchanged at the second and third recording (112.8 and 112.4 msec, respectively; n = 86, p = 0.69). Eyes selected for pathological latency at first recording (> 116 msec) displayed mean latencies of 125.7, 125.0 and 122.7 msec (n = 23, p = 0.27). In few individual eyes, improvement up to 7 msec (95 % confidence interval) was observed. ON patients had a mean P 100 latency of 128.9 msec in the affected eye (n = 32), and 108.7 msec in the unaffected eye (n = 29). Over the next two recordings, affected-eye latencies improved to 124.6 and 120.7 msec (p = 0.91, not significant due to variance), while non-affected eyes remained stable (107.2, 108.9 msec respectively, p = 0.26). Conclusion: Results confirm remyelination after ON, while non-acute demyelination of the fellow-eye was less frequent than previously reported. According to our retrospective, yet large sample, optic nerves that never suffered an acute attack of inflammation, but display electrophysiological signs of subclinical demyelination, show spontaneous improvement to a limited extent (beyond 7 msec is a rare event). Data will help define eligible patients and outcome requirements. Variance in this dataset may be particularly large due to retrospective analysis, repeat measurements at variable intervals and VEP evaluation by different physicians. Different methods to improve reproducibility should be applied in clinical trials. P536 A longitudinal diffusion tensor magnetic resonance imaging study of brain damage progression from the earliest clinical stage of multiple sclerosis E. Judica, M. Rovaris, A. Ceccarelli, A. Ghezzi, V. Martinelli, G. Comi, M. Filippi Scientific Institute Ospedale San Raffaele (Milan, IT); Ospedale di Gallarate (Gallarate, IT) Objective: This longitudinal study was performed to investigate the patterns of brain damage progression in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) and to assess whether they may be associated with the clinical disease evolution. Methods: Thirty patients with CIS and paraclinical evidence of disease dissemination in space were enrolled within three months from the onset of the disease. Conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) scans of the brain were acquired at baseline and after 3 years. Percentage brain volume change (PBVC) between baseline and follow-up scans was computed. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) were produced for the normal-appearing white matter (NAWM) and histograms of MD for the grey matter (GM). Results: At follow-up scans, 21 patients (70 %) showed MRI evidence of disease dissemination in time, while 15 patients (50 %) experienced one or more disease relapses during the study period. Mean PBVC was –0.81 %. In the whole patient group, average NAWM FA decreased and average NAWM MD increased at follow-up, but these changes were not statistically significant. Average GM MD showed a significant increase at follow-up (p = 0.002), whose magnitude was greater in patients who developed clinically definite MS than in those who did not (p = 0.06). There was no correlation between PBVC and average GM MD changes. Conclusions: In patients with CIS suggestive of MS, significant GM damage accumulates soon after the onset of the disease, which might be associated with the concomitant clinical evolution. Long-term follow-up studies are warranted to investigate the potential prognostic value of these preliminary findings. P537 Multiple sclerosis and interleukin 2 (114) gene polymorphism in Greek patients K. Aggelakis, F. Zacharaki, P. Kolia, M. Gkaraveli, V. Tsimourtou, E. Dardiotis, M. Dardioti, G. Xiromerisiou, A. Papadimitriou, G. Hadjigeorgiou University Neurological Clinic (Larissa, GR) Objectives: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder of the central nervous system, of autoimmune etiology. It results from an interplay between as yet unidentified environmental factors and susceptibility genes. Interleukin-2 (IL-2) is a crucial immunoregulatory cytokine derived from helper T cells and has both pro-inflammatory and anti-inflammatory actions, promoting T-cell proliferation during all mediated responses.A novel polymorphism of IL-2 (114) has been studied in various autoimmune diseases, presenting controversial evidence in MS. Methods: Using standard methods (PCR/RFLP) we studied whether this polymorphism was associated with susceptibility to and clinical variants of MS in Greek patients.

We analyzed DNA from 223 consecutive Greek patients (148 women and 75 men) with clinically definite MS, ascertained at University Hospital of Larissa, and from 240 healthy age- and sex-matched controls. One hundred and twenty-three patients with relapsing remitting and 70 patients with secondary progressive MS were classified as bout-onset (BO) (n = 193, 129 women, 66.8 %) whilst 30 patients (17 women, 56.6 %) referred progressiveonset (PO). The age-at-onset was 32.12 ± 9.51 (mean ± SD) years for the patients with BO and 32.09 ± 9.45 years for the patients with PO, whilst the disease duration was 8.41 ± 7.3 years and 8.32 ± 7.23 years respectively. Disability was assessed using the Kurtzke expanded disability status scale (EDSS) and was graded as mild (0–3.5), moderate (4–5.5) and severe (6–10). The EDSS score was 3.98 ± 2.07 for patients with BO and 3.99 ± 2.07 for patients with PO. Statistical analysis was performed using the Fisher’s exact test and the Mann-Whitney U test. Results: The population was in H-W equilibrium. The distribution of genotypes were as follow: a)Patients: G/G = 7.2 %, T/T = 55.1 %, G/T = 37.7 %, Allele-G = 26 % and Allele-T = 74 %; b)Controls: G/G = 9.6 %, T/T = 55.2 %, G/T = 35.2 %, Allele-G = 27.2 % and Allele-T = 72.8 %, indicating the lack of association between this polymorphism and disease susceptibility. Furthermore, no association was observed after stratification of patients according to type of the disease, age at onset, duration, sex and severity. Conclusion: Our finding suggests that IL-2 (114) polymorphism makes no major contribution to susceptibility to or to other clinical characteristics of MS in Greek patients. P538 Is the combination of different treatment response indicators useful to identify patients with a sub-optimal response to interferon beta? C. Rivoiro, P. Barbero, A. Cucci, G. Contessa, C. Ferrero, M. Bergui, E. Versino, B. Ferrero, G. Giuliani, E. Montanari, M. Clerico for the OPTIMS Study Group Objective: To assess individual and combined predictivity of different treatment response indicators of interferon beta (IFNB) treatment in MS. Methods: In a multicenter prospectice study of patients treated with 250 mcg IFNB-1 b for 24 months we evaluated the correlation between the occurrence of clinical activity over the long term with an early (during the first 6 months of treatment): (1) MxA(myxovirus resistance proteins) protein (two-site chemiluminescent sandwich assay), or (2) IL-10 mRNA levels (RTPCR) below an identified (ROC analysis) threshold; or (3) NAb(Neutralizing Antibody) confirmed positivity (IFNB-induced Mx production neutralization assay); or (4) active (i. e., with new T 2 or enhancing lesions) scan. Sensitivity, specificity, and predictive values and ROC curves have been calculated for each single indicator and for the various combinations. Bonferroni’s adjustment for multiple comparisons was made when needed. Results: 120 patients always treated with 250 mcg IFN beta-1 b for 2 years received also serial MRI scan; 88 of them were serially tested for Nab; 55 for MxA and 27 for IL-10 mRNA (tests requiring whole blood samples). Thresholds discriminating between responders and patients with a not satisfactory clinical response were 45 ng/mL (MxA) or 459 AU (IL-10). An active scan or a NAb positivity during the first 6 months of IFNB treatment had a significant (p < 0.01) predictivity of the risk of clinical disease activity; while both an MxA as well as an IL-10 mRNA level below the thresholds had not. The combination of a positivity at the MRI and at the NAb test increased the sensitivity with good predictivity and specificity (p = 0.02). Other combinations of the different indicators did not yield better results. Conclusion: Most biological indicators require sophisticated techniques and whole blood samples not easily manageable by all MS centers. An MRI scan can be repeated by most MS center and, in our study, was predictive of the risk of subsequent clinical activity. Adding a NAb test maintained a significant predictivity, increasing the sensitivity. Adding the other biological indicators (MxA or IL-10 mRNA levels, in our study) did yield a pattern of indicators with a significant predictivity. In addition, the latter tests, requiring whole blood samples, could be done only in a few selected centers. P539 Reduction in T 2 burden of disease is greater with interferon beta-1 a 44 mcg administered subcutaneously three times weekly than 30 mcg administered intramuscularly once weekly: 1-year analysis of the EVIDENCE study data A. Traboulsee, A. AL-Sabbagh, R. Bennett, P. Chang, R. Glanzman, H. Russell, D. Li on behalf of the EVIDENCE Study Group and UBC MS/MRI Research Group Objectives: The EVIDENCE (Evidence of Interferon Dose-response: European North American Comparative Efficacy) study has demonstrated that patients with relapsing–remitting multiple sclerosis are significantly more likely to remain relapse-free and have fewer active magnetic resonance imaging (MRI) lesions when treated with subcutaneous (sc) interferon

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(IFN) beta-1 a, 44 mcg three times weekly (tiw), than with intramuscular (im) IFN beta-1 a, 30 mcg once weekly (qw). This analysis of 1-year data from the EVIDENCE study evaluated changes in T 2 burden of disease (BOD) to establish whether IFN beta-1 a, 44 mcg sc tiw, is also superior to IFN beta-1 a, 30 mcg im qw, for this MRI assessment – a measure of total brain lesion load. Methods: All patients with evaluable T 2 MRI scans at baseline and week 48 were included in the analysis. The primary endpoint was percentage change in BOD (mm3) over 48 weeks. Other assessments included absolute change in BOD and correlation (Spearman’s Rank) between percent change from baseline in combined unique lesion activity (CUA) to week 24 and BOD to week 48. Changes in BOD were compared using ANCOVA with baseline BOD as covariate. Results: Baseline demographic and disease characteristics were similar among the 44 mcg sc (n = 279) and 30 mcg im (n = 274) IFN beta-1 a treatment groups. Median percentage reduction in BOD from baseline to week 48 was greater in the 44 mcg sc treatment group than in the 30 mcg im group (–6.7 % [range: –65, 431] versus –0.6 % [range: –61, 197]); adjusted mean treatment difference (AMTD) was –4.6 % (SE = 2.6; p = 0.002). Correspondingly, median absolute reduction in BOD was greater in the 44 mcg sc group (–189.5 mm3; range: –23454, 56869) than the 30 mcg im group (–19.0 mm3; range: –13337, 10161). The distributions of absolute and percent changes in BOD from baseline to week 48 indicate that more patients in the 44 mcg sc group had greater reductions in BOD than the 30 mcg im group. Percent change in BOD from baseline to week 48 significantly correlated with percent change in CUA from baseline to week 24 in the 44 mcg sc group (r = 0.290; p < 0.0001) and the 30 mcg im group (r = 0.178; p < 0.01). Treatment effects for neutralizing antibody-positive patients were similar between groups; AMTD was 0.5 % (SE = 3.9; p = 0.583). Conclusion: Patients treated with IFN beta-1 a, 44 mcg sc tiw, had significantly greater reductions in T 2 BOD than those receiving IFN beta-1 a, 30 mcg im qw, consistent with other EVIDENCE study outcomes. This study was supported by Merck Serono P540 Cognitive impairment in subtypes of multiple sclerosis using the Brief Repeatable Battery of Neuropsychological Tests E. Giogkaraki, C. Potagas, G. Koutsis, D. Mandellos, M. Karouli, C. Sfagos University of Athens (Athens, GR) Objective: To investigate the pattern of cognitive impairment of patients with relapsing-remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis, relative to control participants in the Greek population. Methods: RR patients (N = 65), SP patients (N = 25), PP patients (N = 23), and healthy control participants (N = 43) were assessed by the Brief Repeatable Battery of Neuropsychological Tests (BRBN). Two multivariate procedures with all BRBN scores as dependent variables, were performed to examine differences between controls, MS patients, and between MS subtypes. Demographic and clinical data were used as covariates. We classified as cognitively impaired patients who failed on at least 3/9 of the included measures. We considered that patients had failed a particular test if they scored below the 5th percentile for controls. Results: The overall prevalence of cognitive dysfunction in our patients was 52.8 %. All MS patients differed significantly from controls in all BRBN measures. The comparisons between patients groups revealed some differences in the performance mainly in favour of RRMS patients. Those differences were largely disappeared after controlling for physical disability (EDSS). Conclusion: All MS subtypes present a pattern of cognitive impairment across the studied cognitive domains failing to support a core deficit. P541 Product enhancements decrease the incidence of injection site reactions and pain resulting in improved adherence to therapy in patients with multiple sclerosis J. Scanzillo, R. Bennett, P. Biancucci, V. Divan, S. Sherman, A. AL-Sabbagh EMD Serono, Inc. (Rockland, US); Pfizer, Inc (New York, US) Objective: Evaluate the impact of product enhancements such as a new autoinjector (Rebiject II) and finer needles upon adherence to therapy for patients receiving subcutaneous (sc) Interferon-beta-1 a (IFNB-1 a) 44 mcg tiw. Injection site reactions (ISRs) are a common cause of treatment discontinuation in patients with multiple sclerosis. Support organizations such as the MS LifeLines program may help patients to manage ISRs more effectively by providing support, education, and training on injection technique; however, simplifying the injection process such as autoinjectors and finer gauge needles may help to decrease ISRs.

Methods: Data were gathered by the MS LifeLines program between August 2003 and November 2004 (before product enhancements) and between December 2004 and March 2006 (after product enhancements). Patients were contacted by nurse educators at regular intervals and asked a series of questions to determine whether they were adherent to therapy or had discontinued, and, if they had discontinued, why they had done so. The reason for discontinuation was recorded and divided into 3 categories: ISRs, pain and/or burning at the injection site, or other reasons. Interim data from this ongoing analysis are presented. Results: Between August 2003 and November 2004, 11.783 total patients received subcutaneous (sc) IFNB-1 a 44 mcg tiw. Of those, 17.6 % (n = 2.079) discontinued therapy. 82.4 % (n = 1.714) of these patients, cited reasons other than ISRs or injection pain and burning. Of the remaining discontinuations, 9.1 % (n = 190) were due to ISRs and 8.4 % (n = 175) were due to pain and/or burning at the injection site. Between December 2004 and March 2006 when Rebiject II and finer needle were well incorporated, 12.968 total patients received subcutaneous (sc) IFNb-1 a 44 mcg tiw. Of those, 13.7 % (n = 1.780) discontinued therapy. 92.6 % (n = 1.648) of these patients cited reasons other than ISRs or pain or burning. Of the remaining discontinuations, 5.6 % (n = 99) were due to ISRs and 1.9 % (n = 33) were due to pain and/or burning at the injection site. Conclusions: These results demonstrate that product enhancements such as Rebiject II autoinjector and finer needles have dramatically decreased discontinuation due to overall ISRs and injection pain or burning in patients administering (sc) IFNB -1 a 44 mcg tiw. The decreased discontinuation to therapy may potentially improve long-term outcomes. Supported by EMD Serono & Pfizer Inc. P542 Using number needed to treat to compare the efficacies of disease-modifying therapies in relapsing-remitting multiple sclerosis D. Mikol, R. Bennett, V. Divan, B. Hughes, A. AL-Sabbagh University of Michigan (Ann Arbor, US); EMD Serono, Inc. (Rockland, US); Pfizer, Inc (New York, US); 2Ruan Neurology Clinic and Research Center (Des Moines, US) Objective: To use number-needed-to-treat (NNT) to compare the clinical efficacies of currently approved disease modifying therapies (DMTs) in patients with relapsing-remitting multiple sclerosis (RRMS). The treatment of RRMS has become more effective over the last decade, with the advent of the currently available DMTs. Pivotal clinical studies differ in many characteristics, making cross-comparisons of limited value. Absolute risk reduction (ARR) is the absolute difference between the outcome of the placebo and treatment groups. The inverse of ARR, known as the number needed to treat (NNT), refers to the number of patients required to be treated for the duration of that trial in order to prevent one outcome. Methods: A systematic search was performed of all FDA-reviewed, randomized, placebo-controlled trials of currently available DMTs in RRMS. The techniques of meta-analysis were used to calculate NNT estimates. Results: Seven clinical trials of DMTs in patients with RRMS were identified for analysis. Clinical efficacy endpoints compared across the studies included the following: proportion of patients who were relapse-free at 1 and 2 years, annualized relapse rate at 2 years, proportion of patients who were progression-free at 2 years, and proportion of patients who were free of gadolinium (Gd)-enhancing lesions at one year or 9 months. In general, clinical endpoints showed little differentiation among the treatments. The most sensitive efficacy endpoint appeared to be the prevention of Gd-enhancing lesions (NNT: Avonex®, 8.3; Copaxone®, 33; Novantrone®, 6.3; Rebif®, 3.2, and Tysabri®, 3.6). Using this approach, Rebif® and Tysabri® have comparable effectiveness in treating RRMS. Conclusions: Head-to-head trials are the preferred means to compare efficacy. In the absence of head-to-head studies, NNTs can be used to compare efficacies among DMTs, but this approach has limitations, including the fact that different patient populations and different placebo group behavior are being compared. Other outcomes will be presented for the DMTs. Supported by EMD Serono & Pfizer Inc.

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P543 Cerebrospinal fluid of multiple sclerosis patients impairs the astrocytic syncytium in an astrocyte/microglia co-culture model in vitro A. Haghikia, D. Smikalla, D. Hinkerohe, A. Chan, R. Dermietzel, P. M. Faustmann St. Josef Hospital (Bochum, DE); Ruhr-University (Bochum, DE); Knappschaftskrankenhaus (Bochum, DE) Objectives: Autoimmune inflammatory diseases of the central nervous system (CNS) such as Multiple Sclerosis (MS) are accompanied by chronic changes of the cerebrospinal fluid (CSF). Besides the occurence of oligoclonal bands, a shift of pro- and antiinflammatory cytokine profiles is known to appear. Astrocytes fulfill distinct functions in the CNS, as the maintenance of homeostasis by forming a well coupled syncytium via gap junctional communication (GJC). We recently showed the disruption of the astroglial network conducted by microglial activation which plays a crucial role during inflammation caused by inflammatory cytokines. Here we evaluated the effect of MS-CSF on the coupling efficacy of astrocytes and degree of microglial activation. Methods: We investigated GJC of rat primary astrocyte/microglia cocultures containing 5 % microglia by Lucifer Yellow dye-transfer with a patch clamp pipette after previous incubation with MS- and control-CSF for 24h. The fraction of activated microglia was quantified by immunocytochemistry using ED-1 monoclonal antibody. MS-CSF was used immediately after initial diagnosis before starting treatment. 9 MS patients and 9 control patients who had been examined for the purpose to exclude an inflammatory disease were studied. We performed ELISA analysis of the CSF on the following cytokines (IL-12, TNF alpha, IL-10, IL-6, IL-1 beta and IL-8) to detect a possible correlation between the CSF and in vitro findings. Results: Cocultures treated with MS-CSF showed a significant decrease of coupling (p = 0.004**) compared to control-CSF. Also a significant activation of microglia (p < 0.001***) was observed in the cocultures treated with MS-CSF. However the only significant change of cytokine level was measured for the proinflammatory cytokine/chemokine IL-8 (p = 0.0129*) which was increased in the CSF of MS-patients. Conclusion: Our results show a clear decoupling effect of MS-CSF on astrocytes indicating an impaired GJC followed by constricted capacity of astroglial function in the CNS. Microglial cells are activated by this stimulus which might even occur prior to the astrocytic reaction, in turn leading to another burst of secretion of proinflammatory cytokines. Further studies aim at identifying the molecular mechanisms involved in mediating this decoupling effect of MS-CSF.

P544 A voxel-based analysis of diffusion tensor images and cognition in relapsing-remitting multiple sclerosis M. Summers, S. Drapier, L Fisniku, M. Cercignani, L. Cipolotti, D. Miller, M. A. Ron Institute of Neurology (London, UK) Background: Abnormalities detected by diffusion tensor imaging (DTI) may be related to cognitive deficits in RRMS patients. To date, such analyses have used whole brain or region of interest methods.Voxel-based analysis is a sophisticated tool for detecting highly region-specific associations between structural abnormality and cognition, without making prior assumptions about the regions in question. Methods: 27 patients (22F, 5M) with RRMS (duration 7.1 y) underwent cognitive testing. Patients and 18 controls, matched for age and gender, underwent DTI. FA and MD images of all subjects were normalised onto a custom template. Voxels containing lesions were masked and images smoothed using an 8mm kernel. T-tests were used to compare lesion-masked normalised FA and MD maps of patients and controls. FA and MD maps of patients were compared to detect subgroup differences between patients who were impaired (n = 6) or unimpaired (n = 21) on the Symbol-Digit Modalities Test.A linear regression was run in SPM 2 to detect associations between neuropsychological test scores and DT parameters, covarying for age and premorbid IQ. Results: Patients (vs. controls) had lower FA in voxels in the optic radiations, splenium and body of the corpus callosum and cingulate. MD was higher in the patient group in these regions and in the internal capsule, caudate, hippocampus, fornix and genu of the corpus callosum (significant after application of a False Discovery Rate correction). Poor performance on the SDMT was associated with increased MD in both temporal lobes and in the left frontal lobe. Poor performance in Hayling Sentence Completion Task was associated with reduced FA in the R cerebellum and with increased MD in the cerebellum (bilat.), areas adjacent to L temporal and frontal gyri, L postcentral gyrus and inferior parietal lobule, L occipital cortex and cingu-

late (bilat.). Patients impaired (vs. unimpaired) on SDMT had higher MD in the R middle and superior temporal gyri and adjacent white matter. Conclusions: In our patients, changes in MD were more widespread than those in FA in keeping with previous observations (Henry et al 2003), possibly because the greater number of T 1 lesions affects MD preferentially, whereas T 2 lesions affect FA (Werring et al. 1999). Cognitive performance was thus more closely related to MD. The focal R temporal abnormality in patients impaired on the SDMT suggests short term/iconic visual memory may be a key cognitive component in the SDMT.

P545 Assessing the net clinical benefit and absolute risk reduction of diseasemodifying drugs in relapsing-remitting multiple sclerosis A. AL-Sabbagh, R. Bennett, V. Divan, B. Singer EMD Serono, Inc. (Rockland, US); Barnes Jewish Hospital (St. Louis, US) Objective: To compare the baseline disease severity levels and ARRs across the Class 1 studies with DMDs for RRMS. Clinicians and payers tend to compare the results of individual clinical trials utilizing relative risk reduction (RRR) for each therapy. However, the significance of inter-study variability, heterogeneity of the patient population, different baseline characteristics, and inconsistent placebo behaviors from different clinical trials makes comparison based on RRR inappropriate. Measurement of absolute risk reduction (ARR) may be a more appropriate assessment of benefit. Methods: Class 1 studies published for the respective DMDs were reviewed and analyzed to compare the baseline EDSS and relapse rates across DMD study populations. The clinical benefit of DMDs versus placebo for two-year relapse rates and proportion of progression-free patients were compared across all studies using ARR and number needed to treat (NNT). Results: For patients enrolled in the PRISMS study, the proportion of patients with 2, 3, or 4 relapses at baseline for Rebif-treated patients were 41 %, 33 %, and 26 % respectively. For Tysabri-treated patients, the proportion of patients with 1, 2, or 3 relapses at baseline were 58 %, 32 % and 9 %, respectively with no reported data for Avonex, Betaseron, and Copaxone. The proportion of patients with baseline EDSS scores of 3 or more were higher in the Rebif treated patients compared with Avonex and Tysabri (41 %, 33 % [1], 33 %, respectively) with no reported data for Betaseron and Copaxone. The ARR for annualized relapse rates were 0.15, 0.24, 0.40, 0.41, and 0.45 [2] for Avonex, Copaxone, Betaseron, Rebif, and Tysabri (NNTs: 6.7, 4.2, 2.5, 2.4, 2.2), respectively. ARR for progression-free patients were 0.13 [3], 0.03, 0.08, 0.12, and 0.12 for Avonex, Copaxone, Betaseron, Rebif, and Tysabri (NNT: 7.7 [3], 33.3, 12.5, 8.7, 8.7) respectively. Conclusion: Given the difference in baseline risk and severity levels across studies, ARR is the appropriate way to compare across DMDs in the absence of head-to-head clinical trials. Results based on ARR showed that Rebif has comparable therapeutic effect on efficacy measures when compared to Tysabri. Supported by EMD Serono & Pfizer Inc.

P546 Multiple sclerosis and autoimmune disease in Dubai, UAE and Toronto, Canada: a comparative hospital-based study J. Inshasi, M. Thakre, A. Almadani, O. O’Connor Rashid Hospital (Dubai, AE); SMH (Toronto, CA) Objectives: We aimed to study the association of multiple sclerosis (MS) with autoimmune (AI) diseases, and to identify the commonest AI diseases. We aimed also to compare this association between the UAE and the Canadian groups. Methods: It is prospective Hospital based case control study which included 100 patients from Dubai/UAE and 100 patients from Toronto/Canada. Patients were selected from MS clinic in SMH in Toronto and UAE patients were selected from Neurology clinic, Rashid hospital in Dubai. Consent was taken, medical records were reviewed and same questionnaire was asked for both groups. The study was conducted from June 2005- Feb. 2006 for the Canadian patients and from June2005- January 2006 for UAE patients.Data was collected regarding: Age, sex, ethnicity, onset of MS, MS type, Immune modulator drugs, autoimmune diseases, and family history of multiple sclerosis and other autoimmune diseases. Results: In the Canadian group: 20 % were males, and 80 % were females. 90 % were citizens, 80 % were born in Canad. 58 % were Relapsing Remitting (RR),18 % were Secondary Progressive (SP), 22 % were Primary Progressive (PP) and 2 % were Clinically Isolated Syndrome (CIS). In the UAE group 25 % were males and 75 % were females, 91 % were citizens, 92 % were RR, 5 % were SP, 1 % were PP and 2 % were CIS.

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In the Canadian group 2 % had more than one AI diseases and 4 % had F/H of multiple AI diseases. In the UAE group 2 % had more than one autoimmune disease. And 3 % had F/H of multiple AI diseases other than MS. Thyroid disease (12 %) and DM type 1 (7 %) account for the majority of the AI diseases in the UAE group as compared to (9 % and 0 %) in the Canadian group. Asthma (12 %), Ulcerative colitis (4 %) and Psoriasis (4 %) were higher in the Canadian group as compared to the UAE group, (2 %), (0 %) and (1 %) respectively. Myasthenia Gravis was 2 % in both groups. Family history was positive for MS in 22 % of UAE group and 14 % in the Canadian group. Conclusion: This study is considered the first in the Middle East to look for epidemiology of MS. With other autoimmune diseases. Autoimmune (AI) diseases are common in MS patients. Type 1 helper T cells (Th1) mediated AI diseases are more common in the UAE group, Type 2 helper T cells (Th2) mediated AI diseases are more common in the Canadian group. These differences between the two groups could be due to the younger age, consanguineous marriage, the nutritional habits and the lack of MS clinics in UAE. P547 Betaseron vs. copaxone in multiple sclerosis using triple-dose gadolinium 3 Tesla MRI endpoints: spectroscopic findings in normal appearing white matter L. Wolansky, B. Hubbi, Y. Vidgop, M. Haghighi, P. Baladandapani, T. Phatak, V. Sheynzon, J. Skurnick, B. Biswal, W. C. Liu, S. Cook, D. Cadavid New Jersey Medical School (Newark, US) Background and purpose: The BECOME trial (Betaseron vs. Copaxone in MS with triple-dose gadolinium and 3-T MRI Endpoints) is the first headto-head trial focusing on the MRI outcomes of subjects treated with these two medications. The primary outcome measure, the mean # of enhancing lesions plus the # of new T 2/FLAIR lesions unassociated with enhancement per scan per patient, has been reported elsewhere. The purpose of this communication is to report on the spectroscopic features of the normal appearing white matter (NAWM). Methods: 75 subjects with MS were randomized to one of two treatment arms: 20 mg glatiramer acetate (GA) injected subcutaneously (sc) on a daily basis vs. 250 mcg of interferon beta-1 b (IFNbeta-1 b) injected sc every other day for up to 24 months. MR Spectroscopic (MRS) measurements were obtained in a subgroup of subjects at baseline, 12 and 24 months.A single voxel, measuring 1 to 1.5 cm cubed, was placed on the NAWM selected by reviewing T 1, T 2, FLAIR, proton density, and Gadolinium enhanced images so as to avoid lesions. The pulse sequence utilized was Point Resolved Spectroscopy (PRESS) with TE of 90 msec. The metabolites evaluated included nacetyl aspartate (NAA), Choline (Cho), and Creatine (Cr). NAA/Cr and Cho/Cr were calculated, using Cr as a reference metabolite. Results: At the time of this writing the complete baseline and 12 month MRS data but not 24 month data are available. 11 of the subjects in the GA group and 15 of the subjects in the IFNbeta-1 b group had both baseline and 12 month MRS. For the GA group there was a median decrease in NAA/Cr of 0.188 from baseline to 12 months. In the IFNbeta-1 b group there was a smaller median decrease of only 0.004. In terms of the Cho/Cr, for the GA group, there was a median decrease of 0.160. In the IFNbeta-1 b group the median Cho/Cr increased by 0.070. Conclusions: In the NAWM of MS subjects treated for one year with GA or IFNbeta-1 b, there was a more pronounced drop in the neuronal marker NAA for GA subjects than for IFNbeta-1 b subjects, in terms of median NAA/Cr, implying less neuronal death in the IFNbeta-1 b group. For the membrane marker, Choline, there was a slight increase in IFNbeta-1 b subjects and a slight decrease in GA patients, implying more membrane turnover in the former group. BECOME is an investigator initiated trial, which is supported by Berlex/Schering AG (marketers of Betaseron),but is the intellectual property of New Jersey Medical School

General neurology P548 Patient with stiff-person syndrome and negative anti-GAD antibodies Z. Petelin, V. Brinar, J. Honnorat, Z. Budisic, P. Podolski University Hospital Centre (Zagreb, HR); INSERM, Institut Fédératif des Neurosciences (Lyon, FR) Stiff person syndrome is a rare disorder of the central nervous system (CNS) characterized by progressive rigidity and painful episodic spasms which are most prominently affecting paravertebral muscles and proximal limb muscles. According to past knowledge there are two variants of this syndrome. In most cases it is presented as autoimmune variant with positive antibodies against glutamic acid decarboxylase (GAD). Paraneoplastic variant is very rare and is connected with antiamphiphysin antibodies. Amphiphysin is a 128 kDa synaptic protein situated in presynaptic nerve terminals, important to the trafficking of synaptic vesicles. Co-occurrence of both antibodies is unlikely. Authors describe a case of the 49-year-old woman who 3 months before admission to the hospital started to feel painful spasms and stiffness in the neck, right shoulder and right arm, which after some time extended to the right leg. Her symptoms were triggered by tactile, auditory and sight stimuli. A neurological examination revealed markedly increased muscular tone on all four extremities. Active and passive movements in the shoulders and neck were aggravated and painful. Her gait was cautious and slow. In cerebrospinal fluid (CSF) there were 24 white blood cells /mL, raised total protein (1.00 g/l) and glucose level (4.12 mmol/l). Oligoclonal bands were negative. Magnetic resonance imaging (MRI) of the brain and spinal cord was unremarkable. Electromyoneurographic finding (EMNG), characterised by absence of relaxation after activation of muscle, supported the diagnosis of Stiff person syndrome. Anti-GAD antibodies were negative, but positive antiamphiphysin antibodies were revealed in serum and CSF. Patient was treated with intravenous methylprednisolone (IVMP) followed by tapering oral steroids, baclofen and diazepam with improvement of her symptoms. As a result of long-term and extensive diagnostic treatment ductal invasive carcinoma of the left breast with metastases in axillary lymph nodes was revealed. In conclusion we want to stress out that special attention in patients with Stiff person syndrome should be given to etiological factors, since this rare syndrome can be the first manifestation of breast cancer, asking for quick, extensive and careful diagnostic verification. P549 Evaluation of autonomic nervous system in patients with dystrophy myotonic type I S. Palao, N. Lebrato, G. De Blas, J. M. Vázquez, A. Jiménez-Escrig Ramón y Cajal Hospital (Madrid, ES) Background: Dystrophy myotonic type 1 (DM 1) is a muscle dystrophy with characteristic myotonia and multisystemic involvement. Clinical manifestations related with Autonomic Nervous System (ANS) dysfunction have been anecdotically reported but never have been systematically searched. Objective: To evaluate the presence of ANS dysfunction in a series of patients with DM 1 and analyze their relationship with the size of the CTG (19q13) expansion, clinical severity, age and presence of endocrinological or cardiac dysfunction. Methods: 7 patients with a genetic diagnosis of DM 1, 4 women and 3 men, with age mean 44 years (range 19–78) and CTG repeats mean 462 (range 98–800) were prospectively evaluated for the presence of clinical dysautonomic manifestations, endocrine disorders (diabetes mellitus, insulin resistance and hypothyroidism) or cardiopathy. ANS was studied by testing 1) R-R interval variation with normal breathing, deep inspiration, and Valsalva’s maneuver; 2) blood pressure changes with standing and 3) sympathetic skin reflex response after electrical stimulation. In addition, we test for the presence of peripheral neuropathy to exclude it as the reason for ANS dysfunction. Results: Peripheral nervous system was normal in all except one case that had an axonal polyneuropathy. This patient had a history of alcohol habit and hepatitis C viral infection. R-R interval study and skin sympathetic response were normal in all cases. Regarding blood pressure, there were no drops in blood pressure on standing but a high correlation was observed between systolic blood pressure and CTG repeats both in supine and standing positions. Conclusion: There is no remarkable ANS dysfunction in MD 1 patients, although the finding of a reduction in systolic blood pressure in these patients should be considered in the clinical management of this disease.

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P550 Voxel-based morphometric analysis reveals cortico-subcortical changes in an epileptic patient with incontinentia pigmenti and concomitant sarcoidosis R. Weber, M. Obermann University Hospital Essen (Essen, DE)

months after completion of radiotherapy. We believe that the history of diabetes and the underlying immunological disorder that was found in our patient played a major role in the development of the extended brainstem lesion which is not the most usual among the lesions after irradiation for extracranial malignancies.

Objective: Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare X-linked dominant genodermatosis causing variable abnormalities predominantly of the skin. Approximately 30 % of patients with IP show central nervous system involvement with epileptic seizures, spastic paralysis and mental retardation as most frequently symptoms.When neurological symptoms are present in IP patients, conventional magnetic resonance imaging (MRI) showed associated neural tissue defects. We present a 21-year-old Caucasian female with genetically proven incontinentia pigmenti and epileptic seizures but normal conventional MRI. However, a more thorough voxel-by-voxel analysis using voxel-based morphometry (VBM) revealed grey and white matter decrease in the right temporal lobe. Methods: Repeated conventional MRI at age 10, 20 and 21, including T 1and T 2-weighted, diffusion-weighted, gadolinium-enhanced T 1-weighted and time-of-flight MR angiography showed no brain abnormalities. A T 1weighted 3D dataset was obtained from the patient at age 21 and compared to 20 healthy age and sex matched female control subjects (mean age 21.3 ± 2.2 years) using a magnetization prepared rapid acquisition gradient echo (MP-RAGE) sequence (TR/TE/TI = 1540 ms/ 3.93 ms/ 800 ms, flip angle = 12°, field of view = 256 mm, 160 slices, voxel size 1 x 1 x 1 mm3). Results: Significant grey matter decrease was found in the right inferior temporal lobe (z-score 3.74, t-score 4.85, x = 40, y = -18, z = –30, p < 0.05) associated with an adjacent white matter decrease (z-score 3.24, t-score 4.31, x = 42, y = –7, z = -25, p < 0.05). Grey and white matter decrease in the right temporal lobe was consistent with intermittent theta waves and sharp-slowwaves over this region in repeated electroencephalography recordings. Conclusion: We demonstrate the usefulness of voxel-based morphometry to identify subtle cerebral changes causing epileptic seizures in a patient with incontinentia pigmenti.These changes were not visible on conventional MRI. Previous studies had found a strong relationship between structural brain changes visible on conventional MRI and concomitant neurologic disorders in patients with incontinentia pigmenti. The brain lesions comprised hypoplasia of the corpus callosum, cerebral and cerebellar atrophy and microcephaly.

P552 Hypocupraemic myeloneuropathy – a literature review G. P. Winston, S. R. Jaiser National Hospital for Neurology and Neurosurgery (London, UK); Newcastle General Hospital (Newcastle, UK)

P551 Brainstem radionecrosis in a patient with nasopharyngeal carcinoma A. Angelou, T. Afrantou, M. Gelagoti, M. Paschalidou, N. Taskos, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Cerebral radionecrosis is one of the late complications of radiation therapy for head and neck tumors. So far there are reported more than 300 cases of cerebral injury after radiation treatment for extracranial malignancies; the nasopharynx is the most common primary site followed by the scalp and the sinonasal tract. Case report: A 28year old female was admitted with a progressive gait disturbance, difficulty in swallowing, diplopia and dysphonia. In neurological examination there was severe spastic paraparesis, pyramidal signs on the upper limbs, spastic dysphonia, paresis of the left VI and VII and bilateral impairment of all the lower cranial nerves. She had a history of diabetes and 1.5 years ago had undergone to radiotherapy for nasopharyngeal carcinoma and received a total dose of 83 Gy in 2 Gy fractions, in 3 phases that lasted for a period of 7 weeks. MRI revealed an extended lesion to the brainstem from midbrain to medulla oblongata which was shown hypointense on T 1,hyperintense on T 2; the lesion presented a marked homogenous enhancement. The routine blood tests were normal except from her immunological profil which was proved to be extremely impaired; she presented high titers of ANCA and ENA screen. Course and treatment: The patient received 1gr of methylprednizolone for 5 days and she continued with lower doses of methylprednisolone.A mild clinical improvement was observed after 2 months of corticosteroid treatment. Conclusions: Although modern radiotherapeutic techniques minimize the amount of normal tissue within the treatment field, it is impossible to totally exclude normal tissues because a margin of normal tissue is required to cover microscopic disease. The severity of the post radiation injury depends on the total dose and the fractionation protocol used. In our case the total dose of radiation given was within the therapeutic limits, however in a number of cases already reported there were postradiation complications even when the total radiation dose was referred much lower than 70 Gy. Our patient presented her neurological symptoms 18

Objectives: Review of all reported cases of hypocupraemic myeloneuropathy, summarising the demographics, aetiology, serum copper and zinc indices, treatment and neurological outcome. Methods: Search of the PubMed database using the terms copper, hypocupraemic, myelopathy, myeloneuropathy and subsequent review of the references cited by the papers obtained. Results: 36 published cases were identified; one further unpublished case had been seen by one of the authors. Age at presentation ranged from 36 to 78 (mean 56.4) with a marked female preponderance (female:male ratio 3.6). The predominant causes for the low copper were previous upper gastrointestinal surgery (46 %), malabsorption (14 %) and zinc overload (14 %). The copper level was below the reference range in all cases and in 18 of 37 cases was markedly low being below 0.1microg/ml (typical reference range 0.75–1.45microg/ml). Caeruloplasmin values were low in all 25 cases in which they were reported, and were below 4microg/dl (typical reference range 23–43microg/dl) in 16 of them. Zinc levels varied widely with 17 of 24 (71 %) having a zinc level above the reference range and 6 of 24 (25 %) having a level below the reference range. Treatment was typically by oral copper supplementation equivalent to 2mg of elemental copper per day. Neurological outcomes were reported in 31 cases, and represented an improvement in 12 cases (39 %) with stabilisation of the neurological deficit in the other 19 (61 %); no deterioration was reported with sufficient copper supplementation. Conclusions: Copper deficiency is a rare but treatable cause of potentially devastating myeloneuropathy, and occurs predominantly in females of middle and old age. It is readily diagnosed using standard copper and caeruloplasmin assays. The coexistence of haematological abnormalities, previous gastric surgery, malabsorption or zinc overload may point to the diagnosis. P553 Spontaneous haemorrhagic lumbar synovial cyst R. Santos Silva, M. Arantes, H. Romão, M. Resende, M. Costa Hospital Pedro Hispano (Matosinhos, PT) Objectives: To display the characteristic clinical and magnetic resonance imaging (MRI) appearance associated with hemorrhagic lumbar synovial cyst. Intraspinal synovial cysts of the lumbar spine are rare and generally associated with osteoarthritis of the facet joints, particularly at level L 4-L 5. Symptoms are uncommon, but may occur when the cysts become great enough to occupy the neural foramen or the spinal canal, compressing the dural sac and the adjacent nerve roots, originating motor and sensitive dysfunction. Acute onset of radicular symptoms have been reported in rare cases following hemorrhage into lumbar synovial cysts. MRI is the best method to visualize the synovial cysts. Surgical decompression is indicated when there are important neurological deficits. Methods: Correlation of imaging and clinical findings. Results: 61 year old man presented with a two months history of intermittent bilateral lumbar ache. Eight days before admission he had a sudden exacerbation of the lumbar pain and began to fall frequently and noticed weakness and tingling in his lower members. He had no further complaints. He denied any traumatic event and didn’t make regular medication. Neurological examination revealed a distal assymetrical hyporeflexic paraparesis grade 2/5 in the right lower member and grade 3/5 in the left. Hyposthesia in the right L 4, L 5, S 1 and in left L 5 and S 1 territories. Bilateral steppage gait. Laboratory evaluation was unrevealing. Lumbar computed tomography (CT) showed L 4-L 5 right ligamentum flavum thickness deforming the dural sac. Lumbar MRI revealed a L 4-L 5 lesion adjacent to the right posterior articulation, hyperintense in T 1-weighted image (T 1WI), hypointense in T 2WI and with no contrast enhancement suggesting an hematic collection associated with a synovial cyst, with mass effect in the roots of the cauda equina. He was submitted to surgery one day after. Conclusions: We presented a man with a subacute lumbar pain and paraparesis, whose MRI suggested an hemorrhagic synovial cyst. Synovial cysts are unusual lesions of the spine and hemorrhagic cysts are rare. The hem-

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orrhage cause the sudden exacerbation of the patient’s pain, but it is not clear whether sudden expansion of the cyst or the inflammation that resulted from the hemorrhage is the cause. Generally, the hemorrhage into lumbar synovial cysts is secondary to trauma or anticoagulation therapy. In our case there was no description of traumatic episodes or the use of medication. P554 Severe bradycardia requiring artificial pacing associated with a relapse of multiple sclerosis R. Pugh, A. Jha, R. Lee, A. Jafari, D. McKee Manchester Royal Infirmary (Manchester, UK); Greater Manchester Centre for Clinical Neurosciences (Salford, UK); Manchester University (Manchester, UK) Case report: A 29 year old woman developed unilateral optic neuritis. She was treated with intravenous steroids and her visual acuity normalised over four weeks. Ten months later she presented with a second neurological event causing rapidly progressive neurological deterioration until she was bedbound. On examination she had signs of a severe brainstem syndrome and spastic tetraparesis. Magnetic resonance imaging of the brain was markedly abnormal with widespread white matter lesions in both cerebral hemispheres, midbrain and brainstem, oligoclonal bands were isolated from the cerebrospinal fluid and further investigation failed to identify an alternative inflammatory, vasculitic or infective cause therefore a diagnosis of multiple sclerosis (MS) was made. Treatment was started with high dose intravenous methylprednisolone but the patient’s neurological condition continued to deteriorate. Her body temperature started to fluctuate between pyrexia and significant hypothermia, and subsequently developed an increasingly severe sinus bradycardia with corresponding hypotension until emergency transvenous pacing was necessary to maintain the cardiac rate and output. An echocardiogram was normal.Within a week the patient’s neurological status began to improve. Her heart rate returned to normal and the pacing wire removed after five days. There were no further temperature fluctuations. Although she continued to improve neurologically over the next few months until independently mobile, she remained significantly disabled. She has since had further relapses unassociated with any cardiac problems. Discussion: MS which takes a particularly aggressive course with rapid development of severe disability, as in this case often from near the outset of the disease, has been termed the Marburg variant. Autonomic disturbances including hypothermia and cardiac rate and rhythm dysfunction have been described in MS, variably associated with lesions in the corpus callosum, temporal lobes, brainstem and cervical cord. This case is the first described in which a catastrophic demyelinating relapse was associated with bradycardia severe enough to require artificial pacing to maintain cardiac output. In a patient with a severe MS relapse it is important to monitor cardiac and autonomic status, particularly with the increasing use of the potentially cardiotoxic drug mitoxantrone in these situations. P555 Painful muscle weakness as the presenting feature of osteomalacia secondary to Sjögren’s syndrome related renal tubular acidosis A. Jha, R. Lee, R Pugh, D. Mckee, M. Kellett Hope Hospital (Manchester, UK); Manchester University (Manchester, UK); Manchester Royal Infirmary (Manchester, UK) Case report: A 25 year old woman presented with a twelve month history of aching discomfort of the limbs, gradually increasing in severity and associated with unpleasant musculoskeletal chest wall pain. More recently she had developed progressive proximal weakness of the limbs until she was struggling to mobilise even with crutches. There was a past history of bilateral renal calculi, and also of punctuate keratitis treated with artificial tears. On direct questioning she reported ongoing ocular discomfort and dryness of the mouth. On examination there was livedo reticularis over the legs, and clinical evidence of both xerostomia and xerophthalmia. There was moderately severe proximal weakness of all limbs associated with pain on movement, and severe discomfort was elicited over the anterior ribs on compression of the chest wall. Serum creatine phosphokinase was normal, as was electromyographic (EMG) examination of the limb muscles. However, serum alkaline phosphatase was markedly raised, and there was significant hypocalcaemia and hypophosphataemia, with reduced 25-hydroxy Vitamin D levels, in keeping with osteomalacia. Further investigation demonstrated a hyperchloraemic metabolic acidosis with normal anion gap, in the presence of inappropriately alkaline urine, typical of distal (type 1) renal tubular acidosis (RTA). Antibodies to antinuclear antigen, Ro and La were found in the serum.

A diagnosis of osteomalacia secondary to RTA, itself secondary to Sjogren’s syndrome, was made. The patient was treated with oral sodium and potassium bicarbonate, alfacalcidol, calcium supplementation, artificial tears and saliva. Within six months she was completely asymptomatic. Discussion: The thoracic wall pain experienced by this patient is highly characteristic of osteomalacia, which is otherwise a very rare cause of painful generalised muscle weakness. Distal RTA is a well recognised cause of osteomalacia, and Sjogren’s syndrome is known to be the commonest cause of acquired RTA. This case illustrates the importance of considering a metabolic cause, including osteomalacia, as the explanation of diffuse muscle weakness with accompanying limb and chest pain in a patient with normal muscle enzymes and EMG examination. P556 Neurological complications caused by lightning stroke I. Nestrasil, P. Kanovsky Palacky University (Olomouc, CZ) Objectives: The spectrum of neurologic lesions after lightning injury includes the entire neuraxis from the cerebral hemispheres to the peripheral nerves. We describe an interesting case of lightning injury with persistent neurologic complications where the central nervous system was injured. To demonstrate lasting impairments after lightning strike, repeated clinical, MRI and electrophysiological examinations were performed during 3 years of follow-up. Methods: A 53-year-old man struck by lightning became unconsciousness for approximately 10–15 minutes and then reported amnesia. Second to third-degree skin burns were found on his head frontoparietally right and on both lower limbs. Around 1 week after the injury he reported a weakness of lower extremities. Consecutively, he underwent neurological, electrophysiological examinations (somatosensory and motor evoked potentials, nerve conduction studies with electromyography) and brainMRI. Neurologic state, brain MRI, electrophysiological studies were assessed repeatedly 1 and 3 years after the lightning strike. Results: Neurological examination disclosed the presence of pyramidal signs mainly in the lower limbs with mild neocerebellar dysfunction and spastic-ataxic gait. MRI of brain revealed discrete hyperintensities in the frontal white matter on the right side (skin burns were exactly over this location). Somatosensory evoked potentials and motor evoked potentials verified the lesion in the central part of the tracts. The findings were more expressed in the lower limbs. Nerve conduction studies and electromyography were normal. The repeated examination after 1 and 3 years demonstrated the improvement of clinical state as well as of electrophysiological findings. The final outcome after 3 years showed partial regression of neurological symptoms with corresponding improvement of electrophysiological parameters. Conclusion: A lightning strike can cause serious injury of the nervous system. It is of interest to note that location of MRI changes in the brain corresponded to the skin lesions on the head in the case presented. The consequential improvement of neurologic state was observed with considerable neurophysiological correlation within the 3-year-long follow-up. The neurophysiological examinations showed good applicability to follow the recovery after lightning injury. P557 Steroid-responsive encephalopathy with or without thyroid autoimmunity: clinical and immunological features G. Ardolino, F. Terenghi, B. Bossi, C. Giannotta, E. Nobile-Orazio IRCCS Istituto Clinico Humanitas, Milan University (Rozzano, Milan, IT) Objective: To compare the clinical and immunological features of four patients with steroid responsive encephalopathy with or without thyroid autoimmunity. Background: Hashimoto encephalopathy is characterized by its association with autoimmune thyroiditis and frequent response to steroids. The pathogenetic relationship with thyroid autoimmunity is however unclear since a few patients with steroid responsive encephalopathy without antithyroid antibodies have been reported. Methods: We report the clinical and immunological findings in four patients (2 men, 2 women) with steroid responsive encephalopathy in whom other causes of encephalopathy were excluded. Results: The mean age at onset was 73 years (range 57–81). The disease presented with rapidly progressive myoclonus, ataxia, gait disorders, partial seizures, sleep disturbance, cognitive impairment and coma. In all patients brain MRI and CT scan were normal.An extensive search for tumor was negative in all patients as were anti-Hu, -Yo, -Ri and -amphyphisin antibodies. PCR for common viral infections was also normal in CSF. Anti-thyroid anti-

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bodies (anti-TPO and anti- TG) were found in only one patient who had normal thyroid function. Two other patients had anti-nuclear antibodies while antibodies to extractable nuclear antigen (anti-SSA, SSB, Sm, RNP, Scl, Jo1), gangliosides, MAG, sulfatide and brain homogenates and glycolipids were negative in all patients. CSF studies revealed moderately increased lymphocytes (mean 31 cells/mm3; range 17–48 cells/mm3) and protein (mean 106.4 mg/dl) in 3 patients without anti-thyroid reactivity and were normal in the one with anti-thyroid antibodies. Oligoclonal bands were only found in a patient with a mirror pattern. All patients responded to steroid treatment (intravenous dexamethasone 16mg/day for 5 to days followed by tapering oral dose for at least two months) with rapid recovery of vigilance and complete symptom regression within a few days or weeks. All three patients without thyroid autoimmunity remained stable after therapy suspension while the only one with anti-thyroid antibodies worsened after steroid suspension becoming steroid dependent. Conclusions: In this small consecutive series of patient with steroid-responsive encephalopathy, only one patient had thyroid autoimmunity indicating that the absence of thyroid autoimmunity does not exclude this diagnosis. CSF studies may help identifying patients with this treatable encephalopathy. P558 Neurological manifestations of myeloproliferative and lymphoproliferative disorders in Alexandria university hospitals: a prospective study H. Marouf Alexandria University (Alexandria, EG) Background: Though neurological syndromes are recognized complications in hematological malignancies, studies of their precise frequencies are relatively rare. Objective: The aim of the present work is to study the prevalence and characterization of neurological involvement in patients with myeloproliferative and lymphoproliferative disorders, in Alexandria University Hospitals during the period from January 2001 to January 2004. Material & Methods: 689 patients were included in the present study. All the patients were subjected to: history taking and complete general examination, laboratory and hematological work up including bone marrow aspiration and trephine biopsy, thorough neurological evaluation including, CSF examination, electrophysiological and neuroimaging studies. Results: Neurological manifestations were seen in 225 (32.6 %) patients. Most of these manifestations were due to direct infiltration of the nervous system or therapy related adverse effects. Leptomeningeal infiltration occurred in 34 % of patients with acute lymphoblastic leukemia (ALL), 32 % of patients with acute myeloblastic leukemia (AML), and in 47 % of patients with non-Hodgkin’s lymphoma (NHL). Only three patients (8.5 %) with chronic myeloid leukemia (CML) had meningeal infiltration. Cranial nerve palsy was usually associated with meningeal infiltration and was seen in 28 % of NHL patients, 23 % of ALL patients, 8 % of AML patients, and in 11 % of patients with multiple myeloma (MM). CNS masses or deposits were less frequently seen and usually associated with NHL, being seen in 7 patients (53 %), all of them had diffuse large cell lymphoma. Lower cord and root manifestations were frequently seen in MM (47 % of patients), occasionally as the first presentation.Therapy related adverse effects were frequently seen in patients receiving vincristine, cytosine arabinoside (ara-C), steroid, and interferon alpha-2a. Methotrexate induced neurotoxicity occurred in only one patient with ALL and was reversible. Other complications including metabolic, paraneoplastic or hyperviscosity syndrome were less frequently seen. Conclusion: Neurological complications are frequently encountered in patients with hematological malignancies and can be the presenting sign. CNS involvement is usually associated with poor prognosis. Early diagnosis and introduction of CNS-directed treatment is important to improve the prognosis and prevent further neurological disabilities.

Poster session 4 Cerebrovascular disorders P559 Stroke in young adults: results from the first 227 patients enrolled during a 5-year period in the Athens Registry of Stroke in Young Adults – ARSYA G. Tsivgoulis, S. Vassilopoulou, M. Papadopoulou, A. Papapostolou, A. Tsivgoulis, G. Papadimas, A. Konstantinopoulou, K. Spengos University of Athens (Athens, GR) Background: Stroke in young adults differs from stroke in older age groups in terms of etiopathogenesis,risk factors and outcome.There is no published data from Greece regarding causes, risk profile and prognosis of stroke in this age subgroup.At our tertiary care referral center we designed a prospective stroke registry to evaluate systematically patient presentation, etiopathogenic mechanisms, evolution and outcome in Greek young stroke patients. Methods: Consecutive first-ever stroke patients, aged 15–45 years and hospitalised in the stroke wards or referred to the stoke outpatient clinic of our tertiary care University Hospital over a 5-year period,were prospectively included in a computerized observational databank. According to the TOAST criteria, ischemic stroke (IS) was classified into the following groups: large artery atherosclerotic stroke (LAA), cardioembolic stroke (CE), lacunar infarction (LI), infarction of other determined origin (IOE) and infarction of undetermined cause (IUC). Stroke severity was assessed using the NIHSS. Functional outcome at 1 month after the index event was evaluated by the modified Rankin Scale (mRS). Results: During this 5-year period we investigated 227 patients (mean age 38±7 years, male gender 57 %, median NIHSS-score 4 points/ interquartile range 5 points). The distribution of IS (n = 165, 73 %) subtypes was as follows: LAA 12 % (19/165), CE 13 % (22/165), LI 18 % (30/165), IOE 25 % (41/165) and IUC 32 % (53/165).Among patients with IOE, dissection (29 %), paradoxical embolism (14 %) and cerebral venous thrombosis (12 %) were the most common causes of stroke. Smoking (56 %) and hypercholesterolemia (34 %) were the most prevalent risk factors. The 1-month mortality rate was 3.5 %. Functional independence (mRS:0–1) at 1-month was 64.7 %. The most frequent complications during hospitalisation were cerebral edema (3.5 %) seizures (2.2 %) and infections (2.2 %). Discussion: Among Greek young adults with first stroke smoking and IUE are the most common risk factor and underlying pathogenic mechanism respectively. The short-term mortality is not negligible, but the overall early prognosis is rather favourable. P560 Arterial stiffness and cerebral circulation in untreated hypertension Z. Bajko, K. Csapo, S. Molnar, T. Magyar, P. Soltesz, L. Csiba Medical University Targu Mures (Targu Mures, RO); University Hospital (Debrecen, HU) Arterial stiffness appears to be an independent predictor of all-cause and cardiovascular death, and is related to endothelial dysfunction and NO availability. The aim of this study was to investigate the relationship between peripheral and central arterial stiffness and cerebral circulation. Methods: 28 recently diagnosed, untreated hypertensive patients (mean age: 48.3±8.1SD, M/F: 1) and 28 healthy volunteer (mean age: 46.1±6.5, M/F:1.07) were included in this study. The diagnosis of hypertension was confirmed with ABPM. We investigated the cardiovascular haemodynamics (cardiac output, stroke volume, peripheral resistance) with a complex hemodynamic monitor (impedance cardiograph, beat to beat blood pressure measurement device, ECG), the arterial stiffness (augmentation index:AIX and pulse wave velocity:PWV) with TensioClinic arteriograph, and cerebral circulation with transcranial Doppler (bilaterally fixed transducers above the middle cerebral arteries) during tilt table examination. All the data was recorded simultaneously on line in beat to beat manner and exported in Excel file for further analysis. Results: Significantly higher brachial AIX and PWV was found in the hypertension group (–0.35±29 versus –26±23 %, p = 0.001 and 10±2 versus 7.9±1.33 m/s, p < 0.0001). The cerebral vascular resistence was also significantly higher in hypertensives (1.64±0.47 versus 1.32±0.31 mmHg·s/cm, p = 0.007) The cerebral blood flow velocity correlates in the hypertension group significantly with brachial artery augmentation index (Pearson R = 0.424, p = 0.017) and aortic pulse wave velocity (Pearson R = 0.336, p = 0.05). Conclusions: The arterial stiffness and cardiovascular risk is significantly higher also in recently diagnosed hypertensives. There is an impor-

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tant relationship between central and peripheral vascular dysfunction (endothelial dysfunction) and the impairement of the cerebral circulation in untreated hypertensive patients This research was supported in part by the RO-19/05 grant. P561 Perfusion abnormalities in cerebral magnetic resonance imaging in two patients with prolonged mirgrainous aura J. Kraus, S. Golaszewski, G. Luthringshausen, R. Hold, G. Pilz, G. Ladurner Paracelsus Private Medical University (Salzburg, AT) Objective: Differential diagnosis between stroke and prolonged migrainous aura can be difficult, in particular if the patient suffers from deficits such as aphasia or severe dysarthria when exploration might be quite difficult. However, in the age of systemic lysis treatment for acute ischemic it is extremely important to come to the right diagnosis in such a situation. Case reports: We report on two patients who were sent to our hospital for lysis treatment after suddenly appearing global aphasia and slight rightsided hemiparesis. We excluded acute cerebral infarction by the aid of diffusion weighted cerebral magnetic resonance imaging (cMRI), however, leftsided cerebral hypoperfusion was seen in both patients. After resolution of neurological symptoms unilateral headache occurred and both patients reported pre-existing migraine with aura. Discussion: Contralateral hypperfusion in cMRI has only been described in a few patients with migraine with prolonged aura. We conclude from our two cases that – only provided a rapid availability of cMRI – cMRI can add important information for differential diagnosis, in particular when lysis therapy is a treatment option. P562 Predictive value of N-terminal pro-brain natriuretic peptide in early prognosis of acute ischaemic stroke K. H. Cho, M. S. Park, M. K. Kim, S. H. Lee, S. M. Choi, K. R. Lee Chonnam National University Medical School (Gwangju, KR) Objectives: Brain natriuretic peptide (BNP) which is produced in response to cardiovascular alterations is expected to play a role in hemodynamic modulation. Its biologically inactive fragment, the 76-amino-acid N-terminal proBNP (NT-pro-BNP), was known as one of the biologic markers of congestive heart failure and other clinical situations, such as chronic renal failure, pulmonary disease. But, there are controversies about clinical significance of NT-pro-BNP in ischemic stroke. This study was performed to find predictive value of NT-pro-BNP in early prognosis of acute ischemic stroke. Methods: From March 2005 to January 2006, NT-pro-BNP levels were measured in 610 consecutive patients who were admitted to department of neurology, Chonnam national university hospital. Two hundred five patients were excluded due to incomplete follow-up period in ischemic stroke patients (< 2 weeks), systemic infection (i.e, meningitis, pneumonia), unknown etiology of dizziness, and etc. 286 ischemic stroke patients and 119 patients as control subjects were enrolled. Stroke subtypes were determined according to TOAST classification. NT-pro-BNP levels between stroke group and control were analysed. In stroke group, high group was regarded that the patients with more than 300 pg/mL of NT-pro-BNP, and others were low group. National Institute of Health Stroke Scale (NIHSS) was checked at admission and 2 weeks later. Relationship between changes of NIHSS and the NT-proBNP level was also investigated. Results: The NT-pro-BNP levels were significantly increased in ischemic stroke patients (830.87 pg/mL) compared with control group (378.27 pg/mL) (p = 0.002). And the high levels of NT-pro-BNP in stroke patients were related to severity on admission and cardioembolic infarction. But there was no relationship between NT-pro-BNP and improvement of NIHSS. Conclusion: In this study, the significant relationship between severity of ischemic stroke and NT-pro-BNP was found, however, NT-pro-BNP was not related to early prognosis of ischemic stroke. P563 Acute ischaemic stroke in women N. Yesilot, B. Aksay, O. Coban, R. Tuncay, S. Zarko Bahar Istanbul University (Istanbul, TR) Objectives: There are studies indicating differences between men and women with ischemic stroke regarding risk factors, clinical features, diagnosis, treatment methods and response to treatment. In this study we aimed to evaluate the differences of female patients in comparison to male patients registered in the Istanbul Faculty of Medicine Stroke Databank (IFMSD). Methods: Demographic features, risk factors, clinical and etiologic sub-

types, laboratory findings, clinical course and in-hospital prognosis of 1522 patients with ischemic stroke prospectively registered in the IFMSD from 1994 to 2004 were analyzed by grouping them into two groups as males and females. Results: Of the 1522 patients with ischemic stroke 771 were male, 751 were female.Women were (mean age: 65.1±15.4) older than men (mean age: 62.2±13.7) (p < 0.0001). Smoking (p < 0.0001), ischemic heart disease (p < 0.0001), peripheral arterial disease (p < 0.0001) and transient ischemic attacks (p: 0.004) were prominent risk factors in men whereas atrial fibrillation (p < 0.0001) and hypertension (p: 0.027) were more common in women. Posterior circulation infarcts (POCI) (p < 0.0001) and lacunar strokes (LACI) (p < 0.0001) were more commonly seen in men while total anterior circulation infarcts (TACI) (p < 0.0001) were more frequently encountered in women. Cardio embolic stroke was more common in women, strokes due to large artery atherosclerosis were more common in men (p < 0.0001). There were more women with modified Rankin Scale score 3–5 at admission and at discharge than men (p < 0.0001), and there were more women with severe paresis at discharge from the hospital. In-hospital complication, recurrent stroke and death rates were not different between women and men. Conclusion: It is noteworthy that female patients are older, have more frequent history of hypertension and atrial fibrillation with severe ischemic stroke findings, cardio embolism as a stroke etiological subtype and more disability at the end of hospital stay. These findings are similar to those reported in the literature. P564 Bilateral internal carotid artery dissection mimicking demyelinating disease K. Oikonomidi, V. Kalpakidis, A. Petridis, O. Argiropoulou, S. Bostantjopoulou G.Papanikolaou Hospital (Thessaloniki, GR) Objective: We present a patient with bilateral internal carotid artery dissection. Case report: A 40-years old man was admitted with a three day history of dysarthria and dysphagia. Neurological examination revealed ptosis of the right eyelid, reduced range of tongue movements, brisk tendon reflexes and bilateral Babinski sign. Brain MRI showed multiple hyperintense lesions in the paraventricular white matter and in the left frontal lobe without gadolinium enhancement.After three days the patient deteriorated with left hemiparesis. He was normotensive, with no carotid bruits. Routine blood tests were unremarkable. Visual and somatosensory evoked potentials were normal. DSA detected bilateral occlusion of the internal carotid arteries. Cervical MRA demonstrated intramural haematoma in both internal carotid arteries indicating artery dissection with no evidence of fibromuscular dysplasia. Echocardiography examination was normal. Antithrombine III, protein C and protein S were within normal limit. Mutation of factor V Leyden was not detected. There was mild increase of blood homocysteine and he was heterozygote for the CG 77T mutation of the MTHFR. Anticardiolipine antibodies were mildly increased. Anticoagulation was started with improvement of clinical symptomatology. Conclusion: Bilateral carotid artery dissection is rare and the cause is often not found. The clinical manifestations are variably ranging from atypical or minimal symptoms to unilateral or bilateral cerebral ischaemic signs. Higher index of clinical suspicion together with multiparametric MRI techniques will improve the diagnostic accuracy. P565 Echomorphological carotid plaque instability in ischaemic stroke: prevalence and associated factors M. A. Abbas, S. Galantucci, M. Spinelli, M. Sessa, V. Martinelli, G. Comi, F. Corea INSPE IRCCS S. Raffaele (Milan, IT) Introduction: The presence of carotid artery atherosclerosis is considered a major risk factor for cerebrovascular events. Recent studies have shown that unstable carotid plaques are associated with higher risk for future ischemic stroke than stable plaques independent of the degree of carotid stenosis. The terms “high-risk”,“vulnerable” or “unstable” can be used as synonyms to describe plaques with an increased risk of thrombosis through different mechanisms. There is a need for a semplified approach to the identification of such plaques in daily practice. Patients and methods: We studied 152 consecutive ischemic stroke patients, admitted to stroke unit during the period (Feb-2006 to Sep-2006). Demographic data, risk factors, NIHS scale, laboratory investigations, ECG, echocardiography and neuroimaging of the patients are recorded.All the pa-

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tients are studied with B-mode Doppler Ultrasonography, transcranial Ultrasonography was done for 69 patients. A single prospective protocol according to Gomez-modified criteria was tested: i)stenosis > 70 %; ii) ulceration; iii) irregular surface; iv) hypoechoic. Three out of 4 items indicated instability. Results: Carotid stenosis was found in 44 internal carotid arteries (ICAs) (50–69 %: 23 ICAs, 70–89 %: 8 ICAs, 90–99 %: 7 ICAs, Occlusion: 6 ICAs). Carotid plaques were present in 103 (67.8 %) of patients. Twenty four were unstable carotid plaques (UCP) (19 symptomatic and 5 asymptomatic) and 145 were stable (70 symptomatic and 75 asymptomatic). Symptomatic UCP were present in older group of patients. There was a significant association between UCP and homolateral symptomatic events (P < 0.05). Symptomatic UCPs were significantly associated with hypertensive nephropathy (p < 0.04), more severe stroke according to the NIH scores (p < 0.025), larger cerebral infarction OR 8.6 (1.9 to 37.4), mass effect OR 4.6 (1.3 to 16.2), higher IMT median values (p < 0.025), compromised MCAs (p < 0.05). UCP patients had less often markers of left atrial enlargement OR 15.06 (1.2 to 176.3). Conclusion: Carotid ultrasound is an established method for visualizing and quantifying carotid stenosis. A detailed study of plaque morphology is needed since the degree of stenosis is not the only marker of plaque vulnerability. Our study revealed that UCPs are associated with multiple vascular risk factors. They are related to the volume of cerebral infarction and the severity of stroke. P566 A rapid elevation in leukocyte anti-sedimentation rate differentiates acute ischaemic stroke from transient ischaemic attacks earlier than S 100 b T. Molnar, A. Peterfalvi, L. Szereday, L. Szapary, S. Komoly, L. Bogar, Z. Illes University of Pecs (Pecs, HU) Objectives: Leukocyte antisedimentation rate (LAR) is an early test to detect activation of leukocytes and predicts the severity of systemic inflammatory response syndrome (SIRS) in many clinical setting. Here, we examined the role of LAR in patients with acute ischaemic neurologic deficit. Methods: A prospective, observational study was performed on consecutive patients.Venous blood samples were taken serially for measurement of LAR and S 100 b within 6 hours after onset of first symptoms (T 0), after 24 hours (T 24) and 72 hours (T 72). After 24 hours, the enrolled patients were divided based on the clinical signs and neuroimaging into a definitive stroke (AIS) or a transients ischemic attack (TIA) group. For statistical analysis Mann-Whitney U test was used and data are presented as median, minimum and maximum values. Results: Twenty-two patients with AIS and 6 patients with TIA were examined. Median LAR was significantly higher in AIS compared to TIA group at T 0 (0.256, 0.018–0.779 vs. 0.174, 0.159–0.385, p < 0.05), however at T 24 and T 72 LAR was increased in both groups without significant differences but with differing kinetics. Median S 100 b was significantly higher in patients with stroke compared to TIA at T 24 (0.17, 0.05–2.24 vs. 0.09, 0.06–0.15) and T 72 (0.26, 0.03–2.64 vs. 0.08, 0.06–0.14, p < 0.05, respectively). Conclusion: In contrast to S 100 b, the simple LAR test was capable to predict definitive stroke and differentiates from TIA within 6 hours after onset of symptoms. In addition, our results indicate a very early and rapid activation of leukocytes in stroke contrary to TIA, where activation of leukocytes is delayed and transient. P567 Association of cancer and stroke: a population-based study V. Bourg, C. Lebrun-Frenay, M. Mahagne CHU de Nice (Nice, FR) Introduction: Cancer is considered as a risk factor of stroke. We tried to estimate the frequency of cancer in patients hospitalized for stroke and compared these patients to those with isolated stroke. Demographic, clinical and biological data were analyzed. Material and methods: A data-base was initialized including all patients hospitalized for stroke in the department of Neurology since January, 2004. Patients with intra-tumoral and post-traumatic haemorrhage were excluded. The analysis was realized when 700 patients were included and separated in 2 groups: absence of cancer (group 1), report of cancer (group 2). For every patient, were collected: demographic data, medical history, type, location and mechanism of stroke, cardiovascular risk factors, treatment. When cancer was reported we collected date of diagnosis, location, date and type of treatment (surgery, chemotherapy, radiotherapy, hormonotherapy) and status of neoplasia. The group 2 was compared with the Regional Cancer Registry.

Results: On 700 patients (292 women, 408 men, mean age: 65.8 years), 78 (11 %) had an history of cancer (group 2). These patients were older (mean age: 70.7 years versus 64.8 years), mostly women (51 % versus 41 %). No difference was found concerning type and location of stroke. Stroke of unknown origin was more frequent in group 1, lacunar type in group 2. The main cardiovascular risk factors were identical in the 2 groups with the exception of diabetes (more frequent in the group 1) and biological abnormalities (more frequent in the group 2). In group 2, specific data were collected: aseptic endocarditis (1 case), veinous thrombosis with carcinomatous meningitis, intra vascular coagulation, stroke during chemotherapy or hormonotherapy, radiation induced carotid stenosis, concomitant diagnosis of cancer. Discussion: When our data were crossed with the Regional Cancer Registry, some specificities were enhanced for the group 2: (I) more cancer for women, without differences for age, location of cancer; (II) underrepresentation of pulmonary and prostatic cancers for men. The prevalence of the association stroke-cancer was 11 % and according to the literature. The discovery of a cancer remained exceptional (6 /700). The role played by biological abnormalities and cancer treatments is discussed. Conclusion: Association of cancer and stroke is a frequent phenomenon but the role of cancer is not always obvious. Our study fits with the literature. P568 Postacute intravenous delivery of adult neural precursor (stem) cells promotes functional recovery after focal cerebral ischaemia in mice M. Bacigaluppi, E. Kilic, S. Pluchino, A. Spudich, M. Deleidi, L. Zanotti, C. L. Bassetti, G. C. Comi, D. Wolfer, G. Martino, D. M. Hermann San Raffaele Hospital (Milan, IT); University Hospital Zurich (Zurich, CH); IRCCS San Raffaele (Milan, IT); University of Zurich (Zurich, CH) Background and aims: Adult neural precursor (stem) cells (NPCs) are promising candidates for the treatment of neurological disorders. Unlike embryonic stem cells, their use has not raised safety and ethical concerns. They can be easily expanded in vitro and still retain competence to integrate and to promote repair of injured brain tissue in vivo. We here investigate whether delayed intravenous delivery of adult NPCs facilitates functional recovery after transient focal cerebral ischemia. Methods: Adult C 57bl6 mice were submitted to 45 min intraluminal middle cerebral artery (MCA) occlusion, which causes tissue loss of the striatum and overlying cortex.After 3 days, animals were randomized in two groups, one group receiving intravenous transplantions of 106 adult NPCs into their tail veins, the other group being sham-treated with carrier solution. Starting prior to ischemia, continued after cell delivery up to 45 days following stroke, neurological performance was repeatedly evaluated using a neurological stroke scale (NSS), using rotarod and grip strength tests. Results: Laser Doppler flowmetries revealed that the severity of ischemia and the degree of early post-ischemic reperfusion did not differ between NPC-treated and sham-treated control mice. Starting from day 3 after cell transplantation, a gradual but slowly increasing amelioration of functional deficits assessed by the mNSS, rotarod and grip strength tests was noticed in NPC-treated animals, which achieved significance starting on day 15 after cell delivery. In contrast to NPC-treated animals, which gradually improved throughout the 45 days observation period, sham-treated mice did not exhibit any functional changes throughout this time. Conclusion: Our data provide evidence that post-acute systemic transplantation of adult NPCs promotes recovery of function in this clinically relevant stroke model. The precise mechanisms involved in the restoration of function yet remain to be determined. Histological analysis of cell differentiation and integration as well as assessments of brain plasticity are presently ongoing. P569 How often does pure sensory hemisyndrome turn out as acute brain attack? A one-year survey of a municipal hospital’s stroke registry S. Tentschert, U. Paukner, M. Krichmayr, C. Prainer, T. Schlager, E. Fertl Krankenanstalt Rudolfstiftung (Vienna, AT) Objectives: Transient pure sensory hemisyndrome may be caused by many medical conditions and frequently urges consultation of a neurologist. Our aim was to describe frequency and pathogenesis of disease in patients with pure sensory hemisyndrome in a highly selected cohort (admissions to a stroke unit) and to identify clinical characteristics. Methods: We analysed 181 prospectively documented patients admitted to the stroke unit of our department during the time period of one year (2006) with special focus on patients presenting with pure sensory hemisyndrome which was defined as isolated sensory loss of face and/or arm and/or leg in absence of any motor deficit. Admission to stroke unit was restricted

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to patients with acute symptom onset. NIH stroke scale was used to document focal neurological deficit. Results: Those (n = 20) in whom detailed information about sensory loss was lacking were excluded from analysis. 11 (7 %) of the remaining 161 patients (20 % Transient Ischemic Attack/TIA, 70 % ischemic stroke, 7 % haemorrhage, and 3 % sequela of cerebrovascular disease) had pure sensory symptoms (n = 7 TIAs, n = 3 ischemic strokes and n = 1 sequela of cerebrovascular disease). These patients (6 female: 5 male; age, median = 51 yrs) were younger (p = 0.003) and more often diagnosed with lacunar syndrome (p = 0.035) and microangiopathic pathogenesis. No difference in the prevalence of vascular risk factors (hypertension, diabetes, hyperlipidemia, smoking habits, peripheral arterial disease, history of stroke or myocardial infarction) was found. There was a trend towards lesions being allocated more often in the right hemisphere (p = 0.162). Conclusions: The frequency (7 %) of patients with pure sensory hemisyndrome in our cohort suffering from suspected stroke stands in line with former studies. These patients were younger and more often diagnosed with lacunar syndrome than all other stroke patients. Sensory symptoms presented preferentially on the left side of the body. No difference regarding classical vascular risk factors has been found compared to other stroke patients. Clinical outcome was expectedly benign since the majority of pure sensory stroke patients could experience a complete remission of symptoms within 24 hours. We conclude that pure sensory syndrome is definitely a cerebrovascular warning sign and should be taken very serious, but more long-term data are needed to estimate its impact on recurrent stroke to justify an intensive diagnostic workup in a stroke unit.

pleural tumor resected 11 years earlier presented four episodes of mild transient right hemiparesis and mild confusion upon awakening on four consecutive mornings. On admission, mild right ataxic hemiparesis was present. At the end of her first night in the stroke unit, worsening of the right ataxic hemiparesis and decreased vigilance occurred. Investigations: head CT and CT-angiography were performed. Blood sugar, insuline, cortisol, C-peptide, insuline-like growth factor-I (IGF-I) and IGF-II were measured. Thoraco-abdominal CT and PET were done. Results: Cerebral CT with angiographic sequences didn’t reveal any abnormality. Hypoglycemia of 1.2 mmol/l was detected during worsening and neurological status normalized promptly with treatment. Recurrent hypoinsulinemic hypoglycaemia (glycemia 1.0–2.2 mmol/L; insulin < 2mUl/l (5.0–18.0); C-peptide < 0.30 μgL (0.7–3.0)) was documented and required continuous glucose perfusion. Cortisol and IGF-I were normal. IGF-II (740ng/ml) and “big IGF-II” fraction (212 ng/ml; 28.7 % of total IGF-II, N< 15 %) were elevated. An extrapulmonary tumor occupying most of the right hemithorax was found, consistent with a benign pleural tumor on PET. Thoracotomy revealed a benign pleural fibrous tumor of the fuso-cillary type, identical to the one resected 11 years earlier. After complete resection, no more symptoms occurred, and IGF-II and its fractions normalized. Conclusion: This elderly lady presented with recurrent ataxic hemiparesis suggestive of a lacunar warning syndrome. Demonstration of severe hypoglycaemia during these episodes led to the detection of a fuso-cillary pleural tumor. This stroke-imitating paraneoplastic syndrome was related to hypersecretion of a fraction of IGF-II, and was completely cured by resection of the tumor.

P570 Glutathione peroxidase gene198pro/leu polymorphism and the risk of different aetiologies of ischaemic stroke in a Polish population A. Slowik, D. Wloch, T. Dziedzic, J. Pera, A. Klimkowicz-Mrowiec, A. Szczudlik Jagiellonian University (Cracow, PL)

P572 Incidence and subtypes of intracerebral haemorrhage in a suburb of Tbilisi: results of the first prospective population-based study in Georgia A. Tsiskaridze, M. Djibuti, T. Vashadze, R. Shakarishvili Sarajishvili Institute of Neurology (Tbilisi, GE); Tbilisi State Medical University (Tbilisi, GE)

Background: Selenium-dependent glutathione peroxidase (GPX 1) is a cytosolic antioxidant enzyme that neutralizes H2O2 to water and oxygen. A 198Pro/Leu polymorphism of the GPX 1gene affects the stimulation of the enzyme activity during selenium supplementation, with the Leu allele being less responsive. Studies suggest that oxidative stress is involved in the pathogenesis of ischemic stroke. We evaluated for the first time the significance of the GPX 1 gene 198Pro/Leu polymorphism in patients with different etiologies of ischemic stroke compared with healthy controls. Methods: We prospectively screened consecutive unrelated patients with ischemic stroke, diagnosed according to WHO criteria, who were admitted to the Stroke Unit, Department of Neurology, Jagiellonian University, Krakow, Poland between 2003 and 2006. Stroke etiology was established according to the TOAST criteria. One hundred sixty three patients with small vessel diseases (SVD) stroke, 162 with large vessel disease (LVD) stroke, and 170 with cardio-embolic (CE) stroke agreed to participate in the study, along with 686 age (±3 years) and sex matched controls. Data on demographics and conventional risk factors of ischemic stroke were collected. The GPX 1 gene198Pro/Leu polymorphism was detected by polymerase chain reaction amplification and restriction enzyme digestion. Results: The distribution of the studied GPX 1198 Pro/Leu polymorphism was in Hardy-Weinberg equilibrium among both the cases and the controls (P> 0.05). The genotype distribution of the GpX 1 gene was similar in patient’s groups and in their respective controls. LVD stroke: Pro/Pro: 76 (46.9 %), Pro/Leu: 70 (43.2 %); Leu/Leu: 16 (9.9 %) vs. controls: Pro/Pro:107 (46.7 %), Pro/Leu: 103 (45 %), Leu/Leu: 19 (8.3 %), P = n. s.; SVD stroke: Pro/Pro: 77 (47.2 %), Pro/Leu: 73 (44.8 %), Leu/Leu: 13 (8 %) vs. controls: Pro/Pro: 110 (46.2 %); Pro/Leu: 104 (43.7 %), Leu/Leu: 24 (10.1 %), P = n. s.; CE stroke: Pro/Pro: 67 (39.4 %), Pro/Leu: 91 (53.5 %), Leu/Leu: 12 (7.1 %) vs. controls Pro/Pro: 99 (45.5 %), Pro/Leu: 96 (44 %), Leu/Leu: 23 (10.5 %), P = n. s. Discussion: We showed that the GPX gene 198Pro/Leu polymorphism was not associated with the risk of different etiologies of ischemic stroke in a Polish population.

Objectives: Although stroke is considered a major non-communicable disease with enormous burden on the society, studies about epidemiological patterns of the disease in the developing countries are still lacking. The purpose of the present study was to determine incidence of spontaneous intracerebral hemorrhage (ICH) and its subtypes in Tbilisi, capital of Georgia, a country with transition economy in the South Caucasian region. Methods: In the framework of the joint Swiss-Georgian epidemiological project we prospectively identified all first-ever strokes from November 2000 to July 2003 in a defined population with 51.246 residents in Sanzona suburb of Tbilisi using overlapping sources of information and standard diagnostic criteria. Results: A total of 62 first-ever ICHs occurred during the study period with annual incidence rate of 44 (95 % CI 34–57) per 100,000 inhabitants. As to the distribution of the ICH subtypes on the basis of hematoma localisation, the most frequent was putaminal hemorrhage (in 32 % of cases), followed by lobar (23 %), thalamic (18 %), cerebellar and whole basal ganglia region (11 %–11 % each), and pontic (5 %) hemorrhages. Conclusion: Incidence rate of ICH in the urban population of Georgia is higher than analogous rates in majority of other countries. This might be explained by high prevalence of hypertension together with genetic, lifestyle and dietary variations typical for Georgia. On the other hand, the distribution of the main topographical subtypes of ICH does not differ markedly from those in other registries. The study was supported by the Swiss National Science Foundation

P571 Recurrent transient ataxic hemiparesis revealing a hypoglycaemic paraneoplastic syndrome P. Olivier, P. Michel, J. Zapf University Hospital (Lausanne, CH); University Hospital (Zurich, CH) Aim: We describe a patient presenting with recurrent ataxic hemiparesis as a consequence of hypoglycaemia due to a benign pleural fibrous tumour. Case description: A 80 year old hypertensive woman with a history of a

P573 Extracranial vertebral artery dissection causing multiple cervical radiculopathies H. Morais, P. Carneiro, R. Rego Hospital Pedro Hispano (Matosinhos – Oporto, PT) Introduction: There are few reported cases of cervical radiculopathy related to extracranial vertebral dissection. Usually dissection occurs at the C 1-C 2 level, where the artery is more mobile and susceptible to injury. We report a case of multiple cervical radiculopathies caused by a documented vertebral artery dissection with no signs of posterior circulation ischemia. Clinical case: The patient is a 60 year-old male who presented with a oneweek history of progressive right upper limb paresis and pain over his scapula and proximal right arm. The patient had fallen over his right side one week before. Prior medical history was non-significant. Neurological examination disclosed a predominantly proximal right upper limb paresis mainly affecting shoulder abduction, and elbow flexion and extension. Deep tendon reflexes were absent on the right upper limb. Sensation was intact

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throughout. Electromyography revealed signs of active denervation of the right cervical roots C 5 to C 7. Nerve conduction studies disclosed normal sensitive conduction velocities, pointing to a lesion proximal to the dorsal root ganglion. On cervical MRI (including MR angiography) the right vertebral artery appeared dilated and showed a characteristic double lumen image at levels C 4 to C 7 compressing anteriorly multiple cervical roots, specially C 5 and C 6. The patient was started on physiotherapy and prescribed clopidogrel 75 mg/day. Pain subsided over the next 4 weeks and he has had significant, albeit incomplete, recovery of strength. Discussion: This case is distinctly unusual as it shows an extensive extracranial vertebral artery dissection presenting with multiple cervical radiculopathies. It is likely that the reported traumatic history had an etiological role.Vertebral artery dissection is a very rare cause of cervical radiculopathy (1 % in one series), and is usually reported as causing a single radiculopathy. Cervical root dysfunction in this context is believed to result either from compression at the root exit level by the dissecting haematoma enlarging the artery, or from nerve ischemia. The proximity of vertebral artery to the anterior roots explains the finding of predominantly motor deficits without sensory impairment. P574 Association between cytokine genes variants and risk of stroke in patients with essential hypertension Y. Timasheva, T. Nasibullin, A. Zakirova, O. Mustafina Ufa Science Centre RAS (Ufa, RU); Bashkir State Medical University (Ufa, RU) Objective: There is growing evidence that alteration in the pro- and anti-inflammatory cytokines production balance may contribute to the pathogenesis of cardiovascular disease. However, the role of certain cytokines genetic variants on disease risk is not well understood.We tested the hypothesis that specific genetic polymorphisms are associated with an increased risk of essential hypertension (EH) and its cardiovascular complications. Cytokines with potent pro-inflammatory action (interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, interleukin-12) and anti-inflammatory cytokines (interleukin-10 and interleukin-1 receptor antagonist) were chosen for our study. Material and methods: 355 patients with EH and 343 unrelated healthy age-matched individuals without family history of cardiovascular disease were studied. Both patients and control originated from Tatar ethnic group from Bashkortostan, Russia. DNA was isolated from peripheral venous blood. Polymerase chain reaction and restriction analysis was used for genotyping. Statistical analysis was performed using Fisher’s exact test, Pvalue of < 0.05 was considered statistically significant. Odds ratios (OR) with 95 % confidential interval were calculated. Results: We have shown that IL-10 -627*C/*C genotype is associated with decreased hypertension risk (OR = 0.53, CI: 0.22–0.78). IL 1B -511*C/*C genotype was less frequent in the group of hypertensive patients with stroke than in those with non-complicated EH (37.5 % versus 57.52 %, P = 0.03). TNFA -308*G/*G was also found to be protective against stroke in hypertensive patients (OR = 0.48, CI: 0.24–0.97). IL-6 -572*G/*G genotype frequency was increased in EH patients with stroke (82.5 % versus 65.82 %, P = 0.03, OR = 2.86, CI: 1.13–7.25). In the same group, 1159*A/*A IL 12B genotype frequency was associated with lower stroke risk (OR = 0.43, CI:0.21–0.9). Conclusions: We demonstrate that common genetic variants of IL 10, IL 1B, TNFA, IL 6 and IL 12B genes are significantly associated with the risk of stroke in patients with EH, suggesting a role for inflammation in cardiovascular complications of hypertension. P575 The Ludwigshafen Stroke Study: first data from a population-based stroke registry F. Palm, B. Bode, F. Buggle, H. Becher, A. J. Grau Klinikum Ludwigshafen (Ludwigshafen, DE); Universität Heidelberg (Heidelberg, DE) Background and Purpose: Regarding the increasingly aging population within Western societies stroke represents an increasing social and economical burden. There are locoregional differences considering stroke incidence rates. In order to provide optimal treatment in each area stroke incidence rates have to be observed. Here we report first data of a population-based stroke registry in an industrial city in Southwestern Germany. Methods: The Ludwigshafen Stroke Study (LuSSt) is a population-based stroke registry in the city of Ludwigshafen (167.757 residents), RhinelandPalatine, Germany. Starting in January 1, 2006 multiple overlapping methods

of case-ascertainment are used in order identify all cases of stroke. Subgroup analyses were performed using standard definitions. Annual incidence rates were extrapolated from data of the first nine months; data of the first year will be presented at the meeting. Results: From January to September 2006, 438 cases with stroke or TIA were identified. Among them 94 patients were diagnosed as having a transient ischemic attack. 275 patients suffered a definitive first-ever-in-a-lifetime stroke (FES). The crude annual incidence rate per 100.000 inhabitants per year for FES was 219 (212 for men and 225 for women) overall, 188 (185 for men and 192 for women) for cerebral infarction, 20 (18 for men and 22 for women) for intracerebral hemorrhage and 10 (10 for men and 11 for women) for subarachnoid hemorrhage. After age-adjustment to the European population, the incidence rate per 100.000 inhabitants for FES was 149 (95 % CI 130–168), 165 for men (95 % CI 136–195) and 133 for women (95 % CI 130–168). Conclusion: Compared to other Stroke Studies crude annual incidence rates are relatively high. After age-adjustment for the European population, incidence rates of FES are still higher than in other European Stroke Registries. Further research is required to analyse whether socioeconomic factors or other factors in our population cause such high incidence rates. P576 Migraine-induced stroke of atypical location C. Balla, K. Boutsi, N. Taskos, I. Milonas Ahepa University Hospital (Thessaloniki, GR) Introduction: Migaine is common and usually considered benign. However, several studies suggested that it could be a risk factor for ischaemic strokes. This association seems to be restricted to particular subgroups of patients (women under 45 years-old, suffering from migraine with aura, who smoke or receive oral contraceptives). On neuroimaging studies, these migraine-induced strokes are usually located in the cerebral territory of the posterior circulation, especially in the cerebellum and the occipital lobes; supratentorial white matter lesions are also frequent in these conditions.However, some migraine-induced strokes, like the case described below, do not fulfill all these caracteristics. Patient: A 24-year-old woman suffering from migraine without aura established following International Headache Society’s criteria presented with right hemiparesis, dysarthria and right-sided facial nerve palsy. These symptoms occured 6 hours after the onset of a migraine attack and deteriorated during the next few hours to complete right hemiplegia. There were no sensory, visual or cerebellar signs. The patient was non-smoker and did not received oral contraceptives. CT scans at the first and second day of admission were normal. MRI at the fifth day of the admission showed an infarct in the posterior peduncle of the left internal capsule and subcortical white matter hyperintensities in T 2-weighted images. MRA was normal. Extracranial sonography was normal while transcranial Doppler revealed a vasospasm of the intracranial part of the left carotid artery.Transthoracic and transoesophageal echocardiography did not reveal abnormalities. Complete biochemical/haematological profile was normal. Auto-immune diseases and coagulation disorders were excluded. After exclusion of all classical risk factors for stroke, particularly in a young patient, it has been assumed that migraine was the cause of this subcortical infarct. Conclusion: The relationship between migraine and stroke remains complex and largely unknown. After exclusion of any other risk factors for stroke, true migraine-induced cerebral infarcts are rare and the majority of them are located in the cerebral posterior circulation territory of patients suffering from migraine with aura. Nevertheless, this clinical case shows that a true migraine-induced stroke can occur in a migraineur without aura and in an atypical location like the territory of the anterior choroidial artery.

Dementia/Higher function disorders P577 Granulomatous angiitis associated with cerebral amyloid-angiopathy: a case report with radio-pathological correlation M. G. Ziller, K. Letourneau, C. Fisch, S. Gosselin, A. M. Tsanaclis University of Sherbrooke (Sherbrooke, CA) Objective: Cerebral amyloid-angiopathy (CAA) is a common cause for intracranial hemorrhage and cognitive deterioration in the elderly population. It has rarely been associated with a granulomatous vasculitis attributed to amyloid-deposition. Methods: We report a case of a patient presenting with subacute cogni-

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tive deterioration and a diffuse leucoencephalopathy without previously known CAA. Clinical evolution, EEG, radiological and post-mortem pathological data are presented. Results: An 85-year old right-handed woman with mild cognitive impairment presented with a 3-week history of cognitive decline and psychomotor slowing. Clinical examination revealed mild left hemiparesis and hypoesthesia, left hemianopsia and apraxia. MMSE was 18/30 with mnestic and visuospatial deficits. CSF protein was elevated, cell count was normal. MRI showed diffuse extensive T 2/FLAIR hypersignal of the white matter of both hemispheres. Right hemispheric slowing was present on EEG. 2 weeks later the patient acutely deteriorated due to multifocal intralobar hemorrhages. Post-mortem examination confirmed the presence of diffuse perivascular amyloid deposits and granulomatous angiitis with vascular occlusion. Conclusion: We report a case of Amyloid-beta associated angiitis presenting with vasculitic features before the occurrence of multifocal intracranial hemorrhage. Early recognition of this entity may lead to anti-inflammatory treatment. P578 Effect of dementia severity and age on posterior cingulate cortex metabolism in Alzheimer’s disease N. Withofs, E. Salmon, C. Bernard, P. Desfontaines, S. Laureys, G. Moonen, R. Hustinx CHU ULg Sart Tilman (Liège, BE); St Joseph (Liège, BE) Objectives: The posterior cingulate cortex (PCC) is known to be impaired in Alzheimer’s disease (AD). We assessed the usefulness of voxel-based PETFDG imaging in a clinical setting and aimed to evaluate the heterogeneity of PCC dysfunction and it’s correlation with AD severity and taking the confounding effect of age into account. Methods: We included 68 patients (aged 53–86 years) with a probable diagnosis of AD according to DSM IV and NINCDS-ADRDA criteria. Mean ± SD mini mental state examination (MMSE) was 21±5. Healthy control subjects were aged 51–81 years (n = 16). FDG-PET was acquired in all subjects during wakefulness and in standardized conditions of minimal sensory input. Data were spatially normalized, smoothed (12 mm FWHM) and analysed using Statistical Parametric Mapping (SPM 2 version). The first (subtraction) analysis compared AD patients to elderly controls and looked for brain areas showing significant hypometabolism. The second (correlation) analysis included the 68 patients’ scans and looked for areas showing linear decrease in metabolism as a function of MMSE values and of patients’ age. All results were considered significant at p < 0.001 and corrected for multiple comparisons using small volume corrected p < 0.05. Results: Our first confirmatory analysis comparing the AD patient group to the control group showed a significant metabolic reduction in a wide network encompassing the posterior midline cortex (i. e., posterior cingulate cortex and precuneus) and fronto-parietal associative cortices. The peak voxel was localized in the ventral PCC (coordinates –16 –56 10; Z = 3.69). At the individual patient level, however, 10 out of the 68 AD patients showed normal metabolic activity in vPCC. All of these patients showed MMSE above or equal to 20. The next analysis identified a significant correlation between MMSE and vPCC metabolic decrease (coordinates 10 –54 2; Z = 3.35). This effect was not explained by age as demonstrated by an exclusive masking approach (anterior cingulate cortex showed age-related metabolic decline). Conclusion: Our data confirm the metabolic impairment of PCC in AD. About 15 % of our patients with a clinical diagnosis of probable AD showed normal PCC activity. A correlation analysis showed that dementia severity (as assessed by MMSE), and not age, explains the variance in PCC resting metabolism. P579 An autopsy case of Creutzfeldt-Jakob disease with Lewy body disease T. Haraguchi, H. Ishizu, S. Terada, K. Sakai, Y. Tanabe, T. Nagai, H. Takata, K. Nobukuni, Y. Ihara, S. Kuroda Minami-Okayama Medical Center (Okayama, JP); Zikei Institute (Okayama, JP); Okayama University (Okayama, JP) Objectives: To report an autopsy case of Creutzfeldt-Jakob disease (CJD) with Lewy body disease (LBD). Methods: A 77-year old man began to suffer from forgetfulness in Augst 2003. In September 2003, he was unable to do work of an officer. In October 2003, he could hardly speech and became restless in the night. His mental deterioration progressed rapidly, and he could neither walk nor stand by himself on October 24, 2003. On examination, he was disoriented and confused on October 30, 2003. His limbs were both rigid and spastic, the arms flexed

at the elbows, and the legs held extension. Myoclonus is remarkable in his face and limbs. Typical type of periodic synchronous discharges on EEG was recorded.Head MRI (DWI) revealed high intensity area in the temporal lobe, frontal lobe cortex and caudate nucleus. He got akinetic mutism on November 2003. He died of pneumonia on January 2004.All course was five months. Results: Post-mortem examination revealed neuronal loss, astrocytosis and patchy spongiosis in the cerebral cortex and lenticular nucrei. Synaptic type deposits of prion protein were present in the temporal cortex. Additionally, Lewy bodies were observed in the cerebral cortex. Lewy neuritis were distributed in CA 1 and CA 2 of the hippocampal formaton. Although the substantia nigra and locus ceruleus showed almost no neuronal loss and gliosis, Lewy bodies were observed in these areas. Conclusions: Although this case was clinicopathologically diagnosed to be sporadic CJD, this case showed the features of both CJD and diffuse LBD by histological findings. There are a few reported cases with CJD accompanied by Parkinson disease. This case was typical clinical course of sporadic CJD, in addition, there was neither dementia nor parkinsonism before the CJD onset. Because neuronal loss and gliosis of substantia nigra and hippocampus were slight, symptoms of dementia and parkinsonism might not have developed before the CJD onset.

P580 Clinical battery for diagnosis of mild cognitive impairment due to Alzheimer’s disease J. Alom, I. Llinares, S. Fajardo Hospital General Universitario Elche (Elx, ES) Objective: To evaluate clinical and neuropsychological features to identify among Mild Cognitive Impairment (MCI) patients those who will progress to Alzheimer disease (AD) dementia. Methods: Longitudinal prospective study of 89 consecutive patients assessed in our memory unit affected with MCI in the following clinical inclusion criteria: a) memory complaint corroborated by an informant; b) Clinical Dementia Rating 0.5; c) MMSE 24; d) complete autonomy for activities of daily living (ADL). Clinical evaluation consisted of clinical protocolized interview and neuropsychological evaluation (compared with control group n = 63), standard laboratory test and CT scan. A half-yearly check-up with consensus decision from ADL and/or neuropsychological results to determine if patients remained in MCI, improve or progresse to AD or another dementia. Results: At 3 years follow-up, 47 % patients developed AD dementia (25 % in the first year, 12 % in the second and 10 % in the third). The following univariate predictors were significant: age, sex, sensorial deficits, other concomitant diseases, time evolution, depressive antecedents, attend alone or accompanied, repeat comments, difficulties to understand explanations (difunex), CDR sum,WMS-R MC,WMS-R Logical Memory,WMS-R Associated Learning, Word Fluency animals (WFA). These significant univariate variables were entered into Logistic Regression analysis (LRA) to identify optimal diagnostic sensitivity/specificity remaining: age, time evolution, repeat comments, difunex, depressive antecedents, sensory deficits, WFA. At 0.25 cut-off, LRA selected variables diagnose correctly at 97.1 % of patients: 94.4 % MCI-no progressive and 100 % of MCI- progressive to AD dementia. As a whole, these variables are called MCI-ADB. Conclusions: In our sample, at 3 years follow-up, MCI-ADB diagnoses properly, with clinical and neuropsychological data from the initial visit, at 94.4 % of MCI-no progresssive and 100 % MCI-progressive to AD dementia patients.

P581 An analysis of the subjective straight ahead in patients with spatial neglect and pusher syndrome A. Saj, J. Honoré, T. Bernati, M. Rousseaux CHRU de Lille (Lille, FR) Objective: The pusher syndrome (PS) is characterized by a severe postural tilt and an active resistance to any attempt to rectify it. This disorder would result from an erroneous perception of the postural vertical. In these patients, no data is available about the representation of body orientation in the horizontal plane. Our objective was to compare the subjective straight ahead (SSA) of neglect patients with and without PS. Methods: Patients suffered from a right hemisphere stroke. None had hemi- or quadrantanopia. Out of the 13 who were neglect in the conventional clinical tests, 3 with PS (N+P+) and 10 without PS (N+P). They were compared with 5 non-neglect patients without PS (N-P-) and 10 healthy control subjects (C). Participants were right handed and the groups were comparable in age. The SSA was evaluated by the adjustment of a luminous rod

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“straight ahead of the navel” in the horizontal plane. This visuo-haptic method allowed the simultaneous measurement of the translation (lateral) and the rotation (yaw) errors. Participants were tested in sitting position and in darkness. Results: N+P+ patients showed a contralesional deviation of the SSA in translation (N+P+: –8.7 cm), whereas the N+P- showed the classical ipsilesional deviation (N+P-: +4.7 cm). The other groups did not present any significant bias (N-P-: +0.5 cm; C: +0.04 cm). No rotation error could be demonstrated in the four groups. Conclusions: We found translation errors of opposite signs in N+P+ and N+P patients. This observation is to be put in relation with the postural bias characterizing PS, which is also opposite to that classically observed in neglect patients without PS. These data confirm the connection between the SSA and the postural disorders.

P582 Vascular dementia and thymidylate synthase tandem repeat polymorphism H. S. Song, J. H. Lee, S. B. Lee, K. D. Park, K.G Choi, B. O. Choi Ewha Womans University College of Medicine (Seoul, KR); Kyunghee EastWest Neomedical Center (Seoul, KR) Objectives: Vascular dementia (VaD) is a type of dementia resulting from cerebral blood vessel disease. It has been reported the association between moderately elevated plasma homocysteine levels and vascular dementia. Thymidylate synthase (TYMS), which catalyzes the rate limiting step in DNA synthesis, is an essential enzyme in one carbon metabolism. Moreover, TYMS and methylenetetrahydrofolate reductase (MTHFR) are both involved in homocysteine metabolic pathway. To explore whether TYMS may play an important role in VaD, we investigated the association between TYMS tandem repeat polymorphism and VaD. Methods: We analyzed TYMS, MTHFR C 677T, and A 1298C polymorphisms in 71 VaD patients (male, 28; female, 43) and 413 healthy controls (male, 230; female, 183), and examine the effect of polymorphisms on occurrence of VaD. Results: Subjects who carried at least one TYMS 2R allele [2R(+)] (AOR, 2.07; 95 % CI, 1.20–3.57) or TYMS 2R 3R genotype (AOR, 2.20; 95 % CI, 1.23–3.94) showed the increased risk of VaD. MTHFR 677TT genotype (AOR, 2.28; 95 % CI, 1.00–5.19) was also associated with VaD. Comparing in paired combinations, the frequencies of [2R(+)/T(+)] (AOR, 3.82; 95 % CI, 1.58–9.23), [2R(+)/C(+)] (AOR, 2.69; 95 % CI, 1.24–5.84), and [T(+)/C(+)] (AOR, 2.61; 95 % CI, 1.02–6.69) were higher in VaD than those of controls. When analyzed odds ratios in combinations of all three polymorphisms, the risk of VaD was highest in subjects with [2R(+)/T(+)/C(+)] genotype (AOR, 5.00; 95 % CI, 1.37–18.25). Therefore, combined TYMS, MTHFR C 677T, and A 1298C polymorphisms might be a more predictive genetic biomarker for VaD than TYMS alone. Conclusion: The frequency of TYMS tandem repeat polymorphism is significantly higher in VaD patients than that of healthy controls.

P583 Is apraxia linked with deficits in motor working memory? M. D. Hesse, P. H. Weiss, W. Huber, G. R. Fink University Hospital RWTH (Aachen, DE); Institute of Neurosciences and Biophysics (Julich, DE); University Hospital Cologne (Cologne, DE) Objectives: Patients with apraxia often show an aggravation of their deficit with increased movement complexity. This aggravation may result from an impaired working memory (WM) for movements. Methods: 71 patients with lesions of the left (n = 52) or right (n = 19, RH) hemisphere as well as 25 elderly and 13 young control subjects were examined with a new test for motor WM and two standard WM-tests (Corsi block span and digit span forward). According to imitation and object use performance, patients with left-hemisphere damage were divided into patients with (n = 28, LH+) and without (n = 24, LH-) apraxia. For the motor WM test, pictures of manipulable objects (O), actions with objects (AO), meaningful actions (MF) and meaningless actions (ML) were presented. Similarly to standard WM-tests, the motor WM span for each category was defined as the maximal number of pictures correctly reproduced in the proper order. Results:Young subjects performed better than elderly controls in the motor WM test, while the latter still performed better than the three patient groups. Interestingly, there was no significant difference between LH- and RH patients for any category. However, LH+ patients consistently scored lower than LH- and RH patients. A similar block span of all three patient groups indicated that the motor WM deficit of the LH+ patients did not result from an unspecific greater cognitive impairment. Conclusion: These results suggest that patients with apraxia suffer from

a specific deficit of the motor WM leading to the clinically observed disturbances of complex actions. supported by German Research Foundation (KFO 112 TP 1) and START AZ 35/04 P584 Remembering the future, predicting the past: a neurophysiological study of mental time travel S. Arzy, I. Molnar-Szakacs, O. Blanke Hadassah Hebrew University Hospital (Jerusalem, IL); LNCO, EPFL (Lausanne, CH) Objectives: States of consciousness that modulate awareness of the self as continuous across time is an essential ability of human behavior, enable us to re-experience the past and predict the future and is often called “mental time travel” (MTT). It has been proposed that MTT to the past is based on episodic autobiographical memory that is defined as the subjective “projection” of the self to a specific place and time in the past. Comparatively, MTT to the future is thought to be based on “episodic future thinking”, or the ability to project the self forward to the future and to pre-experience an event, relying on similar patterns and brain activations in both times. Methods: By incorporating methods from behavioural memory research we designed a MTT paradigm that extended our previously used mental imagery paradigm employing spatial aspects of the self to temporal aspects of the self. Participants were asked to make judgements about future events (Forward in time) and past events (Backwards in time) from three different time-points: the present (Now), ten years earlier (Past) or later (Future). We used behavioural measures, evoked potential (EP) mapping and electrical neuroimaging in healthy participants. In addition, we measured behaviour and local field potential (LFP) via intracranial electrodes in a 28 year-old patient undergoing presurgical epilepsy evaluation. This paradigm was further checked in patients with lesions in memory and visuo-spatial systems. Results: (1) MTT to the future proceeded MTT to other time points; (2) participants were faster and brain activation more prominent to Forward than Backwards direction independently of time–point; (3) Patients with certain brain damage lose this future-orientation; (4) self-projection in time is comparable to self-projection in space. Conclusions: MTT is directed to future predictions more than to past recollection, and is different than memory. Distributed brain activity at the anterior temporal and occipito-temporal cortex as well as their timing are crucial for the coding of the self as temporally located within the present and for the ability to mentally “travel” to past and future. Patients with brain lesions at these regions are also disturbed in their future-orientation and MTT ability. P585 To live with an aged, demented relative worsens quality of life for university students: a pilot study developed in Madrid, Spain J. Fernández Domínguez, J. Trébol López, M. Grande, D. Alvarez, R. Herruzo, A. Frank García Hospital Universitario La Paz (Madrid, ES) Background and objective: Dementia is an acquired and progessive organic mental disorder characterized by decline of intellectual abilities as well as mood and behavior impairments that interfere with social and occupational tasks. This syndrome also affects patient main carers by leading them to a loss of their quality of life (QOL) and so could it occur among the rest of the family components, namely, the “secondary caregivers”. In this study our objective was to know whereas living with a demented person produces any impact in the QOL of university students, who represent some group of “secondary caregivers”. Methods: This is a Pilot study developed in Madrid between 2003–2006. We used a brief survey including demographic, clinic and socio-economic data, as well as the SF-36 Questionnaire (Spanish 1.4 version modified). We divided the sample in 3 groups: Cases Group: university students living with an old relative (> 60 years old) with signs or symptoms of dementia; Control A: those who lived with a cognitive non-impaired old (> 60 years old) relative and Control B: students who did not live with any old relative. SPSS statistics program (11.5, 12.0 and 13.0 versions) was used to analyze results. Results: Participant students (25 % Cases, 25 % Control A and 50 % Control B) fulfilled correctly 500 questionnaires valid for statistical analysis. In this series 35.8 % of participants where Medicine students and 91.4 % lived with their parents. Most of the primary caregivers of dementia patients were daughters. Results of SF-36 Questionnaire show a statistical worser score in emotional role (ER) and mental health (MH) in Cases compared with both Control Groups, whereas physical role (PR) resulted worser in Cases and Control A Groups compared with Control B.

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Conclusion: In a series of university students living in Madrid (Spain), to live with an elder relative (> 60 years old) -either demented or not- has a negative influence on their QOL, especially in the physical area. Moreover, when the relative has a dementia, students (“secondary caregivers”) also suffer a significant worsening in other QOL areas (emotional role and mental health). It appears important to make more studies in this field of knowledge in order to confirm these results and to establish appropiate socio-economic resources in favour of primary as well as of secondary caregivers of demented patients.

3 does not exclude AD because this protein is not specific. The result of 143-3 and tau dosage in CSF, though not specific, aids to start the appropriate therapy, both pharmacological and cognitive.

P586 Leukoaraiosis and cardiac performance Angelo Bulboaca, Adriana Bulboaca, D. F. Muresanu Rehabilitation Hospital (Cluj Napoca, RO); Neurology Hospital (Cluj Napoca, RO)

Objective: Galantamine treatment (GAL) for up to 6-months in patients with mild to moderate Alzheimer’s disease (AD) was effective in randomized placebo–controlled clinical trials. Open-label extension trials for up to 36 months have suggested long-term (LT) benefits, that need to be confirmed in LT placebo-controlled studies. GAL-ITA 2 was designed to assess whether LT GAL delays cognitive deterioration in AD. Methods: Mild to moderate AD patients according to NINCDS-ADRDA (MMSE score 11–24) were to enter a 12-month open label phase (OL) with GAL 16 mg/day. At the end of OL, responders (i. e. patients with a deterioration of < 4 points on the 11-item Alzheimer’s Disease Assessment scale cognitive subscale (ADAS-cog), were randomized to GAL (16 mg/day) or placebo (PBO). This double-blind phase (DB) lasted for up to 24 months or until patient met the predefined endpoint (change in ADAS-cog score ≥ 4 points vs. end of OL). Primary efficacy measure was time to deterioration (time to meet the endpoint), analysed by stepwise regression analysis according to the Cox proportional hazard model Responder rate at the end of OL was also measured. Safety parameters (vital signs, laboratory tests, ECG and adverse events-AE) were monitored. Results: 254 pts entered the OL (mean baseline and SD values: age 74.2±7.3 years, MMSE 18.9±3.9, ADAS-cog 24.7±9.3). Responders were 80 % of the 176 pts who completed the OL (and 55 % of pts who entered the study). In the DB, 139 pts were randomized to GAL (76) or PBO (63); 36 (47 %) and 20 (32 %) completed the DB phase up to 24 months with GAL or PBO, respectively. Median time to deterioration was significantly longer in the GAL group (days ± SE = 726±16- vs. 552 days – SE ±83 in PBO; p < 0.05). Half of the pts experienced at least one AE in OL (most common AE: agitation, nausea and vomiting, > 5 %) and 15 % discontinued treatment due to AE. In DB, 34 % and 27 % of pts experienced at least one AE in GAL and PBO groups, respectively. At least a SAE was experienced by 15 % and 6 % of pts in GAL and PBO respectively. Discontinuations due to AE (any AE) occurred in 11 % and 6 % of GAL- and PBO-treated pts, respectively. Globally, 7 pts died in DB (5 in GAL, 2 in PBO); none of the precipitative AE was unexpected in elderly pts and related to study drug. No clinically relevant changes in laboratory or ECG tests were observed. Conclusion: This study supports the LT use of GAL as effective in delaying time to cognitive deterioration in patients with mild to moderate AD. Funded by Janssen-Cilag SpA.

Changes in the cerebral white matter are detected by CT and MRI (rarefaction of the periventricular white matter and isolated lacunar infarction) in aged people. The pathogenesis of these lesions is still uncertain, but a particular cerebral vasomotor reactivity and a hypoxic cause have been suggested. Leukoaraiosis is variable associated with cognitive impairment, motor dysfunctions and gait disturbances. But these patients have a poor prognosis in terms of death (myocardial infarction and stroke) and leukoaraiosis may be a strong predictor of dementia in stroke patients. Objective: we try to make a correlation between extension of leukoaraiosis and cardiac performance criteria (parameters). Methods: we determined systolic (ejection fraction) and diastolic function (trans-mitral diastolic flux) in 53 patients with leukoaraiosis. For diagnosis we use: neurological examination, neuropsychological tests, ultrasonographic examination, and MRI examination (T 2 weighted scans). Results: a strong association was found between impaired systolic and diastolic function and periventricular white matter lesions. No association was found between presence of leukoaraiosis and carotido-vertebral stenosis. Conclusions: our data confirm the importance of cardiac pump for this sensitive hemodynamic region in central nervous system which is periventricular white matter. P587 Diagnostic value of 14-3-3 and tau proteins in cerebrospinal fluid of patients with rapidly progressive dementia A. Russo, E. Farina, R. Nemni IRCCS S. Maria Nascente-Don Gnocchi (Milan, IT) Objectives: Our objective is underlining the importance of cerebrospinal fluid (CSF) analysis for differential diagnosis in rapidly progressive dementias; this is often fundamental for therapeutic aims. Methods: We will describe two clinical cases of dementia recently diagnosed in our Centre. The first patient was a 74 years old woman with mute anamnesis; rapidly progressive dementia began two months before clinical observation with hallucinations, insomnia and prosopoagnosia for relatives. At neurological examination, she exhibited marked cognitive deterioration (Mini Mental State Examination-MMSE = 14/30) with minimal pyramidal and cerebellar signs; Magnetic Resonance Imaging showed diffuse cerebral cortical and subcortical atrophy. The second patient was a 73 years old man, with a history of slight ongoing memory deficits with preserved Activities of Daily Life, rapidly worsening in the last eight months after an episode of loss of conscience due to acute anemia. At neurological examination, he presented clear dementia with fluent aphasia (MMSE = 15/30), apathy and slight reflex asymmetry. Computed Tomography scan showed cerebral cortical and subcortical atrophy. Results: At CSF analysis, for the first patient 14-3-3 protein research was negative and tau protein was faintly increased; a diagnosis of possible Lewy Body Dementia (LBD) was formulated and she started therapy with rivastigmine and quetiapine: cognitive status stabilized and behavioural disturbances improved. In the second patient 14-3-3 protein research was very weakly positive, while tau was drastically augmented(more than triplicated in comparison to normal range); diagnosis of possible Alzheimer’s Disease was put, he started therapy with donepezil, improving his performance at MMSE (17/30 at the last clinical examination), and could also begin Cognitive Stimulation Therapy. Conclusion: Many authors have described the use of CSF biomarkers in differential diagnosis of dementia: almost all patients with sporadic Creutzfeldt-Jacob Dementia (CJD) show clear positivity to 14-3-3 protein and marked increase of total tau (t-tau) protein (usually more than 1000–1500 pg/ml), while in degenerative dementias 14-3-3 protein is usually negative and t-tau is less increased than in CJD. A slight positivity for 14-3-

P588 Long-term treatment with galantamine in Alzheimer’s disease: GAL-ITA 2, an Italian, multicentre, randomised, double-blind, placebo-controlled trial E. Scarpini, I. Guidi, G. Zappalà, V. Carrera, R. Cotrufo, G. Bruno on behalf of GAL-ITA 2 Study Group

P589 Claudin 11 in Alzheimer’s disease and vascular dementia M. O. Romanitan, B. Winblad, O. A. Bajenaru, N. Bogdanovic Emergency University Hospital (Bucharest, RO); Karolinska Institute (Stockholm, SE) Objectives: The tight junctions (TJs) are the intercellular junctions responsible for barrier and fence function of the blood brain barrier and for maintaining the cell polarity. TJs contain integral membrane proteins: occludin, claudins and junctional associated molecules. Claudin-11 is expressed in the TJs of central myelin sheaths and Sertoli cells in testis.This oligodendrocytespecific protein (OSP), as it is also called, may be important in the formation and maintenance of myelin and may also play a role in regulating proliferation of oligodendrocytes and Schwann cells. The aim of this study is to analyze the morphological features of the neurons, glial cells and vessels endothelial cells in Alzheimer’s disease (AD) and Vascular Dementia (VD). Methods: The brain material was obtained from the Huddinge Brain Bank, Stockholm. One region of interest was chosen where specific anatomical and hemodynamic conditions are noted: cerebral frontal cortex (Brodmann area 46/9). The study was based on 19 cases: 5 ageing control, 4 AD and 6 VD post-mortem human brains. Immunostaining with rabbit polyclonal antibody against claudin 11 from Zymed Laboratories (dilution 1:200) was performed on paraformaldehyde-fixed embedded sections (ultrathin sections of 7 m) followed by quantitative approach using stereological principles. The neurons, astrocytes and oligodendrocytes were quantified. The stained vessels were appreciated only qualitatively. Results: Our first observation was OSP expression by neurons, glial cells and vessels. The stained neurons were predominantly pyramidal and the predominant stained type of glial cells was astrocytes. The vessel endothe-

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lium was stained both in white matter and gray matter, as well. In AD and VD groups the percent of OSP stained neurons was 70 % compared to control group (25 %), the percent of stained oligodendrocytes was 45 % and respectively 22 % compared to control group (18 %) and the percent of stained astroglia was 50 % in both diseases compared to control (22 %). Conclusion: OSP is present in neurons, neuroglia and vessels and it is upregulated in AD and VD frontal region in specific cellular and regional manner. Its expression in the arteries may differ between VD and AD. The different expression of Claudin 11 in these pathological conditions may lead towards the understanding of the involved mechanisms providing at the same time ideas for new biomarkers useful to diagnose easier either AD or VD. P590 Evaluation of brain damage of sporadic Creutzfeldt-Jakob disease by magnetic resonance diffusion tensor imaging H. Kishida, K. Kimura, T. Nishiyama, S. Koyano, H. Toda, Y. Kuroiwa Yokohama City University (Yokohama, JP) Objectives: Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. MR diffusion-weighted imaging (MR-DWI) is an indispensable method to diagnose CJD. We newly examined MR diffusion tensor imaging (MR-DTI), which is a new technique to visualize and evaluate the cerebral white matter, for diagnosis in the early stage of CJD. Quantitative diffusion indices such as fractional anisotropy (FA) have been used for the evaluation of normal appearing white matter in multiple sclerosis, schizophrenia and amyotrophic lateral sclerosis. Methods: Brain MRI was performed in 6 patients with sporadic CJD (sCJD) using diffusion tensor imaging and results were compared with those of normal controls.All patients (65 y, range 55–80 y) were diagnosed as probable CJD at Yokohama City University Hospital. Two patients initially had visual disturbance (Heidenhain variant of CJD). All patients were akinetic mutism state with myoclonus when MR-DTIs were performed. All tested cases were homozygous for methionine at codon 129 of the prion protein gene and had no mutation. These results were obtained by using the free software dTV for DTI analysis developed by Image Computing and Analysis Laboratory, Department of Radiology, The University of Tokyo Hospital, Japan. The software dTV is available via following URL. http://www.ut-radiology.umin.jp/people/masutani/dTV.htm. The regions of interest (ROIs) were placed on internal capsule (IC), corpus callosum (CC) and optic radiation (OR), and FA values within the ROI were calculated. Results: The mean FA value of the ROIs at IC and CC in the sCJD patients was significantly lower than that of controls. FA values at OR in two Heidenhain variants wewe lower than that of others. When FA value was examined in same ROI with the same patient after one month,it decreased significantly though the MR-DWI intensity of the same ROI did not have a change. Discussion and Conclusion: We reported MR-DTI of sCJD patients for the first time. The decrease of the mean FA values is thought to evaluate the degeneration of white matter. MR-DTI may be useful for a diagnosis for atypical CJD (for example, MM 2 thalamic form etc.) and evaluation of brain degeneration. P591 Myelin basic protein and cognitive impairment in patients with systemic lupus erythematosus and systemic scleroderma M. Dzhurko, N. Spirin, N. Pizova, I. Tzelinskaya, I. Marusina Kostroma City Hospital #1 (Kostroma region, RU); Yaroslavl State Medical Academy (Yaroslavl, RU) Background: The affection of central nervous system is one of significant signs in systemic lupus erythematosus (SLE) and systemic scleroderma (SS) and it often entails cognitive impairment. Objective: to investigate the level of myelin basic protein in SLE and SS and trace its connections to the neuropsychological data. Methods: We have examined 79 women (56 with SLE and 23 with SS). Mean age was 38 years. The level of myelin basic protein (MBP) in blood was determined by the immuno-enzyme technique “DSL-10–5800 Active MBP Elisa” in 32 patients (18 with SLE, 14 with SS). For cognitive inspection we have used Shulte’s tables, Benton’s test, Burdon’s editing test, Rybakov’s test and 10 words memory test. Results: Cognitive impairment was found in 73 % of SS patients and 87.5 % of SLE patients. It was displayed as non-specific memory and attention loss, decrease of its volume and efficiency. The mean level of MBP was 3.28±4.95 ng/ml (the normal value 0 °C 4 ng/ml): in SLE 4.67±5.54 ng/ml, in SS 1.99±4.09 ng/ml. There was a positive correlation between the high level of MBP and low attention, high MBP and high clinical damage index in SLE

(r = 0.6; p = 0.01 and r = 0.5; p = 0.006). The level of MBP was also connected with the activity of the disease (r = 0.51; p = 0.04). In SS the level of MBP was closely connected to the intensity of pyramidal signs (r = 0.58; p = 0.03) and vasospastic syndrome (r = 0.61, p = 0.02). Conclusions: The CNS involvement and cognitive impairment are common signs in SLE and SS patients. The intensity of neurological damage and cognitive disturbance is connected with the level of MBP. That is why it is important to determine MBP as the biomarker of CNS damage in SLE and SS. P592 Neuropsychological patterns and markers of DAT in patients with MCI of vascular or degenerative aetiology G. Gainotti, M. Ferraccioli, M. G. Vita, C. Marra Neuropsychology Unit (Rome, IT) Objectives: The aim of our study consisted in studying if neuropsychological patterns and markers of Alzheimer’s disease (AD) are different in patients with mild cognitive impairment (MCI) considered as affected by a vascular or degenerative brain pathology, on the basis of clinical and MRI criteria. Methods: An extensive neuropsychological battery, comprising the MMSE and various tests of anterograde episodic verbal and visual-spatial memory, short-term memory, visual-spatial and executive functions, language, attention, praxis and psychomotor speed were administered to 39 patients classified as vascular and 40 as degenerative forms of MCI and to 65 age- and education-matched normal controls (NC). Scores obtained in the various tests and on ‘neuropsychological markers’ of AD provided of high diagnostic value (Gainotti et al., 1998) were used to evaluate if vascular and degenerative forms of MCI can be distinguished on the basis of neuropsychological criteria Results: Both groups of MCI were very mildly impaired, obtaining only slightly abnormal scores at the MMSE.. In the comparison between degenerative and vascular forms of MCI, the former were significantly more impaired on episodic memory tasks (delayed recall and delayed recognition of the Rey’15 words) and tended to obtain a lower primacy effect in the same task. The latter showed a non-significan trend to be slower on attentional or executive tasks and to be more impaired on a phonemic fluency test. Conclusions: Our results confirm that anterograde episodic memory is selectively affected since the earliest stages of AD, whereas psychomotor speed is an early characteric aspect of subcortical vascular dementia. Reference Gainotti G. et al (1998) Sensitivity and specificity of some neuropsychological markers of Alzheimer’s dementia. Alzheimer dis Assoc Disord 12:152–162 P593 Clock drawing test: new simplified scoring system M. Rakusa, A. Kogoj Teaching Hospital Maribor (Maribor, SI); University Psychiatric Hospital (Ljubljana, SI) The goal of our study was to simplify scoring system of Clock Drawing Test (CDT), as to make it a screening tool in GP offices for dementia, and comparable in sensitivity (SE) and specificity (SP) to more widely used MiniMental State Examination (MMSE).A total of 115 volunteers were examined. On the basis of clinical evaluation of a psychiatrist, volunteers were grouped either as healthy, mild cognitive impairment (MCI) (n = 21) or Alzheimer’s demented (AD) (n = 55). On CDT 4 point could be obtained, 1 for each of the following: number 12 correct position; numbers 3, 6, 9 symmetrical; each hand in correct position showing 11:10. On the MMSE mean scores were: healthy subjects 28.05; MCI 24.93; AD 18.80. Results of both tests in our patients show good correlation (0.632; p < 0.001), which implies that both test are complemental. CDT test correlates well with the diagnosis of MCI (–0.62; p < 0.001) and AD (–0.78; p < 0.001). Cut-off score between healthy and demented persons was set to 3 out of 4 points.At that value SE 67 % and SP 90 % for MCI and SE 89 % and SP 90 % for AD were calculated.With the use of CDT and MMSE (cut-off 25/26 points), we could improve recognition of MCI (SE 93 %, SP 79 %) and AD (SE 98 %, SP 79 %). The results suggest that in Slovenian demented patients CDT score is comparable to more elaborate CDT scoring systems and MMSE. Test can be accomplished in less than 2 minutes and can be used as a tool for substantiating clinical suspicion of dementia.

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P594 Familial and sporadic Alzheimer’s disease: a cognitive comparison F. Buttari, M. Gasparini, G. Talarico, M. Canevelli, E. Salati, G. Tosto, E. Piacentini, G. L. Lenzi, G. Bruno La Sapienza University (Rome, IT) Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a high prevalence in the general population.A genetic transmission has been demonstrated only for less than 5 % of all AD cases: in some families there is an autosomal pattern of inheritance, in others a simple familial aggregation without a mendelian pattern of inheritance. Over the past decade several studies have been conducted to identify clinical, cognitive and neuropathological differences between Familial (FAD) and Sporadic (SAD) Alzheimer’s Disease. The aim of our study is to compare a group of mild FAD patients with a group of mild SAD patients both for cognitive and behavioural variables. Methods: We selected 18 patients (6 males and 12 females) with FAD and 25 patients (12 males and 13 females) with SAD matched for age (range 47–79), educational level (4–17 yrs), age of onset (45–77), illness duration (1–6 yrs.) and MMSE scores (19–28). All patients met the NINCDS-ARDRA criteria for probable AD. FAD was defined by using the presence of 3 patients affected in two generations with a pattern of transmission > 40 % while the criterion for SAD was a negative history of AD in two generations. All patients underwent a neuropsychological evaluation exploring memory, language, executive and visuo-spatial functions. Moreover the two groups were compared for MMSE, everyday living activities (ADL, IADL) and neuropsychiatric (NPI) scores. Statistical analysis was performed by using the Student t-test for continuous variables (neuropsychological tests) and the MannWhitney test for discrete values (no. of perseverations) Results: Student t-test did not show any difference between the two groups neither in cognition nor in behavioural symptoms. On the MannWhitney test a significant, higher number of perseverations emerged in FAD patients (p = 0.003); a post-hoc analysis showed an Odd Ratio estimate of 5. for the FAD group (C. I. 95 %; OR 1.29–19.3) on the Mantel-Haenszel test Conclusions: our study indicates that FAD and SAD patients are not distinguishable on the basis of cognitive performances; on the other hand we suggest that subtle differences could emerge in cognition when a qualitative approach is devised for the evaluation of neuropsychological performances. P595 Antiparkinsonian treatment and behavioural disturbances Y. Higueras, D. Mateo, S. Giménez-Roldán HGU Gregorio Marañón (Madrid, ES) Objective: description of conductual disturbances related with misregulation of antiparkinsonian treatment. Methods: two patients that developed conductual alterations were selected to make a complete neuropsychological assessment with special interest in executive function. this protocol included verbal memory test (Spanish version of California Learning Verbal Test), Trail Making Test, ReyOsterrieth Complex Figure Test, Direct and inverse Digits from Wechsler Memory Scale, Stroop test and verbal fluency test. Results: neuropsychological profile in both patients were typical in a parkinsonian subject. Patient DS was a long evolution Parkinson disease patient and he developed a zoophilic behavior and hypersexuality after pergolide treatment. The second patient JP developed a compulsive slot machine use that remitted when pergolide were washed out. Both cases were compulsive behavior, patients were conscious of that wrong behavior but they could not stop. After a wash out period, both symptoms disappeared. Conclusions: We propose that this kind of behavioral disturbances may be caused by three possible causes together: fontal liberation pattern, monoaminergic misregulation and neuropsychological dysfunction. It is important to know that some medical treatments can cause behavioral disturbances because of missregulation of neurotransmitter function and that this alteration is reversible. We review the literature and comment outcomes of other authors in this field.

P596 Human adult mesenchymal stem cell neuroprotective potential to support neurons’ survival V. Silani, M. Armentero, E. Zennaro, G. Levandis, C. Calzarossa, P. Bossolasco, M. Mellone, L. Cova, D. Soligo, G. Lambertenghi Deliliers, E. Polli, F. Blandini University of Milan (Milan, IT); IRCCS C. Mondino Neurological Institute (Pavia, IT); Fondazione Matarelli (Milan, IT); Maggiore Hospital University of Milan (Milan, IT) Objectives: The purpose of the study was to evaluate adult human mesenchymal stem cells (hMSC) potential to support neurons survival after unilateral intrastriatal 6-hydroxydopamine-induced (6-OHDA) lesion in rats, which causes progressive and retrograde degeneration of the nigrostriatal pathway. Methods: Commercial hMSCs were expanded and characterized for the expression of stem (as nestin, CD 133) and neuro-glial (i. e. GFAP and NFM) genes (by RT-PCR) or proteins (by immunochemistry) while neurotrophin production was quantified by ELISA kits. In addition, we tested the hMSCs resistance to acute or chronic exposition to 6-OHDA (50 and 320 μM). We subsequently characterized the co-cultures of stromal and neural progenitors (NPs) in response to 6-OHDA toxicity. Several parameters, such as cellular morphology, viability (through Ki67 staining), and apoptosis (by TUNEL analysis) were analyzed. Thereafter male Sprague Dawley rats received a stereotaxic injection of 6-OHDA in the right striatum and, 5 days later, a Hoechst 33 258 labelled hMSCs implant (32.000 or 180.000 cells) in the same region with immunosuppression. Animals were tested for behavioural response to systemic injection of apomorphine and sacrificed 28 days after lesion. Immunochemical stainings defined the proliferation state of endogenous or transplanted cells (Ki67/tyrosine hydroxylase), the host astroglial/microglial response (GFAP/CD 11) and the endogenous neurogenesis activation. Results: In vitro hMSCs characterization revealed stromal specific markers presence in conjunction with a reduced percentage of neuro-glial antigens and no detectable expression of dopaminergic proteins. 6-OHDA treatment was ineffective on hMSCs biology while we identified a clear neuroprotective effect exerted by hMSCs on NPs after the toxin insult. hMSCs, in vivo, persisted along the lesion, induced a significant dose-dependent behaviour improvement and, in addition, endogenous/hMSCs proliferation was concentrated around the injection site where reactive astrogliosis and microglial activation were stably maintained. A clear enhancement of host neurogenesis was observed in relation to the transplanted hMSCs. Conclusion: hMSCs protect NPs from 6-OHDA insult in vitro, can be maintained and stably integrated in 6-OHDA treated striatum in vivo with an active role on endogenous neurogenesis. Our results demonstrate hMSCs homing capability, their neuroprotective action and sustain their use in Parkinson’s therapy. P597 Creutzfeldt-Jakob disease in a hospital in Madrid, 1976–2004 M. Valentí Soler, E. García Fernández, F. J. Arpa Gutiérrez, M. Gutiérrez Molina, C. Morales Bastos, A. Frank García Hospital Universitario La Paz (Madrid, ES) Objective: To analyze the clinical and neuropathological characteristics and the trends in incidence rates of definite Creutzfeldt-Jakob disease (C-J) diagnosed in our hospital population of around 800.000 inhabitants from 1976 to 2004. Methods: We searched through the files of the department of Pathology cases of C-J confirmed by biopsy or autopsy, and then we undertook a detailed clinico-pathological analysis. Results: 23 patients (13 women and 10 men, with a median age of 63 years) at onset had a quickly progressive dementia (52.2 %), cerebellar symptoms (21.7 %), vascular-like symptoms (8.7 %), and extrapyramidal signs (65.2 %). During the course of the disease the patients presented dementia (87 %), myoclonias (87 %), cerebellar ataxia (82.6 %), extrapyramidal signs (65.2 %), neuropsychiatric symptoms (65.2 %), dystonia (43.5 %), pyramidal signs (39.4 %), and ocular movements/visual alterations (26.1 %), death happened after 5 months (1–18 months). MRI showed hypersignal in the caudate nucleus and putamen in 22.2 % (2 patients of 9 studied). EEG typical pattern was seen in 76.2 % (21 patients studied). Protein 14-3-3 was positive in cerebrospinal fluid of 3 patients (5 studied). 2 familial cases were confirmed by genetical analysis, the rest were sporadic. Neuropathological study revealed: cerebral cortical atrophy in 60 %, caudate head atrophy 7 %; spongiform change in cerebral cortex in every case, 70 % in striatum and 65 % in cerebellar cortex. Accumulated incidence of confirmed cases: 1.58/1.000.000 inhabitants/year. Conclusions: In our serie the clinical and neuropathological features of C-J were similar to those described in the international literature but the ac-

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cumulated incidence is higher.We think that the fact that autopsies were performed along those years despite concern about possible transmission accounts for this increased incidence.

P598 Dementia with Lewy bodies: an individual entity or a link between Parkinson’s disease with dementia and Alzheimer’s disease? A neuropsychological study F. Baglio, E. Farina, F. Mantovani, F. Olivotto, M. Alberoni, R. Nemni Don C. Gnocchi Foundation, Neurorehabilitation Unit, University of Milan (Milano, IT) Objective: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are now believed to represent a disease spectrum characterized clinically by a variable admixture of cognitive, neuropsychiatric and extrapiramidal features. However, clinical differentiation of DLB and Alzheimer’s disease (AD) is sometimes difficult.Aim of this study was to delineate a distinct cognitive profile among DLB, AD and PDD. Methods: 22 patients clinically diagnosed with DLB (McKeith, 1996–2005), 20 with AD (NINCDS-ADRDA) and 17 with PDD were recruited. Patients were matched for age, education and MMSE. The neuropsychological assessment included: Token Test, forward and backward digit span test, Dual Task, phonemic and categorical fluency test, figure classification and recall test (Incisa della Rocchetta,1986), fragmented letter subtests from the Visual Object Space and Perception battery, visuoperceptual tasks (Mori et al,2000) and a test of constructional praxis ability. Moreover, visual attention, response inhibition and visuospatial abilities were evaluated with computerized tests in subgroup of patients. Results: The comparison (ANOVA) between the three groups showed significant differences only in the performance of tests exploring frontal and memory functions. PDD patients performed significantly worse on executive function (Incisa number categories p = 0.006) and better on memory ability (Incisa immediate recall p = 0.044 delayed recall p = 0.031) than AD. Furthermore, DLB showed lower scores than PDD subjects on memory tests (Incisa immediate and delayed recall p = 0.05). No significant differences were found between AD and DLB on any neuropsychological test. Group analysis of computerized tests is actually in process. Conclusion: According with our study, PDD and AD show a clear different neuropsychological pattern (PPD exhibits a “frontosubcortical” pattern, in contrast with the “cortical” profile of AD) whereas DLB patients are not significantly different from AD, and do not show the same profile than PDD. This result could be related to neuropathological data, which reported, in many DLB post-mortem examination cases, an overlapping of cortical neuropathological findings between DLB and AD (AD/DLB variant). So, there is reason to believe that DLB may be considered a link between PDD and AD and that just neuropsychological profile, without clinical data, does not seem to be able to differentiate DLB from AD.

P599 No correlation of dementia and depression evaluation scores in post-stroke mixed dementia patients B. O. Popescu, O. Bajenaru, E. G. Manga, D. F. Muresanu University Hospital Bucharest (Bucharest, RO); ‘Iuliu Hatieganu’ University of Medicine and Pharmacy (Cluj-Napoca, RO) Objectives: To search correlations between cognitive impairment and depression in post-stroke patients with history of cognitive decline. Methods: 18 patients hospitalized for ischemic stroke and with history of progressive cognitive decline were evaluated. Brain CT demonstrated in all cases both hippocampal atrophy and vascular lesions. None of the patients had aphasia as a symptom of the current stroke or positive history for a previous stroke. The patients were evaluated in days 3–5 after onset of stroke symptoms by MMSE, ADAS-cog, dementia Blessed scale, Hamilton depression scale and ischemic Hachinski score. The statistical analysis of the data was done using SPSS 12.0 statistical software. Results: Sexual distribution was even (9 females, 9 males). Age was 72.7 ± 9.0 years (between 53 and 84 years). Identified vascular risk factors were hypertension (55 % of cases), diabetus mellitus (50 % of cases), dyslipidemia (44 % of cases) and smoking (38 % of cases). Cardiovascular comorbidities were frequent: ischemic heart disease was present in 44 % of cases, atrial fibrillation in 22 % of cases. Average MMSE score was 15.3 ± 5.6 (between 6 and 26).We found no correlation between the MMSE score and the age of the patients, ADAS-cog score or dementia Blessed scale. As classified by ischemic Hachinski score, vascular dementia cases were associated with a lower MMSE score and to more severe depression as evaluated on Hamilton scale as compared to

mixed dementia cases. No correlation between MMSE score or ADAS-cog score and Hamilton scale score was found. Conclusions: Both cognitive decline and depression are frequent in poststroke patients. In our pilot-study no correlation was found between cognition and depression evaluation scores, probably due to the limited number of patients analyzed. However, interference of depression with cognitive testing and evaluation of depressive states in demented people are still matters difficult to sort out.

P600 Clinical and epidemiological data of Creutzfeldt-Jakob disease in Greece C. Kilidireas, P. Davaki, E. Patsouris, D. Vassilopoulos University of Athens (Athens, GR) Objective: Surveillance of Creutzfeldt Jacob disease in Greece. Methods: Data collection from referral cases for 14-3-3 test and Hospital Notification. Use of Clinical Neuropathological, EEG, 14-3-3 test for diagnostic procedure (Euro CJD criteria). Results: Eighty two CJD (43 definitive and 39 probable cases) cases were diagnosed in Greece during the decade 1997–2006, all of them sporadic and the mean incidence rate is 0.71 per million. Autopsy study in 53.7 % of total cases. The age of onset range from 31 to 88 years old with a mean of 63.The majority of the patients are in the 60–80 years old but there were 4 cases in the decade of forties. The 14-3-3 test was performed in 69 cases, positive in 68 (98.5 %). The test was initially negative in 9 cases (four definite and five probable) and became positive within three months. The test seems superior to the diagnosis than EEG or MRI. The 31.03 % of the cases presented a pure cerebellar onset of the disease and the 38 % of the patients presented rapidly progressive dementia as symptom of onset. In conclusion, CJD is a rare disease and seems to have an unusual high percentage 31 % of the cerebellar type in the Greek population.

P601 Cognitive impairment in spinocerebellar ataxia type 2 J. Masopust, A. Urban, Z. Rihova, M. Valisˇ, E. Urbanova, A. Zumrova University Hospital (Hradec Kralove, CZ); University Hospital (Prague, CZ) Objective: Patients with SCA 2 may develop poor memory, concentration problems, impairments of conceptual reasoning, and executive dysfunction, as well as emotional changes. Methods: We performed psychiatric, neuropsychological and functional neuroimaging examinations in eight SCA 2 patients. Results: We established psychiatric diagnosis in seven patients with SCA 2. In most cases we diagnosed mild cognitive impairment, organic affective disorder and organic personality disorder. Neuropsychological assessment identified the impairment of executive functions. Patients often failed cognitive tasks linked to prefrontal cortex. This findings correlated with results of SPECT. The examination by SPECT detected decreased rCBF in the cerebellum in seven patients. Six of seven these patients had low rCBF in the left frontal cortex by visual assessment. Discusion and conclusions: Cognitive impairment in patients with SCA 2 was particularly found in executive functions and attention. SPECT hypoperfusion was detected in left frontal areas, in addition to cerebellum, in most patients. These preliminary data support the notion that cerebellum is also associated with cognitive information processing and behavior. The work was supported by research support funding: VZ MSM 002 160 816 and MZO 0064203–6505.

Muscle disorders P602 Mitochondrial cytopathy uncovered by metformin therapy G. O’Connor, F. Molloy, M. Farrell, O. Hardiman Beaumont Hospital (Dublin, IE) Objective: To describe an unusual mitochondrial cytopathy presenting with metformin-induced type II respiratory failure. Background: A 35 year old female was referred to Neurology with recent onset type II respiratory failure. There was a past history of polycystic ovarian disease which had been treated with metformin. Family history revealed a brother with bilateral ptosis, and a son with mild learning disability.

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Results: Neurologic examination revealed mild bilateral ptosis. There was marked exertional dyspnoea and orthopnoea. Sniff nasal insipiratory pressure was reduced to 40cm H 2O, (N> 85cmH 2O) and vital capacity to 40 % of predicted. Quantitative muscle testing revealed diffuse muscle weakness throughout (< 10th percentile for age and sex). A detailed neurophysiologic examination revealed normal EMG with mild decrement on repetitive stimulation. Muscle biopsy revealed mild fiber type variation.Acetyl choline receptor antibody titers were negative. Serum lactate in repose was markedly elevated 5.5mMol/l (normal < 2mMol/l), and there was a mild metabolic acidosis. Mitochondrial DNA analysis revealed a common deletion in both blood and muscle. Metformin was discontinued, and the patient made a rapid recovery. Review 4 weeks following discontinuation of metformin revealed normalization of both respiratory function and lactate levels, and improvement in general muscle strength. Quantitative muscle testing performed 6 months later revealed normal strength throughout. Conclusions/Relevance: Metformin, a biguanide, is a mild inhibitor of complex I of the mitochondrial respiratory chain. Treatment with metformin can induce reversible lactic acidosis and type II respiratory failure in patients with subclinical mitochondrial dysfunction. P603 Isolated dropped head in a case of MuSK-positive myasthenia gravis with thymus hyperplasia K. Spengos, S. Vassilopoulou, G. Papadimas, A. Tsivgoulis, G. Tsivgoulis, P. Manta University of Athens (Athens, GR) Background: Most of AchR-Ab negative myasthenia gravis (MG) patients present MuSK-Ab. It was believed that MuSK positive MG is a severe disease, usually involving bulbar and respiratory muscles. However recent studies reported cases with a more benign course. In terms of thymic histology it was showed that MuSK-Ab positive MG is distinguished from AchR-Ab positive and MuSK-Ab negative MG through its lack of germinal centers or lymphocytic infiltrates. We report the unusual case of a MuSK-Ab positive myasthenic patient who presented with isolated weakness of neck extensor muscles in the presence of thymic hyperplasia. Case report: We present a 46-year-old woman with a 4-year history of progressively worsening weakness of the neck extensors (MRC grade 3/5) with a vague sense of fatigability around the shoulders and no involvement of ocular, shoulder girdle and upper limbs’ muscles. No muscle atrophy was found. The Tensilon test was positive. No AchR-Antibodies were detected, whereas elevated MuSK-Ab titers were found twice. Repetitive nerve stimulation revealed a significant decrement of the CMAP in both trapezius and deltoid muscles (> 15 %). SFEMG of the splenoid muscles showed a markedly increased jitter with blocking; whereas in the extensor digitorum communis muscle it was normal. Needle EMG revealed a combination of neurogenic and myopathic changes in the splenoid and C 7 innervated paravertebral muscles, whereas examination of other muscles on both upper and lower limbs revealed no abnormalities. Based on all these findings the diagnosis of MuSK-Ab positive MG was established. Oral pyridostigmine led to a remarkable improvement. However, symptom remission was achieved after prednisone was added. Further workup additionally revealed thymic hyperplasia. Thymectomy was then performed. Histological evaluation of the excised thymus revealed focal nodular hyperplasia. Three months after surgery the patient was asymptomatic. Conclusion: The present case underlines the heterogeneity of seronegative myasthenia gravis with anti-MuSK antibodies concerning the clinical features, the severity of the disease course, the laboratory findings as well as the therapeutic strategy and management. It should also be included in the differential diagnosis of dropped head syndrome. P604 Isolated persistent hyper-CK-emia V. Zouvelou, C. Chrysovitsanou, P. Kokotis, G. Terzis, C. Kontou, P. Manta University of Athens (Athens, GR) Objective: Elevated serum creatine kinase (CK) activity may be associated with many conditions, such as use of certain drugs, exercise, muscle trauma, malignancy, electrolyte and endocrine disorders. It may also be the early or the single manifestation of a neuromuscular disease or it may be idiopathic (“idiopathic hyper-CK-emia’’). Little is known about the clinical course and the prognosis of patients with “idiopathic” hyper-CK-emia. Methods: We report the early results of a prospective study of 34 patients

(32 males and 2 females) with persistent hyper-CK-emia, with no muscle weakness or other conditions associated with hyper-CK-emia. Subjects underwent neurological and cardiac evaluation, thorough laboratory investigation, electrodiagnostic testing (needle electromyography, nerve conduction studies) and muscle biopsy with histological, histochemical and immunohistochemical studies. Biochemical analysis and genetic testing were added when indicated. Results: The mean age at referral was 40.0 years and the mean CK level was 1310.26 U/L. Sixteen subjects had CK > 1000U/L and eighteen subjects had CK< 1000U/L. Mean duration of hyper-CK-emia prior to evaluation was 2.5 years. Hyper-CK-emia was detected incidentally during routine health assessment in 27 patients (79.4 %). Seventeen patients were totally asymptomatic, while the rest were minimally symptomatic (muscle-related symptoms emerging when clinical history was taken). Muscle biopsy findings were abnormal (including mild non-specific changes) in 26 subjects (78.8 %) and consistent with definite histopathologic diagnosis in 10 of them. There was no association of CK activity with either symptoms or muscle biopsy abnormalities. On the whole, definite or probable diagnosis of a neuromuscular disease was made in thirteen patients (35.3 %): 4 Mc Ardle disease, 2 Kennedy’s disease, 1 dystrophinopathy, 1 carrier of dystrophinopathy, 1 macrophagic myofascitis, 1 necrotizing myopathy, 1 congenital myotonia, 1 mitochondrial myopathy and 1 caveolin deficiency. Conclusion: Muscle biopsy is essential in diagnostic evaluation; otherwise the diagnosis of “idiopathic” hyper-CK-emia remains uncertain. It is also the unique tool, along with genetic testing to possibly achieve a diagnosis. Establishment of diagnosis has implications for normal daily life, long term prognosis and genetic counseling. P605 Pharmacokinetics, safety, and tolerability of idebenone in healthy adult men K. Kutz, P. Vankan AccelPharm (Basel, CH); Santhera Pharmaceuticals (Liestal, CH) Objectives: To determine the pharmacokinetics (PK) of idebenone, to evaluate the effect of food on the PK of idebenone, and to assess the safety and tolerability of idebenone. Methods: Four single-center, open label, clinical studies were conducted (Studies I, II, III, IV). Each study enrolled healthy men aged 18 to 45 years. Subjects received either single oral doses of idebenone 150 mg, 750 mg, or 1050 mg under fasted or fed conditions (Studies I, II, III), or multiple oral doses at 150 mg tid or 750 mg tid for 14 days (Study IV). Plasma concentrations of pharmacologically active parent idebenone and its metabolites were measured to determine PK. Safety assessments included adverse event (AE) monitoring, physical exams, vital signs, electrocardiograms (ECGs), haematology, serum chemistry, and urinalysis. Results: A total of 69 subjects enrolled in the 4 studies (Study I, n = 8; Study II, n = 8; Study III, n = 28; Study IV, n = 25). One subject withdrew from Study IV due to an adverse event (hypertension). There was high inter-subject variability in idebenone PK. Maximum plasma concentrations (Cmax) of unchanged idebenone increased in a dose-dependent manner, ranging from 1.64 ± 0.99 ng/mL (single 150 mg dose) to 10.23 ± 8.40 ng/mL (single 1050 mg dose). There was no accumulation of idebenone when dosed for 14 days at 750 mg tid. Absorption was moderately quick; time to Cmax (tmax) was 3.5 h after a single dose, and decreased to 0.67 h after repeated dosing. Systemic bioavailability of parent idebenone increased approximately 4-fold when administered with a fat-rich meal. Idebenone metabolites appeared in the plasma nearly synchronously with unchanged idebenone, indicating a high first-pass effect. Most idebenone (65 %) was excreted in the urine as conjugated metabolites after side chain reduction. A total of 4 AEs occurred during Studies I, II, and III; all were mild in severity. There was a higher incidence of AEs in Study IV; the most common were chromaturia (n = 6, all in the 750 mg tid group), headache (n = 9), fatigue (n = 9), and gastrointestinal disorders (n = 11). No subjects withdrew from the study as a result of these events. There were no serious AEs and no clinically relevant changes in physical exams, vital signs, ECGs, or laboratory values in any study. Conclusions: Idebenone exhibits linear PK over a range of 150–2250 mg/day. The relative bioavailability of idebenone increases after a meal. Idebenone is generally safe and well tolerated in healthy adult men. This study was funded by Santhera Pharmaceuticals.

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P606 Acute tetraparesis caused by oxandrolone consumption I. Adelt St. Marien-Hospital (Lunen, DE) We report the case of a 38 year old man who noticed acute tetraparesis, tachycardia after climbing 24 stairs. The cranial nerve examination was unremarkable. Investigation of the patient revealed flaccid tetraparesis with diminished tendon reflexes, however, cranial muscles were not affected. These findings were consistent with hypopotassemic periodic paralysis. Serum potassium was determined as 2,2mmol /l. Thyrotoxicosis and Hypokalemic thyrotoxic periodic paralysis (HTPP) were not found.The cranial and cervical spine magnetic resonance imaging (MRI) with Gadolinium showed normal. Background: Differential diagnosis of acute tetraparesis includes paraplegia caused by ischemia, inflammation or tumoir, trauma, Guillain-Barré syndrome. Periodic paralysis, myasthenia gravis and dissociative paralysis. Case report: A 38 year old man with acute tetraparesis and tachycardia. The onset of weakness occurred after climbing 24 stairs. Physical examination revealed a resting tachycardia and symmetrical, proximal weakness involving both arms and legs.The electrolyte analysis showed a severe hypokalemia 2.2 mmol/l. The thyroid function test showed normal antibodies were not found. He describes himself as a bodybuilder For more muscle strength and mass he used the anabolic steroid Oxandrolone 30 mg per day for two weeks. After intravenous administration of potassium tetraparesis resolved completely. Discussion: Anabolic steroids have taken to enhance muscle development, strength or endurance. After a series of scandals and publicity in the 1980s (Such as Ben Johnson’s improved performance at the 1988 Summer Olympics) prohibitions of anabolic steroid use were designated a “controlled substance” by the United States Congress in 1990. In bodybuilding Oxandrolon is exclusively used to build up strength and mass this usually goes hand in hand with a strong water retention. Clinical signs of hypokalemia associated with oxandrolone change the cellular energy cascade and the muscular electrical excitability mediated by ion channels and activity of sodium-potassium-ATPase. P607 Statins and myasthenia gravis: 11 cases of unmasked MG after the intake of these drugs M. Rugiero, F. Zabala Mendez, J. Rojas, E. Cristiano, C. Mazia Hospital Italiano de Buenos Aires (Buenos Aires, AR); Myasthenia Gravis Foundation of Argentina (Buenos Aires, AR) Objective: Statins drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediate in the cholesterol biosynthetic pathway. The use of these drugs has been associated with a variety of skeletal muscle-related complaints. In myasthenia gravis (MG), few cases about exacerbation of the disease associated to this drugs have been reported. We present 11 well-documented MG patients who developed the disease after the intake of this group of lipid lowering agents. Methods and Results: 11 patients between 1999 and 2005 developed clinical, electrophysiological and serological well defined Myasthenia gravis after the use of different statins: six received atorvastatine(54.5 %), three simvastatine(27.27 %) and two rosuvastatine(18.18 %). Male to female ratio was 1:2.6. Mean age at the time of diagnosis was 65 years old (54–82 y). Six patients were seronegative and five seropositive. Two patients showed Ocular MG and nine patients the generalized form of this disease. CT scan showed thymus enlargement in two patients Mean time from statins intake onset to the development of MG symptoms was 9.54 months (1m-38ms) Conclusion:. We reported 11 patients with MG related to previous statin treatment. Few patients have previously been reported to develop MG after receiving statins. Statins are not related to interfere with the neuromuscular junction transmission but the following pathogenic mechanism had been proposed: immunomodulatory properties of the drug, mitochondrial dysfunction and exacerbation of underlying weakness or disease Seropositive and seronegative MG patients were reported in our series. It suggests that more than one underlying pathogenic mechanism woul be involved. Myasthenia Gravis has been reported to be unmasked by different drugs and as far as we know this is one of the first reports related to statins.

P608 Incidence of myasthenia gravis in Buenos Aires, Argentina M. Rugiero, F. Zabala Mendez, C. Zurru, J. Diaz, E. Soriano, C. Mazia, E. Cristiano Hospital Italiano de Buenos Aires (Buenos Aires, AR) Introduction and Objective: Myasthenia Gravis (MG) is a syndrome of fluctuating muscle weakness that worsens with use and improves with rest. Its etiology is heterogeneous and it is divided between those rare congenital myasthenic syndromes that are genetic and those of which the most common form is acquired and autoimmune. The reported annual incidence rates range from 2.5 to 20/ 100.000 population. No statistical studies have been performed in our country. Our objective was to evaluate the incidence of this disease in Buenos Aires, Argentina (lat 34˘ 38’S; long 58˘ 28’O). Patients and Methods: Patients: members of a Health Medical Organization (HMO) at the Hospital Italiano of Buenos Aires who were at risk of exposure between January 1999 and December 2004, until the time of discharge or death. Search: in the following sources: a) clinical records of the Neurology Department; b) centralized electronic clinical records of the Hospital Italiano of Buenos Aires; and c) a data base of patients treated with piridostigmine. Patients who fulfilled the MGFA diagnostic criteria for MG were included. Statistical Analysis: annual incidence (AI) and incidence density (ID) were calculated. Results: Between December 1998 and December 2004, 534.249 people/year were followed; 38 (mean age: 59.5 years; range: 27–83) developed MG. Incidence Density (ID) was: 7.11/100,000 population/year (CI 95 %: 4.84–9.35). 23 were female: ID: 7.4 1/100,000 people/years (CI 95 %: 5.43–12.0) and 15 were male: ID: 6.7 /100,000 population/year (CI 95 %: 3.62–10.57). Conclusion: Incidence density (ID) in this period was 7.11/100,000 population/year. This is the first report of MG incidence in our country and one of the few in the literature in which incidence of density was measured. P609 Myotonic dystrophy type 2: clinical characteristics of 23 patients A. Lusakowska, A. Sulek, W. Krysa, A. Nadaj-Pakleza, E. Szmidt-Salkowska, P. Pruszczyk, A. M. Kaminska Medical University of Warsaw (Warsaw, PL); Institute of Psychiatry and Neurology (Warsaw, PL) Objectives: Myotonic dystrophy is of a particular interest to clinicians and geneticists because of its remarkable phenotype heterogeneity. Clinical phenotype of myotonic dystrophy type 1 (DM 1) is relatively well characterized, whereas the clinical spectrum of myotonic dystrophy type 2 (DM 2) is still expanding. Our aim was to define the clinical features of 23 DM 2 mutation verified patients. Patients and Methods: All 23 patients were assessed by a neurologic questionnaire and physical examination. EMG was performed in all subjects. Ophthalmologic assessment consisted of ophthalmoscopy and a slit lamp examination. All patients underwent laboratory tests (CK, glucose, lipid and hormonal profile). Cardiologic evaluation included ECG, HolterECG and echocardiography. Brain MRI was performed in 7 patients. Muscle biopsy, taken before genetic diagnosis was available at our center, was evaluated in 15 clinically affected patients. Results: In most cases typical symptoms of mild myotonia, muscle pain, proximal legs weakness and stiffness occur between third and fifth decades. At the time of DNA testing the mean age was 45 years. It is of special interest that the youngest symptomatic patient was diagnosed at the age of 3 years. In addition to the core clinical features, prominent calf hypertrophy and exaggerated reflexes were observed in majority of patients.Another frequent clinical finding among our patients was haearing impairment. Cataract was diagnosed in 84 % of the patients. Mildly elevated CK and abnormal lipid metabolism were present in 50 % and 80 % cases, respectively. Hypothyroidism was the most frequent hormonal abnormality. Of the 9 affected men tested for testicular function, one patient had lowered testosterone level.EMG demonstrated myotonic discharges in all patients,whereas changes consistent with a myopathic pattern were recorded in 26 % cases. Muscle biopsy showed characteristic constellation of pathologic features such as nuclear clump fibers, type 2 muscle fiber prevalence and atrophy. MRI confirmed white matter hyperintensive changes in 3 patients with exaggerated tendon reflexes. Dilated cardiomyopathy was a rare finding in our patients, whereas cardiac arrythmias were frequently observed. Conclusion: Our study provides the first report on genetically defined DM 2 among Polish patients. We confirm that remarkable clinical variability can be observed among DM 2 patients.

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P610 INQoL Italia: extended cultural validation from the UK to the Italian population with muscle diseases M. C. Panzeri, S. Gandossini, C. Angelini, A. Palmieri, G. Siciliano, L. Volpi, T. Mongini, L. Politano, M. Grandi, R. Massa, M. B. Panico, V. Pisani, A. Toscano, O. Musumeci, C. Rodolico, M. R. Rose, G. Meola, V. Sansone IRCCS Policlinico San Donato (San Donato, IT); University of Padua (Padua, IT); University of Pisa (Pisa, IT); University of Turin (Turin, IT); University of Naples (Naples, IT); Villa Beretta (Como, IT); Hospital Tor Vergata (Rome, IT); Department of Neuroscience (Messina, IT); King’s College (London, UK) Objectives: The aim of our study is to perform a cross cultural analysis between English and Italian patients with muscle diseases in whom INQoL Italia (an individualized quality of life questionnaire created for UK adult patients with neuromuscular disorders) has been administered. This will allow to identify whether the same items considered relevant to health-related quality of life for the UK population are applicable to the Italian population. Methods: We administred INQoL Italia to 253 patients (A myotonic distrophies; B facio-scapulo-homeral distrophy; C limb girdle distrophies; D Becker muscular distrophy; E inflammatory miopathies; F skeletal muscle channelopathies; G spinal muscular atrophy), asking them to add comments on the questionnaire. Qualitative analysis was made by elaborating every comment, and separating items already considered in the questionnaire from new items. Results: 67 of 253 patients (44 men, 23 women, mean age 44.5±13, range 22–72 yrs) made comments distributed as follows: group A: 20 of 100, B: 15 of 53, C: 15 of 42, D: 5 of 34, E: 4 of 17, F: 2 of 2, G: 6 of 12. All ages and both sexes were equally represented. Most comments (78 %) were about items already considered in the questionnaire (activities > relationships > therapy > emotion and independence). 22 % of comments concerned new items, such as: (i) lack of information about the disease and insufficient exchange of clinical information with the referring physician (29.4 %); (ii) expectations from research studies (41.2 %); (iii) lack of sufficient attention for architectural devices and facilitations for the disability (11.8 %); (iv) need for better psychological support (11.8 %); (v) insufficient importance of sex life limitations due to disease (5.9 %). Conclusions: Most comments are in agreement with the UK population confirming the importance of the aspects of life considered in INQoL and emphasizing the validation to the Italian culture. Our preliminary data indicate that Italian patients with neuromuscular disorders have a greater need than expected for more information about their disease (either from neurologists, referring physicians, but also from mass-media) and for greater exchange and update between different specialists, including psychologists. Ongoing studies will examine the clinical utility of INQoL Italia and will possibly direct research studies and target human and economic resources to a better understanding of the patients’ needs. (Telethon grant GUP 05001) P611 Muscle magnetic resonance imaging in muscular dystrophies and inflammatory myopathies A. Degardin, D. Morillon, A. Lacour, P. Vermersch, T. Stojkovic CHRU Lille (Lille, FR); La Pitié Salpêtrière (Paris, FR) Muscle magnetic resonance imaging (MMRI) has an increasing role in diagnosis and follow up of muscular dystrophies and idiopathic inflammatory myopathies. The aim of our study is i) to determine if MMRI is really useful in the diagnosis workup by describing muscle involvement topography and ii) to describe muscle signal abnormalities and their specificity. We performed 33 MMRI: 8 in myotonic dystrophy type 1 and 2 (DM 1, DM 2), 15 in limb girdle muscular dystrophy (LGMD) (including dysferlinopathy, calpainopathy, sarcoglycanopathy and dystrophy associated with fukutin related protein mutation (FKRP)), 3 in Becker muscular dystrophy (BMD) and 11 in idiopathic inflammatory myopathies (including polymyositis (4 cases) (PM), dermatomyositis (1 case) (DM), sporadic (4 cases) and hereditary (2 cases) inclusion body myositis (IBM)). Comparing our results with previous studies, we establish a specific muscular involvement pattern for each muscular disease. Furthermore, we observed that T 2 STIR weighted hyper intensities are absolutely not specific of myositis since they are present in 62 % of our muscular dystrophies.

P612 Cognitive impairment in myotonic dystrophy type 1: a longitudinal followup study A. Modoni, G. Silvestri, M. G. Vita, M. Masciullo, P. A. Tonali, E. Ricci, C. Marra Catholic University (Rome, IT) Objective: Here we report the results of a neuropsychological longitudinal study performed in a group of dystrophy type 1 (DM 1) patients. Methods: 36 DM 1 patients, including 5 congenital and 31 classical forms, were re-evaluated within a 2 years clinical and neuropsychological followup. Patients were divided into 4 groups, according to the degree of the n(CTG) expansions. We assessed a detailed neuropsychological study, including MMSE, memory, linguistic, level, praxis, attentional and frontal-executive tasks. Statistical analysis of data was performed by ANOVA for multiple tests. Results: Our study confirmed the occurrence of two distinct patterns of cognitive impairment in DM 1: a condition of retardation in congenital cases, and a progressive, ageing-related decline of frontal and temporal cognitive functions in adult onset classical forms. In particular, we documented a significant worsening of cognitive dysfunction in all groups of patients (p = 0.000001), with a predominant involvement of “frontal lobe” functions (p = 0.0001).A different evolution of the cognitive impairment characterized the different groups of patients, according to the genotype (p = 0.001). Conclusions: Central Nervous System involvement in myotonic dystrophy type 1 (DM 1) is characterized by an aberrant tau-protein expression in brain tissues of patients causing the presence of neurofibrillary tangles in temporal and frontal cortex. This longitudinal follow-up study confirmed a progressive decline, with aging, of frontal and temporal functions in adultonset DM 1 patients. P613 Genotype and phenotype correlation in dysferlinopathies M. Guglieri, F. Magri, R. Cagliani, M. G. D’Angelo, A. Prelle, R. Del Bo, S. Ghezzi, F. Fortunato, C. Lamperti, L. Morandi, M. Mora, M. Moggio, N. Bresolin, G. P. Comi University of Milan (Milan, IT); I. R. C. C.S. E.Medea (Bosisio Parini, IT); Neurological Institute Besta (Milan, IT) Objective: Dysferlinopathies are a heterogeneous group of allelic disorders caused by mutations in the dysferlin (DYSF) gene. Three different forms can be recognized: the autosomal recessive Limb Girdle Muscular Dystrophy (LGMD 2B), the distal Miyoshi Myopathy (MM) and a recently identified form of muscular dystrophy characterised by involvement at onset of both proximal and distal limb muscles. The correlations between genotype and phenotype are still undefined. Aim of our study is to characterise a large group of patients affected by dysferlinopathy, to identify possible correlations between genotype, protein expression and phenotype and to evaluate its prognostic importance. Material and Methods: We studied 51 patients (42 probands) with a clinical phenotype of dysferlinopathy. All probands underwent neurological examination and muscle biopsy. They all showed a dystrophic muscular pattern and a dysferlin deficiency at Western Blot analysis (WB), classified as mild, moderate, severe or total. Genetic analysis was performed in order to confirm the diagnosis. Results: 17 patients presented a MM phenotype; 23 patients were affected by LGMD 2B, 3 patients showed paucisymptomatic hyperCPK and 8 patients were characterized by a proximal and distal muscular involvement at onset. Proximal and distal forms presented a similar age of onset (21.3 vs. 25.3) and comparable creatine kinase (CK) levels. The pace of symptoms evolution was variable. Eighteen probands showed complete absence of dysferlin at WB analysis; while the other maintained a partial protein expression. All patients showed mutations within DYSF gene although in 7 patients we identified only one mutation. 17 out of 48 mutation were novel. The distribution of mutations along the gene is similar in both distal and proximal forms; MM patients presenting a higher proportion of missense substitutions. Mann-Whitney test showed a strong correlation between type of mutation and clinical severity at the age of onset, both in MM and LGMD 2B patients (p = 0.001). A similar correlation was observed when residual protein amount was considered (Fisher test p = 0.01). Conclusions: Molecular data and residual dysferlin levels are correlated with age at disease onset, a relevant parameter of clinical history in dysferlinopathies. Even with a large group of patients, no molecular features differentiate proximal versus distal phenotypes.

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P614 Hypokalaemic periodic paralysis: a new nonsense mutation in KCNJ 2 gene S. Lucchiari, S. Pagliarani, M Moggio, S. Corti, C. Lamperti, G. P. Comi University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico (Milan, IT) Objectives: A 44 year-old Italian male patient showed at the age of 33 years an episode of marked generalised muscle weakness following intense physical exercise. Recently, he experienced the same symptoms neither preceded by any physical exercise, nor by high carbohydrate intake. During these episodes, serum CK was high (up to 1544 I. U. during the crisis, to become normal in intercritical periods), whereas serum K level was decreased (3.0 mMol, n. v.: 3.5–5.5). ECG showed abnormal QRS profile and T inversion in aVF, without conduction defects. After the last attack, the patient has been suffering from muscle pain and contractures. EMG examination showed a slight myopathy. Andersen-Tawil syndrome (ATS, OMIM #170390), a rare dominantly inherited channelopathy, is characterized by the triad of periodic paralysis, ventricular ectopy and skeletal anomalies without myotonia. Onset is with episodic weakness in the first or second decade; permanent proximal weakness may develop later in life. Patients generally show altered serum K level, which may be reduced or elevated, but they can also be normokalaemic. The disease maps to chromosome 17q23 and the implicated gene is KCNJ 2 (GenBank #NM_000891). Our goal was to screen muscle channelopathy-related genes KCNJ 2 and CACNA 1S (GenBank #NM_000069) and correlate mutation with phenotype. Methods: Genomic DNA was extracted from peripheral blood leukocytes and the coding exons, with their splice junctions, were PCR-amplified. The obtained fragments were directly sequenced. No alterations were found in CACNA 1S sequence. Results: Genetic analysis showed the presence of a single nucleotide substitution leading to the heterozygous nonsense mutation R 423X, located in exon 2 five codons upstream the wild-type TGA. As far as we know, no other nonsense mutations were reported in ATS patients to date, missense and microdeletions being the only alterations found. Conclusion: The nonsense codons are commonly considered pathogenic mutations as they cause a premature termination in the protein synthesis. This particular one is placed few codons from the physiologic stop and in a protein region lacking structural/functional domains. Nevertheless, it conceivably may decrease mRNA and/or protein stability or, in case of Nonsense Associated Splicing of exon 2, may produce a null protein, since exon 1 represents 5’UTR. Elucidations will come from transcript analysis. Our results are consistent with a non-Andersen channelopathy. P615 Disease natural history in a large group of genetically diagnosed glycogen storage disease type III D. Santoro, S. Lucchiari, S. Pagliarani, A. Bordoni, M. Filocamo, M. Di Rocco, C. Rodolico, A. Toscano, D. Melis, R. Parini, S. Paci, M. Giovannini, M. Donati, N. Bresolin, G. P. Comi on behalf of the Associazione Italiana Glicogenosi Objective: Deficiency of debrancher enzyme (AGL) causes Glycogen Storage Disease (GSD) type III,an autosomal recessive disorder,characterized by tissue accumulation of abnormally structured glycogen. This report reviews the disease clinical history in a large group of genetically diagnosed Italian GSDIII patients. Methods: We reviewed clinical, biochemical and genetic data of 51 GSD III Italian patients.All had absent or severely reduced AGL activity.AGL gene was analyzed by direct sequencing of the coding region and splicing sites.All our informative patients are affected by GSD type IIIa. Liver damage was monitored over lifetime by Aspartate and Alanine Amino Transferase (AST, ALT) levels. Liver echography was useful to differentiate patients with mild or severe liver involvement. Muscular weakness and disability were evaluated using a modified Walton Functional Rating Scale. Signs and symptoms of heart function were also evaluated. Results: We observed an inverse correlation between AST and ALT levels and age, with high transaminase levels in the first years and a progressive reduction in adulthood. Liver echography showed mild changes in most cases. At older ages none had normal liver findings and some developed moderate or severe liver disease. Only two patients developed liver failure, leading to liver transplantation after the age of 20 years. Regarding muscle involvement, we observed a direct correlation between age and disease progression. Functional impairment is mild in patients younger than 35 years. Older patients present a higher variability of the functional score. CK values were instead higher among children and young adults. Evaluation of heart function showed either normal echographic findings or mild hypertrophy in most cases.

Mutations giving rise to null alleles were found in 75 % of patients, while missense account for the remaining 25 %. The IVS 21 +1G/A intronic change is the most frequent mutation. Mutations are widespread along the whole gene and no hot spot could be found. No correlation could be found between any mutation and a particular clinical phenotype. Conclusion: Detailed clinical history of several aspects of tissue involvement in GSDIII showed a relatively high degree of muscle impairment in patients older than 35 year, the persistence of signs of liver dysfunction in adult patients, while heart function is relatively less affected in our cohort. No predictive molecular data has been so far identified. P616 Early-onset ptosis in type II glycogenosis A. Repetto, S. Ravaglia, A. Pichiecchio, C. Danesino, M. Rossi, A. Costa, A. Moglia Institute of Neurology “C. Mondino” (Pavia, IT) Objective: to report the frequency of ptosis in a series of patients with lateonset type II glycogenosis (GSDII). Background: GSDII is a progressive myopathy caused by the deficiency of the enzyme alpha-glucosidase, leading to lysosomal accumulation of glycogen. Muscle weakness involves the proximal muscles and the diaphragm. Ptosis is usually not described. Recently, as many as 33 % of cases have been reported from a single-center series of 12 patients; in 3/4 patients, ptosis had been the presenting symptom, suggesting that it may help in the early diagnosis of GSDII. Methods: in our series of 22 GSDII we investigated the presence of ptosis by the analysis of eyelid fissure and levator function. Results: A woman with genetically defined GSDII developed ptosis two years before the development of skeletal muscle weakness. She developed unilateral ptosis at 46; at 48 she began to complain of walking difficulties. Neurological examination showed proximal lower limb muscle weakness, unilateral ptosis, and raised CK levels, suggesting mitochondrial myopathy. Examination of muscle biopsy revealed increased glycogen content and acid maltase deficiency. Sequence analysis of the alpha glucosidase gene showed a compound heterozygous mutant genotype IVS 1 13T>G)/525delT. Family history was negative for neurological abnormalities. Ocular movements and pupillary reflexes were normal. No abnormality was present by brain and orbital MRI, chest CT scan, and single-fibre EMG of the orbicularis oculi. Ptosis became bilateral at 58 years and is now severe at 60: the eyelid fissure at rest is 3 mm on the right and 5 mm on the left; the levator function is 5 mm on the right and 7 mm on the left. In spite of proximal lower limb weakness she still walks unassisted, but her vital capacity is decreased by 52 %. The ptosis has remained unmodified after 2 months of therapy with Myozyme. Conclusions: our patient developed ptosis at an early stage of disease. However, in our series of 22 patients, she was the only one who developed ptosis. Full genetic analysis was completed for 17/22 cases: a second female patient with the same genotype has no ptosis. If the data of other series are combined with ours, ptosis was present in 5 cases (4 females)/34 (14.7 %), and was consistently an early onset clinical sign. It seems not to be associated with any specific mutation; all patients shared the common IVS 1 (13T>G), while the 525delT was present in 2 patients with, and in 5 without, ptosis. P617 Cysteine donor enriched dietary intake is able to reduce oxidative stress markers in myotonic dystrophy type I L. Volpi, M. Falorni, C. Carlesi, G. Ricci, M. Franzini, L. Petrozzi, A. Paolicchi, G. Siciliano University of Pisa (Pisa, IT) Myotonic dystrophy type 1 (MD) is the most frequent muscular dystrophy in adulthood, and an autosomal dominant multysystem disease, characterized by myotonic phenomena, muscle weakness, with involvement of ocular, endocrine, cardiac, gastro-enteric and respiratory systems. Although the pathogenetic mechanism is still not completely clear, an increased susceptibility to the oxidative stress and increased levels of circulating free radicals in MD suggest a role of the oxidative stress in this disease. Objectives: To analyze the occurrence of oxidative stress in DM before and after 30 days of treatment with an anti-oxidant therapy (with a food-integrator cysteine donor: Prother, AFR, 10 mg/die). Methods: We assessed blood levels of the following oxidative stress markers in 14 DM patients compared to healthy controls: glutathione (GSH), advanced oxydation protein products (AOPP) and ferric reducing ability (FRAP).

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Results: We found that before therapy, patients blood AOPP levels were significantly higher than in controls, and that it was reduced after the 30days treatment. Blood FRAP level was higher in DM patients than in controls, even though it didn’t reach statistic significance, and after treatment it was unchanged. GSH level was lower in patients compared to controls (n. s.), and it raised after cysteine donor food-integrator treatment even though without statistic significance. Conclusions: Our results, in confirming the role of oxidative stress in DM., underline the beneficial effects of antioxidant cysteine-donor therapy on biochemical markers of oxidative stress in DM. P618 Myasthenia gravis treatment with tacrolimus A. A. Barreira, J. A. Flauzino, C. Sobreira, V. Borguetti, D. G. B. Souza, C. C. Resende, W. Marques Jr. Medical School of Ribeirão Preto -USP (Ribeirão Preto – SP, BR) Objectives. The conventional therapy for MG includes anticholinesterasic drugs, corticosteroids, azathioprine, plasmapheresis and, eventually, other non-steroids immunosuppressors like cyclosporine. There are few case reports and no controlled study about the effect of tacrolimus for treatment of MG. It is believed that tacrolimus is safety for patients with hepatitis C, being a safety option for these patients. This drug could also be used for those patients that do not respond to the conventional treatments. Methods.We have treated four patients with MG, two of them with hepatitis C, with 2 to 6 mg/day of tacrolimus. A carefull and periodic clinical and laboratory surveillance was kept during the period of treatment Results: Tree of the patients became asymptomatic while the fourth – without hepatitis C – had a numeric reduction of the myasthenic crisis but remained with residual fluctuant deficits. The patients with hepatitis C did not have any increase in their viral load. No important side effect was observed. Conclusion. Although double blind controlled studies are necessary to a definitive conclusion about the effectiveness of tacrolimus to treat patients with MG, our results favours the use of tacrolimus as an alternative option for patients with MG and hepatitis C or for those patients that are not responsive to the conventional treatments. P619 Human leukocyte antigen as predictor of outcome in autoimmune myasthenia gravis A. Ariatti, G. Galassi, P. Miceli, F. Girolami, M. Stefani, M. De Palma, P. Faglioni Institute of Neurosciences (Modena, IT) Objective: Aim of study was to evaluate Human leukocyte Antigen system (HLA) impact in relation with long term outcome and thymectomy in autoimmune Myasthenia Gravis (MG). Methods: We studied 102 unrelated Caucasian MG patients (mean age 66.4 years; range 20.6–91.3): 43 (42 %) were males (mean age of 69.3; range 33.2–86.2). 59 (57 %) were females (mean age of 64.3). Mean duration of illness was 87.3 months (range 2–558). Disease severity at diagnosis was defined according to Osserman’s and Myasthenia Gravis Foundation of America (MGFA) clinical classifications. 51 patients were graded stage I (50 %; 25 female, 26 males), 27 (26.4 %; 18 female, 9 males) in stage IIa, 23 (22 %; 17 females, 6 males) as IIb. One patient (1 man) was in stage III. No patients at time of diagnosis were asymptomatic, neither in stage IV. Anti-AChR antibody titre was determined at time of diagnosis and yearly: 75 patients (73.5 %) were seropositive, whereas 27 (26.4 %) seronegative. 35 patients (34 %; 23 females, 12 males) underwent extended thymectomy either for neoplastic thymus (n = 17) or for thymus hyperplasia (n = 18). 67 patients (66 %; 36 females and 31 males) were not thymectomized. Clinical outcome was evaluated during the observational time. In patients and controls, typing of HLA class I (A and B loci) antigens was performed by complementdependent microcytotoxicity assay. HLA DRB 1* typing was performed by protein chain reaction (PCR) amplification with sequence-specific primers or PCR products hybridised with sequence-specific oligonucleotides probes. Controls were 3.528 healthy Caucasian bone marrow donors: 1824 females and 1704 males, aged 30 to 65 years. Results: Distribution of HLA A, B antigens and DRB 1* alleles was compared.Statistical results are as follows: 1) HLA A, B antigen and HLA DRB 1* allele distribution did not significantly differ between AChR negative and positive MG patients: exact p = 0.4780 (antigen A), exact p = 0.6547 (antigen B), exact p = 0.3620 (DRB 1* allele). 2) HLA A,B antigen and HLA DRB 1* allele distribution did not significantly differ among thymectomized and not thymectomized, whereas HLA B 61 and HLA B 63 antigens prevailed in those MG who underwent thymectomy (chi square 2.9965; df 1, p = 0.0834) 3) In

our cohort of MG patient, HLA class I and II was not significantly different in presence or in absence of improvement. Conclusions: HLA class I and II may not predict clinical outcome in autoimmune MG.

Epilepsy P620 Effectiveness of Oxcarbazepine in one family with temporal lobe epilepsy C. Zuliani, M. D. Marchi, F. Zara, A. Panico Civil Hospital (Mirano, IT); Civil Hospital (Vicenza, IT); Civil Hospital (Genoa, IT); Civil Hospital (Noale, IT) Temporal lobe epilepsy (TLE) is the most frequent form of partial epilepsy in adults. The genetic predisposition appears to be an important causative factor, and current evidences suggest that TLE represent a complex phenotypes with a polygenic or multifactorial inheritance. The commonest pathology underlying this type of epilepsy is mesial temporal sclerosis (MTS), that usually occurs on one side of the brain, but in 10 to 15 percent of cases it is bilateral. We report a family with TLE who responded to Oxcarbazepine (OXC) treatment. B. R., the father, B.F and B. P., respectively his daughter and son, in whom several crisis/per day appeared at the age of 47, 19 and 15 years. B. R. experienced partial complex seizures characterized by feeling of déjà vu with fear sensation; B. F. by “dreaming state” preceded by feeling of anxiety. B. P., who had at the age of one year a single episode of febbrile seizure, showed: 1) seizures characterized by rising epigastric sensation and déjà vu feeling; 2) crisis with hypermotor automatisms on the right arm, loss of awareness and oro-alimentary automatisms lasting a few seconds; 3) seizures preceded by a rising and distressing heat epigastric sensation and “dreaming state”. None of them showed cognitive impairment and post-ictal confusion or headache. Magnetic Resonance Imaging (MRI) showed in B. R. MTS in the left side of the brain; it was normal in his children. Inter-ictal EEG in all patients showed spikes and focal discharges in the left temporal lobe, with contralateral diffusion. Neurogenetic investigations are in progress. All patients are seizures free from two years with OXC treatment (respectively at the dose of 1200, 1500 and 900 mg/day). Our cases allow us the following considerations: complex partial seizures in TLE are often drug-resistant, but in our patients, although also the EEG characteristics, according to literature, had an unfavourable outcome, long term seizures control resulted excellent with OXC monotherapy. Finally, all cases manifested stereotypic semiology, and only in one of them MRI had shown MTS. P621 The complex relationship between seizures and psychosis O. Koutoula, K. Boutsi, K. Papadopoulos, N. Taskos, I. Milonas AHEPA University Hospital (Thessaloniki, GR) Introduction: Psychosis of epilepsy (POE) comprises a group of disorders that are closely associated with epileptic seizures. These include ictal, interictal, postictal POE and alternative psychosis (also known as “forced normalization”). Psychotic disorders are classified as ictal if they are an expression of the seizure activity and associated with ictal discharges on EEG. Ictal psychosis is relatively uncommon and its prevalence and incidents rates remain unknown. Methods: We report three patients without previous history of epilepsy in whom ictal psychosis developed during the course of viral encephalitis. Case 1. A 23-year-old right-handed woman developed a variety of psychotic symptoms under clear consciousness: auditory (voices commencing) and somatic hallucinations, delusions of persecution and reference in association with oro-alimentary automatisms (lip smacking). Case 2. A 34-year-old right-handed man developed visual hallucinations and persecutory delusions in association with gestural automatisms (fumbling movements of the hands). Symptoms included delusions of reference, persecution, guilt and religion; suspicious, aggressive and hostile behavior caused by the hallucinations and delusional thoughts. Case 3. A. 14-year-old-boy developed visual hallucinations and psychomotor excitement with a degree of clouded consciousness in association with pedal automatisms (bicycling movements). Results: CSF results were compatible with viral encephalitis in all three cases. Ictal EEG recordings showed electrical status epilepticus during wakefulness, which was consisted of nearly continuous generalized discharges of spike-slow wave complexes (SSWC) of 2–3.5 Hz, continuous discharge of SSWC of 4–5 Hz in the left midtemporal region and nearly continuous discharges of SSWC of 2–5 Hz in the right parietal regions respectively. Brain

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MR images were normal in the first, showed left mesial temporal lesion in the second and right parietal lesion in the third case. Conclusion: Ictal psychotic episode should always be considered in the differential diagnosis of postictal psychosis and primary psychiatric disorders. Typically, it is an expression of nonconvulsive status epilepticus, including simple partial, complex partial and absence status. The ictal psychosis is necessarily brief, usually hours to few days. By definition, ictal psychosis is concurrently associated with epileptic discharges in the brain, and EEG studies are mandatory for the diagnosis. P622 Gobbi’s syndrome and its variants: the importance of early diagnosis D. M. García Alvarez, M. Pueyo Morlans, M. L. Fernandez Sanfiel, H. Perez Perez, A. Gutiérrez, M. González, V. García Marín, R. Marrero, M. Zea, J. Rojo, J. Pérez, F. Carrillo, N. Martinón, P. de Juan Hospital Universitario Canarias (La Laguna Tenerife, ES) Background: Gobbi’s syndrome is an unusual condition defined by the association of epilepsy, celiac disease (CD) and bilateral occipital calcifications, with 3 clinical variants. It is a genetically based, non-hereditary syndrome, influenced by ethnic and environmental factors, whose early diagnosis has clear therapeutic implications. Aims and Purpose: to study the features of Gobbi’s syndrome in our patients and the influence of CD in the prognosis and evolution of epilepsy. Methods: In a retrospective review of patients attended at our epilepsy clinic in the past ten years, we’ve found 6 patients that showed, at least, two of the definitory characteristics of the syndrome. Medical record, activity of the CD, type of epilepsy, evolution and outcome were registered. Results: All cases suffered epilepsy and CD, and 3 of 6 also showed occipital calcifications in CT scan.Another autoimmune condition was present in the medical record of all patients. In 3 patients, epilepsy was diagnosed prior to CD. Three patients developed epilepsy in the first 3 years of life, with seizure-free periods lasting 4–7 years. Partial motor seizures and visual aura occurred in 4 patients; in 3 cases tonic-clonic seizures were present, a higher percentage than expected. In all the cases EEG was abnormal. Epilepsy’s course was benign in five cases and moderate in the other one. All of them improved with a diet free of gluten. Discussion: Our cases illustrate 2 of the 3 clinical variants of Gobbi’s syndrome: 3 patients showed the whole syndrome, and 3 cases had atypical variants, lacking one of the defining characteristics (namely, the occipital calcifications). The last group presented with early epilepsy and late CD diagnosis. CD screnning in epilepsy is important, even in absence of digestive symptoms, because of the high prevalence of silent or late forms. Early diagnosis and dietary treatment determines the course and prognosis of epilepsy. P623 Interictal period and psychiatric disorders Y. Kaplan, S. Sarikaya Gaziosmanpasa University (Tokat, TR); State Hospital (Tokat, TR) Purpose: The purpose of study is to investigate the psychiatric disorders during the interictal period in epilepsy patients. Methods: 68 adult epilepsy patients with psychiatric disorders in the interictal period were evaluated by clinicopsychopathalogic evaluation and structured interview. The diagnosis psychiatric disorders was set according to the diagnostic criteria of ICD-10. Results: In those patients, mood disorders are stated for the most. 21 (30.8 %) patients met the criteria of major depression, 6 (8.8 %) patients met the criteria of dysthymic disorder, 4 (5.8 %) patients met the criteria of bipolar effective disorder. There were 18 (26.4 %) anxiety, 6 (8.8 %) panic disorder of the patients. 5 (7.3 %) of the patients were accompanied by psychotic disorder. In 8 (11.8 %) of the patients, personality alterations, which do not meet ICD-10 criterion, were stated. Conclusion: In epileptic patients, it is known that psychiatric disorders are seen more often compared with normal population. Epilepsy is alone a life-limiting disease which affects both the social life of the individual and body health because of the traumas it causes, in a bad way. In epileptic patients determining the additional psychiatric disorders which increase morbidity and considering them during the treatment is an important factor which improves the life standards of those people. Moreover,disorders developing dependent on epilepsy are not separately categorized in classification of ICD-10. Descriptions of these diorders may play significant roles in studies aimed at understanding of relationship between epilepsy and psychopathology and in establishing the models containing neurological, biological and social factors.

P624 Epilepsy and kleptomania: case presentation Y. Kaplan, B. Elbozan-Cumurcu, S. Kurt, H. Karaer Gaziosmanpasa University (Tokat, TR) Introduction: Kleptomania is characterized by a recurrent failure to resist the impulse to steal object not necessary for personal use or their monetary value. In epileptic patients, it is known that psychiatric disorders are seen more often compared with normal population. However, the relationship between kleptomania and epilepsy is not know clearly in the literature. Case: A 20 year old woman with the complaint of stealing little things like ornament, pencil, eraser, magazine, which started two year ago, had consulted psychiatry polyclinic. In the neurological evaluation of the patient, who were directed to our clinic because of the epileptic seizures, the presence of complex partial seizures (CPS) which initiate simultaneously with those complaints, are determined. In the psychiatric evaluation, patient pointed out that, before the act of steal she feels an intensive tension which turns in to pleasure during the act, then she feels glad only for a short time, however afterwards she feels regretful and disgrace shows up on the foreground. According to the criteria of DSM-IV, patient is diagnosed as kleptomania. MRI of the brain was normal, interictal EEG showed slow waves over the left temporal region. Conclusion: Neuronal hyperexcitability in limbic areas, especially the amygdala, is a significant underlying mechanism associated with CPS. CPS may be comorbid with emotional disturbances, especially major mood disorders, anxiety, and aggression. Because the amygdala has important functional roles in epilepsy, emotion, and behavioral control, there may be common biological mechanisms involving neuronal excitability that contribute to both seizure activity and psychopathology. P625 Physiological study of parasympathetic cardiovascular regulation in patients with epilepsies V. Sirrou, P. Polychronopoulos, G. Kagadis, A. Argyriou, E. Chroni University of Patras (Patras, GR) Objectives: To test the integrity of parasympathetic control on the cardiovascular homeostasis in patients with various epilepsies and to identify potential epilepsy-related factors that might be associated with the possible impairment of parasympathetic nervous system function. Methods: Forty-four patients (17 men, 27 women; mean age 37.1±14.1 years-old) attending the epileptic clinic in our institution were included in the study; in 15 of them seizures were classified as complex partial, in 3 as simple partial, in 16 as secondary generalized and in 10 as primary generalized. All patients were asked about seizure frequency, epileptic disorder duration and the administrated therapeutic regimen and were subjected to a battery of 3 cardiovascular tests: a. heart rate variability during 6 deep breaths/min (algorithm:[RR max – RR min interval] x 100/ RR mean interval) b. Valsalva maneuver (ratio of the shortest RR interval during phase II to the longest RR interval in phase IV) c. heart rate response to standing up (ratio 30th beat /15th beat). Cut-off point for each of the 3 tests’ variable was defined as the fifth percentile of normal values, adjusted for patient age and sex, which were obtained from a pool of healthy individuals in our laboratory. Results: Fourteen patients (31.8 %) had abnormal values in at least two or all three tests. In this sub-group, as compared to the remaining 30 patients, there is a tendency of older mean age (42.7±13.8 vs. 34.3±13.5 yearsold), longer duration of epilepsy disorder (> 10 years in10 out of the 14 patients vs. 14 out of the 30 patients) and complex partial as the prominent seizure type (7 out of 14 patients vs. 8 out of 30 patients). There was no evidence to suggest that the frequency of seizures, any particular antiepileptic medication or the issue of mono as opposed to multiple drug therapy could interfere with the autonomic tests’ abnormalities. Conclusion: Our results suggested that 3 easily performed and commonly used tests could detect impairment of parasympathetic drive on cardiovascular function. This is more likely to occur in patients with certain characteristics of their epileptic disorder than in others. P626 Elderly secondary epilepsy post-stroke Y. Zhang, K. Dong, Y. Wang Beijing Tiantan Hospital (Beijing, CN) Background and objectives: Epilepsy after stroke has greater influence on the prognosis of the patients. The epilepsy attack at early stroke can further

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aggravate cerebral edema, and lead to the deterioration of the disease and affect the recovery of the neurological function of the patients. To make clear and definite of the factors related to elderly secondary epilepsy post-stroke is of important instructive significance to the prevention and treatment of post-stroke epilepsy, and the promotion of the neurological rehabilitation of stroke patients as well. Methods: 85 inpatients secondary epilepsy post-stroke were included, and all the patients was the first attack of epilepsy and had no history of epilepsy before stroke. The patients were divided into early epilepsy (within 2 weeks post stroke) and delayed epilepsy (after 2 weeks post stroke) according to the time of the first epilepsy attack of post-stroke, and the relationship between stroke type and the time epilepsy attack was analyzed. Based on the imaging results, we divided ischemic stroke into groups of < 1/4, 1/4–1/2, and > 1/2 of hemisphere according to the infracted size, and divided into groups of < 10ml, 10ml-30ml and > 30ml, according to the amount of cerebral hemorrhage, and the association of epileptic attack with the stroke location and size was analyzed. Results: The cases of cerebral hemorrhage, subarachnoid hemorrhage were obviously more in the patients with early epilepsy than those in delayed epilepsy and the cases of cerebral thrombosis were obviously fewer in the patients with early epilepsy than those in delayed epilepsy. The results of association of epileptic attack with the stroke location and size showed that there were more cases with the infracted size of 1/4–1/2 and > 1/2 of unilateral hemisphere than those with the infracted size of < 1/4 of unilateral hemisphere (P < 0.05). There were more cases with the 10ml-30ml, > 30ml cerebral hemorrhage than those with < 10ml cerebral hemorrhage. Conclusion: Early epilepsy is mainly manifested by cerebral hemorrhage, subarachnoid hemorrhage and cerebral embolism, and delayed epilepsy is mainly manifested by cerebral thrombosis. The risk of epilepsy is obviously increased in the patients with the infracted size over 1/4 of unilateral hemisphere, and those with > 30ml cerebral hemorrhage. P627 The comparison of monotherapy and polytherapy in the treatment of epilepsy M. R. Najafi Alzahra University Hospital (Isfahan, IR) Objectives: Monotherapy has been the gold standard in treatment of epilepsy for the last 20 years, Partly because of the reputation for increased toxicity of polytherapy. Some clinicians prefer polytherapy at the first time of management of new onset seizures because decrease of next seizure relapses.The aim of this study answer this question: which prefer, Monotherapy or polytherapy? Methods: This is a prospective, randomized & clinical trial study of patients with new onset idiopathic generalized & focal seizures that referred to neurology clinics between 2005–2006 years. These 152 adult patients divided in two groups randomly. The first group received only one drug (monotherapy with carbamazepine) and the second group treated with two drugs (carbamazepine plus phenobarbital or phenytoin or clonazepam or lamotrigine (as polytherapy). Seizure frequencies & relapses followed up for 6 months. Results: 152 patients included 82 males & 70 females that distributed in two groups equally. In monotherapy group, 6.6 % & in polytherapy group 17.2 % had seizure relapses that were significant (p = 0.038). Conclusion: Full dose carbamazepin as monotherapy has low side effects & more symptom free periods than polytherapy, (93.4 % vs 82.8 %). P628 Value of EEG following sleep deprivation in the elderly S. Dempewolf Klinikum Bremen-Ost (Bremen, DE) Objective: Sleep deprivation (SD) is a commonly used method to increase the diagnostic yield of the electroencephalogram (EEG), particularly in the evaluation of young patients with suspected epilepsy. Its importance in the elderly patient however is controversially discussed. Patients and methods: We retrospectively studied all EEGs of patients aged 16 years or older examined in our department between January 2000 and June 2006. After an initial routine EEG recording, they had been examined with a second EEG recording after full-night SD (n = 831). Patients aged 60 years or older (n = 222) were compared to the group of the younger ones (n = 609). Altogether, most of the patients were admitted to our hospital because of a loss of consciousness of unknown origin (elderly n = 164, young n = 470). Four elderly patients and 39 young were suffering from known epilepsy of unknown etiology. Forty-three of the older and sixty-five of the younger patients were referred to our department because of a focal neuro-

logical deficit and the others (elderly n = 11, young n = 35) because of other complaints. Results: In elderly patients without epileptic symptoms (n = 85), routine EEG showed interictal epileptic activity (IEA) in 1.2 % and 2.4 % in EEG following SD. In elderly patients diagnosed a first epileptic seizure (n = 58) the proportion was 1.7 % vs. 6.9 % and in focal epilepsy (n = 64) 9.4 % vs. 42.2 %. In elderly patients suffering from generalized epilepsy (n = 2), both routineEEG and EEG after SD showed IEA (100 %). In patients diagnosed an unclassified epilepsy (n = 7) and in those, whose symptoms remained unexplained (n = 6), IEA was only recorded after SD (14.3 % and 16.7 %). In the group of younger patients, the percentage of IEA did not differ in routine EEG (2.2 %) and EEG after SD (2.6 %) in patients without epileptic symptoms (n = 228) and in those, whose complains remained unexplained (n = 20, 5 % vs. 5 %). In younger patients diagnosed a first epileptic seizure (n = 212), however, the proportion was 2.8 % vs. 6.1 %, in focal epilepsy (n = 89) 10.1 % vs. 39.3 %, in generalized epilepsy (n = 36) 27.8 % vs. 72.7 % and in unclassified epilepsy (n = 24) 8.3 % vs. 12.5 %. Conclusion: Our data confirm the usefulness of EEG following sleep deprivation in the elderly. Particularly in the diagnosis of focal epilepsy its diagnostic value is in accordance with the results of younger adult patients. P629 Clinical implication of the prolonged remission with medical treatment as a prognostic factor in unilateral mesial temporal lobe epilepsy S. Park, H. S. Koh, D. B. Song, H. J. Park Severance Hospital (Seoul, KP) Objective: About 10 to 15 % of mesial temporal lobe epilepsy (MTLE) responds to medical treatment for a while but the prognostic factors related to medical response have not been clear. We tried to evaluate the clinical implication of remission history as a prognostic factor through long-term medical follow up among the MTLE with unilateral mesial temporal sclerosis (MTS) on MRI. Methods: 116 unilateral MTLE were recruited based on the retrospective review of the registered data base and and MR image. Patients with previous history of the central nervous system infection or with dual pathology in addition to MTS were excluded. Patient with history of remission for at least 24 months to medical treatment grouped as remission group (mean follow duration; 112.2 months, 30–224 month) and the remaining as non remission group (mean follow up duration, 64.7 months; 24–234). The clinical profiles such as antecedent, 2’ GTC, nocturnal preponderance, seizure clustering, aura, and automatism were compared. Result: 33 (28.5 %) belonged to remission group with 43.1 month (24–149) of mean remission duration and remaining 83 did not have medical remission at least 24 months. The age onset of seizure was older in remission group (mean age; 24 years old,2–65) than non remission group (13.9 years old, 1–42). 17 over 33 in remission were adult onset MTLE with seizure onset of 21 years old later. 27 over 33 in remission group showed seizure free or aura only, but only 2 over 83 were in aura only state on study point. Nocturnal preponderance was more in remission group. Clustering and presence of aura or automatism was predominant in non remission group with statistical significance (P < 0.01). Conclusion: This study suggested adult onset with at least 24 months of prolonged seizure remission was a good prognostic factor in addition to nocturnal preponderance in medical treatment of MTLE. But complete withdrawal of the antiepileptic drug in this group should be a big challenge. P630 The evaluation of early and late onset post stroke seizures A. Nigdelioglu Ozkan, S. Gokceer, N. Isik, I. Aydin Canturk, F. Candan Goztepe Training Hospital (Istanbul, TR) Background: Stroke is an important and well known cause of epileptic seizures in adults especially after 50 years of age. In this retrospective study, we evaluated the seizure types, lesion types and localisations, patient’s characteristic, mortality and prognosis in patients with early and late onset poststroke seizures. Material and method: We retrospectively studied the data of 46 patients who admitted to our Neurology Clinic with epileptic seizure after stroke between 2000–2006 years. Two types of seizures were defined; ‘early onset’ seizures (occurring within the 14 days following stroke) and ‘late onset’ ones (after the 14th day). Results: Among the 46 cases; 15 were early onset (%32.6), 31 were late onset (%67.3) poststroke. The late onset poststroke seizures frequently seemed in ischemic stroke,the common seizure type was simple partial seizures with high recurrence rate.

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The early onset poststroke seizures seemed frequently in hemorrhagic stroke, the recurrence rate was lower than late ones, and generalize tonicclonic type was common. Ischemic stroke occurred mostly in Middle Cerebellar Artery location and, hemorrhages were lobar cortical. A hemispheric lateralization was found.While the early onset seizures had left hemispheric lesions, the late onset ones had right hemisphere pathologies mostly (p < 0.038). In two groups, HT was the most seen risk factor and were no differences between the mortality, age, sex rates. Seizures in %73–77 could be managed with monotherapy. Conclusions: In this study, the late onset seizures seem frequently in ischemic and the early ones in hemorrhagic strokes. The recurrence rate was higher in late onset than the early ones. The most common seizure types were simple partial for late onset, JTK for early onset group. It looks like cortical involvement is important in poststroke seizures. HT was most common risk factor and seizures well respond to monotherapy in two groups. P631 The study of biochemical bone changes of chronic Iranian epileptic patients on anti-epileptic drugs M. Reissifar Alzahra University Hospital (Isfahan, IR) Objectives: People with epilepsy experience a variety of disease-related health outcome. Their prevalence and seriousness are under appreciated by the general public and the medical establishment. Bone health is a significant problem for patients with epilepsy. The general purpose of this study is to determine biochemical changes of bone metabolism in patients with epilepsy who receive log-term anti-epileptic drugs (AEDS). Methods: This is a descriptive-analytic, cross sectional study in 2005–6. The patients are chronic epileptic cases that were receiving long term AEDS. Serum samples of cases and Health controlled tested for calcium, phosphor, alkaline phosphates, parathormon (PTH) and albumin. Underlying problem disorders such as endocrinopathies were ruled out in these patients health controls selected of the relatives of patients. Results: After study and statistics analysis of 120 questionnaries, 20 patients had hypocalcemia (16.7 %), 32 patients had hypophosphotemia (%22.6) 49patients had high alkaline phosphatase (%40.8), 12 patients had high PTH (%10) Discussion and conclusion: Considering the findings and interpretation of results, It can be generally concluded that AEDS affect on serum calcium, phosphorus, alkalin phosphatase and PTH level of patients receiving these drugs, this effect in patients that are in 20–45years range in men and women had not significant differences. On the other hand, increase and reduction of serum calcium and phosphorus level have relationship with each other and with serum alkalin phosphatase level and changes of one element affect others. But changes of three markers (calcium, phosphorus, alkalin phosphatase) may have no relation with changes of PTH level. P632 Non-convulsive status epilepticus precipitated by alcohol abuse. Two case reports M. Arnaoutoglou, A. Karlovasitou, A. Tychalas, D. Fotiou, C. Karamanidis, G. Spanos, E. Avdelidou, E. Kalliolia, A. Arnaoutoglou, S. J. Baloyannis AHEPA University Hospital (Thessaloniki, GR); Eurodiagnosis Diagnostic Center (Thessaloniki, GR) Alcohol abuse can provoke epileptic seizures, mainly generalized tonic clonic seizures, some of which escalating to generalized convulsive status epilepticus. Non convulsive status, either as complex partial status or an absence status, has rarely been reported as an aftereffect of alcohol intoxication. We report two cases: Patient A, female, age 35 who was hospitalized after alcohol intoxication in a confused state, unable to orientate in time and place. Patient B, male, age 61 who was hospitalized after alcohol intoxication in a confused state, unable to orientate in time and place and identify close relatives. Neuroimaging (Brain MRI) was normal and neurological examination revealed no focal neurologic deficit in both patients. EEG revealed rhythmic generalized delta activity, with spontaneous clinical and neurophysiological recovery within 24 hours. Patient A reported recurrence of confusion after alcohol intake. Non convulsive status epilepticus triggered by alcohol intoxication with spontaneous recovery is, to our knowledge, a rare clinical entity.

P633 Post-traumatic epileptic seizures following severe traumatic brain injury in children and young patients F. Locatelli, P. Avantaggiato, F. Formica, S. Galbiati, R. Epifanio, N. Zanotta, A. Bardoni, C. Zucca, S. Strazzer IRCCS E.Medea (Lecco, IT) Objectives: A literature review shows that the incidence of seizures in posttraumatic patients varies according to the study samples which often differ in terms of severity (i. e. mild, moderate or severe brain injury). Few studies were carried out on child patients. The aim of this study is to assess the incidence of seizures in a large sample of post-traumatic children and young patients. Methods: Study participants were admitted to Scientific Institute “E. MEDEA” in the 2002–2006 period. The following data were collected: age at trauma, site of the brain lesion, occurrence of seizures, onset age of seizures, prophylaxis at hospitalization and Antiepileptic drugs (AED) administered. All the patients with previous history of epilepsy were excluded from the study. Results: 183 patients with severe brain injury were studied, with a GCS score < 8. Mean age at trauma was 15.88 years (SD: 11.73). 60 % of the patients showed a multifocal lesion, 19 % a diffuse axonal injury, 13 % a focal lesion, and only 3 % of the patients showed normal neuroimaging. 60 patients (32 %) had at least a Post-Traumatic Seizure (PTS). Of this group, 28 patients (15 % of the whole sample and 46 % of the PTS group) showed Early Post-Traumatic Seizures (EPTS), while 48 patients (26.2 % of the whole sample and 80 % of the PTS group) showed Late Post-Traumatic Seizures (LPTS). 16 patients displayed both EPTS and LPTS. Thus, 57 % of the EPTS group later also developed Post Traumatic Epilepsy (PTE). Age at trauma was < 15 years in 53 % of the EPTS patients. 34 (27 %) patients of the group (125 patients) that did not receive any prophylactic treatment had PTE. In contrast, 24 (41 %) patients of the group (58 patients) that received prophylactic treatment had PTE. Conclusions: On the basis of our results, we assumed that severity of trauma, coupled with a GCS score < 8 and multifocal or frontal cerebral lesions, is a potential risk factor for the development of PTS. Age at trauma is another relevant factor: in fact, the risk of EPTS increased at a younger age. EPTS patients are exposed to a greater risk of developing LPTE. Prophylactic treatment does not prevent the occurrence of LPTS. Our observational study is based on the investigation of PTS in a large population of post-traumatic patients, mainly consisting of paediatric and adolescent subjects, and provides a significant data collection that could be further explored in order to expand the related literature. P634 Preliminary data about safety and efficacy of zonisamide in a population of pharmacoresistant epileptic patients S. Llufriu, J. Casanova-Molla, A. Donaire, I. Maestro, M. Carreño Hospital Clínic (Barcelona, ES) Background: Zonisamide (ZNS) is a new antiepileptic drug (AEDs) approved in Europe as add on therapy for pharmacorresistant epilepsy during 2006. Objective: To examine the safety and efficacy of zonisamide when used as add-on therapy in patients with pharmacoresistant epilepsy treated in the Epilepsy Unit of a tertiary center. Mean follow up time was 4.5 months (1–8 mounths). Patients and methods: This was a retrospective study.Data were obtained through patient’s charts reviews and telephone interviews if a recent visit (less than one month) was not available. Most epilepsies were focal (46.7 % temporal, 20 % frontal, 16.7 % occipito-parietal), 13.3 % were multifocal epilepsies and one patient was diagnosed with Lennox-Gastaut syndrome. The most frequent type of seizure was partial complex seizure. Median time since epilepsy diagnosis was 23 years (range 5–44). All patients received more than one antiepileptic drug (mean number of concomitant AEDs was 3). Zonisamide was started at a dose of 50 mg/day, and the dose increased by 50 mg weekly until 400–600 mg/day depending on the response. Concomitant AEDs were decreased in 24 patients and maintained in 6 patients. Results: Adverse effects were reported in 66 % of patients. The most frequently seen were weight loss (23 %), emotional symptoms like irritability and sadness (20 %), and sleepiness (13 %). The treatment was discontinued in five patients (15 %) (3 due to inefficacy, one due to visual hallucinations and another one due to depressive symptoms. Rate of responders (patients who low the number of seizures at least 50 %) was 41 %. One patient is free of seizures at two mounths after treatment was started. Conclusion: Zonisamide seems to be a safe and effective drug as add-on therapy in patients with pharmacoresistant epilepsy.

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P635 Non-convulsive status epilepticus in sporadic Creutzfeldt-Jakob disease N. Canas, I. Lavadinho, M. Maia, L. Guerra, J. Vale Hospital de Egas Moniz (Lisbon, PT); Hospital Distrital de Portalegre (Portalegre, PT) Introduction: non-convulsive status epilepticus (NCSE) has been rarely described as the initial presentation of Creutzfeldt-Jakob disease (CJD). However, its diagnosis is controversial (possible EEG misinterpretations), being mainly supported by a reversion of the clinical/ EEG abnormalities with benzodiazepines (BZD). We describe a case of CJD in which the initial clinical and EEG studies were compatible with NCSE. Case report: a 76-year-old woman was admitted in our department with a two-week history of fluctuating consciousness impairment and right arm clonic jerks. The initial EEG showed prolonged bursts of rhythmic sharp waves/ sharp-and-slow wave complexes (higher amplitude in the left temporal region), intermixed with diffuse irregular teta-delta activity. Intravenous (IV) diazepam (10mg) completely abolished the epileptic activity/ clonic movements. The diagnosis of NCSE was admitted and IV phenytoin started. Video-EEG in the next days showed shorter duration of the burst epileptiform activity, with maintenance of the clinical-EEG response to BZD (diazepam/ midazolam). Despite subsequent treatment with antiepileptic drugs (valproate, levetiracetam), there was no full consciousness recovery. With propofol infusion (3 days; intensive care unit) the clinical and EEG abnormalities completely reversed, but reappeared shortly after its stop. In the following days, sequential EEGs disclosed diffuse periodic sharp wave complexes (PSWC), sharp-and-slow waves and bi-triphasic complexes (1–1,2 Hz), associated with bilateral myoclonic jerks; the clinical-EEG abnormalities continued to respond to BZD. MRI disclosed diffuse cerebral atrophy and left temporal ribbon cortical hyperintensity (FLAIR, T 2 and diffusionweighted images); 14-3-3 protein was positive in the cerebrospinal fluid. The patient died after 4 months and postmortem examination was diagnostic of the sporadic form of CJD. Conclusion: in this case, the initial diagnosis of NCSE was supported by fluctuating consciousness impairment and lateralized clonic jerks/ non-periodic epileptiform activity abolished by BZD. However, BZD also reversed the diffuse myoclonias/ PSWC, suggestive of CJD. These findings suggest that the initial clinical/ EEG manifestations of CJD may be compatible with NCSE, belonging to its clinical/EEG continuum spectrum. In this situation, the reliability of BZD response in diagnosing NCSE should only be considered when it induces consciousness recovery.

P636 Open-label study to evaluate the effectiveness of topiramate in patients with juvenile myoclonic epilepsy B. Schäuble, P. Levisohn, K. Holland, F. Wiegand on behalf of the JME Capss107 Investigators Objective: Open label study to evaluate the effectiveness of topiramate (TPM) in patients with juvenile myoclonic epilepsy (JME). Method: Open-label study enrolling patients age 12–65 years with a confirmed diagnosis of JME (myoclonic jerks and PGTCS or an EEG with generalized epileptiform abnormalities consistent with a clinical diagnosis of JME), age of disease onset 8–26 years. Patients had to have myoclonus and/or > 1 PGTCS within the 3-month retrospective baseline. Eligible patients were randomized (2:1) to 26 weeks treatment with TPM (target, 3–4 mg/kg/day; maximum, 9 mg/kg/day) or VPA (target, 10 mg/kg/day; maximum, 60 mg/kg/day or 750 mg/day if > 16 years of age). Seizure frequency, tolerability, and patient and physician evaluations of response were recorded during each visit (Baseline and Weeks 4, 8, 14, and 26). Results: 28 patients were randomized to TPM (N = 19; median age 15 years; range 9–42) or VPA (N = 9; median age 16 years; range 12–34). 12 patients had one baseline AED. 12/19 patients receiving TPM and 7/9 patients receiving VPA completed the study; mean dose among completers was 189 ± 78 mg/day and 897 ± 375 mg/day, respectively. At the end of the study, all patients but one patient achieved TPM (OXC) or VPA monotherapy. Reasons for discontinuation in the TPM group included adverse events (N = 2), patient choice (N = 1), or loss to follow-up (N = 1); two patients discontinued VPA due to adverse events or other reasons. During the 3-month maintenance phase, seizure-free rates were 47 % with TPM and 33 % withVPA. Seizure-free rates for myoclonic, PGTCS, and absence seizures in the TPM and VPA groups were 7/14 (50 %) vs. 6/9 (67 %), 8/12 (67 %) vs. 3/4 (75 %), and 2/2 (100 %) vs. 1/2 (50 %) respectively. Physician and patient global evaluation of improvement, alertness, and improvement in seizure severity were similar in both treatment groups (TPM 75 %; VPA 71 %). Neurotoxicity scores over time were similar, but systemic toxicity scores were higher with VPA. Most TPM-treated patients lost (mean –4.1 kg), while patients receiv-

ing VPA gained weight (mean, 5 kg); the between group difference was statistically significant (p < 0.001). Conclusion: TPM was effective in the treatment of patients with JME with less systemic toxicity compared to VPA. The results suggest similar effectiveness in seizure control, but because of the small sample size, clinically meaningful differences cannot be ruled out. The study was supported by Ortho McNeil Neurologics, Titusville, US.

P637 Quality of life in patients with epilepsy after transition from valproate to topiramate monotherapy B. Schäuble, A. Schreiner Janssen-Cilag (Neuss, DE) Objective: To evaluate quality of life (QUOLIE-10) and weight change of epilepsy patients transitioned from valproate (VPA) to topiramate (Topamax®, TPM) monotherapy. Methods: Multicenter, prospective, open-label, non-interventional trial (TOPMAT-EPY-403). Patients with epilepsy independent of seizure type ≥ 12 years of age and unsuccessfully treated with VPA due to lack of efficacy and/or lack of tolerability were eligible for this study. Patients were prospectively followed for 20 weeks after initiation of, and transition to a TPM monotherapy. Results: Overall, 147 patients (59 % women, mean age 41±19 years) were enrolled.Reasons for transition from VPA onto TPM were side effects in 81 % (mostly tremor, somnolence or cognitive symptoms) and/or lack of efficacy (61 %). 23 % of patients were seizure free at baseline. 84 % of patients completed the study. Mean weight at baseline was 75.9±17.9 kg and decreased on average by 3.7kg±4.5kg; mean BMI improved from 26.5 to 25.4 kg/qm. Seizure frequency significantly decreased after transition to TPM (p < 0.0001 vs. baseline). QUOLIE-10 subscores mental health, role functioning and severity of epilepsy all improved significantly (p < 0.0001 vs. baseline for all items). Tolerability of TPM was rated as ‘good’ or ‘very good’ in 83 %. TPM was well tolerated with 14 % of patients experiencing treatmentemergent adverse events (AEs). AEs ≥ 3 % were paraesthesia (4 %) and weight decrease (5 %). The only cognitive AE reported was speech disorder in 2.7 % of patients. Conclusion: Transition from valproate to topiramate monotherapy was associated with a substantial improvement in quality of life, a considerable weight decrease and a beneficial tolerability profile including few cognitive side effects. The study was supported by Janssen-Cilag Germany.

P638 Effectiveness of topiramate in patients with epilepsy transitioning from valproic acid – results of an open-label, non-interventional trial B. Schäuble, A. Schreiner Janssen-Cilag (Neuss, DE) Objective: To evaluate seizure frequency and tolerability in patients with epilepsy treated with topiramate (TPM, Topamax®) transitioning from valproic acid (VPA). Methods: Multicenter open-label non-interventional trial (TOPMATEEPY-403) following patients ≥ 12 years of age with epilepsy previously unsuccessfully treated with VPA. Patients were prospectively followed for 20 weeks after transitioning to TPM.A 12-week retrospective seizure frequency was used as baseline. Results: 147 patients (59 % female; mean age 42 yrs (± SD 19)) were followed. Median duration of epilepsy was 9 yrs (range, 0–60 yrs). 77 % had seizures during the 12-week retrospective baseline. Most frequent seizure types at baseline were generalized tonic-clonic (52 %), complex partial (23 %), and simple partial (12 %). Main reasons for transition from VPA to TPM were insufficient efficacy (61 %) and/or side effects (81 %). Mean dose of VPA at time of first administration of TPM was 1286 ± 629mg. Median TPM dose was 125mg/day at endpoint. Mean (± SD) seizure frequency decreased significantly from 32 ± 248 seizures per month during the retrospective baseline to 3 ± 16 seizures/month during the maintenance period (p < 0.001). The responder rate (≥ 50 % seizure reduction) during the last three months of observation was 75 %, and 51 % patients remained seizurefree during this period. 16 % of patients discontinued TPM, 8 % due to an adverse event (AE), and 3 % due to insufficient efficacy. Treatment-emergent adverse events (TEAE) were reported in 14 % of patients. TEAE occurring in 3 % were paraesthesia (4 %) and weight decrease (5 %). 70 % of patients were on TPM monotherapy at endpoint and 77 % continued TPM therapy. Conclusion: In patients previously unsuccessfully treated with VPA, top-

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iramate was well tolerated and was associated with a substantial reduction in seizure frequency and a high seizure-free rate. The study was supported by Janssen-Cilag Germany.

Infection P639 Bilateral lumbosacral plexitis as the presenting feature of seroconversion to hepatitis B virus A. Jha, D. Parsons, A. Jafari, R. Lindley, D. Mckee Hope Hospital (Manchester, UK); Manchester Royal Infirmary (Manchester, UK) Case report: A 37 year old man presented with low back and bilateral leg pain worsening over two weeks. Most intense over both quadriceps, the pain also radiated down the posterior aspect of the legs. He was otherwise asymptomatic. The pain improved over several weeks but was followed by progressive weakness of both legs, with diffuse swelling of the ankles and distal dysaesthesia. There was no sphincter dysfunction, upper limb or craniobulbar dysfunction. On examination, there was bilateral pitting oedema to the knees. There was symmetrical proximal and distal weakness of the legs, with distal areflexia and sensory loss. He was found to have a significantly raised erythrocyte sedimentation rate and raised hepatic tranaminases. Hepatitis B surface antigen was isolated from the serum, along with both IgG and IgM antibodies to hepatitis b core antigen, features suggesting recent infection with Hepatitis B virus, beginning to resolve. Spinal magnetic resonance imaging was normal, as were cerebrospinal fluid constituents. Nerve conduction studies were normal, but on electromyographic examination there were signs of acute denervation bilaterally in multiple leg muscles with normal paraspinal muscles, a pattern suggesting bilateral lumbosacral plexopathies. The weakness and other symptoms began to improve spontaneously, and within three months the patient was asymptomatic. Repeat hepatitis B serology showed evidence of past infection, with disappearance of IgM but persistence of IgG core antibodies, the surface antigen having been cleared by anti-hepatitis B surface antibodies. Discussion: Inflammatory plexopathy is recognised in association with variety of immunological insults. Most commonly affecting the brachial plexus, it may also affect the lumbosacral plexus and may occur bilaterally. Presenting with a biphasic picture of severe pain followed by variable muscle weakness, wasting and sensory disturbance, sympathetic dysfunction of the affected limb causing pitting oedema has also been reported. Hepatitis B infection and vaccination have been associated with a spectrum of neurological complications, but this is the first reported case of inflammatory plexitis in association with seroconversion to this virus. It underlines the importance of investigation for specific infections provoking this uncommon inflammatory condition, some of which, such as the hepatitis viruses, may need further treatment to prevent significant future morbidity. P640 Evaluation of hyperperfusion in single photon emission computed tomography analysed by eZIS in bacterial meningitis K Kimura, H. Kishida, Y. Iwahashi, Y. Baba, Y. Hakii, T. Nishiyama, C. Kugimoto, S. Koyano, Y. Suzuki, Y. Kuroiwa, T. Takahashi Yokohama City University (Yokohama, JP) Background: At the previous meeting,we reported hypoperfusion of Tc-ECD was observed at superior sagittal sinus area in patients with bacterial meningitis. We added cases, and further analysis by software (eZIS: easy Z-score Imaging System ver.3.0) was performed. Objectives: To clarify the distribution of acute brain dysfunction in bacterial meningitis. Methods: We compared six bacterial meningitis patients admitted from April 2005 to August 2006(2 patients: Streptococcus aureus, 2 patient: Streptococcus pneumoniae,2 patients: unknown origin).We examined blood perfusion by single photon emission computed tomography analyzed by eZIS software at the day of starting treatment and the day after first 14 days treatment. Results: In all cases, hypoperfusion of Tc-ECD is observed at superior sagittal sinus area, and the result is compatible with our previous result.Also, strong hyperperfusion of Tc-ECD is observed at near the surface of right lateral temporal lobe area. There is not any change at the opposite side. Following the recovery of mental disorder and normalization of CSF study, hyperperfusion is normalized. Conclusion and discussion: In bacterial meningitis, hypoperfusion of Tc-

ECD is strongly found in superior sagittal sinus area. This result reflects insufficient activity of the cortex. Hyperperfusion of Tc-ECD is found in the surface of right lateral temporal lobe area. Therefore action of emotional system is controlled by right temporal lobe, hyperperfusion of that reflects confusional mental status. These results does not depend upon bacterial types. With normalizing of the Tc-ECD perfusion, clinical symptom such as mental disorder was getting better, therefore Single Photon Emission Computed Tomography analyzed by eZIS is a good predicting marker of clinical symptom recovery in bacterial meningitis. P641 Analysis of prognosticating factors in adult Nigerians with tetanus admitted to medical wards of a tertiary hospital in Nigeria F. Salawu, D. Balami, L. Ahmed, A. Danburam, B. Baba Musa Federal Medical Centre (Yola, NG); State Specialist Hospital (Maiduguri, NG); University of Maiduguri Teaching Hospital (Maiduguri, NG) In spite of the World Health organization’s intention to eradicate tetanus by the year 1995, it remains endemic in the developing world and an important cause of death. Objective: To study the clinical presentation, treatment and outcome of tetanus in a Nigerian population. Methods: All patients who were hospitalized at the State Specialist Hospital, Maiduguri from 1995 to 2005, with a final diagnosis of tetanus were retrospectively studied. There were 29 men (mean age 33.7 years, median age 32) and 23 women (mean age 33.1 years, median age 37). Results: Most of the patients belong to lower socio-economic class. Sixteen patients had a history of a recent wound or had a wound at the time of admission. In 5 patients, the portal of entry could not be assessed. None of the patients received tetanus immunoglobulin. Wound cultures were not taken in all patients at the time of admission. The wounds were located on the lower limb or foot in 13 patients and on the finger or hand in 3 patients bitten by snakes. Most of the wounds were acquired while farming.A history of previous tetanus immunization was obtained only from 5 patients. Ten patients had an incubation period of less than 1 week and 8 of them suffered from severe disease. Forty-five patients developed the severe generalized type of the disease. A mild or localized type was seen in 7 patients. No cephalic type was recorded. All the patients had trismus, muscular rigidity and dysphagia. Eighty percent had nuchal rigidity, 40 % had dysarthria and risus sardonicus. Abdominal pain was recorded in a third of patients. Penicillin, TT and chloramphenicol were administered. The entire patient had diazepam and chlorpromazine. The mean duration of admission was17.8 days (range 7–34 days). Twenty-nine patients had atelectasis, 10 had autonomic dysfunction and 3 had renal impairment. Overall mortality was 29 % (15 out of 52). Conclusion: Tetanus is a totally preventable disease through routine immunization in childhood and regular booster injections thereafter. The socio-economic status of the patients, immunization status, incubation period, age of patient, severity of spasms, and duration of hospital stay affected the outcome of our patients. A national vaccine promotion campaign and enhanced effort to educate the general public against the so called western propaganda particularly in northern Nigeria where this study was carried out seems warranted. P642 Reversible leucencephalopathy in fulminant pneumococcal sepsis M. P. te Lintelo, P. J. Koehler, T. Dormans, R. Beekman Atrium MC (Heerlen, NL) Objectives: To describe three consecutive patients who had reversible diffuse cerebral oedema of the white matter in the course of a fulminant pneumococcal meningitis. Methods: Retrospective, case series of 3 patients. Results: Three patients were admitted to the intensive care unit because of a pneumococcal sepsis without evidence of meningo-encephalitis. After 2–3 weeks of treatment neurological consultation was necessary because of epileptic seizures. Imaging studies showed a similar pattern of diffuse bilateral symmetric hypodensities of the white matter in all three cases. All patients recovered without neurological deficit. The clinical characteristics of these patients will be presented as well as the possible pathophysiological mechanisms. The syndrome is different from the critical-illness encephalopathy previously described. Direct pneumococcal infection of the brain or meninges was not very likely. We hypothesize an infection-associated encephalopathy, possibly caused by cytokine release in the lung compartment. Conclusion: A diffuse reversible infection-associated leucencephalopathy (DRIL) may occur in the course of a fulminant pneumococcal sepsis.

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P643 Uncommon pseudotumoural MRI lesion of cerebral toxocariosis in an immunocompetent patient F. A. Antochi, C. Tiu, O. Bajenaru University Hospital Bucharest (Bucharest, RO) Background: Toxocariosis is caused by toxocara canis – a multicellular parasite living in dogs, wolves, foxes and cats. The eggs are expelled with stools contaminating the enviroment. Man becomes infected after taking in the eggs together with water and food. The larva is expelled from the egg in the small intestine and migrates with the blood through the lungs and then to the other organs. Objective: To describe an immunocompetent young female patient with a pseudotumoral MRI lesion of cerebral toxocariosis. Result: A 36-year-old-woman, with an episode of meningites of unknown cause one year ago, presented with 6 generalised epileptic seizures in 48 hours and was admitted to our department. The CT scan performed showed a calcified right frontal lesion. CSF presented normal protein and glucose content, but few cellular elements (20 leukocytes/ml). The first cerebral MRI assesment revealed 2 right frontal lesions, which were sugestive for cerebral parasitosis. The patient was serologically positive only for tests of Toxocara (enzyme-linked immunosorbent assay for Toxocara canis antibodies were positive in serum and CSF). After 5 repeated anti-helmintic therapies in 5 months, the patient had another cerebral MRI examination, which showed a pseudotumoral right frontal lesion with contrast enhancement, perilesional edema and mass effect on homolateral ventricle. The patient received corticotheraphy, anticonvulsivant drug and repeated antihelmintic therapy for several months. After 3 months a new cerebral MRI assessment of the patient showed a smaller right frontal lesion than the anterior examination without perilesional edema and mass effect, but with the parasitic larva encysted into the cerebral lesion. Conclusion: We report a case of an immunocompetent young woman, who presented an uncommon pseudotumoral right frontal lesion of cerebral toxocariosis. The MRI assessment after 3 months showed the parasitic larva encysted into the cerebral lesion. P644 Acute disseminated encephalomyelitis developed after herpes simplex encephalitis P. W. Vanwalleghem, A. Terwecoren, A. Sieben, P. Santens University Hospital Ghent (Ghent, BE) Objective: To describe a patient with an acute disseminated encephalomyelitis (ADEM) developed after Herpes Simplex Virus (HSV) encephalitis. Case report: A previously healthy, 42-year old female presented to the emergency department reporting headache, fever and malaise. After a diagnosis of “viral illness”, she was discharged. 24 hours after first presentation she became agitated and incoherent. She returned to the emergency department were neurological examination showed disturbance of consciousness without other neurological deficits. Brain CT was normal. Lumbar puncture (LP) showed 286 WBC/μL (83 % lymphocytes), 1 RBC/μL, normal values of sugar and protein. HSV encephalitis was suspected and the patient was treated with acyclovir IV 12.5mg/kg tid. PCR of HSV DNA on lumbal fluid was positive and confirmed the diagnosis. Initially there was a gradual improvement of the mainly cognitive symptoms, but four days after readmission the patient developed a subacute progressive paraplegia and neurogenic bladder. Neurological examination showed full paralysis of both lower limbs, bilateral brisk patellar reflexes, Babinski reflexes and ankle clonus. Initial MRI of the spine was normal. Initial MRI of the brain showed bitemporal damage consistent with encephalitis. Control MRI total spine and brain showed diffuse white matter lesions with gadolinium enhancement, besides the bitemporal cortical edema. A new LP showed 5WBC/μL, PCR HSV DNA was negative. The diagnosis of ADEM was considered, patient was treated with combination therapy of acyclovir and 250mg SoluMedrol a day (with slow tapering) wich resulted in a dramatic clinical and radiological improvement. One month after the acute event the patient was discharged from our rehabilitation center without neurological sequelae. Discussion: ADEM is an inflammatory demyelinisating disease of the central nervous system and often develops after viral infection. ADEM developed after infection of HSV is relatively rare compared with other viral infections including measles, rubella, varicella and mumps. We report a patient with ADEM after acute HSV encephalitis with dramatic improvement of the neurological picture after addition of corticosteroids to the treatment with acyclovir. In cases of HSV encephalitis, the possibility of ADEM should be considered when acyclovir seems ineffective or symptoms suggesting spinal dysfunction appear. Repeated MRI is useful in these cases to support the diagnosis.

P645 TLR 2 and TLR 4 are responsible for the host detection of Streptococcus pneumoniae during pneumococcal meningitis M. Klein, B. Angele, C. Kirschning, H. Wagner, H. W. Pfister, U. Koedel Ludwig Maximilians University (Munich, DE); Technical University (Munich, DE) Subarachnoid inflammation is a key feature of pneumococcal meningitis. The crucial step for the initiation of this inflammatory response is the detection of the invasive pneumococci by the host. One possibility how pneumococci can be detected is their interaction with toll-like receptors (TLRs). In a recent study, TLR 2 seemed to be one (albeit not the only) pathogen recognition receptor involved. Here, we investigated the additional role of TLR 4 (receptor for peptidoglycan and pneumolysin) and TLR 9 (receptor for bacterial DNA) during pneumococcal meningitis in vitro and in vivo. For in vitro analysis, macrophages of C 57BL/6 mice lacking TLR 2 (TLR 2-/-), TLR 2 and 4 (TLR 24-/-) or TLR 2, 4, and 9 (TLR 249-/-) were stimulated with ethanol killed Streptococcus (S.) pneumoniae type 3 and cytokine release was measured. For in vivo analysis,WT, TLR 24-/-, and TLR 249-/- mice were infected intracisternally with 1.5x10^5 colony forming units of S. pneumoniae type 3. All animals were investigated 24 hours after infection. The in vitro experiments revealed a lower TNF-alpha and Il-6 production of stimulated TLR 2-/-, TLR 24-/-, and TLR 249-/- macrophages in comparison to stimulated WT macrophages. The production of TNF-alpha and Il-6 was lowest in TLR 249-/- macrophages, followed in TLR 24-/- and TLR 2-/macrophages. In vivo, both TLR 24-/- and TLR 249-/- mice developed higher cerebellar bacterial titers and lower cerebrospinal fluid pleocytosis than WT control animals.Accordingly, this was accompanied by a reduced production of Il-1beta and MIP-2 in TLR 24-/- and TLR 249-/- mice. The reduced inflammatory response in TLR 24-/- and TLR 249-/- animals translated into a decreased damage of the blood brain barrier (measured by brain albumin concentration) and brain oedema (measured by brain volume).A significant difference between TLR 24-/- and TLR 249-/- mice could not be observed. Thus, although the in vitro experiments suggested a role for TLR 2, TLR 4, and TLR 9 in the recognition of S. pneumoniae, only TLR 2 and TLR 4 seem to play a role in the activation of the innate immune response in vivo during pneumococcal meningitis. The financial support of the Deutsche Forschungs-Gemeinschaft DFG to UK (SFB 576/A 5) is greatly appreciated.

P646 Herpes simplex encephalitis in the adult: experience of 15 years L. Gubieras, L. Romero-Pinel, A. Riera, S. Martínez-Yélamos, J. Niubó, C. Cabellos, P. Fernández-Viladrich, T. Arbizu Bellvitge University Hospital (Hospitalet de Llobregat, ES) Objective: The objective of this study is to describe our experience with patients who had been admitted to our hospital and diagnosed of herpes simplex encephalitis (HSE) during the last 15 years. Methods: This is an observational study in which we studied the patients diagnosed of HSE from 1992 to 2006 in the Bellvitge University Hospital. We analyzed demographic, clinical, diagnosis and therapeutical data. The neurological sequelae were evaluated at the moment of discharge as well as 6 months later. Results: We found 35 patients diagnosed of HSE during the mentioned period. The basal characteristics of this cohort showed a mean age at onset of the disease of 54 years (18–89). The rate of men was 63 %. The percentage of patients with other weakening diseases was 14.3 %. The mean duration of symptoms was 5 days before admission and included cephalea (68.6 %), confusion (57 %), behavioural changes (54 %), nausea/vomiting (43 %) and seizures (40 %). In the physical examination all of them had fever (mean 38.7°C). In the neurological examination the level of conciousness was impaired in 54.3 % of the patients, meningeal signs were found in 14.3 %, impairment of long tracts and/or aphasia in 51.4 % and cranial nerves in 8.6 %. The mean level of leukocytes, proteins and glucose in the CSF were 97/mcL, 0.83g/L and 3.7 mmol/L, respectively. The PCR of Herpes Simplex Virus (HSV) was performed in 26 patients and it was positive in 24. Their brain CT scan was pathological in 45.7 %. The EEG performed after a mean time of 2 days after admission was compatible with HSE in the 84 %. The MRI was performed in 27 patients and it showed typical signs of HSE in the 100 %. in the 100 %. They all were treated with acyclovir, the 66 % also received anticonvulsant treatment and the 31.4 % antiedema treatments. The 25.7 % were admitted in an intensive care unit. They were discharged after a mean time of 29 days. The mortality was of 8.6 %. When discharged, the 31 % had moderate-severe residual disability, the neurological sequelae were aphasia (41 %), affectation of memory (28 %), behavioural changes (16 %) and seizures (12.5 %).After 6 months, the 22 % still had moderate-severe disability, the se-

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quelae were aphasia (31 %), behavioural changes (16 %), affectation of memory (16 %) and seizures (3 %). Conclusions: The PCR of the VHS was positive in the 92.3 %. The 100 % of MRI performed showed typical signs of HSE. P647 Neuroradiological appearance of neurosyphilis, presenting as hypertrophic pachymeningitis with spinal gumma and secondary arachnoid cyst formation C. Koutsona, C. Mohs, V. Jost, U. Meyding-Lamade, B. Kress Krankenhaus Nordwest (Frankfurt am Main, DE) Objectives: We present the neuroradiological findings in a case of syphilitic meningitis characterized from a spinal gumma and secondary arachnoidal cyst formation in the cervical spinal canal. Methods: MRI of the head and cervical cord was performed on a 1.5 MR scanner. T 1-weighted spin echo and T 2- weighted fast spin echo images were obtained before and after the application of contrast medium. Results: The patient was a 36-year-old woman with a history of heroin abuse, who presented with a paralysis of the right extremities and a moderate weakness of the left extremities. The cranial MRI showed a leptomeningeal enhancement along the surface of the pons, medulla and cerebellum. The MRI of the neck revealed an extramedullary, contrast enhancing mass lesion, which was located in the anterior epidural space at level C 2- C 4 and led to a severe compression of the spinal cord. The medulla and the cervical spinal cord displayed increased signal intensity in the T 2 weighted images. These findings were consistent with basal meningitis and the epidural mass lesion was assumed to be a spinal granuloma or gumma. The investigation of the cerebrospinal fluid (CSF) proved a syphilitic meningitis and treatment began. The follow up MRI of the neck showed a second mass lesion in the left portion of the cervical spinal canal at the level of foramen magnum, which compressed and ventrally displaced the spinal cord. This lesion displayed a CSF- like signal intensity in all sequences and the diagnosis of a secondary arachnoid cyst formation was considered. This cyst showed a progress, so that a neurosurgical decompression was needed twice. Discussion: A gumma is an exuberant granulomatous response of the meninges. Most of the reported cases refer to intracranial gummas in the cortex of the brain, whereas gummatous mass lesions in the spinal canal are extremely rare. Intradural spinal arachnoid cysts are secondary to severe leptomenigeal infection. The majority occurs in the thorasic region and only 15 % in the cervical region. Secondary intradural arachnoid cyst formation and spinal gummas can be a rare cause of progressive myelopathy in patients with syphilis, which still deserves to be included among the causes of basal meningitis beside tuberculosis.

Multiple sclerosis P648 From EAE to an MS clinical trial: DR 2/MOG-35–55 recombinant T cell receptor ligand treats relapses of experimental encephalomyelitis in DR 2 transgenic mice A. Vandenbark, G. Burrows, H. Offner, J. Link Portland VA Medical Center (Portland, US); Oregon Health & Science University (Portland, US) Objectives: To evaluate the ability of a newly designed monomeric recombinant TCR ligand, RTL 342M, containing HLA-DR 2 peptide-binding domains covalently linked to MOG-35–55 peptide, to prevent and treat both the initial episode and subsequent relapses of experimental autoimmune encephalomyelitis (EAE) in HLA-DR 2 transgenic mice, in preparation for a safety trial in patients with multiple sclerosis (MS). Methods: Single or multiple doses of RTL 342M were given either i. v. or s. c. to HLA-DR 2 mice prior to, at onset, or during relapses of paralytic EAE. Results: RTL 342M produced a rapid (within 24 h) and dose dependent reversal of clinical signs of paralytic EAE, and even a single dose < 2μg could produce a significant treatment effect. Multiple daily doses were even more effective than the same total amount of RTL given as a single dose. By establishing the minimal effective dose, we determined that RTLs may be 50 times more potent than molar equivalent doses of myelin peptide alone. RTL 342M given prior to induction of EAE prevented disease in most mice, and the remainder could be successfully re-treated with RTL. Most important for clinical application, RTL 342M was highly effective for treating EAE relapses when given periodically prior to the relapse or even after relapses had occurred. Conclusions: These data demonstrate the rapid and potent clinical ef-

fects of RTL 342M at disease onset and during relapses in EAE and establish important principles governing the application of this novel, highly selective therapeutic approach for regulating pathogenic T cells. The data from this study provide key preclinical information for a Phase I safety study in patients with MS (outline to be presented) that is now in progress. Drs. Vandenbark, Offner, & Burrows, and the OHSU have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the result of this research and technology. P649 Cognitive impairment and polymorphisms of cathepsin D in multiple sclerosis M. J. Stone, J. A. Woolmore, P. Jenkinson, R. Stephens, T. Mihalova, D. Langdon, A. A. Fryer, R. Strange, C. P. Hawkins University Hospital of North Staffs (Stoke-on-Trent, UK); Keele University (Stoke-on-Trent, UK); Royal Holloway – University of London (London, UK) Introduction: Cognitive impairment in Multiple Sclerosis (MS) affects 45–60 % of patients and significantly impairs quality of life. Cathepsin D has been indicated to be significantly associated with general intelligence in a healthy elderly population. A functional Cathepsin D polymorphism at position 224 in exon 2 (RS 17571), which results in an Ala38-toVal substitution has been linked to an increase risk of developing Alzhiemer’s disease. The CTSD polymorphism, RS 17571, may enchanced the susceptability conferred by the APOE*4 allele in Alzheimer’s disease. We have examined cathepsin D single nucleotide polymorphisms (SNPs) to see if there is an association with cognitive impairment in MS. Method: 194 unrelated Northern Europeans diagnosed with MS using the Poser Criteria, at the University Hospital of North Staffordshire underwent neuropsychological assessment. The battery of tests included Wisconsin card sorting test 64 (WCST 64), Rey auditory verbal learning test (RAVLT), Judgment of line orientation, Controlled oral word association (COWT), Symbol digit modalities task (SDMT). The National Adult Reading Test (NART) and Hospitals Anxiety and Depression Questionnaire (HADS) were used to control for potential covariates. Three tagged cathepsin D SNPs RS 17 571 (C>T), RS 2 292 962 (G>A) and RS 2 292 963 (C>T) were genotyped using pyrosequecing technology. Scores from each task were transformed to z-scores and summed. A multiple linear regression model was used to analyse for association between the total neuropsychological scores (NP) and genotypes. Results: The mean age of onset was 34 years with a mean duration of 15 years. 78 % were female and 22 % male. There was no association between overall neuropsychological (NP) scores and patients with the RS 17 571 functional mutant T allele (n = 29) p = 0.45. There was no association between overall NP scores and the two intronic SNPs RS 2 292 962 and RS 2292963. Analysis of the individual neuropsychological test results and genotypes showed no relationship. Conclusion: There was no relationship between the cathepsin D polymorphisms and neuropsychological disability in MS patients. The effect of the APOE*4 allele may be enhanced by the cathepsin D polymorphism RS 17 571 and analysis of such genotype combinations with neuropsychological outcome would be worthwhile. P650 The predictive ability of magnetic resonance imaging to progression of clinical disability in patients with multiple sclerosis M. Vaneckova, Z. Seidl, J. Krasensky, E. Havrdova, D. Horakova, O. Dolezal, T. Vitak, M. Masek General Teaching Hospital (Prague, CZ) Objectives: To correlate the change of lesion load and whole brain volume using MRI scans in patients with multiple sclerosis (MS) with clinical disability, which is represented by EDSS (Expanded Disability Status Scale). Materials and methods: A large cohort of 181 patients with clinically definite relapsing-remitting (RR) MS and 45 healthy control subjects (used for normalization of brain atrophy with respect to age) underwent magnetic resonance imaging for period up to 5 years. Mean age was 31 years, mean duration of disease 6 years and median EDSS score 2. MRI was made every 8 weeks at the first two years, then EDSS was determined every year, in same time with MRI. Lesion load in MRI were assessed automatically from FLAIR images, brain atrophy from T 1W 3D with the help of software developed in our department. Data on lesion load and atrophy were correlated with the clinical status rated by EDSS. Semiautomatic procedure was used for signal evaluation. Results: Moderate correlation was found between the change of lesion load, together with decrease of the brain volume (corrected for age) of patients with MS and the EDSS score change, while using Spearman rank cor-

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relation. Increased brain atrophy was statistically significant for RR MS patients, when compared to the healthy control group. Conclusion: Study analyzed the correlation of MR with clinical disability. Partial predictive power of MR has been observed, an increase in lesion load was followed by the increase in EDSS score after some time delay. Brain atrophy appeared as a reliable marker of clinical deterioration. This study was supported by the grant MZO/00064165. P651 First demyelination and cognition in multiple sclerosis J. Faiss, A. Apel, K. Baum, D. Dähne, R. Deppe, L. Daume, T. Göttken, F. Hoffmann, W. Köhler, A. Kunkel, G. Prawdzik, M. Sailer, S. Scheerschmidt, H. Schilling, U. Wachowius, U. Zettl Asklepios Fachklinikum Teupitz (Teupitz, DE); Universität Rostock (Rostock, DE); Klinik Hennigsdorf (Hennigsdorf, DE); Städtisches Krankenhaus Martha-Maria (Halle, DE); Fachkrankenhaus Hubertusburg (Wermsdorf, DE); Universitätsklinikum Magdeburg (Magdeburg, DE) Objectives: Within the scope of Multiple Sclerosis (MS) 40 to 60 % of patients develop cognitive impairment mostly in the later course of the disease. Only little is known about cognitive deficits in the very early stage of the disease. The aim of the present study is to evaluate cognition directly after the first clinical presentation in patients with MS. Methods: We recruited 47 patients (15 male, 32 female, age 31.2 ± 8.9 years) after a first MS-related clinical event. At this time 53 % of all patients were classified as clinically isolated syndrome and 47 % as relapsing remitting MS (McDonald criteria). Functional disability of the cohort measured according the Expanded Disability Status Scale (EDSS: median = 1.5, range 0.0–4.0) was mild. Three to six months after the first neurological examination a neuropsychological test battery, specifically validated for MS was applied. It consisted of verbal and figural memory, attention an executive function tasks. Furthermore, a depression scale, the Modified Fatigue Impact Scale (MFIS), the scale for Functional Assessment in MS (FAMS), a test for intellectual capabilities and the Multiple Sclerosis Functional Composite (MSFC) were used. Results: The percentage of patients classified as impaired was based on a performance lower than two standard deviations of the normative sample. In detail, neuropsychological assessment demonstrated in 13 % of all patients a divided attention deficit, in 6 % a reduced information processing speed and working memory performance, in 17 % figural learning impairment and in up to 15 % executive dysfunction. Depressive symptoms were evident in 11 % of our cohort and fatigue in 36 %. Intellectual capabilities were not affected (z-norm M = 0.0 ± 0.6). Conclusions: Specific cognitive deficits, e. g. impaired divided attention, disturbed figural learning function and impaired executive functions, can be shown even after a first MS-related clinical event in up to 17 % of the patients. P652 Interferon beta therapy increases serum ferritin levels in multiple sclerosis patients A. Sena, R. Pedrosa, V. Ferret-Sena, M. J. Cascais, R. Roque, C. Araújo, R. Couderc Faculdade de Ciências Medicas (Lisbon, PT); Hospital dos Capuchos (Lisbon, PT); Cooperativa Egas Moniz (Lisbon, PT); Hôpital Trousseau (Paris, FR) Objectives: Abnormalities in iron metabolism have been suggested to be involved in the pathogenesis of multiple sclerosis (MS). Supporting this view, increased ferritin levels in cerebrospinal fluid and serum have been associated with the chronic progressive form of the disease. This up-regulation of ferritin expression is thought to protect against oxidative injury. However, ferritin levels have been found unchanged in relapsing-remitting (RR) MS patients. In order to gain insights about its role in the disease, we decided to investigate the influence of interferon (IFN) beta therapy on serum ferritin levels. Methods: Serum ferritin was determined in 35 no anaemic RR-MS female patients (35.17±9.83 years) and 32 age-matched female controls. Patients were studied in stable clinical conditions before and 12 months after the beginning of IFN-beta therapy (19 Betaferon, 9 Rebif, and 7 Avonex). Clinical data were recorded and correlated with the biochemical findings. Ferritin concentrations were determined by using a chemiluminescent microparticle immunoassay (Abbott). ANOVA and Student’s t-tests were used for comparison between groups and Student’s t test for paired data for comparison of ferritin levels in the same patients before and during treatment. Results: Before treatment, ferritin levels in patients were comparable to those found in controls (41.33 ± 31.93 ng/ml vs. 49.68 ± 38.63 ng/ml,

p = 0.337).However,these levels increased to 64.82 ± 56.01 ng/ml (p = 0.0016) after the beginning of IFN-beta therapy. This induction was most pronounced for subjects treated with Betaferon (p = 0.0083). No correlations were found between these levels and the clinical response to the therapy. Conclusion: Our results indicate that IFN-beta therapy may increase serum ferritin levels in MS patients. This up-regulation of ferritin expression is consistent with a protective role of this acute phase protein. Larger prospective studies are needed to determine the clinical implications of these findings. Supported by Bayer-Schering. P653 Paroxysmal dystonia in multiple sclerosis M. Karouli, C. Potagas, D. Mandellos, G. Koutsis, C. Sfagos University of Athens (Athens, GR) Objectives: Clinicoanatomical correlation of paroxysmal dystonia in Multiple Sclerosis (MS). Material and Methods: Among 567 patients with MS or clinically isolated syndrome (CIS), indicative of MS, followed at the demyelinating diseases Unit of our hospital during the period 2003–2006, we found and studied seven patients with paroxysmal dystonia (five women and two men, mean age 31.5, range 23 to 46 years). Results: Paroxysmal dystonia was the initial manifestation of the disease in six patients; one had presented with optic neuritis two years earlier. All seven patients presented with brief, recurrent episodes of abnormal posturing of right or left limbs. Facial muscles were affected in one patient. Pain was present in three and dominated clinical presentation in two. A large, gadolinium enhancing lesion, located at the posterolateral thalamus, contralateral to the affected limbs, was found in the brain MRI of all patients. In two, this lesion was unique at presentation. Five patients responded well to carbamazepine and two were efficiently treated with cortisone per os. Discussion: Paroxysmal dystonia is a rare but well recognized symptom of MS, appearing mostly at the early stages of the disease. Anatomical correlates of paroxysmal dystonia are not well understood as the usual multiplicity of lesions in MRI prevents the identification of a causal lesion. In all seven cases presented here, identical, gadolinium enhancing, thalamic lesions were found; in two there were nï other lesions. This allows us to hold this lesion as responsible for the clinical manifestation of paroxysmal dystonia in the present cases. P654 Magnetic resonance imaging of the cervical spinal cord in patients with relapsing-remitting multiple sclerosis during immunomodulating therapy E. Shipova, N. Spirin, D. Kasatkin, E. Shumakov, I. Stepanov Yaroslavl State Medical Academy (Yaroslavl, RU); Yaroslavl Railway Hospital (Yaroslavl, RU); Yaroslavl City Hospital #8 (Yaroslavl, RU) Background: Involvement of the cervical spinal cord in multiple sclerosis (MS) is extremely common and an important element in the development of disability. There is no enough information about changes of cervical lesions and atrophy after immunomodulating therapy. Objective: To measure lesion volume and cord size during a 1-year period of treatment. Method: Magnetic resonance imaging (MRI) of the cervical part of the spinal cord was made in 34 patients with definite relapsing-remitting MS (RRMS). Cervical lesions were found in 30 patients (88.2 %) and below we are discussing only the results of this group. It consisted of 12 men and 18 women, the mean age was 31.7 year (28.5–35.0, alpha< 0.05), the mean EDSS was 2.7 (2.3–3.0, alpha< 0.05), the mean duration of MS was 4.3 year (3.1–5.5, alpha< 0.05). Each patient underwent T 1 and T 2 weighted imaging of the cervical cord, and all sequences were acquired as contiguous 4 mm thick, sagittal, frontal and axial slices. The examination was made twice with the 14-months interval. During the observation period patients have been receiving immunomodulating therapy (Interferon-beta 1 a – 7 patients, Interferon-beta 1 b – 13 pts, Glatiramer acetate – 10 pts). The volume of lesions and the size of spinal cord at the C 2 level were counted before and after treatment. We have used programmes SPM 5 based on MATLAB 7.0 and Jim 4.0 for processing of the images and morphometry. Results: Cervical lesions presented as well-circumscribed fusiform foci of increased T 2 signal, ranging in length from 2 to 15 mm. The significant decrease of lesion volume was detected: before treatment – 10 993 mm3 (8098–13888, alpha< 0.05, ME = 9336), after – 5630 mm3 (7400–3860, alpha< 0.05, ME = 4180) (p = 0.002). These changes were more prominent in patients treated with Interferon-beta 1 b and Glatiramer acetate (p = 0.026 and p = 0.027). There was also a difference in atrophy in-

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creasing (H(2, N = 30) = 8.06 p = 0.0178). The atrophy extent was less after therapy with Glatiramer acetate in comparison with Interferons-beta (p < 0.02). Conclusions: The serial measurement of spinal cord lesions and atrophy may make an important contribution to the evaluation of therapeutic efficacy, especially in patients with prevalence of spinal plaques. Further research could help to choose the best medication to prevent spinal atrophy and lesion increasing.

P655 Intrathecal triamcinolon as a disease-modifying therapy in advanced multiple sclerosis: an open study S. Bölch, H. Heilmeyer-Kohler, J. Kohler Center of Neurology, Neurogeriatrics (Emmendingen, DE) Objectives: MS is a chronic demyelinating disease with compartmentalisation of inflammation in the central nervous system (CNS). This advanced stage also is characterised by a fully functional blood-brain-barrier. Therefore orally or intravenously administered immunological active agents can not be efficient. So far intrathecal Triamcinolon therapy (ITT) is a rare therapeutic option in symptomatic therapy of MS but the method is not accepted as a disease modyfing therapy (DMT)in MS. Patients & Methods: Between February and December 2006 we investigated 23 patients (12 females, median age 45 years) with advanced chronic MS (EDSS 4.5–7.5). 11 patients had a mild to moderate cognitive impairment. In the early course of MS all patients received an immunological medication (Beta-Interferons, Glatiramer acetate, Mitoxantron, Methylprednisolon) prior to ITT. 81 injections with a median dose of 52 mg Triamcinolon/injection (1–7 injections of Triamcinolon/patient, median 3 injections/patient with a median interinjection intervall of 33 days in patients with more than 2 injections) were done with an 26 gauge lumbar spinal needle after local anesthesia in aseptic procedure. The indication for ITT was made by the treating neurologist after clinical criteria, the injection itself was done by the anesthesiologist and pain specialist in the center. The evalutation was made by the clinicans and the patient himself according to clinical global impression (CGI) on an 5 point Likert scale (worse, unchanged, mild, moderate, dramatic response). Results: Adverse events (AE) were observed in 2 patients (8.7 %). 1 patient developed a postpuncture headache in combination with temporary hear loss and paralysis of the abducens nerve. Another patient developed a marked weakness of the legs after the first ITT. In these cases ITT was terminated. 21 patients showed no further AE or worsening. 11/23 patients had an unchanged to a mild response, 6/23 a moderate and 4/23 patients (17.4 %) an unexpected dramatic positive response. These 4 patients were characterised by improved motor control of the spastic tetraparesis and a better performance of the marked subcortical cognitive deficits prior to ITT. Conclusion: In the advanced stage of MS ITT is a save and effective treatment, especially for patients who have no option for further causal therapy. In knowledge of the recent neuropathological results ITT now acts as a DMT. Further controlled studies are on their way in our center.

P656 Brain MRI lesions and mental disorders in multiple sclerosis patients: a preliminary investigation G. Papazisis, K. Katsigiannopoulos, G. Garyfallos, T. Afrantou, A. Angelou, M. Paschalidou, I. Milonas, A. Adamopoulou Community Mental Health Center North-West District (Thessaloniki, GR); Aristotle University (Thessaloniki, GR) Objectives: The aim of the present study is to investigate the association between involvement of specific brain areas and the occurrence of anxiety, depressive and personality disorders in patients with multiple sclerosis (MS). Methods: 26 patients with clinically definite MS were studied. Psychiatric diagnoses were made according to DSM-IV criteria. All subjects underwent brain MRI. Calculation of regional and total lesions was performed. Results: 6 (23 %) of the patients had no diagnosis on axis I. The number of patients with diagnosis of major depression was 17 (65 %), 4 (15 %) of them in comorbidity with an anxiety disorder. 3 (11 %) patients suffered only from an anxiety disorder. 10 (38 %) had no diagnosis on axis II. The rest of them were mostly classified in cluster B of personality disorders, in which histrionic and borderline traits were more common. 5 (19 %) patients exhibited traits of cluster C personality disorders. The majority of the depressed patients had lesions cited in the right frontal and parietal lobe. No differences were noted for the temporal lobe. The anxiety disorders did not correlate significantly with any of the measures of regional and total lesions. Patients with cluster B personality disorders exhibit more frequently lesions

on the right than on the left hemisphere. No difference was observed in the group of cluster C personality disorders. Conclusions: The findings of the present study although preliminary suggest a correlation between depression and lesions on the right hemisphere, thus supporting the causative role of an organic brain damage. The finding that patients with a cluster B personality disorder had predominantly lesions on the right hemisphere has not previously reported. Further structural and functional studies are required in order to evaluate the possible relationship between lesions in specific brain areas and personality disorders in MS patients.

P657 Immunomodulatory treatments for preventing conversion from clinically isolated syndromes to multiple sclerosis: a Cochrane review on their efficacy M. Clerico, F. Faggiano, J. Palace, G. Rice, M. Tintore’ Subirana, L. Durelli San Luigi Gonzaga University Hospital (Orbassano, IT); Piemonte Orientale University (Novara, IT); Radcliff Infirmary Hospital (Oxford, UK); University of Western Ontario (London, CA);Val d’Hebron Hospital (Barcelona, ES) Objective: To assess the efficacy of Interferon(IFN) beta treatment in reducing the risk of conversion from clinically isolated syndromes (CIS) to clinically defined multiple sclerosis (CDMS). Design/method: Following the Cochrane methodology inclusion criteria (types of studies, types of participants, type of interventions, types of outcome measures) and search strategies (medical literature, data bases, abstracts books) have been established. Results: 454 papers identified; 430 not eligible; 6 all referred to CHAMPS and ETOMS studies, both using once-weekly low-dose (22 or 30 mcg) IFN beta 1 a; 1 referred to BENEFIT study, using multiple weekly 250 mcg IFN beta 1b. The three studies had different outcomes (occurrence of a second clinical episode or of disease progression in CHAMPS; occurrence of a second clinical episode in ETOMS; time to CDMS in BENEFIT). We calculated the risk of conversion to CDMS in per protocol and Intention to Treat sensitivity (best, worst, and likely scenarios) analyses. Per protocol analyses showed that IFN beta treatment significantly prevented the outcome in all studies. Results of CHAMPS study were not statistically significant in both worst and likely scenarios at 1 year (analyses at 2 years were not possible because not all the enrolled patients completed the 2-year follow up). ETOMS results were statistically significant in all scenarios but the worst one at 1 year; significant only in best scenario at 2 years. BENEFIT results were statistically significant in all scenarios. The metanalysis at 1 year for CHAMPS and ETOMS, made taking off the 5 CHAMPS patients whose conversion was due to progression was significant in per protocol analysis and in all sensitivity analyses but the worst scenario. The metanalysis at 2 years for ETOMS and BENEFIT, made taking off the 2 BENEFIT patients whose conversion was due to progression was significant both in per protocol as well as all sensitivity analyses. Conclusion: The efficacy of low-dose once-weekly IFN beta1 a treatment in preventing conversion to MS was modest at 1 year, and not strongly confirmed beyond the first year. The efficacy of multiple-weekly high-dose IFN beta1 b was confirmed in all sensitivity analyses at 2 years, as it was the case for the metanalysis of BENEFIT and ETOMS data at 2 years. Merging data obtained with the multiple-weekly high-dose protocol (BENEFIT) with those obtained with the low-dose once-weekly one (ETOMS) increased and extended to 2 years the statistical significance.

P658 TRAIL, CXCL 10 and CCL 2 plasma levels during long-term interferon-beta treatment of patients with multiple sclerosis do not predict therapeutic response M. Buttmann, C. Merzyn, H. H. Hofstetter, P. Rieckmann Julius-Maximilians-University (Wurzburg, DE) Objectives: High serum levels of soluble TRAIL before or during the first year of Interferon-beta (IFN-beta) therapy were shown to predict an individual therapeutic response of patients with relapsing-remitting multiple sclerosis (RRMS). Here, we investigated whether TRAIL or chemokine plasma levels during long-term IFN-beta treatment correlate with future therapeutic response or adverse effects of treatment. Methods: Plasma levels of soluble TRAIL, CXCL 10 and CCL 2 in 37 longterm IFN-beta-treated MS patients were determined with commercial ELISA kits. Measurements were performed immediately before, six hours and 24 hours after injection. The patients had to fill out a self-administered questionnaire on flu-like symptoms. 30 of these patients were prospectively followed for two years by blinded clinical investigators and the correlation

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between TRAIL as well as chemokine levels and clinical treatment response was analyzed. Results: Postinjection short-time bursts of soluble TRAIL were associated with flu-like symptoms and IP-10/CXCL 10 as well as MCP-1/CCL 2 induction, and were detected after up to 6 years of continuous IFN-beta therapy. However, neither TRAIL nor chemokine levels correlated with the oneand two-year clinical treatment response. Conclusion: In this cohort of long-term-treated RRMS patients neither TRAIL nor chemokine levels allowed prediction of the therapeutic response. This study was supported by an unrestricted educational grant from Serono and local funds from the state of Bavaria. Serono had no role in the planning, performance and report of this study. The authors have no competing financial interests.

P659 Impact of relapses on total costs of care for patients with multiple sclerosis A. AL-Sabbagh, M. Cisternas, A. Foreman, D. Miller, R. Bennett EMD Serono, Inc. (Rockland, US); Ovation Research Group (San Francisco, US) Objective: We investigate the impact of recurrent relapses on short- and long-term healthcare costs in the United States. Relapses in multiple sclerosis (MS) are a major burden on patients’ welfare and related healthcare costs, and have been shown to impact residual disability (1). While relapse costs have been reported previously (2), no publication has examined the impact of recurrent relapses on total healthcare costs. Methods: We used medical (International Classification of Diseases-9 diagnoses) and pharmacy claims from a large, US National Health Plan database to identify MS patients with ≥ 1 relapse who had enrolled in the plan between 2002–2004, and who had continuous enrolment 6 months pre- and 12 months post-index relapse. Costs were estimated based on claim charges, and were adjusted to project the amount in 2005 US dollars. Analyses were stratified by whether patients were newly diagnosed or previously diagnosed, and by the number of relapses they had experienced (1 or ≥ 2). Costs were analyzed in 90-day intervals in reference to the index relapse period (days 0–30). Results: Newly diagnosed patients with ≥ 2 relapses had higher monthly costs compared with patients with 1 relapse only at days 0–30 (index relapse) ($26.890 vs. $16.121), 31–90 ($3597 vs. $1506), and 271–360 ($3768 vs. $1074). Although previously diagnosed patients with ≥ 2 relapses had costs similar to those of patients with 1 relapse only at index relapse at days 0–30 ($21 350 vs. $21015), monthly costs were higher for patients with ≥ 2 relapses at days 31–90 ($3792 vs. $2712) and remained higher at days 271–360 ($3636 vs. $1676). Monthly costs were generally higher for previously diagnosed patients; however, the cost of the acute phase of relapse (days 0–30) in the ≥ 2 relapses subset was lower for previously diagnosed patients compared to their newly diagnosed counterparts ($21.350 vs. $26.890). Conclusion: Recurrent relapses are associated with increased costs, both in the acute phase of managing a relapse and during the follow-up year in both newly diagnosed and previously diagnosed patients. Study supported by EMD Serono, Inc.

P660 Modulation of the immune response in malaria-infected mice and its effects on experimental autoimmune encephalomyelitis A. S. Farias, R.L Talaisys, C. G. Pereira, B. O. Carvalho, L. M. B. Santos, F. T. M. Costa UNICAMP (Campinas, BR) Objective: EAE is used as an animal model for human multiple sclerosis (MS), an inflammatory demyelinating autoimmune disease of the central nervous system that is characterized by activation of Th1 cells. Many of immunological changes can modulate EAE; however it is believed that the mainly process relies on regulatory T cells and the expression of anti-inflammatory cytokines such as; TGF-beta, IL 4 and IL 10. Globally, malaria represents the most nefarious infectious disease, and affects more than 500 million people per year. In subtropical regions, particularly in Africa, malaria results in extensive and debilitating health and economic burdens. In Brazil, 400,000–600,000 cases of malarial infections are reported annually. The balance of cytokine levels and the timing of their production control the parasite growth and the development of severe forms of the disease. Recent study demonstrates that regulatory T CD 4+CD 25+ cells, through to their immunosuppressive effects, would allow the persistence of the parasitemia. This immunosuppressive state may control the evolution of autoimmune diseases and allergy. In this study, we verified whether modulation of the immune system in malaria-infected mice can interfere with the evolution of au-

toimmune disorders such as experimental autoimmune encephalomyelitis (EAE). Materials and Methods: C 57BL/6 mice were infected with 10E 6 P. chabaudi chabaudi AS-parasitized erythrocytes before or concomitantly with the peak of EAE clinical symptoms. Results: We have observed that the concomitant induction of EAE in malaria-infected mice reduced significantly (p < 0.001) the clinical symptoms of EAE. This reduction of the severity of the disease was negatively correlated (p < 0.0001; = –0.888; r2 = 0.750) with the levels of parasitemia. In contrast, when EAE was induced after malaria infection, an increase in the symptoms of EAE was observed. Conclusions: These data demonstrate that the immune response against malaria parasites can modulate either positively or negatively the autoimmune disorders and open perspectives to better understanding the immune mechanisms that may modify the course of autoimmune disease and the possible impact of this modulation in malaria endemic areas. Financial support: FAPESP, CNPq and FAEP-UNICAMP. P661 Effect of early interferon beta-1 a therapy on conversion to clinically definite multiple sclerosis in Iranian patients with a first demyelinating event H. Pakdaman, A. Fallah, R. Pakdaman, M. A. Sahraian, M. Ghafarpour, K. Gharaeghouzli Beheshti University of Medical Sciences (Tehran, IR); Tehran University of Medical Sciences (Tehran, IR) Background: A new treatment approach to multiple sclerosis (MS) is the initiation of interferon therapy in the early phase of the disease when a patient presents with clinically isolated syndrome. Aims of the study: The goal of this study, which is the first of its kind on Asian patients with MS, was to assess the effect of early interferon beta-1 a treatment on the risk of conversion to clinically definite MS in Iranian patients. Methods: Eligible patients had presented with a first episode of neurological dysfunction suggesting MS within the previous 3 months and had positive brain MRI scan. Patients were randomly assigned Avonex 30 g or placebo intramuscularly once weekly for 3 years. Neurological and clinical assessment and brain MRI scan were done on a regular basis. Results: Of the 217 patients randomized, 202 patients completed the study; 104 received Avonex treatment and 98 received placebo. Fewer patients converted to CDMS in the Avonex group than in the placebo group during the 3-year study (36.6 % vs. 58.2 %, p < 0.003). The number of new T 2weighted and enhancing MRI lesions were significantly lower in Avonex group. Conclusions: The results of our study, which are in consistent with those from western studies on white patients, show that Avonex treatment at an early stage of MS delays conversion to defenite MS and has positive effects on MRI outcomes. P662 Delayed allergic reaction to natalizumab associated with early formation of neutralizing antibodies M. Krumbholz, H. L. Pellkofer, R. Gold, L. A. Hoffmann, R. Hohlfeld, T. Kümpfel Klinikum Grosshadern (Munich, DE); University of Bochum (Bochum, DE) Objective: Natalizumab is a new therapeutic option for relapsing-remitting (RR) multiple sclerosis (MS). As with other antibody therapies hypersensitivity reactions have been observed, which developed usually within 2 h after starting the infusion. Patient and methods: We report a significant delayed, serum sicknesslike type III systemic allergic reaction, which developed over several days after the second infusion of natalizumab in a 23-year old male patient with RR MS. His symptoms, consisiting of fever, arthralgias and an urticarial rash, completely resolved with a short course of low-dose glucocorticosteroids. Five weeks after initiation of therapy the patient tested positive for anti-natalizumab antibodies and exhibited persistent antibody titers 9 and 12 weeks later. Therapy with natalizumab was discontinued and replaced by therapy with mitoxantrone. Conclusion: Clinicians and patients should be alert not only to immediate but also to significantly delayed allergic reactions to natalizumab.

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General neurology P663 Evaluation of frontal brain activation in response to an attention task by functional near-infrared spectroscopy F. Locatelli, M. Butti, S. Galbiati, F. Formica, P. Avantaggiato, M. Caffini, S. Cerutti, A. Bardoni, S. Strazzer IRCCS E. Medea (Lecco, IT); University of Milan (Milan, IT) Objectives: Functional near-infrared spectroscopy (fNIRS) is an optical brain imaging system that enables continuous, non-invasive and portable monitoring of changes in the levels of deoxy-hemoglobin (Hb), oxy-Hb and blood volume related to human brain function. Recent findings indicate that a multichannel time domain (TD) fNIRS can provide spatial maps of homodynamic changes in the frontal areas during cognitive tasks. Moreover, attention is a cognitive function attributed to frontal and more complex cerebral activation. Our study aims to evaluate if multichannel TD fNIRS is a useful and valid procedure to monitor frontal activity during an attention task under physiological conditions. Methods: Six healthy subjects carried out the modified Connor’s Continuous Performance Task (CPT) test. Subjects were instructed to press the response button with the index finger of their right hand as fast as possible when any letter other than X appeared on screen, and to inhibit their response when an X appeared. The activation time was 10 min. A dual wavelength (690/820nm) multichannel TD fNIRS was used.An optical probe consisting of 16 canals was placed over the subjects’ head to cover the underlying prefrontal cortex and was centred at Fp1 and Fp2 for the left and right sides, respectively. The levels of oxy and deoxy-Hb, total Hb and tissue oxygen saturation were derived from data collection (Lambert-Beer Law, see Nomura). Results: Results apply to all the subjects.A significant difference in blood changes was found between activation and rest. The grand-average curves demonstrated a progressive increase of oxy-Hb during activation, which remained higher than the baseline after the task, while deoxy-Hb rapidly decreased at the beginning of the task to gradually approach the baseline at the end of the task. An increase in oxy-Hb was found both in the right and left prefrontal cortex with an asymmetrical prevalence on the right side. Deoxy-Hb showed a symmetrical distribution in the central region of the prefrontal cortex. Conclusions: The multichannel TD fNIRS proved useful in measuring hemispheric differences in oxygen supply and consumption after standardized cognitive activation. This technique could be applied to pathological conditions in order to detect cognitive changes for rehabilitation purposes.

P664 Evaluation of autonomic functions in patients with selected diseases of the central nervous system B. Labuz-Roszak, K. Pierzchala Silesian University School of Medicine (Zabrze, PL) Background: Autonomic dysfunction in patients with diseases of the central nervous system occurs as a result of structural or functional lesions of autonomic centers. It worsens health state of the patients and can be the reason of life-threatening complications. The aim of the study was to evaluate autonomic nervous system in chosen diseases of the central nervous system and to assess clinical usefulness of applied methods. Objectives: 88 patients were examined: 24 pts with multiple sclerosis (mean age: 37.8 ± 9.7 years), 21 pts with epilepsy (mean age: 36.9 ± 10.6 years), 21 pts with Parkinson’s disease (mean age: 68.7 ± 8.07 years) and 22 pts with ischaemic stroke (mean age: 64.6 ± 8.09 years). Methods: The evaluation of autonomic system was made using questionnaire, cardiovascular reflex tests (Ewing’s battery) and neurophysiological method (sympathetic skin response, SSR). Results: All the tests reveal coexistance of dysautonomia in most of the patients. Abnormal score of the questionnaire was present in 75 % pts with multiple sclerosis, 57.1 % pts with epilepsy, 72.7 % pts with ischaemic stroke and 71.4 % pts with Parkinson’s disease. Cardiovascular autonomic neuropathy (at least 2 abnormal cardiovascular tests) was diagnosed in 20.8 % pts with multiple sclerosis, 4.8 % pts with epilepsy, 31.8 % pts with ischaemic stroke and 42.8 % pts with Parkinson’s disease.Abnormal SSR (prolonged latency or absent SSR in at least 1 limb) was found in 75 % pts with multiple sclerosis, 33.3 % pts with epilepsy, 68 % pts with ischaemic stroke and 66.7 % pts with Parkinson’s disease. Results of all the autonomic tests correlate with the disability status in pts with multiple sclerosis and Parkinson’s disease. Positive correlation of cardiovascular tests’ results and duration of the dis-

ease was present in Parkinson’s disease and epilepsy. Results of Ewing’s battery correlate with SSR in all, except multiple sclerosis. Conclusions: Poor correlation of the questionnaire with the results of the other tests indicates its limited value. Ewing’s battery is unuseful in patients with great disability. Neurophysiological method, sympathetic skin response, is a quick non-invasive examination, which can be done in patients with every degree of disability. Evaluation of autonomic functions in patients with diseases of the central nervous system needs to be made using some different tests. Every patient should be individually treated. P665 Blepharospasm secondary to thalamic lesion A. Angelou, T. Afrantou, S. Tsounis, D. Karakostas, M. Paschalidou, N. Taskos, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Blepharospasm has been rarely reported as a consequence of structural lesions involving the thalamus, upper brainstem and basal ganglia. In these cases the lesions are observed to the non dominant cerebral hemisphere and sometimes are bilateral. The important role of basal ganglia and thalamus in the control of eyelid movements has been recently shown by functional brain imaging studies in patients with essential blepharospasm. Case report: A 63 year old, hypertensive, right-handed woman presented to our department with bilateral blepharospasm and blinking that started 3 months ago. She reported photophobia. Although most of the time she was able to open her eyes, a reflex blepharospasm could be produced by stretching the lids. On neurological examination there was no evidence of pyramidal signs or extrapyramidal disorder. At the time of admittion she had been already treated with botulinum toxin so the severity of her symptom had become milder. The brain MRI revealed a lesion to the right thalamus which was isointense on T 1, hyperintense on T 2 and FLAIR, without enhancement on T 1 images. The involved, affected areas were centromedian nucleus of thalamus, lateral thalamic nuclei and red nucleus while the lesion seemed to extend to the upper brainstem(right mid brain). Since there were no typical signs of ischaemic infarction we performed a second MRI 3 months later which showed the very same findings; the absence of hypointesity on T 1 images was indicative of a space-occupying lesion. Conclusions: Blepharospasm is rarely reported after structural damage and it may reflect a disruption among internuclear pathways linking the nondominant cerebral hemisphere, the basal ganglia and thalamic nuclei and the brainstem. We observed, in our case, an isolated eyelid movement disorder, without any evidence of hemiparesis, ataxia or hemisensory loss, which was not trancient because of the non ischaemic origin of the lesion, emphasizing the role of specific areas of thalamus in the pathophysiology of eyelid motor disorders. P666 Carbon monoxide poisoning from liquid natural gas M. K. Kim, T. H. Park, K. S. Lee, B. J. Kim Seoul Medical Center (Seoul, KR); The Catholic University (Seoul, KR); Samsung Medical Center (Seoul, KR) Objective: This study is to describe the clinical manifestations and therapeutic responses of acute encephalopathy from liquid natural gas (LNG). Background: There had been many patients intoxicated by carbon monoxide(CO) produced from hard coal in Korea, which has markedly reduced in number because heating oil of LNG has been substituted for hard coal in the house. Recently we experienced acute encephalopathy from LNG poisoning which showed similar clinical features of CO poisoning by hard coal. We report 25 patients, who manifested with acute CO poisoning from LNG. Design/Methods: We retrospectively analyzed clinical manifestations, EEG, brain MRI or CT findings, and responses to hyperbaric oxygen (HBO) therapy in 25 patients with acute encephalopathy by LNG for 8 years from 1995 to 2002. Results: Subjects were 11 men and 14 women, aged 13 to 65 years old. The source of the poisoning in all the 25 patients was faulty operating heating system in the houses or buildings. Among 25 patients with acute encephalopathy, 22 patients presented purely altered mentality and the other 3 patients showed convulsive movement. Initial levels of COHb were from 6.0 to 76.1 %, which were not correlated with the level of consciousness. The levels of serum creatine phosphokinase were increased in 14 patients, maximally upto 4.440 IU/L. electroencephalography showed generalized delta activities in one patients. Brain imaging study was performed in 8 patients, of which 2 patients showed abnormal lesions. Immediate HBO therapies were performed in all patients and the initial results were excellent. All patients

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except two who showed delayed anoxic encephalopathy were discharged without any sequelae. Conclusions: We experienced 25 patients with acute encephalopathy from LNG. Clinical features were identical to CO poisoning and therapeutic responses to HBO were also excellent. We suspected the cause of acute LNG poisoning was CO made from incomplete combustion of LNG.We concluded that LNG poisoning must be ruled out for the patients who showed unusual acute encephalopathy. P667 Erdheim-Chester disease: a rare cause of late-onset sporadic ataxia E. Salsano, M. Savoiardo, S. Nappini, D. Chinaglia, G. Finocchiaro, D. Pareyson C.Besta Neurological Institute (Milan, IT); Ospedali Riuniti di Bergamo (Bergamo, IT) Objective: To report a case of progressive gait ataxia due to Erdheim-Chester disease (ECD). ECD is a rare, non-Langerhans histiocytosis characterised by systemic infiltrates of non-Langerhans cell histiocytes, usually involving bones, retroperitoneum, orbits, and central nervous system. Neurological symptoms as first clinical manifestations of ECD have been reported in less than 1/3 of cases, although, for most patients, the diagnosis of ECD is not done before the onset of neurological signs. Diabetes insipidus, due to infiltration of the pituitary stalk, and ocular involvement, secondary to retrobulbar masses, have been frequently described. Here, we report a case of progressive gait ataxia due to ECD. Case Report: A 60-year-old man was evaluated because of a one-andhalf-year history of progressive unsteadiness during walking. A retroperitoneal fibrosis of uncertain cause with mild pericardial and pleural effusions had been diagnosed two years earlier and treated with corticosteroids and methotrexate. His physical examination demonstrated a moderate gait ataxia, impaired pursuit, and mild pyramidal signs. Brain MRI showed a slightly hyperintense, infiltrative pontine lesion on T 2-weighted images, associated with a nodular gadolinium enhancement in the left middle cerebellar peduncle, and a mild cortical atrophy. CSF examination and orbital CT scan were normal. Auditory evoked potential abnormalities were consistent with a brainstem lesion. Long-bone X-rays and technetium bone scan revealed osteosclerosis and increased uptake of the metaphyseal areas of long bones, respectively. Proton magnetic resonance spectroscopy imaging of the pontine lesion showed an abnormal increase of choline and low N-acetyl-aspartate. The diagnosis of ECD was confirmed by re-evaluation of a retroperitoneal biopsy, which demonstrated a prominent infiltrate of CD 68+ histiocytes with abundant foamy cytoplasm. Chemotherapy with vinblastine and steroids was prescribed. Conclusions: ECD, although exceptional, should be regarded as a rare cause of late-onset sporadic ataxia, especially when extra-neurological manifestations such as retroperitoneal fibrosis are present. Moreover, ECD should be always considered in the differential diagnosis of pontine lesions, particularly when they are infiltrative and show persistent enhancement after gadolinium injection. P668 Measuring the immeasurable: benchmarking clinical activity A. Shukralla, O. Hardiman Beaumont Hospital (Dublin, IE) Introduction: A current paradigm in health care management is what cannot be measured cannot be managed. Contextualized methods of measuring the extent of best practice for common clinical disorders are urgently required within the Irish healthcare system. Objective: To generate coherent algorithms for in-patient care of 3 common neurological conditions, and to test current clinical management in the Irish context against international standards of good clinical practice. Methods: A prospective audit of all inpatients on the neurologic service over a 3 year period was performed. Demographic data, length of stay, reason for admission, reason for delays in discharge, and reason for all investigations were recorded. Clinical decision algorithms were generated for epilepsy, multiple sclerosis and amytrophic lateral sclerosis and compared with international best practice. Results: Data from 1490 admissions was collected. Details from 358 patients with Epilepsy, 200 patients with MS and 103 patients with ALS were reviewed and recorded, and clinical algorithms generated for each condition. Comparison with other health services demonstrated similar clinical practice parameters. However, in the Irish context, there was a bias in favour of emergency over elective admissions and longer lengths of stay compared to international norms for each of these conditions. There was no difference in clinical management of public patients in comparison to those with pri-

vate health insurance. Delays in discharge were primarily due to deficiencies in hospital infrastructure. Conclusion: Clinical algorithms can be generated for inpatient management of common conditions. Using standardized management protocols, factors leading to deviation in management, including excessive lengths of stay can be analysed and addressed. P669 ANCA-related primary vasculitis of the central nervous system A. Angelou, D. Karakostas, T. Afrantou, N. Karantani, M. Daniilidis, I. Milonas, N. Taskos Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Despite the remarkable progress that has been made in the classification and diagnosis of CNS vasculitis there are still problems in determination of the cause in specific cases when biopsy can not be performed. Case report: A 35year old man had firstly admitted 3 years ago because of dysarthria, and right sided hemiparesis which lasted for two months and was followed by full recovery. Brain and cervical MRI revealed disseminated lesions, some of them enhancing, in the brainstem, cerebellum and cervical cord. Immunological screening, coagulation tests and investigation for infectious agents were all negative whereas CSF analysis did not show oligoclonal bands. Consequently the patient had a number of relapses which consisted exclusively of neurological signs and symptoms while corticosteroid administration seemed to help the symptoms. Repeated examinations failed to lead to a certain clinical entity; tests for connective tissue disorders, inflammatory, infective diseases, coagulopathies were always normal. His clinical state deteriorated dramatically the last 6 months and finally he got bedridden. We reinvestigated towards every possible cause of systemic or neurological disorder that could be responsible for his symptoms. For the first time a positive c and pANCA were found as well as a pathological ENA screen. The suspicion of vasculitis was supported by an extensive laboratory evaluation; T and B cell panels were indicative for autoimmune process, CSF analysis showed 10 neutrophils and raised protein, absence of IgG bands, absence of antibodies against infectious agents, SPECT revealed abnormal cerebral blood flow and hypoperfusion areas on the right parietal lobe. Brain MRA and ultrasound study of the intracranial arteries showed normal flows of the large cerebral arteries. Nerve conduction velocities were within normal range and temporal artery biopsy had no specific findings. Additionally there was no clinical or laboratory evidence for involvement of other organs. Biopsy could not be performed due to the location of the lesions in the brainstem. Treatment and course: the patient received cyclophosphamide, consequently methyprednisolone and his neurological state was significantly improved. Conclusion: In our case ANCA became positive 3 years after the onset of the disease; although this is rarely observed, it emphasizes the necessity of repeated immunological testing despite the initial negative results. P670 A novel mutation as a cause of L-2-hydroxyglutaric aciduria: a case report and review of the literature G. O’ Connor, O. Hardiman, M. King, G. Salomons, C. Jackobs Beaumont Hospital (Dublin,IE); The Children’s University Hospital (Dublin, IE); University Hospital VU (Amsterdam, NL) Background: L-2-hydroxyglutaric aciduria (L 2HGA) is a rare inherited disorder of metabolism, which commonly presents in childhood. Rarely, it can present in childhood. Objective: To describe a case of L 2HGA in adulthood associated with a previously unreported genetic mutation. Results: A 26-year-old male presented for further investigation following a slow recovery from a fall and loss of consciousness.He carried the diagnosis of cerebral palsy, manifested by learning disability and mild motor delay from early childhood. Functional ability, speech and gait declined progressively from the age of 12 years, and he developed a seizure disorder at age 16 years. Examination at age 26 revealed macrocephaly, learning disability, signs of cerebellar dysfunction, generalised hyperreflexia, and hypertonia in the lower limbs with upgoing plantar responses. Routine laboratory investigations and nerve conductions were unremarkable. EEG revealed diffuse slowing. Lumbar puncture revealed an elevated protein of 113 mg/dL (normal range 15–45). MRI brain revealed diffuse white matter hypomyelination and cerebellar vermian atrophy. Urinary amino acid analysis showed an elevated L 2HG acid level of 1,354 mmol/mol creat (normal range 1.3–18.9). Genetic analysis revealed a novel pathogenic mutation in the C 14orf160 gene (du-

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ranin gene) at 14q22.1 – a C>G transversion in exon 7, which has not been previously reported. Conclusion: L 2HGA can present in adulthood and should be considered in cases previously diagnosed with cerebral palsy who develop progressive neurological decline, seizures, and increased sensitivity to head trauma. Hypomyelination on MRI and elevated L 2HGA in CSF or urine support the diagnosis, which is confirmed by mutational screening of the C 14orf160 gene.

Poster session 5 Cerebrovascular disorders P671 Effective anticoagulation therapy in stroke prevention – lesson never learnt I. Bilic, G. Dzamonja University Hospital Split (Split, HR) Objectives: Atrial fibrillation (AF) is the most common heart rhythm disturbance and is responsible for about 3 % to 7 % of the new and recurrent strokes that occur every year. This risk for stroke attributable to AF increases with age. Observational data have shown that the initial stroke that occurs with AF is nearly twice as likely to be fatal as strokes that are not associated with AF. Randomized trials have documented the benefits of anticoagulant therapy (AT) usage to prevent stroke. A growing body of evidence indicates that AT is routinely underutilized for stroke prevention in patients with AF. Methods: Retrospective study included all patients with stroke treated in Department of Neurology, University Hospital Split, Croatia in one year period (2005.) Results: 1110 patients were treated beacuse of stroke and 153 of them had AF. AT was prescribed to 20 patients with AF before hospitalization. No patients taking AT because of AF, in our survey, had hemorrhagic stroke. Out of 120 patients with AF who survived stroke, only for 5,AT was prescribed as secondary prevention. AT before stroke was prescribed for 49 patients (for reasons other than AF) and 6 of them had hemorrhagic stroke. Conclusion: Although treatment for acute stroke is improving, the mainstay of stroke therapy is still prevention. Considerable evidence has shown that AT is the treatment of choice in patients with AF. AT is highly effective in both,primary and secondary prevention of stroke.Despite this facts,other factors than this seem to determine if patients with AF will get optimal pharmacoprevention of stroke. The dana indicate that only a minority of patients with AF who do not have contraindiciations for AT actually receive it. Furthermore, of those treated, less than half are adequately protected (i. e. maintained within a therapeutic INR range). Continuous physician education of benefit of AT in stroke risk population and education to make better judgement on risks and benefits of AT is essential. P672 Clinical variability of cerebral venous thrombosis: description of a series of 19 cases J. M. Flores, A. Hernández, M. J. Gallardo, M. A. Del Real, J. Vaamonde Hospital General de Ciudad Real (Ciudad Real, ES) Objectives: The development of the neuro-radiological techniques has allowed to diagnose the Cerebral Venous Thrombosis (CVT) more frequently, and to know its great clinical variability. We reviewed the diagnosed cases of CVT in our Service in the period of 1999–2006. Methods: We describe 19 patients (13 women and 6 men), with ages of 22 to 75 years. Data of the initial symptomatology, etiology, diagnosis techniques, treatment and evolution were recorded. Results: The most frequent symptom was headache (57 %), followed of intracranial hypertension syndrome and disorders of consciousness. We remark unusual presentation as transitory ischemic stroke and progressive optical neuropathy. Subacute or chronic onset were more frequent than the acute one. Diverse etiologic factors (sometimes in combination) were found: post-partum period (2), hyperthyroidism (2), Crohn’ disease (1), meningitis (1 aseptic, 1 bacterial, 1 by listeria), oral contraceptives (2), factor V of Leyden mutation (1), multiple myeloma (1), ulcerative colitis (1), meningioma (1). No cause was uncovered in 8 cases (42 %), despite an exhaustive etiology study. The Computerized Tomography was negative in 68 % of the cases. Only patients in the acute/subacute phase received IV heparin. Five patients had sequels: epilepsy, paresthesias and cranial neuropathies.

Conclusions: In our series, we have found a large variety of etiologies and different patterns of clinical presentation of CVT, some of them infrequently described in the literature. The outcome was very favourable, with no mortality and sequels in only 26 % of the cases. We emphasize the necessity to suspect CVT in presence of a subacute headache and other atypical presentations, also in ambulatory patients. Magnetic Resonance Imaging at present is essential in the diagnosis.We suggest that the therapy could depend on the phase of CVT diagnosis. P673 Independent risk factors for development of early infection in Egyptian patients with recent cerebral infarction N. Kitchener, B. E. Z. Fouad, O. Shorbagy General Organization for Teaching Hospitals (Cairo, EG); Ain Shams University (Cairo, EG) Background: Most deaths occurring in the first week, in cerebral infarction patients, were due to brain edema, but most deaths in the second and third week after a stroke could be attributed to medical complications, mainly infection, which may hamper resolution and efficient rehabilitation. Studies of risk factors for infection after cerebral infarctions are scant in the literature. Objective: Determination of risk factors for early infection after a recent cerebral infarction. Material and Methods: Medical records of patients admitted within 48 hours of onset of symptoms to Mataryia Teaching Hospital and Coptic Hospital from January 1st 2003 to January 1st 2005, with a diagnosis of cerebral infarction, confirmed with CT of the brain were retrospectively studied. Collected data included clinical features, risk factors for stroke, co morbid conditions, infection, and results of diagnostic tests. Univariate and multiple logistic regression analyses were used to determine factors that were associated with the risk of early infection. Results: During the 24-month study period, 824 (466 from Mataryia Teaching Hosp., and 358 from Coptic Hosp.) cerebral infarct patients were identified. Early infection occurred in (103) 12.5 %. The most common infection was pneumonia (58) (7.03 %). In the final multiple logistic model, independent risk factors for early infections were atrial fibrillation, thromboembolic infarction (large vessel disease), disturbed conscious level at admission, age and previous stroke. Conclusion: Atrial fibrillation, thromboembolic infarction (large vessel disease), admission conscious level, age, and previous stroke were independent risk factors for development of early infection. P674 Calpain activation plays a role in the pathophysiology of focal cerebral ischaemia and determines loss of tissue viability at the ischaemic penumbra M. Gutiérrez, M. Alonso de Leciñana, M. Salinas, J. Masjuan, I. Ayuso, E. DíezTejedor University Hospital La Paz. UAM (Madrid, ES) Background and aims: Calpains are calcium-dependent intracellular cysteine-proteases implicated in the pathophysiology of global cerebral ischemia causing proteolysis of different substrates: eIF 4G cleavage by calpain induces down-regulation of translation and protein synthesis, and cleavage of p35, leads to abnormal activation of CdK 5 that destroyes cytoskeletal proteins. We investigate calpain activation after focal cerebral ischemia Materials and methods: Long- Evans rats were subjected to middle cerebral artery occlusion (MCAO) for 5min (n = 4), 30min (n = 4), 1 h (n = 5), 3 h (n = 4), 24 h (n = 3), 72 h (n = 6), 7 days (n = 3). Samples were obtained from the cortex at the infarct core, the boundary zone between the core and the normal tissue in the affected hemisphere (penumbra) and from symmetrical areas in the contralateral hemisphere. Calpain activation in terms of espectrin degradation and cleavage of its substrates eIF 4G and p35 was determined by immunoblot. The ischemic lesion was measured in H&E stained brain sections in rats subjected to the same procedure (n = 6 each group). Results: Calpain activation was observed after 1 h of ischemia. At 3 h activated calpain is demonstrated at the infarct core but not at the penumbra and after 24 h calpain activation is maximal in all the ischemic area. Parallel degradation of eIF 4G and p35 was observed. Conclusions: Calpain activation depends on the duration, and probably the severity, of focal cerebral ischemia and is maximal at the infarct core. Lowest degree of calpain activation and degradation of eIF 4G and p35 in some areas of ischemic tissue identifies the existence of ischemic penumbra, while maximal activation may indicate irreversible damage.

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P675 Temperature modulates stroke severity by brain energy metabolism changes B. Karaszewski, W. M. Nyka Medical University of Gdansk (Gdansk, PL)

The study was supported by B. Braun-Melsungen AG Germany. The research fund is controlled by our administration so that no personal advantages for the researchers result. The sponsor did not influence the data analysis.

Objectives: There is a strong association between raised body temperatures and ischemic lesion progression or poor functional outcome after stroke.We hypothesized that hypothermic treatment of ischemic stroke or post-stroke pyrexia influence stroke severity by modulation of brain energy metabolism and its product lactate. In an animal model of ischemic stroke, we investigated whether body temperature is correlated with lactate concentration in ipsilateral brain tissues and whether induced deep systemic hypothermia (stroke treatment measure) may decrease and hyperthermia (pyrexia is a frequent condition after stroke significantly deteriorating disease severity) increase lactate concentration in these tissues. Methods: A permanent occlusion of MCA main trunk was performed in 10 anesthetized (isoflurane) mice. 5 healthy mice were used as controls. Within several hours of MCA occlusion, in anesthetic conditions, 5 mice were placed in a low-temperature environment to obtain deep systemic hypothermia. The remaining 5 mice were placed in a high-temperature environment to induce hyperthermia. In these conditions 5 “hypothermic” and 5 “hyperthermic” animals were sacrificed and contralateral and ipsilateral brains quickly collected and frozen. Enzymatic methods were used for lactate concentration determination in each hemisphere. Results: Rectal temperatures ranges between 25.8–27.9, mean 27.1°C, in hypothermia-treated mice, and between 37.1–42.2, mean 39.7°C, in “hyperthermic” animals. Ischemic hemisphere tissue lactate concentration in hypothermia-treated individuals was lower than in “hyperthermic” individuals (607 and 822 nmol/mg protein respectively, p < 0.05) and was not significantly lower than in healthy animal brains. Mean lactate concentration in ischemic brains of “hyperthermic” animals was higher than in healthy brains (822 and 639 nmol/mg protein respectively, p < 0.05). Conclusion: Tissue lactate formation was significantly reduced by induced deep systemic hypothermia compared to hyperthermia. Ischemic brain lactate concentration in hypothermic conditions was similar to healthy brain whereas induced hyperthermia caused an increase in lactate formation in ischemic and healthy hemispheres. Hypothermia (an effective stroke treatment measure) or pyrexia (a common condition early after stroke onset, associated with ischemic lesion progression or poor functional outcome) might influence stroke severity by modulation of ipsilateral brain tissue energy metabolism. Research was founded by Polish Ministry of Science and Higher Education and Medical University of Gdansk scientific grants.

P677 Effects of short-term atorvastatin treatment on cerebral haemodynamics in CADASIL N. Peters, T. Freilinger, C. Opherk, T. Pfefferkorn, M. Dichgans Klinikum Grosshadern (Munich, DE)

P676 Influence of hypervolemic volume therapy with gelatin solution 4 % or hydroxyethylstarch 6 % (HES 200/0.5) on haemodynamics in patients with acute ischaemic stroke J. Treib, R. Woessner, M. Herber, S. B. Hoock, M. T. Grauer Westpfalz-Klinikum GmbH (Kaiserslautern, DE); Bezirksklinikum (Haar, DE) Introduction: The intention of this study was to compare the hemodynamic effects of a daily infusion of 500 ml of a 4 % modified fluid gelatin (Gelafundin 4 %) versus 6 % hydroxethyl starch 200/0.5 (Hemohes 6 %) in patients suffering form acute ischemic stroke. Methods: This double-blind, randomised, monocenter, phase III, parallel-group study prospectively investigated the impact of two different colloidal solutions for volume replacement on hemodynamics. 40 patients with acute cerebral ischemia were allocated randomly to receive either 4 % modified fluid gelatin (Gelafundin 4 %) or 6 % hydroxyethyl starch 200/0.5 (Hemohes 6 %). The patients received a loading dose of 500 ml during the first 4 hours and subsequently a hypervolemic infusion of 1000 ml/24 h over 4 days. Blood pressure, pulse and cerebral flow velocity were measured daily, the latter with transcranial Doppler. The study was approved by the national Ethics Committee. Results: With transcranial doppler sonography a statistically significant increase of cerebral blood flow velocity was seen in both groups (26.7 % vs. 26.3 % in the Gelafundin vs. Hemohes-group). The measurements of blood pressure and pulse frequence showed a temporary significant increase in both groups on the first day (7,14 % vs. 6.67 % Gelafundin vs. Hemohes), but normalized in the following days. No significant differences were found between both groups. Discussion: This study demonstrated, that the therapy is associated with positive changes in hemodynamic variables. There were no significant differences between Hemohes- and Gelafundin treated patients with regard to systemic or cerebral hemodynamics.

Objectives: HMG-CoA-reductase-inhibitors (statins) exhibit pleiotropic beneficial effects on the vascular system, including induction of endothelial nitric oxide synthase (eNOS), expression which is important for vasodilation. Recent studies suggest a beneficial effect of statins on cerebral vasoreactivity in patients with cerebral small vessel disease (SVD). CADASIL is a monogenic form of SVD caused by mutations in the NOTCH 3 gene. Treatment options are limited and little is known about the therapeutic role of statins in CADASIL. Methods: Twenty-four CADASIL subjects were treated with atorvastatin for eight weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after four weeks. Transcranial Doppler sonography (TCD) measuring mean flow velocity (MFV) in the middle cerebral artery was performed at baseline (prior to treatment) and at follow-up (at the end of the treatment period). Vasoreactivity was assessed by hypercapnia (CO 2 ventilation) and intravenous application of L-Arginine, which is the substrate for eNOS. Results: There was no significant treatment effect on MFV (p = 0.5) or cerebral vasoreactivity as assessed by hypercapnia (p = 0.5) and intravenous L-Arginine (p = 0.4) in the overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2 and L-Arginine-induced vasomotor response (both p < 0.05). Conclusion: Short term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects. However, there may be a beneficial effect in patients with pronounced impairment of cerebral vasoreactivity. P678 High-resolution magnetic resonance imaging in detection of regression and progression of atherosclerosis in human carotid arteries V. Nemtsova, I. Fedotova, E. Semyatichko Kharkov Medical University (Kharkov, UA) Objective: Magnetic resonance imaging (MRI) can accurately and reproducibly measure the volume of atherosclerotic plaque in human carotid arteries. Atherosclerotic plaques may either progress or regress over time, depending on individual risk factors and treatment regimens. The aim of this study was to determine if regression or progression of human carotid atherosclerosis in patients receiving statin therapy over 24 months can be detected by high-resolution MRI. Methods: In 14 subjects who had undergone unilateral carotid endarterectomy and were on statin therapy, volumes for total carotid artery, concentric wall (normal wall), eccentric wall (plaque), and lumen were quantified at 16 and 24 months using a 1.5-T human imager equipped with 6-cm phased array coils. Results: The interobserver mean coefficient of variation (CV) was lowest for the lumen volume (3.2 %) and highest for the plaque volume (9.7 %). The interscan mean CV was lowest for the total artery volume (3.3 %) and highest for the plaque volume (9.6 %). As much as 24 % regression and 33 % progression were observed in individual subject’s carotid artery eccentric wall (plaque) volumes over time. Mean eccentric wall volume increased 4 % by 16 months and 9 % by 24 months. Mean total wall volume increased slightly at both 16 and 24 months (1.3 % and 1.9 %). Conclusions: High-resolution MRI provides a noninvasive reproducible method of tracking changes in carotid atherosclerosis. This study detected changes in individual subjects at both 16 and 24 months. MRI tracking of changes in atherosclerotic plaques should prove useful in assessing vascular disease risk and monitoring the efficacy of interventions designed to induce regression or retard progression.

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P679 Davidenkow’s syndrome: a case with peculiar MRI findings D. Ulbricht, G. Wildanger Centre Hospitalier Emile Mayrisch (Esch-sur-Alzette, LU) Introduction: Davidenkow’s syndrome is defined by scapuloperoneal muscle atrophy with acrodistal sensitive trouble. The nosological status in unclear, ranging from spinal muscle atrophy, genetic link to hereditary neuropathy with pression palsy, and myopathy. Case report: a 60 year-old otherwise healthy man had slowly progressive muscle wasting of shoulder girdle muscles since the age of 23, followed by insidious onset of trouble walking. Repetitive work-ups in the 1970 s yielded no definitive diagnosis according to the patient, but results were lost. There was no family history of neurological disease, and no other significant diseases. Clinical examination disclosed atrophic paresis of the shoulder girdle muscles as well as the distal legs. There was acrodistal hypoaesthesia and pallhypoaethesia, and the distal tendon jerks were abolished. EMG and evoked potentials were in line with this finding, in favor of axonal polyneuropathy, but without conduction blocks. Somatosensory evoked potentials were normal at the cervical level, but delayed and badly configured at the cortical level. MRI disclosed focal atrophy of the cervical spine at the C 2 level. Genetic testing was refused by the patient. Discussion: Davidenkow’s syndrome was diagnosed clinically, and imaging showed asscociated focal spinal atrophy. It is tempting to causally link this findings, although the pathogenesis is unknown either on the formal or the causal level. P680 Clinical-CT mismatch in ischaemic stroke patients: influence on 6-month functional outcome M. Spinelli, A. Faggi, F. Fumagalli, G. Nuzzaco, M. A. Abbas, M. Sessa, V. Martinelli, G. Comi, F. Corea IRCCS San Raffaele (Milan, IT) Introduction: The recent large diffusion of thrombolytic therapy in patients with acute ischemic stroke, increased the need to quantify any irreversible brain damage. According to Kent criteria, a considerable mismatch between patient’s clinical severity and CT scan early abnormalities, seen at presentation might identify the patients more o less likely to benefit thrombolytic therapy. Methods: In agree with above-mentioned Kent and Barber’ s criteria, we prospectvely analyzed a consecutive stroke population recording: demographic data, risk factors, neuroradiological findings, clinical data at admission (NIHS scale) and 6-month functional outcome (rankin modified). Every admission CT scan was blindly evaluated through the ASPECTS scale (ranges 0 -10): 0 implyng a complete MCA territory infarct, 10 if normal. The expected ASPECT points according to the NIHSS admission score have been extrapolated by the Kent model (cut at 20 points), using the combined database of NINDS, ATLANTIS ed ECASS III trials. Residual ASPECT score was thereby calculated with the following calculation ASPECTS expected – ASPECTS actual = ASPECTS residual Results: We studied 179 patients admitted to the Stroke Unit (median age 74 y). In our study the admission NIHSS was ranging from 0 to 24, with a median score of 4. The expected ASPECTS median score was 9 (range 3–10). The median actual ASPECTS score was 10 (ranges from 2 to10) and the residual ASPECTS median score was 1, (range from –5 to 7). The logistic regression analysis, adjusted for age, gender and TPA therapy (2 % of the population), using 6 months disability as dependent variable, found residual ASPECTS scores as indipendent variable (p < 0.01). Conclusions: A significant mismatch between the patient’s clinical stroke severity (marker of the compromised brain tissue) and the CT scan lesion seen at presentation (marker of irreverible damage) is an indipendent predictor of functional independency at 6 months according to the Modified Rankin Scale. Moreover such Clinical-CT mismatch may lead to a better outcome independently by TPA treatment.

P681 Plasma levels of inflammatory C-reactive protein and interleukin-6 predict outcome in elderly patients with stroke I. Alexanian, P. Georgoutsou, E. Paximadakis, E. Tsougos, Z. Alexiou, K. Abdelidou, E. Kyriakidou, C. Mihas, F. Dimopoulos, K. Mavrou, C. Manti, G. Panoutsopoulos. General Hospital of Elefsina Thriassio (Athens, GR) Objectives: Cerebral ischemia initiates an inflammatory response in the brain that is associated with induction of a variety of cytokines, including interleukin-6 (IL-6), a pleiotropic cytokine involved in diverse inflammatory functions. The relationship between peripheral inflammatory markers and outcome in stroke patients remains poorly understood. Several studies have shown that stroke induces a very early inflammatory response sustained for a long time that might predispose to further cardiovascular events. The aim of the present study was to examine the relationship between the inflammatory response, as determined by plasma levels of IL-6, tumor necrosis factor-alpha (TNF-a), C-reactive protein (CRP), white blood cell (WBC) count in acute ischemic stroke, and the long-term outcome in elderly patients. Methods: Fifty four elderly patients with acute ischemic stroke without prior history of cardiovascular events were consecutively enrolled for this study from January to December 2004. CT scan was performed within 24 hours after stroke onset. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score.We monitored all patients during hospitalisation; thereafter, they were followed up regularly as outpatients for 1 year. Plasma concentrations of WBC, IL-6, TNF-a, d-dimers, fibrinogen were obtained at admission, at day 3 and 5. Results: 54 elderly patients (mean age 73.43±8.68) were included in this study. After 1 year 11(20.3 %) patients had died or had a non- fatal cardiovascular event. Il-6 levels were significantly higher 30.36±23.77 in those who died or had a cardiovascular event compared with those who remain eventfree 13.42±14.01 (p: 0.024). CRP levels were significantly higher 25.39±21.76 in the former than in the latter 13.35±23.58 (p: 0.034). WBC count was also significantly different 11390±2404.83 vs. 8714.29±2384.01 (p: 0.007). NIHSS at presentation appeared to correlate with worse prognosis 12.17±9.48 vs. 5.92±6.01 (p: 0.030). TNF-a, fibrinogen and d-dimers did not differ significantly between the two groups. Conclusion: Elevation of interleukin-6, C-reactive protein, WBC at hospital admission and stroke severity (NIHSS) were associated with mortality and non-fatal cardiovascular events in elderly one-year after an ischemic stroke.

Dementia/Higher function disorders P682 Neuropsychological impairment in a cohort of Nigerian patients with chronic hepatitis C without liver cirrhosis F. Salawu, A. Wakil, S. Pindar, O. Beida, A. Danburam, T. Martins, J. Agbo Federal Medical Centre (Yola, NG); Federal Neuropsychiatry Hospital (Maiduguri, NG); State Specialist Hospital (Maiduguri, NG) There is evidence that hepatitis C virus (HCV) is neurotropic and may cause neuropsychological impairment even in the absence of advanced liver disease.Although cognitive abnormalities in hepatitis C disease probably occur just as frequently in Africa as in Europe, there is still a dearth of reliable information on the subject from Africa and indeed none from Nigeria Objective: We therefore investigated the prevalence of cognitive impairment of Nigerians with chronic hepatitis C (CHC) in the absence of liver cirrhosis and compared test performance to those of patients with other types of chronic liver disease to explore whether infection with HCV was associated with greater cognitive dysfunction. Method: This prospective study included 35 patients with chronic active HCV infection without cirrhosis, 35 patients with other chronic liver diseases [hepatitis B (N = 14), cryptogenic (N = 2), alcoholic hepatitis (N = 10), autoimmune hepatitis (N = 4), non-alcoholic fatty liver (N = 5)] and 35 healthy controls, matched for sex and age. Patients were pre-screened and excluded from participation if other factors were present that could influence cognitive performance. The Community Screening Instrument for Dementia (CSI-D) was administered to all subjects under standard condition. We choose this neuropsychological test battery on the basis of previously published research. It was developed from existing cognitive screening instruments with a view to identifying items that were equally discriminating for subjects with high and low levels of education and literacy and for subjects from developed and less developed communities. Impairment was operationally defined by at least 1 score two standard deviations (s.d) below the

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normative mean for a given test or 2 or more test scores at least one s.d below the mean. Results: The HCV-infected patients were impaired on more cognitive tasks than the healthy controls (p < 0.05). Test scores of patients with CHC did not differ from those of patients with other chronic liver diseases. However, both groups experienced cognitive deficits in all domains of language expression, memory recall, attention and calculation, memory and orientation. Conclusion: These preliminary findings suggest that perhaps black Nigerians with HCV infection even before the development of cirrhosis showed neurocognitive impairment similar to most previous reports from Europe and North America. Our findings will require verification in larger studies. P683 Cognitive aspects of Hallervorden Spatz disease M. J. Gallardo, J. M. Flores, M. A. Del Real, A. Hernandez, J. Vaamonde Hospital General de Ciudad Real (Ciudad Real, ES) Objective: The cognitive aspects of Hallervorden Spatz (HS) Disease have not been described with details in literature. The possibility of affection has been mentioned or HS is included among pathologic entities with subcortical dementia. We describe the cognitive aspects of an HS patient. Methods: We present a woman of 44 years without perinatal antecedents of interest, with a normal psychomotor development.When she was 14 years old developed a psychotic disorder with visual hallucinations, paranoid delusions and behavior deviations. Subsequently paretospastic gait, dystonias and disturbances in the ocular motility were added. Ferritine, transferrine and ceruloplasmin, copper in serum and urine, pyruvic acid, lactic acid, A, E, B 1 and B 6 vitamins, thyroid hormones and parathormone levels were normal. Cerebral SPECT showed temporo-occipital and bilateral hypoperfusion. Cranial MRI showed a reduction in the size of both globus pallidus with a symmetric and marked peripheric hypointensity and central hyperintensity. Results: The neuropsychological evaluation showed a normal MMT and an extensive battery of neuropsychological tests demonstrated intellectual delay, hard difficulties in the divided attention capacity, low personal orientation, lightly altered memory, deficit in visuospacial, visuoperceptive, visuoconstructive and premotor functions and in complex mental calculation. The thought was slightly altered and there were difficulties in the flexibility of thinking. Conclusions: our patient presents a widespread cognitive disorder that surpass the one corresponding to the affection of basal ganglia. The MMT is normal, showing that is not an useful test in the cognitive evaluation of HS. We remark the necessity of a more extensive neuropsychological examination to determinate posible dysfuntions and to trace the best therapeutic orientation. P684 Cognitive deficits, mood disorders and neurological signs in alcoholics M. Sieminski, A. Nitka-Sieminska, A. Jaszczuk, P. Bialon, W. M. Nyka Medical University of Gdansk (Gdansk, PL) Objectives: The aim of this study was to assess the prevalence of cognitive impairment, mood disorders and neurological signs in population of chronic alcoholics. We also wanted to analyze relation between those disorders and duration of addiction. Materials and methods: We have examined 27 subjects with diagnosed alcoholism. The following tools were used: Mini Mental State Examination (MMSE) for screening for cognitive impairment, Hospital Anxiety and Depression Scale (HADS-A and HADS-D, respectively). All subjects were examined neurologically to evaluate presence of lesions of central nervous system. Results: The mean age of the examined group was 47.5 years. The mean duration of addiction was 20.2 years. The mean result of MMSE was 28 points. In 4 cases (14.8 %) we have found score in MMSE < 27, suggestive of cognitive impairment. This subgroup did not differ significantly from the rest of the population, as the age and duration of addiction are concerned. There were 7 (25.9 %) subjects with definitive and 5 (18.5 %) with probable anxiety disorder (according to HADS-A) and 2 (7.4 %) subjects with definitive and 2 (7.4 %) with probable depression disorder (according to HADSD). No sigs of focal neurological deficits were found. Conclusions: Chronic alcoholism should be considered as a risk factor of cognitive impairment in relatively young subjects. Cognitive decline is not associated with signs of focal brain lesions. Anxiety disorders were more common in the examined population than depression.

P685 Effects of 6-months treatment with donepezil and rivastigmin on results of neuropsychological tests in patients with Alzheimer’s disease R. Abolfazli, M. Nazeman, S. Ghazanshahi, H. Taebei Tehran University of Medical Science (Tehran, IR); Shahid Beheshti University of Medical Science (Tehran, IR) Background: AD is one of the most important degenerative diseases of brain. Nowadays, the most common treatment being used to slow down disease progression. General purpose of our study was to show effects of treatment with Donepezil and Rivastigmine, as two drugs that commonly used for treatment of AD in Iran, on results of four neuropsychological tests including MMSE, NPI, Clock and Bender; and to compare these effects between two drugs. Methods: We started a before&after type study. Samples selected from patients who were candidate of receiving Donepezil or Rivastigmin, as treatment of AD, for the first time. We used four neuropsychological tests including MMSE, NPI, Clock and Bender to assess patient’s cognitive and behavioral changes during treatment with two drugs. 70 Patients divided to two groups randomly; 35 Patients with plan of taking Donepezil entered into one of the groups and 35 patients with plan of taking Rivastigmin entered into another. The four tests were completed once before starting treatment and then, 1 month, 3 months and 6 months after treatment with Donepezil and Rivastigmine. Results: According to results of analysis, MMSE, 6 months after treatment with Donepezil, improved from 20.63 before treatment to 21.83, which is statistically significant (p = 0.04). Also, MMSE, 6 months after treatment with Rivastigmin, improved from 20.03 before treatment to 22.71, which was statistically significant (p = 0.007). About Clock test, there was a moderate improvement from 5.74 before treatment to 6.4 after 6 months of treatment with Rivastigmin; while this improvement was not seen in patients receiving Donepezil. In two other tests, no significant differences were seen before and after treatment. Conclusion: As mentioned before, there was significant improvement in MMSE after 6 months in patients receiving donepezil and Rivastigmin.Also, No significant difference was detected between two groups. In according to results of Clock drawing test after 6 months treatment, this may suggest that rivastigmine is better than donepezil in improving visuo-spatial perception of the patient but not that much to create significance. During the study, there were complaints of drug side effects in patients treated with rivastigmin, mostly GI upset (nausea, diarrhoea . . .) but almost nothing for donepezil. P686 Follow-up study of olfactory deficits in patients with mild cognitive impairment W. Lojkowska, M. Gugala, A. Bochynska, H. Sienkiewicz-Jarosz, B. Sawicka, W. Kuran, E. Lojek, A. Scinska, A. Korkosz, D. Ryglewicz Institute of Psychiatry and Neurology (Warsaw, PL); University of Warsaw (Warsaw, PL) Objective: Mild Cognitive Impairment (MCI) is a risk factor for the Alzheimer’s disease. There are also some reports on olfactory deficits in Alzheimer’s disease. In the present study, we tested if olfactory deficits can be observed in MCI, and whether these deficits increase with duration of MCI. This is an important issue for further research as olfactory tests may become one of the diagnostic tools in MCI. The aim of the work was to assess the utility of olfactory tests in the diagnosis of MCI. Method: Two groups of patients were investigated: an MCI group, composed of 49 patients with MCI deficits, and a control group (31 subjects). The groups were tested twice, with time span of 24 months. Mean age of onset of cognitive deficits was 64.8 ± 7.6 yr. Odour detection thresholds and odour identification abilities were measured by using the “Sniffin’ Sticks” test. Cognitive deficits were assessed by using a battery of tests, including MMSE, and depressive symptoms were scored with the aid of GDS. Results: Comparison of olfactory function at the beginning of the study and after 24 months indicated a significant increase of the odour detection threshold and decrease in odour identification abilities in the MCI group as compared to the controls. The cognitive functions index of the patients with MCI was also significantly decreased. GDS scores did not change with time. Conclusions: Increase of olfactory threshold and slight decrease of identification abilities may be considered as risk markers for MCI progression.

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P687 Accuracy of Fototest to diagnose dementia in neurological patients: FOTOTRANS study C. Carnero-Pardo, R. J. de la Vega, A. Zambrano Toribio, M. Goñi Imízcoz, E. Franco Macías, F. Moreno Izco, C. Sáez-Zea, M. T. Montoro-Ríos on behalf of the FOTOTRANS Study Group Objectives: The Fototest (www.fototest.es) is a simple short (< 3-min) test applicable to illiterate subjects and its results are not influenced by age or educational level. Preliminary studies demonstrated its diagnostic accuracy (DA) to detect dementia. FOTOTRANS is a cross-sectional multi-centre study with the objective of evaluating the DA of the Fototest under routine clinical conditions. Methods: The Fototest, Eurotest and verbal fluency test (VFT) were applied to neurological patients aged > 60 years with an established diagnosis; the Mini-Mental test (MMSE) was also applied to a sub-sample. Patients were classified as “Non-Demented” (ND) or “Demented” (DEM) [DSM-IV criteria]. We calculated sensitivity (Sn) and specificity (Sp) values with their corresponding 95 % interval and the area under the ROC curve (AUC),which was used to compare the DA of the different instruments. Results: Twenty neurologists selected a total of 627 subjects: 467 ND, 122 DEM and 38 excluded patients (due to incomplete data or protocol violations). Out of the 589 study subjects, 41 (7 %) were illiterate and 230 (39 %) lacked formal education. Out of the ND subjects, 106 (22.7 %) had cognitive impairment (CI) and another 75 (16 %) reported memory loss. Out of the subjects without CI or DEM, 120 (33.2 %) suffered a condition that can potentially induce CI and 76 (21.1 %) received drugs that can induce CI. The best cut-off Fototest score was 26/27, with a Sn of 0.88 (0.81–0.94) and Sp of 0.87 (0.84–0.90). Both Fototest and Eurotest showed a high DA (0.94 ± 0.01, AUC ± SEM) that was superior to that of VFT (0.90 ± 0.01) and MMSE (0.91 ± 0.03), although the difference was only significant with respect to that of the VFT (p < 0.01). Conclusions: In this large and naturalistic sample of neurological patients with very low educational level, the Fototest showed a high diagnostic accuracy for dementia, similar to that of the Eurotest and MMSE, despite being much easier to apply and taking less than three minutes. Partially supported by Junta de Andalucía grants (Exp. 441/06). P688 Detection of cognitive impairment in the FOTOTRANS study C. Carnero-Pardo, M. Llanero Luque, M. S. Barquero Jiménez, I. Casado Naranjo, F. Castellanos Pinedo, A. Frank García, A. Zambrano Toribio, R. J. de la Vega on behalf of the FOTOTRANS Study Group Objectives: The diagnosis of cognitive impairment (CI) allows therapeutic measures to be applied to normalise the patient or prevent or delay the onset of dementia. However, the most widely used screening tests are not useful to detect this clinical condition. Our objective was to evaluate and compare the CI diagnostic accuracy (DA) of screening tests used in the FOTOTRANS study. Methods: The FOTOTRANS is a cross-sectional multi-centre study of neurological patients aged > 60 years with an established diagnosis, who were administered with the Fototest, Eurotest and a verbal fluency test (VFT); the Mini-Mental test (MMSE) was also applied to a sub-sample. The patients were classified as “Non Cognitive Impairment” (NoCI) or “Cognitive Impairment” (CI), which included subjects with dementia (DSMIV-R criteria) or mild cognitive impairment (GENCD-SEN criteria). The DA of the instruments was compared by using the area under the ROC curve (AUC). Results: Twenty neurologists selected a total of 627 subjects: 361 NoCI, 228 CI and 38 excluded subjects (due to incomplete data or protocol violations). The DA of the Fototest (0.86±0.01,AUC±SEM) was superior to that of the Eurotest (0. 84±0.01),VFT (0.78±0.02) and MMSE (0. 83±0.04), although the difference was only significant with respect to that of the VFT (p < 0.001). Conclusions: All screening tests showed only a modest DA (< 0.90), therefore a strategy of dichotomized results (positive/negative) cannot be effective for the detection of CI with these instruments. The Fototest has the advantages of simplicity, speed and the non-influence of educational factors. Partially supported by Junta de Andalucía grants (Exp. 441/06).

P689 A degree of Alzheimer’s disease severity influences performance on implicit procedural learning task A. Klimkowicz-Mrowiec, A. Slowik, L. Krzywoszanski, R. Herzog-Krzywoszanska, A. Szczudlik Jagiellonian University (Cracow, PL); Academy of Physical Education (Cracow, PL) Objectives: Studies of memory organization in humans and experimental animals give evidences that memory is organized in multiple, parallel memory systems. Based on the type of information processing, purpose served by each system and their anatomical localization, explicit and implicit memory systems were distinguished. Although anatomically and functionally dissociated, both systems interact during learning. The nature of this interaction is still a fundamental question. Studies of implicit learning in Alzheimer’s disease (AD) patients provide an unique opportunity to better understanding mutual interactions between explicit and implicit memory systems. Methods: We examined three different hypotheses of interaction: independence, competition and cooperation between both memory systems. We tested patients with explicit memory impairment due to AD and healthy controls on modified, more difficult version of a weather prediction task that depends on implicit system. A total of 87 subjects participated in the study: 36 with a mild AD (MMSE: 25.06; DS 2.66) (19 females, age 75.81, range: 60–91), 15 with a moderate AD (MMSE: 18.59; SD 6.25) (9 females, age 73.53 range:62–88), and 36 controls (MMSE 27.54; SD 1.96) (21 females, age 72.36, range: 60–82). Results: Patients with moderate explicit memory impairment performed the implicit procedural learning task significantly better than those with mild AD and controls. Conclusion: Results of our study support hypothesis on competition between implicit and explicit learning systems in humans. This results, for the first time reported in humans, are very important, not only in regard of the nature of interaction between systems but also because they give a chance for a possible rehabilitation strategies for people with Alzheimer’s disease. P690 Mild cognitive impairment – a clinical assessment of different drug therapies I. Buraga, I. Davidescu, S. Nica University of Medicine and Pharmacy (Bucharest, RO) Background: Dementia is a serious brain disorder that interferes with a person’s ability to carry out everyday tasks. The key feature of dementia is a decline in cognitive functions: mental processes such as thinking, reasoning, learning, problem solving, memory, language, and speech. In recent years, the term minimal cognitive impairment (MCI) is commonly used to refer to a stage of cognitive impairment prior to attaining clinical criteria for dementia in Alzheimer disease (AD) and related disorders.In fact, the relatively recent formulation of MCI follows previous attempts to characterize cognitive decline associated with aging, including benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline. Objectives: to assess the clinical improvment of higher functions after 2 years of treatment with different drugs. Methods: We followed up, during 2 years, 30 patients with mild cognitive impairement, having mild, slowly worsening memory loss, and less common symptoms as disturbances of language (word finding), attention (poor concentration), and orientation (disorientation in familiar surroundings), as MCI is a transitional zone between age-related memory loss and Alzheimer disease.There were 17 women and 13 men with a mean age of 67.96 years. There were nor physical or imagistic changes, and we excludded all potentially curable situations as: thyroid disorders, chemical imbalances, vitamin deficiencies, and infections. The mean score of MMSE was 24.70. We made three lots: one treated with donezepil(Aricept), one treated with rivastigmine (Exelon) and one treated with Piracetam. They were examined every 3 months by MMSE, Clock Drawing Test (CDT) and The Short Test of Mental Status (STMS). Results: The mean score of MMSE after 2 years improved by 2.4 points in the lot treated with donezepil, by 1.9 in those treated with rivastigmine and with 0.2 in those treated with piracetam. Conclusions: We concluded the benefit of cholinesterase inhibitors in improving cognition function, clinical global impression and activities of daily living, comparing with the patients treated with Piracetam. Cholinesterase inhibitors stop the breakdown of this neurotransmitter and they increase the amount of acetylcholine in the brain, improving and stabilizing cognitive functions in MCI, also having positive effects on behavior and every day activities. The most positive effect is that they may slow down conversion of MCI into dementia.

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P691 Working memory for the identification of facial expression of emotions in patients with mild Alzheimer’s disease A. Frank-García, A. Tallón Barranco, B. García Rodríguez, S. Oliván Torres, E. Díez-Tejedor, H. Ellgring Hospital Universitario La Paz (Madrid, ES); UNED (Madrid, ES); University of Wurzburg (Wurzburg, DE) Objectives: Working memory (WM) allows to recall necessary information when various mental operations are simultaneously carried out. It has three components: the central executive processor, the mechanism of attention control, the phonological loop, responsible for processing and keeping the procedural information for speech and the viso-spatial sketchpad, which allows to retain and to manipulate visual images. WM is one of the first processes which becomes distorted in Alzheimer’s disease. The recognition of facial emotional expressions is a important aspect of emotional processing and it depends actively on the WM, in particular of the viso-spatial sketchpad. It is of general believe that in Alzheimer’s disease emotional process remains intact until advanced stages. The goal of our study was to analyze how the emotional processing of facial expressions (FE) changes in healthy people as well as in patiens with mild Alzheimer’s disease when the functioning of the viso-spatial programme is experimentally impeded. Methods: After signing of a consent inform, emotional processing of facial expressions were compared in three groups: patients with probable mild Alzheimer’s disease (NINDS-ADRDA criteria), healthy adults and young healthy persons. To test the performance for identifying FE six basic emotions (according to the Facial Action Coding System) were used. Tests were carried out under two experimental conditions: without impeding the processing of the viso-spatial programme and during impeding it by introducing a secondary task (Corsi Blocks). Statistical analisis of parametric and non-parametric variables was done with a SPSS. 12 program. Results: 36 participants were enrolled: Alzheimer’s group: N = 12, mean age = 78.8 years; healthy adults: N = 12, mean age = 74.5 years and young healthy persons: N = 12; mean age: 35 years. Results showed a less performance when mental images retention was impeded in all the three groups. The Alzheimer’s patients group showed the most significant differences between both experimental conditions. Conclusion: Emotional processing of FE worses when mental images retention is impeded both in healthy subjects and in mild Alzheimer’s disease patients. In contrast to general belief, these results indicate that on the early stages of Alzheimer’s disease there are difficulties in the emotional processing. More studies with larger series should be done to confirm these results. P692 Heat shock protein 70: implication for Alzheimer’s disease C. Iarlori, M. Reale, M. Onofrj, L. Velluto, A. Thomas, D. Gambi University of Chieti (Chieti, IT) Introduction: Heat shock protein (Hsp) form a large family of protein that are ubiquitously present in all organisms. Under normal physiological conditions, Hsp are expressed at low levels, however they are highly induced in response to various noxious conditions. Hsp acts as a cytokine to human monocytes by stimulating a pro-inflammatory signal transduction cascade that results in an upregulation in interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha expression. Hsp enhance antigen presentation to T lymphocytes and they are important in targeting cytotoxic cells. Hsp 70 is the most inducible by stress. Endotoxin and cytokines can induce intracellular Hsp 70 expression in peripheral blood mononuclear cells. Alzheimer’s disease is the most common degenerative disorders of the central nervous system (CNS) characterized by cerebral degeneration, neuronal cell death and by multiple disregulation of peripheral blood mononuclear cells, including increased production of proinflammatory molecules as mediators in response to brain injury. Objectives: To evaluted the Hsp70 production in sera from 40 clinically diagnosed AD patients (according to DMS IV-R and NINCDS-ADRDA criteria), attending to the Neurological Clinic of University of Chieti, and age and habits matched control group (HC) of 40 healthy individuals were selected. Subjects with history of acute or chronic inflammatory diseases were excluded from the study. None of the subjects had received glucocorticosteriods or non-steroidal antinflammatory drugs. Methods: Blood has been withdrawn in the morning. After having been aliquoted, serum was frozen and stored at –80°C until the tests were performed. Hps 70 in serum of AD and HC subjects was detected by sandwich immunoassay using the specific monoclonal antibody. Intra- and inter- assay coefficient of variation was < 10 %. Results and conclusions: We shown that serum levels for Hsp 70 in AD patients were significantly higher when compared to serum levels in HC (p < 0.05). These results support the hypothesis that a potent pro-inflamma-

tory response was present in AD. Although the precise influence of Hsp on inflammation is unclear, our data suggest that Hsp 70 may contribute to the chronic inflammatory reaction associated with AD probably promoting the production of proinflammatory cytokines, chemokines and costimulatory molecules involved in the pathogenesis of AD. P693 Cognitive functions and symptoms of depression in patients with diabetes mellitus I. Kozub-Doros Silesian Medical University School (Zabrze, PL) Objective: Diabetes mellitus impairs the peripheral nervous system. The published data about the influence of carbohydrate metabolism disturbances on cognitive function are often contradictory. The cause of depression in diabetics may be attributed to the stress related to the presence of a chronic disease, as well as to CNS (central nervous system) damage in the course of DM. Depression has an impact on hyperglycaemia and increases the risk of developing DM. The aim of my study was to determine the association between the intellectual state, the level of emotion and appearing of peripheral nervous system damage symptoms in diabetics. Methods: I examined 60 diabetic patients at the age 55.6±13.7 (Males: Females = 1:1): 17 (28.3 %) with IDDM (Insulin Dependent Diabetes Mellitus) and 43 (71.7 %) with NIDDM (Non Insulin Dependent Diabetes Mellitus). The conrol group consists of 43 persons without chronic disorders at the age 49.4±18.2 (M:F = 2:3). Methods of the research were psychometric tests- 3 subtests of WAIS-R (Wechsler Adult Inteligence Scale): forward and backward digit span, block design and digit symbols; MMSE (Mini Mental State Examination) and MADRS (Montgomery- Asberg Scale of Depression); examination of vibratory sensibility by Arezzo and neurographic examination. Results: There is the significal difference in results of MADRS (p = 0.0001) and 2 subtests of WAIS-R (block design p = 0.04, digit symbols p = 0.05) between diabetics and control group. The difference in results of MADRS is associated with female group (p = 0.00003) and low level of education (p = 0.04). The difference in results of subtests WAIS-R is associated with low level of education (p = 0.01). Insulin-therapy comparing to oral hypoglycemic agents deteriorates results of subtest WAIS-R and MADRS. There is a correlation between results of MMSE and the level of vibratory sensibility. Conclusions: DM deteriorates attention, visuospatial memory, constructional ability and increases frequency of depression. The low level of education and female sex increase deficits. Insulin-therapy comparing to oral hypoglycemic agents deteriorates immediate memory, durability of attention and increases frequency of depression. The peripheral nervous system damage correlates with cognitive function disorders in patients with DM. P694 Neurocognitive profiles of non-demented Parkinson’s disease patients H. Y. Jo, J. W. Kim, S. H. Kim, S. M. Cheon Dong-a University Hospital (Busan, KR) Objectives: Even in the early stages of Parkinson’s disease, cognitive alterations can be demonstrated by careful neuropsychological test. The purposes of this study are to investigate the patterns of cognitive impairment in non demented Parkinson’s disease (PD). Materials and Methods: Total 141 PD patients (65 males, age 40–76 years, Hohen and Yahr (H&Y) stage 1–4) were recruited. Patients who showed clinically overt dementia or had less than 3 years of education period were excluded. Patients were divided into two groups according to age (> 60 and < 60) and predominant clinical symptom (tremor vs. akinetic-rigid type). They were all matched for education periods, symptom duration and H&Y stage. The author compared the patterns of cognitive impairment between the two groups. Results: Of 141 patients, 103 (73 %) showed some abnormalities in at least more than one domain. They showed abnormalities in the SVLT (38 %), stroop (35 %) and Rey Complex Figure Test (34 %) in the order of frequency. Compared to the younger group, the older group showed more frequent abnormalities in all tests, particularly in the test for frontal executive function. Patients with tremor-dominant type showed worse performance, particularly on the attention test. Conclusion: It is concluded that, if specifically looked for, abnormalities of cognitive function be detected very commonly even in the early stage of patients with PD. The patterns of cognitive impairment in the patients with early stage of PD showed much differences depending on the age and clinical symptom.

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P695 Language disorders of a primary progressive aphasia K. Dong, Y. Zhang, N. Wei, X. Zhao, Y. Wang Beijing Tiantan Hospital (Beijing, CN)

with characteristic speech and repetition disturbance without arcuate fasciculus lesion. Limb-kinetic apraxia may be due to sensory motor integration disturbance.

Backgrouds and purposes: Primary progressive aphasia is clinically characterized by the progressive decrease of speech function, and the patients are usually diagnosed as dementia when their cognitive ability is gradually declined and the activities of daily life are affected during the disease course, but it is different from other dementia because their memory is relatively well preserved. Therefore, primary progressive aphasia should be distinguished from other diseases that can lead to dementia in clinic. The study reported one patient with primary progressive aphasia in the hospital in 2004, and analyzed his clinical characteristics of primary progressive aphasia. Methods: The spoken fluent types of the patient were evaluated with the standards for the fluency of spoken language in Aphasia battery of Chinese (fluent spoken language was manifested by significant decrease of words, exertion in speaking, dysarthria or phonetic disintegration, low and single intonation, there were difficulties in using relative pronoun and pronoun; Fluent aphasia was characterized by the increased spoken words, lamprophony, normal intonation, difficulties in finding words, common occurrence of verbosity and wrong words). Western battery aphasia was used to assess the type of aphasia of the patient. Boston diagnostic aphasia examination severity grading standard was applied to grade the severity of aphasia. The cognitive psychological tests of visual character- figure matching, denomination for figures and oral reading were used to judge whether the patient had verb-noun dissociation, and the memory of the patient was assessed with clinical memory scale. Results: The patient presented the spontaneous talking that named the fluent type, there were wrong meanings in his talks so that he was diagnosed as Wernicke’s aphasia. The severity of aphasia was separated into 3 levels. The correct rates of verbs and nouns in the test of denomination for figures were 15 % and 53 % respectively, and there was obvious difference (t = 0.231, P < 0.05). The memory quotient was 111, and the clinical memory grade was higher than normal. Conclusion: The most outstanding clinical characteristics of patients with primary progressive aphasia is speech dysfunction, and there is verb specific injury.

P697 The differential diagnosis of Creutzfeldt-Jakob disease and long-term carmabide pesticide poisoning K. Papadopoulos, O. Koutoula, A. Triantafillou, I. Milonas Ahepa University Hospital (Thessaloniki, GR)

P696 Broca-like aphasia and limb-kinetic apraxia due to left precentral cortical lesion N. Kasahata, T. Ozawa, T. Hidaka, I. Satou, T. Kotani Makita General Hospital (Tokyo, JP) Objective: Broca reported the Broca aphasa “tan” as an “Aphemia” for the first time. But tan’s lesion was larger than the Broca area and reached the deep white matter. Thus, there have been discussions regarding which area is important for Broca aphasia or whether the Broca area causes Broca aphasia. Especially, Marie and Dejerine’s discussion was famous.Although the left precentral gyral cortex seems to be critical for apraxia of speech, no patient with a lesion restricted to the precentral cortex has been reported. Thus, the role of the precentral cortex or white matter for apraxia of speech or other speech disturbances of Broca aphasia remains unclear. Fortunately, I experienced a patient with a lesion predominantly located in the left precentral cortex and will describe its characteristic semiology and discuss the role of the left precentral cortex, particularly on speech disturbance and limb-kinetic apraxia. Methods: Comparison of clinical and radiological data of a patient from previous reports. Results: 64-year-old right-handed male patient was admitted to our hospital for pneumonia. At about 19:00 on seventh hospital day, whenever others asked him anything, he was heard to say only “hi, hi” (Japanese word for “yes, yes”) instead of “tan, tan”. Neurological examination showed Broca-like aphasia with charateristic speech disturbance, orofacial apraxia and limbkinetic apraxia of the right hand without any sensory or motor disturbance. Neuroimaging showed a lesion predominantly located in the left precentral cortex. Somatosensory evoked potentials with median nerve stimulation showed normal cortical potentials. Western Aphasia Battery (WAB) examination showed severe disturbance of spontaneous speech, good auditory comprehension, severe disturbance of repetition, moderate disturbance of naming and severe disturbance of writing. He had characteristic speech disturbance. His speech of monosyllable letters sounded predominantly distorted but inconsistency was not so remarkable. However, when he spoke spontaneously, his articulatory disturbance was not so apparent. His prosody disturbance was not so apparent compared with his articulatory disturbance or prosody disturbances observed in typical Broca’s aphasia. Conclusion: Left precentral cortical lesion may cause Broca-like aphasia

Objectives: Prion diseases are degenerative disorders of the nervous system caused by transmissible particles that contains isoform of the prion protein, a normal constituent of cell membranes. The most common human prion disease is Creutzfeldt-Jakod disease (CJD). The clinical features of CJD include progressive cognitive decline, ataxia, myoclonus, extrapyramidal features, cortical blindness, polyneuropathy and the last stage is akinetic mutism. However, the long term poisoning of carmabide pesticide (it belongs to fungicides) may produce the same clinical picture as well according to research environmental medicine. The prognosis is fatal for both of the two conditions.We report a 69 years old man, whose his initial symptom was blindness after dermatic exposure to carbamide pesticide. Methods: The patient is a farmer and due to an accident he exposed himself to the pesticide. For one month, he didn’t have any symptoms. One month later on, the patient admitted to our clinic due to blindness and painful extremities. Three days later on, he started to be confusional and ataxic and five days later on he suffered from diffuse myoclonic seizures. Results: The clinical features of the patient were, cortical blindness (preserved eye pupillary response), pyramidal signs in all extremities, marked rigidity, diffuse myoclonic seizures, confusional state and ten days later on he exerted permanent loss of consciousness. The patient’s end clinical point was akinetic mutism. His laboratory testing was unremarkable. Brain magnetic resonance was unremarkable for lesions. The lumbar puncture was positive for the protein 14-3-3. His electroencephalogram revealed periodic paroxysms of triphasic and sharp waves bilaterally with a frequency of 2.0Hz. The patient treated with levetiracetam for the seizures relatively sufficient. He remains in akinetic mutism stage for eight months. Conclusions: Although poisoning with carmabide pesticide and CJD share the same clinical features, the laboratory and neurophysiological examinations may be extremely useful for the final diagnosis. However the brain biopsy will set unquestionably the definite diagnosis despite the fact that the electroencephalogram for CJD is exclusively characteristic. P698 Reversible pure apraxic agraphia due to ischaemic stroke in the left caudate nucleus and corona radiata C. de Andrés, J. Guzmán de Villoria, I. Tormo, D. Ezpeleta, J. A. Villanueva Hospital General Gregorio Marañón (Madrid, ES) Objectives: Impairment of the ability to produce written language due to acquired brain abnormalities is termed agraphia. When it is not accompanied by other relevant language, movement or confusional disorders is named, pure apraxic agraphia. Our aim is to describe the clinical and MRI characteristic of a patient with pure apraxic agraphia due to ischaemic stroke in the left caudate nucleus and adjacent corona radiata. Methods/Patient: A 51 year old, right handed female, without any history of disease, was admitted because she noticed sudden impairment in his writing. Results: On examination she was alert, voluntary movements with her right hand were slow, otherwise unassociated to cogwheel rigidity, weakness, sensory or coordination defects. Her speech was fluent, and the comprehension, reading and simple math were normal. She had no impairment in ideomotor or ideational apraxia, and either had no constructional or spatial disturbances. Handwriting on spontaneous, dictation, copy, and signing was abnormal in the height and spacing of the letters and in between the words. The letters were incomplete and illegible. The patients recognized the errors.At the re-examination 15 days after onset, in the same writing test administered earlier, the patient wrote correctly. A cranial MRI showed an ischaemic lesion in the left caudate nucleus and the adjacent corona radiata. Conclusion: The patient’s symptoms can be interpreted as a focal sign of ischaemic stroke in the left corona radiata and caudate nucleus, and was consistent with subcortical pure apraxic agraphia. We suggest that pure apraxic agraphia implying a disorder at the motor output transcoding sequences. The reasons for the disturbance in the process of the execution of writing may be attributed to an acute cortico-subcortical disconnecting phenomenon. Brain plasticity might limit the clinical impact of damaging stroke pathology, and may have a role in their clinical recovery.

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Pain and headache P699 Prevalence of anticardiolipin antibodies, lupus anticoagulant, and antibeta 2-glycoprotein I antibodies in migraine with aura C. Burcin, I. M. Cojocaru, M. Cojocaru, A. Atanasiu C. Davila University of Medicine and Pharmacy (Bucharest, RO); Colentina Clinical Hospital (Bucharest, RO) Background: The pathogenesis of migraine is not well understood. Objective: This aim of the study was to determine whether migraine with aura is associated with antiphospholipid antibodies (aPL). Material and methods: Forty patients with migraine and aura (27 women and 13 men) mean age 52±5 years, and 18 controls matched for age and sex underwent laboratory evaluation for aPL, namely anticardiolipin antibodies (IgG-aCL), lupus anticoagulant (LA), and anti-beta 2-glycoprotein I antibodies (IgG anti-beta 2-GPI). Anticardiolipin antibodies and IgG anti-beta 2-GPI were measured by enzyme-linked immunosorbent assay (ELISA), and LA was detected by activated prolonged partial tromboplastin time (aPTT), kaolin clotting time or Russell’s viper venom test (RVVT). Results: Thirteen patients (32.5 %) had IgG-aCL. The mean level of IgGaCL was 18.2±2.7 GPL U/mL (normal value is up to 7.5 GPL U/mL. In controls, only one subject (6 %) was IgG-aCL positive. Eight patients (20 %) presented LA. Four patients (10 %) had IgG anti-beta 2-GPI. The mean level of IgG anti-beta 2-GPI was 4.8±0.6 U/mL. Five patients (12.5 %) presented IgGaCL and LA, three patients (7.5 %) presented IgG-aCL and IgG anti-beta 2GPI, only one patients (2.5 %) was simultaneously positive for both LA and IgG anti-beta 2-GPI. The prevalence of aPL positivity in migraine patients was statistically significant (p = 0.01). Conclusion: Patients with migraine and aura and moderate elevated levels of IgG aCL presented persistent headache. Management should include antiplatelets or even anticoagulant agents. Antiphospholipid antibodies measurement should included in the investigation of all individuals with migraine unresponsive to conventional treatment. P700 The efficacy of repetitive prophylactic treatment in long-term relief from migraine N. Kouroumalos, D. Korakaki, C. Labiris, K. Kalamafkianaki, L. Karatzaferis, E. Kalafatis, G. Georgakakis, E. Nikolakaki General Hospital of Chania (Chania, GR) Objectives: The fact that migraine (M) attacks start reoccurring at variable time after interrupting prophylactic treatment (PT), generated the idea that patients might benefit (increasing headache free time), if repetitive doses of the medication used for prophylaxis are given at intervals after withdrawal from initial PT. We thus thought of re-administering the prophylactic medication for a short time period once every 6 months after cessation of initial PT. We called this repetitive PT for M. Methods: In this retrospective study the files of 350 patients suffering from M (using ICHD 1988 criteria) were initially examined with reference to: a) whether patients received initial PT and whether M attacks reoccurred (or worsened concerning frequency and intensity) within 24–36 months after withdrawal from initial PT. 83 patients fulfilled the above criteria and thus may be included in the study. Medication used and time administered concerning initial PT was similar for those patients. 39 out of 83 patients received repetitive PT for M whereas 44 did not.Those 39 initially abstained from medication for 2 months. Then, they started taking again the medication used as PT but using the following therapeutic scheme: For 4 weeks, patients were receiving the maximum dose reached before interrupting initial PT, for another 2 weeks dose was reduced and then treatment was again discontinued. Patients then abstained from medication for another 3 months and then repeated the above scheme (lasting 6 weeks). Finally, they were advised to repeat the scheme once every 6 months. Results: All 39 patients who took long term repetitive PT maintained the result achieved by initial PT during the whole 24–36 month period for which they were followed up. Among the rest 44 patients who didn’t, rebound of M occurred with respect to attack frequency and intensity within the same period and needed to start fulltime PT again. Conclusion: All 39 patients on repetitive PT maintained for the result achieved by initial PT for 2–3 years.Among the rest 44, M either re-appeared or worsened within the same time.We are aware of no similar studies.Further studies with more patients are probably needed to prove the efficacy of repetitive PT.

P701 Conventional and atypical neuroleptics in chronic daily headache N. Kouroumalos, D. Korakaki, K. Kalamafkianaki, C. Labiris, L. Karatzaferis, E. Kalafatis, C. Tsitou, G. Georgakakis, E. Nikolakaki General Hospital of Chania (Chania, GR) Objectives: Neuroleptics have long been used for headache treatment; however, they have not been widely utilized because of their adverse effect profile. With the recent advent of atypical neuroleptics and their improved adverse effect profile, our armamentarium for headache treatment has expanded. In this study, we explore evidence for antipsychotics’ efficacy in treating Chronic Daily Headache (CDH). We also report our experience on the use of conventional and atypical neuroleptics on CDH treatment. Methods: We reviewed the files of 20 patients with CDH (using ICHD-II criteria). Ten of them were treated with perphenazine and another ten with olanzapine for at least 3 months. All had previously failed treatment with at least three preventive medications. The daily dose of perphenazine varied from 2–8 mg and that of olanzapine varied from 2.5 to 10 mg. t- test was used to measure efficacy by comparing headache days, duration and severity before and after treatment. Results: Treatment with perphenazine resulted in a statistically significant decrease in headache days per month, from 29 before treatment to 6.2 after treatment (P <.001).The difference in headache duration (hours per day) reduced from 15.4 before treatment, to 3.5 after treatment (P <.001). The difference in headache severity (0 to 10 scale) before treatment (6.5) and after treatment (1.8) was also statistically significant (P <.001). Treatment with olanzapine resulted in a statistically significant decrease in headache days, from 27.5 before treatment to 4.9 after treatment (P <.001). The difference in headache duration (hours per day) reduced from 20.2 before treatment to 2.3 after treatment (P <.001). The difference in headache severity (0 to 10 scale) before treatment (6) and after treatment (1.5) was also statistically significant (P <.001).Treatment with perfenazine had failed in 4 patients who were then successfully treated with olanzapine. Conclusion: Our study was retrospective. Placebo – controlled trials will be required to confirm our findings. Even so, as three or more other preventive medications had failed in our patients, we doubt that placebo effect significantly influenced our results. Neuroleptics seem effective for preventive treatment in refractory chronic daily headache. Olanzapine may be more effective for patients with chronic daily headache than perphenazine. We believe that neuroleptics to be more appropriate as second line medication. P702 Prevalence of primary and associated headaches in multiple sclerosis C. Labiris, N. Kouroumalos, K. Kalamafkianaki, D. Korakaki, L. Karatzaferis, E. Kalafatis, C. Tsitou, G. Georgakakis, E. Nikolakaki General Hospital of Chania (Chania, GR) Objectives: The International Headache Society in headache classification (ICHD-II) has recently recognized that secondary headaches may occur in patients affected by inflammatory diseases (ID) of the Central Nervous System (CNS) but Multiple Sclerosis (MS) is not mentioned in ICHD-II. Although headache is not a common symptom of MS, some reports suggest that people with MS have an increased incidence (may even reach 58 %) for certain headache types. The relationship of headache with clinical features of MS on one hand and MS therapy on the other, were also investigated. The aim of this study was to investigate the prevalence of headache, primary and secondary, in MS patients. Methods: In a prospective study, a group of 66 patients suffering from definite MS were given a questionnaire to obtain information about their headache frequency, duration and other characteristics such as quality, intensity and pain localization. We then described the prevalence of primary and secondary headache in our patients with MS (diagnoses according to ICHD-II criteria). Results: The prevalence of all headache types among patients with MS in our sample was 36.36 % (24/66). Migraine was found in 5(20.8 %), tensiontype headache in 16 (66.6 %) and secondary headache in 5 patients (20.8 %). Among patients who were on disease modifying therapy (DMT) for MS with interferon, 3 were suffering from migraine, 12 from tension headache and 26 were not suffering from any headache. Conclusion: Recent data show a high incidence of headache in MS (58 %) and that the association between migraine and MS, might suggest a pathogenetic relationship. In our study we had no matched group of people without MS but we have a previous study with the prevalence of primary headache throughout the general population in our region.According to this previous study, the prevalence was 46 % for migraine and 36 % for tension type headache. In contrast, among our patients with MS, prevalence of migraine was 20.8 % (almost twice less than prevalence among general population) and

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that of tension-type headache was 66.6 % (almost twice than that among the general population). This might be due to other causes of headache in MS patients such as cervical paraspinal spasm or depression (in case of tension headache). P703 Prolactinoma associated with trigeminal neuralgia: a case report D. Parissis, C. Balla Aristotle University of Thessaloniki (Thessaloniki, GR) Objectives: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome) and the closely related SUNA (short-lasting unilateral neuralgiform headache attacks with cranial autonomic features) syndrome are rare primary headache syndromes belonging to the group of trigeminal autonomic cephalalgias. Secondary SUNCT cases have recently been described, especially in the setting of posterior fossa abnormalities and pituitary tumors. Activation of the trigemino-autonomic reflex probably due to defective hypothalamic modulation on trigemino-vascular pathways has been proposed as the pathophysiological mechanism of idiopathic SUNCT/SUNA. On the other hand, the marked clinical similarities between first-division (V 1) trigeminal neuralgia and SUNCT/SUNA have led to the suggestion that these conditions belong to a spectrum of a single disorder. Methods: A-33-year-old female presented to our Department for evaluation of disabling episodic headache periods. She experienced 3 distinct cycles of severe pain over the last months, each lasting 7 days. The bouts consisted of repeated stereotyped attacks of left-sided supraorbital headache of stabbing quality, with duration of 2–3 s, continuously occurring every 2-min during day and night. The patient did not report any trigger factors or migrainous features, whereas the paroxysms were not alleviated by simple analgesics and codeine. The more severe attacks were accompanied by mild ipsilateral lacrimation and facial flushing. Her medical history was remarkable for amenorrhea and galactorrhea attributed to hyperprolactinemia, which was diagnosed 4 years ago and an MRI revealed a pituitary microadenoma. The patient was prescribed cabergoline and no change of the regimen before or during headache periods were reported. Results: In our case, the ultra-short duration (< 4 s) of the attacks, along with the presence of refractory period between attacks and the mild autonomic phenomena favored a diagnosis of V 1 trigeminal neuralgia. However, the bouts occurred in the context of a microprolactinoma under dopamine agonist treatment, which has the potential to trigger SUNCT pathophysiology, as recent literature data have shown. Conclusion: Our case supports the proposed concept that V 1 trigeminal neuralgia and SUNCT/SUNA are not distinct entities, but overlapping clinical conditions sharing at least in some cases a common central origin. P704 Detection of patent foramen ovale with transcranial Doppler sonography and magnetic resonance findings in two different types of migraine E. Motta, Z. Kazibutowska, P. Puz, A. Golba, A. Bal, M. Debski Silesian Medical Academy (Katowice, PL) Objectives: Patent foramen ovale (PFO) may play a role in the pathophysiology of migraine and a closure of PFO is associated with improvement in migraine in some patients. Migrainic aura may be a symptom of paradoxical cerebral embolism. Transcranial Doppler sonography (TCD) is one of the method to diagnose a PFO. The aim of our study was to evaluate the frequency of microbubble signals assessed with TCD in patients with different types of migraine and to determine if there is any relationship between microbubble signals and white matter hyperintense lesions on magnetic resonance imaging (MRI). Methods: 50 patients (12 men and 38 women), aged 24–49, (mean 36.6) were studied. The diagnosis of migraine with or without aura was based on the criteria adopted by the International Headache Society (2004). 17 patients suffered from migraine with aura and 33 patients suffered from migraine without aura. TCD was performed in every patient using Doppler instrument Pioneer 2020 with 2 MHz transducer during Valsalva maneuver after inravenously injection of air contrast (9 ml saline – 0.9 % NaCl and 1 ml of air). The blood flow velocity of the right middle cerebral artery was recorded at an insonation depth between 50–60 mm with hand-held transcranial Doppler probe. A PFO was considered when at least one microbubble signal was detected during 6 seconds after injection of the air contrast. The grading of PFO was based on the recorded number of signals (grade 1 – single bubbles, grade 2 – many bubbles). All patients underwent transthoracic echocardiography and MRI.

Results: The microbubble signals were detected in 12 (24 %) from among 50 patients, in 7 (41 %) patients with migraine with aura and 5 (15 %) patients with migraine without aura. The difference was statistically significant. White matter hyperintense lesions on MRI were elicited in 20 (40 %) patients. In patients with migraine with aura white matter changes were present in 8 (47 %) objects while in those with migraine without aura in 12 (36 %). Conclusion: 1. In patients with migraine with aura microbubble signals were significantly more frequent than in patients with migraine without aura. 2. White matter hyperintense lesions revealed by MRI occur somewhat more frequent in patients with migraine with aura than in patients with migraine without aura, but the relationship between MRI white matter changes and microbubbles signals detected in TCD remains unclear and needs further investigations. P705 Pregabalin prophylaxis in chronic tension-type headache P. E. Bermejo, R. Saez, R. Velasco Puerta de Hierro Hospital (Madrid, ES) Objectives: Pregabalin has been recently suggested as a therapy for anxiety disorder. As known, anxiety is frequently associated with tension type headache. We evaluated the efficacy and tolerability of pregabalin for chronic tension type prophylaxis in refractory patients. Methods: Thirty patients with refractory chronic tension type headache according to International Headache Society criteria were evaluated. Headache frequency, headache severity and anxiety associated before and after treatment initiation with pregabalin were compared.The patients had failed an average of 3.1 prophylactic drugs prior to pregabalin. The average pregabalin daily dose was 190 mg and the average duration of treatment was 152 days. Results: The average number of days with headache per month was reduced in the entire study population from 20.2 before pregabalin treatment to 17.1 after its initiation; headache severity was reduced according to Analogic Visual Scale from 7.1 to 5.2, and anxiety was reduced, according to Hamilton Scale from 22.0 to 17.1. Pregabalin was well tolerated, the principal adverse event was somnolence and none patient abandoned the treatment because of that. Conclusion: Pregabalin has efficacy in tension type headache and anxiety reduction. According to our results, this drug may be a safe and effective agent in tension type headache prophylaxis. Double-blind studies are warranted to confirm these findings. P706 Zonisamide prophylaxis in refractory migraine P.E Bermejo, R. Dorado Puerta de Hierro Hospital (Madrid, ES); Clínica La Zarzuela (Madrid, ES) Objectives: Zonisamide is a new anticonvulsant drug with multiple mechanisms of action, some of them may confer efficacy in the treatment of migraine headaches. We evaluated the efficacy and tolerability of zonisamide for migraine prophylaxis in refractory patients. Methods: Thirty-two patients, with International Headache Society-defined episodic migraine, were initiated on a 100mg/day zonisamide dosage, which was titrated to 200 mg/day as tolerated. The patients had failed an average of 5.1 migraine prophylactic drugs prior to zonisamide. Headache frequency and severity before and after treatment initiation were compared. The average zonisamide daily dose was 182 mg and the average duration of treatment was 152 days. Results: Statistically significant improvements in headache severity (P < 0.05), and frequency (P < 0.05) were evident after 1 month of zonisamide therapy and persisted after 5 months of treatment. Zonisamide was well-tolerated and the most common adverse events were drowsiness and difficulty in concentration. One patient discontinued because he developed a restless legs syndrome. Conclusions: These results suggest that zonisamide may be a safe and effective drug for migraine prevention and may be useful in refractory patients.

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P707 Electrophysiological study of masseter muscle weakness after percutaneous trigeminal ganglion balloon compression for treatment of trigeminal neuralgia E. Chroni, C. Constantoyannis, G. Kagadis, A. Argyriou, P. Polychronopoulos University of Patras (Patras, GR) Objectives: To estimate the frequency of appearance and analyse the severity of masseter muscle weakness after percutaneous balloon compression (PBC) of the trigeminal ganglion. Methods: Eight patients (4 males), between 43 to 80 years of age, with intractable trigeminal neuralgia were examined. The study included: a. needle electromyography of masseter muscle and b. motor evoked potentials (MEPs) recorded with surface electrodes from the masseter muscle, evoked by contralateral and ispilateral transcranial magnetic stimulation. The response to contralateral stimulation was considered central elicited by excitation of the pyramidal truck, whereas the ispilateral response was regarded as peripheral due to stimulation of the trigeminal branch supplying the masseter muscle. All patients were studied before and 1 month after unilateral PBC. In three patients, additional studies at 6 months and 1 year post PBC were performed. Results: Masseter muscle weakness was electrophysiologically verified in all 8 patients at the 1st month post PBC: the motor unit recruitment pattern on maximal voluntary effort was? 20 % of normal in 6 patients and absent in 2; no denervation potentials (positive sharp waves or fibrillation potentials) were disclosed. Long follow-up of 3 patients showed improvement of recruitment pattern to 60–80 % of normal at the 6 months study and to 100 % at the 1 year post PBC study. The MEPs’ latency was significantly prolonged 1 month after PBC: mean latency ± sd following contralateral stimulation was 4.6±0.6 ms before vs. 5.9±0.9 after PBC, p < 0.02 and following ispilateral stimulation was 3.1±0.6 ms before vs. 4.4±1.4 after PBC, p < 0.03. MEPs were absent in two patients at the post PBC study. Conclusion: Our results indicate that masseter muscle weakness is unavoidable after PBC and this was confirmed by electromyographic examination. The nature, however, of muscle dysfunction appears to be benign. The combination of reduced electromyographic recruitment pattern without denervation potentials and prolonged MEPs latencies points towards a neurapraxic/demyelination process with axon sparing.

P708 Left atrial myxoma presenting with migraineous aura episodes A.L. Guerrero, S. Florez, Y. Carrascal, E. Guillén, J. Martín-Polo, M.A. Tejero, F. Gutiérrez, F. Iglesias Hospital Rio Carrion (Palencia, ES); University Hospital (Valladolid, ES) Objectives: From observation of data linking patent foramen ovale (PFO) and migraine with aura, it has been postulated that cardiac pathology may have an effect on migraine pathophysiology. Myxomas are the most common benign cardiac tumours. They may present clinically with many different features, mainly constitutional, cardiac of neurological symptoms.We report the case of a patient with left atrial myxoma whose presenting symptom was migraineous visual aura with no other neurologic symptom or magnetic resonance imaging (MRI) lesions. Methods: 43-year-old female with no cardiovascular risk factors apart from smoking. She complained of visual disturbances consisting of flashing lights and colours, suggesting typical visual auras. Half of them were followed by migraineous headache. No abnormalities were found during neurologic examination. A brain MRI showed no lesion. Nine months later, she suffered an acute congestive cardiac failure. A transthoracic echocardiography showed a mass in the left atrium with the typical features of myxoma. Echocardiographic diagnosis was confirmed during intraoperative examination and histological analysis. Myxoma was excised without complications. In postoperative follow-up, six months after surgical procedure, the patient has remained free of neurologic symptoms. Results: Neurological complications are well-known manifestations of cardiac myxomas; embolic stroke is, by far, the most common single neurological presentation. Other non-focal events include syncope, seizures, psychiatric problems or headache. Acute headache as a general neurological symptom may be associated with cerebrovascular events or MRI o computed tomography (CT) demonstrated infarctions. Changes in characteristics or frequency of pre-existence migraines related to myxoma diagnosis, or their resolution after surgical removal have also been described. Conclusion: Cardiac pathology may have a role in migraine and pathophysiological hypothesis have been proposed. Increased platelet aggregability favoured by left atrial tumours may contribute to a transient occipital hypoperfusion as postulated in visual aura. This clinical presentation illustrates that a left atrial myxoma can lead to a new onset and reversible

migraineous aura as the only neurological symptom with no other clinical or radiological manifestation.

P709 Neurological versus general practice in headache service: a perspective from Thailand K. Phanthumchinda, T. Asawavichienjinda Chulalongkorn University (Bangkok, TH) Objective: Standard headache practice has slowly gained recognition among general practitioners (GPs). To improve appropriate education for GPs, this study is purposed to probe information gap between neurologists and GPs. Method: A cross-sectional survey was performed. Participants were neurologists and GPs recruited from a neurological meeting. Self-administered questionnaires were developed to assess baseline data, strategies for migraine treatment and pattern of continuing education. Results: 76 physicians participated. 46 were neurologists, 30 were GPs. Most of them were working for government hospitals. Mean age and duration of practice of neurologist were more than GPs; but not significantly different. Neurologists had more significant number of headache patients than GPs (P=0.04) and their patients had better compliance (P<0.001). Both neurologists and GPs used monotherapy and combined therapy for acute headache in the same proportion. Neurologists and GPs commonly used simple analgesics and non-steroidal anti-inflammatory drugs(NSAIDs) for acute attacks. For monotherapy, NSAIDs were commonly used by neurologists (79%) while ergots were commonly used by GPs (40%) and triptans were used in the same percentage. For combined therapy, most neurologists and GPs used NSAIDs and ergots. Beta-blockers, calcium channel blockers, tricyclic antidepressants were commonly used as prophylactic drugs in both groups.Valproic acid and topiramate were significantly used by neurologists (70%, 85%) as compared to GPs (13%, 53%) (P<0.01 and P=0.003, respectively). Ergots were significantly used as prophylactic drugs by GPs (P=0.03). Both neurologists and GPs commonly used monotherapy in migraine prevention (50% and 63%, respectively). When combination was considered, beta-blockers plus tricyclic antidepressants was the most popular combination (45% in neurologists, 40% in GPs). The average duration of prophylaxis was 3-6 months (70% in neurologists, 57% in GPs). For continuing education, neurologists commonly used journals (65%) as well as short tutorial course programs (61%) as their resources while GPs preferred short course programs (80%). Conclusion: GPs trended to use ergots in migraine. Anti-convulsants were slowly taken into use by GPs. Migraine patients who are taken care by GPs can be managed better by setting intensified short course programs in migraine management.

P710 Analgesic effect of transdermal buprenorphine in patients with uncontrolled painful neuropathy P. Penza, L. Maggi, A. Martini, A. Campanella, G. Lauria National Neurological Unit “Carlo Besta” (Milan, IT) Buprenorphine is a low molecolar weight, lipophilic, opioid analgesic, recently available as a transdermal matrix patch formulation (Buprenorphine TDS). The efficacy of Buprenorphine TDS in chronic painful neuropathies has not been adequately examined. Aim of this open-label, pilot, non-randomized study was to assess if Buprenorphine TDS administered as add-on treatment allowed achieving a satisfactory pain control in patients with chronic painful neuropathies. Secondary aims were to assess the optimal dose schedule and the sparing of pre-trial analgesic medication. Patients with peripheral neuropathy and unsatisfactory pain control (VAS score ≥5) with pre-trial analgesic medications under stable regiment for at least 4 weeks were recruited. Primary endpoint was a reduction of 30% in pain severity at VAS analysis. Secondary efficacy variables were number of responders, patient global impression of change (PGIC), and short sleep quality questionnaire (SQNRS). Buprenorphine TDS was started at the dosage of 35.0 mcg/h and could be increased to 52.5 and 70.0 mcg/h in case of unsatisfactory pain control as assessed by fortnightly therapeutic result visits. After achieving a satisfactory pain control, patients could start a progressive tapering of pre-trial analgesic medication, whereas Buprenorphine TDS was maintained at the same dosage. Preliminary data in 17 patients are presented. All except one patient had previously withdrawn pre-trial medications because of inefficacy or side effects. Five patients who started the treatment with Buprenorphine TDS at the dosage of 35.0 mcg/h dropped out during the first week because of side effects (nausea, blood hypotension, or daily sleepiness). Slower increasing of the starting dosage by 25% every 3 days was much better tolerated. In 12 responders, Buprenorphine TDS in-

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duced an improvement of 30% in pain severity that was stable up to the 70day visit (baseline mean VAS=6.8; 70-day visit mean VAS=4.6). Only 4 patients needed to increase the dosage from 35 to 52.5 mcg/h to achieve satisfactory pain control. PGIC was slightly improved in all responders, whereas SQNRS did not change. Buprenorphine TDS appears a well tolerated and effective treatment in patients with uncontrolled painful neuropathy. This study is supported by an unrestricted grant by Grünenthal-Formenti Italia. P711 Study of mechanisms of the ACTH (4–10) analogue Semax analgesic activity D. A. Vilensky, N. G. Levitskaya, D. M. Ivanova, L. Andreeva, A. A. Kamensky Lomonosov Moscow State University (Moscow, RU); Institute of Molecular Genetics RAS (Moscow, RU) It is well known that ACTH/MSH-like peptides (melanocortins) apart from their classical endocrine effects exert pleiotropic non-endocrine actions. Heptapeptide Semax (MEHFPGP) is the analogue of ACTH(4–10). Our previous data and clinic investigations have shown Semax analgesic activity.According to literature data semax interact with serotonin (5HT), noradrenalin (NA) and dopamine (DA) systems. Furthermore high concentrations of semax antagonize MC 4 and MC 5 receptors in vivo and in vitro. Also it has been reported that melanocortin (MC) and opioid systems have opposite activities. The aim of the present work was to study the mechanisms of Semax influence on pain sensitivity and peptide interaction with opioid, DA and 5HT systems. The work was carrying out in white rats. Pain sensitivity was measured by using Randall-Selitto paw-withdrawal test. Semax was administrated intraperitonealy at dose 0.5 mg/kg. Semax reduced pain threshold in paw-withdrawal test. To study the mechanisms of Semax analgesic effects we used ciproheptadine (serotonin receptors antagonist), clebopride (dopamine receptors antagonist), naloxone (opioid receptors antagonist) and morphine (mu-opioid receptor agonist). Pre-treatment with serotonin and dopamine antagonists eliminate semax analgesia. Intraperitoneal pretreatment with naloxone (1mg/kg, 15 min before peptide injection) failed to influence Semax analgesic effect, naloxone 5 mg/kg reduced Semax analgesia in paw-withdrawal test. Also we have shown that Semax attenuates morphine (5 mg/kg, 15 min after peptide injection) induced analgesia and decreases opioid form of stress-induced analgesia. So peptide has antiopioid properties at the same time display analgesic activity itself. We can suppose that Semax effects on nociception depend on the level of opioid system activity. The work was supported by Program MCB RAS and Russian Foundation of Basic Research (Grant 04-04-48511). P712 Warm complex regional pain syndromes (CRPS) to cold CRPS – are there differences beyond skin temperature? T. Eberle, R. Rolke, M. Dieterich, F. Birklein University of Mainz (Mainz, DE) Objectives: The complex regional pain syndromes (CRPS) can be clinically subdivided into two types: the primary warm and the primary cold CRPS. The subtypes are clinically clearly to distinguish. A different pathophysiological mechanism underlying each subtype is possible. This study aims the question if there is a different pain characteristic for each subtype. Methods: 89 CRPS patients were investigated clinically and also underwent quantitative mechanical and thermal sensory testing. Results: Patients suffering from cold CRPS had significantly more “neglect-like” phenomena than the warm CRPS group (p < 0.005, chi2). On the other hand cold CRPS patients were significantly more sensitive to heat (p < 0.03, Wilcoxon) and pressure pain as compared to the warm CRPS subtype (p < 0.003, Wilcoxon). Conclusion: Patients suffering either from warm or cold CRPS not only differ in respect to skin temperature but also in their pain characteristics. This supports the assumption of different pathophysiological aetiologies. P713 Visual-evoked potentials and colour Doppler sonography of ocular arteries in migraineurs with visual aura H. Marouf Alexanria University (Alexandria, EG) Background: Disorders of the visual function in migraineurs have been recognized by neurophysiological methods for many years. However, studies of the cortical visual evoked potentials have yielded contradictory results.

Changes in the retrobulbar hemodynamic in migraineurs with visual auras, have not been researched extensively. Objective: The aim of the present work is to study the visual evoked potentials as well as the blood flow velocity,pulsatility index (PI) and resistance index (RI) in the ophthalmic and central retinal arteries in migraine patients with and without aura. Methods: The present study included thirty five migraine patients and fifteen healthy control subjects. Twenty patients have exclusively migraine with visual aura (MA), and fifteen without aura (MO). The study was carried out during the headache-free periods, and all the patients and control groups were subjected to: complete general examination, thorough neurological and full ophthalmic examination, pattern-shift visual evoked potential (PS-VEP) assessment, and color doppler sonography of the ophthalmic (OA) and central retinal (CRA) arteries. Results: PS-VEP assessment showed prolongation of the N 75, P 100, and N 145 latencies of the MA group, than in the MO and control groups, but significant difference was found only between the N 75 and N 145 latencies of the MA and control groups (P = 0.032, 0.039 respectively). The mean P 100N 145 amplitude of the MO group was significantly higher than that of the control group (P = 0.021). The mean P 100-N 145 amplitude of the MA group was lower than that of the MO group but still higher than the control group although none of the differences reached significant level. The mean PI of OA and CRA, mean RI of CRA, and mean end diastolic velocity of the CRA were significantly higher in MA group than in the control subjects. Migraineurs without aura (MO), when compared to the controls, they showed the same trend as the MA group, but none of the differences was statistically significant. Conclusion: The present study gives support to the role of cerebrovascular factors and ischemic damage in the prolongation of the VEP wave latencies and decreased P 100 amplitude in migraine patients with visual aura. It also showed evidence of dysfunction in the retrobulbar circulation and hemodynamic changes that may explain some of the visual symptoms reported by most migraineurs. P714 Characteristics of headache and magnetic resonance imaging findings in patients with primary headache S.J. Han, S.W. Chung, Y.S. Shim, I.U. Song, S.R. Han, J.W. Park, K.S. Lee, Y.I. Kim, D.G. Lee The Catholic University of Korea (Seoul, KR) Background & Objective: Headache is not only one of the most common discomforts worldwide, and shows diversities according as gender, age, ethnics, life style and socio-economic status et al. However, to date, studies of epidemiology, characteristics and neuroimage of patients with primary headache are yet lacking. Thus we investigated relationship of brain magnetic resonance imaging (MRI) abnormalities and primary headache subtype, and each distribution of age and gender in primary headache subtypes. Methods: 922 consecutive patients only with primary headache, who had no neurological deficits, participated in this study. They were interviewed by neurologist and classified subtypes of headache (tension type headache; vascular type headache) on the basis of the diagnostic criteria of the International Headache Society. They also underwent magnetic resonance image to identify brain lesions, including cerebrovascular lesion and mass-like lesions. All images had been interpreted by a neuroradiologist. Clinical information was obtained by chart review. Result: Tension type headache was more common than vascular type headache (75.2% vs 24.3%). The mean age of patients with tension type headache was older than that of patients with vascular headache, significantly (49.7±14.9: 47.2±10.9, respectively). The male: female ratio was 1:1.2 in tension type headache group and 1:4.2 in vascular type headache group (p<0.05). In tension type headache, abnormal MRI findings were 20.3%, whereas abnormality of MRI in vascular type headache was 27.1% (p<0.05). Conclusions: The present study showed that younger female patients revealed higher prevalence of vascular type headache than tension type headache, consistent with prior other reports, and vascular type headache also had more m! any freq uencies of MRI abnormalities, but these abnormal findings may be unrelated to primary headache . Therefore, authors suggest that if patients complain the continuous severe headache of vascular type, the clinicians would have to perform detailed neurological examination and consider neuroimaging studies, including brain computer tomography and MRI.

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P715 Exteroceptive suppression of temporalis muscle in tension type headache and migraine T. Avramidis, I. Anastasopoulos, T. Rallis, K. Dinos, T. Thomaides Red Cross Hospital (Athens, GR) In this study we measured exteroceptive suppression (ES) in order to confirm this method as a tool in the differentiation of tension type headache (TTH) and Migraine. For this purpose we applied an average of 3 stimuli (25 mA) , separated by 30 second intervals ,on the third (mandibular) division of the trigeminal nerve during voluntary teeth clenching. EMG of the right temporalis muscle was recorded by surface electrodes. ES1 and ES2 were measured in 30 controls , 32 with migraine (14 during attacks and 18 in remission) and 72 with TTH ( 28 with pain and 44 symptom-free). Migraineurs demonstrated similar ES values, in comparison to normal controls, during acute pain and remission. TTH patients demonstrated normal ES1, independently of the headache phase. From the 28 TTH patients with pain, ES2 was absent in 13 (46%) while 12 (42%) showed significant deviation from normal values. From the 44 TTH patients studied in remission , 6 (13%) had abnormal ES2. In conclusion, the above findings indicate that ES studies can play an important role as a neurophysiological method used in the differential diagnosis of TTH and Migraine. P716 Protein-biochemical investigations on serum and cerebrospinal fluid parameters in patients suffering from chronic idiopathic pain syndromes under treatment with intravenous immunoglobulins M. Stock, H. Vogel, M. Rott, C. Melzer, A. Weishaupt, S. Jarius, A. SchubertUnkmeir, R. Schedel, G. Sprotte University of Wurzburg (Wurzburg, DE); University of Munich (Munich, DE) Introduction: The pathogenesis of chronic widespread pain syndromes (CWP), including fibromyalgia syndrome, complex regional pain syndrome or myofascial pain syndrome is still unknown. Recent findings suggest a role of immunopathological mechanisms in those disorders. Objectives: To assess biochemical markers in serum and cerebrospinal fluid (CSF) indicative of inflammation of the central nervous system (CNS) and to evaluate the effect of intravenous immunoglobulins (IVIg) on those parameters. Methods: Serum and CSF were obtained from 30 patients with CWP, most of which had shown a marked analgesic response to IVIg in the past, and from 15 controls with no history of chronic pain or other neurological symptoms. CWP patients received a fixed dose of 30 g IVIg and serum and CSF were obtained immediately before and two weeks after IVIg treatment. Pain was assessed using the visual analogue scale (VAS). Results: CSF-restricted oligoclonal bands (OCB, ≥2 bands) were detected in 4/30 CPW patients and in none of the controls. Matched bands in serum and CSF (≥2), indicative of systemic humoral immune response, were present in 7/30 CWP patients and in none of the controls. In OCB+ patients, the number of bands was significantly reduced by IVIg in CSF but not in serum. IgG concentrations in serum and CSF were significantly higher in the CPW group (QIgG was normal) and IVIg treatment resulted in a significant increase of serum and CSF IgG. Qalb was elevated in 8/30 CWP patients and 2/15 controls. Neither QIgG nor Qalb were significantly altered by IVIg. Mean CSF total protein (TP) levels were significantly higher in CWP patients before, but not after IVIg treatment. 4/30 CWP patients, but none of the controls, had mildly elevated (>50 mg/dl) TP. In 2/11 OCB+ CPW patients, intrathecal production of antibodies (Ab) against measles, rubella and/or herpes zoster, indicated by elevated Ab indices, was found. Ab to Borrelia burgdorferi were present in serum and CSF in 4, and additionally in serum only in 2 further OCB+ CWP patients.Pain according to the VAS was reduced in 26/30, increased in 2/30 and stable in 1/30 two weeks after IVIg treatment (p<0.0001). Conclusion: Our findings support previous data suggesting a possible role of immunopathological mechanisms in a subgroup of patients suffering from CWP, which are thus far considered to be of psychosomatic origin. This study also gives insight to possible immunomodulatory properties of IVIg on the level of the CNS. S. Jarius was funded by a an ENS fellowship grant.

P717 Heart rate recovery in migraine D. Yerdelen, T. Açil, M. Karatas Baskent University Faculty of Medicine (Adana, TR) Objectives: Although there is increased knowledge about migraine, the pathophysiological basis of the disease is still unclear and the possibility of autonomic nervous system (ANS) involvement has been suggested. An attenuated decrease in HRR is believed to reflect decreased parasympathetic activity. In this study, it was aimed to evaluate parasympathetic function by measuring heart rate recovery in patients with migraine. Methods: 47 pure migraine patients (average age 31.9 ± 7.2 years), 5 with aura symptoms and 42 without aura diagnosed according to the criteria of the International Headache Society were studied. To aviod a sex effect, we confined the study to women. Migrain duration was 6.4 ± 6.1 years, and the frequency of migraine attacks were 4.9 ± 3.4 per month. The presence of systemic disease (eg, diabetes mellitus), disorders, and drug use that could affect the ANS were exclusionary. All patients were sudied during the headache-free period. Age-matched 25 women (30.5 ± 4.7 years) were selected as control subjects who were free of migraine, and other chronic pain syndromes, or systemic diseases. Subjects with normal electrocardiography and transthoracic echocardiographic findings underwent exercise tolerance test according to modified Bruce protocol using Quinton treadmill system. During each exercise stage and every minute for 3 min after recovery, blood pressure, heart rate and cardiac rhythm were recorded. Heart rate recovery was calculated as the difference between heart rate at peak exercise and heart rate at the relevant minute of recovery. In an example, heart rate recovery at 1 min (HRR1) was calculated as the difference between heart rate at peak exercise and 1 min into the recovery cool-down period. We considered HRR1 and HRR2 in this study. Results: HRR1 were 29.8±9.8, 29.1±12.6, and HRR3 were 63.5±11.1, 65.3±16.2 in migrain, and control subjects, respectively. There wasn’t a significant difference between these two groups regarding HRR1 and HRR3. Heart rate at rest and peak heart rate during the exercise (beats/min), systolic and diastolic blood pressure (mmHg) at rest and peak values measured during exercise were also similiar in two groups. Conclusion: Although evaluations of autonomic function in migraine have been reported, the results are confliciting. We found HRR1 and HRR3 similiar in migraine, and control groups. These results show that parasympathetic functions are not affected in patients with migraine. P718 Gallium-67 SPECT scintigraphy is useful in diagnosis of temporal arteritis G. Quintanilha, O.J.M. Nascimento, M.R.G. de Freitas, J.C. Azevedo, P.F. Moreira Filho Universidade Federal Fluminense (Rio de Janeiro, BR) Background: Giant cell (temporal) arteritis (TA) is a vasculitis of unknown origin occurring most frequently in the elderly. It consists on a persistent pain in the temporal area of the skull, sudden visual loss, jaw claudication, high erythrocyte sedimentation rate, and tenderness on palpation in the temporal area. Arteritis in the temporal artery biopsy is seen in half of the patients. Non-invasive vascular methods may be helpful but they do not discriminate between inflammatory and non-inflammatory temporal artery disease. Quantitative Ga single SPECT may raise the accuracy of the diagnosis. Gal-67 binds to the transferrin receptor expressed on the surface of activated macrophages and therefore concentrates in the areas of inflammation. Objective: To report the usefulness of Gallium-67 SPECT scintigraphy for the diagnosis of TA. Patients and Methods: Three female patients, respectively 68, 72 and 74 year old, with clinically suspected TA, received 8–10 mCi Gal intravenously 48 hours before the scan. Clinical findings included new onset headache in the temporal area, and visual loss. Laboratory investigation revealed increased sedimentation rate in all three cases. Other causes of headache were ruled out. Gal uptake ratios were calculated on transaxial and coronal slices. Results: All three TA patients had an unequivocal increase of Gallium-67 uptake in the temporal area. Corticosteroid treatment was then prescribed resulting in the improvement of symptoms, mainly pain, in all cases. Conclusion: Our findings suggest that Gal skull SPECT may be an useful and non-invasive diagnostic method for TA diagnose, especially if the uptake ratio in the area of interest is calculated. Taking this finding into account immunesupresive therapy should be prescribed for TA with good results.

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P719 Sildenafil citrate a possible option for neuropathic pain due to ischaemia O.J.M. Nascimento, G. Quintanilha, M.R.G de Freitas, R.R. Silveira, M. Maroco, T.M. Escada Universidade Federal Fluminense (Rio de Janeiro, BR) Background: Sildenafil enhances the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells. This activity has been the rationale for the treatment of symptomatic pulmonary arterial hypertension. In a recent multicenter double-blind, placebo-controlled study, randomly assigned 278 patients with symptomatic pulmonary arterial hypertension to placebo or sildenafil. It was shown that sildenafil improves exercise capacity, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. Good results were also reported in patients with severe Raynaud phenomenon. Taking into account the good results with sildenafil for these condictions we treated patients complaining of severe neuropathic pain due to peripheral neuropathy with severe ischaemic compromise. Objective: The goal of this preliminary open study is to observe the efficacy of sildenafil in severe neuropathic pain cases due to ischaemia, non responders to other pain therapy. Patients and methods: A 69 y.o. diabetic woman suffering of severe neuropathic pain in the distal lower limbs with plantar ulcers due to ischaemia, and three women (respectively 36, 40 and 56 y.o.) with late painful neuropathy after conventional leprosy treatment with vasculitis were studied. All of them were previously treated with triciclics antidepressants, anticonvulsants and opyoids for severe neuropathic pain with no response. The reason for this treatment failure could be the severity of nerve ischaemia. Sildenafil was initially administered at a 50 mg daily dosis. Results: Neurological examination revealed pin and temperature anesthesia with allodynia in distal legs in all the patients. Pain improvement was observed in all four cases.Visual analogue scale decreased more than 40% in all patients. Other pain scales also showed unequivocal pain symptoms reduction. Plantar ulcers showed improvement in all cases. Conclusion: The results of this preliminary open study of sildenafil for neuropathic pain due ischemic and inflammatory neuropathy suggest that this type 5 phosphodiesterase inhibitor can be a possible ischaemic pain therapy option.

Motor neuron disease P720 Identification of compound exonic and intronic mutations in the superoxide dismutase 1 gene in a family with amyotrophic lateral sclerosis S.W. Chung, J-S. Kim The Catholic University of Korea (Incheon, KR); The Catholic University of Korea (Seoul, KR) Background: Since 1993, different mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported in approximately 20% of familial amyotrophic lateral sclerosis (ALS). Methods: A subpopulation of the family here reported has been presented in another report.We found that the proband and his immediate family were not included in the previous report. In this study, we have analyzed the SOD1 gene in this family group. Results: The mutations were a transition of GGC to GTT at codon 10 in exon 1 and/or [IVS4+15_16insA; IVS4+42delG; IVS4+59_60insT] at intron 4. Patients with compound mutations of SOD1 represent divergent phenotypes, including age of onset, and clinical symptoms, mostly depending on the nature of the SOD1 mutation. Acceleration of the age of onset in successive generations called anticipation was observed. Conclusion: We describe a large family with FALS that showed autosomal dominant inheritance and two distinct compound mutations in the Cu/Zn-SOD1 gene; affected family members had different phenotypes including varied age of onset and clinical symptoms. P721 Amyotrophic lateral sclerosis and transcranial magnetic stimulation sensitivity L. Bolokadze, I. Fedotova Kharkov Medical University (Kharkov, UA) Background: An upper motor neuron (UMN) lesion in amyotrophic lateral sclerosis (ALS) is often difficult to identify because clinical signs may be discrete or masked by severe simultaneous LMN lesions. We compared the di-

agnostic sensitivity of transcranial magnetic stimulation (TMS) to cranial muscles and limb muscles in the detection of UMN lesions. Method: We investigated corticobulbar and corticospinal tract function to the tongue/orofacial muscles and abductor digiti minimi/tibial anterior muscles with TMS in 59 patients with ALS to compare the diagnostic yield in the detection of UMN dysfunction.An UMN lesion was assumed when the following were found: the peripheral conduction time and amplitude of the M-wave were within the normal range, the response to cortical stimulation was absent, the TMS evoked/M-wave amplitude ratio was reduced, and the central motor conduction time or the interside difference was delayed (> mean+2.9 SD). Results: On the basis of these criteria a UMN lesion to the orofacial muscles was identified in 21 patients (45%), to the tongue in 31 (57%), and to the upper and lower limbs in 11 (24%) and 25 patients (45%), respectively. Combined abnormalities from all sites increased the diagnostic yield to 33 patients (72%). TMS of the limb muscles confirmed a UMN lesion in only 15 (54%) of the 28 patients with clinically confirmed UMN involvement. This number increased to 25 patients (86%) if tongue and orofacial muscles were taken into acount. Conclusion: Our results indicate the early and in most cases subclinical corticobulbar tract involvement of the central motor pathways to the orofacial muscles and tongue in ALS.TMS of the tongue and orofacial muscles had a higher sensitivity in identifying UMN lesions than that of the upper and lower limbs.

P722 Immunohistochemical studies of neurotrophin-3 of skin in amyotrophic lateral sclerosis S. Ono, T. Watanabe, H. Mikami, T. Irie, T. Yamazaki, M. Suzuki Teikyo University Chiba Medical Center (Ichihara, JP) Objective: To elucidate whether neurotrophin-3 (NT-3) is increased in the skin in patients with amyotrophic lateral sclerosis (ALS). Background: Recently, it was found that immunoreactivities of ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF) and insulin-like growth factor-I (IGF-I) were markedly increased in the skin of ALS patients compared with controls. These observations serve to emphasize the potential importance of neurotrophic factors in ALS. NT-3 also belongs to the neurotrophic factors and is known to promote motoneuron survival. However, there have been very few reports dealing with NT-3 in ALS and little is known concerning NT-3 of skin in ALS patients. Methods: We examined NT-3 immunoreactivity of biopsy specimens of skin overlying the left biceps from 13 ALS patients (mean age 60.6 years) and 13 control subjects with other neurologic disorders (mean age 60.4 years). A densitometric analysis was performed using an image analysis program. Results: NT-3 immunoreactivity was markedly positive in the epidermis and was moderately positive in the reticular dermis in ALS patients. These findings became more conspicuous as ALS progressed. On the other hand, the epidermis and the reticular dermis showed a weak NT-3 immunoreactivity in control subjects. The optical density for NT-3 immunoreactivity of the epidermis in ALS patients (measn ± SD, 1.07 ± 0.38) was significantly higher (p < 0.01) than in control subjects (0.52 ± 0.22). The optical density of the reticular dermis in ALS patients (mean ± SD, 0.71± 0.36) was also significantly higher (p < 0.001) than in controls (0.23 ± 0.31). The above densities of NT-3 immunoreactivity in ALS patients showed a progressive increase in relation to duration of illness. This positive correlation was highly significant (r = 0.89, p < 0.001 and r = 0.73, p < 0.001, respectively) in the epidermis and in the reticular dermis. Conclusion: NT-3 was found to be significantly up-regulated in skin samples from ALS patients. Since NT-3 is known to promote motoneuron survival, NT-3 may have a trophic role in skin of ALS patients and may help to explain why decubitus formation is rare in ALS.

P723 Long-term follow-up study of amyotrophic lateral sclerosis patients on tracheostomy positive pressure ventilation Y. Tanabe, K. Nobukuni, H. Takata, Y. Ihara Minami-Okayama Medical Center (Tsukubogun, Okayama, JP) Objectives: The preparation of advance directives is one of the challenges faced in the management of amyotrophic lateral sclerosis (ALS). Some longsurviving patients with ALS who have received tracheostomy positive pressure ventilation (TPPV) develop a totally locked-in state (TLS) in which they are completely unable to communicate. The request from patients for ventilator removal once they develop TLS has been raised as an issue. At the root of the debate is the long-term prognosis of patients with ALS who have re-

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ceived TPPV. However, much remains unknown about the long-term prognosis of these patients, such as the percentage who develop TLS. Methods: The aim of this study was to obtain further information about the long-term prognosis of these patients for the purpose of preparing advance directives. This was performed by investigating the percentage of patients with ALS using TPPV at our hospital (Minami-Okayama Medical Center) who develop TLS, the long-term prognosis of these patients, and the causes of death. Results: Five (18.5%) of 27 patients developed TLS. Five (33.3%) of the 15 patients who survived for longer than 5 years developed TLS. The percentage of patients who developed TLS tended to increase as the duration of TPPV increased. Twenty-two of the 27 patients receiving TPPV died. Of the 22 patients who died, 9 (40.9%) died from pneumonia, 5 (22.7%) from heart disease, and 2 from renal failure. Among the patients using TPPV, pneumonia was the most common cause of death in the early stage of TPPV. However, as the time on TPPV increased, pneumonia became less common and heart disease, renal failure, and septicemia became more common. Conclusion: Clarification of the status of the long-term care of patients with ALS using TPPV is likely to become an important source of information for patient self-determination using advance directives. P724 Recombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of amyotrophic lateral sclerosis by preventing motor neuron death and inflammation K-Y. Lee, S-H. Koh, Y. Lee, G. Han, Hyun Kim, Hee Kim, J. Kim, S. Kim Hanyang University Guri Hospital (Guri-si, Gyeonggi-do, KR); Hanyang University Seoul Hospital (Seoul, KR) Multifactorial pathogenic mechanisms including inflammation, attenuated survival signals and enhanced death signals are involved in amyotrophic lateral sclerosis (ALS). Erythropoietin (EPO) has recently been highlighted as a cytokine with various potent neuroprotective effects including reduction of inflammation, enhancement of survival signals and prevention of neuronal cell death. This study was undertaken to evaluate the effect of recombinant human EPO (rhEPO) on ALS model mice. We treated 96 ALS model mice with vehicle only, or 1, 2.5 or 5 iu of rhEPO per gram of mouse once per every other week after 60 days of age. The treatment significantly prolonged symptom onset and life span, preserved more motor neurons, enhanced survival signals, and attenuated inflammatory signals in a dose-dependent manner. These data suggest that treatment with rhEPO represents a potential therapeutic strategy for ALS. This work was supported by the Korea Research Foundation Grant funded by the Korean Government(MOEHRD) (KRF-2005-041-E00338). P725 Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis J. Brettschneider, V. Lehmensiek, T. Ahlert, H. Mogel, S.D. Süssmuth, C. Palm, A.C. Ludolph, H. Tumani University of Ulm (Ulm, DE) Objectives: Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease characterized by progressive degeneration of spinal and bulbar innervating motor neurons as well as the pyramidal motor neurons. Cerebrospinal fluid (CSF) is a promising source of biomarkers in ALS to advance the understanding of disease pathology as well as to support clinical diagnosis and identification of different subtypes of disease. Methods: Using the two-dimensional difference in gel electrophoresis (2-D-DIGE) technology, we compared CSF samples from patients with ALS (n=37) with neurologically normal controls (n=25). Each 2-D-DIGE experiment was performed three times. Protein spots that showed a significant difference in spot volume over three independent 2-D-DIGE gels between patients and controls were selected for further analysis with MALDI-TOF mass spectrometry. Results: 30 different spots were identified. Analysis of only those spots with a significant difference (p < 0.05) between ALS and controls revealed 17 spots, corresponding to 9 different proteins. We identified 8 proteins that were upregulated (serum vitamin D-binding protein precursor, transthyretin, transferrin, alpha-2-HS-glycoprotein, serum albumin, carboxypeptidase E precursor protein (proCPE), transthyretin-related amyloid fibril protein, alpha-1-antitrypsin) and 1 protein (proapolipoprotein) that was down-regulated in CSF in ALS. Conclusion: Carboxypeptidase E precursor protein (proCPE) and the transthyretin-related amyloid fibril protein have not been reported in CSF of ALS patients so far. Neuronal damage in ALS could be associated with a blockade in the proteolytic processing of CPE, leading to an upregulation of proCPE in CSF. In contrast, several other proteins (serum vitamin D-bind-

ing protein precursor, transthyretin, transferrin, alpha-2-HS-glycoprotein) seem to be unspecifically upregulated in different neurological diseases and may therefore be of limited value as disease-related biochemical markers in ALS. Though the pathophysiological role of the above mentioned proteins still remains to be further elucidated and additional validation will be needed, our findings may have a relevant impact on the identification of disease-specific markers in ALS.

P726 Asymmetric neurogenic calf hypertrophy in a patient with proximal spinal muscular atrophy type III D. S. Shim, B. C. Suh, B-J. Kim, I. N. Sunwoo, S. M. Kim Yonsei University College of Medicine (Seoul, KR); Korea University College of Medicine (Seoul, KR) Objective: To report a case of proximal spinal muscular atrophy (SMA) type III that the calf muscle was enlarged asymmetrically. Patient and methods: A 25 year-old female patient presented with progressive gait disturbance since the age around 10. Before the onset of the symptoms, she had reached the developmental milestone normally. At the age of 20, she had gradually developed painful left calf enlargement. Her medical and family history was unremarkable. Neurologic examination revealed mild to moderate weakness dominating proximity of her both lower extremities, correlated with bilateral thigh atrophy and unilateral calf hypertrophy. The tendon reflexes were generally absent. She complained generalized undulating movement lasting whole day long. We performed electrodiagnostic study, magnetic resonance image (MRI) of legs, muscle biopsy and laboratory/genetic study. Results: Nerve conduction study was unremarkable. Electromyography (EMG) demonstrated large-amplitude long duration motor unit potentials with spontaneous denervation potentials in the lower limbs. In addition, perpetual spontaneous motor unit potentials were observed in all relaxed muscles, whose nature was not fully scrutinized because EMG was not performed during sleep. The MRI showed that left gastrocnemius was enlarged, of which medial belly much larger than the lateral one, in contrast to the atrophied bilateral thigh muscles, bilateral soleus and peroneus, and right medial gastrocnemius. Its lack of fatty change was indicative of true hypertrophy rather than pseudohypertrophy. Pathologic finding of left vastus lateralis was compatible to chronic denervation atrophy. Creatine kinase was elevated 8 times higher than the upper normal limit. Homozygous deletion of telomeric exon 7 and 8 of survival motor neuron (SMN-1) gene on 5q11.2–13.3 was shown by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) technique. Conclusion: We observed a rare case of SMA type III accompanied by asymmetric calf enlargement. The present study illustrates that asymmetry may be a transient form of the disease process because this condition was not only from neurogenic focal hypertrophy, but also from simultaneous atrophy of other muscles in the lower extremities.

P727 Angiogenin levels in cerebrospinal fluid J. Phukan, W. McCormack, P. Anderson, P. Jakeman, O. Hardiman Beaumont Hospital (Dublin, IE); University of Limerick (Limerick, IE); Umeå University Hospital (Umea, SE) Background: Hypoxia responsive proteins may play a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Deletion of the hypoxic response element of the VEGF promoter resulted in an ALS phenotype in experimental animals, and administration of VEGF enhances survival in the SOD 1 model of ALS. Mutations in a related hypoxia responsive protein ANG cause familial ALS, and multiple haplotype associations with ANG have been identified in the Irish sporadic ALS population. We have recently reported that serum angiogenin levels are elevated in Irish ALS patients. Thus mounting evidence suggests a role of angiogenin in the pathogenesis of some forms of ALS, particularly in those of Irish or Scottish origin. Objective: To determine whether angiogenin is present in cerebrospinal fluid (CSF), and to quantify the range of angiogenin levels in CSF in nonIrish ALS patients and controls. Methods: 187 Swedish patients with ALS were recruited. All fulfilled the El Escorial criteria for probable or definite ALS. Control DNA was isolated from 120 unrelated, ethnically matched controls with no known history of a neurologic disorder. Commercially available kits (Quantikine) purchased from R&D Systems (Abingdon, UK) were used to perform in vitro enzymelinked immunosorbent assay (ELISA) for the quantitative measurement of human angiogenin.

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Results: Angiogenin is expressed in CSF. The range of angiogenin ranges from 1.4596ng/ml to 45.68ng/ml. No age or gender effect was observed. The range of levels in CSF did not differ between ALS patients and controls, although further analysis is required to determine whether site of onset, duration of disease and the presence of an “at risk” haplotypes affect CSF levels. Conclusion: Angiogenin is expressed in CSF. Levels of expression are unaffected by age, gender or duration of disease. No clear differences in levels were observed between controls and ALS patients. Further analysis is underway to determine whether “at risk” haplotypes affect CSF levels of the protein. P728 A progressive ascending myelopathy of unknown aetiology V. Nociti, A. P. Batocchi, A. Conte, M. Luigetti, G. Frisullo, P. A. Tonali, M. Sabatelli Catholic University (Rome, IT); Don Gnocchi (Rome, IT) Objective: We describe 10 patients who developed a progressive ascending myelopathy after an acute episode of partial transverse myelitis (PTM). Methods: All patients underwent complete neurological examination, brain and spinal cord MRI, somatosensory and motor evoked potentials (SEPs and MEPs), electromyography (EMG), analysis of cerebrospinal fluid (CSF), haematological, microbiological and autoantibodies screening at first observation and every examination thereafter during the follow-up period. Results: All patients were male and showed at the onset of the disease an acute PTM, characterised by weakness and sensory symptoms of the lower limbs or urinary disturbances, preceded, 2–3 weeks before, by an infectious event. Brain MRI did not show specific abnormalities. Spinal cord MRI showed? 1 lesions with contrast enhancement and oedema. The MRI performed during progressive phase showed spinal cord atrophy. EMG was negative, while SEPs and MEPs were abnormal. In acute phase the CSF analysis showed a mild pleocytosis with an increase of proteins; the research (PCR and IgM) for common neurotropic infective agents was negative. Next CSF analysis were negative. Serum anti-HTLV-1 antibodies were also negative in all patients. A partial and total recovery was observed in 8 and 2 patients respectively after therapy with corticosteroids (CS) i. v. and/or IVIg. Then all patients showed a progressive course.A satisfying response to CS and/or IVIg was observed in 5 patients for 4.6±2.5 years followed by no response either to aforesaid treatments nor to other therapeutic attempts (anti-microbial, anti-viral, anti-mycotic, immunosuppressive and immunomodulatory drugs).All these patients developed a progressive ascending myelopathy until to tetraplegia. To date the other 5 patients show a partial response to CS and/or IVIg. Conclusions: In our patients the acute lesions in the spinal cord and the response to CS and IVIg, at disease onset, indicate a possible acute inflammatory phase followed by a degenerative phase characterized by spinal cord progressive atrophy and no responsiveness to immunosuppressive therapies. To explain the pathogenesis of progressive ascending myelopathy, we hypothise that an infective agent can survive in the spinal cord inducing a direct toxicity or an autoimmune response by a molecular mimicry or a bystander activation mechanism. Further studies are necessary to understand the aetio-pathogenesis of this unknown disease. P729 Muscle mitochondrial oxidative defects in amyotrophic lateral sclerosis V. Crugnola, V. Lucchini, S. Corti, L. Addobbati, A. Ciammola, N. Ticozzi, M. E. Fruguglietti, A. Prelle, D. Santoro, R. Virgilio, V. Silani, N. Bresolin, M. Moggio, G. P. Comi IRCCS Fondazione Policlinico (Milan, IT); Istituto Auxologico Italiano (Milan, IT) Objective: (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons both anterior horns of the spinal cord and cerebral cortex.About 10 % of ALS cases are familial, and 20 % of these are caused by dominant mutations in Cu, Zn-superoxide dismutase (SOD 1). Mitochondrial dysfunction may play a role in the pathogenesis of this disease. Reduction in mitochondrial number has been reported in intramuscular nerves, spinal cord and skeletal muscles of sporadic ALS patients. Also, abnormal mitochondria were seen in the skeletal muscle of ALS patients studied at electron microscopy. Finally in some patients, mitochondrial respiratory chain activity (COX) was decreased in spinal cord and muscle. We studied muscle mitochondrial oxidative metabolism, both morphologically and biochemically, in 50 patients affected by ALS; among these, 22 show some degree of COX deficiency in skeletal muscle, though only one confirmed biochemically.

Methods: The patients underwent skeletal muscle biopsy which we studied by morphological and biochemical methods. Mitochondrial DNA integrity and sequence were investigated by Southern blot and sequence analysis. SOD 1 gene was sequenced. Results: Histopathologic study of muscle biopsy showed a chronic neurogenic atrophy, with small angular fibers, small group atrophy and fiber type grouping (indicative of reinnervation) in all patients. Histochemically, COX deficiency was mild to moderate in 21 patients and severe in one. Only the latter, a 33 years old male, was also biochemically confirmed and dramatically worsened in the second biopsy taken after nine months. Pathogenetic mitochondrial DNA mutations were excluded in all patients, while a patient with a moderate muscle COX deficiency showed a missense mutation in SOD 1 gene. Conclusion: Our study has confirmed that mild to moderate/severe histochemical COX deficiency is a quite common finding in skeletal muscle from ALS patients (44 % of our cases). In the isolated case with severe progressive COX deficiency, the respiratory chain defect is likely to play a relevant pathogenic role. Furthermore, the finding of a secondary partial COX defect in a genetically proven SOD 1 mutated patient suggests that some of the observed COX defects may arise secondarily to other yet unidentified genetic defects. P730 Protective effect of N-acetylcysteine against oxidative stress- and glutamate-induced damage of motor neuron-like NSC-34 cells J. G. Lim, D. K. Song, W. K. Baek, S. S. Jang Keimyung University (Daegu, KR); Pohang Sullin Hospital (Pohang, KR) Objectives: Amyotrophic lateral sclerosis (ALS) is characterized by selective motor neuron death. Mouse neuroblastoma x spinal cord (NSC) hybrid cells have been developed as motor neuron cell lines. Moreover, modification of the growth conditions of NSC-34 cells by serum depletion (0.1 %) promotes the expression of functional glutamate receptors.We have compared protective effect of N-acetylcysteine (NAC) with those of vitamin E and riluzole against hydrogen peroxide (H2O2)- and glutamate-induced cell death using NSC-34 cells. Methods: To elucidate what to extent NSC-34 cells are damaged by oxygen free radicals, various concentrations of H2O2 were applied for 30 min to each medium containing undifferentiated NSC-34 cells and then washedout. After 6 h, the cell viability was assessed. Antioxidants were applied 6 h after H2O2 insult and then maintained in the media for 24 h, at which time the cell viability was assessed. Results: When treated with 1 mM H2O2 for 30 min, the cell number was reduced to around 50 % of control after 24 h. Cell fraction in sub-G 1 phase was markedly increased indicating that apoptosis appeared to take place. When post-treated with vitamin E, riluzole, or NAC for 24 h from 6 h after H2O2, cell survival was increased. Whereas NAC showed protective effect dose-dependently, the effect of riluzole became diminished from 10 microM. With differentiated cells at serum-deficit culture conditions, 1 mM glutamate reduced the survived cell number by 30 %. Each of three drugs cotreated with glutamate was effective on cell survival but the potency of NAC was greatest. Remarkably, NAC and vitamin E decreased cell death in glutamate-free, serum-deprived condition. Conclusions: These results suggest that NAC protects NSC-34 cells more than vitamin E and riluzole for both excitotoxic and non-excitotoxic oxidative injury. New approach with NAC may become a method to prolong the life of ALS patients. P731 Coincidence of sporadic amytrophic lateral sclerosis and parkinsonism: a case report K. Kollarova, E. Obdrzalkova, R. Herzig, P. Kanovsky University Hospital (Olomouc, CZ) Objectives: Overlapping syndromes of amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and dementia, defined as ALS plus, are rather rare outside of the Guam island and Kii peninsula. Some authors reported the coincidence of ALS, PD and dementia in 5–10 % of patients. A higher prevalence of parkinsonism was observed in family members of ALS patients. Case report: A 51-year-old female developed both parkinsonism and ALS. Her family history was negative concerning neurological diseases. The patient underwent hysterectomy and adnexectomy at the age of 39 due to adenocarcinoma, without any adjuvant therapy. Tremor and clumsiness of the left hand occurred at the age of 46. Resting tremor and cogwheel sign of the left upper and the left lower limbs, absent arm swing on the left side, bradykinesia, dysphonia and masked face were present. A good responsiveness to L-dopa treatment was observed. During 4 years she developed

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dysarthria with slurry speech, mild weight loss and muscle weakness. Hyperactice jaw jerk, decreased palatal reflex, hypotrophy of the tongue, arms and interosseal muscles, fasciculation of the tongue and both arms, exaggerate deep tendon reflexes, bilaterally positive Babinski’s sign were present. All sensory modalities were normal. The hematology, biochemistry (including paraneoplastic antibodies and oncological markers), immunoelectrophoresis and CSF findings were normal. Electromyography (EMG) revealed a diffuse pattern of chronic denervation with fasciculations, motor evoced potential showed a diffuse lesion of pyramidal tract. Magnetic resonance imaging (MRI) of the brain and spinal cord were normal. According to the neuropsychological investigation, a mild cognitive deficit (executive memory deficit, involved auditive short term deficit) was present. The patient fulfilled the El Escorial ALS diagnostic criteria. Riluzol therapy was started. Conclusion: An early age of PD onset was observed in the reported patient, while the onset of ALS symptoms at the age of 51 seems to be typical. The mean age of the onset of this overlapping syndrome is usually 10 years higher when compared to the development of ALS without parkinsonism. The clinical and mainly the neuropathological evidence of nigral neuronal loss in ALS patients (even in an absence of extrapyramidal signs) suggests a common pathogenic mechanism of this overlapping syndrome. P732 Tau isoforms expression in SOD 1 and Cra1 transgenic mouse models of amyotrophic lateral sclerosis M. Kuzma, E. Usarek, B. Schwalenstoecker, A. Ludolph, H. Kwiecinski, A. Baranczyk-Kuzma Medical University of Warsaw (Warsaw, PL); University of Ulm (Ulm, DE) Objective: Tau is a member of microtubule-associated proteins (MAPs) involved in stabilization of microtubules, axonal transport and dendrites outgrowth. Hyperphosphorylated tau protein was found in naurofibrillary tangles of amyotrophic lateral sclerosis (ALS) of Guam. Motor neuron degeneration was also proved to be caused by mutations in a gene encoding heavy chain of dynein (Dnchc1), one of the MAPs responsible for fast retrograde axonal transport along microtubules (Cra1 transgenic mouse model). The impairment of this type of transport was also found in the commonly used mouse ALS/MND SOD 1G 93A model. Unexpectedly, the expression of the Dnchc1 mutation in the SOD 1G 93A model (double transgenic model SOD 1/Cra1) increased the survival of SOD 1 animals, what was accompanied by a complete recovery in axonal transport deficits. The aim of this study was to establish tau expression profile in three ALS/MND transgenic mouse models (SOD 1, Cra1, SOD 1/Cra1) considering N-terminal (0N, 1N, 2N) isoforms. Methods: Competitive RT-PCR of tau-mRNA isoforms was performed in transgenic B 6-C 3H hybrids harbouring SOD 1G 93A, Dnchc1, and double SOD 1G 93A/Dnchc1 mutations. All studies were performed on brain frontal cortex obtained from 70- and 140-day-old mice. Due to differences in disease onset, SOD 1 transgenics were at presymptomatic and symptomatic stage, whereas other animals were still asymptomatic. Age- and genetic background-matched wild-type hybride mice were used as controls. Results: The total tau-mRNA expression in SOD 1 model at symptomatic stage was lower than in presymptomatic and wild-type mice as a result of the 2N isoform decrease. In both age-groups of Cra1 model the total tau expression was slightly reduced compared to controls. Unlike in SOD 1 model, the isoforms pattern was uniform. In SOD 1/Cra1 hybrids, age 140 days, the total tau-mRNA was higher than in wild-type (by 36 %), Cra1 (by 40 %), and SOD 1 (by 150 %). The increase was due to higher 2N isoform expression. Conclusion: Since the tau N-terminal region interacts with cytoskeletal elements being crucial for axons stabilization and organization, the significant increase of 2N expression in SOD 1/Cra1 model may contribute to restoration of retrograde transport. The observed decrease of 2N expression in symptomatic SOD 1 mice might result from down-regulation of tau expression due to axonal strangulation. The lack of significant changes of tau expression in Cra1 model can be explained by later ALS/MND onset. This work was supported by grant nr 1WK/N/06 from the Medical University of Warsaw, Poland. P733 Neural stem cell intrathecal transplantation ameliorates the phenotype of a spinal muscular atrophy murine model D. Papadimitriou, S. Corti, F. Locatelli, M. Nizzardo, M. Nardini, C. Donadoni, S. Salani, R. Del Bo, S. Ghezzi, F. Fortunato, S. Strazzer, N. Bresolin, G. P. Comi University of Milan (Milan, IT); I. R. C. C.S. E. Medea (Bosisio Parini, IT) Objectives: Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder characterized by degeneration of the spinal cord motor neurons

(MNs), manifesting with progressive muscle weakness and paralysis. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to reduced levels of SMN protein. Aim of this project is to explore the potential of a transplanted spinal cord neural stem cell (NSC) population, to replace damaged neurons and modify neuronal environment delaying disease progression in SMN mice, an animal model of SMA 5q. Methods: NSCs were isolated from the embryonic and adult spinal cord of HB 9-GFP mice (specifically expressing GFP only in MNs) and cultured to form neurospheres, were isolated on the basis of the aldehyde dehydrogenase activity (ALDHhiSSClo Neural Stem Cells) by FACS. ALDHhiSSClo positive cells were tested in vitro for their neuronal potential by immunocytochemistry and Real-time RT-PCR and were transplanted intrathecally into SMN pups (FVB.Cg-Tg (SMN 2*delta7) 4299Ahmb Tg (SMN 2) 89Ahmb Smn1tm1Msd/J). Immunohistochemistry for specific neuronal markers and confocal analysis were performed on host tissues as well as TUNEL staining and MN count for the study of the apoptosis rate. Neuromuscular function of transplanted animals was evaluated and survival was recorded. Results: Isolated ALDHhiSSClo cells differentiate in MNs and create neuromuscular junctions in vitro. Examination of the spinal cord of transplanted SMN mice demonstrated the capacity of donor cells to migrate in the parenchyma and generate MN like cells. Furthermore NSCs transplantation reduced the apoptosis rate of lumbar anterior horn MNs, ameliorated motor performance and increased survival by 39.26 %, an average of 5.4 days (18.16 vs. 13.04) compared to untreated animals. Conclusion: In conclusion, the beneficial outcome of NSC transplantation on SMA mice suggests that further investigation of stem cell biological properties in the spinal cord and their environmental interactions may harness their potential as a possible therapeutic strategy for spinal cord regeneration. P734 Increased CSF MCP-1 and IL-8 levels in amyotrophic lateral sclerosis patients J. Kuhle, R. L. P. Lindberg, A. Regeniter, A. J. Steck, L. Kappos, A. Czaplinski University Hospital Basel (Basel, CH) Objectives: Amyotrophic Lateral Sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation, especially activation of microglia and presence of dendritic cells, has been observed in CNS tissue in ALS patients. Current data suggests that MCP-1/CCR 2 and chemokine signaling play a role in the amplification (and presumably initiation) of inflammation in ALS. In the present study, we investigated the expression of various proinflammatory chemokines in ALS patients as compared to noninflammatory neurological disease (NIND) patients. Methods: We analyzed 9 chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1 b and TARC, simultaneously by using multiarray technology based on electrochemiluminescence detection (Meso Scale Discovery, Maryland, USA), in serum and CSF of 20 ALS patients and 20 ageand gender matched NIND patients. Results: MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml versus 1055 pg/ml, p = 0.013 and 22.7 pg/ml versus 18.6 pg/ml, p = 0.035, respectively). In ALS and NIND the expression of MCP-1 and IL-8 were higher in CSF than in serum (p < 0.001), in contrast to the levels of the other measured chemokines, which were higher in serum than in CSF. CSF/serum albumin ratio was normal in 18/20 ALS and 19/20 NIND patients with no correlation to chemokine levels. We did not find any association between chemokine levels and age of the patients or site of symptom onset but there was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis (which in most cases was also the time of the lumbar puncture) (p = 0.083). Conclusions: We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in CSF in patients with a shorter diagnostic delay, who are known to have faster disease progression and shorter survival. In light of previous studies demonstrating a correlation between intrathecal MCP-1 levels and disease severity, this finding may suggest an association of higher MCP-1 levels with rapidly progressing disease. Larger follow-up studies are needed to evaluate the diagnostic and prognostic value of chemokines as markers for disease progression and clinical outcome in ALS.

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P735 Mitochondrial peripheral benzodiazepine receptor in amyotrophic lateral sclerosis S. Piazza, C. Cecilia, B. Chelli, C. Giacomelli, L. Volpi, M. Mancuso, C. Martini, G. Siciliano University of Pisa (Pisa, IT) Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease of unknown origin characterized by the progressive loss of motor neurons of the anterior horns in the cortex, bulb and spinal cord. Among the several pathogenetic mechanisms considered in the attempt to explain motor neuron death in ALS, the hypothesis of the occurrence of mitochondrial dysfunction has received a considerable interest. Permeabilization of mitochondrial membranes,due to the opening of the mitochondrial permeability transition pore (MPTP), is considered an important step in the apoptotic or necrotic cell death cascade. MPTP is a multiprotein complex in which the peripheral benzodiazepine receptor (PBR) represents a core structural protein. PBR has been recently reported to play an important role in the regulation of MPT and in the control of apoptotic cell death. Objectives: to evaluate the kinetic binding parameters of the specific PBR ligand, PK 11195, in platelets obtained from patients affected by ALS. Methods: 16 ALS patients (mean 64.1 ± 2.39 years) and 18 control healthy volunteers (mean, 40.3 ± 3.06 years) were recruited for the study. Platelets obtained from each ALS patient and healthy volunteer were centrifuged and stored at –80°C. Aliquots of platelet membrane suspensions were incubated with increasing concentrations of [3H] PK 11195, either in the absence (total binding) or in the presence (non-specific binding) of PK 11195. After incubation, the samples were filtered, washed and the radioactivity was counted, using a liquid-phase scintillation counter. Results: The PBR kinetic binding parameters in platelet membranes from ALS and controls were saturable and with high affinity. Scatchard plots were linear for all analysed subjects, suggesting the presence of an homogeneous population of binding sites. A significant decrease in PBR Bmax values was observed in platelets of ALS patient as compared to controls (p = 0.002), whereas the Kd values did not differ significantly. The relationship between the reduction of platelet PBR Bmax and the disease progression showed a significant correlation (r = 0.62, p < 0.01) Conclusion: The present data are consistent with an alteration of PBR density in ALS patients. This indicates a possible role of PBR in the pathogenesis of ALS and, at the same time suggests a perspective use of it as candidate biomarker to trace disease severity and progression. P736 Prognostic values of clinical and laboratory parameters at the time of diagnosis in a large cohort of amyotrophic lateral sclerosis patients C. Carlesi, A. Del Corona, S. Piazza, M. Falorni, G. Ricci, V. Ravelli, G. Siciliano, L. Murri University of Pisa (Pisa, IT) Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder of unknown cause characterized by a progressive upper and lower motor neurons loss with a mean survival time not longer than 3 years from the diagnosis. The disease incidence is 1.5–2.7 new cases for 100 000 inhabitants/year, with a pick of incidence between 53 and 63 years. ALS is more frequent in men that in women (ratio: 1.3:1). The disease prevalence is 2.7–7.4 for 100 000 inhabitants year. Objectives: To evaluate some predictive prognostic factors as disease onset, sex, first clinical affected body district, interval between clinical manifestation and diagnosis according to El Escorial criteria; other considered items have been functional scale score, motor evoked potentials and electromyography parameters as well as cerebrospinal fluid analytical results at the time of diagnosis. Methods: 185 ALS patients (mean age at diagnosis was 60.7 years ± 11.97 in men, and 63.8 years ± 11.78, in women), observed from 1997 to 2006, were recruited for this study. The effect on the survival rate was calculated using the Kaplan-Meier method. The comparison between the curves was performed with the log rank test, while the Cox regression method was used for multivariate analysis, adjusted for sex and age. Results: our results confirm the previously reported predictive prognostic value of age of onset, time between first symptoms and diagnosis and severity of functional scales at the time of diagnosis. Borderline significance was present at log rank test for the considered electromyographic neurogenic signs. Conclusions: our results confirm the usefulness, in terms of predictive prognostic value, of specific clinical and laboratory parameters as assessed at the onset or at the time of diagnosis in ALS. These data can be used to stratify uniform clinical groups, on the basis of clinic characteristic and life expectance, to test new therapeutic treatments in ALS.

P737 ALS – An indicator of neurodegenerative susceptibility? A pilot study P. N. Brennan, B. J. Traynor, C. Sheehan, B. Corr, O. Hardiman RCSI and Beaumont Hospital (Dublin, IE); NIH (Bethesda, US); Beaumont Hospital (Dublin, IE) Background: There is increasing evidence that amyotrophic lateral sclerosis (ALS) is part of a wider spectrum of neurodegeneration. Clinical, neuroradiological and neuropathological evidence indicates that the neurodegenerative process in ALS extends beyond the motor system. Overlap syndromes of ALS with Parkinson’s Disease (PD) and dementia have been long recognized, and more recent studies have recognized the presence of cognitive impairment in patients with otherwise typical ALS. These observations suggest a shared pathogenic mechanism for neurodegenerative diseases, which may be genetically governed. Objective: To determine whether neurodegenerative conditions aggregate in kindreds of patients with ALS. Methods: Using the Irish ALS register, all patients diagnosed with ALS in the years 2005 and 2006 were approached and invited to complete a detailed family history questionnaire. Ethnicity-matched controls were selected from spouses, or geographic matched individuals living in the vicinity. Results: 42 case controlled kindred pairs (1458 individuals, 369 (170 siblings) 1st degree relatives from ALS kindreds) (2.003 individuals, 354 (149 siblings) 1st degree relatives from controls kindreds) were analysed. Preliminary findings suggested an increased incidence of ALS in affected kindreds (Lambdasiblings = 1.120. Lambda1o = 1.435, Lambda2o = 172). PD was overly represented in affected kindreds compared to controls (Lambdarisk total = 5.02). An increased rate of occurrence of all Non –ALS neurodegenerative diseases was observed in ALS kindreds when contrasted with the control cohort, Lambdaneurodegenerative disease total = 2.91, Lambdaneurodegenerative disease 1 o = 1.91, Lambdaneurodegenerative disease 2 o = 4.36 Conclusions: Other neurodegenerative diseases occur more frequently in family members of patients with ALS. This observation supports the view of ALS as part of a larger continuum of neurodegenerative disease, susceptibility to which is likely to be genetically determined. ALSA have provided financial support for the study. P738 How frequent are parkinsonian symptoms in patients with ALS/MND? P. Szczudlik, M. Zach, S. Owsiak, M. Kuzma-Kozakiewicz, P. Janik, H. Kwiecinski Medical University, Warsaw (Warsaw, PL) Objective: Some patients with ALS may exhibit parkinsonian features, but a recent PET study suggests such parkinsonism is not caused by nigrostriatal dysfunction (Hideyama et al., 2006). We aimed to assess the frequency of parkinsonian symptoms in patients with ALS/MND. Methods: Clinical data of all ALS/MND patients admitted to our Department from January 2000 to January 2007 were reviewed retrospectively. The patients were Caucasians, mainly recruited from central Poland. All patients were diagnosed with ALS/MND based on medical history, neurological examination, electrophysiological studies, and by using the revised El Escorial criteria. The presence of parkinsonian symptoms such as bradykinesia, rigidity, pulsion, tremor, and the effect to levodopa treatment was analyzed. Results: Four patients (1.9 %) with parkinsonism features were found in the total group of 216 patients with sporadic ALS/MND. The first patient was a 45-year-old female, with a 4-year-history of PLS, showing rigidity and retropulsion. Her parkinsonian symptoms started 2 years after the onset of MND, and were resistant to levodopa treatment. The second patient was a male of 43 years,initially diagnosed with PLS,which evolved into typical ALS after 5 years follow up. He had marked rigidity and bradykinesia, nonresponsive to levodopa treatment. A moderate improvement was observed with amantadine therapy. He had simultaneous onset of symptoms of PLS and parkinsonism. The third case was a 47-year-old female with the diagnosis of PLS, who also had bradykinesia and retropulsion. Her PLS symptoms (spasticity) preceded the onset of parkinsonism by 15 years. The fourth patient was a 65-year-old male with the diagnosis of ALS/FTD, who also had retropulsion and rest tremor. In this case tremor preceded the onset of dementia and amyotrophy. Conclusion: In this study we confirm the results reported by other authors that clinical manifestation of parkinsonism is a very rare finding (< 2 %) in patients with sporadic ALS/MND. In our cohort, parkinsonian features were found in patients with non-classic ALS.

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P739 Frontotemporal dementia with lower motor neuron disease and extrapyramidal signs: case description A. Dwornik, E. Szmidt-Salkowska, D. Dziewulska, M. Gawel, H. Kwiecinski Central Clinical Hospital (Warsaw, PL); Medical University (Warsaw, PL)

cryptococcus. Only 6 cases have been reported in the literature, and 14 cases caused by other pathogens. We have carried out a review of the reports of this infrequent localization and have examined the differential diagnosis that must be considered.

Objective: Fronto-temporal dementia (FTD) has been observed in some cases of motor neuron disease (MND), whereas parkinsonism is associated with only specific forms of MND, and rarely, with FTD.We would like to present a case of a neurodegenerative process presenting as dementia of frontotemporal type, together with lower motor neuron involvement, and mildly expressed extrapyramidal signs. Clinical case: A 65-year old man was admitted into Neurology Department because of progressing lower limb weakness. Additionally, there were progressive memory disturbances and personality changes. There were two cases of dementia in the patient’s family. On neurological examination, the patient presented massive flaccid distal paresis of both lower limbs and slight paresis of the upper limbs, with significant muscle atrophy. There were vivid palmomental reflexes bilaterally, and increased jaw reflex. Knee reflexes were brisk, but no pathological pyramidal signs were observed. Other deep tendon reflexes were weak or absent. Head and upper limbs resting tremor of mild intensity was present, as well as typical parkinsonian posture. There were no significant abnormalities in routine laboratory blood tests, except for moderately increased level of creatine kinase. Magnetic resonance imaging of the brain showed symmetrical, generalized, massive cortical and subcortical atrophy. Electromyography revealed chronic neurogenic changes in the proximal and distal muscles of upper and lower limbs, with signs of active denervation in the distal muscles. Psychological examination revealed disturbances of working memory, perseverations, and emotional instability, while executive functions were relatively spared. In summary, the psychological examination result suggested dementia of fronto-temporal type. The patient’s condition continued to deteriorate, and he died due to respiratory muscle failure 8 months later. Neuropathological examination confirmed neurodegenerative changes. Conclusion: The patient presents a familial case of dementia, most probably of the autosomal dominant inheritance. The neurodegeneration in this patient, but not in the family, involved also lower motor neuron, and extrapyramidal structures. This case is especially interesting because of the presence of extrapyramidal symptoms, which are not typical in cases of frontotemporal dementia with motor neuron disease (FTD/MND), and suggests looking for mutation in the tau proteins or dynactin.

P741 Cerebral toxoplasmosis in an immunocompetent patient F. A. Antochi, A. Roceanu, O. Bajenaru University Hospital Bucharest (Bucharest, RO)

Infection

P742 Epistaxis and brain abscess: a new case of a known relationship A. Sanchez, A. Lalueza, R. Gordo, H. Martin, M. Gomez, L. Martin, S. Moreno, J. Hernandez-Gallego Hospital 12 de Octubre (Madrid, ES)

P740 Choroid plexitis: a rare variant of cerebral cryptococcosis G. A. Cárdenas Hernandez, J. I. Castro-Macias, G. E. Soto-Cabrera National Institute of Neurology (Mexico City, MX) Introduction: Cryptococcosis is the most frequent mycosis involving the central nervous system; the prevalence is quite different between HIV and non HIV subjects. Most patients with cryptococcal meningitis present signs and symptoms of subacute meningitis or meningoencephalitis, such as headaches, fever, lethargy, coma or memory loss over 2 to 4 weeks Frequent radiological findings are dilated Virchow Robin spaces filled with a gelatinous cyst and adjacent to the basal ganglia and corticomedullary junction. Another pattern is multiple milliary enhancing parenchymal and leptomeningeal nodules with involvement of the choroid plexus in the trigone, spinal cord and spinal nerve roots. Less common findings include widening of the basal cisterns, hydrocephalus and diffuse atrophy. Objective: We report the case of a non immunosuppressed female with a rare form of cryptococcosis, involving mainly the choroid plexus. Case report: A 39 year old female began 3 months before admission with a progressive symptomatology that associated headache, nocturnal cough, nausea, vomiting, diplopia and confusion. Clinically, she presented poor attention, mutism, right central facial palsy, gait ataxia, bilateral Babinski and papilledema. Results and conclusion: HIV test was negative, IRM showed bilateral dilation of temporal horns, with contrast enhancement of the ependimum of the ventricular system. She underwent bilateral ventriculoperitoneal shunt, and a biopsy of ependimum of temporal horns showed C. neoformans. Treatment with Amphotericin B was begun with improvement of clinical manifestations. We report a case of a non immunodepressed woman that presented choroid plexitis. This patology is a rare localization of CNS infection by

Background: Clinically evident active infection of acquired form of toxoplasmosis in immunocompetent adults is rare. In the literature, most of the cases of acquired toxoplasmosis are described in association with AIDS or underlying systemic disease (malignant neoplasm, renal transplants, and collagen vascular disease). The neurological onset may consist of signs of a meningoencephalitis, i. e., seizures, mental confusion, meningeal irritation, coma, and a lymphocytic pleocytosis and increased CSF protein. The brain in such cases shows foci of inflammatory necrosis with free and encysted Toxoplasma gondii organisms. Objective: To describe an immunocompetent young female patient with severe cerebral parasitic infection with Toxoplasma gondii. Result: In September 2005, the patient developed fever and a meningeal syndrome with sudden onset, followed by generalized seizures and interictal tetraparesis. CSF presented high protein content, lymphocytic pleocytosis, few erythrocytes and normal glucose level. Imagistic exams (CT and MRI) showed a severe cerebral vein thrombosis with hemorrhagic infarcts and a meningeal enhancement of gadolinium. In addition, the patient had a biologic inflammatory syndrome, negative cultures for bacteria and fungi in CSF and positive serological and CSF tests for Toxoplasma gondii (elevated titers of immunoglobulin type A, G and M). Immunological screening tests for collagen vascular disease were negative and serological repetitive tests for HIV and Treponema pallidum were also negative. Two weeks later, MRI re-exam revealed few bilateral fronto-parietal focal lesions. The aspect of these lesions was cystic, well-delineated, some of them with protein content and two of them sanguinolent. In T 1-weighted image some of this focal lesions showed prominent ring enhancement. Under specific treatment the outcome was favorable. Conclusion: We report a case of an immunocompetent young woman, who presented a sudden onset of a meningoencephalitis syndrome and cerebral vein thrombosis with hemorrhagic infarcts, which etiology was established to be a severe infection with Toxoplasma gondii.

Objectives: The etiology of a brain abscess cannot be established in every case. There are some entities like the Rendu-Osler-Weber syndrome (also known as Hemorrhagic Hereditary Telangiectasia-HHT-) where high level of suspicion is required.Almost every case in this disease is invariably linked to a Pulmonary Arteriovenous Malformation (PAVM). Here we present a patient with this association. Methods: A case description. Results: A 38 year old male who was previously diagnosed of a HHT with an embolized PAVM (5 years before), presented in our hospital with a frontotemporal headache that started trhee months earlier. During the last 4 days there was concomitant emesis and chills. The physical examination was normal except for a light left hiperreflexia and a 37.8˘C temperature. The blood count and biochemistry revealed 13.500 white cells (72 % neutrophils) being all the other parameters within the normal range (including blood culture). In a contrast computer tomography (CT) a low density frontal, ring enhancing lesion, could be delimited. During the inpatient study an MRI (Magnetic Resonance Imaging) disclosed a brain abscess, and we repeated a thoracic CT were a PAVM repermeabilisation could be stated. Initially a conservative management was decided with combined antibiotherapy (Metronidazole plus Ceftriaxone) and corticosteroids (Dexamethasone). Due to the poor improvement with medical treatment, it was decided to drain the abscess, which led to the progressive resolution of the event. A new embolization of the PAVM was completed succesfully. Conclusions: 1) The HHT is an autosomal dominant disorder where the coexistence of epistaxis, mucocutaneous telangiectasias and visceral arteriovenous malformations constitute the core clinical phenotype. Related to the visceral vascular malformations are the PAVM, present in about 15–33 % of the patients. The frequency of a brain abscess is estimated around 5–10 % of the Rendu patients and almost always there is a PAVM. The mechanism

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described for the production of an abscess is thought to be an hematogenous spread. 2) It is compulsory to include the HHT in the diferencial diagnose of a brain abscess, paying attention to physical signs or family history in order to rule out the concomitant presence of a PAVM (preferable with a CT). In case this is done, the succesful embolization of this malformations (when they are bigger than 3mm) could prevent future adverse neurological events improving the global outcome of this patients. P743 Permanent blindness in an immunocompetent patient with cryptococcal meningo-encephalitis E. Alexiou, E. Kalaboki, A. Galanopoulos, G. Gekas General Hospital of Nikea (Piraeus, GR) Objectives: Cryptococcal meningoencephalitis is a fungal infection, most often encountered in immunocompromised hosts; however, it rarely affects individuals with no obvious predisposing factor, leading to severe complications. We present a case of cryptococcal meningoencephalitis in an immunocompetent individual, who developed permanent residual blindness despite immediate initiation of treatment. Case-History: A 23-year old female with a 20-day history of headache, was admitted to our department after having a generalized tonic-clonic seizure. On admission, she demonstrated confusion and marked irritability. The neurological examination revealed neck stiffness, right abducens nerve palsy and dissociative nystagmus in the left eye. There was neither fever nor papilloedema. Brain CT scan was normal and CSF analysis revealed lymphocytic pleocytosis, increased protein and hypoglycorrachia. Indian ink examination was positive, CSF cryptococcal antigen titer was 1/1064 and CSF culture grew Cryptococcus neoformans. The patient was started on intravenous liposomal amphotericin B. Seven days after her admission, she complained of blurred vision that deteriorated rapidly over the next day, until no eye had light perception. Repeated lumbar punctures showed normal CSF opening pressure. Brain MRI demonstrated six enhancing lesions, compatible to cryptococcomas and diffuse meningeal enhancement. 5-fluorocytosine was added to the therapeutic regimen and later switched to intravenous fluconazole. The patient responded well to treatment, with CSF culture sterilization and complete resolution of brain lesions on repeat MRI. She was discharged 12 weeks following her admission, having developed irreversible blindness that probably resulted from direct spreading of the infection to the optic nerves. Conclusion: Visual impairment constitutes a serious complication of cryptococcal meningoencephalitis that may persist notwithstanding the remission of other manifestations. Monitoring of intracranial pressure can improve visual outcome; however direct spreading of the infection to the optic pathways may ensue, despite timely and aggressive treatment. P744 Broad-range PCR as an effective method for the diagnosis of cerebral nocardiosis N. Hamad, K. Isenhardt, S. Albert, R. Schneider Klinikum Aschaffenburg (Aschaffenburg, DE) Introduction: Nocardia is an aerobic actinomycetes that can cause localized or disseminated infections in both immunocompetent and immunocompromised patients. CNS infection occurs in more than 40 % of cases of systemic nocardiosis with high mortality. In cases of brain abscesses with detection difficulties broad-range PCR kann be a good screening method. Case report: A 45 year old patient was presented to our hospital with a 5 days history of right-sided weakness, facial palsy and dysarthria. He had several previous episodes left-sided pneumonia in childhood. 2 weeks before admission he developed fever und exacerbation of a chronic cough. A cranial CT-scan showed mutliple lesions in the parieto-temporal region on both sides, surrounded with noticebal edematous zone. Cerebrospinal fluid (CSF) analysis yielded hyperproteinemia with a normal cell acount and glucose level, yet a high CSF/serum index of IgA suggestiv of a bacterial infection. An intravenous therapy with ampicillin, cefuroxime and metronidazole was started. Chest x-ray showed a complete shadow of the left lung, as seen on previous x-rays. Fine needle aspirate biopsy of the left lung demonstrated neutrophilic leukocytes and both gram stain and bacteriologic cultures were negative. 5 days after admission the clinical status deteriorated. CT-scan revealed increasing edema with midline shift to the left. Therapy with Dexamethasone was initiated. A brain biopsy was performed and histopathological examinations showed normal brain tissue with microcalcifications. Bacteriological cultures were negative. Broad-range 16S rDNA PCR was carried out on both lung and brain biopsies and Nocardia farcinica was detected in the lung biopsy.Accordingly the antimicrobial treatment was

changed to imipenem and amikacine. 12 days after admission the clinical status improved greatly. Disscusion: Although nocardial abscess is rare, it needs to be considered in the differencial diagnosis of cerebral abscesses, as its morbidity und mortality is high.Various specimens (biopsies, sputa, bronchial secretion, blood, CSF) should be investigated, since detection can fail in some of them. In addition to the standard cultural und microscopic methods, molecular diagnosic procedures with broad-range 16 S rDNA PCR plays an essential role in the recent years as it provides the opportunity to screen for bacterial genoms und proves to be a sensitive method in case of nocardia. P745 Neurobrucellosis mimicking multiple sclerosis: a case report M. Zouari, M. Aissi, R. Sebai, F. Hentati National Institute of Neurology (Tunis, TN) Objectives: Brucellosis is a rare disease, affecting the nervous system in 3 to 25 % of cases. The objective of the study is to report the clinical signs of a patient affected by neurobrucellosis and to describe the neuroradiological aspect by brain and medullar MRI. Methods: A 17 years old man, with no medical history, is admitted in the hospital because he complains, since two weeks, from a progressive paraplegia with paresthesia of lower limbs and sphincter disturbance. Neurological examination found a spastic paraplegia with sensory disturbance below D 7D 8 level.A medullar MRI is done in emergency, with different sequences; T 1 weighted images with and without gadolinium injection, T 2 weighted images, FLAIR, and a D 2 Flush sequence. A brain MRI is also done with the same sequences. We have analysed the CSF. A Wright serologic reaction and also a second MRI are done during the hospitalisation. Results: The medullar MRI shows an enlarged medulla with an abnormal signal of the medulla from C 6 to D 8. On brain MRI, these lesions have a nodular aspect in the sub-cortical white matter and in the posterior arm of the internal capsule. These lesions are in hyposignal on T 1 weighted images with important enhancement after gadolinium injection, and in hypersignal on T 2 weighted images. On biological data, the CSF analysis is normal, the immuno-electropheresis is normal, and also the immunological data. The serologic tests for lyme disease,widal, and for VIH infection, are normal. The diagnosis of multiple sclerosis is made initially. The patient is treated first by steroids, but without improvement, and the patient become worse and tetraplegic. The disseminated lesions on brain and medullar MRI, the worsening progressive course on two times, and the neuroradiological images on MRI with extensive and multifocal lesions in the white matter of brain are compatible with an inflammatory demyelinating process. Althought, the clinical worsening on steroids, and the positivity of serum agglutination for Brucella (Wright test), with extensive new lesions on the second MRI, confirm the diagnosis of neurobrucellosis. Conclusion: The neuroradiological aspect of neurobrucellosis by MRI are variable, and can mimic an infectious, inflammatory, and even a tumoral process. The clinical presentation of neurobrucellosis mimicking multiple sclerosis are exceptional. Biological data with Wright serologic test is useful for the diagnosis and especially in endemic area. P746 Eyelid opening apraxia, dysarthria, dysphagia and cerebrospinal fluid oligoclonal bands in an AIDS patient E. Santos, J. Chaves, J. Lopes Lima Hospital Geral Santo António (Oporto, PT) Background: Movement disorders are rarely related to HIV infection. Chorea and ballism are the most frequent and usually associated with basal ganglia toxoplasmosis abscess. There are also few cases of chorea in HIV encephalitis. In these cases can be no pleocytosis in CSF, but inflammation markers like oligoclonal bands are usually present. Biopsy or autopsy in such cases show a neurodegenerative process, focused in basal ganglia and frontal cortex. Case Report: A thirty four years old man, HIV positive known since 2002, in July 2003, began having difficulty in opening his eyes, without variability during the day or fatigability, needing to use his hands to open the eyes. He also complained of difficulty in swallowing liquids and noticed some differences in his voice. These episodes happened usually once-twice a day. There was no history of neurological disorders in his family or other neurological disorders in his past. In September 2004 when he was observed, he presented eyelid opening apraxia (without gaze apraxia, ophtalmoparesis or blepharospasm), dysarthria (scandid voice) and the remaining neurological examination was normal. He had 109/mm3 CD 4 cells, so anti-retroviral agents were started. In September 2005 the complaints persisted. Brain MRI scan was normal.And CSF showed 4 leuc/uL, normal glucose and proteins and in-

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trathecal synthesis of two oligoclonal bands. At this time he had 331/mm3 CD 4 cells. Every other studies were normal (serum serology and immunology, cupper and ceruloplasmin). Orbicularis oculi electromyography was normal. Larynx CT and laryngoscopy was normal. Theses symptoms persisted for six months, then became less frequent and then disappeared. Treatment was maintained. Discussion: In this case, in the absence of another aethiology, the presence of inflammatory markers in CSF and the improvement with anti-retroviral therapy makes the correlation between HIV infection and patient symptoms reasonable. These symptoms suggest a focal mesencephalic encephalitis.

Multiple sclerosis

P747 Legionnaires’ disease with rhombencephalitis and reversible lesion of the splenium of the corpus callosum mimicking Marchiafava-Bignami disease R. Werner, M. Desikan, M. Silomon, J. C. Wöhrle Katholisches Klinikum (Koblenz, DE)

Objective: The effects of repeated intrathecal triamcinolone acetonid (TCA) treatment are complex and its pharmacodynamic effects on cerebrospinal fluid (CSF) interleukin (IL) -6-type cytokine, beta-trace protein (beta-trace) and beta-2 microglobulin (beta 2MG) as potential predictors of treatment response and immunological activation in multiple sclerosis (MS) patients have not been extensively characterized. Methods: In this prospective pilot study 10 patients suffering from MS (4 relapsing remitting [RR], 6 secondary or primary progressive [SP/PP]) were included. Three TCA applications were performed as part of an ongoing trial every second day to reduce spasticity. IL-6, beta-trace and beta 2MG levels were measured using standard ELISA techniques (IL-6) and automated immunonephelometric assay (beta-trace, beta 2MG) techniques at baseline and at each TCA application. Results: The median EDSS was 5.5 (range 1–8) at baseline and 4.5 (1–8) at follow up. The mean CSF IL-6 levels were 3.14 pg/ml at baseline (normal range < 24 pg/ml) and at time 2 (40.75 pg/ml) and 3 (3.83 pg/ml). The mean CSF beta-trace levels were 18.95 mg/l at baseline (normal range 15–36 mg/l), at visit 2 (18.23mg/l) and visit 3 (18.95mg/l). The mean CSF beta 2MG levels were 1.27mg/l at baseline (normal range 0.8–2 mg/l), at visit 2 (1.24mg/l) and visit 3 (1.15mg/l). Correcting for repeated measurements there was no change of the measured CSF biomarker levels over the observation period. Conclusion: This pilot study demonstrated that the TCA treatment causes changes in the measured biomarker levels that can be assessed effectively. While IL-6 levels show a temporary increase during follow-up, betatrace and beta 2MG levels remain unchanged. This treatment trial is ongoing and should clarify the usefulness of these biomarkers in monitoring disease activity and therapy response in MS patients.

Objective: Legionnaires’ disease (LD) typically presents as a respiratory infection with high fever. Although it is frequently accompanied by neurological symptoms there are only few reports on magnetic resonance imaging (MRI) findings in LD. Immunosuppression is a risk factor for LD. Marchiafava-Bignami disease (MBD) is a rare central nervous system (CNS) disorder also most commonly seen in patients with immunosuppression, particularly in alcoholics. It features demyelination and necrosis of the corpus callosum and leads to an often fatal encephalopathy. Case report: A 41 year old man with a history of alcoholism was admitted to our intensive care unit after a grand mal seizure. He had symptoms of a respiratory infection (coughing, dyspnea, fever up to 40 degrees C) and was somnolent. Neurological examination revealed saccadic horizontal smooth pursuit eye movements, vertical nystagmus, dysarthria, and severe postural and gait ataxia). Chest X-ray showed a diffuse infiltration of the left lung, compatible with pneumonia. Cerebrospinal fluid (CSF) analysis found no pleocytosis and no intrathecal antibody production. Cerebral MRI displayed a reduced diffusion in the splenium of the corpus callosum (“boomerang sign”) resembling the extrapontine demyelination in MBD. Biochemical tests showed normal results, especially for thiamine, vitamin B 12 and sodium levels. Urine analysis detected Legionella pneumophila antigen, other infections could be excluded by extended blood and CSF analyses. With moxifloxacin the patient improved and MRI abnormalities were regredient. Conclusions: In patients with clinical signs of rhombencephalitis, LD should be considered as an important differential diagnosis. Urine Legionella antigen testing should be performed particularly in the absence of or only mild CSF pleocytosis as the encephalopathy in LD is mediated by a bacterial endotoxin and not by direct bacterial infiltration of the CNS. As both disorders, LD and MBD, are associated with alcoholism it is important to know that the typical MBD-MRI findings might not distinguish both entities. P748 Gaetano Donizetti’s neurosyphilis and stroke (1797–1848) T. Breitenfeld, V. Vargek Solter, D. Breitenfeld, V. Supanc, V. Basic Kes, K. Jergovic, M. Budisic, V. Demarin Sestre milosrdnice (Sisters of Charity) (Zagreb, HR) Pathography on occasion of 210th anniversary of his birth. Famous Italian composer Gaetano Donizetti was infected by syphilis already at age of 19. The course of illness showed many subsequent fever states with general worsening at his age of 27 and again at age of 37. His illness was complicated with episodes of headache, vertigo, fluctuating palsies followed by subacute organic brain psychosyndrome.Another exacerbation of his illness followed at his age 47 with demented state and palsies. He was escorted to the Ivry hospital in Paris where he was diagnosed “syphilitic general paresis”. Later on he was transported to Italy,to his native town Bergamo where he met temporary improvement. At age of 51 his illness deteriorated with fever – pneumonia, uremia and he finally died of stroke, after 6 years of inactive and useless life. The autopsy showed syphilitic atrophy and inflammatory swelling of brain – spinal cord and meninges.

P749 Effects on cerebrospinal fluid biomarkers of immunological activation in multiple sclerosis patients after repeated intrathecal triamcinolone acetonid application M. Abu-Mugheisib, H. Tumani, F. Kamin, A. Apel, W. Koehler, F. Hoffmann, R. Benecke, U. K. Zettl University of Rostock (Rostock, DE); University of Ulm (Ulm, DE); Saechsisches Krankenhaus Hubertusburg (Wermsdorf, DE); Staedt. Krankenhaus Martha-Maria Halle-Doelau (Halle, DE)

P750 Immunoablative therapy with autologous stem cell transplantation in multiple sclerosis patients: long-term outcome results Y. Shevchenko, A. Novik, A. Kuznetcov, B. Afanasiev, I. Lisukov, O. Rykavicin, A. Myasnikov, T. Ionova, V. Melnichenko, D. Fedorenko, A. Kishtovich, R. Ivanov, G. Gorodokin Pirogov National Medical Surgical Center (Moscow, RU); Pavlov State Medical University (St. Petersburg, RU); Institute of Clinical Immunology (Novosibirsk, RU); Burdenko Central Military Hospital (Moscow, RU); Republican Hospital (Petrozavodsk, RU); Multinational Center of Quality of Life Research (St. Petersburg, RU); Center for Quality of Life and Health Outcome Research (New Jersey, US) During the last decade immunoablative therapy with autologous stem cell transplantation (ASCT) has been used more often as a therapeutic option for MS patients. The major treatment outcomes for MS patients are period free of disease progression and improvement of patient’s quality of life (QoL).We aimed to study the long-term outcomes, namely clinical treatment response and quality of life (QoL) treatment response, in MS patients after immunoablative therapy with ASCT. Forty-three patients with MS (secondary progressive – 22 patients, primary progressive –10, progressive-relapsing – 1, relapsing-remitting – 10) from 6 medical centers were included in this study (mean age – 32.0, range: 17–51; male/female – 18/25). The median follow-up duration was 18 months (range 6–84 months). All of the patients had previously undergone conventional treatment. Neurological and QoL evaluation was provided at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter following HDCT+ ASCT. MRI examinations were conducted at baseline, at 6, 12 months, and at the end of follow-up. FACT-BMT and FAMS were used for QoL evaluation. All 29 patients with the follow-up longer than 1 year, included in the analysis, experienced a clinical stabilization or improvement. More than half of them improved: 8 patients showed significant improvement in EDSS (by more than 1.0 point), 4 – improved by 1.0 point, 4 – by 0.5 points on EDSS. Thirteen patients achieved stabilization. Two patients deteriorated to a worse score after 18 months of stabilization; 2 other patients progressed af-

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ter 12 and 30 months of improvement, respectively. All of the patients with clinical stabilization and improvement had negative MRI scans. Out of 23 patients included in the analysis of QoL response 21 exhibited improved QoL 6 months post-transplantation. At one year after HDCT+ASCT 1 patient exhibited a maximal QoL response; 4 – good QoL response; 7 – moderate QoL response and 9 – minimal QoL response. At 2.5 years post-transplantation 3 more patients had a maximal QoL response. Further QoL improvement was observed at longer follow-up. In conclusion, immunoablative therapy with ASCT resulted in clinical response in all of MS patients included in the analysis. The majority of patients with clinical response had a good or moderate QoL response. Further studies should be done to investigate the clinical and patient-reported outcomes in MS patients receiving immunoablative therapy with ASCT to better define treatment success. P751 Pro-inflammatory phenotype of autoreactive T cell lines expressing high affinity BDNF receptor in multiple sclerosis L. De Santi, L. Cantalupo, C. Cioni, P. Annunziata University of Siena (Siena, IT) Objectives: Sixty percent of myelin basic protein (MBP)-sensitized T cell lines express gp145trkB, the high-affinity full-length receptor for brain derived neurotrophic factor (BDNF), in relapsing-remitting multiple sclerosis (MS). We previously showed that gp145trkB activation by self-released BDNF partially rescues peripheral autoreactive T cells by activation-induced apoptosis. This suggests a role of BDNF/TrkB axis in gp145trkB-expressing MBP-T cell lines in breakdown of tolerance toward myelin antigens in MS. Aim of our study was to evaluate the functional phenotype of MBP-T cell lines expressing (TrkB+) and not expressing (TrkB-) gp145trkB in MS. Materials and methods: We performed mRNA gene expression analysis of 4 TrkB+ and 3 TrkB- MBP-T cell lines from MS patients by OligoGEArray® Human Th1 Th2 Th3 Microarray, a nylon membrane based DNA microarray,profiling the expression of 113 genes, including cytokine genes representing both pro-inflammatory and anti-inflammatory phenotype, T cell activation marker genes and transcription factor and regulatory genes (complete list of genes at www.superarray.com). Saved membrane images were analyzed using GEArray Expression Analysis Suite software. Relative levels of gene expression between arrays were calculated by dividing normalized intensities of spots on the TrkB+ array group by normalized spot intensities on the TrkB- array group. Ratios of gene expression greater than two-fold were considered significant. Results: Twenty-nine genes were found to be overexpressed in TrkB+MBP-T cell lines. These genes encoded for proteins involved in T cell activation (CD 86, IRF 4, IL 12B, IL 2, TNFRSF 7), transcription factors (CD 86, IRF 4, FOS, CREBBP, NFATC 2, STAT 1, STAT 4, STAT 6, TNF), pro-inflammatory cytokines and related proteins (TNF, IL 2, IL 12B, IL 12RB 2, IL 18BP, CD 40LG, SOCS 1). By contrast, only 2 genes encoding for IL-6 and CXCR 3, a chemokine receptor for CXCL 10 involved in effector T cell homing to the CNS, were overexpressed in TrkB–T cell lines. Conclusion: TrkB+-MBP-T cell lines displayed a pro-inflammatory phenotype, suggested by overexpression of a number of genes encoding pro-inflammatory cytokines and related proteins, including IL-2, TNF-alpha, IL12B, IL-12RB 2 and IL-18BP. The underegulation of the gene encoding for CXCR 3, found in TrkB+-T cells, could result in reduced migration of these cells into the nervous parenchyma. Further immunological characterization of these cells is warranted. This work was supported by a grant of the University of Siena to P. A. P752 Development of central atrophy may lead to underestimation of lesion accrual in patients with multiple sclerosis M. G. Dwyer, O. Dolezal, S. Hussein, D. Horakova, E. Havrdova, J. L. Cox, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, US); Charles University (Prague, CZ) Background: Change in brain T 2- lesion volume (LV) is a commonly used secondary endpoint in multiple sclerosis (MS) clinical trials. However, a thorough understanding of the different biological mechanisms affecting T 2-LV is critical to the correct interpretation of these changes. In particular, loss of T 2-LV due to tissue atrophy clearly does not represent a reparatory process, yet may result in decreased LV measures or underestimation of lesion accrual. Objective: To quantify the volume of T 2-LV lost due to central atrophy development over a 5-year period in patients with MS. Methods: We investigated the evolution of T 2-LV and ventricular en-

largement in a group of 38 patients with early relapsing-remitting MS (mean age 32.9±9.1 years, mean disease duration 5.1±5.3 years and mean EDSS 2.1±0.8). Patients received baseline and 5-year MRI examinations, including high-resolution FLAIR and T 1-SPGR images.T 2-LV masks were created from the baseline and follow-up images via a highly-reproducible edge-contouring technique. Lateral ventricle volume (LVV) was also calculated at both baseline and follow-up using a similar technique. For each patient, all images and masks were placed into the same space via linear co-registration. Baseline lesion masks were then overlaid with follow-up ventricle masks to identify voxels which were classified as lesion at baseline and converted to ventricle at follow-up. Results: Patients showed a mean increase in T 2-LV of 4.7ml ± 8.0ml (96 %±96.3 %). Mean increase in LVV was 8.5ml±4.2ml. Mean T 2-LV lost due to LVV enlargement was 0.5ml ± 0.7ml (3.4 %±3.7 %), and represented an average of 5.6 %±1.9 % of the total change in T 2-LV. Some patients lost as much as 17.7 % of their baseline T 2-LV to LVV enlargement, which also accounted for as much as 79.2 % of their overall change in T 2-LV over 5 years. Conclusions: T 2-LV measurement alone may be misleading as a secondary endpoint without the additional context of central atrophy measurement. P753 Characterisation of coping behaviour in patients with multiple sclerosis A. Apel, B. Greim, T. Klauer, N. Koenig, U. K. Zettl University of Rostock (Rostock, DE); Marianne Strauss Clinic (Berg/Kempfenhausen, DE) Objective: Coping with an unpredictable and chronic disease like multiple sclerosis (MS) is a demanding process for psychological adjustment of patients. The aim of the study was to characterise coping behaviour of patients with MS and to differentiate between general and MS-specific coping behaviour. Methods: Data was collected from 243 MS patients. Besides sociodemographic variables like age and gender, MS-specific parameters like duration of illness, course of disease and EDSS were investigated. Further coping behaviour was assessed by standardized questionnaires. The Trier Illness Coping Scales (TSK) with the five subscales rumination (RU), defence of threat (DT), search for social integration (SS), search for information (SI) and search for support in religion (SR) were used to assess general coping strategies. For the evaluation of MS-specific coping behaviour the Coping with MS scale (CMSS) from Pakenham was used including the five factors: problem solving (PS), energy conservation (EC), personal health control (PHC), emotion-focused coping (EFC) and lacking acceptance (LA). Results: The investigated MS patients were on average 44.0 years old, had been diagnosed for 8.2 years and had a mean EDSS from 4. 0. 72.8 % of the investigated patients were women. When comparing general and MS-specific coping behaviour. for different main problems MS patients are confronted with (e. g. physical, emotional, cognitive or financial problems), the scales EC and PHC were able to differentiate between main problems MS patients had reported. In contrast with TSK the CMSS showed differences for course of disease on the scales PS (F = 9.2; p < 0.001) and PHC (F = 37.7; p < 0.001). Post hoc multiple comparisons observed that patients with SPMS reported higher scores for PS than patients with RRMS or PPMS. Furthermore, patients with SPMS and PPMS were using more often active therapy attempts (PHC) to cope than patients with RRMS. CMSS was also closer related to EDSS than TSK. While only the scale SI from TSK was correlated to EDSS (r = –0.131), three scales of CMSS were correlated to EDSS (PS: r = 0.194; EC: r = 0.177; PHC: r = 0.600). Conclusion: MS specific assessment of coping gives further insight in the complexity of coping in MS considering individual differences and unique problems in MS patients. To observe individual changes during course of disease further research is needed on this topic. P754 Protein expression profiling of human glatiramer acetate specific T cell lines from a multiple sclerosis patient and healthy donors M. Knop, A. Jastorff, V. Vargas-Leal, J. Hornung, C. Turck, F. Weber Max Planck Institute of Psychiatry (Munich, DE) Objectives: Multiple sclerosis (MS) is the most common chronic inflammatory neurological disorder in young adults. One approved therapy of patients with relapsing-remitting MS is glatiramer acetate (GA, Copaxone®), which among other effects also induces a shift in the phenotype of CD 4+ T cells, changing from TH 1-type (pro-inflammatory T cells) to TH 2-type (anti-inflammatory T cells). As the molecular mechanisms involved are largely unknown, we were interested in the regulated proteome of GA specific human T cell lines.

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Methods: Using the “split well technique” we generated GA specific T cell lines from three healthy donors and from a MS patient before and after 6 months of GA therapy. Proteomic analysis of activated and resting GA specific, CD 3+ CD 4+ CD 8- T cells was done by SDS-PAGE gel-electrophoresis and MALDI-TOF mass spectrometry. Results: A total of 57 regulated protein spots were detected on the gels. 51 spots were identified as different proteins by MALDI-TOF mass spectrometry. Comparing activated vs. resting GA specific T cells from healthy donors we found 18 proteins differently expressed. In activated T cells more proteins involved in the energy metabolism and cell growth were upregulated. In GA specific T cell lines generated from a MS patient before and during therapy we found 33 proteins differently regulated. Further analysis of these proteins by a pathway analysis software led us to a group of antioxidative proteins, upregulated only before therapy (in resting and activated T cells), and some proteins with anti-apoptotic, anti-proliferative and anti-inflammatory properties upregulated only during therapy. Conclusion: Our results indicate that proteomics are a valuable tool to detect differences in protein regulation among GA specific T cells either in activated or resting state, generated before and during GA therapy. As expected in activated cells of healthy donors mainly proteins involved in cell metabolism were upregulated. In MS before GA therapy we found a group of antioxidative proteins upregulated, one of them is known to be a negative regulator of growth factors that promote myelin regeneration in the central nervous system. During GA therapy a protein with anti-proliferative and anti-inflammatory effects, recently reported to be expressed by TH 2 cells, was detected. Based on their expression profile characteristics, these proteins may be involved in immunological mechanisms operating in MS and/or during GA treatment. P755 Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years: a case-control study D. Horakova, J. L. Cox, E. Havrdova, S. Hussein, O. Dolezal, D. Cookfair, M. G. Dwyer, Z. Seidl, M. Vaneckova, N. Bergsland, R. Zivadinov Charles University (Prague, CZ); Buffalo Neuroimaging Analysis Center (Buffalo, US) Objective: There is growing evidence for the concept of multiple sclerosis (MS) as an inflammatory-neurodegenerative disease, with a different pattern of atrophy evolution in gray matter (GM) and white matter (WM) tissue compartments. The objective of this study was to investigate the evolution of different MRI measures over 2 and 5 years in highly clinically active early relapsing-remitting (RR) MS patients and in normal controls (NC). Methods: We investigated 135 patients who had full clinical and MRI assessments at 0, 12 and 24 months. A subgroup of 73 patients was assessed at 36 months, 40 at 48 months and 36 at 60 months. Mean age at baseline was 30.7 years, mean disease duration was 5.5 years and mean Expanded Disability Status Scale (EDSS) score was 1.8. Twenty seven NC were examined at months 0, 12 and 24 using the same MRI protocol. Percent brain volume change (PBVC), GM volume (GMV), WM volume (WMV), and neocortical volume (NCV) were measured annually using SIENA/X software. T 2-hyperintense lesion volume (LV), lateral ventricle volume (LVV), and third ventricle width (3VW) also were assessed annually. Results: Over the period of 0–24 months, MS patients lost significantly more GMV (–4.81 % vs. –0.72 %, p < 0.0001), NCV (–4.5 % vs. –1.03 %, p = 0.0001), PBVC (–1.47 % vs. –0.22 %, p = 0.001), LVV (19.2 % vs. 0.89 %, p < 0.003), and 3VW (22.2 % vs. 2.1, p = 0.003) when compared with NC. Within-person change in MRI measures for MS patients over 5 years was –4.4 % for PBVC, –9.2 % for GMV, –9.2 % for NCV, –2.9 % for WMV, 80.5 % for LVV, and 23 % for 3VW. Conclusions: Our study confirmed a different pattern of GM, WM and central atrophy evolution over 2 years between MS patients and NC. The study showed a different evolution of tissue compartment atrophy measures in MS patients, with faster decline in cortical and deep GM regions, and periventricular WM regions over a period of 5 years. This study was supported by Biogen Idec, Inc. P756 Multiple sclerosis with chronic sialadenitis C. Suzuki, M. Tomiyama, T. Kawarabayashi, M. Shoji, M. Baba Hirosaki University (Aomori, JP); Aomori Prefecture Hospital (Aomori, JP) Background: The relationship between multiple sclerosis (MS) and primary Sjogren’s syndrome (SS) is controversial. The central nervous system is involved in 20 % of patients with SS and they are often misdiagnosed as MS. Minor salivary gland biopsy resulted in a high sensitivity and specificity for diagnosis of SS.

Objective: To demonstrate frequency of chronic sialadenitis (CS) in patients with MS and to compare clinical features, MRI findings, responses to therapy, prognosis and biomarkers between MS patients with and without CS (MSWCS and MSWOCS). Methods: We examined clinical features, autoantibodies (anti-Ro/SSA or anti-La/SSB antibodies) and CSF in consecutive 34 MS patients who fulfilled the McDonald diagnostic criteria. According to the revised version of the American-European criteria for SS, ocular symptoms, oral symptoms, ocular signs (Shirmer’s test, Rose Bengal test), minor salivary gland biopsy and objective salivary gland involvement (salivary flow, parotid sialography, salivary sintigraphy) were examined. Results: CS was found in 11 patients (32.3 %) in patients with MS. However, only one of 11 MSWCS patients fulfilled criteria for SS. There was significant female preponderance in MSWCS (91 % vs. 74 %). The mean age of onset of MSWCS was higher (44.6 years) than that of MSWOCS (32.4 years). Disability score in MSWCS was worse than that of MSWOCS (EDSS 5.1 vs. 2.4). In MSWCS patients, visual disturbance was more frequent (91 % vs. 39 %). Longitudinally extensive spinal-cord lesions in MRI were often observed in MSWCS than in MSWOCS (54.5 %vs. 30.4 %), but no significant difference. Significant increases in cell count in CSF and ESR were found in MSWCS. Conclusion: CS was more frequently present in female and older patients with MS. MS patients with CS had higher disability and more optic involvement than those without CS. MS patients with CS may be a distinctive clinical subgroup of MS. P757 Risk of multiple sclerosis in first-degree relatives of probands affected by multiple sclerosis: a family study using a reconstructed cohort approach F. Martinelli Boneschi, F. Esposito, L. Moiola, M. Radaelli, L. Bernasconi, M. Rodegher, B. Colombo, M. Gironi, L. Collimedaglia, A. Ghezzi, G. Coniglio, R. Capra, V. Martinelli, G. Comi Scientific Institute San Raffaele (Milan, IT); Fondazione Don Gnocchi (Milan, IT); MS Clinics Ospedale Novara (Novara, IT); MS Clinics Ospedale Gallarate (Gallarate, IT); Ospedale Potenza (Potenza, IT); Spedali Civili (Brescia, IT) Objective: To assess the risk of Multiple Sclerosis and other autoimmune disorders among first-degree relatives of probands affected by MS, and to explore whether the risk is influenced by several disease-related features of ascertained probands. Methods: Patients have been recruited from the in-patient and out-patient facilities of 5 different MS centres as part of a multicentric case-control genetic association study. A semi-structured questionnaire has been developed to collect data on familial history among first-degree relatives of the probands by direct interview of the proband. We developed a reconstructed cohort approach, which controls for the number of relatives and the years at risk of the different relatives, and we tested the influence of different factors related to ascertained probands (disease course of the probands, primary progressive (PP) versus secondary progressive (SP)/relapsing remitting (RR; disease onset in probands; progression of disability in probands) on the risk to get the disease in their relatives by means of a regression model. Results: We interviewed a total of about 300 MS patients, of whom 48.1 % affected by PP or PR course, 42.8 % by RR and 9.1 % by SP course. We found that the risk was 0/280 for fathers, 1/280 for mothers (0.4 %), 8/548 for siblings (1.4 %), and 3/277 (1.1 %) in offspring of affected probands (p = ns), leading to an overall risk of disease of 12/1395 (0.9 %) among first degree relatives. The risk of diabetes and tireopathy in first-degree relatives of MS probands was slightly higher, respectively 1.1 % and 1 %. According to Cox proportional hazard models, the familial risk of MS was not influenced by the disease course and by other disease-related features of the probands. Conclusion: We took advantage of our large collection of PPMS sample to compare familial risk among different disease courses of the probands. Our data suggest that: 1) the familial risk of MS is not influenced by the disease course of the probands; 2) it is lower than expected; 3) it is greater in siblings than in parents and offsprings of MS probands. The low familial risk can be due to different factors, including the type of questionnaire used, the Italian geographical origin of the sample studied, and other potential sources of bias, including the fact that MS is still considered a stigma for Italian patients. Additional data are ongoing in order to achieve a greater sample size and statistical power.

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P758 A randomised, placebo-controlled, double-blind, multicentre, phase IIIb study assessing efficacy, safety and tolerability of Rebif® New Formulation in patients with relapsing-remitting multiple sclerosis N. De Stefano, M. Beelke on behalf of the IMPROVE Study Group Objectives: Rebif New Formulation (RNF) has demonstrated improved tolerability and reduced immunogenicity (Sørensen, ENS 2007). This study (27178) will assess magnetic resonance imaging (MRI) markers of pathology in patients with relapsing-remitting multiple sclerosis (RRMS), to provide supportive efficacy data for RNF. Methods: Patients recruited to this study will have RRMS of > 12 months duration according to revised McDonald criteria (2005). Key eligibility criteria are: age 18–60 years, an Extended Disability Status Scale score ≤ 5.5 and active disease characterized by ≥ 1 clinical event and ≥ 1 gadoliniumenhancing MRI lesions during the previous 6 months. Patients will be randomized 2:1 to receive RNF 44mcg administered subcutaneously (sc) threetimes-weekly (tiw), or matching placebo for 16 weeks. For the following 24 weeks, all patients will receive active treatment with RNF 44mcg sc tiw. Monthly MRI assessments will be performed. The primary efficacy endpoint is the difference between the number of combined unique (CU) active MRI lesions in the RNF and placebo groups at Week 16. The secondary endpoint is the difference in the mean number of CU active MRI lesions per scan per subject between baseline and Week 16, and Weeks 17–40, among patients who originally received placebo. Further efficacy evaluations include the presence of other MRI markers of pathology (e. g. new T 1-lesions, new ringenhancing lesions, number and volume of black holes) and immunological biomarkers. Safety measures include the occurrence of adverse events (AEs) and serious AEs. Immunogenicity will also be assessed. Results: The placebo period is limited to only 16 weeks before switching to active treatment, in line with EMEA ethical recommendations. Frequent MRI assessments will allow within-patient comparisons and close monitoring of inflammation. MRI measures will also be assessed for correlation with clinical outcomes. The use of objective MRI outcomes will allow evaluation of efficacy in a shorter period and with a smaller sample size than using clinical endpoints. A total of 150 patients will provide 80 % power and a twosided significance of 0.05, and allow detection of a mean difference of –1.3 in the primary endpoint between RNF and placebo groups, which is considered clinically meaningful based on PRISMS data. Conclusion: It is anticipated that this study will provide useful additional information for RNF in patients with RRMS. This study was supported by Merck Serono.

well as a NAb positivity during the first 6 months of treatment increased the predictivity to 92 % (p = 0.02), with good 73 % sensitivity and 60 % specificity. Conclusions: The combined used of the evaluation of MRI scans and of the detection of NAb during the first months of IFN beta-1 b treatment could be useful in predicting the clinical response over the next follow-up, therefore allowing an early identification of patients at risk of clinical disease activity in spite of treatment. Study supported by Schering AG, Berlin. P760 Physical dimension of fatigue correlated with disability change over time in patients with multiple sclerosis S. Louis, M. Debouverie Teaching Hospital (Nancy, FR) Objectives: To determine the value of fatigue in predicting the change in disability status in patients with Multiple Sclerosis (MS), we realized a prospective population-based cohort study of 196 patients with clinically definite MS. Methods: In 2002, baseline data were collected on fatigue (Fatigue Impact Scale and modified Fatigue Impact Scale), health-related quality of life (SF-36), and disability status (EDSS score). The EDSS scores were determined again at least three years later. Univariate and multivariate analysis were performed to determine the predictive value of different dimensions of fatigue and other variables (depression and SF-36) on the change in disability status. Results: Of the 196 patients, 106 (54 %) patients had an unchanged status or improvement and 90 (46 %) showed a worsening of disability. After three years, with control for gender, age, and baseline disability status, a high baseline level of physical fatigue was associated with a worsening of disability status, whereas a low baseline level of physical fatigue was associated with the absence of worsening of the EDSS score. Other dimensions of fatigue, depression and SF-36 were not associated with a worsening of disability. Conclusion: A patient’s perceived fatigue may be not only a clinically and psychosocial meaningful outcome but also a predictor of objective outcomes such as changes in disability status at three years.

P759 Neutralising antibody and MRI activity during the first 6 months of interferon beta-1 b treatment for multiple sclerosis correlate with the clinical response over the long term L. Durelli, P. Barbero, M. Bergui, E. Versino, B. Ferrero, G. Giuliani, E. Montanari, M. Clerico on behalf of the OPTIMS Study Group, Italy

P760A The BENEFIT study: characteristics of patients with potentially benign multiple sclerosis L. Kappos, G. Edan, M. Freedman, H-P. Hartung, D. Miller, X. Montalban, C. H. Polman, F. Barkhof, L. Bauer, V. Lanius, C. Pohl, R. Sandbrink University Hospital (Basel, CH); Centre Hospitalier Universitaire (Rennes, FR); The Ottawa Hospital (Ottawa, CA); Heinrich-Heine-Universität (Düsseldorf, DE); The National Hospital for Neurology & Neurosurgery (London, UK); Hospital Vall d’Hebron (Barcelona, ES); Vrije Universiteit Medical Centre (Amsterdam, NL); Bayer Schering Pharma AG (Berlin, DE)

Objective: To analyse the correlation between the occurrence of MRI activity or NAb(Neutralizing Antibody)positivity during the first 6 months of interferon beta(IFNB) treatment with the clinical response in the long term (2year) follow-up. Methods: 147 patients from 16 centers prospectively followed up during the first 2 years of treatment with 250 mcg every other day IFNB-1b. Neurological assessments performed by investigators trained in EDSS scoring every 3 months with additional visits within 10 days of suspected relapses. Monthly MRI scans centrally assessed for activity (i. e., either new T 2 or gadolinium-enhancing T 1 lesions). Serum samples (of a subgroup of 88 patients from 14 centers) tested for NAb using the IFNB-induced Mx production neutralization assay. NAb positivity defined by two consecutive NAb positive titers, i. e., ≥ 20 NU/mL. We evaluated the predictivity of the occurrence of an active scan or of a confirmed NAb positivity during the first 6month of treatment on the occurrence of clinical signs of disease activity (relapses or confirmed disability progression) during the further long term follow-up. The association between baseline demographic, clinical, and MRI characteristics (independent variables) with the occurrence of clinical activity (dependent variable) analyzed with multiple logistic regression. Results: Neither univariate or multiple logistic regression analysis showed any significant association between baseline characteristics and clinical activity during the on treatment follow-up. 38/147 patients (26 %) had an active scan and 18/88 (21 %) a NAb positivity status during the first 6 months of treatment. 82 % of NAb positivity occurred during this period. An active scan during the first months of IFN beta-1 b had an 85 % predictivity (p = 0.007) with a good 86 % specificity and a modest 54 % sensitivity. A NAb positivity, had also a good 87 % predictivity (p = 0.01), with a high 85 % specificity and a modest 44 % sensitivity. Having both an active scan as

Objectives: There is uncertainty regarding how to identify patients with a potentially inactive course of multiple sclerosis (MS) after a clinically isolated syndrome (CIS) suggestive of MS. Possible predictors include clinical and MRI-related baseline disease characteristics, or the absence of any clinical or subclinical disease activity in the immediate follow-up period. This analysis aimed to determine baseline features associated with an inactive further course of MS. Methods: In the BENEFIT study (BEtaferon® / BEtaseron® in Newly Emerging multiple sclerosis For Initial Treatment), 176 CIS patients with magnetic resonance imaging (MRI) evidence suggestive of MS received placebo for up to two years or until they developed clinically definite MS (CDMS). Within this period, patients were monitored by clinical visits at months 1, 2, 3, 6, 9, 12, 18 and 24 after start of treatment, with cerebral MRI obtained at months 3, 6, 9, 12, 18 and 24. Baseline characteristics of patients without disease activity (i. e. patients without: relapse, disability progression measured by the expanded disability status scale, new Gadolinium-enhancing lesions on T1-, new or enlarging lesions on T2-weighted MRI) were compared with patients exhibiting any such activity. Results: Of the 176 placebo-treated patients, 12 (6.8 %) were inactive and 164 were active (93.2 %, of which 142 developed McDonald MS and 77 developed CDMS). At the time of the CIS, inactive patients were significantly older, had a lower T2-lesion number and volume, and less frequently positive cerebrospinal fluid (CSF) findings. Clinical characteristics (including symptoms of the first event) did not differ between the groups. Conclusion: Older patients have a higher chance not to show any further disease activity after a first presentation with symptoms suggestive of MS. Baseline MRI and CSF findings and possibly molecular analysis may help to identify such patients with possible inactive MS. Based on the ongo-

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ing three-year interim analysis of the BENEFIT studies, further follow-up data for these patients will be presented. Study supported by: Bayer Schering Pharma AG, Berlin, Germany

General neurology P761 Positive anti-ganglioside antibodies associated with eye movement disorders: two unusual case reports L. Strens, A. Grubneac, C. Carroll, A. Shehu University Hospitals Coventry & Warwickshire (Coventry, UK) Objectives: We present two unusual case histories of patients with eye movement abnormalities in association with positive anti-ganglioside antibodies. Case One: A 41-year old female presented with a 6-week history of intermittent convergence spasm associated with unilateral left-sided headache, mild left-sided ptosis and fluctuating left-sided sensory symptoms. There were no other objective neurological abnormalities. MRI brain, CSF analysis and neurophysiology were normal. Extensive blood tests yielded normal results except for positive serum anti-GQ 1 b antibodies. There was complete resolution of symptoms following intravenous immunoglobulins (IVIg). Her anti-GQ 1 b antibodies subsequently became negative and have remained so. Case Two: A 45-year old male presented with a 10-year history of recurrent episodes of diplopia and right-sided ptosis, always associated with severe bouts of flu-like symptoms. This occurred 1–2 times per year and previously had always resolved fully within 7–10 days. However, the current episode had lasted longer than usual. On examination, he had a partial ptosis, miosis and restriction of up-gaze, all on the right side. Facial sweating was normal and there were no other objective neurological signs. MRI brain, MRI orbits and neurophysiology were normal. Extensive blood tests and CSF analysis were unremarkable except that he was found to have positive anti-GM 2 IgM antibodies in both blood and CSF. Treatment on this occasion with IVIg was of little symptomatic benefit. Discussion: Anti-GQ 1 b antibodies have been closely correlated with ophthalmoplegia and ataxia syndromes, including Miller-Fisher. Anti-GM 2 antibodies have been found in patients with cytomegalovirus-associated Guillain-Barre syndrome, chronic motor neuropathies and sensory demyelinating neuropathies. However, there are no reports in the literature of anti-GQ 1 b antibody-associated convergence spasm or of anti-GM 2 antibody-associated ophthalmoplegia. We recommend considering the testing of anti-ganglioside antibodies in patients with unusual or otherwise unexplained eye movement disorders. P762 Kimmerle’s anomaly mimicking amyotrophic lateral sclerosis G. Xiromerisiou, E. Koutsouraki, M. Arnaoutoglou, G. Andriopoulou, G. Psillas, A. Arnaoutoglou, V. Costa, S. J. Baloyannis Aristotelian University (Thessaloniki, GR) Many anatomical variations occur in the region of the cranial cervical junction. One of these variations is the ponticulus posticus of the first cervical vertebra or a calcified or a thickening ligament in this region often described as Kimmerle’s anomaly. Under certain circumstances this anatomical variant may alter substantially the anatomical conditions in the region and lead to the development of complex clinical manifestations associated with impairment of adjacent structures. The prognosis is usually benign. We describe the case of a 59 years old female patient with progressive weakness of the left upper and lower extremity, district muscular wasting and pyramidal signs. MRI shows clearly the thickening and enlargement of Kimmele ligament. The progression of the disease stopped after the application of cervical support. This is the first reported case of Kimmerle’s anomaly presented with the clinical picture of A. L. S. The reported case underlines the necessity of exclusion of every abnormality of the cervicooccipital relationships prior to the establishment of the diagnosis of A. L.S.

P763 Catatonia as clinical presentation of Hashimoto’s encephalopathy with severe demyelination of white matter E. Cuadrado-Godia, A. Rodriguez-Campello, C. Pont, G. Cucurella, R. M. Vivanco, J. Roquer Hospital del Mar (Barcelona, ES) Objective: Hashimoto’s encephalopathy (HE) is a rare condition characterized by neuropsychiatric symptoms in the context of an autoimmune thyroid disease. Two subclinical types have been described: one remittent-recurrent vasculitic type and a second diffuse and progressive type. This second subtype is associated with psychiatric symptoms such as depression, bipolar disorder or dementia. Catatonia as a symptom of HE has never been described. HE is more frequent in women about middle age. Patients are usually euthyroids. CSF and EEG are abnormal in the majority of patients. Half of the patients could have focal or diffuse white matter abnormalities in neuroimaging evaluations. The objective of our study is to report a case of HE of atypical presentation and extensive lesions in magnetic resonance imaging (MRI). Methods: 49 years male was admitted in the Psychiatric Emergency room with subacute behaviour disorder. He was diagnosed as catatonic schizophrenia. He had a previous history of autoimmune thyroid disease and vitiligo. General exam evidenced cutaneous vitiligo with Hertoghe sign and nail dystrophy. Patient held unusual postures. Neurological examination showed severe disorientation, bradypsychia and echolalia. Frontal released signs (grasp, snout, root, and suck reflexes) were present. He had also motor impersistence with rigidity and bradykinesia and intentional tremor. Tendon reflexes were present and symmetrical with bilateral Babinski sign. Results: Laboratory evaluation showed severe hypothyroidism with high levels of thyroid antiperoxidase and antithyroglobulin antibodies. Microbiologic serologies and determination of 14-3-3 protein were negative. Cranial-CT was normal. CSF disclosed a mild increase in protein content. EEG showed slow and low voltage activity. MRI showed extensive subcortical and periventricular white matter hyperintense lesions in T 2 and Flair sequences, with hypersignal in diffusion weighted images. HE was diagnosed and treatment with endovenous high-dose steroids and levothyroxine was started. Patient showed a fast clinical, electroencephalographic and radiological improvement. Conclusion: HE is a well defined rare disease which pathophysiology that still remains unclear. It might be manifested as a pure psychiatric disorder. MRI abnormalities could be very extensive. High-dose steroid therapy results in a favourable outcome when administered early. P764 The roles of cytokines and chemokines in the immunoinflammation of neuro-Behçet syndrome B. Kocer, C. Irkec, C. Betul, N. Bijen, S. Kurt Gazi University Medical Faculty (Ankara, TR); Gaziosmanpasa University Medical Faculty (Tokat, TR) Background: During recent years, immunoinflammatory mechanisms have gained importance in the etiopathogenesis of Neuro-Behcet’s disease. Important actors of immunoinflammation IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IL18, TNF-alpha, IFN-gamma and MCP-Ialpha have been shown to have increased during the acute phase of the disease. Methods: In this study we have recruited 48 patients with neuro-Behçet, and measured the levels of serum and cerebrospinal fluid TNF-alpha, RANTES and MIP-Ialpha in which have not been previously studied by making a comparison with patients with non-inflammatory neurological disease and controls. Results: There was a significant statistically difference on the levels of serum and cerebrospinal TNF-alpha, RANTES and MIP-Ialpha. It was high in the active phase when compared with the inactive phase of Neuro-Behcet’s patients, noninflammatory neurological disease and control groups. Conclusions: The cytokines and chemokines might be important in monitoring the activation of Neuro-Behcet’s disease. P765 Stimulation of brain endothelial cells with VEGF and menadion is independent of P 38 K. Hartmann, K. Voigt, J. Kraus, M. Clauss Max-Planck Institute for Physiological and Clinical Research (Bad Nauheim, DE); Paracelsus Private Medical University (Salzburg, AT); Indiana University School of Medicine (Indianapolis, US) Objective: Menadion is an intracellular free radical donor and has been shown to increase brain endothelial cell monolayer permeability in vitro as

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well as VEGF. We examined, whether the ratio of phosphorylated over unphosphorylated p38-MAPK is influenced by menadion, VEGF, or both after such stimulation of endothelial permeability as compared to untreated controls. Methods: The immortalized endothelioma cell line bEnd5 from mouse brain capillaries was grown to confluence on culture dishes coated with rat tail collagen. The cells were exposed to 300 μM menadion or to 300 μM menadion and 40 ng/ml VEGF for 5 and 15 min in the incubator before cell lysis and compared to untreated controls. We also incubated cells with 1.5 % DMSO for 5 min to exclude potential effects caused by the DMSO used as a solvent for menadion.After lysis, we analysed the amount of phosphorylated and total p38-MAPK by western blotting.For time kinetics,the ratio of phosphorylated over unphosphorylated p38 was used. The experiments were repeated after preincubation for 30 min with the p38-inhibitor SB 202190. Results: Menadion alone stimulated p38 MAPK phosphorylation at 5 min followed by a significant (p < 0.05) decline after 15 min. At both time points phosphorylation was significantly (p < 0.05) higher than in the untreated controls. Time kinetics was similar for the combination of menadion and VEGF, but this did not reach significance.After inhibition of p38-MAPK phosphorylation with SB 202 190 at 5 min, the combination showed significantly (p < 0.05) lower p38 phosphorylation than menadion only. Conclusion: There seems to be no direct correlation between p38-MAPK phosphorylation and the increase of the permeability of bEnd5 brain endothelioma cell monolayers upon the stimulation with menadion or the combination of menadion with VEGF. Rather, the changes in p38 MAPK phosphorylation could be explained by the removal of culture medium during the experimental procedure as we have shown elsewhere. P766 Brain endothelioma cell stimulation with VEGF and H2O2 is independent of P 38 K. Hartmann, K. Voigt, J. Kraus, M. Clauss Max-Planck Institute for Physiological and Clinical Research (Bad Nauheim, DE); Paracelsus Private Medical University (Salzburg, AT); Indiana University School of Medicine (Indianapolis, US) Objective: VEGF and free oxygen radical generators such as H2O2 increase the permeability of brain endothelial cell monolayers in vitro. To investigate the role of p38-MAPK phosphorylation during intracellular signal transduction after such stimulation of endothelial permeability, we examined the effect of VEGF, H2O2, and their combination on the ratio of phosphorylated over unphosphorylated p38 as compared to untreated controls. Methods: The immortalized endothelioma cell line bEnd5 from mouse brain capillaries was grown to confluence on rat tail collagen coated culture dishes. We exposed these cells to 40 ng/ml VEGF, 500 μM H2O2 or both for 5, 15, 60, or 180 min in the incubator before cell lysis, and compared them to untreated controls. After lysis, we analysed the amount of phosphorylated and total p38-MAPK by western blotting. The ratio of phosphorylated over unphosphorylated p38 was used for time kinetics. The experiments were repeated after preincubation of the cells for 30 min with the p38-inhibitor SB 202190. Results: VEGF increased intracellular p38-MAPK phosphorylation significantly (p < 0.05) at 5 min as compared to all other time points. However, this was not significant when compared to untreated controls. Exposure to H2O2 and to the combination of VEGF and H2O2 did not lead to a significant increase of p38 phosphorylation at any time point nor as compared to controls. After inhibition of p38-MAPK phosphorylation with SB 202 190 there was a significant (p < 0.05) decrease of phosphorylation from 60 min to 180 min for VEGF. Combination of VEGF and H2O2 after inhibition by SB 202 190 resulted in a significant change between 15 min, 60 min (p < 0.05), and 180 min (p < 0.05) with a peak at 60 min. With the inhibitor, VEGF alone and the combination of VEGF and H2O2 could cause a significant (p < 0.05 respectively) increase of phosphorylation at 15 and 60 min (combination also at 180 min) as compared to controls. Conclusion: There seems to be no direct correlation between p38-MAPK phosphorylation and increased permeability of bEnd5 brain endothelioma cell monolayers after their stimulation with VEGF, H2O2, or both. The changes observed in p38 phosphorylation might be caused by the removal of culture medium during the experimental procedures as we have shown elsewhere. Therefore, other mechanisms than phosphorylation of p38MAPK may be involved in intracellular signal transduction in these cells.

P767 Prevalence of antinuclear antibodies in 548 inpatients with neurological diseases A. Angelou, T. Afrantou, R. Lagoudaki, M. Paschalidou, N. Artemis, E. Sidiropoulou, N. Taskos, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Objectives: Determination of the prevalence of antinuclear antibodies (ANA) within a neurological population and evaluation of their possible significance. Methods/Patients: A total of 548 inpatients of the 2nd Neurology Department of AHEPA Hospital in Thessaloniki suffering from various neurological disorders underwent immunological control in order to clarify the possible role of autoimmunity. ANA were detected by indirect immunofluorescence technique on fixed Hep2 cells. Titers over 1/80 were considered positive. Results: Stroke (n = 259, m = 167, f = 92, m.age = 53). ANA ≥ 1:80 (29.3 %), ANA ≥ 1:160 (18.1 %). Cerebral Hemorrhage (n = 33, m = 15, f = 18, m.age = 55). ANA ≥ 1:80 (42.4 %), ANA ≥ 1:160 (21.2 %). MS (n = 124, m = 34, f = 90, m.age = 36). ANA ≥ 1:80 (30.6 %), ANA ≥ 1:160 (17.7 %). Neuropathies (n = 66, m = 39, f = 27, m.age = 53). ANA ≥ 1:80 (27.2 %), ANA ≥ 1:160 (21.2 %). Degenerative Diseases (n = 66, m = 34, f = 32, m.age = 56). ANA ≥ 1:80 (25.7 %), ANA ≥ 1:160 (4.5 %). Conclusions: Increased titers of ANA are generally related to systemic immunological disorders and are a good marker of the underlying autoimmune activity since they seem to decrease during effective treatment. On the other hand several neurological diseases are characterized by inflammation and in some of them a strong role of autoimmunity can be presumed or is certain. The increased titers in phases of relapse in patients with MS, neuropathies and young individuals suffering from ischaemic or haemorrhagic stroke, comparing to the general population (ANA?1/80 ranges from 2–5 % in ages < 60) imply that a process, so far not so well-known, is taking place. These findings may reflect a systemic immunological dysregulation especially in cases where inflammation plays an important role in the underlying pathology; inversely low incidence of increased titers(ANA> 1/160) are observed in chronic degenerative disorders such as dementia, extrapyramidal and motor neuron diseases indicating a different pathogenetic process in terms of autoimmunity. However many investigators consider that the presence of these autoantibodies is accidental. Since there are no studies describing the alterations in the titers of ANA during the clinical course, we cannot make clear clinical correlations and their role in the spectrum of neurological diseases will remain unilluminated. P768 Hemihypertrophy and hemiparaesthesia – hemi 3 syndrome? K. Rabe, O. Kastrup, Z. Katsarava University Hospital of Essen (Essen, DE) Objectives: Hemihypertrophy is defined as asymmetry between right and left sides of the body to a greater degree than can be attributed to normal variation. Hypertrophy can be part of a clinical syndrome or an isolated non-syndromic feature. The aetiology of the enlargement is not known. Non-syndromic hemihypertrophy mostly appears sporadically. In 1984 Nudleman et al. described the so-called hemi 3 syndrome – hemihypertrophy associated with hemihypaesthesia, hemiareflexia and scoliosis. Case report: We report a thirty-five year old male patient with a progressive increase of leg circumference of the left side over twenty years. At the age of twenty-seven he first experienced a progressive hypaesthesia, hypalgesia, thermhypaesthesia and paraesthesia on his left side. Current difference in leg circumference was 7.5cm (left thigh 55cm, right thigh 47.5 cm; length: left > right). The deep tendon reflexes of the left leg were decreased compared to the right side. In 1998 a muscle biopsy of the peroneal muscle showed hypertrophic muscle fibres in both sides, accentuated in the left peroneal muscle, and marginal evidence of mitochondrial myopathy. These findings could not be confirmed in a muscle biopsy of the right lateral vastus muscle in 2000. A molecular genetic analysis, normal mitochondrial and glycolytic enzymes and an ischemic work test did not support the diagnosis of a mitochondrial myopathy. To further distinguish between hemihypertrophy and hemihypotrophy an MRI of the thighs was performed which presented a hypertrophic left side and no signs for hypotrophy of the right side. MRI of the brain showed no difference between both sides regarding the pyramidal tracts. Electromyography and neurography displayed no pathological findings. Conclusion: This case report describes a young male patient with pro-

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gressive hemihypertrophy of his left leg, hemihypaesthesia and decreased deep tendon reflexes of the left side. The syndrome is partly consistent with the originally described hemi 3 syndrome.Our case demonstrates that hemihypertrophy-syndrome can have multiple variants. The syndrome should be known to treating physicians to avoid unnecessary auxiliary diagnostics. P769 Superficial cerebral and spinal hemosiderosis caused by secondary tethered cord syndrome after resection of a spinal lymphoma V. C. Zingler, S. Grau, J.-C. Tonn, K. Jahn, J. Linn, T. Brandt, M. Strupp University of Munich (Munich, DE) Objective: Superficial hemosiderosis (SH) results from chronic subarachnoid hemorrhage, during which hemosiderin is deposited in the leptomeninges around the brain, spinal cord, and cranial nerves. We describe an exceptional case of SH caused by a secondary tethered cord syndrome. Case report: A 63-year-old man presented with a 1-year history of progressive gait unsteadiness, weakness of both lower extremities, and increasing bilateral hearing loss. Eight years earlier he had undergone a surgical resection of a low grade malignant B-cell non-Hodgkin’s lymphoma of the thoracic spine (Th6) and subsequent radiation (from Th2 to L 4). Neurological examination revealed a cerebellar and sensory ataxia, paraparesis, hypesthesia at the Th 5–7 levels and below Th 12, and moderate bilateral sensorineural hearing loss. Neuro-ophthalmological examination showed a pathological result for the head-thrust test to the right side, gaze-evoked nystagmus, head-shaking nystagmus to the left side, and saccadic smooth pursuit. In 1998 (before resection of the spinal lymphoma) cerebral and spinal MRIs showed no signs of SH. Eight years after resection of the lymphoma, cerebral and spinal MRIs revealed the typical finding of SH of the central nervous system. A complementary (3D-constructive interference in steady state) MRI showed an adhesion between the spinal cord and the dorsal dura at the level of Th7. A cerebrospinal fluid (CSF) test revealed xanthochromic CSF with a highly increased number of erythrocytes and macrophages loaded with hemosiderin. On the basis of these findings, an explorative operation was performed.After dissection of the scar and a laminectomy of the 7th thoracic vertebra, a thickened, in part calcified tissue string connecting the spinal cord to the arachnoid layer was observed; it caused a tethering of the spinal cord. The tissue string was supplied by multiple capillaries. After coagulation and removal of the tethering tissue, the spinal cord floated freely without restriction. At a 6-month follow-up, clinical examination revealed improvement of audiological and vestibular function. The CSF was normal without xanthochromia. MRI of the brain and spine showed persistent SH. Conclusion: A combination of different MRI techniques suggested a secondary tethered cord syndrome. Because of the progressive course of the disease, an explorative surgical approach and untethering seemed justified. The bleeding and progression were effectively stopped. P770 Acute autoimmune limbic encephalitis: positive outcome following immunomodulatory therapies G. Silvestri, A. Modoni, M. Masciullo, T. Tartaglione, P. Spinelli, M. Mirabella, E. Ricci, P. A. Tonali Catholic University (Rome, IT) Objective: To describe a case of acute autoimmune limbic encephalitis, not associated with paraneoplastic or potassium channel (VGKC) antibodies, showing a dramatic response to a prompt immunomodulatory therapy. Methods: A 30 year-old woman was admitted to our hospital because of grand mal seizures during a viral illness with fever. Neurological examination showed altered consciousness, disorientation, memory impairment, and brief episodes of non convulsive seizures, without meningeal signs. EEG showed diffuse slowed activity with temporal paroxysmal slow wave bursts. CSF analysis documented mild pleiocitosis; search for viral antibodies and PCR for Herpes simplex was negative. Brain MRI with T 2- weighted and FLAIR images revealed hyperintensity in the bilateral medial temporal lobes. Despite administration of antiviral therapy and antiepilectic drugs, her clinical conditions progressively worsened. Blood tests documented a marked and persistent hyponatremia; the patient was transferred to the Intensive Care Unit for a prolonged and resistant status epilepticus. An extended autoantibody screening; total body CT scan, determination of serological tumoral markers and testing for paraneoplastic and VGKC antibodies were all negative. Results: IgIV infusions (0.4 mg/kg for 5 consecutive days) produced a dramatic improvement of her clinical status, with a complete recovery of the subcontinous epileptic EEG activity and restoration of normal natriemia. Re-admitted to our Department, the patient appeared conscious, but confused and disoriented, despite a progressive reduction of anticonvulsivant

therapy. Neuropsychological tests showed an impairment of frontal and temporal cognitive functions. A daily oral administration of prednisone (50 mg/die) was added with marked benefit. Indeed, one month later, clinical examination was normal; neuropsychological tests documented a clear recovery of memory functions; EEG showed the presence of brief bursts of theta activity predominant in the left temporal regions; brain MRI revealed a marked reduction of the hyperintensity signals in the bilateral medial temporal lobes. Conclusions: Acute autoimmune limbic encephalitis is not only caused by VGKC autoantibody. In our patient the autoimmune response producing the limbic system damage was probably triggered by the concomitant viral illness. Our data indicate that an early administration of immunomodulatory treatment may positively influence the clinical outcome. P771 Hyperhomocysteinaemia and polymorphisms of the main enzymes of homocysteine metabolism in the population of northern Poland W. Sawula, L. Kadzinski, Z. Banecka-Majkutewicz, W.M. Nyka, G. Wegrzyn, J. Jakóbkiewicz-Banecka, B. Banecki IFB UG/MUG (Gdañsk, PL); University of Gdañsk (Gdañsk, PL) Objectives: Hiperhomocysteinemia is an independent risk factor in ischemic brain stroke. Our main goals were to study the frequency of polymorphisms of the genes of two enzymes involved in homocysteine metabolism in the population of northern Poland, to investigate whether there is a relationship between any of the polymorphisms and the occurrence of ischemic brain stroke and to check, if any of the polymorphisms are bound to patients’ homocysteine level. Methods: The first step of the procedure allowing to study the frequency of occurrence of polymorphisms of the genes coding for two main enzymes of homocysteine metabolism, CBS - cystathionine beta-synthase and MTHFR - methylenetetrahydrofolate reductase, was isolation of DNA from whole blood using a QIAGEN DNA isolation kit. Next, the purity of the isolated DNA was assured spectrophotometrically and DNA was amplified in a RedTaq Polymerase reaction. Two of the amplified fragments were located on the CBS gene (one at exon 4, corresponding to protein fragment connected with a deletion of 22 b.p. and the other at exon 8, corresponding to polymorphism T833C / ins 68 b.p. 844) and two on the MTHFR gene (a fragment at exon 4, corresponding to polymorphism C677T and another at exon 7, corresponding to polymorphism A1298C). Then, amplified DNA was digested by restriction enzymes and the results were analyzed by agarose gel electrophoresis. Homocysteine level in serum was measured using a modified HPLC method. Results: We have studied 195 subjects in total, 130 of who were in the acute phase of ischemic stroke and the rest were members of a control group, matched by age and sex. 89.8% of ischemic brain stroke patients in total exhibited at least one polymorphism in CBS or MTHFR, compared to 83.3% in the control group. There were no significant differences in individual polymorphism occurrence between patients and the control group. Of the studied polymorphisms, the strongest relationship between the polymorphism variety and homocysteine level was observed for MTHFR C677T. Conclusions: The ratio of polymorphism occurrence in the population of northern Poland is relatively high, which seems to be in accordance with high ischemic brain stroke incidence in this area. Lack of significant differences in total polymorphism level is especially interesting in the context of increased homocysteine level in the control group. Of the studied polymorphisms, MTHFR C677T seems to be a good subject for further in vitro studies. The work was financed by Polish State Committee for Scientific Research grant 1286/P01/06/30. P772 Increased intracranial pressure as a cause of reversible sensorineural hypoacusis A.C. Fonseca, M. Canas Marques, L. Albuquerque Hospital de Santa Maria (Lisbon, PT) Background: Classic manifestations of increased intracranial pressure (IIP) include headache, ocular palsies and visual disturbances. Nevertheless, there can also be otologic manifestations in up to 80% of cases, namely tinnitus, vertigo and hypoacusis which is usually mild. It can be sensorineural (due to nerve/brain stem compression) or conductive (due to cochlear stasis) and usually improves after normalization of IIP. Objective: To characterize and study the evolution of auditory deficits in a patient with IIP. Method: A 27-year-old-woman was first seen after a three months history of headache, followed by progressive worsening of vision and hearing.

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On admission, neurological examination showed bilateral papilledema, bilateral VI nerve palsy, and very diminished hearing and vision (less than 1/10). Cranial-CT was normal. Lumbar puncture showed a pressure above 50 cmH20. CSF examination was normal. Brain angio-MRI disclosed extensive cerebral venous thrombosis (CVT). Laboratory examinations showed increased homocysteine and reduced vitamin B12 and folic acid. Otologic examinations were made at admission and after five therapeutic lumbar punctures plus furosemide, acetazolamide (and low molecular weight heparin, B12 vitamin and folic acid for CVT). Examinations included otoscopy, audiogram and tympanogram. Results: The first examination showed sensorineural deafness with a moderate (41-55 dB) to moderately severe (56-70 dB) hearing loss, mainly for the high and low frequencies and normal tympanogram and otoscopy. Intracranial pressure was 43 cmH2O. Three weeks later, opening lumbar pressure had become 26 cmH2O and the second otologic examination showed a 20 dB improvement in hearing at left and of 10 dB at right ear. However on the long term IIP recurred despite intensive medical treatment, so a lumboperitoneal shunt was placed three months after the first observation. One month afterwards audiogram was normal (left ear) or nearly normal (right ear) with major improvement (40-45 dB respectively). Conclusion: In this case, lowering of IIP was followed by normalization of hearing. In CVT there is rare mention of hypoacusis. Also, if CVT and ischemic damage were the direct cause of hypoacusis it should not be reversible and concomitant with lowering of IIP. Furthermore hypoacusis was sensorineural, long-lasting and moderately severe, but still improved remarkably, contrarily to expected.

confusional state, aggressive outbursts, unsteadiness of gait and a probable seizure on the day of admission.He admitted to have inhaled heroine vapour 1 day prior to the onset of symptoms. There was a history of multiple recreational drug abuse between 1988 and 2003 after which he was “reportedly clean”.There was also a past medical history of Hepatitis-C virus infection successfully treated with IFN alpha and Ribavirin (1997). Physical examination showed a bite wound on the left lateral margin of the tongue, abrasions on the skin and a laceration on the right knee. Neurological examination revealed bradyphrenia, impaired short term memory, hyperreflexia and severe ataxia of gait. Haematological and biochemical investigations showed a raised creatinine kinase(post ictal) and positive HCV antibodies in serum. Toxicology screen of serum and urine was positive for morphine and cocaine. HIV,JCV,Syphilis and Borreliosis serology were negative. CSF examination was unremarkable. MRI (T2 WI and FLAIR) showed bilateral symmetric confluent hyperintensities in the white matter tracts without any mass effect or contrast enhancement. The lesions were hyperintense in DWI; ADC maps were not available.A diagnosis of “heroin induced toxic leukoencephalopathy” was made.Without any specific therapy, the patient improved gradually and was discharged 10 days later. Conclusion: Toxic leukoencephalopathy needs to be considered in the differential diagnosis of any patient presenting with acute or chronic neurobehavioral deficits and has a known or potential exposure to white matter toxic substances. The clinical spectrum is wide and usually parallels the severity of white matter damage.Since mortality rate could be as high as 23% and treatment options are limited, prevention of illicit exposure to toxic substances is critical.

P773 Oligoclonal immunoglobulin M in cerebrospinal fluid: a comparative study of highly sensitive isoelectric focusing and IgM Index R. Schneider, S. Rauer University Hospital Freiburg (Freiburg, DE)

P775 Evoked potential studies in parenchymal neuro-Behçet’s disease predicting outcome G. Akman-Demir, A. E. Oge, M. Kurtuncu, N. Yesilot, M. Mutlu, A. Boyaciyan, P. Serdaroglu, J. Yazici Istanbul University, (Istanbul, TR)

Objective: To compare oligoclonal immunoglobulin M bands (IgM-OCB) determined by a new established highly sensitive isoelectric focusing technique (IEF) and quantitative estimation by means of the IgM-Index. Methods: Cerebrospinal fluid (CSF) and serum samples of 80 patients with various nervous system diseases were analysed: a)11 cases of neuroborreliosis (NB), 10 out of 11 had elevated CSF total IgM on routine diagnostics (> 0.36 mg/l according to Blennow et al. Eur. Neurol 1996) b) 27 cases without inflammatory parameters on routine CSF diagnostics (cell count, total protein), refered to as non-inflammatory diseases (NID) c) 42 cases of clinically isolated syndrome (CIS) which is suggestive for a demyelinating disease. After IEF, blotting and fixation, the IgM-OCB were visualized with a new chemiluminescence reagent (ECL Advance) The limit of detection for IgMOCB was 0.002 mg/l IgM. The results were compared to IgM-Index values which was refered to as “elevated” when > 0.07 (according to Sharief et al. 1990 J. Neurol. Sci). Results: NB: 10 (90%) showed elevated IgM-Indices, 8 (73%) showed IgM-OCB. NID: 1 (4%) showed an elevated IgM-Index, none showed IgM-OCB. CIS: 18 (42%) showed elevated IgM-Indices, 31 (74%) showed IgM-OCB. Conclusion: We frequently found IgM-OCB in cases of suspected CNS inflammation (NB and CIS). In a high number of CIS without elevated IgM-Indices we detected IgM-OCB (13/24 [54%]). These findings indicate that IgMOCB seem to be more sensitive than IgM-Index elevation in the group of CIS patients. In 3 cases (1 NID and 2 NB) IgM-Indices were elevated without presence of IgM-OCB. However, in the CSF of these patients a blood-brainbarrier (BBB) dysfunction was detectable, which possibly influence the IgMindex. These data may confirm earlier results which suggest that the estimation of IgM-OCB is more reliable to determine an intrathecal IgM-synthesis than the determination of the IgM-Index. P774 Toxic leukoencephalopathy after heroin inhalation (“chasing the dragon”) M. Desikan, R. Werner, E. Schmitt, U. Marczinsky, J.C. Wöhrle Katholisches Klinikum St.Josef Brüderhaus (Koblenz, DE) Objective: Ever since its initial description in 1982,there are about 100 case reports of heroin induced toxic leukoencephalopathy in the literature. 3 clinical stages of encephalopathy have been recognised related to the severity of white matter damage. The aetiopathogenesis is still debated; the pathology is characterised by spongiform degeneration and intramyelinic vacuolation.This case has been presented to highlight that a high index of clinical suspicion is needed to make a correct diagnosis and avoid unnecessary investigations in an essentially untreatable condition. Case report: A 32 year old male was referred with a 2 day history of acute

Objective: Parenchymal neurological involvement is one of the most serious consequences of Behcet’s disease (BD). In this study we evaluated the possible predictive role of evoked potential studies (EPS) concerning the long term outcome of the patients. Methods: Files of all the neuro-Behcet’s disease (NBD) outpatient clinic were evaluated retrospectively in search of patients who had had EPS, and at least 5 years of follow up afterwards. Brainstem auditory EPS, somatosensory EPS, and motor EPS (MEPS) had been performed. Clinical outcome was determined according to a scale where the patients were independent, physically and/or mentally dependent, or deceased due to NBD. Results: There were 38 (26 M, 12F) patients who had been evaluated at least 5 years ago, with adequate follow-up. Mean follow up duration was 8.8 + 2.7 years (range: 5-14 years). Mean age of the patients at the time of the EPS was 38.9 + 8.7 years (range: 25-58 years). Six of the patients had primary headache disorders not associated with BD, 3 had dural sinus thrombosis, and 29 had parenchymal neurological involvement. In the latter group, 13 had “brainstem +” type involvement, 5 had predominantly spinal cord involvement, 4 had hemiparesis and 7 had silent neurological involvement featuring asymptomatic pyramidal findings. In patients with headache and sinus thrombosis, the EPS were unremarkable. In NBD patients among the 23 brainstem auditory EPS, 3 were abnormal indicating brainstem involvement, and among the 23 somatosensory EPS, 7 were abnormal, whereas 11 of the 21 MEPS were abnormal. One notable pattern of abnormality in MEPS was delayed upper extremity response and absent lower extremity response on the hemiparetic side, and delayed lower extremity response on the "normal" leg. This pattern had been seen in 8 of the patients with NBD and 7 were either dead or dependent at the end of follow up. On the other hand, this pattern had not been observed in 13 of the patients and only 3 were dead or dependent in the long run (p<0.01). Conclusion: Evoked potential studies have been well described in patients with parenchymal neuro-Behçet’s disease. However, any predictive role for long term prognosis has not been mentioned before. Our study suggests that motor evoked potential findings compatible with more extensive involvement in earlier stages could predict a poorer long-term outcome.

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Sleep disorders P776 Two patients with restless leg syndrome caused by a large deep subcortical infarct J.H. Lee, J.H. Shin, W.K. Kim, H.K. Song Kangdong Sacredheart Hospital (Seoul, KR) Objectives & Methods: Although various conditions, such as iron deficits anemia, uremia, and peripheral neuropathy, are known to cause restless leg syndrome (RLS), a supratentorial infarction has rarely been reported to be responsible for RLS. We report two cases with RLS, newly developed after deep subcortical infarct. Results: The first patient was a 61-year-old woman presented with sudden-onset unpleasant and bizarre sensations in her whole body, which were more severe in her legs. She felt desire to move the legs, and the movement alleviated the uncomfortable sensations. The symptoms worsen during rest and night, which severely disturbed her sleep. Her physical and neurologic examinations were unremarkable, except mild dysarthria. Suggested immobilization test revealed that the unpleasant sensations were at their maximum after 25 minutes of rest. Periodic limb movement (PLM) during sleep was not found in overnight polysomnography. Magnetic resonance imaging (MRI) showed an acute infarct in right deep subcortical area involving basal ganglia. After taking ropinirole and clonazepam, her sensory symptoms much improved. The next patient was a 81-year-old woman presented with sudden-onset right hemiparesis and numbness in her right sole. MRI showed an acute infart in left deep subcortical area involving corona radiata. Her numbness was compatible with the diagnostic criteria for RLS proposed by Internation RLS Study Group. PLM index was 8.0 in overnight polysomnography. Her numbness improved dramatically after taking ropinirol and clonazepam. Conclusion: The deep subcortical infarction may be a rare cause of secondary RLS. The RLS developed after basal ganglia infarction may be an additional evidence for the role of the dopaminergic system in pathogenesis of RLS. P777 Tissue classification and magnetic resonance spectroscopy in hypothalamus of narcolepsy patients R. Poryazova, B. Schnepf, G. Crelier, E. Werth, P. Boesiger, C.L. Bassetti UniversitätsSpital (Zurich, CH); University and ETH (Zurich, CH) Objective: Different brain matters contain metabolites in different concentrations. In order to account for these variations, the content of grey (GM), white matter (WM) and cerebrospinal fluid (CSF) of a single voxel of interest and the anatomy of the whole brain have to be assessed. Morphometric studies in narcolepsy show conflicting results. One magnetic resonance spectroscopy (MRS) study demonstrated reduction in N-acetylaspartate (NAA)/creatine-phosphocreatine (Cr) in the hypothalamus of narcolepsy patients with cataplexy. Methods: In 14 narcolepsy patients with clear-cut cataplexy, CSF hypocretin deficiency (10/10) and HLA-DQB1*0602 positivity (13/13, 1/1 DR2 positive) and 8 age, gender and body mass index matched controls MRS and a 120 slice T1/3D/TFE measurement with a slice thickness of 1.25 mm (no gap) were performed. Patients were treatment naive or off therapy for at least 14 days before scanning. The data were collected using a 3T Philips Achieva whole body MR scanner. Single-voxel proton MR spectra were acquired from hypothalamus and processed with LCModel to determine metabolite concentration ratios. A fully automatic algorithm was used for the image segmentation analysis. The tissue types in the whole brain and in the region of interest of the single voxel MRS were determined. Results: No metabolic differences were observed in hypothalamus of patients and controls, especially no differences in the (total NAA)/Cr (patients 1.2±0.2, controls 1.1±0.3, mean±SD). The distribution of GM, WM and CSF showed no differences between the patient and the control group in the whole brain as well as in the hypothalamic voxel of interest. Conclusion: Despite the inclusion of homogenous hypocretin deficient group of patients and the use of combined approach no metabolic or GM changes were found in the hypothalamus of narcolepsy patients. EFNS grant.

P778 Motor cortex excitability in narcolepsy M.A. Durka-Kesy, K. Tomczykiewicz, J. Staszewski, A. Stepien Military Institute of Medicine (Warsaw, PL) Background: Narcolepsy is a chronic central nervous system disorder which is characterized by periods of irresistible sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) (also called orexin-A and orexin-B) are newly discovered neuropeptides which are deficient in narcolepsy. Hypocretin containing cells are located exclusively in the lateral and posterior hypothalamus with widespread projections of the nerve fibers into the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brainstem. The influence of hypocretin neurons on the mentioned structures is responsible for emotional arousal and locomotor activity. Transcranial magnetic stimulation (TMS) allows non-invasive study and modulation of cortical excitability in humans. Objective: This report describes results of TMS conducted among three narcoleptic patients. Methods: The excitability of the motor cortex was assessed with TMS in three narcoleptic patients and ten age-matched healthy volunteers. The analysed parameters were motor evoked potential threshold, cortical silent period (CSP) and central motor conduction time (CMCT). Patients were assessed in Epworth scale of daytime sleepiness. All patients underwent MRI of the brain, overnight polysomnography and Multiple Sleep Latency Tests (MSLT). Results:Values of central motor conduction times and thresholds for motor evoked potentials did not differ between groups of patients and control. Among narcoleptic patients the tendency to shortened cortical silent periods (CSP) were observed (median 43.2 ms) compared with control (median 61.5 ms). Conclusions: Narcolepsy is a disease which is seldom diagnosed. Only few studies concerned TMS of patients with this disorder. The CSP changes suggest a decreased cortical inhibition in narcolepsy however further investigations are necessary. P779 Sympathetic and cardiovascular activity during cataplexy in narcolepsy V. Donadio, G. Plazzi, C. Franceschini, S. Vandi, T. Karlsson, P. Montagna, R. Vetrugno, E. Mignot, R. Liguori University of Bologna (Bologna, IT); University of Goteborg (Goteborg, SE); Stanford University (California, US) Objectives: Autonomic changes could have a role in the triggering mechanism inducing cataplexy. Our aim was to investigate the time course of sympathetic and cardiovascular activity during cataplexy to establish their role in inducing cataplexy reflexively. Methods: We studied under microneurographic recording seven cataplectic episodes from two patients with hypocretin-deficient narcolepsy. During microneurography muscle sympathetic activity (MSNA) from the peroneal nerve was recorded simultaneously to ECG, respiratory movements, arterial finger blood pressure, right and left electro-oculogram and superficial electromyogram of mylohyoideus muscle. Results: Our findings showed no significant autonomic changes before the onset of cataplexy. Cataplectic attacks were characterized by muscle atonia (p < 0.001) and alpha activity similar to wakefulness. During the episodes MSNA incidence and amplitude increased (p < 0.01) together with SBP increase (p < 0.01) and HR decrease (p < 0.001) whereas DBP did not change significantly compared to baseline. These changes were most evident at the beginning of cataplectic attacks and returned to baseline during postcataplexy. Conclusions: Our findings did not display significant changes of autonomic nerve activity prior to cataplexy onset, ruling out a role of this system in the triggering of cataplexy. Interestingly, however, we found that cataplexy was associated with a coactivation of sympathetic and parasympathetic nervous systems. P780 Advanced oxidation protein products in patients with sleep apnoea K. Sˇonka, L. Fialova, J. Volna, P. Jiroutek, M. Pretl, J. Vavrova, M. Kalousová Charles University (Prague, CZ) Objectives: Sleep apnea is characterized by episodes of obstruction in the upper airways during sleep leading to apneas or hypopneas and arousals. The main symptoms include snoring, excessive daytime sleepiness and a psychomotor rate decline. Sleep apnea is a risk factor for arteriosclerosis, stroke and hypertension. Advanced oxidation protein products (AOPP) are considered as reliable markers to estimate the degree of oxidant-mediated

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protein damage. Increased levels of AOPP were found in coronary artery disease and in stroke. We were interested in AOPP level in sleep apnea. Method: 17 men with normal neurological status suffering from sleep apnea underwent limited polygraphy (standard monitoring of respiratory sounds, nasal airflow, thoracic and abdominal respiratory movements, heart rate, oxyhaemoglobin saturation, and body position). The mean apnea/hypopnea index was 18.4 (SD 15.5). Cubital vein blood samples were collected in the early morning between 6:00 and 7:00 and were determined by a spectrophotometric method based on a reaction with potassium iodide and acetic acid. The results were compared with those of normal age matched healthy men (T test). The study was approved by the local ethics committee and all the patients had given their informed consent to take part in it. Results: The mean AOPP level in patients group was 93.5 (SD 43.9) umol/l and in controls 67.9 (SD 14.2) umol/l. This difference is statistically significant (p = 0.03). Conclusion: AOPP levels are elevated in patients suffering from sleep apnea. This fact supports the hypothesis that sleep apnea represents an oxidative risk condition. Czech Ministry of Education grant VZ 0021620816. P781 Restless legs syndrome and excessive daytime sleepiness U. Kallweit, M. Siccoli, E. Werth, C. L. Bassetti University Hospital Zurich (Zurich, CH) Objective: To study the frequency and characteristics of excessive daytime sleepiness in restless legs syndrom (RLS). Methods: We studied 30 consecutive idiopathic, non-treated RLS patients, (16 women, 14 men; mean age = 61 ± 11 years) without associated sleep-disorders. Patient assessment included the International Restless Legs Syndrome Study Group Rating Scale (IRLS), Epworth Sleepiness Scale (ESS) and conventional polysomnography (PSG). The PLM-Index was determined by PSG. Patients with ESS > 11 (n = 9) were also assessed by Multiple-SleepLatency-Test (MSLT). Eight sleepy patients received dopaminergic treatment and were again assessed clinically and by sleep-questionnaires after two months. Results: We found an ESS > 11 (mean 14.9 ± 3.6) in nine (30 %) and an ESS > 14 (mean 18.3 ± 2.3) in four (13 %) of the 30 patients. No statistical differences in IRLS-score, PLM- Index, age, gender or body mass index (BMI) were found between sleepy and non-sleepy RLS patients. The mean sleep latency found was 6.9 ± 3.3 min, four (44 %) of the nine patients had a mean sleep latency < 5 min. In 2 of these patients one sleep-onset REM period occurred. At follow-up the ESS was lower (mean 10.4 ± 4.5 vs. 16.2 ± 3.8) in five patients and same or higher in three (mean 14.3 ± 2.1 vs. 12.3 ± 0.5). Conclusion: Excessive daytime sleepiness in RLS is 1) relatively common,2) detectable by MSLT and 3) occasionally in the narcoleptic range (ESS and MSLT). P782 Levetiracetam is equally effective as L-dopa in treating the complaints of restless legs syndrome J. Rémi, A. Simakov, S. Noachtar University of Munich (Munich, DE) Objective: We wished to compare the effect of levetiracetam (LEV) in RLS patients with the standard treatment with L-dopa. Methods: We studied 9 patients with an established diagnosis of RLS in a cross-over, double-blind, randomized clinical trial. Patients received 500mg of LEV and 200mg L-dopa for 2 weeks each after 1 week wash-out phases for previous treatment. At the end of each 2 week drug period a polysomnography was performed and questionnaires for subjective complaints were filled out. Out of the 9 patients, 2 patients dropped out of the study because of increased RLS symptoms after discontinuation of their regular medication. Results: Total sleep time, proportions of different sleep stages, arousals and sleep efficiency did not differ between LEV and L-dopa. Only the amount of periodic leg movements (PLM) was statistically different between LEV and L-Dopa (p=0.28), with no significant change towards baseline after LEV treatment and a 52% reduction in leg movements after L-Dopa treatment. The subjective improvement as rated by the RLS Severity Score did not differ either (baseline: 23.7 points, LEV 24.4, L-Dopa 24.1). Conclusion: As previously shown for other antiepileptic drugs, LEV seems excert an effect on complaints of RLS, which is independent from an influence on periodic leg movements. The UCb company sponsored this study.

P783 Influence of sleep breathing disorders compensation on precapillary pulmonary hypertension – a pilot study M. Pretl, D. Ambrozˇ, P. Jansa, T. Palecek, K. Sˇonka Charles University (Prague, CZ) Objectives: Occurrence of sleep breathing disorders (SBD) in precapillary pulmonary hypertension (PH) is estimated at 20 %. Compensation of SBD (using positive airway pressure – PAP) is successful according to literary data and leads to improvement of precapillary PH. The role of improved blood oxygen saturation through PAP therapy is suspected. Reversible changes of the pulmonary vessels diminish during successful therapy. Methods: Six patients with the diagnosis of SBD (after polysomnographic examination) and severe precapillary PH (echocardiographic evaluation) were treated to compensate SBD and influence precapillary PH. Control echocardiographic and sleep ventilation examination were made 3 and then minimally 6 months after the beginning of SBD therapy. Effect of treatment on precapillary PH was reviewed after echocardiografphic parameters – size of right ventricle, right atrium and pulmonary artery systolic pressure (PASP). Results: SBD was compensated by using PAP therapy at 5 patients (AHI < 5). Maxillomandibular advancement (MMA) was recommended in one patient due to non-toleration of PAP therapy; SBD diminished after MMA. Improvement of all measured echocardiographic (right ventricle size before – after therapy 80.3–38 mm; right atrium size 55.3–42.7; PASP 62.7–47.3 mm Hg) and clinic parameters of precapillary PH was mentioned at 3 cases (in 2 PAP treated patients and in 1 patient after MMA). Continual deterioration of precapillary PH was mentioned after transient improvement of echocardiographic parameters at the remaining 3 patients, on the contrary, despite initiation of the specific vasodilatation therapy. Conclusion: Received results show improvement of SBD and parameters of precapillary PH at 3 patients. We suggest diagnosis of precapillary PH derived from SBD in this group. Idiopathic PH independent to SBD is probable in the group of non-respondent to SBD therapy patients. Supported by VZ 0021620816. P784 Testing of alertness by Performance Vigilance Task (PVT-192) at shiftworking nurses J. Volná, D. Kemlink, K. Sˇonka General Teaching Hospital (Prague, CZ) Objectives: We concentrated on testing alertness parameters at shift-working nurses. Method: For measurement we used Performance Vigilance Task (PVT192). PVT is used for testing of sleep deprivation effect. The principle of the PVT is to react to irregularly appearing light impulses on the PVT display. The test takes 10 minutes and the PVT software is able to analyse reaction times and number of errors. We examined 20 nurses working at 12-hours shift schedule at our department of neurology. Exclusion criteria were any medication with influence on sleep, sleep disorder history and internal polymorbidity. Every nurse was examined at the beginning and at the end of the shift (daytime or nighttime respectively), hence 4 tests were performed. Results: Median reaction time (RT) before and after the day-shift was 261.3ms (SD±38.7) and 260.1ms (SD±33.1) respectively. Before the nightshift RT was 251.3ms (SD±23.5) after this shift 260.5ms (SD±26.1). Significant differences in RTs were found between the start and the end of the night-shift and between RT’s in both evening measurements. Significantly higher difference in RTs before and after the shift was established for nightshift. The number of total errors (TE) before and after the day-shift was 10(SD±2.3) and 25(SD±5.4) respectively. TE before and after night-shift was 13(SD±2.8) and 5(SD±1.4) respectively. Statistically significant correlations for all the measurements were found, especially for TE after the day-shift compared to the end of night-shift. Subjective evaluation of daytime sleepiness according to VAS was 3.3 (SD ± 2.2) before the day-shift and 3.5(SD±2.8) at the end of the day-shift. At start of the night-shift VAS was 3.1(SD±2.4) at the end of the night-shift 5.9(SD±2.3). As reliable was found correlation VAS before and after the night-shift and correlation of VAS difference between the beginning and the end of the shift which was higher for night-shift. Conclusion: Further we determined negative correlation of age and number of children with time of sleep after night-shift. There was no difference in tests between smoking and non-smoking nurses. All described correlations reflect the influence of circadian rhytmicity. Supported by the grant MSˇMT ER Kontakt 701.

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P785 Effect of sleep deprivation on attention and working memory in medical residents and interns J. H. Lee, H. S. Song, H. J. Kim, Y. Hong, K. G. Choi, E. J. Chung, E. J. Kim, H. W. Lee Ewha Womans University College of Medicine (Seoul, KR) Objectives: Most medical residents and interns experience chronic sleep deprivation, which might affect their work performances. The purpose of this study was to investigate effects of chronic sleep deprivation on attention, motor functioning, and verbal learning in medical residents and interns Methods: The fifty residents and interns in training at Ewha Womans University College of Medicine were recruited so far. They completed questionnaires including their sleep and work hours, health complaints, scales on daytime sleepiness, work performance, and so on. The Stroop test, Continuous Performance Test (CPT), Trail Making Test (TMT) and Korean-California Verbal Learning Test (K-CVLT) were also performed. Subjects were divided into three groups according to their average night sleep hours for more

than 2 weeks; less than 4 hours as severe sleep deprivation (S-SD), between 2 and 4 hours as moderate (M-SD), and more than 6 hours as non-sleep deprivation (non-SD) groups. Results: seventy (35/50)% of subjects were sleep deprived (11/50 S-SD and 24/50 M-SD), and mean sleep duration per night was 5.0±1.2 hours. Missed work, and missed familial or social activities were more frequent in S-SD and M-SD than non-SD group (p = 0.002 and 0.035, respectively). The S-SD group showed increased daytime sleepiness (higher Stanford and Epworth sleepiness scales, p = 0.042 and 0.057, respectively), and higher stress index (p = 0.001) than the non-SD group. SD groups more frequently complained difficulties in learning (p < 0.0001) and concentration (p = 0.003). Subjects in SD groups showed delayed reaction time on visual CPT test (p = 0.044), and more common commission errors on auditory CPT (p = 0.029), but no differences in K-CVLT. Conclusion: Many medical residents and interns suffer from chronic sleep deprivation and over-work. Sleep deprivation affects attention and motor performance rather than verbal learning.

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Author index Aarons, L. . . . . . . . . . . . . . . . . . P511 Abbadessa, A. . . . . . . . . . . . . . . . P312 Abbas, M. A. . . . . . . . . . . . . P565, P680 Abdel Moneim, A. . . . . . . . . . . . . . P460 Abdelalim, A. . . . . . . . . . . . . . . . P400 Abdelidou, K. . . . . . . . . . . . . . . . P681 Abdelrahman, N. . . . . . . . . . . O65, O181 Abderrahim, H. . . . . . . . . . . . . . . P277 Abdullahi, I. . . . . . . . . . . . . . . . . P447 Abenza Abildúa, M. . . . . . . . . O150, P452 Abolfazli, R. . . . . . . . . . . . . . P405, P685 Abramsky, O. . . . . . . . . . . . . . . . P233 Abrishamkar, S. . . . . . . . . . . . . . . P521 Absinta, M. . . . . . . . . . . . . . O99, O100 Abu-Mugheisib, M. . . . . . . . . . P402, P749 Aburakawa, Y. . . . . . . . . . . . . P450, P485 Achtnichts, L. . . . . . . . . . . . . . . . P467 Açil, T. . . . . . . . . . . . . . . . . . . . P717 Adam, H. . . . . . . . . . . . . . . . . . . P509 Adam, J. . . . . . . . . . . . . . . . . . . P315 Adamopoulou, A. . . . . . . . . . . . . . P656 Adams, D. . . . . . . . . O79, P444, P445, P517 Adams, R. J. . . . . . . . . . . . . . . . . O130 Addobbati, L. . . . . . . . . . . . . . . . P729 Adelt, I. . . . . . . . . . . . . . . . . . . . P606 Afanasiev, B. . . . . . . . . . . . . . . . . P750 Afrantou, T. . . . P324, P391, P415, P499, P551, P656, P665, P669, P767 Agapii, E. . . . . . . . . . . . . . . . . . . P265 Agbo, J. . . . . . . . . . . . . P334, P446, P682 Aggelakis, K. . . . . . . . . . P281, P282, P537 Aggelou, A. . . . . . . . . . . . . . . . . . P415 Agnetti, V. . . . . . . . . . . . . . . . . . P255 Agosta, F. . . . . . . . . . . O100, O101, O185 Agosti, R. . . . . . . . . . . . . . . . . . O194 Aguilar-Amat Prior, M. . . . O60, O150, O200 Ahlert, T. . . . . . . . . . . . . . . . . . . P725 Ahmed, L. . . . . . . . . . . . . . . P334, P641 Ahting, U. . . . . . . . . . . . . . . . . . P278 Aidaros, M. . . . . . . . . . . . . . . . . P337 Aisen, P. . . . . . . . . . . . . . . . . . . . O56 Aissi, M. . . . . . . . . . . . . . . . . . . P745 Aizawa, H. . . . . . . . . . . . . . . P450, P485 Akman-Demir, G. . . O147, O158, P240, P394, P775 Aksay, B. . . . . . . . . . . . . . . . . . . P563 Al Hail, H. . . . . . . . . . . . . . . . . . P399 AL-Sabbagh, A. . . . . P291, P411, P539, P541, P542, P545, P659 Al-Shahi Salman, R. . . . . . . . . . O62, O97 Albani, G. . . . . . . . . . . . . . . . . . P257 Alberoni, M. . . . . . . . . . . . . . . . . P598 Albert, F. W. . . . . . . . . . . . . . . . . P344 Albert, S. . . . . . . . . . . . . . . . . . . P744 Albuquerque, L. . . . . . . . . . . . P442, P772 Aleksic Shibabi, A. . . . . . . . . . . . . P474 Alexanian, I. . . . . . . . . . . . . . . . . P681 Alexiou, E. . . . . . . . . . . . . . . P285, P743 Alexiou, Z. . . . . . . . . . . . . . . . . . P681 Alfonsi, E. . . . . . . . . . . . . . . . . . . O48 Algarra, L. . . . . . . . . . . . . . . . . . P320 Algra, A. . . . . . . . . . . . . . . . O95, P341 Allievi, S. . . . . . . . . . . . . . . . . . . O122 Almadani, A. . . . . . . . . . . . . . . . . P546 Alom, J. . . . . . . . . . . . . . . . . . . . P580 Alonso, M. E. . . . . . . . . . . . . . . . P309 Alonso de Leciñana, M. . . . . . . O214, P674 Alonso-Magdalena, L. . . . . . . . . . . O178 Alpay, K. . . . . . . . . . . . . . . . . . . P387 Alterman, R. . . . . . . . . . . . . . . . . O105 Alvarez, D. . . . . . . . . . . . . . . . . . P585 Alvarez, S. . . . . . . . . . . . . . . . . . O115 Amadio, S. . . . . . . . . . . . . . O161, P308 Amann, M. . . . . . . . . . . . . . . . . . P467

Amato, N. . . . . . . . . . . . . . . O109, P356 Ambach, H. . . . . . . . . . . . . . . . . P491 Ambrosi, B. . . . . . . . . . . . . . . . . P354 Ambrozˇ, D. . . . . . . . . . . . . . . . . . P783 Amouyel, P. . . . . . . . . . . . . . . . . P426 Anagnostopoulos, A. . . . . . . . . . . . P441 Anagnostou, E. . . . . . . . . . . . P254, P534 Anastasopoulos, D. . . . . . . . . . . . . P254 Anastasopoulos, I. . . . . . . . . . . . . . P715 Anderson, J. . . . . . . . . . . . . . . . . P428 Anderson, P. . . . . . . . . . . . . . . . . P727 André, C. . . . . . . . . . . . . . . . O81, O113 Andreadou, E. . . . . . . . . . . . . P533, P534 Andreeva, L. . . . . . . . . . . . . . . . . P711 Andreoni, S. . . . . . . . . . . . . . . . . P280 Andrich, J. . . . . . . . . . . . . . . . . . P489 Andriopoulou, G. . . . . . . . . . . . . . P762 Andrys, C. . . . . . . . . . . . . . . . . . P403 Andryszak, P. . . . . . . . . . . . . . . . P494 Angele, B. . . . . . . . . . . . . . . O126, P645 Angelini, C. . . . . . . . . . . . . . P276, P610 Angelou, A. . . . . . . P324, P391, P499, P551, P656, P665, P669, P767 Annunziata, P. . . . . . . . . . . . . P288, P751 Antel, J. . . . . . . . . . . . . . . . . . . . P295 Antochi, F. A. . . . . . . . . . . . . P643, P741 Antoine, J. C. . . . . . . . . . . . . . O80, O110 Antonelli, G. . . . . . . . . . . . . . . . . P291 Antoniadou, E. . . . . . . . . . . . P266, P267 Antonini, G. . . . . . . . . . . . . . . . . . O76 Anzellotti, F. . . . . . . . . . . . . . . . . P363 Apartis, E. . . . . . . . . . . . . . . O71, P366 Apel, A. . . . . . . . . . P402, P651, P749, P753 Apostolski, S. . . . . . . . . . . . . . . . P235 Appel, S. H. . . . . . . . . . . . . . . . . O208 Aquino, D. . . . . . . . . . . . . . . . . . O192 Araar, M. . . . . . . . . . . . . . . . . . . P396 Arami, A. . . . . . . . . . . . . . . . . . . P514 Arantes, M. . . . . . . . . . . . . . P434, P553 Araújo, C. . . . . . . . . . . . . . . . . . P652 Arbizu, T. . . . . . . . . . . . . . . O178, P646 Arbusow, V. . . . . . . . . . . . . . . . . O125 Ardolino, G. . . . . . . . . . . . . . . . . P557 Areovimata, A. . . . . . . . . . . . . . . . P533 Argiropoulou, O. . . . . . . . . . . . . . P564 Argyriou, A. . . O195, P331, P439, P625, P707 Ari, S. . . . . . . . . . . . . . . . . . . . . P347 Arias, E. . . . . . . . . . . . . . . . . . . P410 Ariatti, A. . . . . . . . . . . . . . . . O50, P619 Armbruster, L. . . . . . . . . . . . . . . O182 Armentero, M. . . . . . . . . . . . . . . . P596 Arnaoutoglou, A. . . . . . . . . . . P632, P762 Arnaoutoglou, M. . . . . . . . . . . P632, P762 Arnold, D. . . . . . . . . . . . . . . . . . P295 Arpa Gutiérrez, F. J. . . . . . O150, O200, P597 Artemis, N. . . . . . . . . . . P391, P499, P767 Arzy, S. . . . . . . . . . . . . . . . . . . . P584 Asawavichienjinda, T. . . . . . . . . . . . P709 Ashour, S. . . . . . . . . . . . . . . . . . P460 Assimakopoulos, C. . . . . . . . . . P250, P370 Assimakopoulos, K. . . . . . . . . P331, P439 Atanasiu, A. . . . . . . . . . . . . . . . . P699 Ausili Cefaro, L. . . . . . . . . . . . . . . P294 Autret, A. . . . . . . . . . . . . . . . . . O190 Avantaggiato, P. . . . . . . . . . . . P633, P663 Avdelidou, E. . . . . . . . . . . . . . . . . P632 Avolio, C. . . . . . . . . . . . . . . . . . . P414 Avramidis, T. . . . . . . . . . . . . . . . . P715 Avramidou, A. . . . . . . . . . . . . . . . P459 Awadalla, H. . . . . . . . . . . . . . . . . P460 Aydin, I. . . . . . . . . . . . . . . . . . . P347 Aydin, T. . . . . . . . . . . . . . . . . . . P347 Aydin Canturk, I. . . . . . . . . . . . . . P630 Aykut-Bingöl, C. . . . . . . . . . . . . . . P504

Ayranci, O. . Ayromlou, H. Ayuso, I. . . Azevedo, J. C. Azuar, C. . .

. . . . . . . . . . . . . . . . P240 . . . . . . . . . . . . P514, P519 . . . . . . . . . . . . . . . . P674 . . . . . . . . . . . . O114, P718 . . . . . . . . . . . . . . . . P382

Baba, M. . . . . . . . . . . . . . . . P525, P756 Baba, Y. . . . . . . . . . . . . . . . . . . . P640 Baba Musa, B. . . . . . . . . . . . . . . . P641 Bachleda, P. . . . . . . . . . . . . . . . . O131 Bachmann, G. . . . . . . . . . . . . . . . P352 Bacigaluppi, M. . . . . . . . . . . . P225, P568 Badurova, R. . . . . . . . . . . . . . . . . P457 Bae, H. R. . . . . . . . . . . . . . . . . . P429 Baek, W. K. . . . . . . . . . . . . . . . . . P730 Bagkeri, M. . . . . . . . . . . . . . . . . . P459 Baglio, F. . . . . . . . . . . . . . . . . . . P598 Bagnato, F. . . . . . . . . . . . . . . . . . O66 Baier, B. . . . . . . . . . . . . . . . . . . O165 Baillet, S. . . . . . . . . . . . . . . . . . . O213 Bairaktaris, C. . . . . . . . . . . . . . . . P464 Bajenaru, O. A. . . . . P589, P599, P643, P741 Bajko, Z. . . . . . . . . . . . . . . . P456, P560 Bakac, G. . . . . . . . . . . . . . . . . . . P221 Baker, A. . . . . . . . . . . . . . . . . . . O120 Bal, A. . . . . . . . . . . . . . . . . . . . P704 Baladandapani, P. . . . . . . . . . . . . . P547 Balami, D. . . . . . . . . . . . P334, P446, P641 Balasa, R. . . . . . . . . . . . . . . . . . . P413 Baldoli, C. . . . . . . . . . . . . . . . . . O161 Balkowiec-Iskra, E. . . . . . . . . . . . . P421 Balla, C. . . . . . . . . . . . . . . . P576, P703 Ballabio, E. . . . . . . . . . . . . . . . . . P279 Ballesteros Plaza, L. . . . . . . . . . . . . P246 Baloyannis, S. J. . . . . . . . . . . . P632, P762 Balteau, E. . . . . . . . . . . O156, O167, O198 Bamonti, F. . . . . . . . . . . . . . . . . . P529 Bandeira, A. . . . . . . . . . . . . . . . . P232 Banecka-Majkutewicz, Z. . . . . . . . . . P771 Banecki, B. . . . . . . . . . . . . . . . . . P771 Bang, O. Y. . . . . . . . . . . . . . . . . . P342 Bannister, P. . . . . . . . . . . . . . . . . P317 Bär, I. . . . . . . . . . . . . . . . . . . . . P397 Bar-Or, A. . . . . . . . . . . . . . . . . . P295 Baranczyk-Kuzma, A. . . . . . . . . . . . P732 Baratta, S. . . . . . . . . . . . . . . . . . . O85 Barbarash, O. . . . . . . . . . . . . . . . . O69 Barbero, P. . . . . . . . . . . . . . . P538, P759 Barbieri, A. . . . . . . . . . . . . . . . . . P356 Barbieri, F. . . . . . . . . . . . . . . . . . O50 Barbieri, S. . . . . . . . . . . . . . . . . . P440 Bardinet, E. . . . . . . . . . . . . . . . . O213 Bardoni, A. . . . . . . . . . . . . . P633, P663 Barkhof, F. . . . . . . . . . . O64, O219, P760A Barquero Jiménez, M. S. . . . . . . . . . P688 Barreira, A. A. . . . . . . . . . . . . . . . P618 Barros, J. . . . . . . . . . . . . . . . . . . P325 Bartels, E. . . . . . . . . . . . . . . . . . P469 Bartkova, A. . . . . . . . . . O131, O212, P348 Barton, A. . . . . . . . . . . . . . . . . . O144 Bartosik-Psujek, H. . . . . . . . . . . . . P293 Bartova, P. . . . . . . . . . . . . . . . . . P486 Bartsch, V. . . . . . . . . . . . . . . . . . P269 Barulli, M. R. . . . . . . . . . . . . . . . O211 Baruzzi, A. . . . . . . . . . . . . . . . . . O73 Barzaghi, C. . . . . . . . . . . . . . . . . . O82 Basic Kes, V. . . . . . . . . . . . . . . . . P748 Basiri, K. . . . . . . . . . . . . . . . P227, P521 Basoglu, M. . . . . . . . . . . . . . . . . O189 Bassetti, C. L. . . . . . O199, P568, P251, P252, P466, P568, P777, P781 Basta, I. . . . . . . . . . . . . . . . . . . . P235 Bastianello, S. . . . . . . . . . . . . . . . . O48 Bataller, L. . . . . . . . . . . . . . . . . . P320

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Batch, M. . . . . . . . . . . . . . . . . . . P340 Batocchi, A. P. . . . . . . . . . . . . P404, P728 Batti, H. . . . . . . . . . . . . . . . . . . P523 Bau, L. . . . . . . . . . . . . . . . . . . . P339 Baudo, S. . . . . . . . . . . . . . . . . . . O90 Bauer, C. . . . . . . . . . . . . . . . . . . P458 Bauer, G. . . . . . . . . . . . . . . . . . . O132 Bauer, L. . . . . . . . . . . . . . . O219, P760A Baum, K. . . . . . . . . . . . . . . . . . . P651 Baybas, S. . . . . . . . . . . . . . . . . . P221 Baykan, B. . . . . . . . . . . . . . . . . . P513 Bayrak, O. . . . . . . . . . . . . . . . . . P479 Bayreuther, C. . . . . . . . . . . . . . . . P271 Bealmear, B. . . . . . . . . . . . . . . . . P297 Beaugendre, Y. . . . . . . . . . . . . . . . O71 Bebek, N. . . . . . . . . . . . . . . . . . . P513 Becher, H. . . . . . . . . . . . . . . . . . P575 Becker, L. . . . . . . . . . . . . . . . . . . P278 Bednarik, J. . . . . . . . . . . . . . P457, P484 Bednarova, J. . . . . . . . . . . . . . . . . O44 Beekman, R. . . . . . . . . . . . . . . . . P642 Beelke, M. . . . . . . . . . . . . . . . . . P758 Beghi, E. . . . . . . . . . . . . . . . . . . . O76 Begni, B. . . . . . . . . . . . . . . . . . . P280 Beida, O. . . . . . . . . . . . . . . . . . . P682 Belicchi, M. . . . . . . . . . . . . . . . . . O52 Belis, K. . . . . . . . . . . . . . . . . . . P285 Bellomi, F. . . . . . . . . . . . . . . . . . P291 Ben Ali, N. . . . . . . . . . . . . . . . . . P383 Ben Hamouda, I. . . . . . . . . . . P383, P523 Ben-Assayag, E. . . . . . . . . . . . . . . P336 Bender, A. . . . . . . . . . . . . . . P231, P463 Benecke, R. . . . . . . . . . . . . . P402, P749 Benedict, R. . . . . . . . . . . . . . . . . . O67 Benesˇová, Y. . . . . . . . . . . . . . . . . P270 Benjamins, J. A. . . . . . . . . . . . . . . P297 Bennefeld, H. . . . . . . . . . . . . . . . P258 Bennett, R. . . . . . . . . . . P411, P539, P541, P542, P545, P659 Benninger, D. . . . . . . . . . . . . P251, P252 Bense, S. . . . . . . . . . . . . . . . O41, O165 Beránek, M. . . . . . . . . . . . . . . . . P270 Berger, W. . . . . . . . . . . . . . . . . . O164 Bergsland, N. . . . . . . . . . . . . . O68, P755 Bergui, M. . . . . . . . . . . . . . . P538, P759 Berliner, S. . . . . . . . . . . . . . . . . . P336 Berman, P. . . . . . . . . . . . . . . . . . O89 Bermejo, P. E. . . . . . . . . . . . . P705, P706 Bernard, C. . . . . . . . . . . . . . O163, P578 Bernardi, G. . . . . . . . . . . . . . . . . . O86 Bernasconi, L. . . . . . . . . . . . . . . . P757 Bernati, T. . . . . . . . . . . . O93, O139, P581 Berr, C. . . . . . . . . . . . . . . . . . . . P426 Bersano, A. . . . . . . . . . . . . . . . . . P279 Bertolino, M. . . . . . . . . . . . . . . . . P408 Bertolotto, A. . . . . . . . . . . . . . . . O100 Bertora, P. . . . . . . . . . . . . . . . . . . O54 Beslac-Bumbasirevic, L. . . . . . . . . . P497 Best, C. . . . . . . . . . . . . . . . . . . . O41 Betuing, S. . . . . . . . . . . . . . . . . . P419 Betul, C. . . . . . . . . . . . . . . . . . . P764 Bezzi, G. . . . . . . . . . . . . . . . . . . P332 Bhan, V. . . . . . . . . . . . . . . . . . . O218 Bhattacharya, J. . . . . . . . . . . . . . . . O62 Bialon, P. . . . . . . . . . . . . . . . . . . P684 Bianco, A. . . . . . . . . . . . . . . . . . P404 Biancucci, P. . . . . . . . . . . . . . . . . P541 Bieniaszewski, L. . . . . . . . . . . . . . P526 Biffi, A. . . . . . . . . . . . . . . . . . . . O161 Bigoni, M. . . . . . . . . . . . . . . . . . P361 Bijen, N. . . . . . . . . . . . . . . . . . . P764 Bilge, C. . . . . . . . . . . . . . . . . . . P268 Bilic, I. . . . . . . . . . . . . . . . . . . . P671 Bilz, S. . . . . . . . . . . . . . . . . . . . P300 Birklein, F. . . . . . . O111, O136, O154, P712 Birnbaum, T. . . . . . . . . . . . . . . . . P314 Biswal, B. . . . . . . . . . . . . . . . . . . P547 Bizzi, A. . . . . . . . . . . . . . . . . . . . O43 Blaes, F. . . . . . . . . . . . . . . . O152, P352

Blanc-brude, O. . . . . . . . . . . . . . . P426 Blandini, F. . . . . . . . . . . . . . . . . . P596 Blanke, O. . . . . . . . . . . . . . . . . . P584 Blatter-Arifi, V. . . . . . . . . . . . . . . P283 Blezer, E. L. A. . . . . . . . . . . . . . . . O64 Blicher, J. U. . . . . . . . . . . . . . . . . P475 Blinkenberg, M. . . . . . . . . . . . . . . P416 Bochynska, A. . . . . . . . . . . . . P392, P686 Boddaert, J. . . . . . . . . . . . . . . . . P426 Bode, B. . . . . . . . . . . . . . . . . . . P575 Bode, U. . . . . . . . . . . . . . . . . . . . O42 Bodet, D. . . . . . . . . . . . . . . . . . . P412 Boe, L. . . . . . . . . . . . . . . . . . . . . O64 Boesiger, P. . . . . . . . . . . . . . . . . . P777 Bogar, L. . . . . . . . . . . . . . . . P228, P566 Bogdanovic, M. . . . . . . . . . . . . . . . O91 Bogdanovic, N. . . . . . . . . . . . . . . P589 Boggild, M. D. . . . . . . . . . . . . . . . O144 Böhm, C. . . . . . . . . . . . . . . . . . . P397 Boiardi, A. . . . . . . . . . . . . . . . . . O43 Boimel, M. . . . . . . . . . . . . . . . . . P233 Bölch, S. . . . . . . . . . . . . . . . . . . P655 Bolgert, F. . . . . . . . . . . . . . . . . . P315 Bolokadze, L. . . . . . . . . . . . . . . . P721 Boly, M. . . . . . . . . O88, O156, O163, O167 Bonaïti-Pellié, C. . . . . . . . . . . . . . . O81 Bonakis, A. . . . . . . . . . . . . . O170, O174 Bonanni, L. . . . . . . . . . . . . . . . . . P363 Bonato, S. . . . . . . . . . . . . . . . . . P304 Bonavita, V. . . . . . . . . . . . . . . . . P312 Bongers, A. . . . . . . . . . . . . . . . . . P467 Bonnaud, I. . . . . . . . . . . . . . . . . O190 Bor, D. . . . . . . . . . . . . . . . . . . . . O88 Borcherding, B. . . . . . . . . . . . . . . P397 Bordoni, A. . . . . . . . . . . . . . . . . . P615 Borg, M. . . . . . . . . . . . . . . . . . . P271 Borguetti, V. . . . . . . . . . . . . . . . . P618 Bornstein, N. . . . . . . . . . . . . . . . . P336 Boroojerdi, B. . . . . . . . . . . . . . . . P495 Borratynska, A. . . . . . . . . . . . . . . P230 Borreca, A. . . . . . . . . . . . . . . . . . O86 Borriello, G. . . . . . . . . . . . . . . . . P294 Boscá, M. . . . . . . . . . . . . . . . . . . O75 Bosoncea, D. . . . . . . . . . . . . . . . . P385 Bossi, B. . . . . . . . . . . . . . . . . . . P557 Bossolasco, P. . . . . . . . . . . . . . . . P596 Bostantjopoulou, S. . . . . . . . . . P487, P564 Bouchard, J.-P. . . . . . . . . . . . . . . . O117 Boukhtouche, F. . . . . . . . . . . . . . . P426 Bourg, V. . . . . . . . . . . . . . . . . . . P567 Boutsi, K. . . . . . . . . . . . . . . P576, P621 Bova, I. . . . . . . . . . . . . . . . . . . . P336 Bowes, J. . . . . . . . . . . . . . . . . . . O144 Boyaciyan, A. . . . . . . . . . . . . . . . P775 Boylu, E. . . . . . . . . . . . . . . . . . . P522 Bozkaya, Y. T. . . . . . . . . . . . . . . . O189 Braeuninger, S. . . . . . . . . . . . . . . P351 Bramanti, P. . . . . . . . . . . . . . . . . P262 Brami-cherrier, K. . . . . . . . . . . . . . P419 Brandt, T. . . . . . . . . . . . O40, O125, P241, P244, P245, P769 Brault, I. . . . . . . . . . . . . . . . . . . . O79 Brédart, S. . . . . . . . . . . . . . . . . . O183 Brede, M. . . . . . . . . . . . . . . . . . . P351 Breitenfeld, D. . . . . . . . . . . . . . . . P748 Breitenfeld, T. . . . . . . . . P303, P493, P748 Brennan, P. N. . . . . . . . . . . . O209, P737 Bresch, J. . . . . . . . . . . . . . . . . . . P491 Bresolin, N. . . . . . . . O52, O54, O171, O173, P279, P304, P530, P613, P615, P729, P733 Brettschneider, J. . . . . . . . . . . P516, P725 Briand, R. . . . . . . . . . . . . . . . . . . O56 Briceño, E. . . . . . . . . . . . . . . . . . P309 Brighina, E. . . . . . . . . . . . . . . . . P530 Brighina, L. . . . . . . . . . . . . . . . . P280 Brinar, V. . . . . . . . . . . . . . . . . . . P548 Brinckmann, A. . . . . . . . . . . . . . . P272 Brinker, T. . . . . . . . . . . . . . . . . . P418

Brinkmann, V. . . . . . . . . . . . . . . . O142 Brodacki, B. . . . . . . . . . . . . . . . . P220 Broglio, L. . . . . . . . . . . . . . . . . . . O77 Brook, G. . . . . . . . . . . . . . . . . . . . 23 Brown, M. G. . . . . . . . . . . . . . . . O218 Brown, P. . . . . . . . . . . . . . . . . . . O201 Bruno, G. . . . . . . . . . . . O175, P588, P594 Brusco, A. . . . . . . . . . . . . . . . . . O118 Budisic, M. . . . . . . . P303, P474, P493, P748 Budisic, Z. . . . . . . . . . . . . . . . . . P548 Budrewicz, S. . . . . . . . . . . . . P480, P518 Buehler, R. . . . . . . . . . . . . . . . . . O128 Buggle, F. . . . . . . . . . . . . . . . . . . P575 Bühler, R. . . . . . . . . . . . . . . . . . . P283 Bulboaca, Adriana . . . . . . . . . . . . . P586 Bulboaca, Angelo . . . . . . . . . . . . . . P586 Buraga, I. . . . . . . . . . . . . . . . . . . P690 Burcin, C. . . . . . . . . . . . . . . . . . P699 Burguera, J. A. . . . . . . . . . . . . . . . O75 Burgut, T. . . . . . . . . . . . . . . . . . P319 Burlina, A. P. . . . . . . . . . . . . . . . . O63 Burrows, G. . . . . . . . . . . . . . . . . P648 Buruiana, F. . . . . . . . . . . P379, P380, P381 Burval, S. . . . . . . . . . . . . . . O131, O212 Bussone, G. . . . . . . . . . . . . . O192, O193 Buttari, F. . . . . . . . . . . . . . . O175, P594 Butti, M. . . . . . . . . . . . . . . . . . . P663 Buttmann, M. . . . . . . . . . . . . . . . P658 Büttner, A. . . . . . . . . . . . . . . . . . P258 Büttner, U. . . . . . . . . . . . . . . . . . P358 Buzatu, M. . . . . . . . . . . . . . . . . . P498 Bwala, S. . . . . . . . . . . . . . . . P335, P447 Cabaret, M. . . . . . . . . . . . . . . . . . O93 Cabellos, C. . . . . . . . . . . . . . . . . P646 Caboche, J. . . . . . . . . . . . . . . . . . P419 Cadavid, D. . . . . . . . . . . . . . . . . . P547 Caffini, M. . . . . . . . . . . . . . . . . . P663 Caggiula, M. . . . . . . . . . . . . . . . . P404 Cagliani, R. . . . . . . . . . . . . . . . . P613 Cagnoli, C. . . . . . . . . . . . . . . . . . O118 Calabrese, D. . . . . . . . . . . . . . . . . P327 Calabrese, P. . . . . . . . . . . . . . . . . O42 Calado, A. . . . . . . . . . . . . . . . . . P232 Calado, S. . . . . . . . . . . . . . . . . . O133 Calbi, V. . . . . . . . . . . . . . . . . . . P308 Calzarossa, C. . . . . . . . . . . . . . . . P596 Camdessanche, J. P. . . . . . . . . . O80, O110 Campanella, A. . . . . . . . . . . . . . . P710 Canale, S. . . . . . . . . . . . . . . . . . O161 Canas, N. . . . . . . . . . . . . . . O133, P635 Canas Marques, M. . . . . . . . . . . . . P772 Candan, F. . . . . . . . . . . . . . . P347, P630 Candelise, L. . . . . . . . . . . . . . . . . P279 Candia, V. . . . . . . . . . . . . . . . . . P252 Cândido, J. . . . . . . . . . . . . . . . . . P232 Canevelli, M. . . . . . . . . . . . . O175, P594 Cantalupo, L. . . . . . . . . . . . . . . . . P751 Cantor, F. . . . . . . . . . . . . . . . . . . O66 Capello, E. . . . . . . . . . . . . . . . . . P288 Capilla, O. . . . . . . . . . . . . . . . . . P531 Cappa, P. . . . . . . . . . . . . . . . . . . P264 Capra, R. . . . . O102, O177, P277, P529, P757 Caputo, D. . . . . . . . . . . . . . O101, O177 Cárcamo, C. . . . . . . . . . . . . . . . . P401 Cárdenas Hernandez, G. A. . P248, P393, P740 Cardona, P. . . . . . . . . . . . . . . . . . P339 Cardoso, M. . . . . . . . . . . . . . . . . P325 Carlesi, C. . . . . . . . . . . . . . . P617, P736 Carmona, O. . . . . . . . . . . . . . . . . O178 Carneiro, P. . . . . . . . . . . . . . . . . P573 Carnero-Pardo, C. . . . . . . . . . P687, P688 Carpo, M. . . . . . . . . . . . . . . . . . P529 Carrascal, Y. . . . . . . . . . . . . . . . . P708 Carreño, M. . . . . . . . . . . . . . . . . P634 Carrera, V. . . . . . . . . . . . . . . . . . P588 Carrillo, F. . . . . . . . . . . . . . . . . . P622 Carroll, C. . . . . . . . . . . . . . . . . . P761 Carvalho, B. O. . . . . . . . . . . . . . . . P660

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Carvalho, M. . . . . . . . . . . . . . . . . P442 Casado, V. . . . . . . . . . . . . . . . . . O178 Casado Naranjo, I. . . . . . . . . . . . . . P688 Casagrande, G. . . . . . . . . . . . . . . . O84 Casanova, J. . . . . . . . . . . . . . . . . , P477 Casanova-Molla, J. . . . . . O166, P333, P436, P477, P634 Casarin, A. . . . . . . . . . . . . . . . . . O84 Cascais, M. J. . . . . . . . . . . . . . . . . P652 Casellato, C. . . . . . . . . . . . . . O78, P328 Caso, V. . . . . . . . . . . . . . . . . . . . . 38 Casset-Semanaz, F. . . . . . . . . . . . . . O69 Castelijns, J. A. . . . . . . . . . . . . . . . O64 Castellanos Pinedo, F. . . . . . . . . . . . P688 Castelli, E. . . . . . . . . . . . . . . . . . P264 Castellotti, B. . . . . . . . . . . . . . . . O122 Castillo, J. . . . . . . . . . . . . . . . . . P226 Castro-Macias, J. I. . . . . . . . . . P248, P740 Cataldo, S. . . . . . . . . . . . . . . . . . P257 Ceccarelli, A. . . . . . . . . . . . . O102, P536 Ceccherini, I. . . . . . . . . . . . . . . . . O83 Cecilia, C. . . . . . . . . . . . . . . . . . P735 Cenacchi, G. . . . . . . . . . . . . . . . . P276 Ceppi, D. . . . . . . . . . . . . . . . . . . O109 Cercignani, M. . . . . . . . . . . . . . . . P544 Ceresa, L. . . . . . . . . . . . . . . . . . . O76 Cerna, M. . . . . . . . . . . . . . . . . . O212 Cerny, R. . . . . . . . . . . . . . . . . . . P362 Ceroni, M. . . . . . . . . . . . . . . . . . O123 Cerri, F. . . . . . . . . . . . . O168, P332, P355 Cerutti, S. . . . . . . . . . . . . . . . . . P663 Cesani, M. . . . . . . . . . . . . . . . . . O161 Chabli, A. . . . . . . . . . . . . . . . . . . P382 Chan, A. . . . . . . . . . . . . . . . . . . P543 Chandran, S. . . . . . . . . . . . . O184, P428 Chang, P. . . . . . . . . . . . . . . . . . . P539 Charue, D. . . . . . . . . . . . . . . . . . P426 Chaussenot, A. . . . . . . . . . . . . . . . P271 Chaves, J. . . . . . . . . . . . . . . . . . . P746 Chaves, M. L. . . . . . . . . . . . . . . . O153 Chebut, O. C. . . . . . . . . . . . . . . . . P413 Chelli, B. . . . . . . . . . . . . . . . . . . P735 Chen, M. L. . . . . . . . . . . . . . . . . . P365 Chen, R. . . . . . . . . . . . . . . . . . . P425 Chen, S-S. . . . . . . . . . . . . . . . . . . O57 Cheon, S. M. . . . . . . . . . . . . . . . . P694 Chiapparini, L. . . . . . . . . . . . O192, O193 Chieffo, R. . . . . . . . . . . . . . . O168, P355 Chinaglia, D. . . . . . . . . . . . . . . . . P667 Chinnery, P. . . . . . . . . . . . . . . . . . . 16 Chirca, I. . . . . . . . . . . . . . . . . . . P298 Chitsaz, A. . . . . . . . . . . . . . . . . . P224 Cho, J. H. . . . . . . . . . . . . . . P302, P350 Cho, K. H. . . . . . . . . . . . . . . . . . P562 Cho, S-Y. . . . . . . . . . . . . . . . . . . P329 Cho, Y. J. . . . . . . . . . . . . . . . . . . P424 Choi, B-O. . . . . . . . . . . . P329, P443, P582 Choi, E. . . . . . . . . . . . . . . . . . . . P430 Choi, K. D. . . . . . . . . . . . . . . . . . P239 Choi, K. G. . . . . . . . . . . P443, P582, P785 Choi, S. A. . . . . . . . . . . . . . . . . . P302 Choi, S. M. . . . . . . . . . . . . . . . . . P562 Choi, Y. J. . . . . . . . . . . . . . . . . . . P454 Chokron, S. . . . . . . . . . . . . . . . . P382 Chon, J-M. . . . . . . . . . . . . . . . . . P350 Chrisopoulos, C. . . . . . . . . . . . . . . P234 Christakos, C. N. . . . . . . . . . . . . . P254 Christensen, M. C. . . . . . . . . . . . . . O96 Chroni, E. . . . . . . . . . . O195, P331, P439, P625, P707 Chrysovitsanou, C. . . . . . . . . . . . . P604 Chumillas, M. J. . . . . . . . . . . . . . . P320 Chun, J. U. . . . . . . . . . . . . . . . . . P454 Chung, E. J. . . . . . . . . . . . . . . . . P785 Chung, J. M. . . . . . . . . . . . . . . . . P253 Chung, S. W. . . . . . . . . . P453, P714, P720 Ciammola, A. . . . . . . . . . . . . . . . P729 Ciceri, F. . . . . . . . . . . . . . . . . . . P308 Cioni, C. . . . . . . . . . . . . . . . . . . P751

Cipolotti, L. . . . . . . . . . . . . . . . . P544 Cislaghi, G. . . . . . . . . . . . . . . . . . O54 Cisternas, M. . . . . . . . . . . . . . . . . P659 Citci, B. . . . . . . . . . . . . . . . . . . . P504 Claassen, D. . . . . . . . . . . . . . . . . O205 Claramonte, B. . . . . . . . . . . . . . . . O75 Clarke, J. T. R. . . . . . . . . . . . . . . . O63 Clauss, M. . . . . . . . . . . . . . . P765, P766 Clerici, F. . . . . . . . . . . . . . . . . . . O54 Clerico, M. . . . . . . . . . . P538, P657, P759 Coban, O. . . . . . . . . . . . . . . . . . . P563 Cocco, G. A. . . . . . . . . . . . . . . . . P255 Cochen, V. . . . . . . . . . . . . . . . . . . O71 Coelho, M. . . . . . . . . . . . . . . . . . P376 Cogiamanian, F. . . . . . . . . . . . . . . P440 Cohen, B. . . . . . . . . . . . . . . . . . . P407 Cojocaru, I. M. . . . . . . . . . . . . . . . P699 Cojocaru, M. . . . . . . . . . . . . . . . . P699 Coleman, M. . . . . . . . . . . . . . . . . O88 Coles, A. J. . . . . . . . . . . . . . O143, O216 Collett, J. . . . . . . . . . . . . . . . . . . O91 Collimedaglia, L. . . . . . . . . . . P277, P757 Colombo, B. . . . . . . . . . . . . . O188, P757 Comi, C. . . . . . . . . . . . . . . . . . . P530 Comi, G. C. . . . . . . . . 1, O99, O100, O102, O109, O141, O161, O168, O177, O188, O217, P277, P308, P330, P332, P355, P356, P409, P524, P536, P565, P568, P680, P757 Comi, G. P. . . . . . . P279, P304, P613, P614, P615, P729, P733 Compston, D. A. S. . . . . . O143, O184, P428 Coniglio, G. . . . . . . . . . . . . . P277, P757 Connick, P. . . . . . . . . . . . . . . . . . O184 Connolly, C. E. . . . . . . . . . . . . . . . P319 Constantin, D. . . . . . . . . . . . . . . . P298 Constantinescu, C. . . . . . . . . . . . . P292 Constantoyannis, C. . . . . . P250, P370, P707 Conte, A. . . . . . . . . . . . . . . . . . . P728 Contessa, G. . . . . . . . . . . . . . . . . P538 Cook, S. . . . . . . . . . . . . . . . . . . P547 Cookfair, D. . . . . . . . . . . . . . . . . P755 Cordioli, C. . . . . . . . . . . . . . . . . . P529 Cordonnier, C. . . . . . . . . . . . . O62, O97 Corea, F. . . . . . . . . . . . . . . . P565, P680 Corr, B. . . . . . . . . . . . . . . . O209, P737 Correa, P. L. . . . . . . . . . . . . . . . . O114 Correia Guedes, L. . . . . . . . . . . . . . P376 Cortet-Rudelli, C. . . . . . . . . . . . . . P420 Corti, S. . . . . . . . . P279, P614, P729, P733 Cortini, F. . . . . . . . . . . . O54, O173, P530 Corvol, A. . . . . . . . . . . . . . . . . . P458 Cos, M. . . . . . . . . . . . . . . . . . . . P339 Costa, A. . . . . . . . . . . . . . . . O48, P616 Costa, F. T. M. . . . . . . . . . . . . . . . P660 Costa, M. . . . . . . . . . . . . . . P434, P553 Costa, V. . . . . . . . . . . . . . . . . . . P762 Costes, F. . . . . . . . . . . . . . . . . . . O110 Cotrufo, R. . . . . . . . . . . . . . . . . . P588 Couderc, R. . . . . . . . . . . . . . . . . P652 Counsell, C. . . . . . . . . . . . . . . . . . O62 Court-Fortune, I. . . . . . . . . . . . . . O110 Coutinho, B. . . . . . . . . . . . . . . . . P437 Cova, L. . . . . . . . . . . . . . . . . . . . P596 Coveñas, R. . . . . . . . . . . . . . . . . P412 Covic, B. . . . . . . . . . . . . . . . P388, P389 Cox, J. L. . . . . . . . . . . . . O65, O67, O68, O181, P752, P755 Crelier, G. . . . . . . . . . . . . . . . . . P777 Cretu, L. . . . . . . . . . . . . P379, P380, P381 Creus, K. K. . . . . . . . . . . . . . . . . . O51 Cristiano, E. . . . . . . . . . . . . . P607, P608 Crnjakovic, M. . . . . . . . . . . . . . . . P493 Crocchiolo, R. . . . . . . . . . . . . . . . P308 Crugnola, V. . . . . . . . . . . . . . P304, P729 Crush, A. . . . . . . . . . . . . . . . . . . P284 Cruz, M. W. . . . . . . . . . . . . . O81, O113 Csapo, K. . . . . . . . . . . . . . . . . . . P560

Csiba, L. . . . . . . . . . . . . . . . . . . P560 Cuadrado-Godia, E. . . . . . . . . . . . . P763 Cucci, A. . . . . . . . . . . . . . . . . . . P538 Cucurella, G. . . . . . . . . . . . . . . . . P763 Cumano, A. . . . . . . . . . . . . . . . . . . . 3 Cursi, M. . . . . . . . . . . . . . . O168, P355 Czaplinski, A. . . . . . . . . O208, P321, P734 Czepko, R. . . . . . . . . . . . . . . . . . P230 Czlonkowska, A. . . . . . . . . . . P421, P449 Czlonkowski, A. . . . . . . . . . . . P421, P449 D’Aleo, G. . . . . . . . . . . . . . . . . . P262 D’alfonso, S. . . . . . . . . . . . . . . . . P530 D’Angelo, M. G. . . . . . . . . . . . O52, P613 D’Errico, E. . . . . . . . . . . . . . . . . O211 Dabadie, M. P. . . . . . . . . . . . . . . . P412 Dacci, P. . . . . . . . . . . . . . . . P330, P524 Dafotakis, M. . . . . . . . . . . . . . . . P260 Dahms, S. . . . . . . . . . . . . . . . . . O219 Dähne, D. . . . . . . . . . . . . . . . . . P651 Damas, F. . . . . . . . . . . . . . . . . . . P269 Damas, P. . . . . . . . . . . . . . . O186, P269 Dan, M. . . . . . . . . . . . . . . . . . . . P413 Danburam, A. . . . . . . . . P334, P335, P446, P447, P512, P641, P682 Danesino, C. . . . . . . . . . . . . . O48, P616 Dang, P. T. . . . . . . . . . . . . . . . . . P318 Dang-Vu, T. . . . . . . . . . . . . . . . . O198 Daniilidis, M. . . . . . . . . . . . . . . . P669 Dardioti, M. . . . . . . . . . P281, P282, P537 Dardiotis, E. . . . . . . . . . P281, P282, P537 Darius, H. . . . . . . . . . . . . . . . . . O202 Daume, L. . . . . . . . . . . . . . . . . . P651 Davaki, P. . . . . . . . . . . . . . . . . . . P600 Dávalos, A. . . . . . . . . . . . . . . . . . P226 Dave, J. . . . . . . . . . . . . . . . . . . . P425 Daveluy, W. . . . . . . . . . . . . . . . . . O93 Davidescu, I. . . . . . . . . . . . . . . . . P690 Davis, M. . . . . . . . . . . . . . . . . . . O88 Davitoiu, A. . . . . . . . . . . . . . P379, P380 Dawes, H. . . . . . . . . . . . . . . . . . . O91 Dayan, C. . . . . . . . . . . . . . . . . . . P221 de Andrés, C. . . . . . . . . . . . . . . . P698 De Blas, G. . . . . . . . . . . . . . . . . . P549 De Bleecker, J. L. . . . . . . . . . . . . . . O51 De Caro, M. F. . . . . . . . . . . . . . . . O211 De Feo, D. . . . . . . . . . . . . . . . . . P330 de Freitas, M. R. G. . . O114, P437, P718, P719 De Giglio, L. . . . . . . . . . . . . . . . . P294 de Greiff, A. . . . . . . . . . . . . . . . . . O70 de Haan, E. H. . . . . . . . . . . . . . . . O87 de Juan, P. . . . . . . . . . . . . . . . . . P622 de la Vega, R. J. . . . . . . . . . . . P687, P688 de Leòn, M. . . . . . . . . . . . . . . . . P412 De Paepe, B. . . . . . . . . . . . . . . . . . O51 De Palma, M. . . . . . . . . . . . . . . . . P619 De Riz, M. . . . . . . . . . . P288, P529, P530 De Santi, L. . . . . . . . . . . . . . P288, P751 De Simone, T. . . . . . . . . . . . . . . . O192 De Souza, K. . . . . . . . . . . . . . . . . P425 De Stefano, N. . . . . . . . . . . . . P409, P758 De Toni Franceschini, L. . . . . . . . . . P330 De Wit, L. . . . . . . . . . . . . . . . . . . O89 Debiais, S. . . . . . . . . . . . . . . . . . O190 Debouverie, M. . . . . . . . . . . . . . . P760 Debski, M. . . . . . . . . . . . . . . . . . P704 Deckert, M. . . . . . . . . . . . . . . . . . O42 Dee, A. . . . . . . . . . . . . . . . . . . . P406 Degardin, A. . . . . . . . . . . . . . . . . P611 Degueldre, C. . . . . . . . . . . . . O167, O198 Dejaeger, E. . . . . . . . . . . . . . . . . . O89 Del Bo, R. . . . . . . . O173, P279, P613, P733 Del Carro, U. . . . . . . . . . . . . O161, P308 Del Corona, A. . . . . . . . . . . . . . . . P736 Del Real, M. A. . . . . . . . . . . . P672, P683 Delaunay, D. . . . . . . . . . . . . . . . . . . 3 Deleidi, M. . . . . . . . . . . . . . . P524, P568 Deleu, D. . . . . . . . . P306, P319, P399, P511 Deltour, S. . . . . . . . . . . . . . . . . . O213

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Demarin, V. . . . . . . P303, P474, P493, P748 Demeret, S. . . . . . . . . . . . . . . . . . P315 Demir, G. . . . . . . . . . . . . . . . . . . P240 Demirci, S. . . . . . . . . . . . . . . . . . P221 Dempewolf, S. . . . . . . . . . . . . . . . P628 Denier, C. . . . . . . . . . . . . . . . . . . O79 Denys, V. . . . . . . . . . . . . . . . . . . P315 Denzer, J. . . . . . . . . . . . . . . . . . O176 Deppe, R. . . . . . . . . . . . . . . . . . . P651 Derejko, M. . . . . . . . . . . . . . P359, P392 Derfuss, T. . . . . . . . . . . . . . . . . . O125 Dermietzel, R. . . . . . . . . P310, P311, P543 Deschauer, M. . . . . . . . . . . . . . . . O53 Desfontaines, P. . . . . . . . . . . . . . . P578 Desikan, M. . . . . . . . . . . . . . P747, P774 Desnuelle, C. . . . . . . . . . . . . . . . . O84 Desseilles, M. . . . . . . . . . . . . . . . O198 Deyts, C. . . . . . . . . . . . . . . . . . . P419 Di Bella, P. . . . . . . . . . . . . . . . . . P262 Di Prospero, N. . . . . . . . . . . . . . . O120 Di Rezze, S. . . . . . . . . . . . . . . . . P288 Di Rocco, M. . . . . . . . . . . . . . . . . P615 Di Rosa, G. . . . . . . . . . . . . . . . . . P264 Dianzani, C. . . . . . . . . . . . . . . . . P291 Dianzani, U. . . . . . . . . . . . . . . . . P530 Diaz, J. . . . . . . . . . . . . . . . . . . . P608 Díaz-Otero, F. . . . . . . . . . . . . . . . O214 DiBella, D. . . . . . . . . . . . . . . O85, O118 Dichgans, M. . . . . . . . . O206, P231, P275, P463, P677 DiDonato, S. . . . . . . O82, O85, O118, O122 Diederich, N. J. . . . . . . . . . . . . . . P346 Diehl, V. . . . . . . . . . . . . . . . . . . . O42 Diener, H-C. . . . . . . . . . . . 36, O70, O202 Dieterich, M. . . . . . . . . . O41, O111, O136, O165, O176, P712 Dietz, V. . . . . . . . . . . . . . . . . . . . . 21 Díez-Tejedor, E. . . . . . . . . O60, O61, O191, O214, P226, P345, P452, P674, P691 Dijkhuizen, R. M. . . . . . . . . . . . . . . O87 Dilena, R. . . . . . . . . . . . . . . . . . P440 Dimitraka, M. . . . . . . . . . . . . . . . P243 Dimitrijeski, B. . . . . . . . . . . . . . . O207 Dimitrijevic, R. . . . . . . . . . . . P432, P497 Dimitrova, A. . . . . . . . . . . . . . . . P384 Dimopoulos, F. . . . . . . . . . . . . . . P681 Dimopoulos, M. . . . . . . . . . . . . . . P441 Dinos, K. . . . . . . . . . . . . . . . . . . P715 Dioh, A. . . . . . . . . . . . . . . . . . . P269 Dispot, T. . . . . . . . . . . . . . . . . . . P462 Ditsch, N. . . . . . . . . . . . . . . . . . . O46 Divan, V. . . . . . . . . . . . P541, P542, P545 Djibuti, M. . . . . . . . . . . . . . . . . . P572 Dobesberger, J. . . . . . . . . . . . . . . O132 Dobricic, V. . . . . . . . . . . . . . P432, P497 Doherty, C. . . . . . . . . . . . . . . . . O138 Doitsini, S. . . . . . . . . . . . . . . . . . P234 Dolezal, O. . . . . . . . O68, P650, P752, P755 Domanasiewicz, A. . . . . . . . . . . . . P518 Domínguez González, C. . . . . . . . . . P246 Donadio, V. . . . . . . . . . . . . . . O73, P779 Donadoni, C. . . . . . . . . . . . . . . . . P733 Donaire, A. . . . . . . . . . . . . . . . . . P634 Donati, M. . . . . . . . . . . . . . . . . . P615 Dong, K. . . . . . . . . . . . P263, P626, P695 Donswijk, M. . . . . . . . . . . . . . . . . O59 Dooms, G. . . . . . . . . . . . . . . . . . P318 Dorado, R. . . . . . . . . . . . . . . . . . P706 Dorhout Mees, S. M. . . . . . . . . . . . P341 Dormans, T. . . . . . . . . . . . . . . . . P642 Dormont, D. . . . . . . . . . . . . . . . . O213 Dragasevic, N. . . . . . . . . . . . . . . . O108 Dragomir, D. . . . . . . . . . P380, P381, P385 Drakonaki, E. . . . . . . . . . . . . P266, P267 Drapier, S. . . . . . . . . . . . . . . . . . P544 Drubach, D. A. . . . . . . . . . . . . . . O137 Drubach, D. I. . . . . . . . . . . . . . . . O137 Drzyzga, K. . . . . . . . . . . . . . . . . . P372

Drzyzga, L. . . . . . . . . . . . . . . . . . P372 Ducreux, D. . . . . . . . . . . . . . . . . . O71 Dudel, C. . . . . . . . . . . . . . . . . . . O46 Dufek, J. . . . . . . . . . . . . . . . . . . P249 Duleu, S. . . . . . . . . . . . . . . . . . . P412 Dumitriu, B. . . . . . . . . . P455, P501, P501 Duncombe, P. . . . . . . . . . . . . . . . . O92 Dupré, N. . . . . . . . . . . . . . . . . . O117 Durastanti, V. . . . . . . . . . . . . . . . . O66 Durelli, L. . . . . . . . . . . . . . . P657, P759 Durka-Kesy, M. A. . . . . . . . . . . . . . P778 Durmus, H. . . . . . . . . . . . . . O147, O158 Duyckaerts, C. . . . . . . . . . . . . . . . P426 Dwornik, A. . . . . . . . . . . . . . . . . P739 Dwyer, M. G. . . . . . . . . . . O65, O67, O68, O181, P752, P755 Dzamonja, G. . . . . . . . . . . . . . . . P671 Dzhurko, M. . . . . . . . . . . . . . . . . P591 Dziedzic, T. . . . . . . . . . . O98, P230, P570 Dziewulska, D. . . . . . . . . . . . . . . . P739 Eadie, M. J. . . . . . . . . . . . . . . . . O135 Ebenbauer, B. . . . . . . . . . . . . . . . O172 Eberle, T. . . . . . . . . . . . . . . . . . . P712 Ebner, F. . . . . . . . . . . . . . . . . . . O140 Ebrahimi, A. . . . . . . . . . . . . . . . . P227 Eckhardt-Henn, A. . . . . . . . . . . . . . O41 Eckstein, H. . . . . . . . . . . . . . . . . P471 Edan, G. . . . . . . . . . . . . . . O219, P760A Egenolf, C. . . . . . . . . . . . . . . . . . O111 Egerer, G. . . . . . . . . . . . . . . . . . . O42 Egido, J. . . . . . . . . . . . . . . . O214, P226 Ehrmantraut, M. . . . . . . . . . . . . . . O66 El Assawy, N. . . . . . . . . . . . . . . . . P257 El Fily, A. . . . . . . . . . . . . . . . . . . P460 El Kamel, I. . . . . . . . . . . . . . . . . P366 Elam, M. . . . . . . . . . . . . . . . O73, O154 Elbozan-Cumurcu, B. . . . . . . . . . . . P624 Elles, H. G. . . . . . . . . . . . . . . . . . P384 Ellgring, H. . . . . . . . . . . . . . . . . P691 Ellul, J. . . . . . . . . . . . . . . . . P250, P370 ElShafie, S. . . . . . . . . . . . . . . . . . P399 Elstner, M. . . . . . . . . . . . . . . . . . P427 Embacher, N. . . . . . . . . . . . . . . . O132 Engert, A. . . . . . . . . . . . . . . . . . . O42 Enomoto, H. . . . . . . . . . . . . . P450, P485 Enomoto, S. . . . . . . . . . . . . . . . . P450 Enzinger, C. . . . . . . . . . . O91, O140, P349 Epifanio, R. . . . . . . . . . . . . . . . . P633 Epis, R. . . . . . . . . . . . . . . . . . . . P332 Epis de Fleurian, A. A. . . . . . . . . . . P462 Equia, F. . . . . . . . . . . . . . . . . . . P399 Eraksoy, M. . . . . . . O147, O158, P387, P394 Erbguth, F. . . . . . . . . . . . . . . . . . P397 Ercegovac, M. . . . . . . . . . . . . . . . P497 Erimaki, S. . . . . . . . . . . . . . . . . . P254 Erkorkmaz, U. . . . . . . . . . . . . . . . P520 Escada, T. M. . . . . . . . . . . . . . . . . P719 Escrig, A. . . . . . . . . . . . . . . . . . . P339 Esposito, A. . . . . . . . . . . . . . . . . P286 Esposito, F. . . . . . . . . . . O217, P277, P757 Esposito, L. . . . . . . . . . . . . . . . . . P471 Esposito, M. . . . . . . . . . . . . . . . . P312 Essafi, D. . . . . . . . . . . . . . . . . . . P396 Etemadi, M. M. . . . . . . . . . . . . . . P322 Etemadifar, M. . . . . . . . . . . . P227, P532 Etikan, I. . . . . . . . . . . . . . . . . . . P326 Evangelopoulos, M. E. . . . . . . . . . . P534 Evangelou, I. . . . . . . . . . . . . . . . . O66 Eyre, S. . . . . . . . . . . . . . . . . . . . O144 Ezpeleta, D. . . . . . . . . . . . . . . . . P698 Ezquerra, M. . . . . . . . . . . . . . . . . O55 Fabrizi, G. . Fadel, W. . . Fadrna, T. . Faggi, A. . . Faggiano, F. Fagiolari, G.

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Faglioni, P. . . . . . . . . . . . . . . O50, P619 Faiss, J. . . . . . . . . . . . . . . . . . . . P651 Faist, M. . . . . . . . . . . . . . . . O160, O164 Fajardo, S. . . . . . . . . . . . . . . . . . P580 Falautano, M. . . . . . . . . . . . . O161, P356 Faldum, A. . . . . . . . . . . . . . . . . . O176 Falini, A. . . . . . . . . O99, O102, O141, O188 Fallah, A. . . . . . . . . . . . . . . P375, P661 Falorni, M. . . . . . . . . . . . . . P617, P736 Fancellu, R. . . . . O82, O83, O85, O118, O122 Farias, A. S. . . . . . . . . . . . . . . . . P660 Farina, E. . . . . . . . . . . . . . . P587, P598 Farina, L. . . . . . . . . . . . . . . . O83, O192 Farini, A. . . . . . . . . . . . . . . . . . . O52 Fariselli, L. . . . . . . . . . . . . . . . . . O43 Farrar, J. T. . . . . . . . . . . . . . . . . . O92 Farrell, M. . . . . . . . . . . . . . . . . . P602 Faustmann, P. M. . . . . . . . P310, P311, P543 Faymonville, M. E. . . . . . . . . . . . . O156 Fazekas, F. . . . . . . . O91, O140, O172, P349 Fazio, R. . . . . . . . . . . . . . . . P330, P524 Fechir, M. . . . . . . . . . . . . . . . . . O136 Feclina, I. . . . . . . . . . . . . . . . . . . P435 Fedorenko, D. . . . . . . . . . . . . . . . P750 Fedotova, I. . . . . . . . . . . . . . P678, P721 Fekete, K. . . . . . . . . . . . . . . . . . . P456 Felber, S. . . . . . . . . . . . . . . . . . . O132 Fenoglio, C. . . . . . . O54, O171, O173, P530 Ferini-Strambi, L. . . . . . . . . . . . . . P440 Fernandez, O. . . . . . . . . . . . . . . . P468 Fernández Domínguez, J. . O150, O191, O200, P345, P585 Fernandez Sanfiel, M. L. . . . . . . . . . P622 Fernández-Viladrich, P. . . . . . . . . . . P646 Ferraccioli, M. . . . . . . . . . . . . . . . P592 Ferrante, P. . . . . . . . . . . . . . . . . . O76 Ferrarese, C. . . . . . . . . . . . . . . . . P280 Ferrari, S. . . . . . . . . . . . . . . . . . P308 Ferreira, J. . . . . . . . . . . . . . . . . . P376 Ferrero, B. . . . . . . . . . . . . . . P538, P759 Ferrero, C. . . . . . . . . . . . . . . . . . P538 Ferret-Sena, V. . . . . . . . . . . . . . . . P652 Ferro, J. . . . . . . . . . . . . . . . . . . O215 Fertl, E. . . . . . . . . . . . . . . . . . . . P569 Fialova, L. . . . . . . . . . . . . . . . . . P780 Filippi, M. . . . . . . . . . . O99, O100, O101, O102, O141, O177, O185, O188, O217, P536 Filocamo, M. . . . . . . . . . . . . . . . . P615 Fimmers, R. . . . . . . . . . . . . . . . . . O42 Findling, O. . . . . . . . . . . . . . . . . P283 Fingerle, V. . . . . . . . . . . . . . . . . . O124 Fink, G. R. . . . . . . . . . . . . . . P260, P583 Finocchiaro, G. . . . . . . . . . . . . . . P667 Fisch, C. . . . . . . . . . . . . . . . . . . P577 Fischbeck, K. . . . . . . . . . . . . . . . O120 Fischer, S. . . . . . . . . . . . . . . . . . P352 Fisk, J. D. . . . . . . . . . . . . . . . . . . O218 Fisniku, L . . . . . . . . . . . . . . . . . . P544 Flauzino, J. A. . . . . . . . . . . . . . . . P618 Fliessbach, K. . . . . . . . . . . . . . . . . O42 Flores, J. M. . . . . . . . . . . . . . P672, P683 Flores Rivera, J. . . . . . . . . . . . . . . P398 Florez, S. . . . . . . . . . . . . . . . . . . P708 Floridia, D. . . . . . . . . . . . . . . . . . P262 Floris, R. . . . . . . . . . . . . . . . . . . O86 Floss, T. . . . . . . . . . . . . . . . . . . . P278 Flöth, F. W. . . . . . . . . . . . . . . . . . O47 Flourentzou, A. . . . . . . . . . . . . . . O196 Focaccetti, C. . . . . . . . . . . . . . . . P291 Fogdell-Hahn, A. . . . . . . . . . . . . . O179 Fomina, O. . . . . . . . . . . . . . . . . . O106 Fonseca, A. C. . . . . . . . . . . . . P442, P772 Fontaine, P. . . . . . . . . . . . . . . . . . P420 Foreman, A. . . . . . . . . . . . . . . . . P659 Forloni, G. . . . . . . . . . . . . . . . . . O54 Formica, F. . . . . . . . . . . . . . P633, P663 Fortea, J. . . . . . . . . . . . . . . . O55, P436 Fortunato, F. . . . . . . . . . P304, P613, P733

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Fotiou, D. . . . . . . . . . . . . . . . . . P632 Fouad, B. E. Z. . . . . . . . . . . . . . . . P673 Fracasso, V. . . . . . . . . . . . . . O85, O118 Fragata, I. . . . . . . . . . . . . . . . . . P232 Franceschini, C. . . . . . . . . . . . . . . P779 Franco Macías, E. . . . . . . . . . . . . . P687 Frank García, A. . . . . P585 P597, P688, P691 Franke, C. L. . . . . . . . . . . . . . . . . P451 Franzini, M. . . . . . . . . . . . . . . . . P617 Frascarelli, F. . . . . . . . . . . . . . . . . P264 Fratino, P. . . . . . . . . . . . . . . . . . . O48 Fredj, M. . . . . . . . . . . . . . . . P383, P523 Freedman, M. . . . . . . . . . . . P409, P760A Freedman, M. S. . . . . . . . . . . . . . . O219 Freilinger, T. . . . . . . . . . . . . . P275, P677 Friedrich, C. . . . . . . . . . . . . . . . . P352 Frings, M. . . . . . . . . . . . . . . . . . P384 Frisullo, G. . . . . . . . . . . . . . P404, P728 Fritschy, J. M. . . . . . . . . . . . . . . . P225 Fritz, D. . . . . . . . . . . . . . . . . O65, O67 Frosini, D. . . . . . . . . . . . . . . . . . P373 Fruguglietti, M. E. . . . . . . . . . . . . . P729 Fryer, A. A. . . . . . . . . . . . . . O144, P649 Fu, W. M. . . . . . . . . . . . . . . . . . . P365 Fubelli, F. . . . . . . . . . . . . . . . . . . P294 Fuentes, B. . . . . . . . . . . . O60, O61, O191, O214, P226, P345, P452 Fuglsang-Frederiksen, A. . . . . . . . . . P261 Fuhr, P. . . . . . . . . . O77, P321, P371, P431 Fujiwara, K. . . . . . . . . . . . . . P450, P485 Fumagalli, F. . . . . . . . . . . . . O161, P680 Funch, D. . . . . . . . . . . . . . . . . . . P411 Gabaldon, L. . . . . . O150, O191, O200, P345 Gabranis, I. . . . . . . . . . . . . . P281, P282 Gaindh, D. . . . . . . . . . . . . . . . . . O66 Gainotti, G. . . . . . . . . . . . . . . . . P592 Gais, S. . . . . . . . . . . . . . . . . . . . O198 Galanopoulos, A. . . . . . . . . . . P285, P743 Galantucci, S. . . . . . . . . . . . . . . . P565 Galassi, G. . . . . . . . . . . . . . . O50, P619 Galbiati, S. . . . . . . . . . . . . . . P633, P663 Galbussera, A. . . . . . . . . . . . . . . . P280 Galimberti, D. . . O54, O171, O173, P529, P530 Galistu, P. . . . . . . . . . . . . . . . . . P255 Gallardo, M. J. . . . . . . . . . . . . P672, P683 Galli, M. . . . . . . . . . . . . . . . O90, P361 Gallia, F. . . . . . . . . . . . . . . . . . . . O78 Galvin, L. . . . . . . . . . . . . . . . . . O151 Gambi, D. . . . . . . . . . . . . . . . . . P692 Gamer, M. . . . . . . . . . . . . . . . . . O136 Gandea, M. . . . . . . . . . . . . . P378, P498 Gandossini, S. . . . . . . . . . . . . . . . P610 Garabedian, B. . . . . . . . . . . . . . . . P426 Garavaglia, B. . . . . . . . . . . . . . . . . O82 Garceau, D. . . . . . . . . . . . . . . . . . O56 Garcés, M. . . . . . . . . . . . . . . . . . P320 Garcia, L. . . . . . . . . . . . . . . . . . . P468 García Alvarez, D. M. . . . . . . . . . . . P622 García Fernández, E. . . . . . . . . . . . P597 García Marín, V. . . . . . . . . . . . . . . P622 García Rodríguez, B. . . . . . . . . . . . P691 Garren, H. . . . . . . . . . . . . . . . . . P295 Garyfallos, G. . . . . . . . . . . . . . . . P656 Gasparini, M. . . . . . . . . . . . . . . . P594 Gass, A. . . . . . . . . . . . . O103, P371, P467 Gattellaro, G. . . . . . . . . . . . . . . . . O83 Gaudiello, F. . . . . . . . . . . . . . . . . . O86 Gauthier, S. . . . . . . . . . . . . . . . . . O56 Gawel, M. . . . . . . . . . . . . . . . . . P739 Geber, C. . . . . . . . . . . . . . . . . . . O111 Gebhardt, A. . . . . . . . . . . . . O128, P283 Gedizlioglu, M. . . . . . . . . . . . . . . P369 Geffard, M. . . . . . . . . . . . . . . . . . P412 Gekas, G. . . . . . . . . . . . P243, P285, P743 Gelagoti, M. . . . . . . . . . . . . . . . . P551 Gellera, C. . . . . . . . . . . . O85, O118, O122 Gemignani, F. . . . . . . . . . . . . . . . P327 Génin, E. . . . . . . . . . . . . . . . . . . O81

Genís, D. . . . . . . . . . . . . . . . . . . P476 Georgakakis, G. . . . . . . . P700, P701, P702 Georgakoudas, G. . . . . . . . . . . . . . P459 Georgoutsou, P. . . . . . . . . . . . . . . P681 Gerevini, S. . . . . . . . . . . . . . O161, P524 Gerriets, T. . . . . . . . . . . . . . . . . . P352 Geurts, J. J. G. . . . . . . . . . . . . . . . . O64 Ghafarpour, M. . . . . . . . . . . . . . . P661 Gharaeghouzli, K. . . . . . . . . . P375, P661 Ghazanshahi, S. . . . . . . . . . . . . . . P685 Gheorghe-Dane, R. L. . . . . . . . . . . . P298 Ghezzi, A. . . . . . . . . . . O100, O102, O177, P277, P536, P757 Ghezzi, S. . . . . . . . . . . . P279, P613, P733 Giacomelli, C. . . . . . . . . . . . . . . . P735 Gianettoni, J. . . . . . . . . . . . . . . . . P295 Giannakopoulou, A. . . . . . . . . . . . O146 Giannotta, C. . . . . . . . . . . . . . O78, P557 Gibson, F. . . . . . . . . . . . . . . . . . . O72 Gil-Nuñez, A. . . . . . . . . . . . . O214, P226 Giménez-Roldán, S. . . . . . . . . . . . . P595 Ginsberg, L. . . . . . . . . . . . . . . . . . O63 Giogkaraki, E. . . . . . . . . . . . . . . . P540 Giorelli, M. . . . . . . . . . . . . . . . . O145 Giovannini, M. . . . . . . . . . . . . . . . P615 Giovannoni, G. . . . . . . . . . . . . . . . O69 Girolami, F. . . . . . . . . . . . . . . O50, P619 Gironi, M. . . . . . . . . . . . . . . O76, P757 Giuliani, G. . . . . . . . . . . . . . P538, P759 Gizewski, E. R. . . . . . . . . . . . . O70, P384 Gkaraveli, M. . . . . . . . . . . . . . . . . P537 Glanzman, R. . . . . . . . . . . . . . . . P539 Glasauer, S. . . . . . . . . . . . . . . . . . P358 Glaser, M. . . . . . . . . . . . . . . . O40, P245 Glasmacher, A. . . . . . . . . . . . . . . . O42 Go, T. . . . . . . . . . . . . . . . . . . . . P386 Goebels, N. . . . . . . . . . . . . . . . . O142 Goertler, M. . . . . . . . . . . . . . . . . O202 Gokceer, S. . . . . . . . . . . . . . . . . . P630 Gokyigit, A. . . . . . . . . . . . . . . . . P513 Golaszewski, S. . . . . . . . . . . . . . . P561 Golba, A. . . . . . . . . . . . . . . . . . . P704 Gold, R. . . . . . . . . . . . . . . . P489, P662 Goldbrunner, R. . . . . . . . . . . . . . . P314 Golubovic, S. . . . . . . . . . . . . P388, P389 Gomez, M. . . . . . . . . . . . . . . . . . P742 Gomori, E. . . . . . . . . . . . . . . . . . P307 Goñi Imízcoz, M. . . . . . . . . . . . . . P687 González, M. . . . . . . . . . . . . . . . . P622 González Aguilar, A. . . . . . . . . . . . . P309 Gorani, F. . . . . . . . . . . . . . . . . . . P349 Gordo, R. . . . . . . . . . . . . . . . . . . P742 Gordo Mañas, R. . . . . . . . . . . . . . . P246 Gorodokin, G. . . . . . . . . . . . . . . . P750 Gorzelanczyk, E. . . . . . . . . . . . . . . P494 Gosselin, S. . . . . . . . . . . . . . . . . . P577 Göttken, T. . . . . . . . . . . . . . . . . . P651 Gottlob, I. . . . . . . . . . . . . . . . . . P292 Gottschalk, S. . . . . . . . . . . . . . . . P238 Gotwald, T. . . . . . . . . . . . . . . . . O132 Gourzis, P. . . . . . . . . . . . . . . P331, P439 Gow, D. . . . . . . . . . . . . . . . . . . . P527 Grad, A. . . . . . . . . . . . . . . . . . . P374 Graham, J. . . . . . . . . . . . . . . . . . O135 Grande, M. . . . . . . . . . . . . . . . . . P585 Grandi, M. . . . . . . . . . . . . . . . . . P610 Grau, A. J. . . . . . . . . . . . . . . . . . P575 Grau, S. . . . . . . . . . . . . . . . . . . . P769 Grauer, M. T. . . . . . . . . . . . . P344, P676 Graves, T. D. . . . . . . . . . . . . . . . . O119 Grazzi, L. . . . . . . . . . . . . . . . . . . O83 Greebe, P. . . . . . . . . . . . . . . . O59, O95 Gregoire, S. . . . . . . . . . . . . . . . . . P527 Greim, B. . . . . . . . . . . . . . . . . . . P753 Griebe, M. . . . . . . . . . . . . . . . . . P467 Grigoriadis, N. . . . . O146, P233, P360, P422 Gromadzka, G. . . . . . . . . . . . . . . . P449 Gros-Louis, F. . . . . . . . . . . . . . . . O117 Gross, H. . . . . . . . . . . . . . . . . . . O130

Gross, O. . . . . . . . . . . . . . . . . . . O152 Grosse, P. . . . . . . . . . . . . . . O197, O201 Groumas, N. . . . . . . . . . . . . . P266, P267 Grubneac, A. . . . . . . . . . . . . . . . . P761 Guarneri, D. . . . . . . . . . . . . . . . . O45 Gubieras, L. . . . . . . . . . . . . . O178, P646 Güclü, B. . . . . . . . . . . . . . . . . . . P504 Guerini, F. r. . . . . . . . . . . . . . . . . O76 Guerra, L. . . . . . . . . . . . . . . . . . P635 Guerreiro, M. . . . . . . . . . . . . . . . P376 Guerrero, A. L. . . . . . . . . . . . P531, P708 Guettard, E. . . . . . . . . . . . . . . . . P366 Gugala, M. . . . . . . . . . . . . . . . . . P686 Guglieri, M. . . . . . . . . . . . . . O52, P613 Guidi, I. . . . . . . . . . O54, O171, O173, P588 Guilhaume, C. . . . . . . . . . . . . . . . P462 Guillén, E. . . . . . . . . . . . . . . . . . P708 Guillevin, R. . . . . . . . . . . . . . . . . P382 Gulel, B. . . . . . . . . . . . . . . . . . . P488 Guo, Z. Y. . . . . . . . . . . . . . . . . . . P225 Gupta, A. . . . . . . . . . . . . . . . . . . P465 Guptha, S. H. . . . . . . . . . . . . . . . . P465 Gurses, C. . . . . . . . . . . . . . . . . . P513 Gutiérrez, A. . . . . . . . . . . . . . . . . P622 Gutiérrez, F. . . . . . . . . . . . . . P531, P708 Gutiérrez, M. . . . . . . . . . . . . . . . . P674 Gutierrez, P. . . . . . . . . . . . . . . . . P309 Gutiérrez Molina, M. . . . . . . . . . . . P597 Guveli, B. . . . . . . . . . . . . . . . . . . P513 Guy, C. . . . . . . . . . . . . . . . . . . . . O91 Guzmán de Villoria, J. . . . . . . . . . . . P698 Ha, C-G. . . . . . . . . . . . . . . . . . . P503 Ha, S. U. . . . . . . . . . . . . . . . . . . P429 Häberle, J. . . . . . . . . . . . . . . . . . P382 Habermeyer, B. . . . . . . . . . . . . . . P371 Hadjigeorgiou, G. . . . . . . P281, P282, P537 Haghighi, M. . . . . . . . . . . . . . . . . P547 Haghikia, A. . . . . . . . . . P310, P311, P543 Hakii, Y. . . . . . . . . . . . . . . . . . . P640 Hall, C. H. . . . . . . . . . . . . . . . . . O130 Halter, J. . . . . . . . . . . . . . . . . . . P431 Haluzova, A. . . . . . . . . . . . . . . . . P457 Hamad, N. . . . . . . . . . . . . . . . . . P744 Hamamci, A. . . . . . . . . . . . . . . . . P504 Hamann, G. F. . . . . . . . . . . . . . . . P231 Hamdy, S. . . . . . . . . . . . . . . . . . P400 Hamilton, W. B. . . . . . . . . . . . . . . O130 Hampshire, A. . . . . . . . . . . . . . . . O88 Han, G. . . . . . . . . . . . . . . . . . . . P724 Han, S. H. . . . . . . . . . . . . . . . . . P438 Han, Soo-Jeong . . . . . . . . . . . . . . . P714 Han, Soo-Jung . . . . . . . . . . . . . . . P453 Han, S. R. . . . . . . . . . . . . . . . . . P714 Hanagasi, H. . . . . . . . . . . . . . . . . P387 Hanna, M. G. . . . . . . . . . . . . . . . O119 Hanssens, Y. . . . . . . . . . . . . . . . . P306 Haque, A. . . . . . . . . . . . . . . . . . . P417 Haque, S. . . . . . . . . . . . . . . . . . . P417 Haraguchi, T. . . . . . . . . . . . . . . . P579 Harat, M. . . . . . . . . . . . . . . . . . . P494 Hardiman, O. . . . . . . . . O151, O209, P406, P602, P668, P670, P727, P737 Harms, L. . . . . . . . . . . . . . . . . . P272 Hartmann, A. . . . . . . . . . . . . . . . O207 Hartmann, K. . . . . . . . . . . . . P765, P766 Hartung, H-P. . . . . . . . . . . . O219, P760A Hasebe, N. . . . . . . . . . . . . . . . . . P450 Hatzizisi, O. . . . . . . . . . . . . . . . . P487 Havrdova, E. . . . O68, O104, P650, P752, P755 Hawkins, C. P. . . . . . . . . . . . O144, P649 Hefter, H. . . . . . . . . . . . . . . . . . O164 Heide, W. . . . . . . . . . . . . . . . . . . P236 Heider, P. . . . . . . . . . . . . . . . . . . P471 Heilmeyer-Kohler, H. . . . . . . . . . . . P655 Hein, L. . . . . . . . . . . . . . . . . . . . P351 Hein-Kropp, C. . . . . . . . . . . . . . . P384 Helmchen, C. . . . . . O155, P236, P237, P238

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Hennerici, M. . . . . . . . . . . . . . . . P467 Henriques, I. . . . . . . . . . . . . . . . . P232 Hentati, F. . . . . . . . . . . . . . . P396, P745 Heo, K. . . . . . . . . . . . . . . . . P301, P424 Heran, F. . . . . . . . . . . . . . . . . . . P367 Herber, M. . . . . . . . . . . . . . . P344, P676 Herman, M. . . . . . . . . . . . . . . . . O212 Hermann, D. M. . . . . . . . . . . . P225, P568 Hernández, A. . . . . . . . . . . . . P672, P683 Hernandez-Gallego, J. . . . . . . . . . . . P742 Herruzo, R. . . . . . . . . . . . . . . . . P585 Herzig, R. . . . . . . . . . . O131, O212, P348, P482, P483, P486, P492, P731 Herzog-Krzywoszanska, R. . . . . . . . . P689 Hess, D. C. . . . . . . . . . . . . . . . . . O130 Hesse, M. D. . . . . . . . . . . . . . P260, P583 Hevia-Montiel, N. . . . . . . . . . . . . . O213 Heydon, K. . . . . . . . . . . . . . . . . . . . 3 Hibbeln, R. . . . . . . . . . . . . . . . . . P289 Hidaka, T. . . . . . . . . . . . . . . . . . P696 Hideyama, T. . . . . . . . . . . . . . . . O210 Higueras, Y. . . . . . . . . . . . . . . . . P595 Hillert, J. . . . . . . . . . . . . . . . . . . O179 Hillier, J. . . . . . . . . . . . . . . . . . . P411 Himmelein, S. . . . . . . . . . . . . . . . O125 Himmelmann, M. . . . . . . . . . . . . . P289 Hinkerohe, D. . . . . . . . . P310, P311, P543 Hirsch, J. . . . . . . . . . . . . . . O103, P467 Hitchcock, A. . . . . . . . . . . . . . . . O135 Hladíková, M. . . . . . . . . . . . . . . . P270 Hlustik, P. . . . . . . . . . . O131, P482, P483 Hoban, P. . . . . . . . . . . . . . . . . . . O144 Hodapp, M. . . . . . . . . . . . . . O160, O164 Hoffmann, F. . . . . . . . . . P402, P651, P749 Hoffmann, L. A. . . . . . . . . . . . O46, P662 Hofstetter, H. H. . . . . . . . . . . . . . . P658 Hohlfeld, R. . . . . . . . . . . . . . . . . P662 Hold, R. . . . . . . . . . . . . . . . . . . P561 Holland, K. . . . . . . . . . . . . . . . . . P636 Hommet, C. . . . . . . . . . . . . . . . . O190 Hong, S-S. . . . . . . . . . . . . . . . . . P433 Hong, Y. . . . . . . . . . . . . . . . . . . P785 Honnorat, J. . . . . . . . . . . . . . O80, P548 Honoré, J. . . . . . . . . . . . . . . O139, P581 Hoock, S. B. . . . . . . . . . . . . . P344, P676 Hoppen, M. . . . . . . . . . . . . . . . . O187 Horak, D. . . . . . . . . . . . . . . . . . O212 Horakova, D. . . . . . . O68, P650, P752, P755 Horner, S. . . . . . . . . . . . . . . . . . O129 Hornung, J. . . . . . . . . . . . . . P290, P754 Houliara, V. . . . . . . . . . . . . . . . . O195 Hubbi, B. . . . . . . . . . . . . . . . . . . P547 Huber, W. . . . . . . . . . . . . . . . . . P583 Hüfner, K. . . . . . . . . . . . . . . . . . O125 Hughes, B. . . . . . . . . . . . . . . . . . P542 Huh, K. . . . . . . . . . . . . . . . . . . . P342 Huh, Y. B. . . . . . . . . . . . . . . . . . . P424 Humpert, S. . . . . . . . . . . . . . P283, P419 Hung, S. Y. . . . . . . . . . . . . . . . . . P365 Hunt, D. P. J. . . . . . . . . . . . . O184, P428 Huppert, D. . . . . . . . . . . . . . . . . P241 Hurn, P. . . . . . . . . . . . . . . . . . . P448 Hussein, S. . . . . . . . O65, O181, P752, P755 Hustinx, R. . . . . . . . . . . . . . O163, P578 Hwang, S-H. . . . . . . . . . . . . . . . . P433 Hwang, S-J. . . . . . . . . . . . . . . . . P329 Iarlori, C. . . . . . . . . . . . . . . . . . . P692 Ickenstein, G. W. . . . . . . . . . . . . . . P491 Iconomou, G. . . . . . . . . . . . . P331, P439 Idrovo, L. . . . . . . . . . . . . . . O191, P345 Iglesias, F. . . . . . . . . . . . . . . P531, P708 Ihara, Y. . . . . . . . . . . . . . . . P579, P723 Ilkhani, M. . . . . . . . . . . . . . . . . . P375 Illes, Z. . . . . . . . . . . . . P228, P307, P566 Inci, I. . . . . . . . . . . . . . . . . . . . P369 Inglot, E. . . . . . . . . . . . . . . . . . . P359 Inshasi, J. . . . . . . . . . . . . . . P496, P546

Inuggi, A. . . . . . . . . . . . . . . O168, P355 Ionova, T. . . . . . . . . . . . . . . . . . . P750 Iorio, R. . . . . . . . . . . . . . . . . . . P404 Irani, S. . . . . . . . . . . . . . . . . . . . P317 Irie, T. . . . . . . . . . . . . . . . . . . . P722 Irkec, C. . . . . . . . . . . . . . . . . . . P764 Isaias, I. U. . . . . . . . . . . . . . . . . . O105 Isenhardt, K. . . . . . . . . . . . . . . . . P744 Ishizu, H. . . . . . . . . . . . . . . . . . . P579 Isik, N. . . . . . . . . . . . . . . . . P347, P630 Italo, D. . . . . . . . . . . . . . . . . . . . P493 Iuliano, G. . . . . . . . . . . . . . . . . . P286 Ivanez, V. . . . . . . . . . . . . . . . . . . P505 Ivanov, R. . . . . . . . . . . . . . . . . . . P750 Ivanova, D. M. . . . . . . . . . . . . . . . P711 Iwahashi, Y. . . . . . . . . . . . . . . . . P640 Jablecki, J. . . . . . . . . . . . . . . . . . P518 Jackobs, C. . . . . . . . . . . . . . . . . . P670 Jafari, A. . . . . . . . . . . . P316, P554, P639 Jahn, K. . . . . . . . . . . . . . . . P241, P769 Jaiser, S. R. . . . . . . . . . . . . . . . . . P552 Jakeman, P. . . . . . . . . . . . . . . . . . P727 Jakóbkiewicz-Banecka, J. . . . . . . . . . P771 Jakobsen, J. . . . . . . . . . . . . . . . . . P261 Jang, S. S. . . . . . . . . . . . . . . . . . . P730 Janik, P. . . . . . . . . . . . . . . . O107, P738 Jansa, P. . . . . . . . . . . . . . . . . . . . P783 Jarius, S. . . . . . . . . . . . . . . . . . . P716 Jastorff, A. . . . . . . . . . . . . . . . . . P754 Jaszczuk, A. . . . . . . . . . . . . . . . . P684 Jeffery, D. . . . . . . . . . . . . . . . . . . P407 Jeffries, N. . . . . . . . . . . . . . . . . . O120 Jenkinson, P. . . . . . . . . . . . . . . . . P649 Jenni, W. . . . . . . . . . . . . . . . . . . . O89 Jeong, S. H. . . . . . . . . . . . . . . . . . P239 Jeong, S. W. . . . . . . . . . . . . . . . . P430 Jerabek, J. . . . . . . . . . . . . . . . . . P362 Jergovic, K. . . . . . . . . . . P303, P493, P748 Jha, A. . . . . . . . . . P316, P554, P555, P639 Jiménez-Escrig, A. . . . . . . . . . . . . . P549 Jiroutek, P. . . . . . . . . . . . . . . . . . P780 Jo, H. Y. . . . . . . . . . . . . . . . . . . . P694 Johansen-Berg, H. . . . . . . . . . . . . . O91 Jones, J. L. . . . . . . . . . . . . . . . . . O143 Joniec, I. . . . . . . . . . . . . . . . . . . P421 Jønsson, A. . . . . . . . . . . . . . . . . . P416 Joo, I. S. . . . . . . . . . . . . . . . . . . P342 Jost, V. . . . . . . . . . . . . . . . . . . . P647 Journiac, N. . . . . . . . . . . . . . . . . P426 Jousserand, G. . . . . . . . . . . . . . . . O80 Judica, E. . . . . . . . . . . . O101, O177, P536 Jung, H. Y. . . . . . . . . . . . . . . . . . P259 Jung, S. . . . . . . . . . . . . . . . . . . . P433 Jura, R. . . . . . . . . . . . . . . . . . . . P457 Jürgens, A. . . . . . . . . . . . . . . . . . O42 Kacar, K. . . . . . . . . . . . . . . . . . . O177 Kachuck, N. . . . . . . . . . . . . . . . . P295 Kadanka, Z. . . . . . . . . . . . . . P270, P484 Kadzinski, L. . . . . . . . . . . . . . . . . P771 Kagadis, G. . . . . . . . . . . . . . P625, P707 Kakita, A. . . . . . . . . . . . . . . . . . O210 Kalaboki, E. . . . . . . . . . . . . . . . . P743 Kalafatis, E. . . . . . . . . . . P700, P701, P702 Kalamafkianaki, K. . . . . . P700, P701, P702 Kalbarczyk, A. . . . . . . . . . . . . . . . O107 Kalbermatten, D. . . . . . . . . . . . . . . O77 Kalfakis, N. . . . . . . . . . . . . . O170, O174 Kalliolia, E. . . . . . . . . . . . . . . . . . P632 Kallweit, U. . . . . . . . . . . . . . . . . . P781 Kalofonos, H. . . . . . . . . . . . . P331, P439 Kalokerinou, K. . . . . . . . . . . . P266, P267 Kalousová, M. . . . . . . . . . . . . . . . P780 Kalpakidis, V. . . . . . . . . . . . . . . . P564 Kamensky, A. A. . . . . . . . . . . . . . . P711 Kamin, F. . . . . . . . . . . . . . . P402, P749 Kaminska, A. M. . . . . . . . . . . . . . . P609 Kanovsky, P. . . . . . . . . . O131, O212, P249,

P348, P482, P483, P486, P492, P556, P731 Kapeller, P. . . . . . . . . . . . . . . . . . O140 Kaplan, Y. . . . . . . . P326, P520, P623, P624 Kappelle, L. J. . . . . . . . . . . . . . . . . O87 Kappos, L. . . . . . . . . . O103, O142, O219, P409, P734, P760A Kaps, M. . . . . . . . . . . . . . . . . . . O152 Karachalios, G. . . . . . . . . . . . P274, P533 Karachristianou, S. . . . . . . . . . . . . P487 Karadima, G. . . . . . . . . . . . . . . . . P274 Karadreas, N. . . . . . . . . . . . . . . . P441 Karaer, H. . . . . . . . . . . . P326, P520, P624 Karahalios, G. . . . . . . . . . . . O170, O174 Karakostas, D. . . . . . . . . P499, P665, P669 Karamanidis, C. . . . . . . . . . . . . . . P632 Karantanas, A. . . . . . . . . . . . . . . . P282 Karantani, N. . . . . . . . . . . . . . . . P669 Karantoni, E. . . . . . . . . . . . . . . . . P534 Karaszewski, B. . . . . . . . . . . . . . . P675 Karatas, M. . . . . . . . . . . . . . . . . . P717 Karatzaferis, L. . . . . . . . . P700, P701, P702 Karlikaya, G. . . . . . . . . . . . . . . . . P504 Karlovasitou, A. . . . . . . . . . . . . . . P632 Karlsson, T. . . . . . . . . . . . . . . . . P779 Karouli, M. . . . . . . . . . . P274, P540, P653 Karussis, D. . . . . . . . . . . . . . . . . O146 Kasahata, N. . . . . . . . . . . . . . . . . P696 Kasatkin, D. . . . . . . . . . . . . . . . . P654 Kasper, I. . . . . . . . . . . . . . . . . . . P417 Kasper, L. . . . . . . . . . . . . . . . . . P417 Kassubek, J. . . . . . . . . . . . . . . . . P495 Kastenbauer, S. . . . . . . . . . . . . . . O124 Kastritis, E. . . . . . . . . . . . . . . . . P441 Kastrup, O. . . . . . . . . . . . . . . . . . P768 Katayama, T. . . . . . . . . . . . . P450, P485 Katsarava, Z. . . . . . . . . . . . . . . . . P768 Katsarou, Z. . . . . . . . . . . . . . . . . P487 Katsigiannopoulos, K. . . . . . . . . . . P656 Kawarabayashi, T. . . . . . . . . . . . . . P756 Kawarai, T. . . . . . . . . . . . . . . . . . O86 Kazibutowska, Z. . . . . . . . . . . . . . P704 Keckarevic, D. . . . . . . . . . . . . P432, P497 Keckarevic-Markovic, M. . . . . . P432, P497 Kecmanovic, M. . . . . . . . . . . . P432, P497 Keles, N. . . . . . . . . . . . . . . . . . . P394 Kellett, M. . . . . . . . . . . . . . . . . . P555 Kemlink, D. . . . . . . . . . . . . . . . . P784 Kendall, B. . . . . . . . . . . . . . . . . . O63 Keren, B. . . . . . . . . . . . . . . . . . . P366 Kerkovsky, M. . . . . . . . . . . . . . . . P484 Kern, R. . . . . . . . . . . . . . . . . . . P467 Kerzberg, M. . . . . . . . . . . . . . . . . P410 Kettern, M. . . . . . . . . . . . . . . . . . P306 Khajeh Daluee, M. . . . . . . . . . . . . . P322 Khan, K. . . . . . . . . . . . . . . . . . . O151 Khatami, R. . . . . . . . . . . . . . O197, O199 Kholghi, Y. . . . . . . . . . . . . . . . . . P375 Kikuchi, K. . . . . . . . . . . . . . . . . . P450 Kilic, E. . . . . . . . . . . . . . . . P225, P568 Kilidireas, C. . . . . . . . . . . . . P441, P600 Killer, H. E. . . . . . . . . . . . . . . . . . P300 Kim, Byung Jo . . . . . . . . . . . . P481, P726 Kim, Byoung-Joon . . . . . . . . . . P395, P666 Kim, B. S. . . . . . . . . . . . . . . . . . . P500 Kim, C. H. . . . . . . . . . . . . . . . . . P395 Kim, D. L. . . . . . . . . . . . . . . . . . P438 Kim, D. W. . . . . . . . . . . . . . . . . . P430 Kim, E. J. . . . . . . . . . . . . . . . . . . P785 Kim, G. S. . . . . . . . . . . . . . . . . . P302 Kim, G. W. . . . . . . . . . . . . . . . . . P424 Kim, Hee . . . . . . . . . . . . . . . . . . P724 Kim, Hyun. . . . . . . . . . . . . . . . . . P724 Kim, Hyun Jung. . . . . . . . . . . . . . . P424 Kim, Hyo-Jeong . . . . . . . . . . . . . . . P239 Kim, Hee Jin . . . . . . . . . . . . . P438, P785 Kim, Ho-Jung . . . . . . . . . . . . . . . . P481 Kim, H. Y. . . . . . . . . . . . . . . . . . P438 Kim, I. H. . . . . . . . . . . . . . . . . . O202

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Kim, J-M. . . . . . . . . . . . . . . . . . . P503 Kim, J-S. . . . . . . . . . . . . . . . . . . P720 Kim, J. . . . . . . . . . . . . . . . . . . . P724 Kim, J. E. . . . . . . . . . . . . . . . . . . P502 Kim, J. H. . . . . . . . . . . . . . . . . . . P395 Kim, J. K. . . . . . . . . . . . . . . . . . . P429 Kim, J. S. . . . . . . . . . . . . . . . . . . P239 Kim, J. W. . . . . . . . . . . . . . . . . . P694 Kim, K. J. . . . . . . . . . . . . . . . . . . P323 Kim, Kwang Sik. . . . . . . . . . . . . . . O187 Kim, Kwang-Soo . . . . . . . . . . . . . . P429 Kim, M. J. . . . . . . . . . . . . . . . . . P429 Kim, Myeong Kyu. . . . . . . . . . . . . . P562 Kim, Min-Ky . . . . . . . . . . . . . P395, P666 Kim, M. S. . . . . . . . . . . . . . . . . . P395 Kim, S-B. . . . . . . . . . . . . . . . . . . P329 Kim, S. . . . . . . . . . . . . . . . . . . . P724 Kim, Sang Ho . . . . . . . . . . . . . . . . P694 Kim, Seo Hyun . . . . . . . . . . . . P302, P350 Kim, S. M. . . . . . . . . . . P301, P443, P726 Kim, T. H. . . . . . . . . . . . . . . P259, P454 Kim, W. K. . . . . . . . . . . . . . . . . . P776 Kim, Y. B. . . . . . . . . . . . . . . . . . . P301 Kim, Y. I. . . . . . . . . . . . . . . . P500, P714 Kimmig, H. . . . . . . . . . . . . . . . . P236 Kimura, K. . . . . . . . . . . . . . . P590, P640 Kimura, T. . . . . . . . . . . . . . . P450, P485 King, J. . . . . . . . . . . . . . . . . . . . O69 King, M. . . . . . . . . . . . . . . . . . . P670 Kinter, J. . . . . . . . . . . . . . . . . . . . O77 Kinugawa, K. . . . . . . . . . P315, P367, P426 Kirby, S. . . . . . . . . . . . . . . . . . . O218 Kirsch, M. . . . . . . . . . . . . . . . . . O163 Kirschning, C. . . . . . . . . . . . O124, P645 Kirzinger, S. . . . . . . . . . . . . . . . . P284 Kisacik, B. . . . . . . . . . . . . . . . . . P326 Kischka, U. . . . . . . . . . . . . . . . . . O91 Kiseliova, A. . . . . . . . . . . . . . . . . O106 Kishida, H. . . . . . . . . . . . . . P590, P640 Kishtovich, A. . . . . . . . . . . . . . . . P750 Kitchener, N. . . . . . . . . . . . . O134, P673 Kkolou, E. . . . . . . . . . . . . . . . . . O196 Klauer, T. . . . . . . . . . . . . . . . . . . P753 Klein, M. . . . . . . . . . . . . . . O126, P645 Kleinschnitz, C. . . . . . . . . . . . . . . P351 Klempir, J. . . . . . . . . . . . . . . P247, P368 Klempirova, O. . . . . . . . . . . . . . . . P368 Klimkowicz-Mrowiec, A. . . P230, P570, P689 Klironomos, G. . . . . . . . . . . . . . . P370 Klockgether, T. . . . . . . . . . . . . . . . O42 Klopstock, T. . . . . . . . . . P231, P278, P427 Kneifel, N. . . . . . . . . . . . . . . . . . O152 Knop, M. . . . . . . . . . . . . . . . P290, P754 Kobayashi, A. . . . . . . . . . . . . . . . P449 Koçer, A. . . . . . . . . . . . . . . . P268, P522 Kocer, B. . . . . . . . . . . . . . . . . . . P764 Koçer, E. . . . . . . . . . . . . . . . . . . P268 Koch, H. J. . . . . . . . . . . . . . . . . . P491 Kocher, M. . . . . . . . . . . . . . . . . . O212 Koedel, U. . . . . . . . . . . O124, O126, P645 Koehler, J. . . . . . . . . . . . . . . . . . O176 Koehler, P. J. . . . . . . . . . . . . . . . . P642 Koehler, W. . . . . . . . . . . . . . P402, P749 Koenig, N. . . . . . . . . . . . . . . . . . P753 Kogoj, A. . . . . . . . . . . . . . . . . . . P593 Koh, H. S. . . . . . . . . . . . . . . . . . P629 Koh, S-H. . . . . . . . . . . . . . . . . . . P724 Kohler, J. . . . . . . . . . . . . . . . . . . P655 Köhler, W. . . . . . . . . . . . . . . . . . P651 Kokotis, P. . . . . . . . . . . . . . . . . . P604 Kolia, P. . . . . . . . . . . . . . . . . . . . P537 Kollaras, P. . . . . . . . . . . . . . . . . . P391 Kollarova, K. . . . . . . . . . . . . . . . . P731 Kollias, S. . . . . . . . . . . . . . . P251, P252 Komnos, A. . . . . . . . . . . . . . P281, P282 Komoly, S. . . . . . . . . . . . . . . P228, P566 Kömpf, D. . . . . . . . . . . . . . . P236, P237 Kondziella, D. . . . . . . . . . . . . . . . P418 Konishi, Y. . . . . . . . . . . . . . . . . . P386

Konstantinopoulou, A. . . . . . . . P533, P559 Konstantopoulos, K. . . . . . . . . . . . . P287 Kontaxis, T. . . . . . . . . . . . . . O170, O174 Kontou, C. . . . . . . . . . . . . . . . . . P604 Koo, J. W. . . . . . . . . . . . . . . . . . . P239 Koppelstaetter, F. . . . . . . . . . . . . . O132 Korakaki, D. . . . . . . . . . P700, P701, P702 Korkosz, A. . . . . . . . . . . . . . . . . . P686 Kosmidis, E. K. . . . . . . . . . . . . . . P360 Kostalova, M. . . . . . . . . . . . . . . . P457 Kostera-Pruszczyk, A. . . . . . . . . . . O116 Kostic, V. S. . . . . . . . . . . . . . . . . O108 Koszewicz, M. . . . . . . . . . . . . P480, P518 Kotani, T. . . . . . . . . . . . . . . . . . . P696 Kotowicz, J. . . . . . . . . . . . . . O203, P220 Kotta, K. . . . . . . . . . . . . . . . O146, P422 Kouperberg, E. . . . . . . . . . . . . . . O204 Kouroumalos, N. . . . . . . . P700, P701, P702 Kourtesi, G. . . . . . . . . . . . . . . . . P487 Koutoula, O. . . . . . . P313, P515, P621, P697 Koutras, A. . . . . . . . . . . . . . P331, P439 Koutsis, G. . . . P274, P533, P534, P540, P653 Koutsona, C. . . . . . . . . . . . . . . . . P647 Koutsouraki, E. . . . . . . . . . . . . . . P762 Kovanlikaya, I. . . . . . . . . . . . . . . . P504 Koyama, S. . . . . . . . . . . . . . . . . . P450 Koyano, S. . . . . . . . . . . . . . . P590, P640 Kozak, O. S. . . . . . . . . . . . . . . . . . O58 Kozera, G. . . . . . . . . . . . . . . . . . P526 Kozlowski, O. . . . . . . . . . . . . . O93, P420 Kozub-Doros, I. . . . . . . . . . . . . . . P693 Kral, M. . . . . . . . . . . . O131, O212, P348 Krämer, H. H. . . . . . . . . . . . . . . . O154 Krarup, C. . . . . . . . . . . . . . . . . . O115 Krasenbrink, I. . . . . . . . . . . . . . . O152 Krasensky, J. . . . . . . . . . . . . . O68, P650 Krasulova, E. . . . . . . . . . . . . . . . O104 Kraus, J. . . . . . . . . O187, P561, P765, P766 Krcova, V. . . . . . . . . . . . . . . . . . P348 Krejsek, J. . . . . . . . . . . . . . . . . . P403 Kress, B. . . . . . . . . . . . . . . . . . . P647 Kretz, R. . . . . . . . . . . . . . . . . . . O197 Kreuzfelder, E. . . . . . . . . . . . . . . . P528 Krichmayr, M. . . . . . . . . . . . . . . . P569 Kritzmann, S. . . . . . . . . . . . . . . . O136 Krogias, C. . . . . . . . . . . . . . . . . . P489 Krommyda, M. . . . . . . . . . . . . . . . P415 Kroner, A. . . . . . . . . . . . . . . . . . P401 Kroschinsky, F. . . . . . . . . . . . . . . . O42 Kruger, M. . . . . . . . . . . . . . . . . . P318 Krumbholz, M. . . . . . . . . . . . O182, P662 Krysa, W. . . . . . . . . . . . . . . . . . . P609 Krzywoszanski, L. . . . . . . . . . . . . . P689 Kuchukhidze, G. . . . . . . . . . . . . . . O132 Kucukoglu, H. . . . . . . . . . . . . . . . P221 Kuempfel, T. . . . . . . . . . . . . . . . . O46 Kugimoto, C. . . . . . . . . . . . . . . . . P640 Kuhle, J. . . . . . . . . . . . . . . . . . . P734 Kullmann, D. M. . . . . . . . . . . . . . . O119 Kumar, M. . . . . . . . . . . . . . . . . . P528 Kumar, S. . . . . . . . . . . . . . . . . . . P306 Kümpfel, T. . . . . . . . . . . . . . . . . P662 Kumru, H. . . . . . . . . . . . . . . O153, P357 Kunicka, K. . . . . . . . . . . . . . . . . . P526 Kunkel, A. . . . . . . . . . . . . . . . . . P651 Kunze, S. . . . . . . . . . . . . . . . . . . P289 Kupers, R. . . . . . . . . . . . . . . . . . O156 Kupsch, A. . . . . . . . . . . . . . . . . . O201 Kuran, W. . . . . . . . . . . . . . . . . . P686 Kurkowska-Jastrzebska, I. . . . . . . . . P421 Kuroda, K. . . . . . . . . . . . . . . P450, P485 Kuroda, S. . . . . . . . . . . . . . . . . . P579 Kuroiwa, Y. . . . . . . . . . . . . . P590, P640 Kurt, S. . . . . . . . . . P326, P520, P624, P764 Kurtuncu, M. . . . . . . . . O147, O158, P240, P394, P775 Kutz, K. . . . . . . . . . . . . . . . . . . . P605 Kuzma, M. . . . . . . . . . . . . . . P732, P738 Kuznetcov, A. . . . . . . . . . . . . . . . P750

Kwak, S. . . . . . . . . . . . . . . . . . . O210 Kwiecinski, H. . . . . . . . . P732, P738, P739 Kwon, D. Y. . . . . . . . . . . . . . . . . . P481 Kwon, J. H. . . . . . . . . . . . . . P453, P490 Kwon, K-H. . . . . . . . . . . . . . . . . P433 Kwon, S-B. . . . . . . . . . . . . . . . . . P433 Kwon, S. J. . . . . . . . . . . . . . . . . . P253 Kyriakidou, E. . . . . . . . . . . . . . . . P681 Kyriazis, G. . . . . . . . . . . . . . . . . . P487 Kyrozis, A. . . . . . . . . . . . . . . . . . O148 Labauge, P. . . . . . . . . . . . . . . . . . P409 Labiris, C. . . . . . . . . . . . P700, P701, P702 Labreuche, J. . . . . . . . . . . . . . . . . P223 Labuz-Roszak, B. . . . . . . . . . . . . . P664 Lacour, A. . . . . . . . . . . . . . . . . . P611 Lacroix, C. . . . . . . . O79, P444, P445, P517 Ladurner, G. . . . . . . . . . . . . . . . . P561 Lagoudaki, R. . . . . . . . . . P415, P422, P767 Laguzzi, E. . . . . . . . . . . . . . . . O43, O45 Laherrán, E. . . . . . . . . . . . . . . . . P531 Lahjibi-Paulet, H. . . . . . . . . . . . . . P458 Lai, S-L. . . . . . . . . . . . . . . . . . . . O57 Laird, H. . . . . . . . . . . . . . . . . . . . O72 Lalli, S. . . . . . . . . . . . . . . . . . . . O109 Lalueza, A. . . . . . . . . . . . . . . . . . P742 Lambert, J-C. . . . . . . . . . . . . . . . P426 Lambertenghi Deliliers, G. . . . . . . . . P596 Lamperti, C. . . . . . . . . . . . . P279, P304, P613, P614 Lamperti, E. . . . . . . . . . . . . . . . . O43 Lamprecht, S. . . . . . . . . . . . . . . . P397 Land, S. . . . . . . . . . . . . . . . . . . . P297 Lander, C. M. . . . . . . . . . . . . . . . O135 Langdon, D. . . . . . . . . . . . . . . . . P649 Langen, K. J. . . . . . . . . . . . . . . . . O47 Lanius, V. . . . . . . . . . . . . . . . . . P760A Lapierre, Y. . . . . . . . . . . . . . . . . . P295 Lapitskaya, N. . . . . . . . . . . . . . . . P261 Larsson, H. . . . . . . . . . . . . . . . . . P416 Larsson, N. G. . . . . . . . . . . . . . . . . 20 Lasjaunias, P. . . . . . . . . . . . . . . . . O71 Laskowska, I. . . . . . . . . . . . . . . . . P494 Latov, N. . . . . . . . . . . . . . . . . . . . O77 Laureys, S. . . . . . . . O88, O156, O163, O167, O183, O186, P269, P578 Lauria, G. . . . . . . . . . . . . . . . . . P710 Laurin, J. . . . . . . . . . . . . . . . . . . O56 Lavadinho, I. . . . . . . . . . . . . . . . . P635 Lavini, C. . . . . . . . . . . . . . . . . . . O50 Lavrnic, D. . . . . . . . . . . . . . . . . . P235 Lazarovici, C. . . . . . . . . . . . . . . . P458 Lazoura, O. . . . . . . . . . . . . . P266, P267 Lazzaro, F. . . . . . . . . . . . . . . O85, O118 Lazzerini, A. . . . . . . . . . . . . . . . . P328 Leake, A. . . . . . . . . . . . . . . . . . . O72 Lebrato, N. . . . . . . . . . . . . . . . . . P549 Lebrun, C. . . . . . . . . . . . . . . P271, P567 Ledoux, D. . . . . . . . . . . . . . O186, P269 Lee, B. H. . . . . . . . . . . . . . . . . . . P454 Lee, B. I. . . . . . . . . . . . . . . . . . . P424 Lee, B. R. . . . . . . . . . . . . . . . . . . P454 Lee, D. G. . . . . . . . . . . . . . . P500, P714 Lee, D. H. . . . . . . . . . . . . . . . . . . P481 Lee, D. K. . . . . . . . . . . . . . . . . . . P323 Lee, H. W. . . . . . . . . . . . . . . . . . P785 Lee, I. K. . . . . . . . . . . . . . . . . . . P438 Lee, J-Y. . . . . . . . . . . . . . . . . . . . P350 Lee, Jun . . . . . . . . . . . . . . . . . . . P343 Lee, Ju-Hun . . . . . . . . . . . . . . . . . P776 Lee, Jun Hong . . . . . . . . . . . . . . . . P302 Lee, Jung Hwa . . . . . . . . . P443, P582, P785 Lee, J. J. . . . . . . . . . . . . . . . . . . . P502 Lee, J. M. . . . . . . . . . . . . . . . . . . P481 Lee, K-Y. . . . . . . . . . . . . . . . . . . P724 Lee, K. R. . . . . . . . . . . . . . . . . . . P562 Lee, K. S. . . . . . . . . . . . P453, P666, P714 Lee, P. H. . . . . . . . . . . . . . . . . . . P342 Lee, R. . . . . . . . . . P316, P317, P554, P555

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Lee, S. . . . . . . . . . . . . . . . . . . . . P454 Lee, S. B. . . . . . . . . . . . . . . . . . . P582 Lee, S. H. . . . . . . . . . . . . . . P239, P562 Lee, Soo-Joo . . . . . . . . . . . . . . . . . P454 Lee, Se Jin . . . . . . . . . . . . . . . P343, P502 Lee, S. S. . . . . . . . . . . . . . . . . . . P350 Lee, Y. . . . . . . . . . . . . . . . . . . . . P724 Lee, Y. H. . . . . . . . . . . . . . . . . . . P503 Lehmensiek, V. . . . . . . . . . . . P516, P725 Lehnen, N. . . . . . . . . . . . . . . . . . P358 Leist, T. . . . . . . . . . . . . . . . . . . . P407 Lenzi, G. L. . . . . . . . . . . . . . O175, P594 Leocani, L. . . . . . . . O109, O168, P355, P356 León, L. . . . . . . . . . . . . . . . O166, P477 Leoncini, B. . . . . . . . . . . . . . . . . . O45 Leone, A. . . . . . . . . . . . . . . . . . . P440 Leone, M. . . . . . . . . . . . . . . . . . O193 Lepeintre, J. F. . . . . . . . . . . . . . . . P367 Letourneau, K. . . . . . . . . . . . . . . . P577 Leu, S. . . . . . . . . . . . . . . . . P366, P367 Levandis, G. . . . . . . . . . . . . . . . . P596 Levisohn, P. . . . . . . . . . . . . . . . . P636 Levitskaya, N. G. . . . . . . . . . . . . . . P711 Leyendecker, S. . . . . . . . . . . . . . . O155 Leys, D. . . . . . . . . . . . . . . . . . . . . 39 Li, D. . . . . . . . . . . . . . . . . . . . . P539 Lia, A. . . . . . . . . . . . . . . . . . . . . P414 Liao, Z. . . . . . . . . . . . . . . . . . . . P425 Lienert, C. . . . . . . . . . . . . . . . . . P283 Liguori, R. . . . . . . . . . . . . . . O73, P779 Lim, A. . . . . . . . . . . . . . . . . . . . P425 Lim, J. G. . . . . . . . . . . . . . . . . . . P730 Limmroth, V. . . . . . . . . . . . . . . . . P528 Lindberg, R. L. P. . . . . . . . . . . O142, P734 Lindley, R. . . . . . . . . . . . . . . . . . P639 Link, J. . . . . . . . . . . . . . . . . . . . P648 Linn, J. . . . . . . . . . . . . . . . . P463, P769 Linnebank, M. . . . . . . . . . . . . . . . O42 Lisak, M. . . . . . . . . . . . . . . . . . . P474 Lisak, R. P. . . . . . . . . . . . . . . . . . P297 Lisukov, I. . . . . . . . . . . . . . . . . . P750 Liu, W. C. . . . . . . . . . . . . . . . . . . P547 Livrea, P. . . . . . . . . . . . O145, O211, P414 Lladó, A. . . . . . . . . . . . . . . . . . . O55 Lladó, E . . . . . . . . . . . . . . . . . . . P477 Llanero Luque, M. . . . . . . . . . . . . . P688 Llinares, I. . . . . . . . . . . . . . . . . . P580 Llufriu, S. . . . . . . . . . . . . . . P333, P634 Locatelli, F. . . . . . . . . . . P633, P663, P733 Lojek, E. . . . . . . . . . . . . . . . . . . P686 Lojkowska, W. . . . . . . . . . . . . P392, P686 Lopes Lima, J. . . . . . . . . . . . . . . . P746 Loreth, R. M. . . . . . . . . . . . . . . . . P344 Lotfi, J. . . . . . . . . . . . . . . . . . . . P405 Lotz-Bläuer, I. . . . . . . . . . . . . . . . P371 Louis, S. . . . . . . . . . . . . . . . . . . P760 Loukaidis, P. . . . . . . . . . . . . . . . . P534 Lourbopoulos, A. . . . . . . . . . . O146, P233 Lovati, C. . . . . . . . . . . . . . . . O54, O173 Lovrencic-Huzjan, A. . . . . . . . . . . . P303 Lozeron, P. . . . . . . . O79, P444, P445, P517 Lozza, A. . . . . . . . . . . . . . . . . . . O48 Lu, C-J. . . . . . . . . . . . . . . . . . . . O57 Lu, M. . . . . . . . . . . . . . . . . . . . . P425 Lucchiari, S. . . . . . . . . . . . . . P614, P615 Lucchini, V. . . . . . . . . . . . . . P304, P729 Lüdemann, W. . . . . . . . . . . . . . . . P418 Ludolph, A. C. . . . . . . . . . . . . P725, P732 Luethi, N. . . . . . . . . . . . . . . . . . O128 Lugo-Pon, A. A. . . . . . . . . . . . . . . P248 Luigetti, M. . . . . . . . . . . . . . . . . . P728 Lundblad, L. . . . . . . . . . . . . . . . . O154 Lupescu, T. D. . . . . . . . . . . . . . . . P298 Lusakowska, A. . . . . . . . . . . . . . . P609 Luthringshausen, G. . . . . . . . . . . . . P561 Luxen, A. . . . . . . . . . . . . . . O156, O167 Maccagnano, C. . . . . . . . . . . . . . . . O43 Macek, K. . . . . . . . . . . . . . . . . . P220

Machner, B. . . . . . . . . . . P236, P237, P238 Mader, M. . . . . . . . . . . . . . . . . . P427 Madureira, S. . . . . . . . . . . . . . . . P376 Maertens de Noordhout, A. . . . . . . . O169 Maestro, I. . . . . . . . . . . . . . . . . . P634 Maggi, L. . . . . . . . . . . . . . . . . . . P710 Maghzi, A. H. . . . . . . . . . . . . P227, P532 Magnani, G. . . . . . . . . . . . . . O109, P356 Magri, F. . . . . . . . . . . . . . . . . . . P613 Magureanu, S. . . . . . . . . . . . . P378, P498 Magyar, T. . . . . . . . . . . . . . . . . . P560 Magyarlaki, T. . . . . . . . . . . . . . . . P307 Mahagne, M. . . . . . . . . . . . . . . . . P567 Maia, M. . . . . . . . . . . . . . . . . . . P635 Maier, H. . . . . . . . . . . . . . . . . . . O132 Majerus, S. . . . . . . . . . . . . . O183, P269 Majós, C. . . . . . . . . . . . . . . . . . . P339 Makita, Y. . . . . . . . . . . . . . . P450, P485 Malaguti, M. . . . . . . . . . . . . . . . . P328 Malicka, J. . . . . . . . . . . . . . . . . . P392 Malikkidou, A. . . . . . . . . . . . . . . O196 Mall, V. . . . . . . . . . . . . . . . . . . . O160 Mallat, Z. . . . . . . . . . . . . . . . . . . P426 Manara, R. . . . . . . . . . . . . . . . . . O63 Mancardi, G. . . . . . . . . . . . . . . . . P288 Mancuso, M. . . . . . . . . . . . . P373, P735 Mandellos, D. . . P274, P533, P534, P540, P653 Mandrekar, J. . . . . . . . . . . . . . . . . O49 Manga, E. G. . . . . . . . . . . . . . . . . P599 Mangas, A. . . . . . . . . . . . . . . . . . P412 Mann, D. . . . . . . . . . . . . . . . . . . P426 Manta, P. . . . . . . . . . . . . . . . P603, P604 Manti, C. . . . . . . . . . . . . . . . . . . P681 Mantovani, F. . . . . . . . . . . . . . . . P598 Manzoli, L. . . . . . . . . . . . . . . . . . P363 Maquet, P. . . . . . . . O88, O156, O167, O198 Marcatti, M. . . . . . . . . . . . . . . . . P308 Marceglia, S. . . . . . . . . . . . . . . . . P440 Marchesi, C. . . . . . . . . . . . . . . . . . O52 Marchi, M. D. . . . . . . . . . . . . . . . P620 Marchioni, E. . . . . . . . . . . . . . . . O123 Marcon, E. . . . . . . . . . . . . . . . . . P419 Marczinsky, U. . . . . . . . . . . . . . . . P774 Mareckova, H. . . . . . . . . . . . . . . . O104 Maresˇ, J. . . . . . . . . . . . . . . . . . . P492 Mari, I. . . . . . . . . . . . . . . . . . . . P367 Mariani, C. . . . . . . . . . . . . . . O54, O173 Mariani, J. . . . . . . . . . . . . . . . . . P426 Marino, S. . . . . . . . . . . . . . . . . . P262 Marion, M. . . . . . . . . . . . . . . . . . O72 Mariotti, C. . . . . O82, O83, O85, O118, O122 Marjanovic, I. . . . . . . . . . . . . . . . P235 Markaki, E. . . . . . . . . . . . . . P250, P370 Markakis, I. . . . . . . . . . . . . . . . . P243 Maroco, M. . . . . . . . . . . . . . P437, P719 Marouf, H. . . . . . . . . . . . . . . P558, P713 Marousi, S. . . . . . . . . . . . . . P250, P370 Marques Jr., W. . . . . . . . . . . . . . . P618 Marra, C. . . . . . . . . . . . . . . P592, P612 Marrero, R. . . . . . . . . . . . . . . . . . P622 Marshall, A. . . . . . . . . . . . . . . . . P527 Marti, M. J. . . . . . . . . . . . . . . . . O153 Martin, H. . . . . . . . . . . . . . . . . . P742 Martin, L. . . . . . . . . . . . . . . . . . P742 Martín-Polo, J. . . . . . . . . . . . P531, P708 Martinelli, V. . . . . . . . . O177, O217, P524, P536, P565, P680, P757 Martinelli Boneschi, F. . . . O217, P277, P757 Martinez-Sanchez, P. . . . . . O60, O61, O191, P345, P452 Martínez-Yélamos, S. . . . . . . . O178, P646 Martini, A. . . . . . . . . . . . . . . . . . P710 Martini, C. . . . . . . . . . . . . . . . . . P735 Martino, G. . . . . . . . . . . . . . . . . . P568 Martinón, N. . . . . . . . . . . . . . . . . P622 Martins, T. . . . . . . . . . . . . . . . . . P682 Marusina, I. . . . . . . . . . . . . . . . . P591 Maruyama, J. . . . . . . . . . . . . . . . P450 Marventano, I. . . . . . . . . . . . . . . . O76

Maschke, M. . . . . . . . . . . . . . . . . O70 Masciullo, M. . . . . . . . . . P273, P612, P770 Masek, M. . . . . . . . . . . . . . . . . . P650 Masia, L. . . . . . . . . . . . . . . . . . . P264 Masjuan, J. . . . . . . . . . . . . . O214, P674 Masopust, J. . . . . . . . . . . . . . P403, P601 Massa, R. . . . . . . . . . . . . . . . . . . P610 Mateo, D. . . . . . . . . . . . . . . . . . . P595 Mathiesen, H. . . . . . . . . . . . . . . . P416 Mattei, M. . . . . . . . . . . . . . . . . . P291 Matthews, P. . . . . . . . . . . . . . . . . O91 Mattle, H.-P. . . . . . . . . . . . . O128, P283 Mauro, A. . . . . . . . . . . . O90, P257, P361 Mavromatis, I. . . . . . . . . . . . . . . . P324 Mavrommatis, C. . . . . . . . . . . . . . P459 Mavrou, K. . . . . . . . . . . . . . . . . . P681 Mayda Domaç, F. . . . . . . . . . . . . . P522 Mayer, T. E. . . . . . . . . . . . . . O206, P463 Mayordomo, F. . . . . . . . . . . . . . . . P320 Mazanec, R. . . . . . . . . . . . . . . . . P362 Mazia, C. . . . . . . . . . . . . . . P607, P608 McCormack, W. . . . . . . . . . . . . . . P727 McFarland, H. . . . . . . . . . . . . . . . O66 Mckee, D. . . . . . . . . . . . P316, P317, P554, P555, P639 Mea, E. . . . . . . . . . . . . . . . O192, O193 Meglic, B. . . . . . . . . . . . . . . . . . . P374 Mehling, M. . . . . . . . . . . . . . . . . O142 Mehrabian, S. . . . . . . . . . . . . . . . . O74 Meier, C. . . . . . . . . . . . . . . . P310, P311 Meitinger, T. . . . . . . . . . . . . . . . . P278 Melis, D. . . . . . . . . . . . . . . . . . . P615 Mellone, M. . . . . . . . . . . . . . . . . P596 Melnichenko, V. . . . . . . . . . . . . . . P750 Melzer, A. . . . . . . . . . . . . . . . . . P353 Melzer, C. . . . . . . . . . . . . . . . . . P716 Menegoni, F. . . . . . . . . . . . . . O90, P361 Menna-Barreto, M. . . . . . . . . . . . . O127 Menuel, C. . . . . . . . . . . . . . . . . . P382 Meola, G. . . . . . . . . . . . . . . P354, P610 Meregalli, M. . . . . . . . . . . . . . . . . O52 Meresse, I. . . . . . . . . . . . . . . . . . P223 Merienne, K. . . . . . . . . . . . . . . . . P419 Merse, O. . . . . . . . . . . . . . . . . . . P289 Merzyn, C. . . . . . . . . . . . . . . . . . P658 Mesec, A. . . . . . . . . . . . . . . . . . . P374 Mesquita, C. T. . . . . . . . . . . . . . . O114 Mesraoua, B. . . . . . . . . . . . . . . . . P399 Messerschmidt, D. . . . . . . . . . . . . O164 Messina, R. . . . . . . . . . . . . . . . . O211 Mestre, T. . . . . . . . . . . . . . . . . . O215 Metha, A. . . . . . . . . . . . . . . . . . . O63 Metz, L. . . . . . . . . . . . . . . . . . . . O69 Metz, R. J. . . . . . . . . . . . . . . . . . P346 Meves, S. . . . . . . . . . . . . . . . . . . P489 Meyding-Lamade, U. . . . . . . . . . . . P647 Mezzapesa, D. . . . . . . . . . . . . . . . O211 Miceli, P. . . . . . . . . . . . . . . . . . . P619 Michailidis, K. . . . . . . . . . . . . . . . P234 Michel, P. . . . . . . . . . . . O131, P470, P571 Michelakaki, E. . . . . . . . . . . . . . . O162 Mickeviciene, D. . . . . . . . . . . . . . . P299 Mignot, E. . . . . . . . . . . . . . . . . . P779 Mihalova, T. . . . . . . . . . . . . . O144, P649 Mihas, C. . . . . . . . . . . . . . . . . . . P681 Mijajlovic, M. . . . . . . . . . . . . . . . P336 Mikaeili, H. . . . . . . . . . . . . . . . . P364 Mikami, H. . . . . . . . . . . . . . . . . . P722 Mike, A. . . . . . . . . . . . . . . . . . . P241 Mikol, D. . . . . . . . . . . . . . . . . . . P542 Mikula, I. . . . . . . . . . . . . . . . . . . P474 Milanesi, I. . . . . . . . . . . . . . . . . . O43 Milani, M. . . . . . . . . . . . . . . . . . O112 Milano, E. . . . . . . . . . . . . . . O90, P361 Milic-Rasic, V. . . . . . . . . . . . . . . . P432 Millefiorini, E. . . . . . . . . . . . . . . . P288 Miller, D. . . . . . . . O219, P544, P659, P760A Milonas, I. . . . . . . . O146, P242, P313, P324, P391, P422, P499, P515,

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P551, P576, P621, P656, P665, P669, P697, P767 Minati, L. . . . . . . . . . . . . . . . . . O192 Minciu, I. . . . . . . . . . . . . . . . . . . P378 Minervini, M. . . . . . . . . . . . . . . . O145 Mirabella, M. . . . . . . . . . . . . P404, P770 Mirowska-Guzel, D. . . . . . . . . . . . . P449 Miscio, G. . . . . . . . . . . . . . . . . . . O90 Misrahi, M. . . . . . . . . . . . . . . . . . O81 Mitsikostas, D. . . . . . . . . . . . . . . . P287 Modoni, A. . . . . . . . . . . P273, P612, P770 Mogel, H. . . . . . . . . . . . . . . . . . . P725 Moggio, M. . . . . . . . . . . P279, P304, P613, P614, P729 Moglia, A. . . . . . . . . . . . . . . O48, P616 Mohammad, A. . . . . . . . . . . . . . . O151 Mohr, C. . . . . . . . . . . . . . . . . . . O155 Mohs, C. . . . . . . . . . . . . . . . . . . P647 Moiceanu, M. . . . . . . . . . P379, P380, P381 Moiola, L. . . . . . . . . . . . . . . O217, P757 Moldovan, M. . . . . . . . . . . . . . . . O115 Molinuevo, J. . . . . . . . . . . . . . . . . O55 Moller, J. C. . . . . . . . . . . . . . . . . P421 Molloy, F. . . . . . . . . . . . . . . . . . . P602 Molnar, S. . . . . . . . . . . . . . . . . . P560 Molnar, T. . . . . . . . . . . . . . . P228, P566 Molnar-Szakacs, I. . . . . . . . . . . . . . P584 Monaco, F. . . . . . . . . . . . . . . . . . P530 Mongini, T. . . . . . . . . . . . . . . . . . P610 Montagna, P. . . . . . . . . . . . . . O73, P779 Montalban, X. . . . . . . . O219, P407, P760A Montanari, E. . . . . . . . . O100, P538, P759 Montoro-Ríos, M. T. . . . . . . . . . . . . P687 Moonen, G. . . . . . . . . . . O88, O163, O167, O183, O186, P269, P578 Moonen, M. . . . . . . . . . . . . . . . . O163 Mora, M. . . . . . . . . . . . . . . . . . . P613 Morad, A. . . . . . . . . . . . . . . . . . P460 Morais, H. . . . . . . . . . . . . . . . . . P573 Moraitou, M. . . . . . . . . . . . . . . . O162 Moral, E. . . . . . . . . . . . . . . . . . . O178 Morales Bastos, C. . . . . . . . . . . . . . P597 Morandi, L. . . . . . . . . . . . . . . . . P613 Morandi, U. . . . . . . . . . . . . . . . . . O50 Moreira Filho, P. F. . . . . . . . . . . . . P718 Moreno, S. . . . . . . . . . . . . . . . . . P742 Moreno Izco, F. . . . . . . . . . . . . . . P687 Morfin, P. . . . . . . . . . . . . . . . . . . P398 Morgado, F. . . . . . . . . . . . . . . . . P442 Morillon, D. . . . . . . . . . . . . . . . . P611 Morino, S. . . . . . . . . . . . . . . . . . . O76 Moroney, J. . . . . . . . . . . . . . . . . O138 Morricone, L. . . . . . . . . . . . . . . . P354 Morris, C. . . . . . . . . . . . . . . . . . P427 Morris, H. . . . . . . . . . . . . . . . . . O119 Moschella, V. . . . . . . . . . . . . . . . . O86 Moses, H. . . . . . . . . . . . . . . . . . . P407 Mossini, R. . . . . . . . . . . . . . . . . . P356 Motta, E. . . . . . . . . . . . . . . . . . . P704 Mourad, H. . . . . . . . . . . . . . . . . . P340 Mousavi, S. . . . . . . . . . . . . . . . . . P224 Mrabet, A. . . . . . . . . . . . . . . P383, P523 Mrakic-Sposta, S. . . . . . . . . . . . . . P440 Mshelia, H. . . . . . . . . . . P334, P335, P447 Muelas, N. . . . . . . . . . . . . . . . . . P320 Mueller, C. . . . . . . . . . . . . . . . . . P352 Mueller, J. . . . . . . . . . . . . . . . . . O164 Mueller, T. . . . . . . . . . . . . . . . . . P495 Müller-Spahn, F. . . . . . . . . . . . . . . P371 Muñoz, E. . . . . . . . . . . . . . . . . . P476 Munro, V. . . . . . . . . . . . . . . . . . . O96 Munschauer, F. E. . . . . . . . . . . . . . . O67 Muresanu, D. F. . . . . . . . . . . . P586, P599 Murphy, S. . . . . . . . . . . . . . . . . . O138 Murphy, T. . . . . . . . . . . . . . . . . . O157 Murray, T. J. . . . . . . . . . . . . . . . . O218 Murri, L. . . . . . . . . . . . . . . . P373, P736 Musch, B. . . . . . . . . . . . . . . . . . . P407 Mustafina, O. . . . . . . . . . . . . . . . P574

Musumeci, O. . . . . . . . . . . . . . . . P610 Mutlu, M. . . . . . . . . . . O147, O158, P240, P394, P775 Muto, A. . . . . . . . . . . . . . . . . . . P291 Mutti, E. . . . . . . . . . . . . . . . . . . P529 Muzi-Falconi, M. . . . . . . . . . . O85, O118 Myasnikov, A. . . . . . . . . . . . . . . . P750 Nabavi, D. G. . . . . . . . . . . . . . . . O202 Nadaj-Pakleza, A. . . . . . . . . . . . . . P609 Naegelin, Y. . . . . . . . . . . . . . . . . O103 Naeimi Tabiei, M. H. . . . . . . . . . . . P519 Nagai, T. . . . . . . . . . . . . . . . . . . P579 Najafi, M. R. . . . . . . . . . . . . . . . . P627 Nakamura, M. . . . . . . . . . . . . . . . P450 Napoletano, R. . . . . . . . . . . . . . . . P286 Napoli, L. . . . . . . . . . . . . . . . . . . P279 Nappini, S. . . . . . . . . . . . . . . . . . P667 Nardini, M. . . . . . . . . . . . . . . . . . P733 Nascimento, O. J. M. . . . . . . . . O114, P437, P718, P719 Nasibullin, T. . . . . . . . . . . . . . . . . P574 Nasis, G. . . . . . . . . . . . . . . . . . . P464 Natali Sora, M. G. . . . . . . . . . . . . . P308 Nave, K-A. . . . . . . . . . . . . . . . . . . . 3 Nazeman, M. . . . . . . . . . . . . . . . . P685 Nedelka, T. . . . . . . . . . . . . . . . . . P362 Nedelkoska, L. . . . . . . . . . . . . . . . P297 Nemni, R. . . . . . . . . . . . O76, P587, P598 Nemtsova, V. . . . . . . . . . . . . P435, P678 Neri, G. . . . . . . . . . . . . . . . . . . . P273 Nesti, C. . . . . . . . . . . . . . . . . . . P373 Nestrasil, I. . . . . . . . . . . . . . P249, P556 Neugebauer, H. . . . . . . . . . . . P244, P245 Nevrli, M. . . . . . . . . . . . . . . . . . P492 Nevrly, M. . . . . . . . . . . . . . . . . . P249 Nica, S. . . . . . . . . . . . . . . . . . . . P690 Nichols, F. T. . . . . . . . . . . . . . . . . O130 Nickel, J. . . . . . . . . . . . . . . . . . . . O47 Nickels, W. . . . . . . . . . . . . . . . . . O164 Nielsen, J. F. . . . . . . . . . . . . . P261, P475 Nielsen, J. M. . . . . . . . . . . . . . . . O180 Niesser, R. . . . . . . . . . . . . . . . . . P397 Niewiadomska, M. . . . . . . . . . O121, P359 Nigdelioglu Ozkan, A. . . . . . . . . . . . P630 Nikaki, M. . . . . . . . . . . . . . O170, O174 Niklas, A. . . . . . . . . . . . . . . . . . . P535 Nikolakaki, E. . . . . . . . . P700, P701, P702 Nikolic, A. . . . . . . . . . . . . . . . . . P235 Nippert, I. . . . . . . . . . . . . . . . . . P296 Nishimoto, Y. . . . . . . . . . . . . . . . O210 Nishiyama, T. . . . . . . . . . . . . P590, P640 Nissel, T. . . . . . . . . . . . . . . . . . . P336 Nitka-Sieminska, A. . . . . . . . . . . . . P684 Niubó, J. . . . . . . . . . . . . . . . . . . P646 Nizzardo, M. . . . . . . . . . . . . . . . . P733 Noachtar, S. . . . . . . . . . . . . . . . . P782 Nobile-Orazio, E. . . . . . . . O78, P328, P557 Nobukuni, K. . . . . . . . . . . . . P579, P723 Nociti, V. . . . . . . . . . . . . . . . P404, P728 Nofroni, I. . . . . . . . . . . . . . . . . . O175 Noh, J. H. . . . . . . . . . . . . . . . . . . P430 Nolano, M. . . . . . . . . . . . . . . . . . O73 Norman, H. . . . . . . . . . . . . . . . . P411 Noulas, G. . . . . . . . . . . . . . . . . . P282 Novakova, V. . . . . . . . . . . . . . . . . O152 Novik, A. . . . . . . . . . . . . . . . . . . P750 Novis, S. A. P. . . . . . . . . . . . . . . . O113 Novotny, O. . . . . . . . . . . . . . . . . P484 Nuzzaco, G. . . . . . . . . . . . . . . . . P680 Nyka, W. M. . . . . . . P526, P675, P684, P771 Nytrova, P. . . . . . . . . . . . . . . . . . O104 O’ Connor, G. . . . . . . . . . . . . P406, P670 O’Brien, T.J . . . . . . . . . . . . . . . . . O135 O’Connell, P. G. . . . . . . . . . . . . . . O151 O’Connor, G. . . . . . . . . . . . . . . . . P602 O’Connor, O. . . . . . . . . . . . . . . . . P546 O’Toole, O. . . . . . . . . . . . . . . . . . O209

Obdrzalkova, E. . . . . . . . . . . . . . . P731 Obelieniene, D. . . . . . . . . . . . . . . P299 Obermaier, B. . . . . . . . . . . . . . . . O126 Obermann, M. . . . . . . . . . . . . O70, P550 Ochudlo, S. . . . . . . . . . . . . . . . . . P372 Oelmann, H.-D. . . . . . . . . . . . . . . P289 Offner, H. . . . . . . . . . . . . . . P448, P648 Oge, A. E. . . . . . . . . . . . . . . . . . . P775 Oger, J. . . . . . . . . . . . . . . . . . . . P295 Oh, G. S. . . . . . . . . . . . . . . . . . . P454 Oh, J. Y. . . . . . . . . . . . . . . . . . . . P438 Oh, S. Y. . . . . . . . . . . . . . . . . . . P239 Oh, Y. M. . . . . . . . . . . . . . . . . . . P239 Ohadi, B. . . . . . . . . . . . . . . . . . . P423 Ohayon, J. . . . . . . . . . . . . . . . . . . O66 Oikonomidi, K. . . . . . . . . . . . . . . P564 Ojeda, J. . . . . . . . . . . . . . . . . . . P505 Olausson, H. . . . . . . . . . . . . . . . . O154 Oliván Torres, S. . . . . . . . . . . . . . . P691 Olivier, P. . . . . . . . . . . . . . . O131, P571 Olivotto, F. . . . . . . . . . . . . . . . . . P598 Onar, M. . . . . . . . . . . . . . . . P478, P479 Ono, S. . . . . . . . . . . . . . . . . . . . P722 Onofrj, M. . . . . . . . . . . . . . . P363, P692 Onye-eri, K. . . . . . . . . . . . . . . . . P446 Opala, G. . . . . . . . . . . . . . . . . . . P372 Opavsky, R. . . . . . . . . . . . . . O131, P483 Opherk, C. . . . . . . . . . . . . . . . . . P677 Orban-Kis, K. . . . . . . . . . . . . . . . P456 Orefice, G. . . . . . . . . . . . . . . . . . P312 Orlacchio, Aldo . . . . . . . . . . . . . . . O86 Orlacchio, Antonio . . . . . . . . . . . . . O86 Ortega, M. A. . . . . . . . . . . . . . . . P452 Ortega-Casarrubios, M. A. . . O60, O61, O191 Ortler, M. . . . . . . . . . . . . . . . . . O132 Oruc, K. . . . . . . . . . . . . . . . . . . P478 Oschmann, P. . . . . . . . . . . . . . . . O187 Otruba, P. . . . . . . . . . . . P249, P482, P483 Ott, H. W. . . . . . . . . . . . . . . . . . P300 Owega, A. . . . . . . . . . . . . . . . . . P510 Owen, A. . . . . . . . . . . . . . . . . . . O88 Owsiak, S. . . . . . . . . . . . . . . O116, P738 Owusu-Agyei, P. . . . . . . . . . . . . . . P465 Ozawa, T. . . . . . . . . . . . . . . . . . . P696 Ozcan, H. . . . . . . . . . . . . . . O147, O158 Ozerkan, F. . . . . . . . . . . . . . . . . . O189 Ozkan, S. . . . . . . . . . . . . . . . . . . P488 Ozpeynirci, Y. . . . . . . . . . . . . . . . P394 Paci, S. . . . . . . . . . . . . . . . . . . . P615 Padua, L. . . . . . . . . . . . . . . . . . . P327 Pagani, E. . . . . . . . O99, O102, O185, O188 Pages, C. . . . . . . . . . . . . . . . . . . P419 Pagliano, E. . . . . . . . . . . . . . . . . . O82 Pagliarani, S. . . . . . . . . . . . . P614, P615 Pakdaman, H. . . . . . . . . P375, P405, P661 Pakdaman, R. . . . . . . . . . . . . P375, P661 Pal, J. . . . . . . . . . . . . . . . . . . . . P307 Palace, J. . . . . . . . . . . . . . . . . . . P657 Palao, S. . . . . . . . . . . . . . . . . . . P549 Palecek, T. . . . . . . . . . . . . . . . . . P783 Palm, C. . . . . . . . . . . . . . . . . . . P725 Palm, F. . . . . . . . . . . . . . . . . . . . P575 Palmieri, A. . . . . . . . . . . . . . . . . P610 Palmieri, G. . . . . . . . . . . . . . . . . P291 Panas, M. . . . . . . . . . . . . . . . . . . P274 Panico, A. . . . . . . . . . . . . . . . . . P620 Panico, M. B. . . . . . . . . . . . . . . . . P610 Panoutsopoulos., G. . . . . . . . . . . . . P681 Panoutsopoulou, D. . . . . . . . . . . . . P464 Pantzaris, M. . . . . . . . . . . . . . . . . P473 Panzeri, M. C. . . . . . . . . . . . . . . . P610 Paolicchi, A. . . . . . . . . . . . . . . . . P617 Papacostas, S. . . . . . . . . . . . . O196, P473 Papadaki, P. . . . . . . . . . . . . . P266, P267 Papadimas, G. . . . . . . . . . . . . P559, P603 Papadimitriou, A. . . . . . . P281, P282, P537 Papadimitriou, D. . . . . . . . . . . . . . P733 Papadopoulos, I. . . . . . . . . . . . . . . P234

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Papadopoulos, K. . . . . . . P242, P313, P515, P621, P697 Papadopoulou, M. . . . . . . . . . . . . . P559 Papageorgiou, S. . . . . . . . . . . O170, O174 Papanastasiou, I. . . . . . . . . . . . . . P464 Papanastassiou, V. . . . . . . . . . . . . . O62 Papapostolou, A. . . . . . . . . . . . . . P559 Papasilekas, T. . . . . . . . . . . . . . . . O162 Papathanasiou, E. . . . . . . . . . . . . . P473 Papazisis, G. . . . . . . . . . . . . . . . . P656 Papuc, E. . . . . . . . . . . . . . . . . . . P293 Pardo, G. . . . . . . . . . . . . . . . . . . O69 Parente, E. . . . . . . . . . . . . . . . . . P312 Pareyson, D. . . . . . . . . . O83, O112, O122, P327, P667 Parini, R. . . . . . . . . . . . . . . . . . . P615 Parissis, D. . . . . . . . . . . . . . . . . . P703 Park, H. J. . . . . . . . . . . . . . . . . . P629 Park, J. W. . . . . . . . . . . . . . . . . . P714 Park, K. C. . . . . . . . . . . . . . . . . . P461 Park, K. D. . . . . . . . . . . P438, P443, P582 Park, K. W. . . . . . . . . . . . . . . . . . P481 Park, M. S. . . . . . . . . . . . . . . . . . P562 Park, S. C. . . . . . . . . . . . . . . . . . P629 Park, Sang Hyun . . . . . . . . . . . . . . P350 Park, Sung-Ho . . . . . . . . . . . . P239, P503 Park, S. P. . . . . . . . . . . . . . . . . . . P502 Park, T. H. . . . . . . . . . . . . . . . . . P666 Parkhutik, V. . . . . . . . . . . . . . . . . O75 Parolini, D. . . . . . . . . . . . . . . . . . O52 Parsons, D. . . . . . . . . . . . . . . . . . P639 Pascal, O. . . . . . . . . . . . . . . . . . . P265 Paschalidou, M. . . . . . . . P242, P324, P391, P415, P551, P656, P665, P767 Patanella, A. K. . . . . . . . . . . . . . . P404 Patel, T. . . . . . . . . . . . . . . . . . . . P292 Paterakis, K. . . . . . . . . . . . . . P281, P282 Patrichi, D. . . . . . . . . . . . . . . . . . P381 Patrono, C. . . . . . . . . . . . . . . . . . O86 Patsouris, E. . . . . . . . . . . . . . . . . P600 Patti, F. . . . . . . . . . . . . . . . . . . . P288 Paukner, U. . . . . . . . . . . . . . . . . . P569 Paulson, O. . . . . . . . . . . . . . . . . . P416 Paulus, K. S. . . . . . . . . . . . . . . . . P255 Paximadakis, E. . . . . . . . . . . . . . . P681 Peccatori, J. . . . . . . . . . . . . . . . . P308 Pedrosa, R. . . . . . . . . . . . . . . . . . P652 Peigneux, P. . . . . . . . . . . . . . . . . O167 Pellegrini, S. . . . . . . . . . . . . . . . . O66 Pellkofer, H. L. . . . . . . . . . . . O182, P662 Pels, H. . . . . . . . . . . . . . . . . . . . O42 Penza, Pietro . . . . . . . . . . . . . . . . P312 Penza, Paola . . . . . . . . . . . . . . . . . P710 Pepin, J. . . . . . . . . . . . . . . . . . . O169 Pera, J. . . . . . . . . . . . . . O98, P230, P570 Peralta, A. R. . . . . . . . . . . . . . . . . P442 Perego, E. . . . . . . . . . . . . . . . . . O177 Perego, L. . . . . . . . . . . . . . . . . . O171 Pereira, C. G. . . . . . . . . . . . . . . . . P660 Pérez, J. . . . . . . . . . . . . . . . . . . . P622 Perez Perez, H. . . . . . . . . . . . . . . . P622 Pérez-Saldaña, M. T. . . . . . . . . . . . . O75 Perjesco, L. . . . . . . . . . . . . . . . . . P265 Pestana, R. . . . . . . . . . . . . . . . . . O133 Petelin, Z. . . . . . . . . . . . . . . . . . P548 Peterfalvi, A. . . . . . . . . . P228, P307, P566 Peters, N. . . . . . . . . . . . . . . . . . . P677 Petiot, P. . . . . . . . . . . . . . . . . . . . O80 Petrakova, Z. . . . . . . . . . . . . . . . . P484 Petrarca, M. . . . . . . . . . . . . . . . . P264 Petridis, A. . . . . . . . . . . . . . . . . . P564 Petrova, M. . . . . . . . . . . . . . . . . . O74 Petrozzi, L. . . . . . . . . . . . . . P373, P617 Petzold, A. . . . . . . . . . . . . . . . . . P470 Pfefferkorn, T. . . . . . O206, P231, P463, P677 Pfister, H. W. . . . . . O124, O126, P463, P645 Phanthumchinda, K. . . . . . . . . . . . P709 Phatak, T. . . . . . . . . . . . . . . . . . P547

Phillips, C. . . . . . . . . . . . . . O167, O198 Phillips, K. . . . . . . . . . . . . . . . . . P425 Phukan, J. . . . . . . . . . . . . . . . . . P727 Piacentini, E. . . . . . . . . . . . . O175, P594 Pianta, L. . . . . . . . . . . . . . . . . . . O90 Piazza, S. . . . . . . . . . . . . . . . P735, P736 Pica, C. . . . . . . . . . . . . . . . O145, P414 Pichiecchio, A. . . . . . . . . . . . . O48, P616 Pickard, J. . . . . . . . . . . . . . . . . . . O88 Pierzchala, K. . . . . . . . . . . . . . . . P664 Pilz, G. . . . . . . . . . . . . . . . . . . . P561 Pindar, S. . . . . . . . . . . . . . . P512, P682 Piola, M. . . . . . . . . . . . . . . . . . . P530 Piolti, R. . . . . . . . . . . . . . . . . . . P280 Piret, S. . . . . . . . . . . . . . . . . . . . O186 Pirnay, L. . . . . . . . . . . . . . . . . . . P269 Pirnay, S. . . . . . . . . . . . . . . . . . . P269 Pisani, V. . . . . . . . . . . . . . . . . . . P610 Pizova, N. . . . . . . . . . . . . . . . . . P591 Planté-Bordeneuve, V. . . . . O81, P444, P445 Plazzi, G. . . . . . . . . . . . . . . . . . . P779 Plesca, D. A. . . . . . . P379, P380, P381, P385 Pluchino, S. . . . . . . . . . . . . . . . . P568 Plumari, M. . . . . . . . . . . . . . O85, O118 Podemski, R. . . . . . . . . . . . . P480, P518 Podolski, P. . . . . . . . . . . . . . . . . . P548 Pohl, C. . . . . . . . . . . . . . . O219, P760A Pokryszko-Dragan, A. . . . . . . . . . . . P480 Politano, L. . . . . . . . . . . . . . . . . . P610 Politi, L. . . . . . . . . . . . . . . . . . . P524 Polli, E. . . . . . . . . . . . . . . . . . . . P596 Polman, C. H. . . . . O64, O180, O219, P760A Polychronopoulos, P. . . . . O195, P331, P439, P625, P707 Polyzoidis, S. K. . . . . . . . . . . . . . . P360 Polyzoidou, E. . . . . . . . . . . . . . . . O146 Pomponi, M. G. . . . . . . . . . . . . . . P273 Poniatowska, R. . . . . . . . P359, P392, P449 Pont, C. . . . . . . . . . . . . . . . . . . . P763 Ponzi, D. . . . . . . . . . . . . . . . . . . P304 Ponzoni, M. . . . . . . . . . . . . . . . . P332 Popa, C. . . . . . . . . . . . . . . . . . . P455 Popescu, B. O. . . . . . . . . . . . . . . . P599 Popescu, V. . . . . . . . . . . . . . . . . . P381 Popp, B. . . . . . . . . . . . . . . . O124, O126 Poppert, H. . . . . . . . . . . . . . . . . . P471 Porcelli, G. . . . . . . . . . . . . . . . . . O145 Portenoy, R. . . . . . . . . . . . . . . . . O157 Portnoi, M-F. . . . . . . . . . . . . . . . . P366 Poryazova, R. . . . . . . . . . . . . O199, P777 Potagas, C. . . . . . . . . . . . . . . P540, P653 Poujois, A. . . . . . . . . . . . . . . . . . O110 Poulin, C. . . . . . . . . . . . . . . . . . . P377 Pourova, R. . . . . . . . . . . . . . . . . . P362 Pouwels, P. J. W. . . . . . . . . . . . . . . O64 Pozzilli, C. . . . . . . . . . . . . . . . . . P294 Prainer, C. . . . . . . . . . . . . . . . . . P569 Prandota, J. . . . . . . . . . . . . . . . . P390 Prawdzik, G. . . . . . . . . . . . . . . . . P651 Preissner, K. T. . . . . . . . . . . . . . . . P352 Prelle, A. . . . . . . . . . . . . . . . P613, P729 Pretl, M. . . . . . . . . . . . . . . . P780, P783 Previtali, S. . . . . . . . . . . . . . P330, P332 Pride, G. . . . . . . . . . . . . . . . . . . . O94 Priestley, A. . . . . . . . . . . . . . . . . P408 Prigione, A. . . . . . . . . . . . . . . . . P280 Priori, A. . . . . . . . . . . . . . . . . . . P440 Prokisch, H. . . . . . . . . . . . . . P278, P427 Prosperini, L. . . . . . . . . . . . . . . . P294 Provitera, V. . . . . . . . . . . . . . . . . . O73 Pruszczyk, P. . . . . . . . . . . . . . . . . P609 Psaltopoulou, T. . . . . . . . . . . . . . . O148 Psaras, R. M. . . . . . . . . . . . . . . . . P464 Psillas, G. . . . . . . . . . . . . . . . . . . P762 Pueyo Morlans, M. . . . . . . . . . . . . P622 Pugh, R. . . . . . . . . P316, P317, P554, P555 Pulcifur, A. . . . . . . . . . . . . . . . . . P425 Pulizzi, A. . . . . . . . . . . . . . . . . . O177 Pulyk, R. . . . . . . . . . . . . . . . . . . O98

Purat, T. . Putman, K. Putzki, N. Puz, P. . .

. . . . . . . . . . . . . . . . . O136 . . . . . . . . . . . . . . . . . O89 . . . . . . . . . . . . . . . . . P528 . . . . . . . . . . . . . . . . . P704

Quattrini, A. . . . . . . . . . P328, P330, P332 Quattrone, A. . . . . . . . . . . . . . . . P327 Quintanilha, G. . . . . O114, P437, P718, P719 Rabbebe, I. . . . . . . . . . . . . . . . . . P512 Rabe, K. . . . . . . . . . . . . . . . . . . P768 Rabinstein, A. . . . . . . O49, O58, O149, O205 Racek, P. . . . . . . . . . . . . . . . . . . O104 Radaelli, M. . . . . . . . . . . . . . O217, P757 Radtke, A. . . . . . . . . . . . . . . . . . P272 Radue, E. W. . . . . . . . . . . . . . . . . O103 Rahimian, E. . . . . . . . . . . . . P405, P423 Rakowicz, M. . . . . . . . . . . . . O121, P359 Rakusa, M. . . . . . . . . . . . . . . . . . P593 Ralli, S. . . . . . . . . . . . . . . . P281, P282 Rallis, T. . . . . . . . . . . . . . . . . . . P715 Ramasamy, D. P. . . . . . . . . . . . O65, O67 Rambold, H. . . . . . . . . . . . . . P237, P238 Ramsey, N. F. . . . . . . . . . . . . . . . . O87 Rasmussen, A. . . . . . . . . . . . . . . . P309 Rauer, S. . . . . . . . . . . . . . . . . . . P773 Rausch, L. . . . . . . . . . . . . . . . . . P491 Ravaglia, S. . . . . . . . . . . O48, O123, P616 Ravelli, V. . . . . . . . . . . . . . . . . . . P736 Raycheva, M. . . . . . . . . . . . . . . . . O74 Raza, A. . . . . . . . . . . . . . . . . . . P319 Reale, M. . . . . . . . . . . . . . . . . . . P692 Regeniter, A. . . . . . . . . . . . . . . . . P734 Reggiani, M. . . . . . . . . . . . . . . . . P229 Rego, R. . . . . . . . . . . . . . . . . . . P573 Reich, E. . . . . . . . . . . . . . . . . . . P410 Reichmann, H. . . . . . . . . . . . . . . . O42 Reis, J. . . . . . . . . . . . . . . . . . . . P232 Reissifar, M. . . . . . . . . . . . . . . . . P631 Rembao, D. . . . . . . . . . . . . . . . . . P309 Rémi, J. . . . . . . . . . . . . . . . . . . . P782 Renaud, S. . . . . . . . . O77, P300, P321, P431 Repetto, A. . . . . . . . . . . . . . . O48, P616 Resende, C. C. . . . . . . . . . . . . . . . P618 Resende, M. . . . . . . . . . . . . . . . . P553 Ressner, P. . . . . . . . . . . . . . . . . . P486 Rettig, K. . . . . . . . . . . . . . . . . . . P510 Rettinger, N. . . . . . . . . . . . . . . . . P241 Rewisha, M. . . . . . . . . . . . . . . . . P340 Ribeiro, Clara . . . . . . . . . . . . . . . . P232 Ribeiro, Constança . . . . . . . . . . . . . O133 Ribeiro, J. . . . . . . . . . . . . . . . . . O113 Ribrag, V. . . . . . . . . . . . . . . . . . . O79 Ricci, E. . . . . . . . . . . . . . . . P612, P770 Ricci, G. . . . . . . . . . . . . . . . P617, P736 Riccitelli, G. . . . . . . . . . . . . . . . . O177 Rice, G. . . . . . . . . . . . . . . . . . . . P657 Rieckmann, P. . . . . . . . . . . . . P401, P658 Riera, A. . . . . . . . . . . . . . . . . . . P646 Rifici, C. . . . . . . . . . . . . . . . . . . P262 Rihova, Z. . . . . . . . . . . . . . . . . . P601 Rimes, B. . . . . . . . . . . . . . . . . . . O68 Rimoldi, M. . . . . . . . . . . . . . . . . O122 Ringelstein, E. B. . . . . . . . . . . . . . O202 Rinkel, G. J. E. . . . . . . . . . O59, O95, P341 Ristic, A. J. . . . . . . . . . . . . . . . . . O108 Ritchie, V. . . . . . . . . . . . . . . . . . . O62 Riva, N. . . . . . . . . . . . . . . . . . . . P332 Rivera-Ordoñez, C. . . . . . . . . . . . . . O61 Rivoiro, C. . . . . . . . . . . . . . . . . . P538 Rizea, O. . . . . . . . . . . . . . . . . . . P298 Rizzuto, N. . . . . . . . . . . . . . . . . . P327 Roberts, R. . . . . . . . . . . . . . . . . . O62 Robertson, V. H. . . . . . . . . . . . . . . O143 Robinson, W. . . . . . . . . . . . . . . . . P295 Rocca, M. A. . . . . . . . . . O99, O102, O141, O188, O217 Roceanu, A. . . . . . . . . . . . . . . . . P741 Roche, J. . . . . . . . . . . . . . . . . . . P406

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Rodegher, M. E. . . . . O102, O217, P277, P757 Rodolico, C. . . . . . . . . . . . . . P610, P615 Rodriguez, M. . . . . . . . . . . . . . . . P398 Rodriguez-Campello, A. . . . . . . . . . P763 Roider, J. . . . . . . . . . . . . . . . . . . P314 Rojas, J. . . . . . . . . . . . . . . . . . . . P607 Rojo, J. . . . . . . . . . . . . . . . . . . . P622 Rola, R. . . . . . . . . . . . . . . . O121, P359 Rolke, R. . . . . . . . . . . . . . . . . . . P712 Romac, S. . . . . . . . . . . . . . . P432, P497 Romanitan, M. O. . . . . . . . . . . . . . P589 Romano, S. . . . . . . . . . . . . . . . . . O83 Romão, H. . . . . . . . . . . . . . . . . . P553 Romero-Imbroda, J. . . . . . . . . . . . . P468 Romero-Pinel, L. . . . . . . . . . . O178, P646 Ron, M. A. . . . . . . . . . . . . . . . . . P544 Roncarolo, M. G. . . . . . . . . . . . . . O161 Ropele, S. . . . . . . . . O91, O140, O172, P349 Roque, R. . . . . . . . . . . . . . . P232, P652 Roquer, J. . . . . . . . . . . . . . . . . . . P763 Rosa, M. M. . . . . . . . . . . . . . . . . P376 Rose, M. R. . . . . . . . . . . . . . . . . . P610 Rosenblatt, B. . . . . . . . . . . . . . . . P377 Rosenmann, H. . . . . . . . . . . . . . . P233 Rosset, J. . . . . . . . . . . . . . . . . . . O160 Rossi, M. . . . . . . . . . . . . . . . O48, P616 Rossi, P. . . . . . . . . . . . . . . . . . . P277 Rossignol, S. . . . . . . . . . . . . . . . . P366 Rosso, C. . . . . . . . . . . . . . . O213, P223 Rostrup, E. . . . . . . . . . . . . . . . . . P416 Roth, J. . . . . . . . . . . . . . . . . P247, P368 Röther, J. . . . . . . . . . . . . . . . . . . O202 Rott, M. . . . . . . . . . . . . . . . . . . . P716 Rouleau, G. A. . . . . . . . . . . . . . . . O117 Rousseaux, M. . . . . . O93, O139, P420, P581 Rovaris, M. . . . . . . . . . . . . . O177, P536 Rowbotham, M. . . . . . . . . . . . . . . O157 Rowinska-Marcinska, K. . . . . . . . . . O116 Roze, E. . . . . . . . . . . . . O71, P366, P367, P382, P419 Rozenstein, L. . . . . . . . . . . . . . . . P233 Rubio, F. . . . . . . . . . . . . . . . . . . P339 Rudà, R. . . . . . . . . . . . . . . . . O43, O45 Rudzinska, M. . . . . . . . . . . . . . . . P256 Rüegg, S. . . . . . . . . . . . . . . . . . . P431 Ruggieri, M. . . . . . . . . . . . . O145, P414 Rugiero, M. . . . . . . . . . . . . . P607, P608 Ruiz Miyares, F. . . . . . . . . . . . P306, P399 Rukin, N. . . . . . . . . . . . . . . . . . O144 Rupprecht, T. . . . . . . . . . . . . . . . O124 Russell, H. . . . . . . . . . . . . . . . . . P539 Russo, A. . . . . . . . . . . . . . . . . . . P587 Rüthemann, J. . . . . . . . . . . . . . . . P462 Ryglewicz, D. . . . . . . . . . . . . P392, P686 Rykavicin, O. . . . . . . . . . . . . . . . . P750 Saadah, M. . . . . . . . . . . . . . . . . . P496 Saadatnia, M. . . . . . . . . . . . . P227, P532 Sabatelli, M. . . . . . . . . . . . . . . . . P728 Sabel, M. C. . . . . . . . . . . . . . . . . . O47 Sabri, N. . . . . . . . . . . . . . . . . . . P460 Sacconi, S. . . . . . . . . . . . . . . . . . . O84 Saeidi, M. . . . . . . . . . . . . . . . . . P322 Saez, R. . . . . . . . . . . . . . . . . . . . P705 Sáez-Zea, C. . . . . . . . . . . . . . . . . P687 Sahraian, M. A. . . . . . . . . . . . . . . P661 Said, G. . . . . . . . . . . . . . O79, O81, P444, P445, P517 Sailer, M. . . . . . . . . . . . . . . . . . . P651 Saint Jean, O. . . . . . . . . . . . . . . . . P458 Saj, A. . . . . . . . . . . . . . . . . O139, P581 Sakai, K. . . . . . . . . . . . . . . . . . . P579 Sala, S. . . . . . . . . . . . . . . . . . . . O101 Salani, S. . . . . . . . . . . . . . . . . . . P733 Salas Felipe, J. . . . . . . . . . . . . . . . O150 Salati, E. . . . . . . . . . . . . . . . . . . P594 Salawu, F. . . . . . . . . . . . P334, P335, P446, P447, P512, P641, P682 Saleh, A. . . . . . . . . . . . . . . . . . . P460

Salem, D. . . . . . . . . . . . . . . . . . . P400 Salem, K. . . . . . . . . . . . . . . . . . . P319 Salih, F. . . . . . . . . . . . . . . . O197, O201 Salihovic, D. . . . . . . . . . . . . . . . . P338 Salim, K. . . . . . . . . . . . . . . . P306, P399 Salinas, M. . . . . . . . . . . . . . . . . . P674 Salmaggi, A. . . . . . . . . . . . . . . O43, O83 Salmon, E. . . . . . . . . . . . . . . . . . P578 Salomons, G. . . . . . . . . . . . . . . . . P670 Salsano, E. . . . . . . . . . . . . . . . . . P667 Salviati, L. . . . . . . . . . . . . . . . . . . O84 Samarelli, V. . . . . . . . . . . . . . . . . O211 Samson, Y. . . . . . . . . . . . . . O213, P223 San José, B. . . . . . . . . . . . . . . O60, P452 Sanak, D. . . . . . . . . . . . O131, O212, P348 Sanchez, A. . . . . . . . . . . . . . . . . . P742 Sánchez Ferro, A. . . . . . . . . . . . . . P246 Sanchez-Valle, R. . . . . . . . . . . . . . . O55 Sancricca, C. . . . . . . . . . . . . . . . . P404 Sand, T. . . . . . . . . . . . . . . . . . . . P299 Sandbrink, R. . . . . . . . . . . . O219, P760A Sander, T. . . . . . . . . . . . . . . P237, P238 Sansone, V. . . . . . . . . . . . . . P354, P610 Santens, P. . . . . . . . . . . . . . . . . . P644 Santoro, D. . . . . . . . . . . . . . P615, P729 Santoro, L. . . . . . . . . . . . . . . O73, P327 Santos, E. . . . . . . . . . . . . . . P325, P746 Santos, L. M. B. . . . . . . . . . . . . . . P660 Santos Silva, R. . . . . . . . . . . . P434, P553 Sanz, G. . . . . . . . . . . . . . . . . . . . P320 Saporta, M. . . . . . . . . . . . . . O81, O113 Saragoussi, D. . . . . . . . . . . . . . . . P462 Saresella, M. . . . . . . . . . . . . . . . . O76 Saric, M. . . . . . . . . . . . . . . . P432, P497 Sarikaya, S. . . . . . . . . . . . . . . . . . P623 Sasnauskaite, A. . . . . . . . . . . . . . . O106 Sassi, N. . . . . . . . . . . . . . . . . . . P373 Sassun, T. . . . . . . . . . . . . . . . . . O175 Satou, I. . . . . . . . . . . . . . . . . . . P696 Saumier, D. . . . . . . . . . . . . . . . . . O56 Savic-Pavicevic, D. . . . . . . . . . P432, P497 Savoiardo, M. . . . . . O83, O192, O193, P667 Sawicka, B. . . . . . . . . . . . . . . . . . P686 Sawula, W. . . . . . . . . . . . . . . . . . P771 Scalabrini, D. . . . . . . . . . O173, P529, P530 Scalabrino, G. . . . . . . . . . . . . . . . P529 Scanzillo, J. . . . . . . . . . . . . . . . . . P541 Scarlato, M. . . . . . . . . . . . . . . . . P330 Scarpini, E. . . . . . . . . . . O54, O171, O173, P288, P529, P530, P588 Schäbitz, W. R. . . . . . . . . . . . . . . O187 Schabus, M. . . . . . . . . . . . . . . . . O198 Schackert, G. . . . . . . . . . . . . . . . . O42 Schaefers, G. . . . . . . . . . . . . P305, P353 Schaeren-Wiemers, N. . . . . . . . . . . . O77 Schäuble, B. . . . . . . P506, P507, P508, P509, P510, P636, P637, P638 Schedel, R. . . . . . . . . . . . . . . . . . P716 Scheerschmidt, S. . . . . . . . . . . . . . P651 Schenone, A. . . . . . . . . . . . . . . . . P327 Scherer, P. . . . . . . . . . . . . . . . . . P296 Schestatsky, P. . . . . . . . . . . . O153, P477 Schichor, C. . . . . . . . . . . . . . . . . P314 Schiergens, I. . . . . . . . . . . . . . . . . O42 Schilling, H. . . . . . . . . . . . . . . . . P651 Schilling, M. . . . . . . . . . . . . . . . . O187 Schlager, T. . . . . . . . . . . . . . . . . . P569 Schlegel, U. . . . . . . . . . . O42, P310, P311 Schlereth, T. . . . . . . . . . . . . . . . . O136 Schluep, M. . . . . . . . . . . . . . . . . P470 Schmidt, R. . . . . . . . . . . . . . O172, P349 Schmidt-Wolf, I. G. H. . . . . . . . . . . . O42 Schmitt, E. . . . . . . . . . . . . . . . . . P774 Schmitz, B. . . . . . . . . . . . . . . . . . O197 Schnakers, C. . . . . . . . . O156, O163, O167, O183, P269 Schneider, I. . . . . . . . . . . . . . . . . P278 Schneider, Raphael . . . . . . . . . . . . . P773 Schneider, Ralf . . . . . . . . . . . . . . . P744

Schnepf, B. . . . . . Schoellhammer, M. Schoenwald, G. . . Schorge, S. . . . . . Schorn, C. F. . . . . Schrader, H. . . . . Schreiner, A. . . . .

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. . . . . . . P777 . . . . . . . P489 . . . . . . . P353 . . . . . . . O119 . . . . . . . P384 . . . . . . . P299 P506, P508, P509, P510, P637, P638 Schreuder, A. H. C. M.L. . . . . . . . . . P451 Schubert-Unkmeir, A. . . . . . . . . . . . P716 Schülke, M. . . . . . . . . . . . . . . . . . P272 Schulz, H. . . . . . . . . . . . . . . . . . . O42 Schumm, F. . . . . . . . . . . . . . . . . O182 Schupp, W. . . . . . . . . . . . . . . . . . O89 Schwab, M. E. . . . . . . . . . . . . . . . . . 22 Schwab, M. H. . . . . . . . . . . . . . . . . . 3 Schwalenstoecker, B. . . . . . . . . . . . P732 Sciacco, M. . . . . . . . . . . . . . . . . . P304 Scinska, A. . . . . . . . . . . . . . . . . . P686 Scotti, G. . . . . . . . . O99, O102, O141, O188 Sebai, R. . . . . . . . . . . . . . . . . . . P745 Sebraoui, H. . . . . . . . . . . . . . . . . P535 Sechi, G. P. . . . . . . . . . . . . . . . . . P255 Secil, Y. . . . . . . . . . . . . . . . . . . . O189 Seeger, J. . . . . . . . . . . . . . . . . . . P411 Seewann, A. . . . . . . . . . . . . . . . . . O64 Segura, M. . . . . . . . . . . . . . . . . . O159 Seiberling, M. . . . . . . . . . . . . . . . P408 Seidl, Z. . . . . . . . . . . . . . . . P650, P755 Seilhean, D. . . . . . . . . . . . . . . . . P315 Seitz, R. J. . . . . . . . . . . . . . . . . . . O47 Sellar, R. . . . . . . . . . . . . . . . . . . . O62 Sellner, J. . . . . . . . . . . . . . . O128, P283 Semyatichko, E. . . . . . . . . . . . P435, P678 Sena, A. . . . . . . . . . . . . . . . . . . . P652 Seneviratne, J. . . . . . . . . . . . . . . . O49 Senkarova, Z. . . . . . . . . . . . . . . . P482 Seok, J. I. . . . . . . . . . . . . . . . . . . P342 Serdaroglu, P. . . . . . . . . . . . . . . . P775 Serena, J. . . . . . . . . . . . . . . . . . . P226 Serranová, T. . . . . . . . . . . . . . . . . P476 Sessa, E. . . . . . . . . . . . . . . . . . . P262 Sessa, M. . . . . . . . . . . . O161, P565, P680 Severino, M. . . . . . . . . . . . . . . . . O63 Sfagos, C. . . . . . . . . . . . P274, P533, P534, P540, P653 Shahami, S. . . . . . . . . . . . . . . . . P322 Shakarishvili, R. . . . . . . . . . . . . . . P572 Shapira, I. . . . . . . . . . . . . . . . . . P336 Sharifi, M. . . . . . . . . . . . . . . . . . P472 Sharma, A. . . . . . . . . . . . . . . . . . P417 Sharott, A. . . . . . . . . . . . . . . . . . O201 Shaygannejad, V. . . . . . . . . . . . . . . P227 Sheehan, C. . . . . . . . . . . . . . O209, P737 Shehu, A. . . . . . . . . . . . . . . . . . . P761 Shenhar, S. . . . . . . . . . . . . . . . . . P336 Sherman, S. . . . . . . . . . . . . . . . . P541 Shevchenko, Y. . . . . . . . . . . . . . . . P750 Sheynzon, V. . . . . . . . . . . . . . . . . P547 Shibu, P. . . . . . . . . . . . . . . . . . . P465 Shim, D. S. . . . . . . . . . . . . . . P301, P726 Shim, Y. S. . . . . . . . . . . . P453, P490, P714 Shin, J. H. . . . . . . . . . . . . . . . . . P776 Shipova, E. . . . . . . . . . . . . . . . . . P654 Shoji, M. . . . . . . . . . . . . . . . . . . P756 Shon, Y. M. . . . . . . . . . . . . . . . . . P500 Shopin, L. . . . . . . . . . . . . . . . . . P336 Shorbagy, O. . . . . . . . . . . . . . . . . P673 Shukralla, A. . . . . . . . . . . . . . . . . P668 Shumakov, E. . . . . . . . . . . . . . . . P654 Shyu, W-C. . . . . . . . . . . . . . . . . . O57 Siccoli, M. . . . . . . . . . . . . . . P466, P781 Siciliano, G. . . . . . . . . . P373, P610, P617, P735, P736 Sidiropoulou, E. . . . . . . . . . . . . . . P767 Sieben, A. . . . . . . . . . . . . . . . . . P644 Siegwald, A. . . . . . . . . . . . . . . . . P284 Sieminski, M. . . . . . . . . . . . . . . . P684 Sienkiewicz-Jarosz, H. . . . . . . . . . . P686

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Silani, V. . . . . . . . . . . . . . . . P596, P729 Silomon, M. . . . . . . . . . . . . . . . . P747 Silvani, A. . . . . . . . . . . . . . . . . . . O43 Silveira, R. R. . . . . . . . . . . . . P437, P719 Silvestre, J-S. . . . . . . . . . . . . . . . . P426 Silvestri, G. . . . . . . . . . . P273, P612, P770 Simakov, A. . . . . . . . . . . . . . . . . P782 Simal, P. . . . . . . . . . . . . . . . . . . O214 Simeonidou, C. . . . . . . . . . . . O146, P422 Simone, I. L. . . . . . . . . . . . . . . . . O211 Simsarian, J. . . . . . . . . . . . . . . . . O69 Sinanovic, O. . . . . . . . . . . . . . . . . P338 Singer, B. . . . . . . . . . . . . . . . . . . P545 Sirbu, C. A. . . . . . . . . . . . . . . . . . P298 Sirrou, V. . . . . . . . . . . . . . . . . . . P625 Sitek, M. . . . . . . . . . . . . . . . . . . O107 Skedgel, C. . . . . . . . . . . . . . . . . . O218 Sketris, I. S. . . . . . . . . . . . . . . . . O218 Skoloudik, D. . . . . . . . . . . . . O131, P486 Skurnick, J. . . . . . . . . . . . . . . . . . P547 Slotwinski, K. . . . . . . . . . . . . P480, P518 Slowik, A. . . . . . . . . O98, P230, P570, P689 Smajlovic, D. . . . . . . . . . . . . . . . . P338 Smikalla, D. . . . . . . . . . . . . . . . . P543 Soares, P. . . . . . . . . . . . . . . . . . . O133 Sobreira, C. . . . . . . . . . . . . . . . . P618 Soffietti, R. . . . . . . . . . . . . . . O43, O45 Sokolovic, E. . . . . . . . . . . . . . . . . O194 Solari, A. . . . . . . . . . . . . . . . . . . P327 Soligo, D. . . . . . . . . . . . . . . . . . . P596 Soltesz, P. . . . . . . . . . . . . . . . . . . P560 Somerfield, J. A. . . . . . . . . . . . . . . O143 Sominanda, A. . . . . . . . . . . . . . . . O179 Somme, D. . . . . . . . . . . . . . . . . . P458 Song, D. B. . . . . . . . . . . . . . . . . . P629 Song, D. K. . . . . . . . . . . . . . . . . . P730 Song, H. K. . . . . . . . . . . . . . . . . . P776 Song, H. S. . . . . . . . . . . P443, P582, P785 Song, I. U. . . . . . . . . . . . . . . . . . P714 Sˇonka, K. . . . . . . . . . . . P780, P783, P784 Sørensen, P. . . . . . . . . . . . . . O69, P416 Soriano, E. . . . . . . . . . . . . . . . . . P608 Sormani, M. P. . . . . . . . . . . . . . . . O100 Soto, J. . . . . . . . . . . . . . . . . . . . P398 Soto, O. . . . . . . . . . . . . . . . . . . . P357 Soto-Cabrera, G. E. . . . . . . . . . . . . P740 Soulaeva, E. . . . . . . . . . . . . . . . . P354 Soulban, G. . . . . . . . . . . . . . . . . . O56 Souza, D. G. B. . . . . . . . . . . . . . . . P618 Spackova, N. . . . . . . . . . . . . . . . . P368 Spagnolo, F. . . . . . . . . . . . . . . . . O109 Spandou, E. . . . . . . . . . . . . . O146, P422 Spanos, G. . . . . . . . . . . . . . . . . . P632 Sparing, R. . . . . . . . . . . . . . . . . . P260 Spassky, N. . . . . . . . . . . . . . . . . . . . 3 Spengos, K. . . . . . . . . . . . . . P559, P603 Spinazzi, M. . . . . . . . . . . . . . . . . P276 Spinelli, M. . . . . . . . . . . . . . P565, P680 Spinelli, P. . . . . . . . . . . . . . . . . . P770 Spirin, N. . . . . . . . . . . . . . . P591, P654 Sprecher, E. . . . . . . . . . . . . . . . . O204 Sprenger, A. . . . . . . . . . . . . . P236, P237 Sprotte, G. . . . . . . . . . . . . . . . . . P716 Spudich, A. . . . . . . . . . . . . . P225, P568 Spuler, S. . . . . . . . . . . . . . . . . . . P272 Stachowiak, A. . . . . . . . . . . . . . . . P494 Stancea, I. . . . . . . . . . . . P379, P380, P381 Staszewski, J. . . . . . . . . . O203, P220, P778 Stathopoulos, P. . . . . . . . . . . . . . . O148 Stathopoulou, S. . . . . . . . . . . P266, P267 Steck, A. J. . . . . . . . . . . . O77, P300, P321, P431, P734 Stefan, H. . . . . . . . . . . . . . . . . . . P506 Stefanescu, M. . . . . . . . . . . . . . . . P380 Stefani, M. . . . . . . . . . . . . . . . . . P619 Stefanis, L. . . . . . . . . . . . . . . . . . O162 Steinheimer, S. . . . . . . . . . . . . . . O197 Steinman, L. . . . . . . . . . . . . . . . . P295 Stelmasiak, Z. . . . . . . . . . . . . . . . P293

Stepanov, I. . . . . . . . . . . . . . . . . . P654 Stephens, R. . . . . . . . . . . . . . . . . P649 Stepien, A. . . . . . . . . . . O203, P220, P778 Stock, M. . . . . . . . . . . . . . . . . . . P716 Stoffels, G. . . . . . . . . . . . . . . . . . . O47 Stöffler, A. . . . . . . . . . . . . . . . . . O172 Stojkovic, T. . . . . . . . . . . . . . . . . P611 Stoll, G. . . . . . . . . . . . . . . . . . . . P351 Stolz, E. . . . . . . . . . . . . . . . . . . . P352 Stone, M. J. . . . . . . . . . . . . . O144, P649 Stott, C. G. . . . . . . . . . . . . . . . . . O92 Stourac, P. . . . . . . . . . . . . . . . . . . O44 Stovner, L. J. . . . . . . . . . . . . . . . . P299 Straffi, L. . . . . . . . . . . . O168, O217, P355 Strange, R. . . . . . . . . . . . . . O144, P649 Straube, A. . . . . . . . . . . . . . . P314, P463 Strazzer, S. . . . . . . . . . . P633, P663, P733 Streletz, L. . . . . . . . . . . . . . . . . . P319 Strens, L. . . . . . . . . . . . . . . . . . . P761 Stroman, P. W. . . . . . . . . . . . . . . . O101 Strupp, M. . . . . . . . . . . O40, O125, P241, P244, P245, P769 Stubinski, B. . . . . . . . . . . O69, P408, P409 Stützle, C. . . . . . . . . . . . . . . . . . P300 Stylianidou, G. . . . . . . . . . . . . . . O196 Suessmuth, S. . . . . . . . . . . . . . . . P516 Suh, B. C. . . . . . . . . . . . . . . P301, P726 Sulek, A. . . . . . . . . . . . O121, P359, P609 Sulentic, V. . . . . . . . . . . . . . . . . . P474 Sumitomo, K. . . . . . . . . . . . . . . . P450 Summers, M. . . . . . . . . . . . . . . . . P544 Sunwoo, I. N. . . . . . . . . . P301, P443, P726 Supanc, V. . . . . . . . . . . . . . . . . . P748 Surelova, D. . . . . . . . . . . . . . . . . P484 Surkiene, D. . . . . . . . . . . . . . . . . P299 Süssmuth, S. D. . . . . . . . . . . . . . . P725 Suter, U. . . . . . . . . . . . . . . . . . . . . 3 Sutter, R. . . . . . . . . . . . . . . . . . . P300 Suzuki, C. . . . . . . . . . . . . . . . . . P756 Suzuki, Megumi. . . . . . . . . . . . . . . P722 Suzuki, Miki. . . . . . . . . . . . . . . . . P517 Suzuki, T. . . . . . . . . . . . . . . . . . O210 Suzuki, Yasuhiro . . . . . . . . . . . . . . P450 Suzuki, Yume . . . . . . . . . . . . . . . . P640 Svetel, M. . . . . . . . . . . . . . . . . . O108 Swistak, J. . . . . . . . . . . . . . . . . . P220 Switzer, J. A. . . . . . . . . . . . . . . . . O130 Szabo, K. . . . . . . . . . . . . . . . . . . P467 Szapary, L. . . . . . . . . . . . . . . P228, P566 Szatmari, S. . . . . . . . . . . . . . . . . P456 Szczudlik, A. . . . . . . . . . O98, P230, P256, P570, P689 Szczudlik, P. . . . . . . . . . . . . . . . . P738 Szczyrba, S. . . . . . . . . . . . . . . . . P526 Szereday, L. . . . . . . . . . . P228, P307, P566 Szmidt-Salkowska, E. . . . . . . . . P609, P739 Szocs, I. . . . . . . . . . . . . . . . . . . P456 Tacik, P. . . . . . . . . . . . . . . . . . . . O53 Taebei, H. . . . . . . . . . . . . . . . . . P685 Tagliati, M. . . . . . . . . . . . . . . . . . O105 Tahsini, M. . . . . . . . . . . . . . P405, P423 Takahashi, H. . . . . . . . . . . . . . . . O210 Takahashi, T. . . . . . . . . . . . . . . . . P640 Takata, H. . . . . . . . . . . . . . . P579, P723 Taláb, R. . . . . . . . . . . . . . . . . . . P403 Talaisys, R.L . . . . . . . . . . . . . . . . . P660 Talarico, G. . . . . . . . . . . . . . O175, P594 Tallón Barranco, A. . . . . . . . . . . . . P691 Tamayo, J. . . . . . . . . . . . . . . . . . P468 Tanabe, Y. . . . . . . . . . . . . . . P579, P723 Tanridag, T. . . . . . . . . . . . . . . . . P522 Taoufik, Y. . . . . . . . . . . . . . . . . . . O79 Taroni, F. . . . . . . . . O85, O112, O118, O122 Tarta-Arsene, O. . . . . . . . . . . P378, P498 Tartaglione, T. . . . . . . . . . . . . . . . P770 Tascos, N. . . . . . . . . . . . . . . . . . P360 Tasiou, A. . . . . . . . . . . . . . . P281, P282 Taskos, N. . . . . . . . O146, P242, P313, P324,

P391, P415, P422, P499, P515, P551, P576, P621, P665, P669, P767 Tauscher, G. . . . . . . . . . . . . . . . . P516 Tavazzi, E. . . . . . . . . . . . . . . . . . O123 te Lintelo, M. P. . . . . . . . . . . . . . . P642 Tedgui, A. . . . . . . . . . . . . . . . . . P426 Tejero, M. A. . . . . . . . . . . . . . P531, P708 Teleanu, D. M. . . . . . . . . . . . . . . . P385 Teleanu, R. I. . . . . . . P379, P380, P381, P385 Telman, G. . . . . . . . . . . . . . . . . . O204 Tench, C. R. . . . . . . . . . . . . . . . . P292 Tenembaum, S. N. . . . . . . . . . . . . . O159 Tentschert, S. . . . . . . . . . . . . . . . P569 Terada, S. . . . . . . . . . . . . . . . . . . P579 Terenghi, F. . . . . . . . . . . . . . . O78, P557 Terwecoren, A. . . . . . . . . . . . . . . . P644 Terzic, D. . . . . . . . . . . . . . . . . . . P319 Terzis, G. . . . . . . . . . . . . . . . . . . P604 Thakre, M. . . . . . . . . . . . . . . P496, P546 Théaudin, M. . . . . . . . . . . . . . . . P444 Thees, S. . . . . . . . . . . . . . . . P251, P252 Theil, D. . . . . . . . . . . . . . . . . . . O125 Then Bergh, F. . . . . . . . . . . . . . . . P535 Theobald, K. . . . . . . . . . . . . . . . . O202 Theodore, C. . . . . . . . . . . . . . . . . O79 Theophilidis, G. . . . . . . . . . . . . . . P360 Thill, B. . . . . . . . . . . . . . . . . . . . P318 Thimary, F. . . . . . . . . . . . . . . . . O140 Thodi, C. . . . . . . . . . . . . . . . . . . P473 Thoeni, A. . . . . . . . . . . . . . . . . . O103 Thomaides, T. . . . . . . . . . . . . . . . P715 Thomann, S. . . . . . . . . . . . . . P321, P431 Thomas, A. . . . . . . . . . . . . . P363, P692 Thomas, J. L. . . . . . . . . . . . . . . . . . . 3 Ticozzi, N. . . . . . . . . . . . . . . . . . P729 Timasheva, Y. . . . . . . . . . . . . . . . P574 Timmann, D. . . . . . . . . . . . . . . . . P384 Tintore’ Subirana, M. . . . . . . . . . . . P657 Tiu, C. . . . . . . . . . . . . . . . . . . . P643 Toda, H. . . . . . . . . . . . . . . . . . . P590 Todaro, A. . . . . . . . . . . . . . . . . . P262 Todorovic, S. . . . . . . . . . . . . . . . . P432 Tolnay, M. . . . . . . . . . . . . . . O77, P431 Tolosa, E. . . . . . . . . . . . . . . . . . O153 Tomczykiewicz, K. . . . . . . . . . . . . P778 Tomiyama, M. . . . . . . . . . . . . . . . P756 Tonali, P. A. . . . . . . . . . P273, P404, P612, P728, P770 Toniolo, D. . . . . . . . . . . . . . . . . . P277 Tonn, J.-C. . . . . . . . . . . . . . . . . . P769 Topcular, B. . . . . . . . . . . . . . O147, O158 Tormo, I. . . . . . . . . . . . . . . . . . . P698 Torrente, Y. . . . . . . . . . . . . . . . . . O52 Tortella, F. . . . . . . . . . . . . . . . . . P425 Tortelli, R. . . . . . . . . . . . . . . . . . O211 Tortorella, C. . . . . . . . . . . . . . . . O211 Tortorella, P. . . . . . . . . . . . . . . . . O188 Toscano, A. . . . . . . . . . . . . . P610, P615 Tosto, G. . . . . . . . . . . . . . . . O175, P594 Touloumi, O. . . . . . . . . . O146, P233, P422 Tovar-Moll, F. . . . . . . . . . . . . . . . . O66 Toyota, T. . . . . . . . . . . . . . . . . . . P525 Traboulsee, A. . . . . . . . . . . . . . . . P539 Trajkovic, G. . . . . . . . . . . . . . . . . O108 Trapp, B. . . . . . . . . . . . . . . . . . . . . 2 Traufeller, K. . . . . . . . . . . . . . . . . O53 Traykov, L. . . . . . . . . . . . . . . . . . O74 Traynor, B. J. . . . . . . . . . . . . O209, P737 Trébol López, J. . . . . . . . . . . . . . . P585 Treede, R. . . . . . . . . . . . . . . . . . O111 Treib, J. . . . . . . . . . . . . . . . P344, P676 Trevisan, E. . . . . . . . . . . . . . . O43, O45 Trevisson, E. . . . . . . . . . . . . . . . . O84 Triantafillou, A. . . . . . . . . . . . . . . P697 Trichopoulos, D. . . . . . . . . . . . . . O148 Trichopoulou, A. . . . . . . . . . . . . . O148 Trinka, E. . . . . . . . . . . . . . . . . . O132 Trinkl, A. . . . . . . . . . . . . . . . . . . P231

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Trkanjec, Z. . . . . . . . . . . . . . . . . P474 Trocello, J.-M. . . . . . . . . . . . . . . . . O71 Trojano, M. . . . . . . . . . . . . . O145, P414 Troll, S. . . . . . . . . . . . . . . . . . . . P397 Trotti, C. . . . . . . . . . . . . . . . O90, P361 Troxel, A. . . . . . . . . . . . . . . . . . . O92 Tsanaclis, A. M. . . . . . . . . . . . . . . P577 Tsatsou, K. . . . . . . . . . . . . . . . . . P464 Tschan, R. . . . . . . . . . . . . . . . . . . O41 Tschernatsch, M. . . . . . . . . . . O152, P352 Tscherning, T. . . . . . . . . . . . . . . . P416 Tsimourtou, V. . . . . . . . . . . . . . . . P537 Tsirka, E. . . . . . . . . . . . . . . . . . . P234 Tsirka, V. . . . . . . . . . . . . . . . . . . P234 Tsiskaridze, A. . . . . . . . . . . . . . . . P572 Tsitou, C. . . . . . . . . . . . . . . P701, P702 Tsivgoulis, A. . . . . . . . . . . . . P559, P603 Tsivgoulis, G. . . . . . . . . . . . . P559, P603 Tsougos, E. . . . . . . . . . . . . . . . . . P681 Tsounis, S. . . . . . . . . . . . . . . P391, P665 Tsuji, S. . . . . . . . . . . . . . . . . . . . O210 Tugal-Tutkun, I. . . . . . . . . . . . . . . P240 Tumani, H. . . . . . . . P402, P516, P725, P749 Tuncay, R. . . . . . . . . . . . . . . . . . P563 Turck, C. . . . . . . . . . . . . . . . . . . P754 Ture, S. . . . . . . . . . . . . . . . . . . . P369 Türe, U. . . . . . . . . . . . . . . . . . . . P504 Türk Börü, Ü. . . . . . . . . . . . . . . . P268 Turker, H. . . . . . . . . . . . . . . P478, P479 Turnbull, D. . . . . . . . . . . . . 17, 19, P427 Tuta, S. . . . . . . . . . . . . . . . . P455, P501 Tychalas, A. . . . . . . . . . . . . . . . . P632 Tzelinskaya, I. . . . . . . . . . . . . . . . P591 Uitdehaag, B. M. J. . . . . . . . . . . . . O180 Ulbricht, D. . . . . . . . . . . P318, P346, P679 Umar, I. . . . . . . . . . . . . . . . . . . P334 Umar, U. . . . . . . . . . . . . . . . . . . P335 Unde, C. . . . . . . . . . . . . . . . . . . O189 Unterberger, I. . . . . . . . . . . . . . . . O132 Unti, E. . . . . . . . . . . . . . . . . . . . P373 Urban, A. . . . . . . . . . . . . . . . . . . P601 Urbanek, I. . . . . . . . . . . . . . P457, P484 Urbanova, E. . . . . . . . . . . . . . . . . P601 Us, Ö. . . . . . . . . . . . . . . . . . . . . P522 Usarek, E. . . . . . . . . . . . . . . . . . P732 Utikal, P. . . . . . . . . . . . . . . . . . . O131 Uzuner, N. . . . . . . . . . . . . . . . . . P488 Vaamonde, J. . . . . . . . . . . . . P672, P683 Vácha, J. . . . . . . . . . . . . . . . . . . P270 Vaitkus, A. . . . . . . . . . . . . . . . . . O106 Vajda, F. J. E. . . . . . . . . . . . . . . . . O135 Valadas, A. F. . . . . . . . . . . . . . . . . P442 Valagouti, D. . . . . . . . . . . . . . . . . P391 Vale, J. . . . . . . . . . . . . . . . . O133, P635 Valentí Soler, M. . . . . . . . . . . . . . . P597 Valentine, A. R. . . . . . . . . . . . . . . . O63 Valisˇ, M. . . . . . . . . . . . . . . . P403, P601 Valldeoriola, F. . . . . . . . . . . . . . . O153 Valls-Solé, J. . . . . . . . . . O153, O166, P333, P357, P436, P476, P477 Valone, F. . . . . . . . . . . . . . . . . . . P295 Valsasina, P. . . . . . . . . . . . . . O99, O101 van den Bergh, W. M. . . . . . . . . . . . P341 van der Toorn, A. . . . . . . . . . . . . . . O64 van der Worp, H. B. . . . . . . . . . . . . O87 van Oers, C. A. M. M. . . . . . . . . . . . O87 van Urk, C. . . . . . . . . . . . . . . . . . O64 van Zandvoort, M. J. . . . . . . . . . . . . O87 Vandenbark, A. . . . . . . . . . . . . . . P648 Vandi, S. . . . . . . . . . . . . . . . . . . P779 Vaneckova, M. . . . . . . . . . O68, P650, P755 Vanhaudenhuyse, A. . . . . O163, O183, P269 Vankan, P. . . . . . . . . . . . . . . . . . P605 Vanli, E. N. . . . . . . . . . . . . . . . . . P240 Vanwalleghem, P. W. . . . . . . . . . . . P644 Varanese, S. . . . . . . . . . . . . . . . . P363 Vargas-Leal, V. . . . . . . . . P290, P449, P754

Vargek-Solter, V. Vashadze, T. . . Vasˇku, A. . . . . Vassilopoulos, D.

. . . . . . . P303, P493, P748 . . . . . . . . . . . . . . P572 . . . . . . . . . . . . . . P270 . . . . . . O148, O170, O174, P274, P441, P533, P534, P600 Vassilopoulou, S. . . . . . . . . . . P559, P603 Vavrova, J. . . . . . . . . . . . . . . . . . P780 Vazerian, S. . . . . . . . . . . . . . . . . P405 Vázquez, J. M. . . . . . . . . . . . . . . . P549 Veber, D. . . . . . . . . . . . . . . . . . . P529 Vecchio, R. . . . . . . . . . . . . . . . . . P288 Velasco, R. . . . . . . . . . . . . . . . . . P705 Velikova, S. . . . . . . . . . . . . . . . . . P356 Vellas, B. . . . . . . . . . . . . . . . . . . O56 Velluto, L. . . . . . . . . . . . . . . . . . P692 Ventura, M. . . . . . . . . . . . . . . . . P269 Venturelli, E. . . . . . . O54, O171, O173, P530 Vergani, L. . . . . . . . . . . . . . . . . . P276 Vergari, M. . . . . . . . . . . . . . . . . . P440 Vermersch, P. . . . . . . . . . . . . . . . P611 Verschuuren, J. J. . . . . . . . . . . . . . O182 Versino, E. . . . . . . . . . . . . . . P538, P759 Ververis, N. . . . . . . . . . . . . . . . . P234 Verweij, B. . . . . . . . . . . . . . . . . . O59 Vetrugno, R. . . . . . . . . . . . . . . . . P779 Vial, C. . . . . . . . . . . . . . . . . . . . O80 Vidailhet, M. . . . . . . . . . O71, P366, P367 Vidgop, Y. . . . . . . . . . . . . . . . . . P547 Vikelis, M. . . . . . . . . . . . . . . . . . P287 Vilar, J. . . . . . . . . . . . . . . . . . . . P426 Vilchez, J. J. . . . . . . . . . . . . . . . . P320 Vilensky, D. A. . . . . . . . . . . . . . . . P711 Villa, C. . . . . . . . . . . . . . . . . . . O173 Villanueva, J. A. . . . . . . . . . . . . . . P698 Villarejo Galende, A. . . . . . . . . . . . P246 Villringer, A. . . . . . . . . . . . . . . . . O207 Vink, M. . . . . . . . . . . . . . . . . . . . O87 Virgilio, R. . . . . . . . . . . . . . . . . . P729 Visioli, F. . . . . . . . . . . . . . . . . . . P327 Vismara, C. . . . . . . . . . . . . . . . . P356 Vita, G. . . . . . . . . . . . . . . . . . . . P327 Vita, M. G. . . . . . . . . . . . . . . P592, P612 Vitak, T. . . . . . . . . . . . . . . . . . . P650 Vivanco, R. M. . . . . . . . . . . . . . . . P763 Vivancos, F. . . . . . . . . . . . . . . . . O200 Vivancos, J. . . . . . . . . . . . . . . . . . P226 Viviani, P. . . . . . . . . . . . . . . . . . P401 Vlachova, I. . . . . . . . . . O131, O212, P348 Vlychou, M. . . . . . . . . . . . . . P266, P267 Voeltz, K. . . . . . . . . . . . . . . . . . . P418 Vogel, H. . . . . . . . . . . . . . . . . . . P716 Vogt, T. . . . . . . . . . . . . . . . . . . . O111 Vogt-Schaden, M. . . . . . . . . . . . . . O42 Vohanka, S. . . . . . . . . . . . . . P457, P484 Voigt, K. . . . . . . . . . . . . . . . P765, P766 Vollmer, T. . . . . . . . . . . . . . . . . . P295 Volna, J. . . . . . . . . . . . . . . . P780, P784 Volonté, M. A. . . . . . . . . . . . . . . . O109 Volpi, L. . . . . . . . . . . . . P610, P617, P735 Voltz, R. . . . . . . . . . . . . . . . O46, O182 von Rautenfeld, B. . . . . . . . . . . . . . P418 Vossough, A. . . . . . . . . . . . . . . . . P423 Vranova, H. . . . . . . . . . . P249, P482, P492 Vrenken, H. . . . . . . . . . . . . . . . . . O64 Vry, J. . . . . . . . . . . . . . . . . . . . . O160 Wachowius, U. . . . . . . . . . . . . . . . P651 Wade, D. . . . . . . . . . . . . . . . . . . . O91 Wagner, H. . . . . . . . . . . . . . . . . . P645 Wagner, J. N. . . . . . . . . . . . . . . . . O40 Wakil, A. . . . . . . . . . . . . . . . . . . P682 Wakil, M. . . . . . . . . . . . . . . . . . . P512 Walberer, M. . . . . . . . . . . . . . . . . P352 Waldvogel, D. . . . . . . . . . . . . P251, P252 Wallis, S. . . . . . . . . . . . . . . . . . . P465 Walser, G. . . . . . . . . . . . . . . . . . O132 Wang, C. . . . . . . . . . . . . . . . . . . P263 Wang, Sam . . . . . . . . . . . . . . . . . O130

Wang, Steven . . . . . . . . . . . . . . . . P507 Wang, Y. . . . . . . . . . . . . P263, P626, P695 Wardlaw, J. . . . . . . . . . . . . . . . . . O97 Warlow, C. . . . . . . . . . . . . . . . . . O62 Watanabe, T. . . . . . . . . . . . . . . . . P722 Weber, F. . . . . . . . . P222, P290, P449, P754 Weber, R. . . . . . . . . . . . . . . . . . . P550 Wegrzyn, G. . . . . . . . . . . . . . . . . P771 Wei, H. . . . . . . . . . . . . . . . . . . . P425 Wei, N. . . . . . . . . . . . . . . . . P263, P695 Weier, K. . . . . . . . . . . . . . . O103, P371 Weiller, C. . . . . . . . . . . . . . . . . . . . 24 Weimar, C. . . . . . . . . . . . . . . . . . O202 Weiner, L. . . . . . . . . . . . . . . . . . P295 Weinstock-Guttman, B. . . . . . . . . . . O67 Weintz, E. . . . . . . . . . . . . . . . . . P241 Weis, J. . . . . . . . . . . . . . . . . . . . O53 Weishaupt, A. . . . . . . . . . . . . . . . P716 Weiss, P. H. . . . . . . . . . . . . . . . . . P583 Wermer, M. J.H. . . . . . . . . . . . . O59, O95 Werner, R. . . . . . . . . . . . . . . P747, P774 Werth, E. . . . . . . . . . . . O199, P777, P781 Wick, M. . . . . . . . . . . . . . . . . . . O46 Wieclawska, M. . . . . . . . . . . . O121, P359 Wiegand, F. . . . . . . . . . . . . . P507, P636 Wijdicks, E. . . . . . . . . . . . . . . . . . O49 Wildanger, G. . . . . . . . . . . . . . . . P679 Williams, A. . . . . . . . . . . . . . . . . P425 Winblad, B. . . . . . . . . . . . . . . . . P589 Windisch, M. . . . . . . . . . . . . . . . O172 Winston, G. P. . . . . . . . . . . . . . . . P552 Wissel, J. . . . . . . . . . . . . . . . . . . O164 Wissinger, B. . . . . . . . . . . . . . . . . P276 Withofs, N. . . . . . . . . . . . . . . . . . P578 Wloch, D. . . . . . . . . . . . O98, P230, P570 Woessner, R. . . . . . . . . . . . . P344, P676 Wöhrle, J. C. . . . . . . . . . . . . . P747, P774 Wójcik, M. . . . . . . . . . . . . . . . . . P256 Wolansky, L. . . . . . . . . . . . . . . . . P547 Wolf, O. . . . . . . . . . . . . . . . . . . . P471 Wolfer, D. . . . . . . . . . . . . . . . . . . P568 Wolfkühler, D. . . . . . . . . . . . . P310, P311 Wolnik, B. . . . . . . . . . . . . . . . . . P526 Woolmore, J. A. . . . . . . . . . . . . . . P649 Worthington, J. . . . . . . . . . . . . . . O144 Wunderli-Allenspach, H. . . . . . . . . . P225 Wunderlich, N. . . . . . . . . . . . . . . P231 Wurst, W. . . . . . . . . . . . . . . . . . . P278 Xifara, K. . . . . . . . . . . . . . . . . . . P287 Xifaras, M. . . . . . . . . . . . . . . . . . P243 Xiromerisiou, G. . . . . P281, P282, P537, P762 Yagihashi, S. . . . . . . . . . . . . . . . . P525 Yahara, O. . . . . . . . . . . . . . . P450, P485 Yalcin, D. . . . . . . . . . . . . . . . . . . P387 Yalciner, Z. B. . . . . . . . . . . . . . . . P221 Yaldizli, O. . . . . . . . . . . . . . . . . . . O70 Yamashita, T. . . . . . . . . . . . . . . . O210 Yamazaki, T. . . . . . . . . . . . . . . . . P722 Yang, D. W. . . . . . . . . . . . . . P453, P500 Yang, M. T. . . . . . . . . . . . . . . . . . P365 Yao, B. . . . . . . . . . . . . . . . . . . . P297 Yao, C. . . . . . . . . . . . . . . . . . . . P425 Yapici, Z. . . . . . . . . . . . O147, O158, P387 Yarnitsky, D. . . . . . . . . . . . . . . . . O204 Yazdchi, M. . . . . . . . . . . P364, P472, P514 Yazici, J. . . . . . . . . . . . . . . . . . . P775 Ybot, I. . . . . . . . . . . . . . . . . O60, P452 Ye, B. S. . . . . . . . . . . . . . . . . . . . P301 Yella, V. . . . . . . . . . . . . . . . . . . . O181 Yerdelen, D. . . . . . . . . . . . . . . . . P717 Yesilot, N. . . . . . . . . . . . . . . P563, P775 Yetimalar, Y. . . . . . . . . . . . . . . . . O189 Yi, S-D. . . . . . . . . . . . . . . . . . . . P502 Yildirim, B. . . . . . . . . . . . . . . . . . P326 Yilmaz, A. . . . . . . . . . . . . . . . . . P479 Yollin, E. . . . . . . . . . . . . . . . . . . P420 Yoo, B. G. . . . . . . . . . . . . . . . . . . P429

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P342 P343 P454 P461 O144 O157 P395

Zabala Mendez, F. . . . . . . . . . . P607, P608 Zach, M. . . . . . . . . . . . . . . . O107, P738 Zacharaki, F. . . . . . . . . . . . . . . . . P537 Zaki, Maha . . . . . . . . . . . . . . . . . P400 Zaki, Mona . . . . . . . . . . . . . . . . . P460 Zakirova, A. . . . . . . . . . . . . . . . . P574 Zalc, B. . . . . . . . . . . . . . . . . . . . . . 3 Zambrano Toribio, A. . . . . . . . P687, P688 Zanotta, N. . . . . . . . . . . . . . . . . . P633 Zanotti, L. . . . . . . . . . . . . . . . . . P568

Zapf, J. . . . . . . . . . . . . . . . . . . . P571 Zapletalova, J. . . . . . . . . . . . . . . . O212 Zappalà, G. . . . . . . . . . . . . . . . . . P588 Zara, F. . . . . . . . . . . . . . . . . . . . P620 Zaremba, J. . . . . . . . . . . . . . . . . O121 Zaremba, M. M. . . . . . . . . . . . . . . P421 Zarko Bahar, S. . . . . . . . . . . . . . . P563 Zaros, C. . . . . . . . . . . . . . . . . . . O81 Zdzienicka, E. . . . . . . . . . . . . O121, P359 Zea, M. . . . . . . . . . . . . . . . . . . . P622 Zellini, F. . . . . . . . . . . . . . . . . . . P292 Zennaro, E. . . . . . . . . . . . . . . . . . P596 Zettl, U. K. . . . . . . . P402, P651, P749, P753 Zeviani, M. . . . . . . . . . . . . . . . . . . 18 Zhang, Y. . . . . . . . . . . . P263, P626, P695 Zhao, X. . . . . . . . . . . . . . . . P263, P695 Zhelev, Y. . . . . . . . . . . . . . . . . . . O74 Zidovska, J. . . . . . . . . . . . . . P247, P368

Zierz, S. . . . . . . . . . . . . . . . . . . . O53 Ziller, M. G. . . . . . . . . . . . . . P377, P577 Zima, Z. . . . . . . . . . . . . . . . . . . P456 Zimatore, G. B. . . . . . . . . . . . . . . P414 Zingler, V. C. . . . . . . . . . . . . P241, P769 Zisis, A. . . . . . . . . . . . . . . . . . . O195 Zivadinov, R. . . . . . . . . . . O65, O67, O68, O181, P752, P755 Zoll, J. . . . . . . . . . . . . . . . . . . . P426 Zotta, E. . . . . . . . . . . . . . . . . . . P242 Zouari, M. . . . . . . . . . . . . . . P396, P745 Zouvelou, V. . . . . . . . . . . . . . . . . P604 Zubkov, A. . . . . . . . . . . . . . . . . . O205 Zucca, C. . . . . . . . . . . . . . . . . . . P633 Zuliani, C. . . . . . . . . . . . . . . . . . P620 Zumrova, A. . . . . . . . . . . . . . . . . P601 Zurru, C. . . . . . . . . . . . . . . . . . . P608 Zwergal, A. . . . . . . . . . . . . . P244, P245