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J Neurol (2006) 253 [Suppl 2]: II/1–II/170 DOI 10.1007/s00415-006-2001-2

Sixteenth Meeting of the European Neurological Society 27–31 May 2006, Lausanne, Switzerland Symposia and Free Communications

The abstracts have been reviewed by: Z. Argov, O. A. Bajenaru, J. Bogousslavsky, O. Combarros, G. Comi, V. Dietz, M. Donaghy, C. Elger, J. M. Ferro, C. Krarup, I. Milonas, G. Moonen, Y. Parman, V. Planté-Bordeneuve, G. Said, E. Scarpini, R. Soffietti, E. Schmutzhard, A. Steck, E. Tolosa, J. Valls-Solé, M. J. D. Vidailhet

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Contents Presidential symposium Brain ischaemia, new patterns and treatments II/3

Symposia Neurology of sleep II/3 Imaging brain diseases II/4 New trends in treatment of neurological disorders II/5

FREE COMMUNICATIONS Oral Sessions Session 1: Multiple sclerosis 1 II/6 Session 2: Multiple sclerosis 2 II/8 Session 3: Peripheral neuropathies 1 – Hereditary neuropathies II/9 Session 4: Peripheral neuropathies 2 II/11 Session 5: Extrapyramidal disorders II/13 Session 6: Headache and pain II/14 Session 7: Cerebrovascular disorders 1 II/16 Session 8: Cerebrovascular disorders 2 II/18 Session 9: Epilepsy II/19 Session 10: Higher function disorders and dementia II/21 Session 11: Infection of the nervous system II/22 Session 12: Neuro-oncology II/23 Session 13: Multiple sclerosis 3 II/25 Session 14: Multiple sclerosis 4 II/27 Session 15: Neuro-ophthalmology II/28 Session 16: Motor neuron disease II/29 Session 17: Clinical neuroscience II/31 Session 18: Clinical neurophysiology II/32 Session 19: Cerebrovascular disorders 3 II/34 Session 20: Cerebrovascular disorders 4 II/35 Session 21: Genetics II/37 Session 22: Muscle disorders II/38 Session 23: Dementia II/39

POSTER SESSIONS Poster Session 1 Cerebrovascular disorders II/41 Clinical neurophysiology II/45

Extrapyramidal disorders II/46 General neurology II/48 Genetics II/50 Infection II/53 Multiple sclerosis II/55 Neuro-oncology II/59 Poster session 2 Cerebrovascular disorders II/64 Clinical neurophysiology II/68 Dementia/Higher function disorders II/70 Epilepsy II/74 Extrapyramidal disorders II/76 General neurology II/78 Multiple sclerosis II/80 Peripheral neuropathy II/84 Poster session 3 Cerebrovascular disorders II/88 Dementia/Higher function disorders II/89 Extrapyramidal disorders II/93 Infection II/95 Motor neuron disease II/97 Multiple sclerosis II/99 Muscle disorders II/103 Peripheral neuropathy II/107 Poster session 4 Cerebrovascular disorders II/111 General neurology II/114 Immunology II/117 Motor neuron disease II/120 Multiple sclerosis II/123 Neurobiology II/127 Pain and headache II/129 Sleep disorders II/132 Poster session 5 Cerebrovascular disorders II/135 Child neurology II/139 Extrapyramidal disorders II/140 Multiple sclerosis II/142 Neuro-ophthalmology II/147 Neurorehabilitation II/149 Pain and headache II/154 Sleep disorders II/156

Author index

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Presidential symposium Brain ischaemia, new patterns and treatments 1 White matter ischaemic syndromes M. Hennerici Mannheim, D Subcortical nuclear and white matter ischaemic lesions have long been known to present with less impressive signs and symptoms and cortical ischaemia: these reange from a) often clinically asymptomatic, incidental findings once CT-/MRI studies are performed through b) occasionally oligosymptomatic, uncharacteristic patterns (in particular if overlap exists in diaschisis) to c) few very typical lesions if nuclear structures are heavily involved (brainstem, thalamus, lentiform nuclei etc). Isolated white matter lesions, manifest mostly once disseminated chronic ischaemia occurs as subcortical vascular encephalopathy (SVE), if remote focal strokes coincidentally happen in synergistics syndromes or due to large sensory-motor tract disruption in severe lacunar strokes. Etiologies are widespread and overlap with many other white matter diseases ranging from multiple sclerosis in the younger to cerebral amyloid angiopathy in the elderly often with unknowen mechanisms as far as neurodegeneration is concerned (Alzheimer’s disease, CJD,“paraneoplastic syndromes” etc). This review concentrates on probably the only “vascular” type dementia studied intensively during recent years and attempts to demonstrate potentials of insight to be achived not only for a better understanding of such diseases in increasingly older populations but also what can be tranferred to other diseases still difficult to understand today. 3 Present and future of acute stroke therapy M. Fisher University of Massachusetts Medical School (Worcester, USA) The current status of acute stroke therapy remains limited to one approved drug, intravenous (i. v.) tPA initiated within 3 hours of stroke onset. This limited therapeutic armamentarium is reflected by the small number of acute ischemic stroke (AIS) patients that are currently treated. Other strategies for the use of thrombolytic therapy in AIS, such as intraarterial delivery of the thrombolytic agent, combined i. v. and i. a. therapy and the use of other thrombolytic agents are being explored. Thrombolytic therapy is directed at restoring or improving blood flow to the ischemic brain, but not at ameliorating the consequences of ischemia within brain tissue related to reduced or absent blood flow, i. e. the ischemic cascade. Recent advances regarding thrombolytic therapy have occurred. Intravenous Desmoteplase was shown to improve cerebral perfusion and tended to improve clinical outcome in two small trials with a 3–9 hour treatment window. A larger trial with a 9-hour treatment window is underway. In the DEFUSE study of i. v. t-pa given between 3–6 hours after stroke onset, patients with a diffusion/perfusion mismatch benefited from treatment while those without mismatch did not. This observation supports the results of several observational studies that demonstrated apparent clinical benefit with i. v. t-pa when given 3–6 hours after stroke onset in patients with an MRI-confirmed mismatch. In the United States, the MERCI clot retrieval device has been approved for removing thrombi from intracranial vessels but not as a stroke treatment.Concerns remain about the safety of this device and further clinical trials and registries should provide additional information about safety and efficacy Drugs directed at the ischemic cascade are termed neuroprotectants and many different types of neuroprotective drugs have been developed targeted at the manifold aspects of ischemic brain injury. Many neuroprotective drugs were evaluated in advanced clinical trials, but until recently all of these trials were not positive for a variety of reasons. No neuroprotective drug is currently available for clinical use. In the recently reported SAINT-1 trial of the spin-trap agent, NXY-059 a positive effect on the primary outcome measure was observed. The primary outcome measure was a shift of the modified Rankin scale of at least one point across the whole range of the scale and not a dichotomized outcome as was used in all previous AIS trials. This outcome measure is targeted to look for a modest but likely clinically meaningful treatment effect as opposed to a “cure” when the goal was to assess the percentage of patients with little or no deficit, i. e. Rankin 0–1. In future AIS trials it is likely that the Rankin shift approach will be used as the primary outcome measure. In the SAINT-1 trial no effect was observed on the change from baseline to day 90 on the NIHSS scale but efficacy trends were observed on other relevant outcome measures. The ongoing SAINT-2 trial will provide vital information about the efficacy or lack thereof on NXY-059.

4 Penumbra is brain: targeted neuro-imaging in hyperacute stroke J. Bogousslavsky, P. Michel, M. Reichhart, M. Wintermark, P. Maeder, R.Meuli Centre Hospitalier Universitaire Vaudois (Lausanne, CH); University of California (San Francisco, USA) Given the millions of neurons dying every hour in acute ischemic stroke, we need more advanced methods to treat the appropriate patient with the appropriate method. Shortening symptom-to-treatment delays is mandatory for all stroke patients, but clinicians and scientists have recognized for quite a while that stroke is highly variable from one individual to the other. This applies particularly to the amount of irreversibly damaged and salvageable tissue (“core” and “penumbra”) and to the localisation of arterial occlusions. Measuring tissue perfusion with various methods (PET, SPECT, XenonCt, PWI-DWI MRI, perfusion-CT etc.), we are recognizing that time is not the gold standard but a surrogate marker when it comes to predicting the presence of penumbra. Mounting evidence, most recently from the DEFUSE trial, confirms that patients without penumbra do not benefit from recanalisation, and may even be harmed. On the other hand, the DIAS trial has shown that patients may benefit from thrombolysis well beyond the 3 hour limit if they have a persistent penumbra. These data strongly support the notion that “penumbra is brain” rather than “time is brain”, and that the time clock should be replaced by a pathophysiological clock in most patients when it comes to acute treatment decisions. The second, similarly important requirement for successful stroke treatment is rapid, complete, and persistent recanalisation. Early recanalisation, whether spontaneous or treatment-related, has been associated in most studies with better radiological and clinical outcomes. We therefore should use all efforts available to recanalize arteries in acute stroke. Thirdly, advanced neuroimaging may predict of the neurovascular complications. Examples are haemorrhagic transformation in patients with severe and large volume ischemia who recanalize rapidly, or mass effect from brain ischaemia. When data about perfusion and arterial imaging are combined, the best stroke outcomes occur as expected in patients with a small core, a large penumbra and early recanalisation. Although not proven yet, it is likely that neuroprotective treatments will be particularly effective in exactly the same population, because the therapeutic agents are more likely to reach their intended target. Which acute neuroimaging technique should we use to identify the treatable patient? Plain CT main be a suitable screening tool for non-invasive recanalisation and neuroprotection in the very early phase (< 90 min. or so), where it can be assumed that most patients have a significant penumbra. Thereafter, perfusion-imaging and arterial imaging becomes essential, either to decide about the indication and contraindications of different recanalisation and neuroprotective strategies, or to decide about further treatment in patients who have undergone ultra-early (< 90 min) treatment based on a plain CT. Both perfusion-MRI our perfusion-CT reliably detect and distinguish reversible from irreversible ischemia. For imaging of arterial pathology, CT- and MR-angiography are similary accurate, and transcranial Doppler/Duplex may be a valuable alternative. Only few centers now take the risk of performing conventional angiography without first doing a non-invasive study in candidates for intraarterial therapy. Ideally, all these advanced imaging methods should be available 24/24hours. The technique that fits the patient (contraindications, availability) and his doctor (experience, availability) most may be then be chosen as the “best” imaging in a given situation.

Symposium Neurology of sleep 15 Sleep and synaptic plasticity G. Tononi Department of Psychiatry, University of Wisconsin (Madison, USA) Background: This paper will discuss a novel hypothesis – the synaptic homeostasis hypothesis – which claims that sleep plays a role in the regulation of synaptic weight in the brain [1]. In brief, the hypothesis is as follows: 1. Wakefulness is associated with synaptic potentiation in several cortical circuits; 2. Synaptic potentiation is tied to the homeostatic regulation of slow wave activity; 3. Slow wave activity is associated with synaptic downscaling;

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4. Synaptic downscaling is tied to the beneficial effects of sleep on neural function and, indirectly, on performance. Methods: Evidence for the hypothesis has been obtained using many experimental paradigms, from molecular studies of sleep and wakefulness to neuroimaging studies in humans. Results: The synaptic homeostasis hypothesis can account for several aspects of sleep and its regulation, and several of its specific predictions were confirmed experimentally. Conclusions: According to the hypothesis, plastic processes occurring during wakefulness result in a net increase in synaptic strength in many brain circuits. The role of sleep is to downscale synaptic strength to a baseline level that is energetically sustainable, makes efficient use of gray matter space, and is beneficial for learning and memory. Thus, sleep is the price we pay for plasticity, and its goal is the homeostatic regulation of the total synaptic weight impinging on neurons. The hypothesis accounts for a large number of experimental facts, makes several specific predictions, and has implications for sleep, neurological, and psychiatric disorders. Supported by NIH Director Pioneer Award 16 Sleep apnoea and cardiovascular diseases P. Lavie Technion-Israel Institute of Technology, Lloyd Rigler Sleep Apnea Research Laboratory (Haifa, IL) Obstructive sleep apnea characterized by intermittent and recurrent pauses in respiration during sleep resulting in a decreased oxygen saturation and sleep fragmentation is closely associated with cardiovascular morbidity and mortality. Sleep apnea has been shown to be causally related with hypertension and to be associated with strokes, ischemic heart diseases and cardiac arrhythmias. Evidence accumulated in recent years shed a new light on the natural evolution of cardiovascular morbidity in obstructive sleep apnea. Several studies demonstrated the existence of endothelial dysfunction and early clinical signs of atherosclerosis in patients with sleep apnea who were free of any overt cardiovascular diseases. This suggests that the cardiovascular morbidity in sleep apnea is developing over several years through accumulated damage to the vasculature. Research performed in our laboratory has focused on the pathophysiology of atherogenic processes in sleep apnea syndrome. We showed that hypoxia/reoxygenation, that is the most important characteristic of sleep apnea, promotes the formation of reactive oxygen species that activate critical redox-sensitive signaling pathways and transcription factors. This facilitates the expression of sets of genes that encode proteins essential to adaptation to hypoxia, as well those that elicit inflammatory pathways such as adhesion molecules and inflammatory cytokines. Consequently, inflammatory and immune responses are activated thus resulting in the activation of endothelial cells/leukocytes/platelets. These activated cells express adhesion molecules and pro-inflammatory cytokines that in turn may further exacerbate inflammatory responses and cause endothelial cell injury and dysfunction. This newly acquired insight into the pathophysiology of cardiovascular morbidity in OSA have important implications regarding the diagnosis and treatment of the syndrome. 18 Narcolepsy C. L. Bassetti University Hospital Zurich (Zurich, CH) Narcolepsy is a life-long, usually sporadic (rarely familial) sporadic which usually starts in the 2. or 3. decade of life. The prevalence of narcolepsy is similar to that of multiple sclerosis (about 1:2000 in the adult population). Excessive daytime sleepiness (EDS) is usually the first and most disabling symptom. Cataplexy – a sudden and short loss of muscle tone triggered by emotions with preserved consciousness – is the only pathognomonic symptom of narcolepsy and shares features with physiological REM sleep atonia. Associated, non specific symptoms of narcolepsy include sleep paralysis, hallucinations, parasomnias, weight gain, and psychosocial disability. Biological markers of narcolepsy are diagnostic helpful and include 1) a specific HLA class II-subtype (DQ1*0602, 90–95 % of patients), 2) the appearance of REM-sleep within 15–20 minutes after sleep-onset (sleep onset REM, 70–80 %), and 3) the absence/reduction of the recently discovered hypothalamic peptide hypocretin-1 (orexin A, 90 %) in the cerebrospinal fluid. Narcolepsy usually arises from a combination of genetic and -yet to be identified- environmental factors. In fact, only about one third of monozygotic twins are concordant for the disease. Less commonly, genetic factors (familial narcolepsy) or acquired brain disorders (symptomatic narcolepsy) prevail. Narcolepsy is associated with multiple neurotransmitter signalling

deficiencies (hypocretin, dopamine, dynorphine, neuronal activity-regulated pentraxin, ...). Based also on studies in rodent and canine models of the disease, narcolepsy is thought to be due to an instability of sleep-wake mechanisms with rapid transitions between wakefulness, NREM and REM sleep and appearance of dissociated states (in which elements of different states intermingle). Treatment of narcolepsy is successful in the majority of patients and include information/counselling; scheduled naps; stimulants (e. g. modafinil, methylphenidate); and anticataplectic drugs (e. g. clomipramine, sodium oxybate). Future research will clarify the possibility of an autoimmune origine of narcolepsy, the exact correlation between signalling deficiencies and clinical manifestations, and the value of new treatment strategies (hypocretin agonists, immunomodulation).

Imaging brain diseases 19 Movement disorders D. J. Brooks Imperial College (London, UK) This talk will review findings obtained in movement disorders with recent advances in neuroimaging technology. Application of advances in magnetic resonance imaging such as voxel based morphometry, transcranial sonography, diffusion weighted and magnetization transfer MRI, to parkinsonian syndromes and dystonia are highlighted. The role of postron emission tomography to detect microglial activation in Parkinson’s and Huntington’s disease and measure changes in synaptic dopamine levels is also featured. Finally, some future directions in neuroimaging are presented. 20 Spinal cord disorders M. Forsting Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital of Essen (Essen, D) Spinal cord disorders include a huge variety of totally different diseases starting from congenital malformations over non-neoplastic disorders and ending with tumours and tumour-like lesions of the spinal cord. Congenital anomalies of the spinal cord include open spinal dysraphism, occult spinal dysraphism and anomalies of abnormal canalisation and retrogressive differentiation of the cord. Non-neoplastic disorders start with infectious diseases like spondylitis, epidural and subdural infections and spinal cord abscesses. As in the brain demyelating diseases can occur within the spinal cord as well as vascular problems like spinal cord ischemia and different kinds of vascular malformations. Specifically in young age patients spinal cord injuries are important and have to be diagnosed accurately. Intramedular tumours are usually not benigne and most of them are either astrocytomas or ependymomas. The talk will focus on vascular diseases of the spinal cord and tumour- and tumour-like lesions. The imaging modality of choice for all spinal cord lesions is nowadays clearly MR including MR-angiography. Specifically for vascular malformations the classical DSA is often still mandatory and sometimes endovascular therapy is the matter of choice in vascular malformations of the spinal cord. 21 Cerebrovascular disorders F. Fazekas Medical University Graz (Graz, A) Recent advances of modern imaging technology have greatly expanded our capabilities for the in-vivo assessment of cerebrovascular disorders. In this context treatment-oriented optimization of acute stroke imaging certainly has remained the foremost challenge. The importance of more slowly progressing and diffuse vascular brain damage, however, is now also increasingly recognized. With constant improvement of CT scanners and increasing experience of interpreters, CT nowadays not only serves to rule out intracerebral or subarachnoid bleeding but can display changes indicative of ischaemic damage already within the first hours after stroke. Nevertheless, magnetic resonance imaging (MRI) clearly surpasses the sensitivity for acute ischaemic damage,

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and it is especially diffusion weighted imaging (DWI) that has revolutionized stroke imaging by allowing to depict morphologic brain changes as early as 1 hour after the acute event. Concerns that MRI may fail to depict intracerebral hemorrhage as accurately as CT have also been ruled out. DWI is especially helpful in depicting small acute ischaemic lesions and to separate them from old cerebral damage. This helps to improve clinicoradiologic correlations and can add important information regarding specific stroke mechanisms. Similar to the concepts of “ischaemic penumbra” a mismatch between the abnormality seen on DWI and that indicated by perfusionweighted MRI can serve to identify threatened but still salvageable tissue and thus may help to extend the time window of successful acute thrombolysis and for guiding more complex treatment decisions. The sensitivity of MRI for subtle tissue changes has also served to increasingly recognize the importance of chronic vascular damage most often from microangiopathy which appears to threaten brain functioning in a more global manner. Abnormalities consist of diffuse white matter changes, silent lacunes and infarcts and there is evidence that vascular damage may even promote brain shrinkage. Specific MRI pulse sequences also allow the detection of remnants of minimal blood seepage through damaged intracerebral vessels which is likely to be an indicator of more pronounced microangiopathy. All these abnormalities have been shown to progress over time and are associated with increasing cognitive impairment up to fullblown dementia as well as gait disorders and a higher probability for falls in the elderly. Finally, there is evidence for an association between small-vessel disease-related brain tissue changes and mood disorders especially depression. Efforts to also prevent chronic vascular damage thus become more and more important as its frequency increases in parallel with the life expectancy of western populations. 22 Brain imaging in dementia M. Filippi Ospedale San Raffaele, Neuroimaging Research Unit (Milan, I) The review of all possible dementing conditions and all imaging techniques used to investigate their structural and functional substrates is beyond the scope of the present abstract. As a consequence, this abstract is focussed on the use of magnetic resonance imaging (MRI) in the study of Alzheimer’s disease (AD), as a model for cortical dementia, and multiple sclerosis (MS), as a model for subcortical dementia. AD is the most common form of age-related dementia and affects approximately 1–5 % of the population over 65 years. In AD, seminal conventional MRI (cMRI) studies have shown the presence of gray matter (GM) loss, mainly in the medial temporal structures. Hippocampal size reduction was also found in patients with mild cognitive impairment (MCI) and was predictive for subsequent transition to AD. The atrophy process later spreads to associative temporo-parietal and frontal cortical areas. However, the correlation between regional GM atrophy and global cognitive impairment is relatively weak, suggesting that other pathological processes are at work. Non-conventional MRI techniques have indeed shown that AD also causes marked microstructural damage to the residual GM and that the combined quantification of GM loss and intrinsic damage is strongly correlated to the severity of cognitive impairment. Normal-appearing (NA) WM regions linked to associative cortices are also damaged and the severity of such damage is strongly related to AD cognitive decline. In MCI, damage to the NA brain tissue is intermediate between those of normals and AD patients, suggesting that WM and GM microstructural abnormalities are early events in AD. Functional MRI (fMRI) studies with cognitive tasks suggested that significant functional cortical changes also occur in AD patients with the potential to limit the clinical outcome of the underlying tissue damage. Cognitive impairment affects approximately 40–70 % of patients with MS. In these patients, the extent of WM lesions visible on cMRI scans, and their location in the hemispheric WM were found to be associated moderately with the level of neuropsychological performances. Linear and volumetric MRI-derived quantities reflecting brain parenchymal loss in general and neocortical tissue loss in particular were found to be correlated with neuropsychological test scores and with comprehensive cognitive impairment indexes, at a greater magnitude than the corresponding lesion volumes. More recently, the use of non-conventional MRI techniques has shown that subtle changes to the NAWM, overall intrinsic GM pathology and intrinsic T2-visible lesion damage also contribute to MS-related cognitive impairment. In fMRI studies with cognitive tasks, MS patients contrasted to matched normal controls exhibit different distribution and extent of cortical activations and this is believed to have, at least partially, a compensatory role, which contributes in limiting the neuropsychological manifestations of the disease. All these observations suggest that the in-vivo assessment through imaging-based technology of factors contributing to the cognitive decline asso-

ciated to the different potentially dementing neurological conditions is a rather complicated business. Such an assessment would require a careful assessment of the extent of tissue loss and the status of the remaining tissue in the different brain compartments, as well as the role of compensatory mechanisms.

New trends in treatment of neurological disorders 28 Specific and aspecific immune interventions in multiple sclerosis G. Comi IRCCS San Raffaele (Milan, I) Immunomodulating and immunosuppressive treatments for multiple sclerosis patients are directed against the inflammatory process and are only partially effective. This partial failure could be explained by mechanisms of axonal damage at least partially independent from acute or chronic inflammation. This suggests that there is a need for better use of available treatments and the necessity of alternative new therapeutic options to halt disease progression and enhance recovery mechanisms. Concerning actual treatments, two strategies are quite interesting: early treatment and combination therapy. The former approach is based on converging epidemiological, immunological and pathological studies and is proved by some recent clinical trials. The second one is under evaluation on ongoing clinical trials. Progress in understanding the mechanisms of T cell activation, inactivation and modulation has been translated into new therapeutic strategies aiming at inducing selective immunosuppression. Such an approach is now tested in phase II-III clinical trials. 29 Alzheimer’s amyloid immunotherapy J-M. Orgogozo Hôpital Pellegrin (Bordeaux, F) Accumulation of aggregated beta-amyloid protein in strategic areas of the cerebral cortex is associated to Alzheimer’s diseaise (AD) in the common sporadic form of the elderly as well as in the rare heredidary forms. Schenk et al. (1999) were able, in a milestone experiment, to prevent and even partly revert the amyloid burden and the associated neuropathological changes, in the brain of transgenic mice expressing the human amyloid protein involved in MA, by active anti-amyloid immunization. This remarkable result was shortly after replicated by other groups, either by active immunisation with the human aggregated A-beta or a passive immunization with anti A-beta monoclonal antibodies. A phase 1 study in 20 healthy volunteers of single doses of the Elan aggregated amyloid antigen was first conducted in the USA, with excellent tolerability except minor local reactions at the site of intra-muscular injection (Elan, data on file). Then a phase 2a randomized trial was carried on in 84 patients with AD, in UK, with repeated i. m. injections of the antigen or placebo. The main result was the demonstration of a predetermined antibody response in about 25 % of patients (Wilkinson et al. 2005). Side effects were mainly local inflammatory reactions and a single occorence of neurological worsening, later identified at autopsy as due to a new type of inflammatory meningoencephalitis (Nicoll et al. 2003). Lastly – so far – a phase 2b trial recruited 375 patients, to be given repeated i. m. injections of either the Elan amyloid antigen (AN1792) or matched placebo. The injections were discontinued, after 2 injections in most cases, because of the occurence of several cases of subacute meningoencephalitis (SAME) of presumed auto-immune origin: in total 18 (6 %) of patients developed a syndrome of SAME, severe in 6, followed by death in 2 or a bedridden state in 1 (Orgogozo et al. 2003). Despite the truncated antigen administration the predetermined antibody respose was achieved in 20 % of the exposed patients (none under placebo), without correlation with the occurrence of SAME. Neither the main clinical outcomes (ADAS-cog, MMSE, CDR ...) nor the total brain volume at MRI showed aparent benefit, in total and in the antibody responders (Gilman et al. 2005; Fox et al. 2005). However a positive response was objectived with an ad hoc neuropsychological test battery, correlated with the antibody response and with changes in the A-beta/tau ratios in the CSF towards more normal values (Gilman et al. 2005). In the few patients from this trial who went to autopsy, with or without SAME, a consistent reduction of the expected amyloid deposits with some evidence of amyloid removal was observed (Ferrer et al. 2004).

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All these data strongly indicate that amyloid clearance from the brain is achievable with immunotherapy and thar markers of clinical efficacy are correlated with antibody response. Whether these findings predict a future relevant clinical benefit in AD is currently addressed by at least four ongoing trials, two with actice ant two with active immunization. 30 Disease-modifying treatments for chronic inflammatory neuromuscular diseases R. A. C. Hughes Department of Clinical Neuroscience, King’s College London School of Medicine (London, UK) There are more patients with chronic inflammatory neuromuscular diseases participating in randomised controlled trials (RCTs) now than have cumulatively been included in all the trials undertaken until now. The Cochrane reviews reveal limitations of the current evidence (www.kcl.ac.uk/cochranenmd/www.cochrane.org). The use of corticosteroids in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), myasthenia gravis and dermatomyositis is supported by observational studies but has not been the subject of adequate RCTs. There are RCTs of intravenous immunoglobulin (IVIg) in all three conditions confirming its value but the only licensed neurological indication remains Guillain-Barre syndrome. There are RCTs showing short term benefit from plasma exchange in CIDP and myasthenia gravis but not in dermatomyositis but it is so inconvenient that it is usually kept in reserve as a third line treatment. Immunosuppressive agents such as azathioprine, methotrexate, ciclosporin, mycophenolate and cyclophosphamide are often used in refractory cases of all three conditions and RCTs are in progress to try to establish their value. Autologous peripheral blood progenitor cell transplantation has been used in a number of autoimmune disease and are beginning to be introduced for refractory autoimmune neuromuscular diseases. However it is hazardous, risks death and does not guarantee permanent immunosuppression. Nevertheless there are several reports of a good response in POEMS syndrome. Beta interferon is being tested in CIDP with another RCT, having not been found helpful in one pilot RCT but possibly beneficial in an observational study. Alpha interferon treatment has actually been followed by both CIDP and myasthenia gravis but has also been used as a possible treatment for CIDP. Monoclonal antibodies to the B cell molecule CD20 have been used with variable success in paraproteinaemic demyelinating neuropathy but not so much in CIDP.A single report of the successful use of anti-CD52 in CIDP has appeared. Such monoclonal antibodies provide the opportunity to target specific parts of the immune system and cytokine network which might allow suppression of autoimmune responses without the side effects inherent in broad spectrum immunosuppressive drugs. Problems arise in the development of new treatments because in most chronic neuromuscular disorders the pathogenesis is incompletely understood which makes it difficult to predict whether blocking one component will help or harm. The exacerbation of multiple sclerosis with inhibitors of tumour necrosis factor teaches an important lesson in this regard. There is therefore a need for more research both into the mechanisms of inflammatory neuromuscular disease and more trials of existing and, of course, innovative new treatments.

FREE COMMUNICATIONS Oral Sessions Session 1 Multiple sclerosis 1 O31 Clinical characteristics and familial risk of a sample of 217 Italian patients affected with progressive multiple sclerosis: a multicentre Italian study F. Martinelli Boneschi, F. Esposito, M. E. Rodegher, V. Martinelli, B. Colombo, M. Leone, A. Ghezzi, V. Pilato, G. Coniglio, R. Capra, D. Toniolo, G. Comi Scientific Institute San Raffaele (Milan, I); MS Clinics (Novara, I); MS Clinics (Gallarate, I); MS Clinics (Potenza, I); MS Clinics (Brescia, I) Objective: To characterize clinical and genetic aspects a sample of MS patients with progressive form of disease from onset. Methods: Patients were 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 retrospective informations on demographic and familial aggregation data. Results: A total of 217 MS patients were recruited between January 2002 and December 2005 with an history of progressive symptoms from onset, 73 % of whom were classified as pure PP with no relapses, 17.5 % as progressive-relapsing, and the remaining 9.2 % was classified as a transitional form, as an attack was discovered in the past. The mean age of onset of the disease was 39 years, and there were 112 women and 105 men. Clinical presentation at disease onset was characterized by a paraparesis in 42.9 % of cases, hemiparesis in 32.3 %, brainstem syndrome in 6 %, cerebellar syndrome in 4.1 %, visual loss in 3.7 %, cognitive problems in 0.9 %, combined symptoms in 5.1 %, and unclassifiable symptoms in 5.1 %. Brain MRI data were available in 207 patients, and they were consistent with a diagnosis of MS in 94 % of cases, while cerebrospinal fluid analyses revealed positive oligoclonal bands in 90.6 % of all cases. The mean level of disability, as measured with EDSS, was 5.2 ranging from 1.0 to 8.5. As regards familiarity, 11 out of 185 ascertained PPMS patients had at least 1 first-degree relative affected with MS, while a total of 19 had at least 1 first- or second-degree relative with the disease. However, apart from two sibs each affected with PPMS, in all the other cases there was no concordance in terms of disease courses. Conclusion: Our sample represents one of the largest collection of continental Italian progressive MS patients. Even with the clear limitations of our study design, which is retrospectically-based, we confirmed that patients affected with a progressive course from onset tend to develop the disease at a higher age and to be more frequently male than RR patients. On the contrary, the familial aggregation of the disease is comparable with that of RR patients, and the few familial case are not concordant in terms of disease course. More information will be given by genetic association studies, which are ongoing at the present time.

O32 A voxel-based morphometry study of grey and white matter density changes in multiple sclerosis patients with different clinical phenotypes A. Ceccarelli, M. Rocca, P. Valsasina, B. Benedetti, F. Agosta, B. Colombo, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, I); Dept of Neurology, Scientific Institute San Raffaele (Milan, I) Objectives: Brain atrophy is a well-known feature of patients with multiple sclerosis (MS). In this study, we assessed regional atrophy changes in grey matter (GM) and white matter (WM) in a large cohort of MS patients with different clinical phenotypes, using statistical parametric mapping (SPM) and voxel-based morphometry (VBM). Methods: Dual-echo and magnetization-prepared rapid acquisition gradient echo (MP-RAGE) scans were obtained from 30 patients with clinically isolated syndromes (CIS) suggestive of MS, 37 relapsing-remitting (RR) MS patients, 23 primary progressive (PP) MS, 43 secondary progressive (SP) MS patients, and 27 control subjects. Regional differences in GM and WM densities were assessed using an optimised version of VBM analysis and SPM2 on MP-RAGE scans. Between-group comparisons were assessed using an ANCOVA model, where age, EDSS, disease duration and normalised brain

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volume were used as covariates. The following a-priori contrasts were run: controls vs. CIS, CIS vs. RRMS, RRMS vs. SPMS, SPMS vs. PPMS. SPM maps were thresholded at p < 0.001. Results: Compared to controls, CIS patients had WM density reduction around the ventricular system, in the fronto-temporal lobes and in the parahippocampal gyrus, while no GM density changes were found. Compared with CIS patients,RRMS patients had WM density reduction in the left fronto-parietal lobe, the left cerebellum and around the corpus callosum. They also had GM density reduction in the fronto-parietal cortex, thalami, caudate nuclei, insula and cingulate gyrus, bilaterally. Compared to RRMS, SPMS patients had WM density reduction in the pre- and postcentral gyri, orbital frontal gyri and temporal lobes. They also had GM density reduction in the left central sulcus, left middle frontal gyrus, left substantia nigra and in the hippocampus. Compared to SPMS, PPMS had GM density reduction in the frontal cortex, caudate nuclei, and cingulate gyrus, bilaterally, while compared to PPMS, SPMS had WM density reduction in the fronto-parietotemporal lobes, bilaterally, right cerebellum and insula and left parahippocampal gyrus. Conclusions: In MS patients, brain tissue volume decrease follows different patterns of regional distribution according to disease phenotype. While WM tissue damage seems to be predominant in the early phases of the disease, GM tissue atrophy seems to be more evident in the progressive forms of the disease. O33 Disability after 20 years in a multiple sclerosis cohort followed from onset with a clinically isolated syndrome L. Fisniku, P. Brex, A. J. Thompson, D. H. Miller Institute of Neurology (London, UK) Objective: Clinically isolated syndromes (CIS) such as optic neuritis, brainstem or spinal cord syndromes are usually the first clinical presentation of multiple sclerosis (MS). MS natural history studies have reported a variable prognosis for disability after 15 years from onset. We followed up a prospectively recruited CIS cohort and report the disability status after 20 years. Methods: CIS patients were initially recruited between 1984 and 1987 and all had brain MRI at presentation. Follow-ups have been previously performed and reported after 1 (n = 109), 5 (n = 89), 10 (n = 81) and 14 (n = 71) years. We now report a clinical reassessment of 80 patients after a mean of 19.5 years (17.6–21.7). Diagnosis of clinically definite (CD) MS was made using the Poser criteria and disability determined with the Kurtzke’s EDSS (65 by examination, 12 by telephone and 3 who had died from MS related complication were assigned an EDSS of 10). Results: CDMS developed in 53/80 (66 percent) overall; 47/53 (89 percent) with abnormal MRI scan at baseline and 6/27 (22 percent) with normal MRI. 32 had relapsing remitting MS, 21 of whom could be considered as “benign” (EDSS ≤ 3), 21 had secondary progressive MS (median EDSS 7.5; including 3 who died from severe disease). Overall the median EDSS for CDMS patients was 4.0 and 21 (40 percent) had an EDSS ≥ 6. Conclusion: We observed a wide spectrum of disability at 20 year follow up. However 40 percent with CDMS would be classified as having benign disease which is a larger proportion than found in some previous natural history studies. O34 A 3 tesla functional MRI investigation of the role of the “mirror-neuron system” in patients with relapsing-remitting multiple sclerosis M. Rocca, A. Ceccarelli, P. Tortorella, A. Falini, G. Scotti, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, I); CERMAC (Milan, I) Background: Several functional magnetic resonance imaging (fMRI) studies of simple movement performance in patients with multiple sclerosis (MS) have suggested that the absence of overt clinical symptoms despite the presence of widespread tissue damage might be related to an increased recruitment of brain networks that are usually active in healthy individuals when performing more complex tasks. Aims: To investigate in patients with MS the function of the “mirror-neuron system”, a fronto-parietal network that, in humans is thought to be involved in action observation and imitation learning. Patients and methods: In 16 right-handed patients with relapsing-remitting MS (F/M = 13/3, mean age = 35.0 years, mean disease duration = 9.0 years, median EDSS score = 1.5) and 14 sex- and age-matched healthy volunteers, we acquired fMRI using a 3 Tesla scanner to investigate the performance of two different motor tasks. The first consisted of repetitive flexionextension of the last four fingers of the right hand [simple task (ST)] alternated to epochs of rest, while the second [mirror task (MT)], consisted of observation of a picture showing another subject while performing the

same task alternated to epochs of rest. FMRI analysis was performed using SPM99. Results: During the ST, when compared to controls, MS patients had more significant activations of the contralateral primary sensorimotor cortex (SMC) and bilateral supplementary motor area. During the MT, both groups showed the activation of several visual areas, the intraparietal sulcus (IPS), bilaterally, and the left inferior frontal gyrus (IFG). This latter region was significantly more active in patients than controls. The between-group interaction analysis between ST and MT showed that in MS patients, the IPS was more active also during the ST. Conclusions: Functional cortical changes can be detected in MS patients not only when investigating the performance of active tasks (ST), but also during passive ones (MT), thus indicating the presence of cortical reorganization. During the performance of a simple motor task, MS patients activate cortical regions that are recruited in healthy subjects when performing a more complex task. This might yet represent an additional mechanism with the potential to limit the severity of the clinical outcome associated with MSrelated tissue damage. This study was supported by a grant from FISM (2004/R/7) O35 Predicting cognitive impairment in relapsing-remitting multiple sclerosis M. Summers, V. M. Anderson, L. Fisniku, G. R. Davies, W. Rashid, L. Cipolotti, M. A. Ron Institute of Neurology (London, UK) Objectives: Cognitive impairments (CI) are known to occur in 40–60 % patients with relapsing-remitting multiple sclerosis (RRMS). It is known that visible MS lesions and abnormalities in normal appearing brain tissue (NABT), quantifiable by magnetic resonance imaging (MRI), are associated with CI in cross-sectional studies. However the value of MRI changes early in the disease in predicting future CI has not been investigated. In this study, we investigate which MRI parameters obtained early in the disease predict the presence of CI in patients with RRMS at 5 year follow-up. Methods: 30 patients with early RRMS, part of a prospective follow-up cohort, took part in the study. These patients were assessed at the following timepoints: Baseline: Patients underwent a neurological examination and MRI of the brain. T1-weighted lesion volumes (LV), mean fractional anisotropy (FA) and mean diffusivity (MD) of the NABT were calculated. 12-months: The 12-month atrophy rate was calculated for patients and 16 age-matched controls using Structural Image Evaluation, using Normalization of Atrophy (SIENA). 5 year follow-up: All patients underwent a neuropsychological assessment which examined IQ, IQ decline, memory, attention and executive function. IQ decrease of 15 points or more from premorbid levels was taken as evidence of IQ decline. Otherwise, performance at or below the 5th percentile of age-standardised normative data was considered ‘impaired’. Impaired performance in 4 or more measures denoted general CI. Results: Mean FA and T1-weighted LV significantly predicted patients with CI (Wilks’ lamda = 0.490, p = 0.007, 66.7 % sensitivity, 92.6 % specificity). MD significantly predicted patients with attentional impairment (p = 0.041, 60 % sensitivity, 66.7 % specificity). Thirteen patients (43 %) had a rate of atrophy greater than or equal to the 90th percentile of the control group. These patients had lower Performance IQ (PIQ) (t21 = 1.91, p = 0.069), greater PIQ change (U = 27, p = 0.084) and poorer verbal recall (immediate: U = 29.5, p = 0.026, delayed: U = 33.5, p = 0.051) than patients with a lower rate of atrophy. Conclusion: Diffusion characteristics (FA and MD) and T1 lesion volumes are predictive of future CI in RRMS. IQ decline and memory impairment were more severe in those with higher atrophy scores. Obtaining multimodal MRI measures early in the disease may help in deciding which patients may benefit from disease-modifying treatment and/or cognitive rehabilitation. This research was supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland O36 FDG-PET and cognition abnormalities in early multiple sclerosis J. Koehler, C. Büscher, H-G. Buchholz, M. Schreckenberger Johannes Gutenberg-Universität (Mainz, D) Introduction: FDG-PET analysis of patients with a long history of multiple sclerosis (MS), an expanded disability status scale (EDSS) up to 6.0 and an involvement of verbal, spatial and/or long-term memory showed a bilateral reduction of glucose metabolism in the cingulate gyrus, thalamus, associative occipital cortex and cerebellum. To our knowledge no similar studies in

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early stages of MS are reported. Therefore we stressed the question of possible correlation of cognitive impairment and FDG-PET findings in newly diagnosed definite MS according to McDonald criteria. Methods: In 11 patients (f = 4, m = 7, mean age: 35 years (CI 25–42), IQ 112 (CI 97–118)) with newly diagnosed definite MS and minor disability (mean EDSS = 1.0) neuropsychological testing (VLMT, d2, Benton, TMT) were performed. These findings were correlated with age and education matched healthy group (mean age 33 years (CI 25–38), IQ 112 [100–124]) to evaluate possible neuropsychological disturbances. In addition the patients were investigated by FDG-PET and also correlated with an age matched healthy group. Results: Impairment of alertness, processing speed and concentration detected by neuropsychological testing could be found in the patients with newly diagnosed MS (p < 0.05). In correlation to these abnormalities the FDG-PET showed a increased glucose metabolism at Brodmann-area 7, 18, 19, 21, and a reduced glucose metabolism at the thalamus and cerebellum. Discussion: In patients with newly diagnosed MS an increased glucose metabolism in cortical areas associated with secondary visual alertness processing could be demonstrate in contrast to prior findings in long-term MS. We think subconscious mechanisms in MS patients lead to a hyperactivity in visual cortical regions to equalize an impairment of verbal memory and alertness. In correlation to patients with long-term history of MS reduction of glucose metabolism was found at the thalamus und cerebellum. According to previous studies the significant relationship between reduction of glucose metabolism at the cerebellum and memory scanning speed suggests that functional damage in the posterior fossa may contribute to a decelerated cognitive processing.

Session 2 Multiple sclerosis 2 O37 Determinants of disability in multiple sclerosis: a cross-sectional, multiparametric, quantitative MR-based study of disease phenotypes A. Pulizzi, M. Rovaris, E. Judica, B. Benedetti, M. P. Sormani, V. Martinelli, A. Falini, G. Comi, M. Filippi Scientific Institute H San Raffaele (Milan, I); DISSAL, University of Genoa (Genoa, I) Objectives: Diffusion tensor (DT) MRI is able to quantify the severity of tissue damage in multiple sclerosis (MS), both within T2-visible lesions and in the normal-appearing white matter (NAWM) and gray matter (GM). Proton magnetic resonance spectroscopy (1H-MRS) can be used to measure in vivo whole brain N-acetylaspartate (WBNAA), whose decrease is considered a marker of neuronal loss and/or dysfunction. The aim of this study was to investigate whether DT MRI and WBNAA 1H-MRS can provide us with complementary pieces of information to achieve a better understanding of the nature of disability in MS. Design/Methods: Conventional and DT MRI, as well as WBNAA 1H-MRS scans of the brain were acquired from 27 patients with clinically isolated neurological syndrome (CIS) and paraclinical evidence of disease dissemination in space, 16 patients with relapsing-remitting (RR) MS and 24 with secondary progressive (SP) MS. Their neurological disability was assessed using the expanded disability status scale (EDSS). T2-hyperintense lesion volumes (LV) were measured. Absolute WBNAA amounts (in mmoles – mMol) were calculated using a phantom replacement method and were then corrected for individual subjects’ brain volumes. After the creation of mean diffusivity (MD) and fractional anisotropy (FA) maps, histograms of MD and FA values were produced for NAWM and GM.Average lesion and NAWM MD/FA, as well as average GM MD, were computed and analysed. Results: Median EDSS score was 1.0 for CIS, 1.5 for RRMS and 6.0 for SPMS patients. Significant heterogeneity among the three subgroups of patients was found for all MR-derived variables (p values ranged from 0.001 to < 0.001). At post hoc comparisons, CIS patients had significantly lower T2 LV and average NAWM MD, and significantly higher average lesion FA, average NAWM FA and WBNAA than RRMS patients, whereas SPMS patients had significantly higher lesion and NAGM MD than RRMS patients. Significant correlations were found between patients’ EDSS and all MR-derived variables, the strongest being the one with average GM MD (r = 0.63, p < 0.001). Conclusions: The accumulation of macroscopic lesions and NAWM

damage seems to occur mainly during the earlier clinical phases of MS, while gray matter pathology is associated to the levels of disability in the late, chronic progressive stage of the disease. O38 Multiparametric MRI assessment of brain and cord damage in primary progressive multiple sclerosis: a large-scale, multicentre study M. Rovaris, E. Judica, B. Benedetti, F. Barkhof, N. De Stefano, T. Korteweg, D. Miller, X. Montalban, C. Polman, A. Rovira, J. Sastre-Garriga, A. Thompson, M. Filippi Scientific Institute H San Raffaele (Milan, I); VU University Medical Centre (Amsterdam, NL); University of Siena (Siena, I); Institute of Neurology UCL (London, UK); Hospital Vall D’Hebron (Barcelona, E) Objectives: Although the mechanisms underlying the accumulation of disability in patients with primary progressive MS (PPMS) are still unclear, a major role seems to be played by “occult” rather than by conventional MRIdetectable tissue damage, as suggested by studies conducted with quantitative MR-based techniques. The potential of non-conventional MRI in the work-up of PPMS remains, however, a matter of debate. We investigated the usefullness of a multiparametric approach based upon conventional and magnetization transfer (MT) MRI for large-scale natural history studies and treatment trials of PPMS. Design/Methods: Conventional and MT MRI data from 226 patients with PPMS, which had been locally acquired in participating centers, were sent to Milan for image post-processing and analysis. The imaging protocol consisted of dual-echo, T1-weighted and MT MRI scans of the brain, with axial slice orientation and 5-mm slice thickness. In the vast majority of patients, 3D scans of the cervical cord were also available. Expanded disability status scale (EDSS) score was rated at the time of MRI acquisition and after a median period of 4.5 years. Eighty-three healthy subjects locally underwent the same brain MT MRI protocol to serve as controls. Centralized image analysis comprised T2 lesion volume (LV), normalized brain volume (NBV) and C2 cross-sectional area (CSA) measurement. Following MT ratio (MTR) maps creation, MTR histograms from the whole brain tissue, the normal-appearing white matter (NAWM) and gray matter (GM) were also obtained. Results: The mean values of NBV and CSA, as well as those of MTR histogram-derived metrics, showed a significant inter-center heterogeneity.After correcting for acquisition center, pooled average MTR and histogram peak height values were significantly lower (p < 0.001) in PPMS patients than in controls for whole brain, NAWM and GM, without a significant interaction for tissue type. A weak correlation was found between EDSS at followup and the z-scores of average MTR from all tissue types at baseline. Significant (weak to moderate) relationships were found between MT MRI changes and T2 LV or NBV. Conclusions: MT MRI is sensitive to “occult” tissue damage in PPMS and might provide complementary information to those given by conventional MRI when monitoring the disease evolution. Sequence-related variability of measurements makes a standardization of MT MRI acquisition essential prior to the initiation of multicenter studies. O39 Regulation of adhesion molecules in experimental autoimmune encephalomyelitis S. Doerck, G. Ladewig, A. Kroner, M. Reinhardt, P. Hauff, H. Wiendl, M. Mäurer University of Wurzburg (Wurzburg, D); Schering AG (Berlin, D) The infiltration of inflammatory cells into the central nervous system (CNS) requires a complex molecular interplay especially involving vascular cell adhesion molecule (VCAM) 1 and intercellular adhesion molecule (ICAM).We have recently developed a new ultrasound based approach for molecular imaging of these adhesion molecules on the blood-brain barrier (BBB) in living animals (Linker et al. 2005). Here we used this new technique for sequential imaging of ICAM-1 and VCAM-1 in adoptive transfer experimental autoimmune encephalomyelitis (EAE). Sequential imaging of ICAM-MP and VCAM-MP over the course of active and AT MBP-EAE revealed a significant upregulation of these molecules before the respective onset of disease. Albumin staining and gadolinium enhanced MRI after sonification did not reveal a disturbance of the BBB thereby proving the safety of the method for sequential imaging in vivo. Surprisingly we found a persistent upregualtion of cell adhesion molecules beyond the disease maximum. These imaging results were also confirmed by parallel immunohistochemistry. Subsequently, the analysis of T-cell subsets infiltrating the CNS revealed an increase of CD4 and CD8 cells beyond the clinical disease maximum, suggesting that adhesion molecules mediate not only the influx of inflammatory cells but also of regulatory cells.

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Our data clearly demonstrates that ultrasound based molecular imaging is feasible to perform safe and repetitive molecular imaging in living animals thereby being a tool to evaluate molecular expression pattern on the BBB. This study was supported by Schering AG, Berlin O40 Cortical demyelination in models of autoimmune encephalomyelitis depends on MHC genes and demyelinating antibodies M. K. Storch, R. Weissert, H. P. M. Brok, C. Linington, T. Olsson, B. A. ’t Hart, H. Lassmann, J. Bauer Medical University Graz (Graz, A); University of Tubingen (Tubingen, D); Biomedical Primate Research Center (Rijswijk, NL); University of Aberdeen (Aberdeen, UK); Karolinska Institute (Stockholm, S); Medical University Vienna (Vienna, A) Objectives: Multiple Sclerosis has long been considered a white matter disease. In recent years a number of histopathological studies revealed that the grey matter is equally affected. The mechanisms responsible for cortical demyelination are still unresolved. The aim of this study was to determine the incidence and immunopathology of cortical lesions in a broad spectrum of autoimmune encephalomyelitis (EAE) models. Methods: We analysed a large spectrum of different passively or actively induced marmoset, rat and mouse models of EAE for cortical demyelination. When cortical demyelination was found the total area of cortex as well as the area of cortical demyelination was determined. In addition, the type of cortical demyelination was analysed for each lesion. Results: Cortical demyelination did not occur in models driven by encephalitogenic T lymphocytes alone but was only present in marmoset and certain rat models induced by a combined action of T cells and demyelinating antibodies. Using sets of rat strains with the constant EAE permissive LEW background, but different MHC haplotypes, we demonstrate that considerable cortical demyelination is only found in strains which have the isotypes and alleles RT1.BuDu in the MHC class II region and RT1.Cu in the non-classical MHC class I region in common. Since cortical demyelination was most prominent in LEW 1AR1 rats an additional strong influence is promoted by the RT1.Aa MHC class I allele. Actively demyelinating cortical lesions were characterised by profound meningeal inflammation with only minor lymphocytic infiltration of the parenchyme. Myelin destruction was accomplished by activated microglia in the presence of deposition of immunoglobulins and complement on disintegrating myelin sheaths. Conclusion: Our studies show that cortical demyelination in EAE depends upon intrathecal presence of demyelinating antibodies and on particular combinations of class I and class II isotypes and alleles of MHC genes. O41 A diffusion-tensor MRI study of brain and cervical cord in benign multiple sclerosis patients E. Judica, M. Rovaris, B. Benedetti, P. Valsasina, V. Martinelli, A. Ghezzi, A. Pulizzi, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, I); Department of Neurology (Milan, I); Multiple Sclerosis Center Gallarate (Milan, I) Objectives: Diffusion tensor (DT) MRI is able to quantify the severity of brain and spinal cord damage in multiple sclerosis (MS), thus providing us with information about the extent of tissue damage undetected by conventional MRI. The aim of this study was to investigate the DT MRI patterns of benign (BMS) versus secondary progressive MS (SPMS) patients, to achieve a better understanding of the nature of disability in MS. Methods: DT MRI scans of the brain and the cervical cord were acquired from 40 patients with BMS, 15 with SPMS and 10 healthy controls. After the creation of mean diffusivity (MD) and fractional anisotropy (FA) maps, histograms of MD and FA values were produced for brain normalappearing white matter (NAWM) and gray matter (GM), as well as for the cervical cord. Results: Compared to healthy controls, BMS patients had significantly lower average GM FA (p < 0.001) and NAWM FA (p = 0.003),and significantly higher GM MD (p = 0.005). When compared to BMS patients, SPMS patients had significantly higher average GM MD and lower GM MD peak height (p = 0.007 and 0.012). In comparison with healthy subjects, BMS patients also had significantly increased average cord MD (p < 0.001), significantly reduced cord MD peak height (p = 0.001) and significantly reduced cord average cord FA (p = 0.003). There was no difference in DT MRI cord histogram-derived metrics between BMS and SPMS patients. Conclusions: Only the severity of brain GM damage seems to be less pronounced in BMS than in SPMS, whereas brain NAWM and cervical cord involvement does not differ between these two disease phenotypes, despite the

very different levels of disability. This suggests the role of cortical functional reorganization in limiting the consequences of tissue injury in BMS patients, possibly related to the sparing of their GM compartment. O42 Proposal for a morphologic classification of atypical idiopathic inflammatory demyelinating lesions of the brain based on conventional magnetic resonance imaging A. Seewann, C. Enzinger, M. Filippi, F. Barkhof, D. Miller, X. Montalban, A. Thompson, T. Yousry, M. Tintoré Subirana, A. Rovira, N. de Stefano, J. Palace, C. Polman, F. Fazekas for the MAGNIMS network Background: Magnetic resonance imaging (MRI) has defined characteristic patterns of cerebral white matter lesions typical for multiple sclerosis, the most frequent idiopathic inflammatory demyelinating disorder (IIDD) of the CNS. Rarely, idiopathic inflammatory demyelinating lesions (IIDL) may also present in an atypical manner. However, the morphologic range and significance of such appearances has not yet been systematically explored. Methods: We used PubMed to search for English-language articles between January 1984 and December 2005 that reported on IIDLs of the brain which were felt to be atypical for MS or appeared related to another IIDD. We identified 66 articles with a total of 270 case reports. Selection of those reports, where representative MRI depictions of the respective IIDLs together with clinical, histopathologic, and CSF data compatible with the presumed diagnosis were provided, left a total of 69 individual patient reports for further analyses. Results: The morphologic appearance of IIDLs allowed clustering into 4 different subtypes as follows: a) very large, mostly solitary, fluid-like lesions expanding towards the cortical ribbon – megacystic type (n = 8); b) lesions with multiple concentric rings – Balo-type (n = 11); c) diffuse and ill defined, large areas of signal abnormality – diffusely infiltrating type (n = 11); d) ring-like lesions which have been associated with antibody-mediated forms of MS more recently – MS type (n = 27). Twelve cases appeared less specific and did not fall into any of these categories.A comparison between the subgroups revealed differences in demographic, other morphologic and clinical variables (e. g. higher mean age – 43 yrs. – and multiple lesions with Balo-type; lower mean age – 28 yrs. – and mostly solitary lesions with diffusely infiltrating type), but not in the reported pathologic findings. Discussion: Many atypical IIDLs reported in the literature can be segregated into several distinct subtypes based on their MRI appearance. Such a classification could provide a framework for future prospective case collection studies that aim to clarify diagnosis, prognosis and treatment of these rare conditions.

Session 3 Peripheral neuropathies 1 – Hereditary neuropathies O43 Late-onset axonal Charcot-Marie-Tooth disease: five patients carrying a novel myelin protein zero mutation M. Laurà, M. Milani, M. Morbin, M. Moggio, M. Ripolone, S. Jann, V. Scaioli, C. Ciano, F. Taroni, D. Pareyson C.Besta Neurological Inst. (Milan, I); Milan University, Ospedale Maggiore IRCCS (Milan, I); Niguarda Hospital (Milan, I) Objective: To report a novel mutation of the myelin protein zero (MPZ) gene causing late-onset axonal Charcot-Marie-Tooth disease (CMT). Background. MPZ is a major component of compact myelin in peripheral nerves where it plays an essential role in myelin formation and adhesion. MPZ gene mutations are usually responsible for demyelinating neuropathies, namely Charcot-Marie-Tooth (CMT) type 1B, Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Less frequently, MPZ mutations are associated with axonal CMT (CMT2). Methods/Results: We report five patients (a sporadic case and four subjects from 2 apparently unrelated families) with a late-onset, progressive, axonal peripheral neuropathy. All patients developed gait difficulties between age 47 and 55. Disease course was quite severe with progressive wasting and weakness of lower limbs (LL) starting from

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distal muscles. All patients needed ankle foot orthoses or aid for walking after some years from onset and some developed clear-cut proximal LL weakness. Sensory involvement was milder. None of them had pes cavus. Electrophysiological studies showed severe sensori-motor axonal neuropathy, with absent or markedly reduced CMAPs (compound muscle action potentials) in LL motor nerves, but normal CMAPs in upper limbs. Nerve conduction velocities were normal or only slightly reduced, in the CMT2 range. Sensory nerves were affected in all limbs, but to a lesser extent. Nerve biopsy was performed in two patients and findings were consistent with a classic CMT2 pathology, disclosing a severe axonal neuropathy with clusters of regeneration, but no evidence of myelin outfoldings, tomacula, or other abnormalities. In all patients, molecular analysis demonstrated a novel heterozygous missense mutation in MPZ exon 2 (208C > T), causing the Pro70Ser substitution in the extracellular domain. Conclusion. The diagnosis of CMT2 associated to MPZ mutations should be considered in patients with either familial or sporadic progressive polyneuropathy of late onset. The mechanism by which compact myelin protein mutations result in axonal neuropathy remains to be elucidated. Partially supported by Telethon-UILDM grant GUP02169 O44 X-linked Charcot-Marie-Tooth disease and relapsing-remitting multiple sclerosis: is it a coincidence or an aetiopathogenetic relationship? F. D. Ciftci, M. Poyraz, M. Eraksoy, G. Saruhan Direskeneli, A. Halefoglu, E. Battaloglu, P. Serdaroglu, F. Deymeer, Y. Parman Istanbul University (Istanbul, TR); Sisli Etfal State Hospital (Istanbul, TR); Bogazici University (Istanbul, TR) Objectives: X-linked Charcot-Marie-Tooth Disease (CMT X) is a hereditary demyelinating neuropathy that affects both male and heterozygous female patients. CMT X is associated with mutations in the gap junction protein connexin 32 (Cx32). Cx32 is widely expressed in the myelinating Schwann cell of peripheral nerves. The protein is also found in oligodendrocytes in the central nervous system (CNS). Recently, CNS involvement is reported in some of the patients with Cx32 mutation. Methods and Results: We studied CNS involvement in five [5] unrelated male patients carrying a Cx32 mutation. All had typical signs of CMT, one developped a transient left leg paresis, incoordination, left sensory hemiparesis and parestesia, diplopia attacks in time and space for three years. Last time when he was admitted, he complained of urinary retention and progressive right hemiparesis (August 2005). Brain and cervical Magnetic Resonance Imaging (MRI) showed non Gd-enhancing white-matter and one enhancing cervical lesions. MRIs of the remaining patients were normal. To investigate further the CNS involvement all patients underwent transcranial magnetic stimulation, visual and brainstem evoked responses were also measured. The cerebrospinal fluid analysis (CSF) of the patient with relapsing transient CNS smptoms showed increased protein and oligoclonal IgG bands restricted to CSF. This patient clinically and radiologically met the McDonalds diagnostic criteria (2001) for relapsing-remitting MS. He was treated with IV methylprednisolone 1 g/day for 5 days, with benefit. In our MS unit, among 3050 patients (January 2006) who have been followed with MS and other inflammatory demyelinating diseases, only two have both central and peripheral nervous system involvements. Conclusion: Only one patient among five had transient CNS symptoms with disseminated white-matter cerebral-cerebellar-brain-stem, spinal MRI lesions and intrathecal synthesis of IgG compatible with Multiple Sclerosis (MS). The association of CMTX and MS might be coincidental in this patient. Taken together with the previous observations, we suggest a possible role of the Cx32 mutation in determining the course of a progressive/relapsing central demyelinating disease. Further studies are needed to clarify the pathogenesis of this association. O45 Hereditary neuralgic amyotrophy: clinical and genetical analysis of an Italian pedigree P. Nicolao, M. Spinazzi, A. Nascimbeni, M. Armani, B. Tavolato, C. Angelini II Neurological Clinic (Padua, I); VIMM (Padua, I) Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder, associated with recurrent episodes of painful neuropathy which usually involve the brachial plexus. Attacks of HNA are indistinguishable from idiopathic neuralgic amyotrophy and begin with severe pain which lasts several days and is followed by weakness and mild sensory loss. Recovery occurs in several months, and is usually good; persistent weakness results from subsequent attacks. Linkage to chromosome 17q25 has been established, and mutations in the SEPT9 gene have been reported in HNA families. Objective: We describe the clinical and EMGraphical findings in three fe-

males from the same pedigree who suffer from recurrent attacks of idhiopathic painful brachial and lumbar plexus neuropathy, followed by gradual and incomplete recovery. In addition, we sequenced the coding region of the SEPT9 gene in two individuals from our pedigree. Patients and Methods: A female had three episodes of painful neuropathy, at the age of 33, 44 and 45, which involved the left anterior interosseus nerve and C8 root, the right median nerve, and the left L5 root, respectively. Her elder daughter had a single episode, at the age of 33, involving the left anterior interosseus nerve. At the age of 28, the younger daughter developed complete paresis of the left sovrascapular and radial nerves and moderate paresis of the C8-T1 roots. Three months later right shoulder pain was followed by paresis of the axillar and radial nerves. Needle electromyography and electroneurograpy were performed in all individuals during attacks. The entire SEPT9 gene coding region was sequenced according to the methods described by Kuhlenbaumer et al. (Nat Gen 37 [19]1044–1046) in two patients. Results: In all patients, needle EMG showed reduced recruitment, positive sharp waves and fibrillation potentials in the affected muscles during episodes, followed by progressive recovery. Motor deficits and EMG findings are consistent with axonal mononeuritis or mononeuropathy multiplex. Motor and sensory nerve conduction studies in the unaffected limbs, including the common entrapment sites are normal. Molecular analysis: a single nucleotide polymorphism was detected in an intronic region of the SEPT9 gene; RNA studies are in progress. O46 Studies on the pathophysiology of familial amyloid neuropathy G. Said, V. Planté-Bordeneuve, C. Lacroix, D. Adams Hopital de Bicetre, Centre d’étude des neuropathies amyloides familiales (Le Kremlin-Bicetre, F) Familial amyloid neuropathy (FAP) is mainly due to mutations of the gene coding for the transthyretin (TTR). It is transmitted as an autosomal dominant trait and leads to death in a mean 10 yrs after first manifestations. Liver transplantation (LT) removes the main source of mutated TTR, but does not prevent progression of the neuropathy in all. We assumed that much of the residual mutated TTR released by choroid plexuses gained access to the endoneurium of peripheral nerves through CSF and endoneurial fluid. Method: For this purpose we studied distribution of amyloid deposits in nerve biopsy specimens and autopsy material of FAP patients. Amyloid was characterized by specific tinctorial affinity and anti-TTR immunolabeling and confirmed by TTR gene mutations in FAP patients. Results: Amyloid was found in 34/37 nerve biopsy specimens of TTRFAP. Deposits were located around endoneurial capillaries in 31 nerve specimens, with subsequent occlusion or destruction of some capillaries in 15 nerve samples. Subperineurial deposits were present in 7 specimens. No amyloid was found in the epineurium, with the exception of two patients, one with the Tyr116Ser, the other with the Ser 77Phe mutation, who had amyloid in epineurial and muscle vessel wall. Post-mortem examination of 3 cases showed amyloid in choroid plexuses, Virchow-Robin’s spaces, dorsal root ganglia, root perineurium and around blood vessels penetrating the endoneurium, following arachnoid and connective tissue septae. The distribution of amyloid around the CNS and in the endoneurium of peripheral nerves suggests that TTR amyloid is carried by the CSF and subsequently by the endoneurial flux to accumulate around endoneurial blood vessels and in the subperineurial areas. Tight junctions of the blood-nerve barrier make the endoneurium little or not accessible to blood proteins. Conclusions: Our data illustrate the role of TTR released by choroid plexuses in TTR-FAP. The proportion of TTR released by choroid plexuses varies between individuals, which may account for variation in the clinical outcome after liver transplantation in FAP patients. Supported by a grant from the French Ministry of Health for the study of Rares Disorders – Familial amyloid polyneuropathy O47 Discordant expression of familial amyloid polyneuropathy in a pair of monozygotic Brazilian twins M. Cruz, M. Saporta, M. Misrahi, V. Planté-Bordeneuve Federal University of Rio de Janeiro (Rio de Janeiro, BR); CHU Kremlin Bicêtre, Centre d’étude des neuropathies amyloides familiales (Paris, F) Objective: To describe a case of monozygotic Brazilian twins discordant for the expression of familial amyloid polyneuropathy (FAP). Methods: Case report and literature review. Results: We describe the case of a pair of twins with monozygosity established by analysis of DNA polymorphisms. They were born in 1980 and are heterozygous for the Val30Met mutation at the transthyretin gene. Their

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family has Portuguese origin and several members diagnosed with FAP. Twin 1 is a cargo inspector at Rio de Janeiro Harbour who first presented symptoms at the age of 21, with loss of temperature and pain perception in his feet. His condition gradually progressed and by the age of 25, he has sensory impairment up to his waist and mid-forearm, steppage gait, urinary and faecal retention, sexual impotence and frequent bounds of diarrhoea and vomits. Neurophysiologic studies disclosed a mixed (both demyelinating and axonal) neuropathy. Sural nerve biopsy confirmed a chronic axonal neuropathy due to amyloid deposition. He is currently in the waiting list for a liver transplantation. Hitherto twin 2 is completely asymptomatic. His neurological examination is normal, as are his neurophysiologic, autonomic and cardiologic testing. He is a security guard for a public cleaning company in Rio de Janeiro. Interestingly, these brothers were raised together and have been living in the same house since they were born. The only period they were apart from each other was during the compulsory 6-month military service, at the age of 18, when twin 1 stayed in Rio de Janeiro, while twin 2 moved to Nova Friburgo, a mountain city, 846 m from sea level. They also share similar dietary habits and they are both smokers and non-drinkers. The only difference in their medical history is the fact that twin 2 had hepatitis A when he was 7 years old. Conclusion: There are only a handful of reports of discordant monozygotic twins in the literature. These cases indicate that non-genetic factors either environmental or stochastic events occurring after or during twinning process should play an important role in the expression of FAP in Val30Met carriers. Only a few differences could be found between these cases, the most relevant being the fact that the asymptomatic brother had hepatitis A during his childhood. The reason for the discrepancy in clinical expression in these cases remains to be explained. Supported by a grant from the French Ministry of Health for the study of Rares Disorders – Familial amyloid polyneuropathy O48 Phenotypic variations and diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy V. Planté-Bordeneuve, A. Ferreira, T. Lalu, C. Zaros, C. Lacroix, D. Adams, G. Said Hopital de Bicetre, Centre d’étude des neuropathies amyloides familiales (Le Kremlin-Bicetre, F) Transthyretin familial amyloid polyneuropathy (TTR-FAP) are autosomal dominant neuropathies leading to death within 10 years on average. The diagnosis of TTR-FAPs is often delayed because patients often present as sporadic cases, which has important consequences in the management of patients and genetic counselling. In order to learn more on diagnostic pitfalls that lead to mismanagement of these patients, we reviewed the phenotypic variations of hereditary TTRFAP presenting as non familial cases. The data of 85 patients without a familial history out of the 333 patients of our cohort of TTR-FAP patients were reviewed. There were 20 females, 65 males with a mean age of onset of 61 years (extremes: 38–78).After histological diagnosis, TTR- FAP was ascribed to 17 different mutations of the TTR gene including Val30Met (35 cases); Ser77Tyr (14 cases); Ile107Val (14 cases), Ser77Phe (5 cases). Thirteen additional TTR variants were found in 1 or 2 patients each. Inaugural manifestations included mainly limb paresthesiae (41 patients) or pains (17 patients). Walking difficulty and weakness (5 patients), cardiac or gastrointestinal manifestations (5 patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1–10); 18 patients were misdiagnosed and treated for CIDP. At referral, on average 8 years after the first symptoms, length dependent sensory loss affected only the lower limbs in 4, all four limbs in 21, four limbs and anterior trunk in 60 patients. All sensory modalities were involved in 54 patients (64 %). Severe autonomic dysfunction affected 75 patients (88 %), including 52 with postural hypotension; 50 had gastrointestinal dysfunction; 51/65 males had impotence; 31 patients had sphincter disturbance. Nerve biopsy was positive in 53/64 patients, salivary glands biopsy in 19/28; muscle biopsy in 6/57, rectal biopsy in 5/15. Anti-TTR immunolabeling was not always reliable. Diagnosis was confirmed by DNA analysis in all patients but one. Systemic involvement included cardiac manifestations in 37 patients; cardiac hypertrophy in 66 patients, ECG abnormal findings in 52 patients, of whom 12 required a pacemaker implantation. Ocular and renal involvement occurred in 9 and 6 patients, respectively. Conclusion: Sporadic cases of TTR-FAP represent of large fraction of familial amyloid neuropathies, especially in the elderly. To avoid diagnosis, treatment and genetic counselling delays, DNA testing for TTR-FAP should be performed in patients presenting with a progressive length dependent small fibre polyneuropathy of unknown origin, especially when associated with autonomic dysfunction. Supported by a grant from the French Ministry of Health for the study of Rares Disorders – Familial amyloid polyneuropathy.

Session 4 Peripheral neuropathies 2 O49 Different monoclonal anti-ganglioside antibodies show distinct effects on presynaptic transmitter release and calcium influx B. Buchwald, G. Zhang, A. Vogt-Eisele, W. Zhang, R. Ahangari, J. W. Griffin, H. Hatt, K. V. Toyka, K. A. Sheikh Max-Planck-Institute of Psychiatry (Munich, D); Johns Hopkins University (Baltimore, USA); Ruhr-Universitat Bochum (Bochum, D); University of Wurzburg (Wurzburg, D) Objective: To delineate the mechanism of action of antibodies to different gangliosides with specifities relevant to Guillain-Barré syndrome (GBS) on presynaptic transmitter release. Methods: We investigated the effects on neuromuscular transmission of different monoclonal anti-ganglioside antibodies (mAbs) with specificities (GM1, GD1a, GT1b) relevant for GBS especially for AMAN (acute motor axonal neuropathy) by a perfused macro-patch clamp electrode in mouse hemidiaphragm preparations in the absence of complement. Furthermore we examined the influence of these mabs on calcium influx in cultured principal neurons by calcium imaging. The effects of these antibodies were compared to control mAbs including a mAb with GD1b reactivity, which is relevant to sensory ataxic neuropathy. Results: The IgG mAbs with GD1a and GM1 reactivity depressed evoked quantal release to a significant yet different extent, whereas the amplitude of postsynaptic currents was not significantly affected. At equivalent doses an IgG mAb with GD1b reactivity showed no blockade of neuromuscular transmission but at fourfold higher concentrations this mAb caused a slow and completely reversible blockade.Anti-GM1 and -GD1a mAbs significantly reduced depolarization-induced calcium influx in principal neurons. In contrast, application of anti-GT1b or IgG sham mAbs had neither an effect on neuromuscular transmission nor on calcium influx. Conclusion: Different anti-ganglioside mAbs induce distinct immunopharmacological effects on presynaptic transmitter release and calcium influx in the absence of complement. Anti-ganglioside antibody-mediated reduction in calcium influx may be responsible for the observed presynaptic blockade. These findings suggest that the clinicopathologial heterogeneity in GBS is in part due to differences in the pathophysiological effects of anti-ganglioside antibodies that are present in individual patients. Supported by DFG grants (TO 61/9–1 to BB and KVT, SFB 391 TP8 to BB) and NIH grant NS42888 to KAS. O50 Allograft inflammatory factor 1 in chronic inflammatory demyelinating polyneuropathy and vasculitic neuropathy L. Broglio, B. Erne, M. Tolnay, N. Schaeren-Wiemers, P. Fuhr, A. J. Steck, S. Renaud University Hospital (Basel, CH) Objectives: The Allograft Inflammatory Factor-1 (AIF-1) is a modulator of the immune response during macrophage activation. It has been implicated in neurological diseases since it is upregulated in rat encephalomyelitis, neuritis and uveitis, in human and rat traumatic brain injury, in focal brain infarction and human gliomas. Previous gene expression studies have shown an upregulation of AIF-1 in sural nerve biopsies of patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and vasculitic neuropathy (VAS) compared to normal nerve (NN). The aim of this study is to identify the cellular expression pattern of AIF-1 in sural nerve biopsies from patients with different types of peripheral polyneuropathies. Methods: We performed immunohistochemistry on paraffin sections of human nerve biopsies (cutaneus branch of the superficial peroneal nerve) of 10 vasculitis, 6 CIDP, 6 non-inflammatory axonal neuropathy (NIAN) and 3 NN. The diagnosis was made according to established criteria. AIF-1 positive cells were counted in two tissue sections from each nerve with respect to their cellular localization such as endoneurium, perineurium, epineurium, blood vessels lumen and blood vessel walls. An immunofluorescence study was performed to investigate colocalization of AIF-1 and activated macrophages stained for CD68. Results: There is a small constitutive expression of AIF-1 in normal human nerve. In CIDP and VAS nerve, however, AIF-1 expression was much higher when compared to NN and NIAN (p < 0.05). AIF-1 positive cells were increased in the endoneurium, perineurium, epineurium as well as in blood vessel walls. Most AIF-1 expression was seen in the endoneurium. AIF-1 was also significantly increased in the arterial vessel walls of VAS compared to

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CIDP cases (p < 0.05). In contrast, we could not find any statistical significant difference for the other compartments. By colocalization studies we found that most of the AIF-1 positive cells were CD68 positive macrophages. Conclusion: We identified the CD68 positive macrophages as the predominant AIF-1 expressing cell type, although cells which were CD68 negative, could also be detected. The higher expression of AIF-1 in CIDP and VAS compared to non-inflammatory axonal neuropathies and normal nerves confirms our gene expression study on the cellular level. In summary, AIF-1 seems to be associated with inflammatory polyneuropathies. Its exact pathognetic role remains to be elucidated. This project has been supported by an ENS fellowship

O51 Excitability changes in distal motor axons undergoing Wallerian degeneration M. Moldovan, S. Alvarez, C. Krarup Panum Institute (Copenhagen, DK); Rigshospitalet (Copenhagen, DK) When a nerve fibre is transected, a series of events is set in motion that results in degeneration of the distal axon and myelin. The trigger of Wallerian degeneration is unknown. In the mouse, axonal degeneration normally occurs rapidly over a time course of one day. Nevertheless, in slow degeneration mouse mutant (C57BL/Wlds), axons in the distal stump persist for weeks. It was therefore suggested that Wallerian degeneration may be the consequence of an active process and not just a passive failure of the energydependent pumping in the distal stump. Objectives: The aim of this study was to investigate the early changes in axonal excitability during Wallerian degeneration with particular emphasis on membrane potential. Methods: Experiments were carried out in 7–8-week-old female mice under anesthesia. Right sciatic nerves were crushed in C57BL/Wlds mutant mice (n = 9) and control mice (C57BL/6J, n = 5). Tibial nerves were stimulated at ankle and the evoked CMAPs were recorded from the plantar muscles using subcutaneous needle electrodes. Conduction studies and multiple excitability tests (Bostock H, 1998; Muscle Nerve;21 [2]:137–58) were carried out during the subsequent week. Temperature was maintained with a heating pad. Results: Prior to crush, conduction and excitability studies were similar in control and C57BL/Wlds mice. In control mice, all parameters remained unchanged for 10 hours. At 14 hours, CMAP amplitude dropped to ~10 % without a change in latency. These changes were accompanied by marked abnormalities in excitability consistent with membrane hyperpolarization. After 17 hours, CMAPs with very small amplitudes (~1 % of control) and prolonged latencies (~ 25 %) could still be identified in some nerves. No CMAPs could be identified after 24 hours. In C57BL/Wlds mutant mice, the sequence of the observed changes was similar but at a delayed time-course. At day 3 after crush, CMAPs were reduced to ~25 % without a change in latency but with a change in excitability similar to control nerves at 14 hours. At day 7 after crush small CMAPs with prolonged latency could still be recorded in some nerves. Conclusion: Our data suggests that during Wallerian degeneration, excitability changes consistent with membrane hyperpolarization occur in distal motor axons prior to changes in conduction velocity. It is possible that the observed hyperpolarization reflects hyperactivity of the Na + /K + pumps due to increased Na + entry.

O52 Electrophysiological parameters associated with response to IVIg in multifocal motor neuropathy G. Ardolino, F. Terenghi, F. Gallia, B. Bossi, C. Casellato, M. Carpo, E. NobileOrazio IRCCS Humanitas Clinical Institute (Rozzano, Milan, I); IRCCS Fondazione Policlinico (Milan, I) Introduction: Multifocal motor neuropathy (MMN) is a relatively rare disorder characterized by focal conduction blocks along motor fibres leading to weakness in the territory of individual nerves. Although its pathogenesis is not clear, MMN is thought to arise from dysimmune mechanisms and responds to treatment with intravenous immunoglobulin (IVIg). Objective: To evaluate the effect of the first administration of high dose IVIg on electrophysiological parameters in MMN. Methods: We tested 18 clinically affected nerves from 9 subjects with newly diagnosed MMN before and 7–20 days after the first administration of IVIg (2 g/kg). Only nerves with clinical improvement (at least 1 point in the Medical Council Research scale) were included in the analysis. Distal and proximal CMAP amplitude, conduction velocity (CV), distal latency (DL),

and conduction block (CB) were evaluated. CB was considered only in distal tract (e. g. elbow-wrist). Results: At baseline 10 nerves had abnormal distal and 13 proximal CMAP amplitudes. No significant change in their amplitude was detected after IVIg administration. Seven nerves had CV below lower normal limits at baseline examination including five with definite and two with possible CB. CV increased in six nerves after IVIg (mean 129.4 % ± 13.5; range 84–190 %) and slightly decreased in one nerve with a greater than 90 % CB at baseline. CB remained unchanged despite clinical improvement in five nerve, improved by at least 20 % in two nerves and slightly worsened (8 %) in one. No correlation between CV and CB changes was detected. Only 3 of 17 nerves had abnormal DL at baseline and none improved after therapy. Conclusion: Improvement after IVIg therapy has been inconsistently associated with reduction of CB also because the correlation between clinical and electrophysiological improvement in individual nerves has been seldom analysed. In this study only CV, which is a marker of fast conducting fibres, but not CB, consistently improved in parallel with clinical improvement after IVIg. These findings suggests that the improvement of CV or, as recently reported, temporal dispersion may indicate an improved nerve conduction which may explain response to treatment despite the persistence of CB. O53 Multifocal motor neuropathy: evolution with long-term intravenous immunglobulin treatment A. Baumann, K. M. Rösler, C. Hess, G. Schwegler, I. Andresen, M. Sturzenegger Inselspital (Berne, CH); Kantonsspital (Aarau, CH); ZLB Behring (Berne, CH) Objectives: To evaluate clinical and electrodiagnostic long term evolution of patients with multifocal motor neuropathy (MMN) on intravenous immunglobulin (IVIg) treatment. Methods: We followed 18 patients (14 males and 4 females) for 4.4 (mean, range, 0.3–11.8) years. 6 were classified definite, 5 probable, 5 possible and 3 clinical MMN. All were on repetitive IVIg infusions at regular intervals. Patients were monitored using clinical scores (subjective functional improvement; Medical Research Council (MRC) rating scale in 40 muscle groups; Guy’s Neurological Disability Scale; atrophy score) and electrophysiological studies (nerve conduction velocities, motor conduction blocks and distal compound muscle action potential (CMAP). Results: Age at onset of symptoms was 49 (mean, range 28–66) years, delay between onset of symptoms and treatment was 51 (mean, range 2–156) months, treatment duration was 4.3 (mean, range 0.3–11.8) years. Mean duration of IVIg therapy was 4.3 years (range, 0.3–11.8). Atrophy correlated with disease duration (p = 0.045). Higher ranking in the diagnostic categorization was correlated with longer disease duration (p = 0.08). 14/18 patients were responders within 1 month. Beyond one year of therapy 6/15 patients were persistent responders without difference of IVIg dose to those 9 with loss of treatment efficacy. There was no dependence of IVIg treatment response from diagnostic category whether in the short term (1 month) or in the long term (> 1 year) (p = 0.95). Plasma exchange provided restoration of IVIg efficacy in 2/4 patients with secondary loss of IVIg efficacy and in 1/3 de novo non-responders to IVIg. In all patients followed-up > 2 yrs, the distal CMAP amplitudes decreased progressively despite ongoing IVIg therapy and initial transient amplitude increase. Conclusions: In this study, categorization of MMN patients (definite, probable, possible, clinical) was not predictive for IVIg treatment response. Loss of IVIg efficacy may already have started in the first year of treatment, independent of IVIg dose used. Beyond 2 years there is progressive loss of CMAP suggesting progressive axonal degeneration. The study has been supported by an unrestricted educational grant from ZLB Behring, Berne, Switzerland O54 Painful sensory polyneuropathy responsive to immunoglobulin: a sensory CIDP variant? O. J. M. Nascimento, M. R. G. De Freitas, T. M. Escada Universidade Federal Fluminense (Rio de Janeiro, BR) Objectives: Patients with a painful distal sensory polyneuropathy with or without abnormal findings in electrodiagnostic studies and no cause for the neuropathy are diagnosed as having cryptogenic sensory polyneuropathy (CSPN). Some of these patients are responders to intravenous immunoglobulin (IVIg) treatment. In a recent report these patients were considered as sensory chronic inflammatory demyelinating polyneuropathy (CIDP) cases. The objective of this study is to report patients with a painful distal sensory polyneuropathy with predominant demyelinating findings observed in sural nerve biopsy and responders to IVIg.

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Methods: Seven male patients presenting a painful distal polyneuropathy of unknown cause were submitted to neuroconduction studies, CSF examination and sural nerve biopsy. Results: The mean age of the patients was 51.5 years (range: 44–62 y.). The mean time follow-up was 2 years. All patients reported distal burning pain, numbness and paresthesias and, on neurological examination, had predominantly large fiber distal sensory loss and normal muscle strength. In most patients deep tendon reflexes were reduced in the lower limbs. Electrodiagnostic studies revealed changes consistent with a mild axonal neuropathy in 5 patients. A discrete increase in CSF protein concentration was found in 5 patients. Sural nerve biopsy showed predominant chronic myelinopathic findings. Sensory symptoms improved with IVIG at initial dose of 0.4 g/kg per day for 5 days. Conclusion: Sural nerve biopsy should be considered in patients with a progressive painful CSPN with predominantly large fiber sensory neuropathy. The presence of demyelinating features in sural nerve biopsy could sustain the indication of IVIG therapy. The inclusion of these cases as an atypical painful phenotype of CIDP can be considered.

Session 5 Extrapyramidal disorders O55 An investigation of fine motor impairment in recreational users of 3.4methylenedioxymethamphetamine (MDMA) L. Taurah, S. Pal, K. R. Chaudhuri, C. Chandler London Metropolitan University (London, UK); Institute of Neurology (London, UK); King’s College Hospital (London, UK) Objectives: Despite studies implicating 3.4-methylenedioxymethamphetamine (MDMA) with long-term deleterious neuropsychiatric effects, recreational use of this drug is commonly regarded as safe. MDMA has previously been associated with neurotoxicity specifically targeting serotonergic and dopaminergic systems. It is feasible to suggest such toxicity may contribute towards fine motor symptoms. No previous studies have investigated such an association. The objective of this cohort study was to investigate the presence of fine motor impairment in MDMA users compared with non-drug users and non-MDMA recreational drug users using a fine motor skills tracing task. Methods: 77 participants were recruited using a snowball effect (mean age 32.4 years, 54 % male). Participants were categorised as follows: Nondrug users (n = 20), cannabis/alcohol/nicotine users (n = 16), non-MDMA polydrug users (n = 17) and current MDMA polydrug users (n = 24). All completed a standardised fine motor skills tracing task. In addition, participants were administered a generalised questionnaire documenting basic demographics, detailed drug history, past medical history and familial drug history. Drug exposure was documented by calculating cumulative weekly exposure since initiation of usage. Analysis involved measuring deviation from a fixation marker to give an overall average deviation score for each participant. Results: Analysis demonstrated a significant difference in average deviation scores between the current MDMA polydrug group and the three nonMDMA control groups (Bonferonni test, p < 0.05). There was a positive linear relationship between self-reported lifetime consumption of MDMA and mean deviation score (r = 0.71, p < 0.05). Conclusions: The present findings suggest that current MDMA users demonstrate an impairment of fine motor skills in comparison to other nonMDMA recreational drug users. Such findings raise the possibility that MDMA usage may contribute to clinically significant motor impairment in recreational users of the drug. The difficulties in interpretation of causality will be presented as this is a major problem with such recreational drug research. Further longitudinal studies are required. O56 Reproducibility of sonographic measurement of substantia nigra D. Skoloudik, P. Bartova, T. Fadrna, R. Herzig, P. Kanovsky University Hospital and Medical Faculty (Olomouc, CZ); University Hospital (Ostrava, CZ) Objectives: Alteration of substantia nigra (SN) in Parkinson disease (PD) patients can be detected by transcranial sonography (TCS). Recent studies re-

ported increased echogenicity of SN in PD patients with enlargement of SN area The aim of this study was to evaluate reproducibility and correlations in the assessment of SN echogenicity and area measurement by physiciansonographer (PS), sonographic lab assistant (SLA) and physician without sonographic experience (PN). Methods: 22 patients with extrapyramidal symptoms were examined using TCS. SN area was imaged from the right and the left temporal bone window. The second TCS examination of SN was performed after 7 ± 2 days. SN images were encoded and afterwards evaluated by all 3 readers. Spearman rank correlation and Pearson’s correlation coefficient were used when assessing the agreement of 3 readers both in the semiquantitative evaluation of SN echogenicity (scale I – V) and SN area measurement, resp. Results: All 3 readers identified the same 15 patients with SN echogenicity III or more in at least one image. All correlations between readers in SN echogenicity (r = 0.55–0.82) and in SN area measurement (r = 0.30–0.74) were statistically significant (p < 0.05). All correlation between two evaluations of SN area measurement and echogenicity from images obtained during two examinations by PS were statistically significant (p < 0.05) with correlation coefficients r > 0.64.Also correlations between evaluation of SN area measurement (r > 0.75) and echogenicity (r > 0.46) from homolateral and contralateral temporal window were statistically significant (p < 0.05) only for PS. Conclusion: Evaluations of SN echogenicity and SN area measurement are dependent on sonographer’s experience and quality of temporal bone window. O57 A multicentre case-control study on cigarette smoking, coffee drinking and risk of primary adult-onset blepharospasm D. Martino, G. Defazio, G. Abbruzzese, P. Girlanda, M. Tinazzi, G. Fabbrini, C. Colosimo, M. S. Aniello, L. Avanzino, M. Buccafusca, G. Majorana, C. Trompetto, A. Berardelli University of Bari (Bari, I); University of Genoa (Genoa, I); University of Messina (Messina, I); University of Verona (Verona, I); University of Rome “La Sapienza” (Rome, I) Background and Objective: The role of environmental factors in primary adult-onset dystonia is unclear.A previous report suggested a protective role of cigarette smoking in late-onset dystonia; however some potentially confounding variables, e. g. coffee drinking, were not examined. We conducted a case-control study to explore the effect of cigarette smoking and coffee drinking on the risk of dystonia. Methods: Smoking and coffee consumption lifetime habits were compared, via a standardized questionnaire, between 166 subjects with primary adult-onset blepharospasm (BSP) and 228 control patients with hemifacial spasm, recruited from 5 Italian tertiary referral centres. Differences between groups were examined using the chi-square and Mann-Whitney U tests. The relationships of education, cigarette smoking, and coffee intake to case/control status were estimated with logistic regression models. Odds ratios (ORs) and 95 % confidence intervals (CIs) were always adjusted for sex, age, and referral centre. The relationship of age at dystonia onset to coffee drinking status, duration of coffee intake, number of cups/day and of cup/years was assessed by linear regression models. Regression coefficients (RC) were calculated by the least square methods. Results: On univariate analysis, there was an inverse association of BSP with education > 5th grade, ever cigarette smoking, and ever coffee drinking. On multivariate analysis, the ORs for ever coffee drinking did not change (adjusted OR, 0.41; p = 0.003), whereas the ORs for education > 5th grade and ever cigarette smoking lost significance. The strength of the inverse association between BSP and coffee intake tended to increase with the number of cups/day and cup/years drunk. There was no correlation between age at BSP onset and coffee intake; a trend for a greater frequency of higher daily coffee intake was seen in patients with BSP as part of a segmental dystonia compared to patients with focal BSP and > 5 years of disease duration (11 vs. 2.9 %, p = 0.36). Conclusions: The potential protective association of cigarette smoking with dystonia may depend on decisive confounding factors such as coffee drinking and education. Coffee drinking was inversely associated with lateonset BSP, and this association may partially depend on the amount consumed. Coffee drinking should be considered as a potential confounding factor in studies dealing with environmental and genetic risk factors for primary late-onset dystonia.

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O58 Pharmacodynamic characterisation of different preparations of botulinum neurotoxin type A S. Imke, F. Wegner, G. Gelbrich, A. Wagner, U. Bogdahn, W. Schulte-Mattler, K. Wohlfarth University of Leipzig (Leipzig, D); University of Regensburg (Regensburg, D); Humaine Klinikum Bad Saarow/Fuerstenwalde (Bad Saarow, D) Botulinum neurotoxin type A (BoNT/A) represents the drug of first choice in the treatment of focal dystonias, spasticity and facial lines. Two products are mainly used to treat these conditions, Dysport® and Botox®. However, the bioassays used to measure potency differ and consequently the mouse units (MU) for each product are not equivalent. The aim of the study was to evaluate the biological activity and safety of the two different preparations. Methods: We determined the biological activity and safety of different concentrations (50 and 100 MU/ml) and doses of these two commercially available neurotoxin type A products. 79 healthy volunteers from two study centres were randomly injected with 1.25, 2.5, 5.0, 7.5, 10 and 20 MU BoNT/A into the extensor digitorum brevis muscle (EDB). Neurophysiological tests were performed before injection and 2 and 12 weeks after injection using a modified EDB model. Results: Both products caused a dose-dependent and significant reduction of the compound muscle action potential (CMAP) 2 and 12 weeks after injection. Dose-response curves revealed that the unit doses of Dysport® required for equal effect were twice those of Botox®. There was a significant effect of dilution: for both products a given dose was more effective in the more concentrated solution. We found a minor decrease of the CMAP in adjacent muscles two weeks after injection. No adverse events were noticed within the trial period. Summary: We conclude that in this model one MU of Botox® corresponds to two MU of Dysport®. Measurable effects in adjacent muscles could be briefly observed after injection of both products, indicating diffusion beyond the target muscle. There were no differences in diffusion patterns between the two products. The study was supported by Ipsen Pharma GmbH, Ettlingen, Germany. O59 The perception of passive motion in Parkinson’s disease M. Maschke, K. Krawczewski, P. J. Tuite, J. Konczak University Duisburg-Essen (Essen, D); University of Minnesota (Minneapolis, USA) Background: Recent results show that patients with Parkinson’s disease are impaired in detection of changes in limb position. Yet, it remains unclear whether PD not only affects limb position sense but also passive motion sense. Objective: To determine whether PD patients require larger forearm displacements before detecting motion indicating a possible deficit in perception of motion. Methods: 8 PD patients (mean ± SD age 54 ± 6 years) and 8 control subjects (mean ± SD age 54 ± 5 years) participated. Participants placed their forearm on a padded splint that was moved passively by a torque engine. The forearm was moved passively until subjects detected arm motion and pressed a trigger held in the hand of their non-tested arm (maximum 8°). Subjects indicated verbally the perceived direction of limb motion. Two staircases (72 trials) were employed to present angular velocities (ascending from 0.075°/s, descending from 1.65°/s in steps of 0.15°/s). Kinematic variables were adjusted for differences in reaction time. Results: PD patients needed larger limb displacements before they could judge the presence of passive motion (p < 0.0001). Moreover, the displacement-velocity sensitivity functions showed that the offsets in displacement between the two groups were significantly different (p < 0.001). With decreasing passive motion velocity the detection time increased exponentially in both groups. However, the mean detection times of PD group for each of the 12 velocity conditions were between 92–166 % higher than in the control group. The degree of impairment in the PD group did not correlate with the patients’ L-dopa equivalent dosage. Conclusions: Our results demonstrate that PD patients were impaired in the detection of passive forearm movements. This study underlines a growing body of evidence suggesting that various aspects of kinaesthesis are affected even at early stages of PD (limb position sense, weight perception, passive motion sense). The impaired processing of proprioceptive signals likely contributes to motor symptoms in PD.

O60 Tolerability of switching from an oral dopamine agonist to transdermal rotigotine in Parkinson’s disease J. Whitesides, B. Boroojerdi Schwarz Biosciences, Inc. (Raleigh, USA); Schwarz Biosciences, GmbH (Monheim, D) Objectives: Rotigotine,a nonergolinic,D3/D2/D1 dopamine receptor agonist delivered via a transdermal system, is under investigation for once daily treatment of idiopathic Parkinson’s disease. This trial assessed the safety and tolerability as well as the effect on PD symptoms in subjects with idiopathic Parkinson’s disease when switched overnight from ropinirole, pramipexole, or cabergoline to transdermal rotigotine. Methods: This Phase 3b, open-label trial included a Pretreatment period (within 28 days before the overnight switch), a Baseline visit (Day 0), and a 28-day Treatment period. Subjects received 2–8 mg/24h rotigotine transdermal system corresponding to their previous total daily dose of oral dopamine agonist (maximum doses at entry were 9 mg ropinirole, 2 mg pramipexole, and 3 mg cabergoline). Rotigotine dose adjustments were permitted to achieve the most efficacious dose. Effects on PD symptoms were assessed by changes from baseline to the end of treatment in the UPDRS and other scales. In addition, subjects’ treatment preference was assessed. Results: One hundred and nineteen subjects enrolled – 116 of whom switched to rotigotine (47 from ropinirole, 47 from pramipexole, and 22 from cabergoline). Ninety percent of the subjects who switched completed the Treatment period. Eighty percent of subjects did not require dose adjustment after switching to rotigotine, while 11 of 116 subjects (9.5 %) had one adjustment. Twelve subjects withdrew early, 5 due to AEs (dermatitis, tachycardia, insomnia, depression, nausea). For all subjects completing the Treatment period, mean changes in UPDRS parts II and III were –1.4 and –2.5, respectively. In this trial the majority of subjects (> 75 %) indicated a preference for using a patch versus oral PD medication. Most AEs reported during rotigotine treatment were consistent with stimulation of dopamine receptors and use of transdermal delivery systems. Application site reaction (8.6 %) was most often reported followed by nausea (6 %), somnolence (6 %), and headache (5.2 %). Conclusion: In this trial, patients were switched overnight switch from ropinirole, pramipexole or cabergoline to rotigotine without exacerbating PD symptoms. In this trial subjects indicated a preference for the rotigotine transdermal system. I received investigator grant from Schwarz Biosciences and have served on advisory board

Session 6 Headache and pain O61 Botulinum toxin type A compared with divalproex sodium for the prophylactic treatment of migraine: a randomised, evaluator-masked trial A. Blumenfeld, T. Chippendale The Neurology Center (Encinitas, USA) Objective: To evaluate the efficacy and safety of botulinum toxin type A (BoNTA; BOTOX®: Allergan, Inc., Irvine, CA, USA) compared to divalproex sodium (DVPX; DEPAKOTE®: Abbott Laboratories, Chicago, IL, USA) for the prophylactic treatment of migraine. Methods: A randomized, evaluator-masked single-center study was conducted comparing the efficacy and safety of BoNTA 105 units to 260 units using a follow the pain approach and DVPX 500 mg bid as migraine prophylaxis in patients experiencing at least 2, but ≤ 8 migraine headaches per month (with ≤ 15 headache days). Patients were administered treatment at day 0 and evaluated at days 30, 60, and 90. Several efficacy parameters were measured by headache diary data and the mean changes from baseline in MIDAS scores. Results: 60 patients with a mean of 4.2 moderate-to-severe migraine headaches per month were enrolled (n = 30 per treatment group; mean age 41 years; 93 % female; 93.2 % Caucasian). 100 % of BoNTA patients and 60 % of DVPX patients completed the study (P = 0.0001). By the end of the treatment period, BoNTA patients reported 21 % of their headache days as severe compared with 39.6 % for DVPX patients (P = 0.004). BoNTA patients re-

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ported 23.4 % of their headache days were associated with a discontinuation of normal activity compared with 41.1 % for DVPX patients (P = 0.01). There were significant differences favoring BoNTA at several time points in the percentages of patients who were very satisfied with the effectiveness of their treatment in preventing migraine episodes (46.7 % vs 23.3 %, day 60, P = 0.0006), in addition to reducing the frequency (56.7 % vs 16.7 %, day 30, P = 0.01), and severity of migraine symptoms (46.7 % vs 13.3 %, day 30, P = 0.03). A significantly greater percentage of BoNTA patients indicated they would like to continue receiving treatment (83.3 % vs 47.8 %, P = 0.003). The mean change from baseline in the MIDAS total score at day 90 was significantly greater for BoNTA (–8.05 vs –0.27, P = 0.04, ANCOVA from baseline scores of 21.43 and 21.57, respectively [P = 0, 49]). Fewer adverse events possibly related to BoNTA treatment were observed (9 vs 21,P = 0.14).No patients in the BoNTA group discontinued treatment due to adverse events versus 6 patients in the DVPX group (P = 0.01). Adverse events were predominantly mild to moderate in both groups. Conclusions: BoNTA treatment was more effective than DVPX as prophylactic treatment of migraine. BoNTA demonstrated a superior safety and tolerability profile than DVPX.

O62 Epidemiology of infrequent,frequent and chronic tension-type headache in a large population-based sample M. B. Russell, N. Levi, J. Saltyt-Benth, K. Fenger Akershus University Hospital (Oslo, N); University of Copenhagen (Copenhagen, DK) Objective: To evaluate the one-year-period prevalence of tension-type headache in a large population based sample. Method: The study population included 33.764 twins aged 12 to 41 years old from the population based new Danish Twin Registry. They received a posted headache questionnaire. Results: The questionnaire response rate was 83.5 %. The questionnaire has previously been evaluated against a clinical interview by a physician, and Kappa was 0.74 and 0.77 for self-reported tension-type headache and frequency of tension-type headache, respectively.All twins were included since we found no significant difference between mono- and dizygotic twins or between twin A and B. The self-reported one-year-period prevalence of tension-type headache was 86 %; 78.9 % among men and 92.5 % among women. The one-year-period prevalence of infrequent episodic, frequent episodic and chronic tension-type headache was 63.5 %, 21.6 % and 0.9 %, respectively. Frequent episodic and chronic tension-type headache was significantly more frequent in women than men. The prevalence of frequent episodic tension-type headache increased slightly in men until age 39 then it declined, while it increased about 20 % point in women from age 12 years to age 20–39 years old and then it declined. Congruently, the prevalence of chronic tension-type headache increased until age 39 and declined thereafter in both sexes. Chronic tension-type headache is rare in persons 12–14 years old. These effects were confirmed by age trends of the different subtypes of tension-type headache using a regression model. Conclusion: Tension-type headache is very frequent and more attentions should be directed toward management and research of this type of headache.

O63 Activation of limbic pain network by soft tactile stimulati after injection of sumatriptan H. H. Krämer, L. Lundblad, M. Linde, F. Birklein, T. Karlsson, M. Elam, H. Olausson University Mainz (Mainz, D); Institute of Clinical Neuroscience (Göteborg, S) Patients taking the anti-migraine drug sumatriptan often complain of unpleasant somatosensory side effects including a mild tactile allodynia. We explored how cortical processing of tactile stimulation with a soft brush was influenced by sumatriptan. Six healthy participants attended two fMRI sessions during which we injected either sumatriptan or saline in a doubleblind cross-over design. Four functional scans were acquired during a period of expected high plasma concentration of sumatriptan in both fMRI sessions. Each functional scan consisted of 15 cycles of tactile stimulation on the left calf (hairy skin), rating of brush-evoked sensation on a visual analogue scale (VAS), and rest. In the sumatriptan condition brushing was perceived as 19 % less pleasant than in the saline condition (p < 0.04). Somatosensory cortices were similarly activated in both conditions, posterior insular cortex was less activated in the sumatriptan condition whereas anterior insular cortex, medial or-

bitofrontal cortex, midcingulate part of the anterior cingulate cortex, and thalamus were only activated in the sumatriptan condition. Another six subjects received the same tactile stimulation on the left palm (glabrous skin) and rated the pleasantness of the stimulation on a VAS. No difference between the sumatriptan and saline condition was observed. It has been shown that the human hairy skin is equipped with a system of low – threshold unmyelinated touch (C tactile, CT) afferents that are present in hairy but not in glabrous skin and project to posterior insular cortex and seem to serve emotional aspects of tactile sensation. We propose that sumatriptan inhibits CT afferents. The missing CT input leads to a disinhibition of nociceptive signalling at the level of the spinal dorsal horn as it was shown in animals. CT dysfunction may be part of the development and maintenance of tactile allodynia following other types of peripheral nerve dysfunction as well. This work was supported by the Fellowship 2005 of the European Neurological Society (ENS) O64 Neurosecretory changes and neurogenic flare responses in human pain models: capsaicin-induced versus electrically-evoked pain C. Geber, R. Fondel, H. H. Krämer, R. Rolke, C. Sommer, M. Dieterich, F. Birklein Johannes-Gutenberg Universität Mainz (Mainz, D); Neurologische Klinik der Universität Würzburg (Wurzburg, D) Objective: To evaluate neurosecretory effects of C-fiber stimulation in human pain models we used dermal microdialysis to assess for the release of calcitonine gene-related peptide (CGRP) and laser doppler imaging (LDI) to evaluate the flare. Methods: We investigated 10 healthy subjects. Capsaicin (CP; 50µg) or electrical stimulation (ES; 0–30 mA, 1Hz, 0.5ms) were applied over volar forearm in a balanced order and side restricted manner. Each subject was exposed twice to each stimulus type with a 4 month time interval between 2 identical stimulations. In both surrogate models, two intracutaneous microdialysis membranes (cutoff 3000kDA) were inserted intradermally about 1 cm apart from each other over a distance of 1.5 cm. CP (15µl) was injected intracutaneously between these membranes, ES was applied via 2 stainless steel wires (0.1 mm) embedded in these microdialysis fibers. Electrical current was increased in 5min intervals up to 30 mA with a total stimulationperiod of 35min. Microdialysis membranes were perfused with saline (0.9 %) at a flow rate of 3µl/min. The eluate was collected in 3 fractions of 15min (1xbaseline, 2xstimulation). CGRP (pg/ml) in the eluate was assessed using EIA. Size and intensity of flare were scanned using LDI. Statistical testing comprised ANOVA and paired t-tests. Regression analyses were performed to assess for test-retest correlations. Results: CGRP-release was significantly increased after CP (p < 0.01, n = 10), but ES did not. Maximum flare sizes were not different between both models. However, maximum flare intensities were significantly higher for ES (p < 0.05, n = 10). There was high test-retest reliability for flare sizes in both stimulation types (CP: 0.71; ES: 0.79, both p < 0.001). Conclusions: Although both models induced similar and reproducible flare responses, CGRP release could only be detected after CP. This difference in CGRP-release is most likely due to different stimulation kinetics and induction of neuropeptide degrading enzymes in both pain models. Supported by DFG (Bi 579–1, Bi 579–4); BMBF (GRNNP) and research funds from the University of Würzburg O65 Mirtazapine decreases the pain feeling in healthy subjects P. Arnold, P. Vuadens, T. Kuntzer, C. Gobelet, O. Deriaz CRR (Sion, CH); Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Background: The treatment of neuropathic pain is a difficult challenge, mainly based on antiepileptics, tricyclic antidepressants (TCA) and opiates. These drugs have important side-effects disturbing the patient’s quality of live. Mirtazapine is a new and well tolerated TCA-parented antidepressant with both monoaminergic and opioid properties that might favourably influence the pain feeling. The aim of our study was to attest whether mirtazapine can reduce the pain induced by a standardized stimulus in healthy subjects. The analysis of the nociceptive flexion reflex (NFR) has been chosen to determine the pain threshold. Patients and methods: The effect of mirtazapine against placebo was assessed in 10 healthy subjects following a double-blinded crossover design. The NFR against a painful electric stimulus was measured the day after a unique oral dose of drug or placebo Results: A significant increase in mean (19 %, p = 0.03) and upper limb (29 %, p = 0.006) NFR threshold was observed.

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Conclusion: Mirtazapine increases the pain threshold in healthy subjects. The potential benefit of this effect on pain should be investigated more thoroughly in chronic neuropathic pain patients. The NFR might serve as an additional tool for the monitoring of these patients.

O66 Migraine with and without aura: evidence of cortical function abnormalities from event-related potentials to the stroop test P. Annovazzi, B. Colombo, L. Bernasconi, F. Cerri, G. Comi, L. Leocani Ospedale San Raffaele (Milan, I) Central neuronal hyperexcitability is proposed to be the putative basis for physiologic disturbances in migraine. Studies using Event-Related potentials (ERPs), as well as Transcranial Magnetic Stimulation studies have shown the presence of such hyperexcitability, although results have been conflicting so far. Aim of this study was to investigate differences in patterns of cortical excitability in patients suffering from migraine with aura or without aura using ERPs to the Stroop test, a neuropsychological test involving visuomotor, associative and frontal cortical functions. Twelve patients with migraine with aura (10 females, mean age 38 yrs, 5 pts had brain MRI positive for silent white matter abnormalities), 8 with migraine without aura (8 females mean age 40 yrs, 6 pts had brain MRI positive for silent white matter abnormalities) and 11 normal subjects age and sex matched participated in the study. ERPs during mental performance of the Stroop test were obtained from 32 scalp electrodes. All patients were free from migraine attacks in the 72 hours preceding the test. Compared to controls, both migraine with and without aura patients showed a significant higher amplitude and duration of the positive component at around 300 msec over occipital (p < 0.005) and parietal (p < 0.01) and centro-parietal (p < 0.05) areas, with no significant differences between migraineurs with and without aura in the early component of the wave. After 600 msec migraine patients with aura showed a significant persistence of the positive wave compared to without aura patients. Over frontal regions migraineurs without aura showed potentials of a significant (p < 0.01) higher amplitude compared to both normal subjects and with aura patients The higher expression of long-latency ERPs components over occipital, parietal, and centro-parietal areas supports previous results of lower excitatory threshold in migraine patients. The presence of sustained hyperexcitability in migraineurs with aura suggests that overweight of cortical excitatory vs inhibitory processes in these patients may have a pivotal role for the aura phenomenon Differences in frontal cortical excitability found in migraineurs without aura may be the result of a higher prevalence, in this group, of brain silent white matter abnormalities, compared to patients without aura. Further investigations are needed to determine whether the presence of such lesions may affect patients cortical functions and excitability.

O67 Prevalence, recognition rate and self-awareness of migraine in Germany, 2004 H. Neuhauser, A. Radtke, M. von Brevern, T. Ziese Robert Koch Institute (Berlin, D); Charité (Berlin, D) Introduction: Migraine is a common headache disorder which has a considerable individual and societal impact. However, the recent prevalence of migraine in the general population in Germany and the agreement between diagnoses by IHS criteria, diagnoses by treating physicians and self-awareness of migraine are unknown. Methods: Nation-wide telephone survey of a representative sample of the general adult population in Germany (modified random digit dialing sampling design, n = 7341). A diagnosis of migraine was assigned based on the 2003 IHS criteria if respondents reported 1) severe headaches in the past year, 2) unilateral or pulsatile pain or aggravation of pain by routine physical activity, 3) nausea/vomiting or photo- and phonophobia and 4) a duration of attacks of 4 to 72 hours. A simplified question for visual auras was used (flickering lights or lines for at least 5 minutes). Results: The 12-months prevalences were: headaches 67 % in women and 53 % in men, migraine 15.6 % in women and 5.3 % in men (overall population prevalence 10.6 %), migraine with visual aura 5.5 % in women and 1.5 % in men. The majority of migraineurs (56 %) had more than 20 headache days in the previous 12 months, 25 % had 10–20 headache days and 19 % less than 10 days. However, only 42 % had a medical follow-up for their headaches in the last year and in only 11 % of these the main treating physician was a neurologist. Migraine was recognised by the treating physician in the previous

12 months in only 63 % of migraineurs (moderate agreement, kappa = 0.40). Migraine self-awareness was slightly higher (70 % of all migraineurs, kappa = 0.46). Multivariate analysis of the association of the individual migrainous features with self-awareness and physician recognition of migraine revealed that both awareness and recognition were best in the presence of vomiting, photophobia with phonophobia and unilateral pain. Discussion: Migraine is highly prevalent in the general population in Germany. Our results confirm previous findings which show similar and stable prevalence estimates in industrialised countries despite differences in study methodology. The rate of physician-diagnosed migraine among migraineurs by IHS criteria is unsatisfactory, although it compares favourably with rates reported from other countries. Physician recognition of migraine and patient awareness need to be improved since they are essential for the proper use of current effective treatments of migraine.

Session 7 Cerebrovascular disorders 1 O68 Insular infarcts and electrocardiographic changes at admission M. Pasquini, C. Laurent, M. Kroumova, I. Masse, D. Deplanque, X. Leclerc, R. Bordet, D. Leys Lille University Hospital (Lille, F) Objectives: Previous studies showing that insular strokes are associated with electrocardiographic (ECG) changes took into account continuous ECG recorded up to 72 hours after onset. These studies neither took into account the first ECG recorded at admission, nor detailed the time-course of cardiac changes. Therefore, whether these changes are associated with the cause of the infarct, or are the consequence of the lesion of the brain, remains unsettled. If ECG changes are the consequence of insular infarcts, they should not yet be present at admission. The aim of this study was to test the hypothesis that ECG changes in patients with insular infarcts are not yet present at admission. Methods: we recruited consecutive patients admitted within 48 hours (median 3 hours) after the onset of symptoms of acute hemispheric cerebral ischemia. All CT- and MRI- scans were analyzed by a neuroradiologist (CL), who did not participate to the management of patients, in order to identify patients with and without insular infarct; standard ECG recorded at admission were analyzed by a cardiologist (MK), blinded to clinical data. We compared ECG variables between patients with and without insular infarcts, and with left and right insular infarcts. Results: the study population consisted of 208 patients (94 men; median age: 69 years). Seventy patients had a recent insular infarct (right in 33). ECG variables did not significantly differ between patients with and without insular infarcts, and with left and right insular infarcts. These results were not explained by a lack of statistical power (1-beta > 0.90 for all comparisons). Conclusions: The lack of association between insular infarcts and cardiac changes at admission suggests that ECG changes found in previous studies are not associated with the cause of ischemia, but are the direct consequence of the insular lesion. This study was conducted thanks to an ENS fellowship to Dr Pasquini. O69 Decline of 30-day case fatality for stroke between 1991/1992 and 2005 – comparison of data from population-based studies H. Sienkiewicz-Jarosz, M. Gluszkiewicz, J. Pniewski, A. Czlonkowska, D. Ryglewicz Institute of Psychiatry and Neurology (Warsaw, PL); CSK MSWiA (Warsaw, PL) Objectives: Stroke mortality rates have declined in recent decades in many countries. The aim of the present study was to compare the incidence rates of the first-ever-in-a-lifetime-stroke (FES) and 30-day case fatality for stroke between two studies conducted in Warsaw in 1991/1992 and 2005. Methods: We compared results of two prospective population based studies: Warsaw Stroke Registry (WSR), registration 1991–1992, covering patients from Mokotów and Ursynów districts of Warsaw (population 182649), and population based study conducted as a part of European Registry of Strokes (EROS) Project in Ursynów District of Warsaw in 2005 (pop-

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ulation 120186). Standard criteria were used to defined stroke (WHO criteria) and case fatality. Results: The crude incidence rates of FES decreased from 126 per 100000 in 1991/1992 to 103.3 per 100000 in 2005. After standardization to the European population for 2002 the incidence rates did not change significantly. Ischemic stroke was diagnosed in 90 % of new cases, hemorrhagic stroke in 10 % of patients. The 30-day case fatality decreased from 40 % in man and 51 % in woman to 11.4 % and 22.2 % respectively (mean 16.9 %). The highest mortality was observed for parenchymatous intracerebral hemorrhage – 37.5 %. In ischaemic strokes 30-days fatality was 14.3 %. Most deaths occurred in patients with many risk factors for cerebrovascular diseases and comorbidity. Conclusions: The decline in 30-day-case fatality in the period 1991/1992 through 2005 can be a result of better management of hypertension during last years, development of stroke units in hospitals serving assessed population and better availability of acute hospital care. These are preliminary data from one-year observation. The evidence from the second year of observation are needed. O70 Teleneurology in emergency medicine – how low can we go? First experience using telephone-based consultation in acute stroke R. Handschu, M. Scibor, M. Nückel, J. Heckmann, D. Asshoff, D. Belohlavek, F. J. Erbguth, S. Schwab for the STENO-Project Background: Telemedicine seems to be a promising method to improve stroke care by linking local hospitals to neurologic departments and stroke centers. Feasibility and reliability of video-based telemedicine was already demonstrated. We tried to test if remote consultation by telephone call as a cheap and simple method could be sufficient to improve quality in stroke care. Methods: By funding of the Bavarian state a small network was established linking 2 district hospitals to stroke centers in Northern Bavaria. Every second week a standardized protocol was used to discuss patients’ history, clinical and brain imaging findings of acute stroke cases with the physician of the local hospital by telephone call (TC). An advice for further therapy was given by the expert in the center. Data concerning timing, costs, and quality of care as well as demographical data were recorded. In the remaining time a video-based remote clinical examination (VRE) by an expert in the stroke center was provided followed by direct inspection of brain imaging files using a multimedia telemedicine system. Results: Out of 151 acute stroke patients (51 men, mean age was 67.6 years) 74 cases were done by TC. 31 of these patients were men, mean age was 64.9 years (range 22–92 y). Diagnoses in telephone consultations were TIA in 6.8 %, ICH in 6.8 %, cerebral ischemia in 58.1 %, while in 28.4 % of all cases a non-stroke diagnosis was suspected or the diagnosis was unclear after consultation. Mean duration of TC was 16.8 min, and 34.8 min for VRE. 11 Patients were transferred to the stroke center after TC (14.9 %) compared to 7 after VRE (9.1 %). Fewer patients were admitted to the local stroke ward after TC (20.3 %) than after VRE (68.9 %) Discussion: Telemedicine is a safe and promising method to link rural areas to academic neurology and stroke centers. From first experiences telephone consultation can also provide improvements in quality of care. TC is far less time consuming than video based telemedicine and is extremely cheap and simple.After TC more patients were transferred to the stroke center, less patients were admitted to the local stroke ward and unclear diagnosis was more frequent than after VRE. These findings indicate that TC is feasible and helpful but cannot reach the quality level of full-size telemedicine using remote video examination and transfer of imaging data. The study was funded by the Bavarian State Ministry of Social Welfare O71 Coma in cerebral venous thrombosis F. Falcão, P. Canhão, M-G. Bousser, J. Stam, F. Barinagarrementeria, J. M. Ferro, for the ISCVT Investigators Objectives: Coma is an independent predictor of poor prognosis in cerebral venous thrombosis (CVT). We aimed to describe the characteristics of the subgroup of patients who presented in coma during the acute phase of CVT in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) and their outcome. Methods: ISCVT is a multinational, prospective, observational study including 624 patients with CVT occurring between May 1998 and May 2001. Coma was defined as Glasgow Coma Scale score < 9 at admission. Clinical presentation, site of sinus or veins occlusion, radiological studies, therapy and prognosis were compared between patients in coma and all others (Chisquare, p < 0.05). Bivariate analysis was performed to identify variables as-

sociated with good outcome (Rankin < 3 in the last follow-up) among patients in coma. Results: 31 patients (5 %) were admitted in coma. CVT patients in coma had more often acute onset (58.1 % vs. 36 %; p 0.013), aphasia (41.9 % vs. 17.3 %; p 0.001), seizure (64.5 % vs. 38.3 %; p 0.004) and paresis (61.3 % vs. 36.3 %; p 0.005). Superior saggital sinus thrombosis (93.5 % vs. 60.8 %; p 0.000), deep cerebral venous system thrombosis (25.8 % vs. 9.9 %; p 0.013), more than one sinus occluded (74.2 % vs. 49.3 %; p 0.007), CT/MRI parenchymal lesion (90.3 % vs. 60.2 %; p 0.001) and bilateral lesions on CT/MRI (48.4 % vs. 15.8 %; p 0.000) were more frequent among CVT patients in coma. Twenty eight patients (90.3 %) were treated with heparin and 2 patients (6.5 %) with local fibrinolytics. Nine patients (29 %) died in the acute phase. 13 patients (41.9 %) had a complete recovery (Rankin 0–1) and 12 patients (38.7 %) were dead or dependent at last follow-up (mean duration of follow-up was 18 months). Neurological worsening (53.3 % vs. 20.6 %; p 0.000), new haemorrhage (32 % vs. 10.7 %; p 0.006), acute death (29 % vs. 2.8 %; 0.000) and death or dependency at last follow-up (38.7 % vs. 12.2 %; p 0.000) were also more frequent in coma patients. The only variable associated with good outcome among CVT patients in coma was absence of deep venous sinus thrombosis (73.9 % vs. 25 %; p 0.043). Conclusions: Coma in acute CVT is associated with an increased risk of neurological worsening and acute death. Therefore, more aggressive treatment approaches such as local thrombolysis or decompressive surgery seem to be justified in CVT patients in coma, particularly in those with deep venous sinus thrombosis or large hemispherical lesions. O72 Influence of cognitive impairment on the social outcome within 3 years after stroke M. Pasquini, D. Leys, M. Rousseaux, F. Pasquier, H. Hénon Lille University Hospital (Lille, F) Objectives: Cognitive disturbances are frequent in stroke patients. The influence of pre-existing and new-onset dementia on institutionalization after stroke has never been prospectively evaluated. The aim of this study was to evaluate the influence of cognitive impairment on the social outcome, at discharge and within 3 years after stroke. Methods: in 165 consecutive acute stroke patients living at home before, we evaluated previous cognitive functions with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients were followed up at month-6, then annually over a 3-year period, and underwent extensive neuropsychological tests to evaluate the occurrence of dementia (ICD10 criteria). At each visit, we recorded the place where the patient was living (at home, rehabilitation center, convalescence department, or institution). Results: pre-existing dementia did not influence the proportion of patients discharged at home after the acute stage. Factors available at admission associated with institutionalization within 3 years were age (adjusted OR [adjOR] for 1 year increase: 1.08; 95 % confidence interval [CI]: 1.03–1.15), severity of the clinical deficit (adjOR for 1 point increase in Orgogozo score: 0.98; 95 % CI: 0.96–0.99), and IQCODE score (adjOR for 1 point increase: 1.03; 95 % CI: 1.0001–1.06). Age (adjOR for 1 year increase = 1.17; CI 95 %: 1.07–1.27), and any dementia, pre-existing or new (adjOR = 5.85; CI 95 %: 1.59–21.59), were associated with institutionalization at year-3. Conclusions: dementia (pre-existing or new), is associated with an increased rate of institutionalization within 3 years after stroke, but does not influence discharge at home after the acute stage. The cognitive evaluation at the acute stage of stroke, and during the follow-up, is crucial to predict social outcome and should be part of the diagnostic work-up of stroke patients. O73 Neuroprotection by targeting coagulation factor XII (Hageman factor) in experimental cerebral ischaemia C. Kleinschnitz, T. Renne, M. Bendszus, U. Pauer, B. Nieswandt, D. Gailani, K. Toyka, G. Stoll University of Wurzburg (Wurzburg, D); University of Gottingen (Gottingen, D); Vanderbilt University School of Medicine (Nashville, USA) Background/Objectives: Thrombembolic stroke represents a major cause of death and permanent disability in industrialized countries. During cerebral ischemia the endothelium is converted to a procoagulant state further driving thrombus formation and secondary infarct growth.Anticoagulant drugs during acute stroke have shown no overall benefit with the decrease in stroke progression being offset by bleeding complications. Recently, is has been shown that thrombus formation but not hemostasis is impaired in FXII deficient mice. Thus, targeting FXII activity could be a potential strategy for neuroprotection. In the present study we sought to investigate the efficacy

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and safety of targeting FXII in experimental cerebral ischemia and to clarify the molecular mechanisms underlying neuroprotection. Methods: Experimental stroke was induced in FXII-/-, FXI-/-, wt controls, and in FXII-/- mice reconstituted with human FXII by transient (1h) middle cerebral artery occlusion (tMCAO). After 24h neurological scores (Bederson score, grip test) were assessed and the infarct size was determined by triphenyltetrazolium chloride staining (TTC). The underlying neuroprotective mechanisms were elucidated by Western blot and immunohistochemical assessment of fibrin deposits. Serial magnetic resonance imaging (MRI) was used to assess the risk of intracranial hemorrhage. Results: In FXII-/- and FXI-/- mice infarct volumes were reduced to 50 % compared to wt mice (P < 0.01). Accordingly, the Bederson score (P < 0.01) and grip test (P < 0.0001) significantly improved.Application of human FXII to FXII-/- mice restored the susceptibility to ischemic brain damage. Strokeprotected mice showed less fibrin depositions and vessel-occluding clots in the ischemic hemisphere and did no exhibit an increased risk of intracranial hemorrhage during follow-up MRI at days 3 and 7. Conclusion: These findings show the importance of the activation of the intrinsic pathway of coagulation (FXII; FXI) in experimental stroke. They point to FXII as a novel target for safer anticoagulation in situations with a high risk of brain thrombembolism such as vascular/heart surgery and endovascular procedures. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB 355 and the Stiftung für Pathobiochemie und molekulare Diagnostik der DGKL (to T. R.), M. B. holds a research professorship awarded by the Schering GmbH, Berlin, Germany.

Session 8 Cerebrovascular disorders 2 O74 Histological features of unstable atherosclerotic plaque in the middle cerebral artery and their relationship with cerebral infarcts: a post-mortem study X. Y. Chen, H. L. Zhao, W. M. W. Lam, H. K. Ng, K. S. Wong Chinese University of Hong Kong (Hong Kong, RC) Objectives: To describe the morphological features of atherosclerotic plaques in MCAs, and to investigate their relationship with cerebral infarcts from a routine post-mortem series. Methods: We studied in consecutive post-mortem adults aged 45 years old above, the morphological features of the MCAs. Morphological analysis was performed with the software of MetaMorph imaging system (Version 4.01). The following parameters were evaluated by a single observer blinded to the clinical history: [1] thickness of fibrous cap; [2] extent of lipid area including necrotic core; [3] degree of stenosis of the artery; [4] presence of intraplaque hemorrhage; [5] presence of neovasculature in the plaques; [6] presence of thrombus in the artery and [7] presence of calcification. Those segments that had a > 40 % cross-sectional luminal stenosis were recruited for morphological analysis. The sum of the values of the first two parameters were calculated to produce a new parameter cap-lipid and the sum of values of the first three ones to produce another parameter cap-lipid-stenosis. A semiquantitative assessment of macrophage and T lymphocytes infiltration, assessed by immunohistochemical staining for CD68 and CD45RO were assessed. The above parameters were compared between symptomatic and asymptomatic plaques. Results: For the investigated 152 MCAs, 876 slides were done. Atherosclerotic plaques of more than 40 % cross-sectional area luminal narrowing stenosis were found in 69 MCAs (45.4 %, 69/152)(totally 111 slides). According to the presence of infarctions in MCA territory, 46 slides were categorized as symptomatic, while other 65 ones as asymptomatic. The results demonstrated that the degree of luminal stenosis, the percentage of the plaques containing more than 40 % lipid area, the values of cap-lipid, cap-lipid-stenosis, and the prevalence of intraplaque hemorrhage, neuvasculature and thrombusthere were higher in the symptomatic group. And the mean index of both CD45RO and CD68 were higher in the symptomatic group (p < 0.01, respectively). Binary logistic regression showed that stenosis (p = 0.003, OR = 1.050), lipid area (p = 0.048, OR = 1.698) and presence of neuvasculature (p = 0.040, OR = 3.471) were independent risk factors of MCA infarcts. Conclusions: Luminal stenosis caused by atherosclerotic plaque, per-

centage of lipid area and presence of intraplaque neuvasculature may play a key role in leading to ischemic stroke. O75 Long-term effects of subarachnoid haemorrhage on employment, relationships, personality and mood M. J. H. Wermer, H. Kool, K. W. Albrecht, G. J. E. Rinkel University Medical Centre Utrecht (Utrecht, NL); Academic Medical Centre Amsterdam (Amsterdam, NL) Objectives: Only one third of patients regains functional independence after aneurysmal subarachnoid hemorrhage (SAH). Despite this recovery, many of such patients experience psychosocial problems. We assessed the longterm effects of SAH on employment, relationships, personality and mood. Methods: We included patients who had been treated by clipping after SAH between 1985 and 2001 and resumed independent living. Patients underwent structured interviews regarding employment, relationships and personality before and after the SAH. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS) and scores were compared between the study group and a reference population. Results: 610 patients were interviewed (mean follow-up after SAH 8.9 years). Of the employed patients 26 % stopped working and 24 % worked shorter hours or had a position with less responsibility. On average, patients returned to work 9.4 months after discharge (range 0–96). Seven percent of patients got divorced because of SAH related problems. Fifty-nine percent of the patients reported changes in personality, most commonly increased irritability (37 %) or emotionality (29 %). SAH patients had a statistically significant higher mean depression score than the reference population. Approximately 10 % of the patients had a HADS score in the range of a probable depression or anxious state. Only 25 % reported a complete recovery without psychosocial or neurological problems. Conclusions: The long-term psychosocial effects of SAH are considerable even in patients who regain functional independence. Treating physicians should be aware of these long-term effects of SAH when discussing prognosis and reintegration to work after initial recovery with patients and family 76 The cognitive test for locked-in syndrome. Normalisation and validation M. Rousseaux, E. Castelnot, O. Kozlowski, W. Daveluy CHRU, Hopital Swynghedauw and EA 2691 (Lille, F) Background: Patients with locked-in syndrome (LIS) show severe communication difficulties. Therefore, little is known about the presence of underlying cognitive disorders. Objective: To create and normalise a Cognitive Test for Locked-in Syndrome (CTLIS), assessing the main components of cognition.And to analyse its pertinence in a group of LIS patients suffering from stoke or traumatic brain injury. Methods: The CTLIS comprises of three main parts (20 subtests), dedicated to perception (visual and auditory perception, visual and auditory recognition), motricity (global motricity, oro-facial motricity, ocular motricity), and cognition (oral comprehension of identity, words and sentences; written comprehension of words and sentences; orientation in time and place; short-term and long-term memory for verbal and spatial information; calculation and problem solving; analysis of verbal logic). Responses are always of the yes/no type. Two optional subtests analyse written expression (identity, naming, and sentence building). The CTLIS was presented to 27 normal subjects, distributed in 3 education levels and 3 classes of ages (20–65 years), and to 22 patients (LIS: 13; frontal syndrome and amnesia: 6; pure amnesia: 2). Results: In normal subjects, age only had a significant influence (p < 0.05) on one optional subtest (sentence building), and education level showed more definite effect on sentence comprehension, verbal memory, mental calculation, and sentence building. LIS patients showed significant difficulties in three subtests: auditory recognition, verbal memory and problem solving. Conversely, frontal patients were more severely impaired in eight subtests and amnesic patients in one. In LIS patients, cognitive deficits were often associated with hemispheric or cerebellar injury resulting from other traumatic or vascular lesions. Conclusion: The CT-LIS showed validity and ability in assessing de-efferented patients. Assessing cognitive disorders is important, because of the increased difficulties of communication and consequences on rehabilitation protocols. These cognitive disorders suggest that hemispheric or cerebellar lesions are associated with the basic brainstem injury.

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O77 Impact of initial cerebral infarction volume measured in diffusionweighted MRI on clinical outcome in acute stroke patients with middle cerebral artery occlusion, who underwent thrombolysis D. Sanak, D. Horak, V. Nosal, A. Bartkova, K. Zelenak, R. Herzig, J. Zapletalova, S. Burval, I. Vlachova, J. Bucil, M. Kocher, E. Kurca, P. Kanovsky University Hospital (Olomouc, CZ); University Hospital (Martin, SVK); Palacky University Medical School (Olomouc, CZ) Objectives: Magnetic resonance imaging (MRI) may help to identify those acute stroke patients, who have the most potential benefit from thrombolytic therapy. The aim of our study was to assess the impact of the initial volume of cerebral infarction on resulting clinical outcome in acute ischemic stroke (IS) patients with middle cerebral artery (MCA) occlusion examined with a standard MRI protocol, who subsequently underwent thrombolysis. Methods: We retrospectively analyzed a set of 25 consecutive acute IS patients with MRI verified MCA occlusion (M1–2 segment), who underwent intravenous/intra-arterial thrombolysis according to recent guidelines. The initial infarct volume (VDWI-I) and infarct volume after 24 hours were quantified on diffusion weighted images (DWI) and MCA evaluated on MRI angiography. Neurological deficits were evaluated using NIH Stroke Scale at the admission and 24 hours later, 90-day clinical outcome using modified Rankin Scale (mRS). The relationship between infarct volume and neurological deficit severity was assessed and searching for maximum VDWI-I still associated still with a good clinical outcome, we subsequently divided patients into 2 subgroups (VDWI-I < 70 ml; > 70 ml). Results: VDWI-I ranged from 4.7 to 321 ml. 24-hour clinical outcome improved significantly (p = 0.0001) in patients with VDWI-I < 70 ml (Group 1) and 90-day clinical outcome was significantly better (mRS 0–2 in 78.9 % patients) in Group 1 versus Group 2 (patients with VDWI-I > 70 ml) (p = 0.003). 90-day mortality was 0 % in Group 1 versus 71 % in Group 2. Patients with successful recanalization of MCA occlusion had significantly better 24-hour (p = 0.001) and 90-day clinical outcome (p = 0.009). Conclusions: The patients with VDWI-I < 70 ml have significantly better 24-hour and 90-day clinical outcome. Thus the MRI-DWI quantification of initial infarct volume could be of benefit for clinical outcome prediction in acute stroke patients undergoing intravenous/intra-arterial thrombolysis. Acknowledgement: Supported by the IGA Ministry of Health CR grant number NR/8579–3/2005. Supported by the IGA Ministry of Health CR, grant number NR/8579–3/2005. O78 Predictors of ischaemic stroke and TIA in atrial fibrillation on oral anticoagulant therapy: a case-control study A. M. Basile, S. Tonello, L. Busson, A. Corfini, L. Costa, V. Argentiero, M. Armani, V. Pengo, B. Tavolato University of Padua (Padua, I); ULSS18 (Rovigo, I); S. Antonio Hospital (Padua, I) Objectives: Ischemic stroke in atrial fibrillation (AF) is not fully suppressed by oral anticoagulant therapy (OAT) with target international normalized ratio (INR) of 2–3. Ischemic stroke and transient ischemic attacks (TIAs) occurring during OAT are sporadic events in clinical practice. Aims were to verify if TIA/ischemic stroke onset in AF patients on OAT is correlated with INR and to identify any associated risk factors and coagulation disorders. Methods: Thirty-one consecutive AF cases (mean age: 78.0 ± 7.3 y; F/M: 15/16) with acute TIA/ischemic stroke occurred during OAT, were assessed for demographics, vascular risk factors, stroke severity, stroke subtype, and instrumental examinations including coagulation tests and transesophageal echocardiography. Cases were divided into 2 subgroups on entry INR: in range (INR > 2) and out of range (INR < 2). Previous 3 months’ INR values were also collected. Cases were compared with a control group of AF patients on OAT without ischemic events: for each case, 3 age- and sex-matched controls were randomly taken from the Padova Thrombosis Centre database. Results: Of the 31 cases, 15 had entry INR > 2 and 16 INR < 2. Females were significantly more frequent among patients with INR out of range (75 % vs. 20 %; P = 0.002). Risk factors and comorbidities did not differ significantly between the 2 subgroups. Compared with controls, cases presented significantly more often with hypertension (87.1 % vs. 66.7 %; P = 0.030), diabetes (44.8 % vs. 16.1 %; P = 0.009), previous stroke (58.1 % vs. 8 %; P < 0.001), and G20210A factor II mutation (16 % vs. 3.4 %; P = 0.022). On logistic regression analysis, diabetes (OR: 4.6; 95 % CI: 1.1–18.8), previous stroke (OR: 25.9; 95 % CI: 6.1–109.8), and G20210A mutation (OR: 11.5; 95 % CI: 1.5–90.3) predicted cerebral ischemic events in AF during OAT, independently of all the other factors. Cases had decreasing INR values with wide fluctuations in all measurements preceding stroke, while controls showed more stable anticoagulation intensity.

Conclusion: Despite the small sample size, our results suggest that risk factors, comorbidities, and coagulation disorders contribute to ischemic stroke/TIA in AF during OAT. Anticoagulation intensity variability may affect the efficacy of such therapy. O79 Delayed recanalisation of middle cerebral artery occlusion after intra-arterial thrombolysis: has it any implications on the clinical outcome? T. Haefeli, K. Nedeltchev, L. Kappeler, M. Arnold, C. Brekenfeld, G. Schroth, H. P. Mattle Inselspital (Berne, CH) Objectives: Early recanalization of the occluded artery is a significant predictor of favourable outcome in patients who receive thrombolysis for treatment of acute ischemic stroke.Whether delayed recanalization is also related to the clinical outcome is unclear. The aims of the present study were: 1) to assess the prevalence of delayed recanalization after intra-arterial thrombolysis (IAT) in patients with occlusions of the middle cerebral artery (MCA); 2) to compare the clinical outcome of patients with delayed recanalization to that of patients with persistent occlusion. Methods: From 01/2000 to 7/2005, 280 consecutive patients were treated with IAT at our institution. 193 patients (69 %) had an occlusion of the M1 or M2 segment of the middle cerebral artery. Of the patients with M1/M2 occlusion, 101 (52 %) underwent a TCD examination within 10 days after the ictus. 12 patients had poor temporal bone windows, so 89 patients remained for the analysis. The recanalization rate immediately after IAT was assessed angiographically using the Thrombolysis In Myocardial Infarction Criteria (TIMI). The Thrombolysis In Brain Ischemia (TIBI) grading system, which is based on the TCD findings, was, used to assess the recanalization within the first 10 days after stroke. Clinical outcome was measured by the modified Rankin Scale at 3 months. Results: Immediately after IAT, 58 patients (65 %) had a good angiographic recanalization (TIMI 2 or 3) of the MCA. 22 of the 31 patients with poor angiographic recanalization (TIMI 0 or 1) achieved TIBI grades 2 or 3 within the first 10 days after stroke. On the other hand, 9 of 58 patients with TIMI 2 or 3 regressed to TIBI 0 or 1. Overall, 71 patients (80 %) had a good recanalization of the MCA in the first 10 days after IAT as defined with TCD. At 3 months, 53 patients (60 %) had a favourable outcome. The outcome of patients with delayed recanalization did not differ from that of patients with persistent occlusion (P = 0.83). Conclusion: Delayed recanalization occurs in a significant proportion of patients with middle cerebral artery occlusion, however, it does not seem to be associated with additional clinical benefit.

Session 9 Epilepsy O80 Ictal bradycardia in intractable epilepsy: prevalence and clinical features C. Odier, D. K. Nguyen, P. Cossette University of Montréal (Montréal, CAN) Background: Sudden unexpected death in epilepsy (SUDEP) is a rare, but dramatic complication of refractory epilepsy. Potential mechanisms include ictal autonomic events. Recent studies using prolonged heart rate (HR) recordings have shown that bradycardia and asystole were more frequent and more severe than initially thought, which may require permanent pacemaker (PM). Identification of these potentially high-risk individuals may contribute to prevent SUDEP. Objective: To measure incidence and characterize clinical features of ictal bradycardia in our cohort of refractory epileptic individuals. Method: We analyzed ictal HR in 69 consecutive individuals, who underwent prolonged video-EEG monitoring for intractable epilepsy.We included individuals with clearly established epileptic focus, based on a combination of ictal EEG, ictal SPECT, and MRI. Bradycardia was defined by HR less than 60 beat/min (bpm) and a fall of more than 30 bpm. Bradycardia was considered severe if HR decreases below 42 bpm. Localisation of the epileptic focus and temporal relation between ictal events and bradycardia were analysed. Results: We analyzed 1277 seizures in 69 individuals. Ictal bradycardia

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was observed in five individuals (7.2 %), and 1.9 % of all seizures. In these patients, ictal bradycardia was observed in 18 % of all seizures. Four of them also presented HR decrease between 10 to 30 bpm in 50 % of their seizures. Four other individuals experienced ictal HR decrease of more than 10 bpm. By using such a definition, ictal bradycardia would occur in 13 % of all individuals and in 8 % of all seizures in our cohort. In patients with significant ictal bradycardia (n = 5), epileptic focus was found in frontal (two left, one right), left temporal, and right parieto-occipital lobes. We also documented epileptic focus by subdural recordings in an individual with previously recognized ictal asystole. In this individual, PM (set at 50bpm) turned on after diffusion of epileptic activity from left to right orbitofrontal lobe (n = 3 seizures). Conclusion: Ictal bradycardia occurs more frequently than previously reported in refractory epilepsy, but prolonged EEG and HR recordings are necessary to identify these ictal events. Recognition of individuals with small to moderate ictal HR decrease may help to identify those at greatest risk for severe bradycardia and asystole. Epileptic activity involving bilateral limbic structures is potentially critical for ictal bradycardia. O81 Provision of information for women with epilepsy: an audit of practice E. Stern, H. R. Cock St. Georges, University of London (London, UK) Objectives: During pregnancy both antiepileptic drugs and poorly controlled seizures carry risks. Some drugs also interact with hormonal contraceptives. International consensus and national guidelines highlight adequate information provision to women with epilepsy on such issues, and failure to do so/document this is a common cause of conplaints and medicolegal actions. We set out to examine documentation of information provision to women with epilepsy at a regional centre, and the patient’s recollection of this. Methods: we undertook a retrospective, notes-based audit of 62 unselected consecutive women aged 18–51 presenting for follow-up. 30 of these women also completed a questionnaire. Mention of teratogenicity, risk of seizures, folic acid, and interactions with hormonal contraceptives in the hand written notes, check lists, or clinic letters was accepted as evidence of discussion, even in the absence of further detail. Demographic and relevant clinical information was also recorded (type of epilepsy, drugs prescribed). Post-menopausal, sterilized or post-hysterectomy women were excluded. Results: Most records documented that information had been provided on seizure risks during pregnancy (69.4 %), teratogenicity (75.8 %) and folate supplementation (64.5 %). Women in the 25–35 age range were considerably more likely to have received this information than other women (p < 0.05, Fisher’s exact). There was no association with ethnicity, learning disability, type of epilepsy, drugs prescribed or marital status. 56.7 % of women taking enzyme-inducing medications had a record of being given information about possible interactions with oral contraceptives. Women first seen by a general neurologist waited significantly longer before first receiving pregnancy-related information than those first seen by epileptologists. Less than 50 % of women recalled receiving information in every category, but there was a significant correlation between documentation in the notes and recall. Conclusion: The recently established epilepsy group is improving services, but despite active measures not all women appear to be receiving important information. There is a bias against giving information to women outside the “core” child-bearing age range, and information related to contraceptives is a relative weakness. This illustrates the need for systematic processes, and provides a focus for future improvement. O82 A new and unique animal model of cortical band heterotopia associated with lowered epileptic seizures threshold: the mouse mutant HeCo A. Croquelois, E. Welker Centre Hospitalier Universitaire Vaudois (Lausanne, CH); Université de Lausanne (Lausanne, CH) In human, neuronal migration disorders form a group of malformations of the brain, which primarily affect development of the cerebral cortex. They are commonly associated with developmental delays, mental retardation, and epilepsy. Some form of cortical malformation is frequently observed in patients with intractable epilepsy, the majority of them already presenting seizures in infancy. Mechanisms resulting in these cortical malformations are not well understood, mainly due to the limited number of animal model of these syndromes. We here describe a new and unique mouse mutant that appeared spontaneously in our colony which is characterized by heterotopic cortex (HeCo), that resembles cortical band heterotopia observed in human

cases and share with it an increase tendency to epileptic seizures, as demonstrated in the pilocarpine induced status epilepticus model. Different crossings allowed ascertaining the genetic origin of the HeCo phenotype and the establishment of the autosomic recessive transmission mode. Tracing experiments revealed that the HeCo receives projections from the same brain structures as the homotopic cortex above and extracellular multiunit recording in vivo showed an increase in spontaneous activity in the HeCo as compared with the homotopic cortex. Finally, immunohistochemistry for parvalbumin and calretinin ascertain the presence of GABAergic cells in the HeCo. Study of the development of this cortical malformation is ongoing and results of the bromodeoxyuridine experiments will be available at the time of the meeting. Protein analysis and sequencing (mass spectrometry) by 2D-gel electrophoresis and molecular characterization of the mutation based on DNA and RNA form the next step in discovering the genetic basis of the HeCo phenotype. This animal model represents a new and unique way to better understand cortical development and to investigate future therapeutically strategies for epilepsy in patients with cortical malformation. O83 Ulegyria – electroclinical and imaging findings in ten patients G. Kuchukhidze, I. Unterberger, G. Walser, N. Embacher, J. Dobesberger, A. Auckenthaler, G. Luef, M. Ortler, F. Koppelstaetter, T. Gotwald, S. Felber, G. Bauer, E. Trinka University Hospital for Neurology (Innsbruck, A); University Hospital for Neurosurgery (Innsbruck, A); University Hospital for Radiology (Innsbruck, A) Objectives: Ulegyria is a result of perinatal ischemic brain injury with characteristic MRI gyral pattern: multiple small cirumvolutions with atrophy at sulci bottom and relative sparing of gyral apex. This “mushroom” shape is due to unique vascular supply to infant brain gyri: greater perfusion to apical cortex rather than depth of sulci. Thus, there is a bigger tissue loss at sulci bottom when ischemic event occurs. Ulegyria is associated with epilepsy, cerebral palsy, mental retardation and has to be distinguished from polymicrogyria. We aimed to analyse clinical, EEG and MRI features in patients with epilepsy and ulegyria. Methods: We reviewed 10 patients (6m/4w) with epilepsy and ulegyria from database of the University Hospital for Neurology, Innsbruck, Austria. Past medical records of all subjects were obtained, all were examined clinically, underwent high resolution MRI and repeated EEG recordings. One patient was operated because of refractory seizures. Results: At the time of re-evaluation mean age of patients was 40 yrs (26 to 66).All were born at term; 8 had history of perinatal asphyxia, complicated birth was reported in 2. Five had delayed developmental milestones (4 – with borderline intelligence, one – severely retarded). Four patients suffered from congenital hemiparesis, 2 had hemianopia, in 4 neurological examination was normal. Mean age at seizure onset was 5.4 ± 5.32 yrs. Nine had intractable epilepsy, one was seizure free. Four were diagnosed occipital lobe, 2 – frontal lobe and 1 – temporal lobe epilepsies. One had Lennox-Gastaut syndrome, 2 – multilobar epilepsy. Epileptiform activity was recorded in 4 patients, in 7 – focal slowing was identified on interictal EEG. All subjects, but one, had negative family history of epilepsy. None had any progression of the disease. All patients displayed typical features of ulegyria on brain MRI. Lesions involved whole hemisphere in 2 cases, frontal lobe in 2 and in parieto-occipital area in 6 (2 of them – bilateral). All lesions were associated with subcortical white matter loss. One patient with unilateral occipital ulegyria was operated on with postoperative 90 % seizure frequency reduction (Engel classification, IIA). Conclusion: Ulegyria affects predominantly posterior cortical regions, displaying recognizable MRI features. It is associated with heterogeneous clinical and EEG presentation, often causing refractory epilepsy and severe neurological disability. Condition is usually non-progressive. O84 Public knowledge and attitudes toward epilepsy in Tehran, Iran K. Gharagozli for the Iranian Epilepsy Association Purpose: Despite advances in medical science and modern technology, Epilepsy remains as a stigmatized condition; especially in developing countries such as Iran. Measuring the knowledge and attitudes toward epilepsy is the first step for alleviation discrimination. Methods: We conducted a face-to-face questionnaire interview survey in crowd locations of Tehran 0.1079 subjects were asked to fill questionnaire with age-range 15–81 years. Results: We interviewed 1079 subjects (402 male and 661 female with mean age 30/27); 88/7 % had heard about epilepsy before. 42/2 % knew one

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person with epilepsy. Regarding to the causes of epilepsy, 52/4 % agreed that epilepsy is caused by brain damage. Other responses was genetic(26/4 %),fever(14/3 %),stress(34/8 %) and evil spirits(1/1 %).56/9 % considered pregnancy to be appropriate;94 % believed children with epilepsy could go to school and have normal education. Conclusion: According to this survey, public knowledge and attitudes toward epilepsy in Iranian population is unsatisfied. Iranian Epilepsy Association suggests that more effort be made to improve public awareness of epilepsy through school education. Iranian Epilepsy Association

Results: The M@T is quick, 5-minutes, easy to administer and to score. M@T mean scores were significantly different between all groups: 41.4 (SD = 4.9) in the Primary Care Population, 31.5 (SD = 3.9) in the MCI group and 21.8 (SD = 4.9) in early AD.A cut-off score of 37 had a sensitivity of 96 % and a specificity of 79 % for MCI diagnosis (ABC = 0.932). A cut-off score of 28 had a sensitivity of 92 % and a specificity of 98 % for early AD diagnosis (AUC = 0.99) and a sensitivity of 87 % and specificity of 82 % to differentiate between MCI and AD patients. Conclusion: The M@T provides efficient and valid screening for amnestic MCI and early AD, and discriminates between MCI and early AD patients.

Session 10

O87 Apraxia of speech, orofacial apraxia, and linguistic dysprosody after acute ischaemic stroke: challenging traditional thinking S. Murphy, C. Doherty, J. Moroney Beaumont Hospital (Dublin, IRL); St James’s Hospital (Dublin, IRL)

Higher function disorders and dementia O85 Normal-pressure hydrocephalus: white matter lesions correlate negatively with gait improvement after lumbar puncture P. Bugalho, L. Alves Hospital Egas Moniz (Lisbon, P) Objectives: Normal-Pressure Hydrocephalus (NPH) proved to be less responsive to shunting than first considered. Predictive tests and prognostic factors have been difficult to define. lumbar puncture (LP) is frequently used in clinical settings as a simple method of predicting surgical results. White matter lesions (WML) have often been referred to as markers of bad prognosis. Their relation to NPH pathophysiology remains obscure. Our objectives were to test relations between WML load in NPH patients and: gait characteristics at baseline,duration of symptoms,gait improvement after LP, number of vascular risk factors (VRF), age and blood pressure. Methods: 12 idiopathic NPH patients were admitted to our inpatient clinic, where they underwent a timed walking test, before and after LP. Gait velocity (GV), stride length (SL), stride duration (SD) and number of steps needed to turn 180 [s] (TS) were assessed. Postural responses were assessed by a shoulder tug test (STT). Improvement percentages after LP were calculated for each variable. WML load was rated globally (Total (T) score) and in Frontal (F), Parieto-occipital (PO), Temporal, Basal Ganglia (BG) and Subtentorial regions, in T2 weighted MRI images, using a validated visual scale. Blood pressure, number of vascular risk factors and age were registered during patient in-stay.Relations between variables were tested using Spearman’s correlation coefficient. Results: WML load was higher in F and PO regions. WML did not correlate with duration of symptoms or gait variables before shunting. However, significant correlations were found between T scores and GV and SL improvement percentages (r = –0.668, p = 0.009 and r = –0.668, p = 0.009, respectively) as well as between F and PO scores and GV improvement percentages (r = –0.594, p = 0.021 and r = –0.649, p = 0.011, respectively). Correlations between visual scale scores and vascular risk factors were all postive, and significant in the following cases: diastolic blood pressure and F score (r = 0.510, p = 0.045), BG and number of VRF (r = 0.657, p = 0.010). Conclusions: WML seem to contribute to symptom irreversibility in NPH. Lack of significant correlations with gait variables at baseline and with duration of symptoms suggests that WML did not contribute to the pathophysiological mechanisms leading to NPH symptoms. Regional distribution of WML and correlation with vascular risk factors suggest they could be related to leukoaraiosis and not to NPH. O86 Screening for mild cognitive impairment and early AD with M@T (Memory Alteration Test) in the primary care population L. Rami, R. Sanchez-Valle, B. Bosch, A. Villar, A. Llado, J. L. Molinuevo Hospital Clinic Barcelona (Barcelona, E) Objectives: To design and validate a new screening test for amnestic Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD). Methods: We develop a verbal episodic and semantic memory test: the Memory Alteration Test (M@T). Discriminative validity was assessed in a population sample of 400 aged individuals from primary care population centres in Barcelona, Spain, 50 patients with MCI according to Petersen et al. criteria, and 66 with early AD (Global Deterioration Scale – 4 stage) according to the NINCDS-ADRDA criteria.

Objectives: To establish the frequencies of apraxia of speech (AOS) and linguistic dysprosody after acute hemispheric ischaemic stroke (AHIS). To test the hypotheses that AOS is dissociated from orofacial apraxia; that early dramatic improvement of AOS is uncommon; and that linguistic dysprosody is not exclusive to right hemispheral stroke. Background: AOS is a motor programming disorder affecting the timing and duration of utterances integral to suprasegmental speech processing. The prevalence of AOS in AHIS and its relationship to orofacial apraxia is unknown. Reports of early dramatic resolution of AOS in AHIS have not been validated prospectively. Hemispheric lateralisation of prosody is controversial, with most lesion and functional imaging studies implicating the right hemisphere while recent work supports bihemispheric cooperation. Methods: We administered standardised tests of comprehension, speech apraxia, word/non-word repetition and linguistic prosody to eligible patients with AHIS on admission and again at three days. Results: Mean age was 66 ± 13yr, 57 % were male. We identified AOS in 14/24 (58 %) patients who could complete the test battery. All had left-sided AHIS. We independently found linguistic dysprosody in 13/22 (59 %) patients, eight of whom also had AOS. The majority of patients (12/13, 92 %) with linguistic dysprosody had left-sided AHIS. We observed a dissociation between orofacial apraxia and AOS; five patients with AOS did not have orofacial apraxia. There was no evidence of dramatic recovery in any subtest in our battery. Conclusions: AOS and linguistic dysprosody are common following AHIS. Contrary to earlier reports, we did not find evidence of dramatic early improvement in AOS.AOS appears to be a higher cognitive function distinct from orofacial apraxia. Our data also confirms the observation of left hemisphere involvement as an important part of prosodic processing. Further work is needed to determine whether the presence of AOS influences stroke outcome. Supported by a grant from the Irish Heart Foundation. O88 Subjective memory complaints and cognitive performance in an elderly independent population with age-related white matter changes B. Miranda, S. Madureira, J. M. Ferro University of Lisbon (Lisbon, P) Objectives: To determine whether subjective memory complaints (SMC) are associated with the severity of white matter changes (WMC) and related to cognitive impairment in a nondisabled elderly sample. Methods: Data were drawn from the LADIS (Leukoaraiosis and Disability) prospective multinational European study that investigates the impact of WMC on global functioning in a cohort of independent elderly subjects. WMC severity was rated as mild, moderate and severe according to the Fazeka’s scale. The neuropsychological battery consisted on the Mini-Mental State Examination (MMSE), a modified version of the VADAS-Cog (Alzheimer’s Dementia Assessment Scale plus tests of delayed recall, symbol-digit, digit span, maze, digit cancellation and verbal fluency), Trail-making and Stroop tests.As measures of SMC, we retrieved from the LADIS database the item “reasons for referral” (cognitive/memory vs. other) and the answer to a question about memory complaints. Cognitive performance was analysed test-by-test and in three main domains: memory, executive function and speed/motor control. Data from the Geriatric Depression Scale (GDS) and Euro-QoL were used as measures of depressive symptoms and self-perceived health status respectively. Data were analysed with chisquare, t-test and multiple linear regression examined the effect of confounders. Results: Six hundred and thirty-eight subjects (mean age 74.1 ± 5 years; F/M: 351/287; mean educational level 9.6 ± 3.8 years) were included in this

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study. Subjects referred with cognitive complaints (n = 168) showed a higher GDS score [t [637]= –2.69; p < 0.01] and performed worse on tests of word recognition [t [635]= –3.70; p < 0.001], verbal fluency [t [631]= 2.31; p < 0.05] and on the memory domain [t [633]= 2.74; p < 0.01]. Impairment on the memory domain was independent of depressive symptoms and WMC severity. Participants reporting memory complaints (n = 399) had a lower educational level [t [637]= 2.17; p < 0.05], a higher GDS score [t [637]= –7.15; p < 0.001], a lower Euro-QoL score [t [632]= 5.56; p < 0.001] and performed worse on almost all cognitive tests and on the three cognitive domains. After adjusting for confounders, the worse performance on the memory domain was independent of depressive symptoms and WMC severity. No relationship was found between SMC and WMC severity. Conclusions: SMC are significantly associated with objective memory impairment independently of the presence of depressive symptoms and WMC severity. This study is funded by the University of Lisbon (FML-GAPIC) project “Educação pela ciência”.The LADIS study is supported by the EU (contract no. QLRT-2000–00446) as a concerted action. O89 Neuroplasticity in the recovery from stuttering C. A. Kell, K. von Kriegstein, K. Neumann, A. Giraud Johann Wolfgang Goethe University (Frankfurt, D); FIL Institute of Neurology, UCL (London, UK); Ecole Normale Superieure (Paris, F) Objectives: People who stutter (PWS) overactivate a right-hemispheric network during speech production when compared with controls [1]. After fluency-shaping therapy, these overactivations shift to the left hemisphere as a result of cortical plasticity [2].A subset of PWS recovers from stuttering even without therapy. To identify the network reflecting ‘ideal’ compensation and help to orientate future stuttering therapies, we studied the functional substrates of overt speech in this group compared with normal controls and PWS before and after therapy. Methods: Controls, unaided recovered PWS, and persistent PWS before and after fluency-shaping therapy (13 each, all male) were scanned on a 3 T scanner by acquiring 902 volumes of a standard EPI sequence (TR 2000ms). Syntactically balanced sentences were presented visually for three seconds, preceded by an auditory cue, indicating whether the phrase had to be read silently or overtly. Data analysis in SPM2 consisted of a random-effects group analysis (p < 0.001, uncorrected) and region of interest analyses. Results: Due to noise-induced fluency all subjects produced fluent speech during scanning. Before therapy PWS activated right frontoparietal areas more than controls. After therapy, they activated the left primary auditory cortex more than controls. Recovered PWS activated the right primary auditory cortex and the left opercular Brodmann area (BA) 47 more than controls, the latter activation highlighting the only region to dissociate significantly between recovered and persistent PWS, while the right frontal opercular BA 47 activated in all PWS more than controls. Conclusion: Here we present dissociable cortical networks in separate groups performing the same task without behavioural difference. Our results confirm a pre-therapeutic right-hemispheric overactivation which attenuates after fluency-shaping therapy [1]. The relative overactivation of the primary auditory cortex of persistent and recovered PWS may be a consequence of an altered auditory feedback. Because the right opercular BA 47 had earlier been implicated in the self-initiated reduction of stuttering severity of PWS [3], the here shown overactivation of the left-hemispheric pendant in recovered PWS could be interpreted as a functional correlate of stuttering recovery which could represent a potential target for stuttering therapy. This study was supported by the German Ministry of Education and Research. References 1. Brown S et al. (2005) Hum Brain Mapp 2. De Nil LF et al. (2003) J Fluency Disord 3. Preibisch C et al. (2003) Neuroimage O90 Are depressive symptoms associated with neuropsychological dysfunction in elderly with white matter changes? A. Verdelho, S. Madureira, J. M. Ferro, J. O’Brien, T. Minnet, T. Erkinjuntti, F. Fazekas, P. Scheltens, A. Wallin, G. Waldemar, L. Pantoni, D. Inzitari on behalf of the LADIS group Introduction and objective: Depressive symptoms (DS) in the elderly have been implicated in memory complaints and worse cognitive performance.

On the other hand, white matter changes (WMC) were associated with increasing DS in the elderly. Our aim was to ascertain the influence of DS in cognitive performance in an elderly population with WMC. Methods: The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluate the impact of WMC on the transition of independent elderly subjects into disability. The neuropsychological battery consisted in the Mini-Mental State Examination (MMSE),a modified version of the ADAS-Cog (Alzheimer’s Dementia Assessment Scale) plus tests of delayed recall, symbol-digit, digit span, maze, digit cancellation and verbal fluency, Trail-making and Stroop tests. WMC severity was rated according to the Fazeka’s scale. Three main cognitive compound measures were considered for analysis: memory, executive function and speed/motor control. DS were recorded using the Geriatric Depression Scale (GDS). Patients with GDS ≥ 5 were considered to have DS. Major depression was classified according to the DSM-IV criteria. T tests were used to compare performance in neuropsychological tests between patients with and without DS. Linear regression analysis was performed to evaluate impact of depressive symptoms in neuropsychological testing considering GDS total score. Education, age, gender and WMC severity were included as possible confounders. Results: 637 subjects were included (74.1 ± 5 years old, 55 % women, 9.6 ± 3.8 years of schooling), 26 % [166] with DS. Patients with DS performed significantly worse on MMSE (p ≤ 0.001), tests of speed and motor control (p ≤ 0.001) and executive functions (p ≤ 0.001), but not in memory tests. Linear regression analysis found that GDS total score contributed significantly to worse performance on MMSE and ADAS total score, compound measures and individual tests of executive functions, speed and motor control. This contribution was independent of age, education, gender and WMC severity. GDS was not associated with performance of immediate word recall, delayed word recall, word recognition, visuoconstructional and ideational praxis. Conclusion: DS are related to worse performance in executive functions, speed and motor control, but not to memory and praxis. The worse performance on these domains is independent of the WMC severity.

Session 11 Infection of the nervous system O91 Latency of a-herpesviruses is accompanied by a chronic inflammation in human trigeminal ganglia but not in dorsal root ganglia K. Hüfner, T. Derfuss, S. Herberger, K. Sunami, S. Russell, I. Sinicina, V. Arbusow, M. Strupp, T. Brandt, D. Theil Ludwig-Maximilians University (Munich, D); Osaka Graduate School of Medicine (Osaka, JP); New York University School of Medicine (New York, USA) Objective: In previous work we identified persistent T-cell infiltrates in human trigeminal ganglia (TG) latently co-infected with herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) or infected with latent HSV1 only. Fewer T-cells were detected in TG of an individual infected only with VZV when compared to those infected with HSV-1 alone or coinfected with both viruses. These findings led us to hypothesise that T-cells are more readily attracted to neurons that harbour latent HSV-1 than those harbouring latent VZV. In the present study we systematically evaluated the presence of latent HSV-1 and VZV in human TG and dorsal root ganglia (DRG) of the same individual and compared the local immune responses. Methods: We analysed 37 DRG from 15 subjects as well as the corresponding TG.VZV protein 62, CD3 + and CD8 + T-cells were detected via immunohistochemistry. The presence of latent HSV-1 was evaluated using LAT in-situ hybridisation. The production of RANTES, a chemokine marker secreted by stimulated T-cells, was quantified by TaqMan PCR. Results: We showed that most TG contain a positive hybridisation signal for HSV-1 latency associated transcript (LAT), whereas the DRG from the same individuals lack detectable LAT. In contrast, latent VZV was present in at least one DRG from all subjects tested, while three of the TG were negative for VZV. Consistent with our hypothesis T-cell infiltrates were prominently seen in TG, surrounding individual neurons, and the T-cell chemoattractant RANTES showed high transcript levels. Only a few scattered CD3 + T-cells were present in the DRGs of the same individuals, and this correlated with reduced levels of RANTES. Conclusion: Our study shows that HSV-1 latency in the TG is accompanied by a chronic immune response whereas VZV latency in the DRG is not.

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We detected a few T-cells in the DRG but not in close contact with the neurons. These T-cells are probably sentinel T-cells in the search of an antigen and not memory effector cells as the ones described for HSV-1 latency in the TG. Our findings provide further support for the concept that neurons harboring latent HSV-1 are recognized by T-cells, whereas those containing latent VZV are largely ignored by host immunity. This work was supported by the Deutsche Forschungsgemeinschaft and by Friedrich Baur Stiftung O92 Subarachnoid neurocysticercosis with arachnoiditis B. Pilo, J. L. Lopez-Sendon, A. Cruz, R. Toledano, R. Lopez-Velez, I. Corral, M. Alonso de Leciñana, J. Masjuan Ramon y Cajal Hospital (Madrid, E) Objective: Neurocysticercosis (NCC) is the commonest helmintic infection of central nervous system. Its presentation depends on the number, size and location of the parasites, as well as on the host’s immune reaction against the parasite. Cysticerci can lodge within the parenchyma, the ventricular system, the subarachnoid space or the basal cisterns. Ventricle and basal cysternal localizations are considered to be malignant forms of NCC. Common clinical manifestations include epilepsy, focal neurological signs, intracranial hypertension, hydrocephalus and cognitive decline. The diagnosis is based upon clinical suspicion in the correct epidemiological context, neuroimaging studies, laboratory analysis of the cerebrospinal fluid (CSF) and antibody titres in serum. Albendazole is the cysticidal more often used. Surgery can also play an important role in some cases, specially if hydrocephalus or intraventricular cysts. Methods: We report the case of a 35-year-old woman from Ecuador who presented with headache, nausea and fever. On physical examination, neck stiffness was the only remarkable sign. CT scan showed multiple calcifications, hydrocephalus and asymmetry in left cerebellopontine angle. Lumbar puncture showed 1 mg/dl glucose, 1.5 g/l proteins and 240 leucocytes/mm3 with 30 % eosinophils. Cranial magnetic resonance imaging (MRI) showed numerous cystic lesions in the basal cisterns, associated to arachnoiditis. Spinal MRI also revealed cervical and sacrum arachnoiditis. Diagnosis was confirmed by positive serology for cysticerci in serum and in CSF. Results: The patient was treated with albendazole and prednisone during one month. Control lumbar puncture and MRI after treatment showed an improvement in the CSF analysis and a reduction of the size of cystic lesions. The patient remains asymptomatic five months later. Conclusions: We present a case of subarachnoid NCC with arachnoidtis presenting as a subacute meningitis. Although arachnoiditis and basal cisterns forms usually associate a poorer prognosis, this patient had a good response to pharmacological treatment and remains asymptomatic 5 months later. O93 Role of the chemokine CCL20 and its receptor CCR6 in the pathophysiology of pneumococcal meningitis M. Klein, C. Schmidt, H.-W. Pfister, R. Varona, G. Marquez, U. Koedel Ludwig Maximilians University (Munich, D); Universidad Autonoma de Madrid (Madrid, E) In pneumococcal meningitis, the host immune response is assumed to contribute substantially to the development of intracranial complications, which, in turn, are the main causes for an unfavourable clinical outcome. The immune response is predominantly guided by the interplay of cytokines and chemokines. In the cerebrospinal fluid (CSF) of patients with acute bacterial meningitis, we recently identified an up-regulation of the cytokine CCL20, an important chemoattractant for dendritic cells and lymphocytes. Thus, we examined the role of CCL20 and its only receptor CCR6 in our wellestablished mouse model of pneumococcal meningitis. Briefly, C57BL/6 mice were infected intracisternally with 1.5x105 colony forming units (cfu) of Streptococcus pneumoniae type 3 and investigated 24h and 48h after infection (antibiotic therapy was started 24h after infection). Similar to humans, mice with meningitis showed an elevation of CCL20 as measured by enzyme linked immunosorbent assay. The treatment of infected animals with anti-CCL20 IgG resulted in a reduction of CSF pleocytosis at 24h after infection (anti-CCL20 IgG 4371 ± 3059 cells/µl vs. IgG isotype control 9713 ± 4170 cells/µl, p = 0.014) and an increase in brain bacterial titers (6.84 ± 0.46 log cfu/cerebellum vs. 6.24 ± 0.40 log cfu/cerebellum, p = 0.011). Similar results were observed in mice lacking CCR6.After antibiotic therapy, at 48h after infection, CCR6-/- mice additionally showed a marked increase in mortality (CCR6-/- 56 % vs. WT 4 %) and a significant elevation of the clinical score (12.88 ± 4.27 vs. 5.13 ± 2.75, p < 0.001). This was accompanied by a reduction in CSF pleocytosis (3263 ± 1594 cells/µl vs. 8161 ± 5215

cells/µl, p = 0.027). In conclusion, this data demonstrates a significant role of CCL20 and CCR6 in the pathophysiology of acute bacterial meningitis. O94 Favourable outcome of progressive multifocal leukoencephalopathy in two patient with dermatomyositis S. Vulliemoz, F. Lurati-Ruiz, F. X. Borruat, J. Delavelle, I. J. Koralnik, J. Bogousslavsky, F. Picard, T. Landis, R. A. Du Pasquier University Hospital (Geneva, CH); University Hospital (Lausanne, CH); BIDMC-HMS (Boston, USA) Objective: Progressive Multifocal Leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system which is caused by reactivation of JC Virus (JCV) in immunosuppressed patients. PML in patients with dermatomyositis (DM) has rarely been reported and their outcome was always fatal. We wanted to study JCV-specific CD8 + T lymphocytes (CTL) response after treatment of Ara-C and mirtazapine in two DM/PML patients. Methods: A 52 year-old woman (patient 1) and a 48 year-old man (patient 2), both HIV-negative, had been diagnosed with DM and were on prednisone for one and on mycophenolate mofetil, cyclosporine A, IV immunoglobulins and prednisone for the other. Patient 1 presented with subacute mental slowing, aphasia and right hemibody motor weakness, whereas patient 2 developed rapidly-progressing cortical blindness. The brain MRI showed T2-weighted hyperintense lesions of the white matter (WM) in both. JCV PCR performed on a brain biopsy (patient 1) and on CSF (patient 2) were positive, establishing the diagnosis of PML. Results: Immunosuppressive drugs could be withdrawn in patient 1, but only partially tapered in patient 2 due to DM aggressiveness. Two courses of cytosine-arabinoside (Ara-C) (2 mg/kg/d for 5 days, each) were given to patient 1. After an initial worsening, her neurological condition dramatically improved after the second course of Ara-C. There was a potent JCV-specific CTL response. Patient 2 received one course of Ara-C (2 mg/kg/d for 5 days) and mirtazapine (30 mg/d), a neuroleptic binding to the 5HT2A receptors on glial cells. Interestingly, these are the very same receptors that are used by JCV to infect oligodendrocytes (Elphick et al. Science 2004). Thus, giving this drug might prevent spreading of JCV in the brain. Two weeks after the beginning of treatment, his condition started to improve. Contrasting with patient 1, the JCV-specific cellular immune response was faint. Conclusion: PML patients who are able to develop an inflammatory response have a better outcome (Du Pasquier et al. Brain 2004). The strong immune response in patient 1 following prednisone withdrawal and beginning of Ara-C likely explains her dramatic improvement. However, in patient 2, the JCV-specific CTL response remained weak and yet he improved spectacularly, suggesting that other factors than immunity played a role in his recovery. We hypothesize that Ara-C with mirtazapine might be a promising approach in HIV-negative PML patients.

Session 12 Neuro-oncology O95 Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy – Final report A. Juergens, H. Pels, U. Schlegel, I. G. H. Schmidt-Wolf, A. Glasmacher, H. Schulz, A. Engert, V. Diehl, G. Schackert, H. Reichmann, F. Kroschinsky, M. Vogt-Schaden, G. Egerer, U. Bode, C. Schaller, M. Deckert, R. Fimmers, K. Fliessbach, T. Klockgether, A. Zellner Universitätsklinik Knappschaftskrankenhaus Bochum (Bochum, D); University of Bonn (Bonn, D); University of Cologne (Cologne, D); University of Dresden (Dresden, D); University of Heidelberg (Heidelberg, D); Maximilian Hospital (Kötzting, D) Objectives: To evaluate response rate, response duration, overall survival, and toxicity in primary central nervous system lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From 09/1995 to 12/2002, 88 patients with PCNSL (median age 62 years) were enrolled in a pilot/phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX) (cy-

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cles 1.2,4.5) and cytarabine (ara-C) (cycles 3.6) based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide) was combined with intraventricular MTX, prednisolone and araC. Primary endpoint was time to treatment failure (TTF), secondary endpoints were response, overall survival, response duration, 5-year-survival fraction and (neuro)toxicity. Results: Eighty-four of 88 patients were evaluable for response. Of these, 46 (54 %) achieved complete response (CR), 12 (14 %) partial response (PR), and 14 (17 %) progressed under therapy. Seven (8 %) out of 84 patients died due to treatment-related complications. In five (6 %) of 84 patients therapy had do be discontinued due to severe treatment related complications. Follow-up is one to 120 months (median 37 months). Kaplan Meier estimates for median time to treatment failure (TTF), median overall survival and median response duration are 20 months, 55 months and 38 months respectively. For patients aged 60 years or older, the respective numbers were 9 months, 36 months and 30 months; in patients younger than 60 years Kaplan Meier estimate for TTF is 49 months, estimates for median overall survival and median response duration have not been reached yet. The 5-year survival fraction is 70 % in patients < 60 years and 25 % in older patients. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 18 (20 %) patients. No chemotherapy related permanent cognitive dysfunction was found in any patient at follow up.At treatment failure 34 patients have been irradiated. Some of these developed severe late neurotoxicity. Conclusions: Primary chemotherapy based on high-dose MTX and araC is highly efficient in PCNSL. A substantial fraction of patients < 60 years can obviously be cured with this regimen. O96 Temozolomide in gliomatosis cerebri R. Rudà, E. Laguzzi, F. Giunta, A. Pace, C. Carapella, M. Salvati, M. Scerrati, A. Silvani, R. Merli, M. Omesti, L. Barletta, R. Soffietti for the Italian Association of Neuro-Oncology (AINO) Objectives: To assess the efficacy and toxicity of Temozolomide in patients with gliomatosis cerebri, a diffusely growing neuroepithelial tumor whose optimal treatment is unclear. Methods: Since 1999, 36 patients with histologically confirmed (biopsy or partial resection) gliomatosis cerebri were treated with Temozolomide either at progression after prior radiotherapy/chemotherapy or upfront. Tissue specimens were diagnostic for glioblastoma in 2 cases, malignant glioma in 5, anaplastic astrocytoma in 6, gemistocytic astrocytoma in 2, astrocytoma in 12, oligoastrocytoma in 1, oligodendroglioma in 4, glial proliferation typical of gliomatosis cerebri in 4. Patients characteristics were as follows: median age 49 years (range 14–70 years), 19 males and 17 females, median KPS at diagnosis 80 (range 50–90). Presenting symptoms were as follows: seizures (17 patients), intracranial hypertension [8], motor deficits [6], mental status changes [2], drowsiness and diplopia [2], dizziness and vomiting [1]. Fourteen out of 36 pre-treatment MRI scans demonstrated some contrast enhancement. Twentytwo of 36 patients were treated upfront, while 14 had received either radiation therapy or chemotherapy prior to Temozolomide. All patients were treated with Temozolomide 200 mg/m2 per day for 5 days every 4 weeks until progression or unacceptable toxicity. Response was evaluated, according to Macdonald criteria, on MRI using both T1-weighted with Gadolinium and FLAIR images. Results: The median number of cycles was 7 (range 1–20). One patient (3 %) showed a CR of the contrast enhancing area, 2 patients (5 %) a PR of the FLAIR hyperintense area, 5 (14 %) a minor response, 15 (42 %) a SD and 13 (36 %) a PD. Overall response rate (CR + PR + “minor response”) was 22 %. Median time to tumor progression (TTP) was 9 months (range 1–27), with a median survival of 13 months (range 3–123). A clinical benefit, consisting in a reduction of seizures or improvement of intracranial hypertension, was observed in 10/36 patients (27 %). PFS at 6 months was 61 %, at 12 months 25 %. Three patients showed grade III-IV haematological toxicity (WBC and PLT). Conclusion: Temozolomide seems to be moderately effective and safe in gliomatosis cerebri. O97 Recombinant immunoblot for the detection of paraneoplastic antineuronal antibodies specific for HuD, Yo, Ri, CV2 (CRMP5), Ma2 or amphiphysin F. Graus, C. Rasiah, S. Rauer University Hospital (Barcelona, E); ravo Diagnostika GmbH (Freiburg, D); University Hospital (Freiburg, D) Objective: The aim of the study was to evaluate the concordance of the recombinant ravo PNS-blot in defined cohorts of sera to established methods

like immunohistochemistry (IHCh) and Western blot with neuronal extracts (WNE) as antigens. Methods: The ravo-PNS blot® was performed according to the manufacturers instructions (serum dilution 1:2000) except that strips were left in the developing reaction only 10 minutes. Results: Forty five serum samples from healthy persons were negative suggesting satisfying specificity. The concordance of the ravo-PNS blot® to IHCh/WNE was 100 % in the following cohorts: 49 anti-Hu sera, 31 anti-Yo sera, 19 anti-amphiphysin sera and 14 anti-Ma2 (Ta) sera. Of 19 anti-Ri positive sera 1 was negative in the ravo-PNS blot®, however the positive result of IHCh/WNE was considered as wrong in retrospect. Of 26 anti-CV2 positive sera 3 were negative in the ravo-PNS blot®; in retrospect one of these positive results in IHCh and WNE was considered as wrong. Six of the AntiMa2 and 6 of the anti-Yo positive sera showed in addition to the positive band weak reactions with the Yo antigen (in case of anti-Ma2 sera) or the Ma2 antigen (in case of the anti-Yo sera). In addition, the following clinically defined study groups that were negative by IHCh were tested: Twenty samples from patients with breast cancer and no paraneoplastic neurological syndromes, all were negative in the ravo-PNS blot®. Of 48 samples from patients with small cell lung cancer, 16 revealed weak signals of HuD, CV2, Ri, or amphiphysin suggesting low antibody titres. In 25 specimens from patients with paraneoplastic cerebellar degeneration and lung cancer, 5 showed discordant results. In retrospect three differing cases were considered in favour of the ravo-PNS blot® (one was Ri and two showed weak Hu reactivity). Two sera showed weak Yo reactivity that should be considered as false positive result of the ravo-PNS blot®.). Twenty-one samples from patients with limbic encephalitis were seronegative (100 % concordance to IHCh/WNE). Conclusion: Two findings deserve further study: 1. A few CV2 positive sera are missed by the ravo-PNS blot®; 2. Some positive Yo or Ma2 sera show additional weak cross-reactivity with either Ma2 or Yo antigens respectively. However the overall high concordance rate of the ravo-PNS blot® to the established IHCh/WNE methods suggests that this blot is suitable for the detection of paraneoplastic antineuronal antibodies. Dr. Graus did not receceive any honorarium nor have any economic link with ravo Diagnostika O98 Initial tumour growth rate in low-grade gliomas – a new prognostic factor for early malignant transformation J. Rees, J. Winston, C. Benton, R. Jäger, P. Tofts, A. Waldman National Hospital for Neurology & Neurosurgery (London, UK) Objectives: Adult supratentorial low grade gliomas (LGG) are slowly growing primary brain tumours which eventually undergo malignant transformation into high-grade gliomas. Separation of tumours into those that will remain indolent for many years and those that will progress within one to two years of diagnosis would aid decision making re timing of treatment. A simple, non-invasive measurement of tumour dynamics is serial volume measurement and estimation of growth rate. We present data on the prognostic value of tumour growth rates in patients with LGG. Methods: A prospective study was conducted on patients with LGG who had presented with seizures as the sole presenting complaint. Patients received no treatment but were monitored with serial MR imaging until they reached an endpoint of ‘suspected malignant transformation’ or death. Transformation was defined clinically by the presence of new focal neurological deficits or raised intracranial pressure and/or radiologically by the appearance of new areas of contrast enhancement on thin section T1 weighted sequences after injection of high-dose gadolinium. Whole tumour volumes were measured by summation of consecutive slice volumes. MRI studies, six months apart, were used to measure initial tumour growth rate (ITGR) expressed as ml/year. This was then correlated with likelihood of subsequent clinical/radiological progression. Cox regression analysis was then carried out to determine whether ITGR was an independent risk factor for early malignant transformation. Results: 35 patients were recruited and the median time to reach the endpoint was 30 months (range 12–54 months). ITGR varied from –4.9 to 38 ml/year (mean 14.6 ml/yr). Patients with ITGR greater than the median were more likely to progress earlier (hazard ratio = 6.67; 95 % confidence interval: 2.56–17.34; p = 0.0001) than patients with ITGR less than the median. Trend analysis implied that this effect was “dose-dependent”. ITGR remained an independent prognostic factor after adjusting for other prognostic indicators (patient age, tumour size, astrocytoma histology, tumour crossing the midline). Conclusions: ITGR is an easily measured and potentially useful prognostic indicator of subsequent malignant transformaion in LGG. Patients at risk of early progression can be identified within the first six months after diagnosis and selected for early intervention.

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O99 Efficacy of liposomal cytarabine in neoplastic meningitis E. Laguzzi, R. Rudà, E. Trevisan, R. Soffietti University of Turin (Turin, I) Objective: Neoplastic meningitis (NM) is a common problem in Neuro-oncology occurring in about 5 % of patients with cancer. Although the prognosis of this complication is poor, treatment can provide effective palliation of neurological symptoms and afford improvement of survival in selected patients. Objective of this study was to evaluate, in a prospective series of patients, the efficacy and toxicity of intra CSF chemotherapy with liposomal cytarabine. Methods: patients with clinically and pathologically (neoplastic cells in CSF) defined NM from solid tumors were included into the study and treated with liposomal cytarabine 50 mg every 2 weeks for 5 cycles and then with 50 mg monthly. All patients underwent MR of the brain and spine at diagnosis.Response was evaluated basing on neurological and/or CSF improvement. Results: up to date 5 patients are evaluable: all females, with a median age of 52 years (range 33–61). The primary tumor was breast cancer in 3 patients and NSCLC in 2 patients. Clinical presentation consisted in headache [5] associated with motor deficit [1], visual deficit [2], ataxia and diplopia [1], ataxia and radicular pain [1]. In all patients MRI showed linear and/or nodular enhancement of the cranial and/or spinal leptomeninges and CSF had neoplastic cells. Elevated protein count was present in 3/5 patients. Two patients had a significant neurological improvement in terms of headache reduction, lasting one month and two weeks respectively with a concomitant reduction of tumor cell count in the lumbar CSF greater than 50 %.We didn’t observe any significant acute or subacute side effect attributable to the treatment. Median survival of the patients was 6 weeks (range 4–22 wks). Conclusion: intralumbar chemotherapy with liposomal cytarabine can relieve neurological symptoms of NM and is well tolerated. Early diagnosis and vigorous treatment in some patients with NM yields significant palliation of symptoms and some improvement of survival.

Session 13 Multiple sclerosis 3 O100 Spinal cord atrophy separates early relapsing-remitting and primary progressive multiple sclerosis: a multimodal MRI study M. Bieniek, D. R. Altmann, G. R. Davies, W. Rashid, J. Sastre-Garriga, A. J. Thompson, D. H. Miller Institute of Neurology, University College London (London, UK) Objectives: The onset of multiple sclerosis (MS) is of a relapsing remitting (RR) nature in 85 % and a primary progressive (PP) form in 15 % of subjects. An improved understanding of the pathology that underlies these courses at an early stage could help to explain why the clinical manifestations differ and provide mechanistic targets for early therapeutic intervention. In this study quantitative MRI measures were used to infer five “domains” of MS pathology: brain grey matter (GM) and white matter (WM) atrophy, brain GM and WM magnetisation transfer ratio (MTR) and upper cervical spinal cord atrophy. Methods: 37 subjects with early RR MS, 43 with early PP MS and 58 healthy controls were studied. For brain atrophy GM and WM fractions were calculated on three dimensional fast spoiled gradient (3D FSPGR) images. GM and WM mean MTR was calculated from normal appearing GM and WM maps obtained using two-dimensional dual echo interleaved spin echo MTI sequence. SPM99 was used for tissue segmentation into GM and WM for atrophy and MTR analysis. Mean upper cervical cord area was calculated on axial 3D FSPGR images. Multiple regression and logistic modelling were used for statistical analysis, with age and gender included as covariates. Results: Compared with controls, both patient groups exhibited significant atrophy of brain grey matter and white matter and intrinsic abnormality of normal appearing grey matter and white matter MTR; upper cervical cord atrophy was present only in the early PP group. In a direct comparison of RR versus PP MS, the only significant differences was that cord size was smaller in PP MS (mean cord area: PP = 67.8 mm2, RR = 72.7 mm2, controls 73.4 mm2, p = 0.007). Multivariate analysis of all 5 “domains” plus age and gender revealed that in addition to age and gender, cord area alone was significantly different between the two subgroups.

Conclusion: These findings indicate that there is a diffuse abnormality of brain grey matter and white matter in early MS, whether relapsing or progressive in onset, and that cord atrophy is prominent in early progressive onset cases. The latter observation is concordant with a progressive myelopathy that is the most common clinical presentation of PPMS. This study was supported by a programme grant from the MS Society of Great Britain and Northern Ireland. O101 Gray matter damage is associated with long-term worsening of disability in patients with multiple sclerosis F. Agosta, M. Rovaris, E. Pagani, V. Martinelli, M. P. Sormani, G. Comi, M. Filippi Ospedale San Raffaele (Milan, I) Objectives: In multiple sclerosis (MS) the relationship between conventional magnetic resonance imaging (cMRI) measures of disease activity/burden and the clinical evolution of the disease is relatively weak. The assessment of brain volume and of its changes over time as well as the use of magnetization transfer (MT) MRI can provide adjunctive markers reflecting the more disabling aspects of MS pathology. Both these strategies are sensitive to “occult” MS-related brain damage and able to provide us with paraclinical predictors of the clinical evolution of MS on the medium term. In this study we assessed the value of cMRI and MT MRI-derived metrics in predicting the long-term clinical evolution of patients with different MS phenotypes. Methods: We studied 73 patients, with relapsing-remitting (RR) MS (n = 34), secondary progressive (SP) MS (n = 19) and clinically isolated syndromes (CIS) suggestive of MS (n = 20). Brain dual-echo and MT MRI scans were obtained at baseline and after 12 months. T2-hyperintense lesion volume (T2LV), brain parenchymal fraction (BPF), gray matter fraction (GMF), white matter fraction (WMF) and average lesion MT ratio (MTR) were measured. MTR histograms from GM and NAWM were also obtained. Clinical MS evolution and neurological disability were re-assessed in all patients after a median follow-up of 8 years. A multivariate analysis, adjusted for follow-up duration, was performed to establish which clinical and MRI-derived variables were significant predictors of neurological deterioration at the end of the follow-up. Results: At the final follow-up evaluation, 44/73 patients (60 %) showed a significant neurological worsening. EDSS, T2 LV, GMF, GM average MTR and histogram peak height at baseline, as well as the one-year percentage change of average lesion MTR, were all associated with the long-term worsening of patients’ disability at univariate logistic analysis. The final multivariable model retained baseline GM histogram peak height (p = 0.029) and average lesion MTR percentage change after one year (p = 0.016) as independent predictors of disease evolution. Conclusion: A comprehensive estimation of the short-term MT MRI-detectable changes of T2-visible lesions and GM might provide useful prognostic information for the prediction of long-term MS evolution. These results indicate that GM damage plays a pivotal role in driving the accumulation of irreversible disability in MS. O102 Serial MR spectroscopy of the white matter in the first 3 years after the onset of a clinically isolated syndrome suggestive of multiple sclerosis K. T. M. Fernando, D. T. Chard, M. A. McLean, D. R. Altmann, J. K. Swanton, R. M. Gordon, K. A. Miszkiel, G. T. Plant, A. J. Thompson, D. H. Miller Institute of Neurology (London, UK) Previous work using single voxel proton magnetic resonance spectroscopy (1H-MRS) has shown that normal appearing white matter (NAWM) in patients presenting with clinically isolated syndromes (CIS) has an elevated myoinositol (Ins) but no significant decrease in total N-acetyl aspartyl containing compounds (tNAA) compared with healthy controls. The aim of this study was to explore longitudinal changes over time of these metabolites in NAWM during the first 3 years after the CIS onset. Methods: Single voxel 1H-MRS (PRESS with TR 3000ms, TE 30ms) was performed on the NAWM of 59 patients (51 optic neuritis, 4 brainstem, 4 spinal cord syndromes, 36 female, 23 male, mean age 33 years) at baseline (after 3–6 months), 1 year and 3 years after a CIS.Absolute concentrations of tNAA, Ins, total creatine and phosphocreatine (Cr), choline containing compounds (Cho), and glutamate plus glutamine (Glx) were estimated using the LCModel. Results: The concentration of Ins increased further over the 3 year period (mean 3.67mM at baseline vs 3.90mM at 3 years, p = 0.027) and correlated with EDSS at 3 years (r 0.34; p = 0.009). There was a trend for tNAA to decline over the 3 year period (mean 8.34mM at baseline vs 8.18mM at 3 years, p = 0.121), which was significant in those who developed CDMS (mean

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8.55mM at baseline vs 8.12 mM at 3 years, difference in mean change –0.48mM; p = 0.021). Conclusions: The results suggest that glial proliferation in NAWM (as demonstrated by the increase in Ins) is a persistent feature during the early years following a CIS and may relate to clinical dysfunction. The decrease in tNAA suggests that axonal damage in NAWM also starts to occur in those who subsequently develop CDMS at 3 years. O103 Heavy neurofilament phosphoforms in relapsing-remitting multiple sclerosis: correlation with MRI measures and clinical disability P. Annunziata, C. Cioni, L. De Santi, M. L.Stromillo, C. Di Perri, A. Federico, N. De Stefano University of Siena (Siena, I) Objectives: In the last few years, cerebrospinal fluid (CSF) neurofilament levels have been investigated as surrogate laboratory markers of axonal damage in multiple sclerosis (MS). Changes in neurofilament phosphorylation may be a mechanism underlying the disassembly leading to axonal damage. However, there are little data on phosphorylated isoforms and there is a lack of findings on non-phosphorylated isoform levels and possible correlation with MRI parameters and clinical disability in MS. Material and methods: Using monoclonal antibodies directed to phosphorylated and non-phosphorylated epitopes, we measured by ELISA, heavy neurofilament levels in CSF of 20 patients with relapsing-remitting MS and related circulating and intrathecal humoral immune response directed to heavy and light neurofilaments. In each patient, conventional MRI was performed within 1 month from lumbar puncture. Total and T2- and T1weighted lesion volumes and normalized brain volumes (NBV, obtained by using the SIENA method) were assessed. Expanded disability status scale (EDSS) scores were measured at the time of MRI. Neurofilament and antibody levels were correlated with clinical and neuroimaging measures by calculating Spearman rank correlation coefficient. Results: There was a moderate significant correlation of non-phosphorylated but not of phosphorylated neurofilament levels with disability scores (r = 0.45; p = 0.04). We did not find significant correlations between nonphosphorylated neurofilament levels and disability scores, time from the last relapse and MRI parameters. However, a strong negative correlation (r = – 0.82; p = 0.05) between disability scores and brain volume values was found in 6 patients with a disease duration longer than 4 years. In this patient subgroup, there also was a negative correlation between non-phosphorylated neurofilament levels and NBV (r = – 0.60), although this did not reach statistical significance due to the small size of cohort. No significant correlations between intrathecal synthesis of anti-heavy and light neurofilaments antibodies and MRI parameters were found. Conclusions: These findings demonstrated that CSF non-phosphorylated heavy neurofilament isoforms are closely related to the measures of brain atrophy and are a possible surrogate laboratory marker of axonal damage especially in relapsing-remitting MS patients with a long disease duration. This work was supported by a grant of the University of Siena (PAR 2004) to P. A. O104 T1 intensity differences to normal appearing white matter in hypointense lesions on MRI are related to clinical status in multiple sclerosis D. Fritz, M. G. Dwyer, C. Quadros, N. Abdelrahman, V. Yella, S. Hussein, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Previous postmortem studies showed that degree of black hole (BH) hypointensity correlates strongly with axonal density. However, absolute intensity information has been of limited clinical use due to scanner/sequence-imposed and natural regional intensity variation. Contrasthypointensity ratio may address these issues, providing a better surrogate marker of disability progression than BH T1-lesion volume (LV) alone. Objective: To relate intensity differences of normal appearing white matter (NAWM) to hypointense BH lesions on T1-weighted images (WI) and to the clinical status of patients with multiple sclerosis (MS) using a fully automated analysis method. Methods: We studied 22 relapsing-remitting (RR) and 21 secondary-progressive (SP) MS patients (age 47.3 ± 10.5yrs., EDSS 3.9 ± 2.1, disease duration 14.05 ± 7.87yrs). T1-WI were acquired for each patient and BH masks created. To correct for scanner/sequence intensity variation, an atlas of normal controls was warped to each T1-WI, and a histogram-matching algorithm applied. To correct for normal regional variation, BH intensity difference masks were created by voxel-wise subtraction of BH and

corresponding atlas intensities. Voxels were grouped according to intensity differences, based on a-priori thresholds at single standard deviations in the study group BH histogram. LVs were calculated for each group and statistical comparisons made with EDSS using regression analysis. Results: Total BH-LV explained 16 % of variance in EDSS (p < 0.005). Mean total BH-LV was 3.48 ml. Restricting analysis to single groups showed that the group composed of voxels from the mean to + 1 SD intensity difference explained 33 % of the variance in EDSS (p < 0.001). Mean LV in this group was 0.715 ml. LV in this group showed strong correlation with EDSS (r = 0.573, p < 0.01). The combined group representing tissue from the mean to the greatest intensity difference explained a similar variance in EDSS (R2 = 0.305 p < 0.001). Mean LV of this group was 1.26 ml. Conclusions: The measure of BH-LV adjusted to represent moderately to severely damaged tissue, shows advantages in predicting disability over standard T1-BH LV obtained through ROI analysis. O105 Biplanar whole-cord magnetic resonance imaging using parallel imaging in multiple sclerosis K. Weier, Y. Naegelin, A. Thoeni, J. G. Hirsch, L. Kappos, D. Leppert, E.-W. Radue, A. Gass University Hospital Basel (Basel, CH) Introduction: Although functionally important, the spinal cord is not part of routine MRI examinations in MS patients. Routine assessment in the sagittal plane allows fairly quick reference, but for the detailed visualization of pathology a transverse view is commonly used. Multi-array coils and parallel imaging provide new opportunities to examine the entire cord in the transverse plane. We were interested in the sensitivity and potential gain of fast whole cord MRI schemes when combining high resolution, high sensitivity sagittal and transverse MRI. Methods: A cohort of 256 MS patients (178 women, 78 men, 24–74 years old, EDSS 0–7.0) with different MS subtypes (CIS, RRMS, SPMS and PPMS) were investigated. Examinations were performed on a new MRI system, the SIEMENS 1.5T Avanto unit which offers multi-array-coils and parallel imaging techniques, both essential for the fast and complete assessment of the whole neuro-axis. Results: Abnormal signal change on spinal cord MRI of MS patients were found in 75 % of patients. In more than half of them only focal lesions were identified. Focal lesions were situated primarily in the cervical spinal cord (59 %) and about 2/3 show more than 2 lesions. Diffuse cord abnormalities were found in 21 % and in almost one third diffuse abnormalities in all levels. Transverse MRI varied in quality (due to artifact). The analysis of transverse slices confirmed equivocal abnormality and added 14 % of lesions in total. Equivocal abnormality was confirmed or rejected with the help of transverse slices, in particular lesions in the periphery of the cord were confirmed. Conclusion: This study demonstrates that high resolution screening MRI of the entire cord in 2 planes can be performed in MS patients together with brain MRI. Our data is in line with previous spinal cord studies in regard to the overall frequency and location of spinal cord abnormality in MS. The demonstration of the entire neuro-axis substantiates the clinical assessment of MS patients. It demonstrates that there are various clinical situations, that particularly capitalize on the detection of spinal cord pathology (CIS, primary progressive) and that even a negative spinal cord MRI can be very revealing (e. g. in the presence of multiple brain lesions).Additional transverse MRI adds further information as some focal lesions can be detected, that are difficult to visualize on sagittal slices and that diffuse signal change can be ascertained or detected. Support by Swiss MS Society

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Session 14 Multiple sclerosis 4 O106 Myelin basic protein-T cell lines from patients with multiple sclerosis express high affinity full-length BDNF receptor: implications for T-cell survival L. De Santi, L. Cantalupo, C. Cioni, P. Annunziata University of Siena (Siena, I) Objectives: Brain-derived neurotrophic factor (BDNF), a neurotrophin determining neuronal survival during development and repair, is primarily produced by neurons. However, immunocompetent cells, including T cells, produce BDNF in inflammatory lesions of multiple sclerosis (MS) brains, suggesting a role for BDNF in neuroprotective inflammation in MS. To date, there are conflicting data about the ability of immunocompetent cells to express gp145trkB, the high affinity full-length BDNF receptor, in MS. Aim of our study was to evaluate the expression of gp145trkB by CD3 + T lymphocytes, monocytes, lymphoblastoid B cell lines (B-LCLs), myelin basic protein (MBP)-T cell lines from patients with MS and its functional role in MBP-autoreactive T cell line survival. Material and methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 48 MS patients, 34 with relapsing-remitting (RRMS) and 14 with secondary progressive MS (SPMS) and from 15 sex- and agematched healthy subjects (HS). T lymphocytes and monocytes were stimulated with phytohemagglutinin (PHA) and interleukin-2 (IL-2), and lipopolysaccharide, respectively. B-LCLs were obtained by Epstein-Barr virus (EBV)-transformed PBMCs. MBP-T cell lines were derived from PBMCs and expanded in vitro upon several cycles of antigen stimulation. gp145trkB protein expression was assessed by western blotting and chemiluminescence assay and related mRNA tested by RT-PCR. To assess the role of BDNF signalling in T cell survival, we analyzed apoptosis in anti-CD3 antibody-stimulated MBP-T cells, in the presence of a neutralizing anti-BDNF antibody and K252a, a gp145trkB inhibitor, by annexin V labeling and fluorescence microscopy. Results: gp145trkB was expressed by 5 of 34 (15 %) PHA- and IL-2-stimulated CD3 + T cell cultures from RRMS patients. No gp145trkB protein expression was found in monocytes and in T cells from SPMS patients and HS; by contrast, all EBV + B-LCLs and 6 of 9 (67 %) MBP-T cell lines expressed gp145trkB. In anti-CD3-stimulated MBP-T cell lines expressing high affinity full-length BDNF receptor, apoptosis increased by 42 % (p = 0.03) in the presence of the neutralizing anti-BDNF antibody and by 66 % (p = 0.002) with K252a. Conclusions: gp145trkB protein expression is a cell-specific and activation-induced process in inflammatory cells in MS. gp145trkB signalling is involved in modulation of peripheral MBP-sensitized T cell line apoptosis, suggesting a regulatory role of T cell line survival. This work was supported by a grant of the University of Siena to P. A. O107 Detection of cortical lesions is dependent on choice of slice thickness in patients with multiple sclerosis O. Dolezal, S. Balachandran, Z. Seidl, M. Vaneckova, C. I. Tekwe, N. Bergsland, M. G. Dwyer, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Understanding of the importance of cortical lesions in MS pathogenesis has changed. Histopathological studies using new immunohistochemical methods show cortical lesions can be detected more frequently. Newer MRI sequences also detect cortical lesions more accurately. Objective: To evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). Design/Methods: 41 patients with relapsing remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) received FLAIR and 3D-T1-WI of 1.5, 3 and 5 mm slice thickness on 1.5T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. FLAIR and 3D-T1-WI were co-registered and the matrix of the peripheral gray matter (PGM) segmentation mask (SIENAX-generated) classified the location of the cortical-subcortical lesions. Cortical lesions fell into three classes. Class 1 were defined as lesions located in the PGM, Class 2 as juxtacortical lesions in contact with PGM mask, and Class 3 as cortical-juxtacortical situated in both areas. Results: Of total T2-lesion volume (LV) measured on 1.5 mm th scans, (mean 16108 cu mm), cortical lesions represented 2.4 % (276 cu mm), juxta-

cortical lesions 6.1 % (760 cu mm) and cortical-juxtacortical 3.7 %. (491 cu mm). Compared to 1.5 mm th scans, cortical LV was reduced –28.3 %, p < 0.01 on 3 mm th and –40.78 %, p < 0.01on 5 mm th scans. Results for juxtacortical lesions were: (3 mm th scans:–17.9 %, p < 0.01 and –30.3 %, p < 0.01 for the 5 mm th scans) and (3 mm th scans: –16.22 %, p < 0.01 and –26.7 %, p < 0.01 for the 5 mm th scans) for the cortical-juxtacortical lesions. Conclusions: Lower slice thickness significantly increases detecting accuracy of cortical lesions on FLAIR images. Our results support use of 1.5 mm th for detecting cortical-juxtracortical lesions. O108 Efficacy of a novel oral single-agent fumarate, BG00012, in patients with relapsing-remitting multiple sclerosis: results of a phase 2 study L. Kappos, D. H. Miller, D. G. MacManus, R. Gold, E. Havrdova, V. Limmroth, C. Polman, K. Schmierer, T. Yousry, M. Yang, M. Eraksoy, E. Meluzinova, I. Rektor, G. N. O’Neill Universitätsspital Basel (Basel, CH); University College London (London, UK); University Gottingen and Gemeinnützige Hertie-Stiftung (Gottingen, D); General Teaching Hospital (Prague, CZ); City Hospital of Cologne (Cologne, D); VU Medical Centre (Amsterdam, NL); Biogen Idec (Cambridge, USA); University of Istanbul (Istanbul, TR); Faculty Hospital V Motole (Prague, CZ); Masaryk University (Brno, CZ) Objective: To determine the efficacy of three dose levels of BG00012, a novel oral fumarate preparation, on brain lesion activity as measured by magnetic resonance imaging (MRI) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: This was a randomised, double-blind, placebo-controlled clinical trial of BG00012 in patients with RRMS. Men and women 18 to 55 years of age were eligible for the study if they had a diagnosis of RRMS and an Expanded Disability Status Scale (EDSS) score between 0.0 and 5.0. In addition, patients must have had either ≥ 1 relapse within 12 months prior to randomisation or gadolinium-enhancing (Gd +) lesions on cranial MRI at screening. Patients were assigned to four treatment groups and received BG00012 capsules 120 mg by mouth (PO) once daily (120 mg/day), 120 mg three times daily (360 mg/day), 240 mg three times daily (720 mg/day), or placebo for 24 weeks. The treatment period was followed by a 24-week doseblinded safety-extension period during which all patients received BG00012. The primary end point was the total number of Gd + lesions over four MRI scans at weeks 12, 16, 20, and 24 (calculated as the sum of the four scans). Secondary end points included the cumulative number of new Gd + lesions from week 4 to week 24 and the number of new/enlarging T2-hyperintense lesions at week 24.Additional end points included the number of new T1-hypointense lesions at week 24, relapse rate, and disability progression as measured by EDSS. Results: A total of 257 patients were enrolled in the study; 64 patients each were randomly assigned to receive one of the three BG00012 doses and 65 patients to placebo. Approximately 90 % of patients completed the 24week treatment period. BG00012 (720 mg/day) significantly reduced the mean number of new Gd + lesions (the primary end point) compared with placebo. In addition, BG00012 reduced the cumulative number of new Gd + lesions, the number of new/enlarging T2-hyperintense lesions, and the number of new T1-hypointense lesions compared with placebo. Conclusion: BG00012 significantly reduces brain lesion activity, in a dose-dependent manner, as measured by MRI in patients with RRMS over 24 weeks of treatment. This study was sponsored by Biogen Idec and Fumapharm AG. O109 Phase I/II trial of a MBP encoding DNA plasmid (BHT-3009) alone or combined with atorvastatin for treatment of multiple sclerosis H. Garren, J. Antel, A. Bar-Or, C. Bodner, D. Campagnolo, J. Gianettoni, F. Jalili, N. Kachuck, Y. Lapierre, M. Niino, J. Oger, M. Price, S. Rhodes, F. Shi, F. Valone, T. Vollmer, L. Weiner, L. Steinman Bayhill Therapeutics (Palo Alto, USA); Montreal Neurological Inst. (Montreal, CAN); Barrow Neurological Institute (Phoenix, USA); University of Southern California (Los Angeles, USA); University of British Columbia (Vancouver, CAN); Stanford University (Stanford, USA) Objective: To assess safety and immune modulation by BHT-3009 in MS patients Background: We have previously shown that DNA plasmids induce antigen-specific immunomodulation in animal models of autoimmune disease. We have begun clinical testing of BHT-3009, a DNA plasmid that expresses full-length human MBP. Design/methods: We are conducting a 30 patient, randomized, doubleblind, placebo-controlled trial in relapsing MS patients. The primary out-

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come measures are safety and changes in immune response. BHT-3009 is injected intramuscularly in weeks 1,3,5 and 9 and atorvastatin (80 mg) is taken daily for 13 weeks. Three dose levels of BHT-3009 are being tested (0.5 mg, 1.5 mg and 3.0 mg). Within this trial we are measuring several immune parameters including CFSE based antigen-specific T cell proliferation and intracellular cytokine production by peripheral blood mononuclear cells. Results: All thirty patients have been randomized. To date, the twenty patients in cohorts 1 (0.5 mg) and 2 (1.5 mg) have all completed treatment. There were 22 treatment-related adverse events (AEs), all of which were mild/moderate: 12 on placebo and 10 on BHT-3009 arms. Mean blood levels of BHT-3009 plasmid (per 10 uL) one day after injection were 2973 copies for cohort 1 and 5144 copies for cohort 2. Data from the CFSE assay on four patients from two centers who ran this assay in the first two cohorts demonstrate antigen-specific reduction in MBP reactive T cells by week 9 of treatment in three of them. In the first patient, the proliferation of MBP83–99 reactive IFNg positive cells decreased from 25.9 % to 1.2 %. In a second patient, the proliferation of MBP83–99 reactive IFNg positive cells decreased from 13.3 % to 5.4 %. In the third patient, the proliferation of whole MBP reactive IFNg positive cells decreased from 2.27 % to 0.79 %. In all three of these patients the proliferation to tetanus toxoid did not decrease, pointing to antigen specificity following BHT-3009 treatment. In a fourth patient, there was no change in either the MBP83–99, whole MBP or tetanus proliferative responses. Analysis of the ten patients in cohort three will be complete in mid-2006. Conclusion: To our knowledge this is the first clinical trial of a DNA plasmid for antigen-specific immunotherapy of any autoimmune disease. The data indicate that BHT-3009 is safe and may suppress immune responses in an antigen-specific manner. Based on this, initiation of a 250 patient phase 2 trial in RR-MS has begun. This research is sponsored by Bayhill Therapeutics, Inc. O110 Betaferon® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): clinical outcomes L. Kappos, C. H. Polman, M. S. Freedman, G. Edan, H. P. Hartung, D. Miller, X. Montalban, F. Barkhof, L. Bauer, S. Dahms, C. Pohl, R. Sandbrink on behalf of the BENEFIT Study Group Objectives: To assess the safety, tolerability, and efficacy of interferon beta1b (IFNB-1b; Betaferon®) 250 mcg subcutaneously (sc) every other day (eod) in patients with a first clinical event and magnetic resonance imaging (MRI) findings suggestive of multiple sclerosis (MS). Methods: In this multicentre, double-blind, randomised trial, patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomised in a 5:3 ratio to IFNB-1b (n = 292) or placebo (n = 176) and were treated until clinically definite MS (CDMS) was diagnosed or they had been followed for 24 months. Primary efficacy endpoints were time to CDMS according to the Poser criteria and time to a diagnosis of MS according to the McDonald criteria. Neurological function was evaluated using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Results: IFNB-1b delayed the progression from the first clinical event to CDMS (log-rank test p < 0.0001) and McDonald MS (p < 0.00001).According to proportional hazards regression analysis adjusted for standard baseline covariates, the risk for CDMS in the IFNB-1b group was reduced by 50 % (hazard ratio with 95 % confidence interval: 0.50; 0.36–0.70) and for McDonald MS by 46 % (0.54; 0.43–0.67). From the baseline evaluation until the end of the study, EDSS did not change substantially in either treatment group. MSFC scores indicated an improvement in both arms, but was more pronounced in IFNB-1b-treated patients (p = 0.039). The difference in favour of IFNB-1b was mainly found for the Paced Auditory Serial Addition Test (p = 0.0007), while neither the Timed 25-Foot Walk Test nor the 9-Hole Peg Test revealed significant group differences. Conclusions: The BENEFIT study demonstrates that 250 mcg IFNB-1b sc, eod significantly delays progression to definite MS in patients with a first clinical demyelinating event and MRI findings suggestive of MS.While EDSS did not show changes within and between groups, MSFC assessments indicated a better outcome in terms of neurological impairment for IFNB-1btreated patients. The superior sensitivity of the MSFC in this patient population was primarily based on findings from its cognitive subtest. Study supported by Schering AG, Berlin, Germany

O111 Impact of spatial distribution of T2 and T1 lesion volume on processing speed in patients with multiple sclerosis M. G. Dwyer, R. H. B. Benedict, N. Bergsland, B. Srinivasaraghavan, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Lesion volume (LV) measurement in multiple sclerosis (MS) has consistently demonstrated limited utility in predicting processing speed. This may be due to the fact that volume measures alone do not adequately reflect spatial distribution, yielding similar results for tightly clustered and widely dispersed lesions. Metrics incorporating spatial distribution (geometric size) may therefore be of use in quantitative characterization of lesion burden, and may show a stronger relationship with processing speed. Objective: To examine the relationship between processing speed and lesion measures incorporating both volume and 3D spatial distribution. Methods: We studied 23 patients with MS (age 48.3 8.3 years, disease duration 16.8 11.1 years). Disease course was relapsing-remitting (RR) = 15, secondary progressive (SP) = 8. A semi-automated method was used to create voxel-wise lesion masks, and to determine T2/T1 LVs. From these masks, four distribution-based measures were calculated: spatial standard deviation (SSD), moment of inertia (MOI), Frobenius norm (FN), and centroid size (CS). Each of these measures, except SSD, incorporates both lesion volume and spatial distribution. The Paced Auditory Serial Addition Test (PASAT) was used to evaluate processing speed and concentration. Results: All T2 distribution measures, with the exception of CS, showed higher correlations with PASAT scores than T2-LV alone (r = –0.509 for T2MOI compared to r = –0.410 for T2-LV). In contrast, for the T1 measures LV alone showed the highest correlation (r = –0.352). Stepwise regression analysis including all volume and distribution measures retained only T2-MOI (R2 = 0.259). Conclusions: Spatial distribution of lesions may provide valuable complementary information to volume alone to create a more complete measure of effective lesion burden in MS.

Session 15 Neuro-ophthalmology O112 Aetiology of bilateral vestibulopathy: 255 patients V. C. Zingler, C. D. Cnyrim, C. Frenzel, T. Brandt, M. Strupp University of Munich (Munich, D) Objectives: Bilateral vestibulopathy (BV) is rare among vestibular disorders. Despite its typical symptoms (unsteadiness of gait and oscillopsia), BV is often underdiagnosed in the daily clinical routine, in particular the slowly progressive form. Moreover, its definite cause often remains undetermined. Until now the largest study on the aetiology of BV included 53 patients (Rinne et al. 1998). Methods: Therefore, we performed a retrospective review of 255 patients who had been diagnosed to have BV between 1988–2005 in our department. The aims of this study were to evaluate [1] the relationship between definite, probable, and unknown aetiology, [2] the course of manifestation of the disease, [3] epidemiological parameters, [4] associated clinical signs and diseases. Results: A total of 255 patients with a mean age of 62 ± 16 years (range 12–98 years) were included. The majority of all patients were male (n = 157, 62 %), and there was a significant increase in BV with age. BV showed a slowly progressive course in 64 % and a sequential course with preceding vertigo attacks in the rest. The definite cause of BV was defined in 24 % and the probable cause in 25 % of the patients (antibiotics 13 %, Meniere’s disease 7 %, meningitis/encephalitis 5 %, two different causes (e. g. vestibular neuritis and antibiotics) 5 %, associated with spinocerebellar ataxia 6/episodic ataxia type 2/multiple system atrophy 4 %, systemic autoimmune disease 3 %,deficit of vitamin B12 and folate 2 %,Cogan’s syndrome 1 %,CreutzfeldtJakob disease 1 %, positive family history for inner ear disease 1 %, miscellaneous 8 %: e. g., neurofibromatosis type 2, head trauma, side effect of aspirin, diuretics). The underlying aetiology remained unclear in 51 %. BV was associated with cerebellar symptoms in 25 %. MRI of 214 patients showed cerebellar atrophy in 10 patients and bilateral acoustic neuroma in 2 patients.

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Antibodies against inner ear structures were determined in 77; they were pathological in 44 of these patients. In nine of the patients with pathological antibodies, however,a different aetiology of BV was established.Hearing loss accompanied BV in 25 %. Only 4 % of the patients also suffered from migraine. Conclusion: The incidence of BV increases with advancing age and affects more men than women. BV manifests more often with a slowly progressive course than with a sequential disease course. Despite intensive medical work-up the underlying cause of BV remains undetected in 51 % of all patients. O113 Co-morbid conditions in benign paroxysmal positional vertigo: a survey of the general population M. von Brevern, A. Radtke, F. Lezius, M. Feldmann, T. Ziese, T. Lempert, H. Neuhauser, M. von Brevern Charité (Berlin, D); Robert-Koch Institut (Berlin, D); Schlosspark-Klinik (Berlin, D) Background: Benign paroxysmal positional vertigo (BPPV) is caused by detached otoconia which have entered a semicircular canal. Thus far, the conditions facilitating detachment of otoconia from the utricular matrix – being the prerequisite for BPPV – are only partially understood. Objective: To analyse the associations of BPPV with comorbid conditions in an unselected group affected by BPPV. Methods: A cross-sectional neurotologic survey was conducted emanating from the German National Telephone Health Interview Survey 2003 (GNT-HIS 2003). The GNT-HIS 2003 included a representative sample of 4869 men and women aged 18 years and older residing in Germany and identified 1403 subjects with a history of moderate or severe dizziness or vertigo, 1157 of whom were willing to participate in a detailed dizziness interview conducted via telephone by medical students thoroughly trained in a dizziness clinic. Each interview was discussed with a specialised neurotologist. BPPV was diagnosed according to criteria developed for this survey through piloting and validation in a specialized dizziness clinic. Comorbid conditions and sociodemographic factors were compared between the 53 participants identified with BPPV in the past 12 months and a general population dizziness-free control group consisting of all participants of the GNT-HIS 2004 without vertigo/dizziness in the last 12 months (n = 6136). The associations tested were prespecified in the protocol: age, sex, educational level, depression, migraine, hypertension, increased blood lipids, diabetes, coronary heart disease, stroke, body mass index and smoking. Results: In a multivariate stepwise backward logistic regression model including all tested variables, age, hypertension, increased blood lipids, stroke and migraine had an independent effect on BPPV in the past 12 months. Discussion: Our study found several vascular risk factors to be associated with BPPV and confirmed previously described risk factors including advanced age and migraine. Furthermore, female sex might not be an independent risk factor for BPPV. O114 Eye movement abnormalities in spinocerebellar ataxia type 17 (SCA 17) J. Hübner, A. Sprenger, J. Hagenah, C. Klein, H. Rambold, C. Zühlke, D. Kömpf, A. Rolfs, H. Kimmig, C. Helmchen University of Lubeck (Lubeck, D); University of Rostock (Rostock, D) Background: Spinocerebellar ataxia type 17 (SCA17) is associated with an expansion of CAG/CAA trinucleotide repeats in the gene encoding TATAbinding protein (TBP). The aim of this study was to characterize eye movements in SCA17 and to localize oculomotor deficits. Methods: Eye movements of 13 SCA17 mutation carriers and 13 agematched control subjects were recorded using the video-based EYELINK II system and compared using ANOVA (p < 0.05).We examined horizontal saccades (5–40°), smooth pursuit eye movements with sinusoidal and stepramp-stimuli and gaze-holding function. PCR amplification of the CAG repeat region in the TBP gene was performed as reported previously. Results: SCA17 mutation carriers showed a broad spectrum of symptoms and signs. They all had expanded CAG/CAA repeat alleles in the TBP gene. The velocity gain of horizontal sinusoidal smooth pursuit was strongly reduced (0.4 Hz: 0.56 vs. 0.87). In the step ramp paradigm, initial pursuit acceleration (52.3 °/sec2 vs. 80.4 °/sec2) and steady-state velocity (10.8 °/sec vs. 14.2°/sec) were impaired. Smooth pursuit deficits correlated with the clinical ataxia score and the repeat length. Latency of saccades and the main sequence did not differ between mutation carriers and controls but SCA17 subjects showed considerable saccadic hypometria (20°:0.76 vs. 0.88). Although saccades were not slowed some of them contained multi-step com-

ponents. Spontaneous nystagmus, gaze-holding nystagmus, rebound nystagmus, and saccadic intrusions were not found. Discussion: This first quantitative analysis of eye movements in SCA17 mutation carriers revealed profound smooth pursuit deficits and saccadic hypometria indicative of a predominantly cerebellar (vermal) dysfunction. Multi-step saccade profiles indicate interference with the so-called “latch circuit”. This is compatible with neuropathological and MRI findings showing the most intense neuronal degeneration in the cerebellum. O115 Psychiatric comorbidity in patients with bilateral vestibulopathy C. Best, R. Tschan, A. Eckhardt-Henn, P. Schlindwein, S. Bense, P. Breuer, M. Dieterich Johannes Gutenberg-University (Mainz, D); Georg August-University (Gottingen, D) Objectives: Patients with vertigo exhibit a high coincidence of organic vestibular disorders and psychiatric disorders. This is especially true for patients with Meniere’s syndrome and migraine, but not for patients with vestibular neuritis [1]. The aim of this study was to determine if patients with bilateral vestibulopathy (BVP) suffer from somatoform or psychiatric distress and comorbidity. Methods: In an interdisciplinary study 18 patients with BVP and 12 agematched healthy volunteers were examined in the Departments of Neurology and Psychosomatic Medicine. The neurological diagnostic procedures included a neurological and neuro-otological examination, electro-oculography with both rotatory and caloric testing, and otolith measurements of the subjective visual vertical (SVV) and ocular torsion (OT). BVP was defined as vestibular hyporesponsiveness on caloric and rotatory testing according to the criteria of Baloh and Furman [2]. The psychosomatic diagnostic procedures comprised two interviews and six psychometric instruments. Results: All patients fulfilled the criteria of vestibular hyporesponsiveness. The mean slow phase velocity of maximal caloric nystagmus (MCN) was 6.1° ± 1.4°; the mean side difference on caloric testing was 39.7 %. The mean SVV tilt was 2.17°, and the mean OT 4.33°, i. e., there were no signs of acute vestibular imbalance. On psychosomatic examination 15 patients (83 %) and in contrast only 3 healthy volunteers (25 %) revealed a psychiatric comorbidity (significant difference of p < 0.005). Patients with BVP had an ODDS-Ratio of 15.0 for psychiatric comorbidities, significantly higher scores on psychometric evaluation, and therefore more psychic distress. Negative correlations between MCN and several psychometric parameters were found. Conclusion: Our data prove for the first time that patients with BVP suffer from great psychological distress and are at a significantly higher risk for developing psychiatric comorbidities. Therefore, treatment should be interdisciplinary, and psychological counselling should be involved at an early stage. As vestibular function (MCN) correlated negatively with measures of psychological strain, the bilateral loss of vestibular function must be considered a triggering factor in the pathogenesis of psychiatric disorders in patients with BVP. References 1. Best et al. 2006 2. Baloh and Furman, 1989

Session 16 Motor neuron disease O116 Aggressive familial motor neuron disease associated with GCT to GCA substitution on codon 140 of SOD1 gene S. Blumen, R. Inzelberg, A. Achiron, R. Carasso, P. Nisipeanu, H. Stewart, A. Eisen, P. Andersen Hillel Yaffe Medical Center (Hadera, IL); Sheba Medical Center (Tel Hashomer, IL); Umea University Hospital (Umea, S); Vancouver Gen. Hosp. (Vancouver, CAN) Objectives: To study the clinical, electrophysiological and neuroimmaging features as well as the inheritance in a family where two out of three sisters

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died of an unusually aggressive form of familial amyotrophic lateral sclerosis (FALS). Methods: Neurological examination, electromyography (EMG), brain MRI and DNA testing of all 5 exons of the SOD1 gene. Results: The parents of the affected sisters were unrelated Jews of Moroccan ancestry.The first sister’s disease began at the age of 48 with upper motor neuron (UMN) features dominating the clinical picture: early spasticity, very brisk reflexes, upgoing toes and severe pseudobulbar syndrome. Soon after, diffuse muscle wasting and fasciculations became evident and she died after 16 months.Although formal sensory examination and sensory action potentials (SAP’s) were normal, she complained of dysesthesia and “muscular pain”.The EMG was neuropathic and CPK normal. The second sister’s disease started at the age of 46 with features suggesting primary lateral sclerosis beginning in the hands. The UMN features included spasticity, very brisk reflexes and severe pseudobulbar syndrome leading to anarthria and severe dysphagia. In a few weeks lower motor neuron signs were evident on clinical examination and EMG. Brain MRI, on FLAIR mode, showed bilateral, very symmetrical, hyperintensities of white matter and along pyramidal tracts in the brain-stem. This picture is reminiscent of leukoencephalopathies. DNA screening, testing all 5 exons of the SOD1 gene, found a base substitution (adenine for thymine) at codon 140 in exon five. Conclusions: We describe a very severe form of FALS with UMN features predominance, associated with the GCT to GCA mutation on codon 140 (exon 5) of the SOD1 gene. Although “theoretically” silent, because it does not change the amino acid (alanine) coded for at that position, this mutation has, till now, been found only in sporadic ALS patients and both affected and unaffected individuals belonging to FALS families. It has never been found in controls. Cytotoxicity of mutated CuZn-SOD mRNA was postulated as a possible mechanism. The follow-up of this family may enhance our understanding of SOD1 mutations pathogenesis and evaluate their penetrance. O117 Predictability of disease progression in amyotrophic lateral sclerosis A. Czaplinski, A. Yen, E. P. Simpson, S. H. Appel University of Basel (Basel, CH); Methodist Neurological Institute (Houston, USA) Objective: Survival has been a major study endpoint in ALS clinical trials. However, as an outcome measure, survival has a number of limitations and ALS studies of survival are large, long and expensive. Using disease progression as an alternative clinical trial endpoint would reduce the need for large patient cohorts and reduce the length of the study. However, to reduce the heterogeneity of the population enrolled, and to improve baseline stratification, a greater understanding of the relevant predictors of disease progression is required and at present such data are lacking. In this study, we sought to identify covariates of disease progression, with a particular view toward their use in designing future clinical trials and in patient management. Methods: We performed a historical cohort study of 832 patients with the diagnosis of definite or probable ALS referred to our ALS Clinic in Houston/Texas over the last 20 years. We considered time to 20-point change in Appel score (AALSS) from baseline exam as an index of disease progression. Disease progression curves were calculated with the Kaplan-Meier method and compared with the log-rank test.The prognostic value of each factor was estimated using both univariate and multivariate Cox proportional hazard analyses. Results: The median time to a 20-AALSS-point change in our patient population was 9 months. In the univariate analyses, lower age at disease onset, male gender, limb onset of symptoms, longer time between first symptom and first examination (FS-FE time), lower initial AALSS, lower AALSS preslope (rate of disease progression between FS and FE) and higher initial FVC were each found to be favorable predictors of slower disease progression. In addition, in the multivariate model five parameters: age, site of symptom onset, FS-FE time, total AALSS at first exam and AALSS preslope have been revealed as significant and independent covariates of disease progression. Conclusions: What are the most important consequences of our findings? First, the identification of predictors of disease progression may have some impact on patient management and care planning. Second, these predictors will be essential in designing new treatment trials. The appropriate stratification of eligible patients could result in recruitment of patients at an early stage of the disease, at the time when patients might be more likely to respond to the study medication and more likely to complete the trial.

O118 Ethnic diversity in ALS – a meta-analysis S. Cronin, O. Hardiman, B. J. Traynor Beaumont Hospital (Dublin, IRL); Section on Genetic Epidemiology NIH (Bethesda, USA) Background: It is generally stated that there is a uniform global incidence of amyotrophic lateral sclerosis (ALS). However, there have been no well-conducted population-based studies of ALS occurrence outside of Europe and North America. While epidemiological studies in non-Caucasian populations have generally yielded lower figures, restricted access to medical care among these regions may account for this finding. ALS is increasingly recognized as a complex genetic disease. It is likely that ethnic background may be important in determining the relationship between environmental risk factors and genetic susceptibility. However, we contend that at present there is insufficient data to allow firm conclusions regarding the geographical and racial distribution of ALS. Aim: To examine all published data on the worldwide geographical and ethnic distribution of ALS Methods: We conducted a MEDLINE search to identify all previous studies of ALS incidence, prevalence or mortality. Each study was systematically reviewed for completeness of case ascertainment, method of diagnosis, population size and ethnicity, and for data stratified by ethnicity. Results: We identified 26 European and 28 Non-European studies. ALS incidence ranges from 0.64 (Italy) to 2.4 (Middle Finland) per 100.000/year in Europe and from 0.31 (China) to 1.98 (Estonia) per 100.000/year outside Europe. In the United States 2 prospective incidence studies and 3 mortality studies all suggest greater risk for ALS among whites when compared to Hispanic whites and African Americans. However, these studies were not designed primarily to address the question of ethnicity. Migration studies suggest that some ethnic subgroups may have resistance to ALS when compared to indigenous populations (Italy, UK). There was wide variation in the data quality, and few studies in non-europeans had multiple data sources. Conclusion: There is currently insufficient data to comment whether the incidence of ALS is uniform. Preliminary evidence suggests that the frequency of ALS is lower in populations of African extraction. There is a need for large scale population-based epidemiological studies of mixed racial background, to determine the relevance of ethnicity in disease pathogenesis. O119 Diffusion tensor magnetic resonance imaging of the spinal cord in amyotrophic lateral sclerosis P. Valsasina, B. Benedetti, F. Agosta, D. Caputo, M. Perini, A. Prelle, F. Salvi, M. Filippi University Ospedale San Raffaele (Milan, I); Fondazione Don Gnocchi (Milan, I); Ospedale di Gallarate (Gallarate, I); Fondazione Policlinico Mangiagalli (Milan, I); University of Bologna at Bellaria Hospital (Bologna, I) Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition, associated to spinal cord damage. Diffusion-tensor (DT) MRI provides quantitative information about the structural and orientational features of the central nervous system, and it is an invaluable tool for detecting disease-related subtle damage. Aim of this study was to obtain mean diffusivity (MD) and fractional anisotropy (FA) histograms of the cervical cord from a group of ALS patients and healthy subjects, to quantify the extent of cord damage in these patients and correlate it with the clinical manifestation of the disease. Methods: Cervical cord DT MRI was performed using a single shot SEEPI sequence with 12 non-collinear diffusion gradient direction. A sagittal T1-weighted 3D magnetization-prepared rapid acquisition gradient echo (MP-RAGE) of the spinal cord was also obtained. We studied a group of 20 patients with ALS and 15 healthy controls. For each subject, cord MD and FA histograms were produced and the cross-sectional cord area was measured. Results: Compared to controls, ALS patients had significantly lower cord average FA (p = 0.014). No significant differences were found for MD histogram-derived metrics between the two groups. Cord cross-sectional area was found to be significantly reduced in ALS patients in comparison with the healthy controls (p = 0.005). A significant correlation was found between cord average FA and the ALS Functional Rating Score (r = 0.65, p = 0.003). Conclusions: This study shows that DTI-MRI of spinal cord is feasible in patients with ALS and allows to grade the extent of cord damage. The most likely pathological substrates of the diffusion and atrophy damages found are axonal loss (due to cortico-spinal tract degeneration) and gliosis.

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O120 Cysteine donor enriched dietary intake is able to reduce exercise-related oxidative stress in amyotrophic lateral sclerosis G. Siciliano, S. Piazza, C. Carlesi, A. Del Corona, M. Franzini, A. Pompella, M. Mancuso, A. Paolicchi, L. Murri University of Pisa (Pisa, I)

O122 A diffusion-tensor MRI study of the brain and cervical cord in patients with neurosystemic lupus erythematosus B. Benedetti, P. Valsasina, E. Judica, G. Donadoni, G. Ciboddo, G. Comi, M. Filippi Neuroimaging Research Unit (Milan, I); Hospital San Raffaele (Milan, I)

Background: Although the causes of Amyotrophic Lateral Sclerosis (ALS), a neurological disorder characterized by a progressive upper and lower motor neurons loss, are unknown, accumulating evidences indicate that oxidative stress is involved in the pathogenesis of this disease. Aim of the study: To analyze the occurrence of oxidative stress in ALS before and after 45 days of treatment with a cysteine donor food-integrator. Materials and methods: We assessed blood levels of the following oxidative stress markers in 16 ALS patients, before and after 45 days of treatment with a food-integrator cysteine donor (Prother,AFR, 10 mg/die): glutathione (GSH), the advanced oxydation protein products (AOPP) and the ferric reducing ability (FRAP). AOPP and FRAP were also measured, besides resting condition, during an incremental hand-grip dynamometer muscle exercise test, performed in the two experimental conditions. Results: We found that, in resting condition and before therapy, compared to 7 matched controls, FRAP was unchanged, while GSH was decreased (p < 0.01) and AOPP increased (p < 0.05) in ALS patients. After therapy a significant decrease (p < 0.02), compared to pre-treatment condition, of exercise-related blood AOPP levels in ALS patients occurred. Discussion: Our results confirm the role of oxidative stress in sporadic ALS pathogenesis, also during exercise. In addition the present study underlines the beneficial effects of antioxidant cysteine-donor therapy on biochemical markers of oxidative stress in ALS.

Objectives: Diffusion tensor (DT) MRI allows to quantify the severity of brain and spinal cord damage, providing quantitative information on the extent of tissue damage undetected by conventional MRI in many CNS conditions. In this study, we compared DT-MRI histogram-derived metrics from a group of patients with neurosystemic lupus erythematosus (NSLE) and healthy subjects to investigate the nature of brain and cord tissue damage in this disease. Methods: Brain diffusion-weighted scans and diffusion-weighted sensitivity-encoded (SENSE) echo planar images of the cervical cord were acquired from 10 patients with NSLE, and 10 age- and sex-matched healthy controls. Mean diffusivity (MD) and fractional anisotropy (FA) histograms of brain and cervical cord were produced. Results: Compared to healthy controls, NSLE patients had significantly higher brain average gray matter (GM) MD (p = 0.04) and white matter (WM) MD (p = 0.04), and significantly lower WM FA (p = 0.03). NSLE patients also showed an increase of cord average MD (p = 0.05), when compared to healthy subjects. There was a significant correlation between cord average MD and brain WM average MD (r = 0.65; p = 0.04), as well as with brain WM average FA (r = –0.84; p = 0.002). Conclusions: This study shows a diffuse brain tissue damage in NSLE patients, with a relative sparing of the cervical cord. The strong correlation found between brain and cord metrics suggests that spinal cord damage may be due to Wallerian degeneration of WM fiber tracts, secondary to the extent of brain pathology.

Session 17 Clinical neuroscience O121 Phenotypic spectrum of female adrenoleukodystrophy H. H. Jung, S. Jung, K. Landau, A. Gal, F. Heppner University Hospital Zurich (Zurich, CH); University Hospital Hamburg-Eppendorf (Hamburg, D) Objectives: Adrenoleukodystrophy-adrenomyeloneuropathy (ALD-AMN) is an X-linked disorder of the peroxisomal beta oxidation.Approximately 20 % of heterozygous females develop mild symptoms resembling AMN with a mean onset age of about 40 years. Childhood onset, cognitive decline, visual disturbances, or adrenal dysfunction are only exceptionally found in female heterozygotes. Herein, we describe additional heterozygote manifestations of ALD-AMN. Methods: We examined three consecutive female patients manifesting with ALD-AMN by means of neurological examination, cognitive testing, magnetic resonance imaging (MRI), and molecular genetic analysis of the ABCD1 gene. Neuropathological examination was available from one patient. Results: All patients had progressive spastic paraparesis with onset ranging from 25 to 65 years. Additional manifestations included childhood-onset neuropsychiatric syndrome and neuropathologically confirmed olivopontocerebellar (OPC) syndrome in one patient. The brother of this patient had an adult onset AMN-phenotype and Addison disease without clinical or neuroradiological evidence for cerebral involvement. The second patient had severe visual deficiency due to optic atrophy and central visual processing deficit. Her son died from childhood-onset ALD. The third patient developed late-onset parietal lobe syndrome. She had no relatives with ALDAMN. Cerebral MRI demonstrated pronounced cerebellar leukodystrophy in the first patient, and posterior leukodystrophy in all patients. Conclusion: Female ALD-AMN usually manifests with spastic paraparesis but the phenotypic spectrum may be broader. Additional manifestations in our series included childhood onset neuropsychiatric syndrome, OPC syndrome, optic atrophy, and late-onset cognitive alterations. In addition, our observations demonstrate that intrafamiliar phenotypic variability in ALD-AMN may be considerable with female mutations carriers more severely affected than males.

O123 Autoantibodies in subacute,probably non-paraneoplastic,cerebellar ataxia L. Zuliani, L. Sabater, A. Saiz, B. Giometto, F. Graus University of Barcelona (Barcelona, E); Ospedale di Treviso (Treviso, I) Introduction: Cerebellar ataxia with an acute or subacute onset is generally supposed to have an autoimmune pathogenesis once other causes are excluded. Besides the paraneoplastic aetiology, subacute cerebellar ataxia often follows a previous infection but in many cases a prodromal illness cannot be demonstrated. Moreover a cerebellar encephalitis may also occur in older patients and give rise to persistent cerebellar ataxia. In this study we analyzed the presence of neuronal immunoreactivity in sera of patients with probably non paraneoplastic, subacute sporadic cerebellar ataxia. Methods: Serum samples were selected from those sent to test for the presence of antineuronal antibodies in our laboratories. The selection criteria were the development of a subacute cerebellar ataxia, defined as progression to a stage of loss of independent gait or a Rankin score of at least 3 (symptoms significantly interfere with lifestyle or prevent totally independent existence) within less than 12 weeks, with no established symptomatic cause and no evidence of known onconeural and anti-GAD antibodies and without cancer during the follow-up. Immunological studies included: immunohistochemical analysis on frozen sections of cerebral and non cerebral rat and human tissues and Western Blot of rat brain homogenate. Results: We identified 15 patients. Eleven patients, median age 28 years (range: 13–50) made an important improvement, or the cerebellar syndrome completely resolved, over the ensuing months. None presented antineuronal antibodies in the serum or CSF. By contrast, in four patients, median age 67.5 years (range: 64–75), median follow-up of 28.5 months (range 12–60 months), the cerebellar syndrome never made a clear improvement and all presented antineuronal antibodies. Immunoreactivities were different in each patient. Screening of a cerebellar expression library with the serum of one of these patients, which showed a reactivity against the neurophile, identified the Homer 3, a post-synaptic density antigen linked to mGluR1. No antineuronal antibodies were detected in 64 patients with chronic sporadic degenerative ataxia. Conclusions: Older patients with subacute cerebellar ataxia of non paraneoplastic origin may harbour in the serum and CSF antineuronal antibodies, supporting the hypothesis that this syndrome may be immune-mediated. ENS fellowship grant

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O124 Autoantibodies in stiff-person syndrome T. Chang, P. Brown, A. Vincent University of Oxford (Oxford, UK); University of London (London, UK) Objectives: Autoantibodies to glutamic acid decarboxylase (GAD, the enzyme that synthesises the inhibitory neurotransmitter GABA) are detected in approximately 60 to 80 % of patients with stiff-person syndrome (SPS). However, it is not clear whether antibodies (Abs) to GAD are pathogenic. In general, pathogenic antibodies in neurological diseases are disease-specific, high affinity, IgG1 or IgG3, and bind to the surface of the target cells. The aim was to characterise GADAbs and to look for other autoantibodies in SPS. Methods: Sera from 20 patients with SPS were studied. Radioimmunoprecipitation was used to determine GADAb titres, IgG subclasses, and antibody affinity by Scatchard analysis. Immunohistochemistry and immunoblotting were used to confirm GADAbs and search for other antibodies. Flow cytometry on neuroblastoma cell lines was used to detect neuronal cell surface binding of autoantibodies in SPS. Results: GADAb titres ranged from 0 to 700000 U/ml, with 14/20 patients positive. There was no correlation of GADAb titre in SPS with the age of the patient, the severity or the duration of the illness. There was no significant difference in the GADAb titre between SPS patients who had received immunotherapy and those patients who had not (p = 0.49). The GADAbs were high affinity, KD 0.13 to 0.78 nM (mean 0.35) and predominantly IgG1 isotype (37 to 73 % of total IgG). Immunoblotting showed a positive correlation between the intensity of the binding to GAD and GADAb titre (Pearson r 0.69, p < 0.0001) in patients with SPS. Immunohistochemistry suggested the presence of other possible CNS-directed antibodies in 3 patients with SPS. Flow cytometry on neuroblastoma cell lines showed that some of the sera contained antibodies that bind to the cell surface, and these antibodies were additional to GAD. Conclusions: GADAbs possess the characteristics expected of highly pathogenic antibodies, but GAD is an intracellular antigen and it is not clear how these antibodies would cause disease.Work in progress includes passive transfer of disease to mice, and active immunisation against GAD, to study the relative roles of humoral and cell mediated immune responses in SPS. O125 Evaluation of cerebral blood perfusion with 99mTc-ECD single photon emission computed tomography analysed by easy Z-Score imaging system in bacterial meningitis K. Kimura, Y. Iwahashi, T. Nomiya, M. Endo, M. Shimamura, Y. Suzuki, Y. Kuroiwa, T. Takahashi Yokohama City University (Yokohama, JP) Objectives: To clarify the mechanism of acute brain dysfunction in bacterial meningitis. Methods: In four bacterial meningitis patients admitted to our hospital from April 2005 to November 2005 (Streptococcus aureus was isolated from cerebrospinal fluid of one patient, Streptococcus pneumoniae from that of one, unknown from that of two), we examined cerebral blood perfusion at the day of starting treatment and the day after first 14 days treatment with using 99mTc-ECD Single Photon Emission Computed Tomography analyzed by easy Z-Score Imaging System (eZIS). Results: At the initial images, of all patients, cerebral blood perfusion was generally decreased, particularly in the parietal region adjacent the superior sagittal sinus. Cerebral blood perfusion preserved in the cerebellum, orbital surface in frontal lobe, and the inferior surface in the parietal lobe. Preceding the recovery of consciousness, cerebral blood perfusion was normalized. Conclusion: In bacterial meningitis, cerebral blood perfusion abnormality is strongly found in superior sagittal sinus area, and does not depend upon bacterial species. Cerebral blood perfusion decrease in the parietal lobes might cause unconciousness in bacterial meningitis. Moreover, improvement of cerebral blood perfusion could be a good prediction marker of consciousness recovery.

Session 18 Clinical neurophysiology O126 Subthalamic nucleus deep brain stimulation induces prepulse inhibition of the blink reflex in patients with Parkinson’s disease J. Costa, J. Valls-Solé, F. Valldeoriola, C. Pech, J. Rumià Santa Maria University Hospital (Lisbon, P); Hospital Clínic – Universitat de Barcelona (Barcelona, E); Hospital Hochzirl (Innsbruck, A) Introduction: The disordered output from the basal ganglia to the pontine tegmentum nuclei are considered responsible for a number of abnormalities found in the study of brainstem reflexes in patients with Parkinson’s disease (PD). One of the most conspicuous of these abnormalities is the reduced inhibition of the blink reflex by a somatosensory or acoustic prepulse stimulus. The circuit of prepulse inhibition involves structures and fiber groups that can be reached by stimuli applied through the electrodes used for deep brain stimulation (DBS). Patients and Methods: In 7 PD patients with documented abnormally reduced prepulse inhibition to auditory and somatosensory stimuli before surgery (compared to a control group of 20 volunteers), we examined the prepulse effects of electrical stimuli applied through the electrodes implanted in the subthalamic nucleus (STN) for therapeutic purposes. Prepulse effects were examined by applying weak auditory, somatosensory or STNDBS stimuli preceding, by a predetermined time interval, a supraorbital nerve electrical stimulus capable of eliciting a stable response in the orbicularis oculi (OOc). Each type of stimulation modality was repeated 5 times for each of the intervals tested (0 to 30 ms for STN-DBS and 50 to 110 ms for auditory and somatosensory stimuli). Results: The size of the R2 component of the OOc response to the supraorbital nerve stimulation was only slightly affected by auditory and somatosensory stimuli, and there were no differences before and after surgery. The mean inhibition was 38 % for auditory and 36 % for somatosensory prepulses. On the contrary, STN-DBS caused a significantly larger inhibition, reaching a mean of 92 % (ANOVA; p < 0.05). The amplitude of the R1 component was facilitated by STN-DBS prepulse. Conclusion: Prepulse effects of DBS have not been studied in humans. STN-DBS is capable of inducing an effective prepulse inhibition of the blink reflex in PD patients with abnormal auditory and somatosensory prepulse effects. STN-DBS prepulse also induces facilatory effects at very short intervals. These findings help in defining the prepulse circuit in humans and the eventual site of dysfunction of such circuit in PD. Institutions providing support for this project: Fundaç"o Caloustre Gulbenkian; Fondo de Investigación Sanitaria. O127 “TremorAn” – a new bedside test of an computerized analysis of movement disorders J. Koehler, G. Schäfer, M. Dieterich, A. Faldum Johannes Gutenberg-Universität (Mainz, D) Objectives: The aim of this study was to develop a new bedside test for computerized analysis of movement disorders of the upper extremity to evaluate follow-up investigations quantitatively in a easy and objective way. The test battery consists out of 3 different drawing exercises starting with “drawing the line” over “zick-zack-course” to “star” characterized by an increasing difficulty and one target exercise “target-target” to proof the accuracy of movements. Methods: Based on a tablet pc (Compaq Tablet PC TC1000) a individual software was developed to analyse quantitatively following parameters: 1) Curve under the line, 2) number of maxima, 3) number of intercept points, 4) overshoot distance, 5) number of interruptions and 6) needed time of the drawing tests and 7) sum of distance from target and 8) length of distortion of the target test. Normative data were evaluated by testing 50 healthy subjects (20 women, mean age 25 years). Sensitivity of these data were proofed in 10 patients with different clinical severity codes of movement disorders of the upper extremities (2 patients without, 3 with mild, 4 with moderate and 1 with severe signs and symptoms). In addition the nine-hole-peg-test was documented and the results were compared to the new bedside test. For statistical analysis based on SPSS 11.0 special curve analysis were used with respect to the highest stability index to calculate the normative data of the single tests. Results: All healthy subjects could perform the test battery accurate without any problems. Based on the normative data with this new bedside test subclinical abnormalities in patients without signs and symptoms could be

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found as well as the clinical noticeable disturbances in the other patients. Furthermore a more detailed analysis by this method could be shown compared to the nine-hole-peg-test. Conclusions: The new computerized bedside test “TremorAn” with easy handling could show high sensitivity in detecting movement disorders of the upper extremities as well as severe signs and symptoms. Therefore it could be used for follow-up studies in these patients with respect to therapeutic efficacy of several drugs. This study was supported by Schering Deutschland GmbH. O128 Mapping motor cortical representation using transcranial magnetic stimulation with simultaneous recording of several upper limb muscles: a validation study R. Chieffo, F. Cerri, A. Inuggi, L. Straffi, G. Comi, L. Leocani University Hospital San Raffaele (Milan, I) Objectives: Mapping of motor cortical representation using transcranial magnetic stimulation (TMS) is a useful method for the investigation of brain plasticity in physiological and pathological conditions. Knowledge of relative map position and size of different muscles has the potential advantage of investigating reciprocal interactions. Methods: Eight normal volunteers (5 M, 3 F, age 40.9 ± 15.7; two lefthanded) underwent focal TMS mapping of the two hemispheres with simultaneous recording of 4 upper limb muscles (abductor pollicis brevisAPB; abductor digiti minimi-ADM; extensor carpi radialis-ECR; biceps), at stimulation 15 % above the lowest motor threshold for evoking MEPs in any of the four muscles. Motor threshold, MEPs amplitude, number of responsive sites and position of the hot spot were determined for each muscle tested. Results: At threshold intensity, MEPs were evoked in the three more distal muscles (ADM,APB, ECR).At the stimulation intensity used for mapping, MEPs in the biceps were evoked only in one subject, in the dominant hemisphere. Map size, determined as the number of responsive sites, was significantly greater for the dominant compared with the non dominant side (p = 0.01). Significant differences in map size for the three more distal muscles were present in the dominant hemisphere only, being significantly higher in APB compared with ECR (p = 0.01). For the three more distal muscles tested, displacement of the hot spot along the lateral-medial direction from more distal to proximal muscles was present in four subjects for both hemispheres, in two subjects for the dominant hemispheres, in one subject for the non dominant hemisphere, while a substantial overlap of the 3 muscles was present in two subjects. In the only subject with MEPs on the biceps, the hot spot for this muscle was medial respect to the other muscles. Conclusions: Our method allowed to map intrinsic (APB and ADM) and forearm (ECR), but not upper arm (biceps) muscles, revealing somatotopic disposition and dominance-related asymmetries, consistently with previous literature. We suggest that simultaneous mapping of intrinsic and forearm muscles may be successfully performed using simultaneous recording of MEPs, with considerable time sparing compared with separate mapping. Therefore, this method has a potential usefulness in the investigation of motor cortical representation, such as in the study of brain plasticity. O129 Expanded motor cortical representation in the contralesional hemisphere occurring in the early but not late phases after a stroke: evidence from transcranial magnetic stimulation L. Leocani, R. Chieffo, F. Cerri, A. Inuggi, M. Comola, A. Poggi, G. Comi Hospital S.Raffaele (Milan, I) Objectives: The aim of the present study was to investigate early and later changes in the cortical motor representation the two hemispheres after a stroke. Methods: Nine patients after a first stroke and 6 healthy volunteers of similar age/sex distribution were included. Patients were examined within the first 10 days after stroke and after a mean follow-up of 30 days. Cortical motor representation of motor evoked potentials (MEPs) of 4 upper limb muscles was mapped using transcranial magnetic stimulation. Mirrors to voluntary isometric contraction were also searched with electromyographic recordings. Results: In the earlier post-stroke phase MEPs to the affected side had higher threshold, lower motor evoked potentials amplitude and reduced map size both compared with the unaffected hemisphere (p < 0.02) and with normal subjects (p < 0.014). The unaffected hemisphere showed significantly increased map size (p = 0.034) and MEPs amplitude (p = 0.007) compared with normal subjects, without significant threshold differences. Map size for each unaffected muscle was inversely correlated with MRC of the af-

fected homologous (p < 0.05). Map size was higher for the unaffected muscles with mirror activity during movement of the affected homologous (p = 0.03). At follow-up, MRC on the affected and mirrors on the unaffected muscles were significantly improved. For the unaffected muscles, map size and MEPs amplitudes significantly decreased compared with the early phase. Basal map size and MEPs amplitudes were significantly higher for muscles with persistent mirroring, compared with muscles with no (active sites: p = 0.002; amplitude: p = 0.004) or transitory (active sites: p = 0.016; amplitude: p = 0.006) mirroring. Conclusions: Our findings of increased representation in the unaffected hemisphere, occurring only in the post-acute phases after stroke, is consistent with reports of increased excitability possibly in relation to reduced inter-hemispheric inhibition from the affected hemisphere. Increased muscle representation over the unaffected side was predictive of persistency of mirror to voluntary movement of the affected limb after recovery. The latter finding suggests that early plastic changes of motor representation on the unaffected hemisphere may be an indicator of increased tendency to mirror and bilateral cortical activation to voluntary movement of the affected limb, which have been reported after recovery from stroke. O130 Compensation for central vestibular dysfunction in patients with acute medullary infarction (FDG-PET study) S. Bense, H.-G. Buchholz, C. Best, P. Schlindwein, T. Brandt, P. Bartenstein, M. Dieterich Johannes-Gutenberg University (Mainz, D); Ludwig-Maximilians University (Munich, D) Objective: Earlier functional imaging studies in healthy volunteers during experimental vestibular stimulation and in patients with acute peripheral vestibular neuritis found a reciprocal inhibitory interaction between the vestibular and visual systems. The aim of this fluorodeoxyglucose (FDG)PET study was to define areas involved in the processing of and compensation for central vestibular dysfunction caused by an acute unilaterally medullary infarction affecting the vestibular nucleus. Methods: Twelve patients (10 m, 2 f; mean age 68.3 years) with an unilateral ischemic infarction in the medulla oblongata (6 right, 7 left) which affected the vestibular nucleus and caused signs of acute vestibular dysfunction were examined by FDG-PET (A) in the acute phase on mean day 7 after symptom onset and (B) seven of them again 6 months later after recovery. PET was performed without any stimulation and with eyes closed. Single subject and group subtraction analysis (paired t-test) were done with SPM99. Furthermore, patient data were compared with a data set of 12 agematched controls by a two sample t-test. Results: The contrast of patients PET A vs. B showed differences mainly in the medulla and cerebellar peduncle contralateral to the infarction as well as in both cerebellar hemispheres. The inverse contrast (PET B vs. A) revealed widespread bilateral signal changes in the visual cortex (BA 17–19), including the motion-sensitive area MT/V5 (BA 19/37) and merging into secondary visual areas in the upper occipital cortex (BA 19/39) as well as in temporo-parietal areas (GTm/s, LPi, BA 39/40). The comparison of control vs. patient PET A showed signals mainly in parts of the visual cortex bilaterally, the left posterior insula, the anterior/posterior cingulate gyri, as well as in the limbic lobe bilaterally due to deactivations in the acute stage. The comparison of control vs. patient PET B showed signals in both cerebellar hemispheres and limbic lobes due to deactivations in the disease course. Conclusion: The signal decreases within the visual cortex in the acute stage after disease onset agree with the concept of a reciprocal inhibitory interaction between the vestibular and the visual systems. The data further suggest that central compensation processes after medullary infarction with vestibular imbalance take place in cerebellar loops rather than in cortical areas. O131 Saccade velocity reduced in presymptomatic spinocerebellar ataxia type 2 C. Seifried, L. Velázquez-Pérez, M. Abele, F. Wirjatijasa, N. Santos-Falcón, E. Martínez-Góngora, G. Sánchez-Cruz, L. Almaguer-Mederos, R. Carralero, N. Canales-Ochoa, M. Fetter, U. Ziemann, T. Klockgether, G. Auburger University Hospital (Frankfurt, D); Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias (CIRAH) (Holguin, CUB); Department of Neurology, Bonn University (Bonn, D); Hospital Karlsbad-Langensteinb (Karlsbad-Langensteinb, D) Objectives: In a previous study we found a reduction of maximal saccade velocity (MSV) in spinocerebellar ataxia type 2 (SCA2) patients even at early disease stages, which correlates well with polyglutamine size, and less with disease duration. In the present study we investigated MSV in presympto-

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matic SCA2 mutation carriers. The aim of our study was to evaluate whether there is a slowing of saccades before manifestation of ataxia. Methods: We assessed MSV in 34 presymptomatic SCA2 mutation carriers (expansion sizes ranging from 32 to 41) and in 34 age and sex matched controls. For each mutation carrier, the time to disease manifestation was calculated, as predicted by the respective polyglutamine expansion size. Horizontal saccade velocity was recorded by a two channel AC electronystagmograph (Otoscreen, Toennies) using silver-silver chloride electrodes and measuring 10°, 20°, 30° and 60° saccades. MSV in °/s was obtained through the automatic algorithm contained in the Otoscreen software package. Statistical analyses were performed using the JMP software (SAS Institute). For all tests, a p-value of less than 0.05 was considered significant. Results: MSV of 10-, 20- and 30-degree saccades did not differ between SCA2 mutation carriers and controls. However, MSV at 60 degrees was significantly reduced in mutation carriers compared to controls (SCA2: 231 to 653 degrees/sec; mean, 427 degrees/sec; SD, 108 degrees/sec; controls: 284 to 609 degrees/sec; mean, 490 degrees/sec; SD, 74 degrees/sec, p = 0.0067). Subsequent analyses were therefore restricted to MSV60. Regression analysis showed that saccadic slowing was related to polyglutamine expansion size, but not to calculated time to disease manifestation and age. Conclusions: In SCA2 saccade velocity is reduced before manifestation of ataxia. It represents a sensitive endophenotype which is under strong genetic control and reflects early pontine degeneration.

Session 19 Cerebrovascular disorders 3 O132 Hyperglycaemia higher than 155 Mg/Dl as the threshold level for poor outcome in acute ischaemic stroke B. Fuentes, E. Díez-Tejedor, J. Castillo, A. Dávalos, A. Gil-Nuñez, J. Vivancos, J. Egido for the Stroke Project of the Cerebrovascular Diseases Study Group of the Spanish Society of Neurology Objective: To evaluate the prognostic influence of hyperglycaemia in outcome of acute ischemic stroke (IS) patients, adjusting for other prognostic factors and to establish the capillary glucose level associated to poor outcome. Methods: Multicentre, observational study. We include acute IS patients (< 24 h), excluding patients unconsciousness on admission, previous stroke with modified Rankin Scale (mRS) > 2, other symptomatic intracranial lesion, or impossibility to complete a 3-months follow-up. Capillary glucose, blood pressure, body temperature, and neurological state (Canadian Stroke Scale, CSS) were determined on admission and 3 times a day during the first 48h. Outcome at 3 months was determined by mRS. Statistical analysis: chisquare, t-student, Spearman correlations, ROC-analysis, stepwise logistic regression, and Kaplan-Meyer survival analysis. Results: 476 patients. Mean age 70.78 ± 10.5; time stroke-onset to inclusion: 6.8 ± 5.7 h. Mean glucose on admission (glu_adm): 137.2 ± 57.2 mg/dl. Both glu_adm and maximum glucose within the first 48h (glumax_48h) significantly correlated to lesion volume (r0.204 and 0.189) and mRS_3m (r0.213 y 0.282). Glumax_48h = 155 mg/dl was the point of maximum specificity and sensibility for outcome at 3 months in ROC analysis. Multivariate logistic analysis pointed out as independent prognostic factors for death or dependence at 3 months: glumax_48h > 155 mg/dl (OR 2.1; 95 %IC 1.2–3.7), age (OR 1.05;95 %IC 1.01–1.08) and CSS on admission (OR 0.1; 95 %IC 0.4–0.5). Known and unrecognised diabetic patients had poorer outcome than those non-diabetic (p < 0.05). However, when analysing those patients with glumax_48h > 155 mg/dl there were no differences in outcome regarding the diagnosis of diabetes. Conclusions: Hyperglycaemia > 155.5 mg/dl within the first 48 h is an independent predictive factor for death or dependence at 3 months. Acute stroke hyperglycaemia clearly determines poor outcome at 3 months in both diabetic and non diabetic patients.

O133 Stroke subtype and intima-media thickness D. M. O. Pruissen, S. A. M. Gerritsen, T. J. Prinsen, J. M. Dijk, L. J. Kappelle, A. Algra for the SMART study group Objectives: Ischaemic stroke can be subdivided in several subtypes depending on aetiology. Lacunar infarcts caused by small vessel disease (SVD), should be distinguished from large infarcts caused by large-artery atherosclerosis or large vessel disease (LVD). Common carotid artery intima-media thickness (CCA IMT) offers a reliable estimate of both extent and severity of peripheral atherosclerosis. The aim of this study is to compare CCA IMT value between patients with a stroke caused by SVD or by LVD. Methods: We included patients from the Second Manifestations of ARTerial disease (SMART) study. The SMART study is an ongoing prospective single-center cohort study in patients with manifest arterial disease or cardiovascular risk factors. Patients with an ischaemic stroke or TIA caused by SVD or LVD were included. SVD or LVD was classified by two independent observers (DMOP and JMD) based on both clinical presentation and brain imaging. In case of conflicting findings brain imaging was used to allocate stroke subtype. A test series of thirty cases yielded a satisfactorily kappa for agreement between the two observers (0.72). For each patient a mean CCA IMT was calculated based on six measurements. Results: 561 patients were included in the study, 120 were classified SVD and 441 LVD. Age was higher in LVD (mean 63 years) compared with SVD (mean 58 years). Distribution of sex was similar in both groups. Symptomatic carotid artery stenosis and history of stroke were more common in LVD. The mean IMT for the group with LVD (1.08 mm) was higher than that for the group with SVD (0.92 mm). The crude difference was 0.16 mm (95 %confidence interval (CI) 0.09–0.23). In regression analysis there was still a statistically significant difference after adjustment for age (mean difference 0.12 mm, 95 %-CI 0.03–0.17). Conclusion: intima-media thickness is higher in patients with LVD compared with SVD. These data support the hypothesis that LVD and SVD have a different pathogenesis. Supported by a unconditional grant from the Netherlands Organisation for Scientific Research (NWO) O134 Central sleep apnoea and central periodic breathing during sleep in acute ischaemic stroke M. M. Siccoli, C. L. Bassetti University Hospital of Zurich, Department of Neurology (Zurich, CH) Objectives: Central periodic breathing (CPB) in sleep is present in 20–40 % of patients with acute ischemic stroke and often spontaneously recover during the following weeks. The underlying pathophysiological mechanisms, clinical, and prognostic implications of CPB in sleep remain still poorly known. The aim of our study is to better characterize CPB in sleep and its relevance in acute ischemic stroke. Methods: We included patients admitted within 96 hours after stroke onset. Stroke severity on admission (NIH Stroke Scale, Scandinavian Stroke Scale) and stroke outcome at discharge (modified Rankin Disability Scale) were assessed. Nocturnal breathing was assessed with an ambulatory device the first night after admission. Sleep apnea was defined by an apnea-hypopnea-index ≥ 10/h, a differentiation between obstructive and central apneas was undertaken according to standard criteria. CPB was defined as ≥ 3 cycles of regular crescendo-decrescendo breathing associated with reduction of > 50 % in nasal airflow and respiratory effort lasting > 10 seconds. CPB severity was represented as percentage of recording time. Results: 55 patients were included. 23 (48 %) patients showed CPB during ≥ 10 % of recording time. The mean CPB duration in all patients was 18 ± 22 % [0–74 %]. CPB severity was associated with age (p = 0.016), stroke severity at day1 (p = 0.034) and day3 (p = 0.006) and duration of hospitalisation (p = 0.034). CPB was also associated with ECG abnormalities (p = 0.011) and with a lower left ventricular ejection fraction (p = 0.001). CPB severity was significantly lower in patients with stroke in the insular region (n = 8, p = 0.001). Conclusions: CPB in sleep is a frequent phenomenon in acute ischemic stroke, occurs much frequently in older patients, and is associated with more severe stroke on admission, longer duration of hospitalisation and cardiac abnormalities. The lower occurrence of CPB in sleep in insular strokes suggests an implication of this region in the modulation of respiratory response to acute ischemic brain damage.

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O135 Systemic Risk Score Evaluation in Ischaemic Stroke Patients (SCALA): a prospective cross-sectional study in 85 German stroke units C. Weimar, J. Roether, H. Darius, M. Goertler, I.-H. Kim, B. Ringelstein, D. Nabavi, H. C. Diener on behalf of the SCALA Group Background: Patients with transient ischaemic attacks (TIA) or ischaemic stroke (IS) carry a high risk of stroke recurrence. Stratification of patients according to their risk profiles, e. g. with the Essen Stroke Risk Score (ESRS) can contribute to optimised secondary prophylaxis of such patients. We aimed [1] to describe stroke severity and the risk factor profiles of hospitalised patients with TIA/IS, [2] to stratify these patients in low versus high risk groups according to the ESRS, and [3] to correlate peripheral arterial disease (PAD) as a marker of generalised atherosclerosis with the ESRS. Methods: In this cross-sectional observational study, 85 neurological stroke units throughout Germany documented consecutive TIA/IS patients on standardised questionnaires. Screening on PAD was done with Doppler ultrasonography to calculate the ankle brachial index (ABI).An ABI equal to or below 0.9 was indicative for PAD. Results: 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. The correlation between the ESRS and the ABI according to Pearson product moment coefficient was moderate (r = 0.397). Conclusions: While most documented patients had TIA or IS of low severity, a high proportion had a considerable risk of recurrent stroke 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. The study was funded by Sanofi-Aventis, Berlin, Germany.

order characterized by ischemic episodes, cognitive impairment, and migraine, often with aura. Cerebral MRI reveals signal hyperintensities in the white matter, especially of the temporal lobes. We investigated CADASIL patients with 1H-magnetic resonance spectroscopy (MRS) for different cerebral metabolites, namely N-acetylaspartate (NAA), creatine, choline, myoinositole (MI), and lactate. Methods: To date, we studied 4 CADASIL patients and 4 healthy controls. CADASIL diagnosis was confirmed by skin biopsy and/or genetic analysis. MRS was performed on a 3T Philips MR system. 1H-MRS data were acquired using high resolution multi-spin echo spectroscopic imaging (TSI; TE = 288ms, slice thickness = 1.5 cm, resolution 28x28, FOV = 320 mm) and conventional chemical shift imaging (CSI; TE = 35 ms, resolution 16x16 and TE = 288ms, resolution 12x12, slice thickness = 2 cm, FOV = 320 mm). Bandwidth was 2500 Hz and repetition time 1520 for all measurements. CSI measurements with TE = 288 ms were repeated 6 times consecutively. The 1st and the last two measurements were performed in darkness, in the others visual stimulation with a stroboscope (8 Hz) was applied. Data were obtained from a transversal slice adjusted parallel to the calcarine fissure, including the visual cortex. In addition, we performed single voxel (SV) MRS of the temporal pole. Results: All CADASIL patients showed characteristic MRI findings including the temporal lobe. NAA/creatine ratios were decreased in all patients, most markedly in temporal lobes and periventricular areas. Choline/creatine ratios were unchanged and no myoinositole was detected. Voxels adjacent to the calcarine fissure showed elevated lactate peaks at baseline in 2 patients without change during visual stimulation. Conclusion: NAA/creatine ratios were diminished in all CADASIL patients in areas with visible lesions. Decreased NAA/creatine ratios might therefore be used as an additional, possibly more sensitive marker of neuronal damage in CADASIL. Specificity and sensitivity of NAA alterations as well as the significance of lactate changes will be further evaluted in our ongoing study. T. Akhvlediani was supported by the ENS fellowship and the study was contributed by the CADASIL Foundation of America

O136 Systemic thrombolysis in patients with posterior circulation stroke B. Dimitrijeski, A. Villringer, H. C. Koennecke, A. Hartmann Charite (Berlin, D); Krankenhaus Herzberge (Berlin, D) Objectives: Treatment with rt-PA within a 3-hour time window has been proven effective in acute ischemic stroke. However, most of the data regarding thrombolysis refer to stroke in the anterior circulation. Information about differences in outcome and frequency of intracranial hemorhage between anterior and posterior circulation stroke is rare. Methods: 223 patients were treated between 1998 and 2005 with systemic thrombolysis within a 3-hour time window according to the NINDS-trial protocol, 201 (90 %) patients with anterior circulation stroke (ACS), patients with posterior circulation stroke (PCS) occurred in 22 (10 %). Infarct localisation was n = 10 brain stem, n = 5 occipital lobe, n = 2 thalamic, n = 1 cerebellar and n = 4 combined (n = 2 occipital lobe, thalamic and cerebellar, n = 1 brain stem and cerebellar and n = 1 occipital lobe and cerebellar). Neurological outcome was measured at admission, discharge and at 3months follow-up using the NIH-Stroke-Scale (NIHSS) and the modified Rankin-Scale. Intracranial hemorrhage was classified according to ECASS II-criteria, underlying stroke pathology according to TOAST-Criteria. Results: In the study period 22 patients with PCS were treated within a 3- hour window. (50 % female, Mean-NIHSS ad admission 13.0, mean age 68.4 y). Good functional outcome defined as Rankin ≤ 2 occurred in 14 patients (63.6 %) with PCS compared with 99 patients (49.3 %) with ACS (p = 0.2). Respectively intracranial hemorrhage occurred in 1 patient (occipital lobe infarction) (4.5 %) with PCS and 7 patients (3.5 %) with ACS (p = 0.79) and mortality occurred in n = 3 (14 %) in PCS and n = 27 (13.4 %) in ACS (p = 0.99). Conclusions: Clinical outcome at 3-month follow up and mortality are similar in patients with anterior and posterior circulation stroke after treatment with systemic thrombolysis. Intracranial hemorrhage is not more frequent in posterior circulation stroke. Systemic thrombolysis seems to be safe and effective in patients with posterior circulation stroke. O137 MRS changes in CADASIL: preliminary results T. Akhvlediani, A. Henning, U. Dydak, P. Boesiger, P. S. Sandor, H. H. Jung University Hospital Zurich (Zurich, CH); Institute of Biomedical Engineering, ETH Zurich (Zurich, CH) Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant dis-

Session 20 Cerebrovascular disorders 4 O138 Pain as the only symptom of cervical artery dissection M. Arnold, R. Cumurciuc, C. Stapf, P. Favrole, M-G. Bousser University Hospital Lariboisière (Paris, F) Background: Headache and/or neck pain are frequent symptoms of spontaneous cervical artery dissection (sCAD). Patients presenting with pain as the only manifestation of sCAD, however, have not been systematically studied so far. Patients and methods: Patients were drawn from an ongoing hospitalbased registry of 248 consecutive cases diagnosed with sCAD based on cervical MR imaging and/or diagnostic angiography. Only monosymptomatic cases with isolated pain were included in this series.We analyzed pain topography, dynamics, severity and quality, as well as imaging findings and outcome in affected cases. Results: Overall, 21 sCAD patients presented with pain as the only symptom (mean age: 40 years ± 9SD; n = 15 (71 %) women). Thirteen had vertebral artery dissection, 3 internal carotid dissection and 5 multiple dissections. The median delay from symptom onset to diagnosis was 8 days (range 2 hours to 101 days). Six patients presented with headache, 2 with neck pain, and 13 with both, headache and neck pain. Onset of headache was progressive in 7, acute in 8, and thunderclap-type in 4; neck pain was progressive in 8 and acute in 7. Headache was throbbing in 13 and constrictive in 6 patients; neck pain was throbbing in 4 and constrictive in 11. Twelve patients had unilateral and 9 bilateral pain. Pain was different from earlier episodes in all but one case. All but one patient were pain-free at 3 months. Conclusion: Pain may be the only symptom in sCAD, even when multiple arteries are dissected. Pain topography, dynamics, quality and intensity were heterogeneous, and no uniform pattern could be identified. Our data lend support to recommendations favoring detailed imaging studies of the cervical arteries in patients complaining of new-onset unexplained headache or neck pain.

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O139 Microbubble potentiated transcranial duplex ultrasound during intravenous thrombolysis improves outcome in acute middle cerebral artery stroke F. Perren, J. Loulidi, D. Poglia, T. Landis, R. Sztajzel University Hospital of Geneva (Geneva, CH) Objective: We studied whether transcranial color-coded duplex (TCCD) which allows to visualize basal cerebral arteries and therefore to locate more precisely blood clot site combined to microbubble echocontrast agent during intravenous (IV) rtPA-thrombolysis improves outcome in the acute phase of thromboembolic middle cerebral artery (MCA) stroke. Methods: Non-randomized acute MCA stroke patients treated with 0.9 mg/Kg TPA (10 % bolus) within 3 hours of stroke onset (group 1) were compared in terms of MCA recanalization and/or clinical improvement to those in whom additional TCCD monitoring (2MHz; over 60 minutes) alone (group 2) or associated with continuous microbubble echocontrast agent injection (ECA) (5 ml, SonoVue) (group 3) was performed. Clinical outcome was assessed after treatment (24 hours) using the NIH Stroke Scale (NIHSS). Recanalization of the MCA was recorded pre- and post-thrombolysis using the Thrombolysis in brain ischemia (TIBI) grading system. Results: Of the 53 patients (28 men; mean age 70.2 years), median baseline NIHSS 12.1, range [6–20], who received within 3 hours of stroke onset systemic rtPA thrombolysis, 23 constituted group 1 (iv-thrombolysis alone); 16 constituted group 2 (iv-thrombolysis + TCCD monitoring); and 14 constituted group 3 (iv-thrombolysis + TCCD monitoring + ECA) The three groups differed significantly in their improvement of the NIHSS (KruskalWallis H = 8.0; p < 0.005). Pairwise comparisons showed group 3 to improve the NIHSS significantly more than both group 2 (Mann-Whitney U = 60; p < 0.03) and group 1 (U = 72; p < 0.002). Moreover, the flow signal (measured in improvement of TIBI grades) improved more in group 3 than in group 2 (Mann-Whitney U = 65; p < 0.03).IV-thrombolysis mean time at onset, subsequent intracerebral haemorrhage and mortality rate did not differ between the 3 groups. Conclusion: The results of this pilot study show that the use of ECA in addition to iv-thrombolysis + TCCD monitoring lead to a greater clinical improvement (NIHSS) than both iv-thrombolysis + TCCD monitoring and ivthrombolysis alone. Moreover, the flow signal (in TIBI grades) improves more when ECA is added to iv-thrombolysis + TCCD monitoring. This result encourages the evaluation of the thrombolytic effect of echo-contrast agent combined to transcranial duplex ultrasound on a larger clinical scale.

O140 ESPRIT: Results of a randomised comparison of the effects of aspirin + dipyridamole versus aspirin alone in patients after cerebral ischaemia of arterial origin P. Halkes on behalf of the ESPRIT study group Objectives: Aspirin (ASA) ≥ 30 mg/day prevents only 13 % of subsequent vascular events after minor cerebral ischaemia of arterial origin. The 2nd European Stroke Prevention Trial reported a 22 % (95 % CI 9 to 33 %) relative risk reduction (RRR) of the combination of ASA and dipyridamole (DIP) above that of ASA only. Pooled results of four smaller trials, however, had shown an RRR of only 3 % (95 % CI –22 to 22 %). Hence, uncertainty exists on the efficacy of ASA + DIP. Methods: ESPRIT, the European/Australasian Stroke Prevention in Reversible Ischaemia Trial, is a multicentre, randomised, open, parallel group, controlled trial. Patients with cerebral ischaemia of arterial origin (TIA or non-disabling stroke; modified Rankin < 4) were randomised between ASA (30–325 mg/day) + DIP (2x200 mg/day) and ASA only (30–325 mg/day) within six months of the event. Primary outcome was the composite of vascular death, nonfatal stroke, nonfatal myocardial infarction or major bleeding. Outcome assessment was blinded. Results: We randomised 1390 patients to ASA + DIP and 1407 to ASA only. Patients were randomised in 80 different hospitals in 15 countries. Mean follow-up was 3.5 years. Baseline characteristics were similar in the two treatment groups. Mean age was 63 years, 65 % was male. Thirty-four percent had a TIA (5 % transient monocular blindness) and 66 % a minor ischaemic stroke; 44 % had no residual symptoms at the time of randomisation (modified Rankin = 0), 32 % was randomised within a month of the event. Brain imaging showed a relevant ischaemic lesion in 35 %; a stenosis of the carotid arteries > 50 % was detected in 10 % of the patients. There was no difference in vascular risk factor profile and vascular history between the two treatment groups.The overall annual rate for the primary outcome event (first events only) was 4.4 %. Outcome events will be reported according to allocated trial medication; an updated meta-analysis will also be presented. Conclusion: With the results of this sufficiently large trial we will resolve

the uncertainty whether ASA + DIP or ASA alone should be the preferred prophylactic therapy after cerebral ischaemia of arterial origin.

O141 The relationship of leptin and leptin receptor gene Gln223Arg polymorphism in ischaemic stroke O. J. Kim, Y. H. Ku, K. K. Kim, I. H. Lee, N. K. Kim, W. C. Kim, H. S. Kim Pochon CHA University (Sungnam, KOR) Background & objective: Leptin is a peptide hormone secreted by adipocyte and its function is regulation of body weight through reducing food intake and stimulating energy expenditure. Leptin receptor (LEPR) is located at brain, liver, pancreas, and muscle. The mutation of LEPR gene causes inactivation of LEPR, and then hyperleptinemia and obesity appear. It is known that hyperleptinemia involves in the pathogenesis of ischemic stroke such as atherosclerotic process, endothelial dysfunction, and platelets aggregation. To investigate the effect of LEPR gene to leptin in ischemic stroke, we studied the LEPR Gln223Arg polymorphism and plasma leptin levels in patients with ischemic stroke. Methods: 47 patients (26 men, 21 women) with ischemic stroke were enrolled in this study. We examined their fasting blood sugar (FBS), total cholesterol, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and leptin levels. The LEPR Gln223Arg polymorphism was analyzed using standard PCR-RFLP method. Body mass index (BMI) was calculated with body weight and height. Result: Mean age of the patients was 64.23(SD = 13.99) y-o. The Gln223Gln was found in 16 patients (34 %), Gln223Arg in 15 patients (32 %), and Arg223Arg in 16 patients (34 %). Plasma leptin levels were significantly higher (p = 0.013) in Arg/Arg type (8.95 ± 2.89 microg/l) than Gln/Gln (4.34 ± 2.07 microg/l) and Gln/Arg types (6.24 ± 3.65 microg/l).There were the tendency of higher BMI in Arg/Arg type (24.1 ± 1.47 kg/m2) but statistical significance was not found. The plasma level of FBS, TG, LDL, and HDL were not significantly different among three groups. Conclusion: We found that plasma leptin levels were significantly higher in the Arg223Arg type than other types among LEPR polymorphism in ischemic stroke. Therefore, this finding suggests that LEPR polymorphism is the important factor inducing hyperleptinemia known as risk factor in ischemic stroke.

O142 Ischaemic stroke subtypes in Tbilisi: results of the first prospective population-based study in Georgia A. Tsiskaridze, M. Djibuti, T. Vashadze, G. Lomidze, S. Apridonidze, Z. Kharaishvili, I. Burduladze, I. Beridze, R. Shakarishvili Sarajishvili Institute of Neurology (Tbilisi, GEO) Background: Although stroke is one of the major public health problems worldwide, up to now no population-based study on major epidemiological patterns of stroke has been designed in Georgia. The purpose of the present study was to determine incidence of ischemic stroke (IS) 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 125 first-ever ISs occurred during the study period. Age-adjusted annual incidence rate per 100.000 inhabitants was 89 (95 % CI 74–105). Regarding IS subtypes, using the Oxfordshire Community Stroke Project classification, there were 17 cases (14 %) of lacunar stroke, 32 (26 %) of total anterior circulation stroke, 54 (43 %) of partial anterior circulation stroke, and 22 (18 %) of posterior circulation stroke. Conclusion: Incidence of IS in the urban population of Georgia is not as high as expected for a country in transition with socio-economical difficulties and shortcomings in medical care. Furthermore, IS incidence rate is among the lowest rates ever reported. On the other hand, the distribution of the main clinico-pathological subtypes of IS does not differ markedly from those in other registries. Geographical, genetic and lifestyle variations may explain these findings. The study was supported by Swiss National Science Foundation grant 7GEPJ062287

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O143 Intracranial angioplasty and stenting for symptomatic and asymptomatic intracranial stenosis M. Avila, M. De la Maza, A. Martinez Ponce De Leon Hospital San Jose TEC (Monterrey, MEX) Objective: Describe the clinical outcome in patients with symptomatic or asymptomatic intracranial stenosis treated with intracranial angioplasty with or without stenting. Background: Angioplasty with or without stenting for Intracranial atherosclerosis is being increasingly performed. We report 25 patients who underwent such procedure. Method: We reviewed clinical data of 25 patients, 9 female (mean age 71.4), 16 male (mean age 67.3) with intracranial artery stenosis treated with angioplasty with or without stenting between 2000–2005. We determined age, gender, ethnicity, mayor modifiable risk factors, degree and distribution of intracranial stenosis and 30 day periprocedural mortality rate. A total of 26 procedures (one patient had 2 procedures) all evaluated with computerized tomography (CT scan) and/or magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA).17 procedures in symptomatic cases, 9 of these presented within the first 3 hours of stroke symptoms all evaluated with and NIH stroke scale and 8 procedures in patients with transient ischemic attack (TIA) symptoms. 9 where performed in asymptomatic patients. 12 procedures performed in left vertebral artery (LVA), 2 in right vertebral artery (RVA), 2 basilar artery, 9 in middle cerebral artery (MCA) M1 segment (6 left MCA, 3 right MCA), and one in M2 segment of left MCA. Mean artery stenosis was 90.4 %. Results: Of the 26 procedures, 23 angioplasty with stenting where performed, 12 in LVA, 2 in RVA, 1 basilar artery, 5 in Left MCA-M1, 2 in right MCA-M1, one in left MCA-M2, all with excellent results and no procedural complications. Angioplasty without stenting where performed in 3 patients, one basilar artery, 2 in MCA-M1(left and right), all with excellent results and no complications except for one patient who developed progressive stroke symptoms due to intracranial hemorrhage immediately after the endovascular procedure. In retrospective review of this patient we found early ischemic findings in CT scan that didn’t make him a good candidate for the procedure. Our 30 day morbidity and mortality rate was 4 %. Conclusions: Intracranial symptomatic and significant asymptomatic stenosis can be successfully treated with angioplasty with or without stenting. Patient selection, physician’s endovascular skills, procedure timing and medical periprocedural management are critical factors to reduce morbidity and mortality.

Session 21 Genetics O144 Late-onset autosomal dominant Alzheimer’s disease due to presenilin-1 R269H mutation with reduced penetrance A. J. Larner, P. S. Ray, M. Doran Walton Centre (Liverpool, UK) Objective: To report a kindred with autosomal dominant Alzheimer’s disease (AD) with five affected members in two generations, due to the presenilin-1 (PS1) R269H mutation. Methods/setting: Observational study, Cognitive Function Clinic Results: The proband developed memory problems at age 66, with diagnosis of AD at age 68. He was treated with cholinesterase inhibitors, but continued to decline, developing a profound visual agnosia affecting particularly the dorsal (where) visual stream. Behavioural and psychological features were notably absent. His younger sister developed memory problems aged 67 and was diagnosed with AD two years later. Their mother was also affected, with estimated age of onset in her late 50s. Two maternal aunts were also reported to be affected. Discussion/conclusion: Most PS1 mutations are associated with earlyonset AD (< 65 years). This kindred shows that late-onset AD (> 65 years) may be associated with the R269H PS1 mutation, reflecting reduced penetrance. This has been reported on occasion with other PS1 mutations but not in the three previous reports of R269H cases, nor in two R269G families. If family history is strongly suggestive of autosomal dominant transmission of AD, PS1 testing should be undertaken even in cases of late-onset AD.

O145 Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant PD: identification of two novel LRRK2 variants G. Xiromerisiou, V. Gourbali, E. Dardiotis, M. Dardioti, V. Tsimourtou, K. Aggelakis, I. Papakonstantinou, G. Noulas, A. Papadimitriou, A. Singleton, G. Hadjigeorgiou University of Thessaly (Larissa, GR); General Hospital (Trikala, GR); NIA/NIH (Bethesda, USA) Objectives: To search for mutations in SNCA and LRRK2 genes, encoding alpha synuclein and dardarin, respectively, those cause autosomal dominant Parkinson’s disease (AdPD). To identify the frequency of the LRRK2 G2019S mutation in sporadic PD patients. Methods: We studied 55 unrelated patients with AdPD, 235 patients with sporadic PD, and 235 healthy age- and gender-matched controls all of Greek origin. Patients with AdPD were screened for SNCA and LRRK2 mutations by direct sequencing. SNCA gene dosage analysis was also performed for AdPD using quantitative duplex PCR of genomic DNA. In addition, we investigated the frequency of the LRRK2 G2019S mutation in sporadic PD using Taqman single nucleotide polymorphism assay in the ABI PRISM 7000 sequence detection system. Results: We identified neither missense mutation nor multiplication in the SNCA gene in our AdPD Greek cohort. Hence, SNCA genomic multiplications are a rare cause of AdPD in Greece. Here we report two novel variants, A211V (c 0.632C > T) and K544E (c 0.1630A > G) in LRRK2 gene in two patients with AdPD that was not present in controls. We identified only one patient with sPD (1/235; 0.4 %) carrying the G2019S mutation. Conclusions: Novel LRRK2 variants are associated with AdPD in Greek PD patients with a frequency of 3.6 % in our cohort while the frequency of the G2019S in sporadic PD patients is less than 1 %. The identification of two novel variants could mean that specific LRRK2 mutations are likely to be more frequent in certain populations. Screening of large number of familial and sporadic cases in populations of different ethnic origin will help us estimate the actual rate of different mutations in different populations and identify the most important causes of susceptibility for Parkinson’s disease. O146 Dardarin mutations in Spanish patients with Parkinson’s disease J. Infante, E. Rodriguez-Rodriguez, O. Combarros, I. Mateo, C. Sánchez-Quintana, A. Fontalba, J. Terrazas, J. Berciano University Hospital Marqués de Valdecill (Santander, E); Laredo Hospital (Santander, E) Objectives: To determine the prevalence of LRRK2 G2019S and R1441G mutations in a series of unselected patients with Parkinson’s disease (PD) from Cantabria (Northern Spain) Methods: Over a period of 12 months, 145 consecutive patients fulfilling diagnostic criteria for PD, were recruited from our Department, wich receives neurological patients from Cantabria, a region with 500.000 inhabitants bordering on the Basque Country. DNA samples were obtained from patients and also from 300 non-parkinsonian controls. A Taqman probe on an ABI 7900 (Applied Biosystems, Foster City, CA, USA) was used to screen for G2019S mutation, whereas R1441G mutation was assessed by BstUI digestion of an exon 31 polymerase chain reaction product.All mutations were confirmed by direct sequencing using standard techniques. Results: Of 145 patients, 110 presented with late-onset sporadic PD, 23 reported a late-onset family history of PD, and the remaining 12 patients had early-onset PD. Twelve patients were found to carry mutations in Dardarin gene (10 G2019S and two R1441G). Screening for these mutations in controls was negative. Of the 133 late-onset PD patients screened, we identified 9 (6.8 %,95 % CI 3.6–12.5 %) carrying the G2019S mutation (8 heterozigous and one homozigous). One additional early-onset patient also carried this mutation. Mean age at onset was 64.9 ± 9.8 years, and symptoms were typical of idiopathic PD in all mutation carriers. Three of the patients had a positive family history; two of them belonging to pedigrees compatible with autosomal dominant inheritance, and the third one having one first degree relative with PD. The remaining 7 patients were apparently sporadic with no relevant family history. Of the two patients carrying the R1441G mutation one had a family history compatible with autosomal dominant inheritance whereas the other one was sporadic. Conclusions: Mutations in the Dardarin gene account for 8.2 % of PD cases in Cantabria. G2019S mutation is behind a high proportion (5.4 %) of apparently sporadic, clinically typical, late-onset cases.

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O147 Difference of penetrance in transthyretin amyloid neuropathies across families from European and Brazilian origin V. Planté-Bordeneuve, U. Hellman, M. Sapporta, A. Ferreira, C. Zaros, O. Suhr, M. Waddington Cruz, M. Misrahi, G. Said, C. Bonaiti-Pellié CHU Bicêtre (Le Kremlin Bicêtre, F); University Hospital (Umea, S); University Hospital (Rio de Janeiro, BR); Inserm U535 (Villejuif, F)

O149 Sacsin mutations in six unrelated Italian patients with autosomal recessive spastic ataxia (ARSACS) C. Mariotti, F. M. Santorelli, R. Fancellu, S. Di Giandomenico, C. Gellera, S. Romano, F. Taroni, S. Di Donato Istituto Nazionale Neurologico C.Besta (Milan, I); IRCCS-Ospedale Pediatrico “Bambino Gesù”, (Rome, I)

Transthyretin amyloid neuropathies are dominant affections described in northern Portugal, subsequently diagnosed across Europe and Japan. Depending on the geographic origin of patients, striking differences of age of onset are observed, which account for phenotypic variation. In order to improve our understanding of such discrepancy, we have extended our work on estimation of the penetrance of the disease in families from different European origin. The estimation of penetrance was perfomed with a method previously described based on maximum likelihood, using a survival analysis approach, and correcting for ascertainment bias. Genealogical investigations, clinical information on symptomatic cases and result of the genotyping of voluntary family members were obtained in relatives of 83 Swedish, 46 French, 33 Portuguese and 23 Brasilian kindred. Up to 12 different pathogenic transthyretin variants were detected in the French cases, including the Val30Met, whereas the Val30Met was the only variant in the families of other origin. As expected, similar penetrance estimates were observed between Portuguese and Brasilian families, with a similar mean age of onset (34 ± 10.5 vs 31.5 ± 4.3 years). By contrast, the penetrance curves were quite different between Swedish, French and Portuguese populations, with an age of onset of 54.5 ± 16.1, 58.9 ± 12.3 and 34 ± 10.5 years, respectively. In all 4 samples, penetrance was incomplete by the age of 80 years. At this age, although the lifetime risk of being affected appeared similarly high in Portuguese, Brasilian and French carriers, it was found much lower in the Swedish carriers. These results provide an important input for genetic counselling in different populations of TTR amyloidosis and for understanding the factors underlying the phenotypic variation.

The Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS; MIM 270550) is an early-onset neurodegenerative disease initially described in families from the Charlevoix-Saguenay region in north-eastern Canada. The clinical phenotype is characterized by early onset gait unsteadiness, progressive spastic paraplegia, and peripheral neuropathy. Mutations in a gene (SACS) encoding a protein named sacsin were associated with the disease. Several different mutations in the SACS gene have been described in patients from Tunisia, Turkey, and Japan. In Italy, four ARSACS patients from have been described so far. We screened for mutations 9 unrelated patients with cerebellar ataxia, lower limb spasticity, and peripheral neuropathy. All cases were negative at molecular test for Friedreich ataxia. Mutational analysis was performed by direct DNA sequencing of PCR-amplified overlapping fragments, spanning the entire coding region of the SACS gene. We identified new SACS gene mutations in six subjects. Three cases were homozygous for frame-shift or nonsense mutations, while three cases were compound heterozygous. Five individuals had a sporadic presentation of the disease, while a patient had a sibling with a similar neurological phenotype. The age at onset ranged from 1 to 33 years. The first symptoms were invariably represented by dysequilibrium and gait ataxia: in four cases movement difficulties were noted since the first years of age, whereas two patients presented a later onset of the disease (10 and 33 years).At neurological examination all patients had severe spastic gait, mild limb ataxia, oculomotor abnormalities (nystagmus and saccadic pursuit), increased deep tendon reflexes, increased muscle tone in lower limbs, Babinski sign, and mild reduction of vibratory sensation. Mild dysarthria was present in 5/6 patients. None of the patient had prominent myelinated retinal nerve fibres. Brain MRI consistently showed severe cerebellar atrophy, predominantly of the upper cerebellar vermis. Peripheral sensory neuropathy was also found in all cases. Our study described clinical features and SACS gene mutations in six Italian families. The phenotype in our cases largely corresponded to that described in other patients having mutations in sacsin. Data from our study suggest that the diagnosis of ARSACS should also be considered in patients with a late disease.

O148 PCWH – molecular mechanisms for SOX10 mutations K. Inoue, M. Khajavi, T. Ohyama, C. Akazawa, J. R. Lupski National Institute of Neuroscience (Tokyo, JP); Baylor College of Medicine (Houston, USA) Mutations in the SOX10 gene, that encodes a transcription factor essential for neural crest development, cause two distinct neurocritopathies. One is a complex neurologic form designated peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH; MIM#609136) and the other is a more restricted phenotype known as Waardenburg-Hirschsprung disease (WS4; MIM#277580). The purpose of this study is to delineate molecular mechanism as to how two distinct clinical entities are associated with different mutations in the same gene, i. e., allelic affinity. We performed in vitro assays to examine the stability of SOX10 mRNAs and the function of SOX10 proteins that bear various SOX10 mutations. WS4-causing mutations result in premature termination codons (PTCs) located in upstream exons and appear to trigger the nonsense mediated mRNA decay (NMD) surveillance pathway. Thus, mRNAs carrying such mutations are subject to degradation and no mutant protein is made. The WS4 phenotype is a consequence of haploinsufficiency of SOX10. In contrast, molecular pathoetiology for PCWH-causing SOX10 mutation is distinct. Most mutations associated with PCWH result from PTC within the last exon and such mutant mRNAs can escape from NMD and thus stably translated into mutant proteins. These mutant proteins have a dominant-negative function and compete with wild type SOX10. Furthermore, a rare extension mutation that add an ~80 amino acid tail onto the Carboxyl terminus of wild type SOX10 revealed unique features. A short polypeptide within the tail was apparently responsible for functional toxicity. The extension also changed the level of post-translational regulation of SOX10 proteins. Thus, this type of mutation most likely acts as a gain-offunction allele. Together, our findings suggest that different molecular mechanisms including haploinsufficiency, dominant-negative and gain-offunction, appear to underlie the allelic affinity of SOX10 mutations associated with either PCWH or WS4.

Oral session 22 Muscle disorders O150 Muscleblind-like protein 1 in muscle biopsy: histopathological marker of myotonic dystrophies G. Meola, R. Cardani, G. Rotondo, V. Sansone, E. Mancinelli University of Milan (San Donato Milan, I) Objectives: Myotonic dystrophies (DM) are autosomal dominant multisystemic disorders caused by two different microsatellite expansions. Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion in the 3’ untraslated region of the dystrophya myotonica-protein kinase gene on chromosome 19, whereas myotonic dystrophy type 2 (DM2) is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 gene on chromosome 3. DM1 and DM2 share similar phenotypes and a common pathogenic mechanism that involve the accumulation of mutant transcripts in muscle nuclei producing ribonuclear inclusions, which result in abnormal splicing of a number of genes that are related to DM pathophysiology.Among the RNA-binding proteins that can bind CUG/CCUG repeats, muscleblind-like proteins (MBNLs) appear to be involved in DM splicing defects. MBNL1 knockout mice develop DM-like eye and muscle phenotypes and splicing defects characteristic of DM pathologies. In our study we have examined the in vivo distribution of MBNL1 in muscle sections from DM patients and from patients with other myotonic disorders. Methods: We have used by immunofluorescence an anti-MBNL1 polyclonal antibody on cryostat sections of biceps brachii muscle biopsies from genetically confirmed DM1 (n = 7), DM2 (n = 8), non-dystrophic myotonic disorders (5 chloride channelopathies, 2 sodium channelopathies), nonDM1/DM2 (n = 3) patients and healthy subjects (n = 5) used as control.

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Results: MBNL1 is localised primarily in the nucleus. A similar distribution is observed in nuclei of skeletal muscles from all the 7 non-dystrophic myotonic patients, from the 3 non-DM1/DM2 patients and from controls. In DM1 and DM2 myonuclei, MBNL1 is depleted in nucleoplasm and present in multiple protein foci. As expected, by using FISH ((CAGG)5 probe), it appear that focal accumulation of MBNL1 in DM2 myonuclei co-localize precisely with the foci of transcripts containing the CCUG expansion. Conclusions: Our data indicate that, among patients with myotonic disorders, nuclear accumulation of MBNL1 is an histopathological marker of DM1 and DM2 patients. Loss of MBNL1 function due to sequestration on CUG/CCUG repeat expansions play a major role in DM pathogenesis reproducing the splicing alterations that leads to characteristic DM features like myotonia, insulin resistance and cardiac defects. As alternative splicing factors, MBNLs might be viable targets for therapeutic interventions to correct some of the specific features of DM. O151 Screening of Twinkle gene in POLG1- and ANT1-negative patients with mitochondrial myopathy and multiple mitochondrial DNA deletions: four new mutations R. Virgilio, D. Ronchi, A. Bordoni, L. Adobbati, G. M. Hadjigeorgiou, D. Kafetsouli, E. Tsironi, A. Papadimitriou, M. Moggio, N. Bresolin, G. P. Comi University of Milan (Milan, I); Istituto Auxologico (Milan, I); University of Thessaly (Larissa, GR) Objective: To search for Twinkle gene mutations in 37 patients with mitochondrial myopathy and multiple muscle mitochondrial DNA (mtDNA) deletions, after exclusion of ANT1 and POLG gene mutations. Background: Autosomal dominant and recessive (AD/AR) progressive external ophthalmoplegia (PEO) are mitochondrial disorders caused by mutations in POLG1, ANT1 and C10ORF2 genes, associated with muscle multiple mtDNA deletions. C10ORF2 encodes Twinkle and its mutations may cause AD PEO or Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoplegia, while AR mutations cause Infantile Onset Spino-Cerebellar Ataxia. Mutations in Twinkle are relatively rare. Design/methods: We collected a sample of patients affected by mitochondrial myopathy with multiple deletions of mitochondrial DNA, analysed by Southern Blot and PCR, and resulted negative for POLG1 and ANT1. The sample included 17 patients with a PEO phenotype and 20 patients without extraocular muscle involvement. 13 patients had a positive family history, including large multigenerational Greek and Italian families with AD transmission of adult-onset PEO, autosomal recessive inheritance as well as sporadic cases.Twinkle gene was PCR-amplified and directly sequenced. Mutations were verified in 200 Italian and 100 Greek controls. Segregation was analysed in other family members. Results: We evidenced five heterozygous missense mutations in eight independent families. Four mutations are novel and one has been previously described. All mutations are associated with PEO phenotype and co-segregate with the disease in families with multiple affected members. Novel mutations are detected in AD families (R334P,W315S, F478I) and the fourth one is associated with a sporadic PEO case (E479K). Four PEO patients present the previously described R303W mutation, whose pathogenetic role was not previously demonstrated. The E497K is a de-novo mutation in a 19-year-old PEO female whose parents have a normal phenotype and genetics. The novel mutations affect highly conserved aminoacids and are absent in controls. Conclusions: Twinkle mutations account for 21 % of our cases. They are usually associated with a PEO familial cases,but we also identified a sporadic case. Four novel mutations extend genetic heterogeneity associated with Twinkle gene. The finding of a de-novo mutation in a sporadic case suggests to analyse Twinkle gene in apparently recessive PEO patients. O152 Familial steroid sensitive myotonia associated with multiple myeloma – a new disease entity M. Hauf, L. Kappeler, D. Waldvogel, S. Gallati, A. Schaller, K. M. Rösler University of Berne, Inselspital (Berne, CH); Klinik St Anna (Lucerne, CH) Objectives: To characterise 2 brothers with childhood-onset, non progressive, invalidating generalized myotonia and a marked and sustained response to dexamethasone. Methods: We provide clinical data and results of muscle biopsy, haematologic and preliminary genetic analysis. Results: Severe muscle stiffness, especially during sudden forceful movements occurs generalized in axial, proximal, and distal muscles causing frequent falls and accidents. A marked warm-up phenomena is present in both patients since childhood.Aggravation by nutrition or temperature, and transient paralysis/pain do not occur. Clinical examination discloses a severe ac-

tion and percussion myotonia, but no other abnormalities. Needle myography demonstrates abundant myotonic discharges in distal and proximal muscles, but is otherwise normal. Laboratory results (i. p. electrolytes) are normal. Potassium oral challenge test did not provoke muscle weakness, and muscle biopsy of vastus medialis in one subject was normal. Myotonia did not improve to treatment with carbamazepine, mexiletine, acetazolamide and furosemide. After administration of glucocorticoids (dexamethasone), myotonia disappeared within 48 hours, amelioration starting in the lower limbs 9 hours after administration. This effect was dose dependant. One brother is subjectively asymptomatic with dexamethasone 0.5 to 1 mg/d, the other one with 4 mg/d. In one of the patients, a multiple myeloma (MM) IgA kappa Stadium III A was diagnosed at the age of 53. Subsequently, in his brother (50y) an asymptomatic MM Stadium IA of the same type was disclosed. There is no evidence in the family history for consanguinity, and no other family member (including 5 sisters) are affected by myotonia or MM. The father died at the age of 49 of cardiac disease. Preliminary genetic testing did not demonstrate an association with known myotonia mutations. Conclusion: This is the first report of a disease entity characterised as familial steroid sensitive myotonia. The myotonia is childhood-onset, not progressive, generalized, and invalidating. It responds markedly and in a dose dependant fashion to dexamethasone. There is an association to a multiple myeloma of IgA-kappa in both siblings, suggesting a chromosomal deletion as common genetic basis of the diseases. Screening for known genetic disorders causing myotonia was negative. An extended genetic analysis is ongoing. O153 Normal values for muscle functional magnetic resonance spectroscopy during tetanic electrical nerve stimulation B. Bachofen, L. Graf, W. J. Z’Graggen, A. C. Nirkko, K. M. Rösler, J. Slotboom University Hospital (Berne, CH) Objectives: Muscle metabolites are of special interest in the clinical diagnostics of muscle and nerve diseases. Functional magnetic resonance spectroscopy (fMRS) allows non-invasive monitoring of the energy turnover before, during and after electrically imposed muscle activity. The aim of this study was to derive normal values. Methods: 26 healthy volunteers were included. The peroneal nerve was stimulated with a supramaximal (30–45 mA) electrical pulse train of 20 Hz during 2 min to achieve an isometric maximal tetanic muscle contraction. Proton spectra of the anterior tibial muscle were acquired with a 12 s temporal resolution before, during and after stimulation. Serum creatin kinase (CK) and myoglobin levels were measured before stimulation and 1 hour after. Results: All measurements were technically successful and yielded a robust pattern of a decrease of the phosphocreatine (CrP) associated peaks during, and an incomplete recovery in the first minutes after stimulation, together with an increase in acetyl carnitine (AcCt). The electric stimulation was tolerated by all subjects (average pain-rating was 5.3 on a scale of 0–10). There was a weak correlation between pain and stimulus current (r = 0.4). A clinically irrelevant increase of serum myoglobin by 4.9 ug/l (normal upper limit < 110) was statistically significant (p < 0.005). Conclusion: The application of the method is straightforward, allows for assessment of muscle metabolites during electrically imposed maximal exercise in a clinical setting, and reliable normal values can be obtained. Supported by the Swiss National Science Foundation (SNF grant 3200B0–107499/1).

Session 23 Dementia O154 The value of lumbar cerebrospinal fluid levels of neurofilaments in the differential diagnosis of patients with dementia A. Petzold, G. Keir, N. C. Fox, J. Warren, M. Rossor on behalf of APOPIS Objective: A key feature of degenerative dementias is loss of cortical neurons. Here we test whether cerebrospinal fluid (CSF) neurofilaments (Nf), a biomarker for neuro-axonal loss are of value for the investigation of patients with dementia.

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Methods: Lumbar CSF levels of neurofilaments (NfH-SMI35) were quantified in 367 patients (dementia, Alzheimer’s disease (AD), frontotemporal lobe degeneration (FTLD), FTLD with montor neuron disease (MND) and non–inflammatory neurological controls) using a standard ELISA. Additionally CSF total tau (hTAU) was measured in those patients with AD or FTLD. The mini–mental state examination (MMSE) was recorded at time of lumbar puncture. Results: Median CSF NfH-SMI35 levels were similar in patients with dementia compared with controls (0.19 versus 0.20 ng/mL). Only 3 % of patients with dementia had pathologically elevated CSF NfH-SMI35 levels (above 0.73 ng/mL). These cases are discussed in detail. The differential diagnosis between AD and FTLD could be improved by CSF hTau, but not by CSF NfH-SMI35. CSF hTau correlated inversely with the minimental state examination (R = –0.48, p < 0.001). The literature on CSF Nf in dementia is reviewed. Conclusion: Lumbar CSF NfH-SMI35 levels do not help in the differential diagnosis of AD versus FTLD if used as a screening test. They may however be of some value in a subgroup of patients such as FTLD with MND. We speculate that the high CSF hTau levels found in some patients with dementia may be more closely related to glial pathology as opposed to axonal degeneration as previously thought.

ceptibility to AD. Methods: The study included 321 AD patients (68 % women; mean age 75.6 years; SD 9.0; range 50–98 years) who met NINCDS/ADRDA criteria for probable AD. Control subjects were 315 unrelated individuals (70 % women; mean age 80.3 years; SD 7.7; range 63–100 years) with Mini Mental State Examination scores of 28 or more, which were verified by at least one subsequent annual follow-up assessment. Results: In APOE e4 carriers, homozygous for the CETP [–629] A allele had approximately a three times lower risk of developing AD (odds ratio, OR, 2.33) than homozygous and heterozygous carriers of the CETP [–629] C allele (OR = 7.12; P < 0.001)). Subjects carrying both the LDLR exon 8 allele A and the LRP exon 3 allele T had about a seven times higher risk of developing AD than subjects without these risk genotypes (OR = 7.37; p = 0.015). When compared to CYP46 intron 2 T/T or C/T genotypes, the OR for the CYP46 C/C genotype was 2.91 (p = 0.004), and this association with AD risk was independent of the APOE e4 allele. Conclusions: Gene-gene interaction between LDLR and LRP increases AD risk; interaction between CETP and APOE e4 allele decreases the AD risk associated with the APOE e4 allele; the CYP46 polymorphism may predispose to AD, and this association is independent of the APOE e4 allele. Considering synergistic effects between polymorphisms in cholesterol-related genes may help in determining the risk profile for AD.

O155 Chemokine serum levels in mild cognitive impairment and Alzheimer’s disease D. Galimberti, C. Fenoglio, C. Lovati, E. Venturelli, I. Guidi, B. Corrà, D. Scalabrini, F. Clerici, C. Mariani, N. Bresolin, E. Scarpini University of Milan, Ospedale Maggiore (Milan, I); University of Milan, Ospedale Sacco (Milan, I)

O157 Genetic and clinicopathological correlation of frontotemporal lobar degeneration A. Llado, M. Ezquerra, M. J. Rey, M. Fernández, R. Sanchez-Valle, E. Tolosa, I. Ferrer, J. L. Molinuevo Hospital Clínic Barcelona (Barcelona, E); Universitat de Barcelona (Barcelona, E)

Background: upregulation of a number of chemokines is associated with Alzheimer’s disease (AD) pathological changes. Recent findings demonstrate that Interferon-gamma-inducible Protein-10 (IP-10) cerebrospinal fluid levels are significantly increased in Mild Cognitive Impairment (MCI) and mild AD, but not in severe AD patients, whereas Monocyte Chemotactic Protein-1 (MCP-1) and Interleukin-8 (IL-8) levels are increased in MCI and all AD patients, suggesting that the presence of inflammatory molecules is likely to be a very early event in AD pathogenesis. Objectives: to evaluate IP-10, MCP-1 and IL-8 levels in serum samples from 40 subjects with MCI, 40 AD patients and 40 age-matched controls. To follow longitudinally MCI patients until conversion to AD. Methods: serum samples were collected at time of diagnosis. For MCI patients, a second sampling was done after a 1-year follow up. Chemokine levels were evaluated by ELISA. Non parametric Kruskal Wallis test with posthoc comparisons among groups was used to test for differences. Results: significantly increased serum IP-10 and MCP-1 levels were found in MCI and mild AD, but not in severe AD patients as compared with controls. mRNA levels in Peripheral Blood Mononuclear Cells (PBMC), evaluated by quantitative RT-PCR analysis, paralleled serum levels. Moreover, a progressive chemokine decrease was observed over a 1-year follow up in a subgroup of MCI subjects converted to AD. Conclusions: chemokine serum upregulation is likely to be a very early event in AD pathogenesis, by far preceding the clinical onset of the disease, thus candidating these molecules as early biomarkers. Nevertheless, as chemokines are likely to play a role in several pathologies with an inflammatory component, a possible usfulness as biomarkers would probably be possible only in combination with other factors.

Objective: Frontotemporal lobar degeneration (FTLD) is a clinical syndrome, with different pathological substrates, characterized by progressive personality changes and/or language impairment. The most frequent genetic alteration causing FTLD are mutations in the MAPT gene, which encodes protein tau. The aim of this study was to correlate clinical diagnosis and genetic features with different pathological substrates. Methods: Patients with pathological proven FTLD were selected from the Universitat de Barcelona brain bank. A retrospective review of the medical records was conducted by two neurologists. We clinically classified cases as frontotemporal dementia (FTD) or primary progressive aphasia (PPA) according to consensus criteria. Patients were classified as FTD with motoneuron disease (FTD-MND) if they developed MND symptoms. Genomic DNA was isolated from frozen brain tissue. Coding exons 1 and 9–13 of MAPT gene were screened by direct sequencing. Neuropathological findings were classified according to the presence or absence of immunoreactive inclusions or staining patterns into cases with tau-positive pathology, cases with ubiquitin-positive tau-negative inclusions (FTLD-U), cases with neuronal intermediate filaments inclusions disease (NIFID) and cases with dementia lacking distinctive histology (DLDH). Results: We included 13 men and 7 women. Twelve patients were clinically diagnosed of FTD, 2 patients of PPA and 6 patients of FTD-MND. Only 3 patients had a family history and early onset dementia (< 65y). Two of them presented the P301L mutation. These two patients showed tau positive pathology. The other 10 patients with clinical FTD had heterogeneous pathological substrates (3 Pick, 3 FTLD-U, 1 NIFID and 3 DLDH). Ubiquitin intranuclear inclusions were found only in one patient. All patients with FTD-MND were FTLD-U and both patients with PPA were tau-positive. There were no differences in median age at onset (61.5y, range 37–82y), disease duration (6y, range 1–16y) or age at death (69y, range 43–86y) between the different groups. However, when MND symptoms appeared the mean survival was reduced to 2y. Conclusions: FTD does not correlate with any specific pathological findings; however all patients with FTD-MND showed FTLD-U neuropathology. Tau-positive pathology were the substrate of the two cases with PPA. 10 % of patients presented MAPT mutations. They had early onset FTD, positive family history of the disease and tau deposits in their brain.

O156 Interaction between genes involved in cholesterol metabolism and Alzheimer’s disease risk E. Rodriguez-Rodriguez, I. Mateo, J. Infante, J. M. Polo, J. Berciano, P. SánchezJuan, O. Combarros Hospital Marques de Valdecilla (Santander, E) Background: Cholesterol regulates the production of beta-amyloid (Abeta), which is central to the pathogenesis of Alzheimer’s disease (AD), with high cellular cholesterol promoting Abeta production. Glial cells synthesize de novo and secrete cholesterol bound to APOE (the APOE3 isoform releases more glial cholesterol than the APOE4 isoform), which then is uptaken by neurons via CETP and APOE receptors (LDLR and LRP). One of the most important mechanisms for the elimination of excess brain cholesterol is its conversion into the 24S-hydroxycholesterol catalyzed by CYP46. Objective: Abnormalities in cholesterol-related genes appear to increase the risk of AD probably by increasing production of Abeta. We investigated wheter the combined genetic effects between APOE e4 allele, CETP [–629], LDLR exon 8, LRP exon 3, and CYP46 intron 2 might be responsible for sus-

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POSTER SESSIONS Poster session 1 Cerebrovascular disorders P158 Risk factors, clinical features or neuroimaging findings. How do we diagnose lacunar infarctions? M. A. Ortega-Casarrubios, B. Fuentes, I. Ybot, B. San José, R. Madero, E. DíezTejedor University Hospital La Paz. UAM (Madrid, E) Objectives: Up to 25 % of ischemic strokes correspond to lacunar infarctions (LI), attributed to the occlusion of single, small perforating arteries. Current diagnostic criteria for LI are based on the combination of risk factors (hypertension and/or diabetes),clinical features (classical lacunar syndromes) and neuroimaging findings, together with the absence of other possible etiologies. However, it has been recently called the risk factors criteria into question as they are common to other stroke subtypes. Our goal is to analyse the impact of those criteria (risk factor, clinical and neuroimaging) in LI diagnosis and in in-hospital outcome. Methods: Observational study from the stroke data bank of the Stroke Unit of the Department of Neurology, with inclusion of consecutive stroke patients (January 2000-December 2004). Parameters analysed: Risk factors, clinical syndrome, neuroimaging findings, stroke subtype, stroke severity and functional state at discharge. Results:1522 ischemic stroke patients,460 with diagnosis of LI. They had higher frequency of hypertension (67.8 vs 62.4 %, p = 0.04) than Non-LI but without differences in diabetes (28.9 vs 28.7 %).Classical lacunar syndrome was present in 88.9 % of LI patients (sensorimotor 38 %; pure motor 35.9 %; pure sensory 9.6 %; dysarthria-clumsy hand 4.1 % and ataxic hemiparesis 1.3 %). Brain CT showed LI in 63.7 % (new LI in 26 % and old LI 27.4 %). Final diagnosis of LI was based on the combination of risk factors and classical lacunar syndrome in 41.7 %;risk factors, classical lacunar syndrome and neuroimaging data in 24.3 %;classical lacunar syndrome alone in 14.5 %,classical lacunar syndrome and neuroimaging in 8.2 %;only risk factors in 5.8 %; risk factors and neuroimaging in 2.8 %,only neuroimaging findings in 0.8 % and atypical lacunar syndrome in 1.5 %. Diagnosis of LI based on the combination of two or more of those criteria was associated to a higher stroke severity on admission and poor functional state at discharge (p < 0.05) Conclusion: The most frequently used diagnostic criteria for LI is the presence of a classical lacunar syndrome, followed by the risk factors profile (hypertension and/or Diabetes). The combination of two or more diagnostic criteria is associated to worse evolution. P159 Comparison of MRI findings and blink responses in brainstem strokes K. Basiri, M. Shirzadi Alzahra University Hospital (Isfahan, IR) Introduction: Blink Reflex (BR) is the electro diagnostic equivalent of corneal reflex. BR responses are classified as R1, R2 and R2c. Abnormalities of these responses has been reported in brainstem lesions. Diagnosis of brainstem strokes by BR, in comparison to MRI finding is evaluated in this article. Methods: Twenty-two brainstem stroke patients were evaluated. Brain MRI and BR were obtained within the first 48 hours in all of them. Ten control cases of similar age and sex were enrolled to the study for determination of normal and abnormal range of BR responses. At last MRI finding were compared with BR responses. Results: Correct diagnosis of brainstem strokes by Brain MRI and BR were obtained in 21 and 20 patients respectively. BR revealed a brainstem stroke patient with normal MRI, and in two patients with normal BR responses, brainstem lesion was identified by MRI. BR responses were also analyzed in midbrain, pons, medullary and cerebellar lesions. Brain MRI and BR were successful in diagnosis of the brainstem lesions in 95.4 % and 90.9 % cases respectively, and each test revealed some cases unidentified by other method. Conclusion: In diagnosis of brainstem lesions, it is better to use clinical findings, MRI and Electrophysiologic tests together. This policy can minimized the undiagnosed fraction of brainstem stroke and may prevent a catastrophic outcome.

P160 First symptom and chief complaint of admission in patients with cerebral venous thrombosis M. Saadatnia, M. Mojarrad, S. Haghighi, F. Karkhiaran Isfahan University of Medical Science (Isfahan, IR); Isfahan Endocrin and Methabolism Center (Isfahan, IR) Objectives: The mode of presentation of cerebral venous thrombosis (CVT) is highly variable, rendering CVT a diagnostic challenge. However, the difference between chief complain of admission and the first presentation of CVT has been rarely reported. The aim of this study is to investigate the first symptom, chief complain of admission and the delay time in admission of CVT patients. Methods: Medical files of 121 patients who had CVST between 2001 and 2004 were reviewed. The diagnosis was confirmed by conventional angiography or magnetic resonance imaging and angiography. In all patients data concerning the chief complain of admission, the first presentation, delay time in admission, early prognosis and existence of venous infarct were obtained. Results: The first symptoms of CVT were headache (90.9 %), weakness (4.1 %), seizure (3.3 %), loss of consciousness (0.8 %), and blurred vision (0.8 %), and the chief complains of admission were headache (35.5 %), loss of consciousness (25.6 %), weakness (18.2 %), seizure (15.7 %), and blurred vision (5 %).The median delay time from onset of symptoms to admission was 5 days (mean = 6.5; SD = 5.7 days). Significant relations between venous infarct, and prognosis with the delay in diagnosis were obtained. Conclusion: The high frequency of focal symptoms as chief complain of admission and low frequency of focal symptoms as first symptom of CVT patients shows that delaying in diagnosis of CVT can be associated with more focal symptoms, infarct and poor prognosis. Hence, to early diagnosis of CVT, MRI/MRV should be used to investigate the signs of CVT in all patients with recent headache (progressive or thunderclap), as the most frequent non-focal first symptom, even when the CT scan and CSF examinations are normal. P161 Observation of non-response under different aggregation-inhibitor regimes in stroke patients of a community hospital K. H. Grotemeyer Klinikum Saarbrucken (Saarbrucken, D) Objectives: Laboratory non-responders under ASA-treatment have a 10 fold higher risk of stroke recurrence. Primary non-response under ASA is dosedependent (Thromb.Res 0.63; 587–593). However the non-response-phenomena with a consequence to treatment success are not limited to ASA treatment alone (J Neurol Sci 0.181:65–72.). So it was the aim of the observation to determine the frequency of stroke-patients from our community department with activated platelets despite the treatment with aggregationinhibitors. Methods: Platelet-reactivity in each case was determined 12 hours after first drug application. 369 new diagnosed stroke-patients under different therapy regimes were examined. 208 patients (91male(m))(68 ± 15 years(y)) under 3x200 mg ASA, 33 patients(18m)(65 ± 13 y) with 2x 25 mg ASA plus 200 mg dipyramidole (Aggrenox®)/d, 97 patients (36m)(68 ± 13 y) got clopidrogel (1x75 mg/d), 12 patients(5m)(74 ± 7 y) were given ticlopidine (2x250 mg/d) and 21 patients(7m) (70 ± 17 y) were given piracetam (3x1600 mg).All treatment decisions were based on clinical reason. However ticlopidine was introduced only in case of non-response to other drugs. Piracetam was introduced in few patients with stroke and high bleeding risk. Instead ASA Aggrenox® according to the “German Leitlinien” was introduced in the therapy concept of our department since 10/2005. Reasons for non-response were checked in all cases and could be managed in most cases before demission. Results: Activated platelets (non-response) 12 hours after medication were seen in 7.6 % under ASA, 45 % under Aggrenox®, 9.2 % under clopidrogel,10 % under piracetam and 0 % under ticlopidine.Only the non-responserate under Aggrenox® (compared to – ASA) differs significantly (Fishers exact test p < 0.000). At least all Aggrenox® -non-responders could be treated successfully with ASA (3x200 mg) und became a responder only in one case ticlopidine was needed. Conclusion: Non-response has a lot of different reasons i. e. under ASA one is susceptibility conditions of the drug that mostly can be managed. In the case of Aggrenox® – treatment it is not to exclude that ASA dosage of 25 mg is too low to modify platelet function in all cases under the given clinical circumstances. However a correct comparison of all the drugs used concerning non-response can be done only if all drugs were tested in all patients. i.e in a prospective clinical study under identical conditions.

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P162 The effects of antidepressant prophylaxis on prognosis of non-depressed acute stroke patients A. Guneri, E. Gursoy, A. Celebi, E. Arslan, N. Vardar, S. Kaya Vakif Gureba Hospital (Istanbul, TR) Objectives: To investigate the effects of antidepressant prophylaxis on prognosis of nondepressed acute stroke patients. Methods: We evaluated 132 patients that admitted to our clinic with acute stroke for depression and apathy. Patients that were nondepressed and nonapathic in the first 3 day after admittion were enrolled to treatment group with 20 mg/day citalopram or nontreatment group. Patients were evaluated at admittion, and at the 2nd and 8th week with Hamilton Depression Scale, Barthel Index and NIH- NINDS stroke scale. Results: At the initial stage 22 patients (17 %) had depression and 4 patients (3.5 %) had apathy The devolepment of depression was 9 % in antidepressant treatment group and %40 at in nontreatment group 8th week. Hamilton Depression Scale results were significantly different at 8 week, but no significant difference was find in BI and NIH-NINDS results. Conclusion: Antidepressant prophylaxis with 20 mg/day citalopram was effective to prevent depression in acute stroke patients. P163 Potential applicability of the ABCD score in identifying individuals with extracranial carotid artery disease after a transient ischaemic attack: a hospital-based case series study K. Spengos, G. Tsivgoulis, E. Manios, A. Papapostolou, M. Papadopoulou, A. Tsivgoulis, S. Vassilopoulou, N. Zakopoulos, D. Vassilopoulos University of Athens (Athens, GR) Background: A simple score derived in the Oxfordshire Community Stroke Project (ABCD score) and validated both in a population-based and a hospital-referred clinic cohort has recently been reported as a practical tool able to predict individuals at high early risk of stroke after a transient ischemic attack (TIA). Aim of the present study was to investigate the potential ability of the former score to identify individuals with extracranial carotid artery disease (CARAD) in a cohort of hospitalised TIA patients. Methods: All patients hospitalised in our Department with definite TIA according to the WHO criteria during a 5-year period were identified and their medical charts during hospitalisation as well their hospital records at the Emergency Department (ED) were retrospectively reviewed. Patients with previous history of carotid artery disease and individuals who did not undergo high-resolution B-mode ultrasonographic evaluation of their internal carotid arteries (ICA) during hospitalisation were excluded. The degree of stenosis was evaluated according to the ECST criteria, while the presence of ICA stenosis > 50 % ipsilateral to the TIA symptoms was mandatory was for the diagnosis of CARAD. Logistic regression models were used to evaluate the potential association of the six-point ABCD score [Age (< 60years = 0, b 60years = 1), Blood pressure (systolic b 140 mmHg and diastolic b 90 mmHg = 0, systolic > 140 mmHg and/or diastolic > 90 mmHg = 1), Clinical features (unilateral weakness = 2, speech disturbance without weakness = 1, other symptom = 0), Duration of symptoms in min (< 10 = 0, 10–59 = 1, b 60 = 2)] with the presence of CARAD. Results: During hospitalization CARAD was diagnosed in 20 patients (9.3 %) of the present case series (n = 214). A significantly (p = 0.022) higher prevalence of ABCD score > 4 was documented in patients with CARAD (50 %) in comparison to subjects without carotid artery stenosis (23.8). After adjustment for stroke risk factors and vascular comorbidities, history and number of prior TIA, an ABCD score > 4 was independently (p = 0.026) associated with the diagnosis of CARAD during hospitalization (OR:3.03, 95 %CI:1.14–8.05). Conclusion: An ABCD score > 4 is independently associated with carotid artery stenosis ipsilateral to the TIA symptoms. The findings of the present hospitalised cohort provide further evidence for the potential applicability of the former score in clinical practice. P164 Common APO E polymorphism in different microangiopathy-related brain diseases A. Slowik, D. Wloch, W. Turaj, A. Borratynska, A. Klimkowicz-Mrowiec, J. Pera, T. Dziedzic, A. Szczudlik Jagiellonian University (Krakow, PL) Apolipoprotein E (ApoE) plays a crucial role in maintaining cholesterol homeostasis. Three common polymorphisms, E2, E3, E4 code for apo E protein isoforms in plasma. Studies suggest the role of genetic heterogeneity of ApoE polymorphism in stroke; however, the results are inconclusive. Scarce

data imply the role of genotype with E2 allele as a risk factor for microangiopathy-related cerebral damage. In this study we focused on the two phenotypically different types of stroke affecting small perforating vessels of the brain, i. e. deep brain hemorrhage (DBH) and small vessel disease (SVD) stroke. The aim of this study was to look for the association of Apo E polymorphism with DBH and SVD stroke in a homogeneous Polish population. We genotyped 115 patients with SVD stroke and 119 patients with DBH and 228 controls matched by age and sex. The diagnosis of SVD stroke was based on TOAST criteria. All hemorrhagic stroke patients underwent computed tomography, angiography, and where needed MRI or MRA to exclude vascular malformations, hemorrhage to tumor amyloid angiopathy, etc. The APO E polymorphism was analyzed by PCR followed by restriction enzyme digestion. Only patients with SVD stroke presented with a significant over-representation of genotypes with at least one E2 allele of ApoE gene when compared to the controls [SVD stroke: E2E3–20 (17, 4 %), E2/E4–3 (2, 6 %), E3/E3–69 (60 %), E3/E4–22 (19, 1 %) E4/E4–1 (0, 86 %), controls:E2/E2–3 (1, 3 %) E2E3–19 (9, 6 %), E2/E4–4 (1, 8 %), E3/E3–165 (72, 4 %), E3/E4–37 (16, 3 %)]. This association was not seen when patients with DBH [E2E3–19 (16 %), E2/E4–1 (0, 8 %), E3/E3–72 (60, 5 %), E3/E4–27 (22, 7 %) E4/E4–0 (0 %)] were compared with the controls (P > 0.05). A logistic regression analysis showed that possession of genotype with E2 allele of APOE gene was an independent risk factor only for SVD stroke (OR = 2.69, 95 %CI:1.34–5.40, p = 0.005) This data show that that the two brain diseases, both related to small vessel pathology, differ in respect to this aspect of their genetic backgrounds.

P165 Axonal damage and outcome in subarachnoid haemorrhage A. Petzold, G. Keir, A. Kay, M. Kerr, E. Thompson Institute of Neurology (London, UK); University Hospital Birmingham (Birmingham, UK); National Institutes of Health (Bethesda, USA) Objective: Preliminary evidence from patients with subarachnoid hemorrhage (SAH) suggests that axonal degeneration may be an underestimated pathological feature. Methods: A longitudinal study in 17 patients with aneurysmal SAH.Ventricular cerebrospinal fluid (CSF) was collected daily for up to 14 days. The neurofilament heavy chain (NfH-SMI35, a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/mL). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3months. Results: Seventy-eight of 148 samples (52.7 %) from patients with SAH showed pathologically high CSF NfH levels compared to 20 of 416 samples (5 %) of the reference population (p < 0.0001). A pathological increase in NfH was observed in 100 % of patients with bad outcome (GOS 1–3) compared to 8 % of those with good outcome (GOS 4–5,p < 0.0001).This increase typically became significant 7 days after the hemorrhage (p < 0.01). The finding was confirmed by analyzing the individual mean CSF NfH levels (3.45 versus 0.37 ng/mL, p < 0.01) and was reinforced by the inverse correlation of CSF NfH with the GOS (R = –0.65, p < 0.01). Injury severity correlated with CSF NfH levels (World Federation of Neurological Surgeons, R = 0.63, p < 0.01 and Glasgow Coma Score, R = –0.61, p < 0.01). Conclusion: These findings suggest that patients with SAH suffer from secondary axonal degeneration which may adversely affect outcome.

P166 High leptin level is a risk factor of recurrent ischaemic stroke in women J. Staszewski, J. Swistak, K. Bialas, J. Kotowicz, A. Stepien Military Medical Institute (Warsaw, PL) Background: Leptin the product of the ob. gene, is a hormone secreted by adipocytes. Serum leptin concentrations are correlated with the percentage of body fat and are usually higher in women. Leptin is involved in the body weight regulation, insulin sensitivity and number of other hormonal interactions. Although it is a strong risk marker for acute myocardial infarction, it was not proved to correlate with first-ever ischemic stroke. The aim of the study was to find out if leptin level (LL) was correlated with risk for recurrent stroke. Methods: We identified 35 patients with recurrent ischemic stroke (RIS group) and 35 patients with first-ever ischemic stroke (FIS group). Referents were matched for sex and age. Body mass index, presence of smoking, diabetes, hypertension, carotid artery stenosis, atrial fibrillation, hypercholesterolemia were recorded. The groups were further divided into subgroups regarded to hypothetical stroke etiology (cardioembolic, macroangiopathy,

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microangiopathy). Leptin level was analysed two weeks after the stroke onset separately in men and women. Results: There was no significant difference in the mean LL between the two main groups (RIS group- women: 35 ± 11 ng/ml; men: 16 ± 7 vs FIS group- women: 24 ± 8; men 18 ± 12). There was also no difference between LL in cardioembolic and macroangiopathy stroke subgroups. We have noticed however the significant difference between the leptin levels in microangiopathy subgroup. The mean LL in RIS group for women was 50 ± 20 ng/mL vs 19 ± 6 in FIS group, p = 0.02. No difference between LL among men in RIS (11 ± 7) and FIS (19 ± 13) microangiopathy subgroup was noticed. High LL in women remained a significant risk marker of recurrent stroke in multivariate model (OR 1.9; 95 %CI, 1.1–2.3). There was also no difference between the BMI among the subgroups. Conclusions: Leptin level is a significant risk marker of lacunar stroke recurrence in women.

P167 Echocardiographic predictors of long-term mortality and dependence in patients with ischaemic stroke due to atrial fibrillation J. Staszewski, J. Kotowicz, A. Stepien Military Medical Institute (Warsaw, PL) Background and purpose: Atrial fibrillation (AF) is one of the most frequent risk factor of ischemic stroke. Echocardiographic predictors of cardioembolic stroke outcome are not well known. Our goal was to study the impact of transthoracic echocardiography (TTE) findings on long-term mortality and dependence in patients with acute AF-related stroke. Methods: Prospective analysis of 95 consecutive patients with acute stroke and concomitant AF with presumed cardioembolic aetiology according to TOAST criteria followed-up for 6 months. All patients received standardized stroke management, no thrombolytic agents were used. TTE was performed according to AHA guidelines and Henry el al. normograms for weight and age. Patients were assessed in modified Rankin Scale (mRS) at 6 month follow-up visit and were regarded as dependent with mRS ≥ 3 or non dependent with mRS ≤ 2. Results: Median age was 76 years, 61 % of patients were female. The 6 month mortality was 11 %, 65 % of survivors were still nondependent 6 months after stroke. TTE findings included left atrial enlargement (80 %), mitral insufficiency (68 %), mitral stenosis (5 %), aortic insufficiency (27 %), aortic stenosis (3 %), diminished left systolic ventricular function (45 %), left ventricular wall enlargement (53 %), pericardial suffusion (17 %), left ventricle hypokinesis (28 %), presence of embolic material in the left ventricle (4 %). In the univariate analysis the significant predictors of unfavourable stroke outcome (death or dependence) were diminished left systolic ventricular function (OR 2.89 95 % CI 1.04–8.05, p = 0.002), left ventricular wall enlargement (OR 1.4 95 %CI 1.03–2.22, p = 0.05), left ventricle hypokinesis (OR 3.24 95 %CI 1.42–10.6, p = 0.00002). After the multivariate analysis the only independent predictor of mortality and dependence was hypokinesis (OR 4.02 95 % CI 1.7–9.3, p = 0.001). Conclusions: TTE is useful in assessing the risk of unfavourable stroke outcome in patients with AF. Left ventricle hypokinesis predicts long-term mortality and dependence in patients with AF-related ischemic stroke.

P168 High frequency of IgM antiphospholipid antibodies in young Iranian patients with stroke M. Zare, M. Saadatnia, S. Haghighi Isfahan University of Medical Science (Isfahan, IR); Isfahan Endocrin and Methabolism Center (Isfahan, IR) Objectives: In recent years, antiphospholipid antibodies (aPL) and anticardiolipin antibody (aCL) have been recognized as predisposing factors for stroke. There is difference in prevalence of type of aPL in countries. In this study, the presence of IgG and IgM types of aCL and aPL antibodies has been investigated in younger Iranian patients with ischemic stroke. Methods: Both IgG and IgM types of aPL (Cardiolipin, Antiphosphatidyl Inositol, Antiphosphatidyl Serin, Antiphophatidic Acid and beta 2 – Glycoprotein I) and aCL alone (Cardiolipin and B2-GPI) were measured in 117 pateints with ischemic stroke (aged < 45 years) during 18-month period (since September 2002) in Al-Zahra hospital, Isfahan, Iran and demographic, clinical and labroatory characteristics of patients with positive titer were recorded. Results: Seven men and 16 women (23 patients, 19.6 %) had increased IgG types of aPL antibodies. Increased titers of IgM and IgG were found in 19 (82.6 %) and 6 (26 %) patients for aPL antibodies and in 15 (83.3 %) and 8 (44.4 %) cases for aCL alone, respectively. Embolic and thrombotic stroke

was seen in 7 and 16 patients respectively. History of previous stroke was seen in 7 patients. Conclusion: Despite European studies, high titers of IgM antiphospholipid antibodies found in a large number of patients can be due to the presence of unknown triggering factors (infections or poisons) in developing countries that are seen more than developed countries. These hypothesis should be investigated in future. P169 Computational fluid dynamics of cerebral haemodynamic in Willis Circle model with occlusion C. Falup-Pecurariu, A. Postelnicu, I. Pascu Transilvania University (Brasov, RO); UMF (Targu-Mures, RO) In a previous work [J Neurol 2005, 252, Suppl 0, 2] we presented our results regarding debits and pressures of cerebral blood flow in Willis Circle with external occlusion. Here we extend our research by evaluating these parameters with internal Willis Circle artery occlusion. The aim of this study was to characterize blood flow and pressures in symmetrical Willis Circle model with one of the component artery occluded. Material and method: in a validated computerized model in MATLAB we imposed 3 situations: a.) posterior cerebral artery (PCA) occlusion; b.) posterior communicating artery (PCoA) occlusion; c.) anterior cerebral artery (ACA) occlusion. For each situation we evaluated blood flow debits and pressures. Results: a.) posterior cerebral artery (PCA) occlusion – ipsilateral internal carotid artery have an debit of 5.04 cm3/s and contralateral internal carotid artery a 4.04 cm3/s. Basilar artery debit have 2.02 cm3/s which was the same in PCA, so blood has circulated from the posterior to the anterior territory. The difference of 0.34 cm3/s between right and left anterior cerebral artery suggest that blood circulated from right to the left. The lowest pressure of 6.33 mmHg was at the confluence point between PCA and PCoA which shows the vulnerability of this point; the rest of Willis Circle points were in a narrow range (8.6961–8.9424 mmHg). b.) posterior communicating artery (PCoA) occlusion – the highest debit was in contralateral ICA of 3.99 cm3/s versus 3.92 cm3/s in ipsilateral ICA and 3.77 cm3/s in basilar artery. c.) anterior cerebral (ACA) occlusion – contralateral ICA debit was the highest of 5.07 cm3/s and in basilar artery 3.69 cm3/s. In the ipsilateral PCoA was an low debit of 0.14 cm3/s which suggest the vulnerability of this artery and a high debit in ipsilateral medium cerebral artery (MCA). The pressures distribution was in limited range 8.67–8.84 mmHg which suggest an efficient functionality of Willis Circle as a compensatory mechanism of pressures. Conclusions: depending of the type of occluded artery Willis Circle demonstrated a great variability of its functionality. P170 Motor neuron disease and HIV infection: three new cases L. Alves, M. Viana-Baptista, J. Martins, L. Santos, E. Medeiros Hospital Egas Moniz (Lisbon, P) Objectives: A review of the literature found only 21 cases of motor neuron disease (MND) associated with Human Immunodeficiency Virus (HIV) infection. Its pathophysiology remains to be established and coincidental association can not be definitely ruled out. Our aim is to describe 3 new cases of MND and HIV infection. Methods: The authors reviewed the records of 3 cases of male HIV-1 seropositive patients from our Outpatients Clinic, with a clinical picture suggestive of MND. Results: Case 1 developed subacute lower right limb muscular atrophy and weakness at the age of 39, 10 years after the diagnosis of HIV infection. Eight months later, he was put on highly active antiretroviral therapy (HAART) and no significant clinical change occurred during the next 5 years. Clinical and electromyogram (EMG) abnormalities remained confined to the right lower limb muscles. The patient died at age 45, due to upper gastrointestinal bleeding. Case 2 had been on HAART therapy for 2 years when motor symptoms developed (at the age of 42, seven years after HIV diagnosis). Clinical and EMG evidence of upper and lower motor neuron (U and LMN) compromise was detected in all four limbs. There was also clinical evidence of bulbar U and LMN involvement. A slight improvement in lower limb strength was observed since the upgrade of the previous mentioned medication. Case 3, 19 years after HIV diagnosis and 8 after initiation of HAART, developed weakness and cramps in the lower limbs as well as bulbar symptoms. Clinical and EMG evidence of U and LMN disease was documented in the 4 limbs. His antiviral therapy was upgraded 1 year after onset of the neurological disease. Since then his clinical condition has remained stable. All patients had CD4 counts above 200 at the onset of neu-

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rological disease. CSF studies revealed mild hyperproteinorraquia in patients 1 and 3. MRI and laboratorial investigations in the 3 cases ruled out other conditions that mimic amyotrophic lateral sclerosis (ALS). Conclusion: Case 1 had monomelic lower motor neuron disease, while cases 2 and 3 have definite ALS (EL Escorial Research Criteria). Our patients were not severely immune depressed and 2 of them were already on HAART at onset of MND. As in other reported cases, clinical course seems to be milder and age at onset lower than in non-HIV MND patients. Nevertheless, the significance of the association of HIV infection and MND remains to be clearly understood.

dysarthria. Angiography showed basilar stenosis, left V1 stenosis, right carotid artery occlusion and left internal carotid artery critical stenosis. 3.5 x 14 mm Radius stent was placed in the basilar and a 4.5 x 14 mm in the left V1. 8 x 27 mm carotid wall stent was positioned in the left ICA. The patient recovered completely

P171 Endovascular coiling for ruptured and unruptured intracranial aneurysms M. Avila, M. De la Maza, A. Martinez Ponce De Leon Hospital San Jose TEC (Monterrey, MEX) Aneurysmal subarachnoid hemorrhage (SAH) has a 30 day mortality rate of 45 %. Endovascular coiling has proven significantly better in survival free disability than neurosurgical clipping. Treatment of unruptured intracranial aneurysm will depend mostly on size, symptoms and SAH history. Objective: Describe the clinical outcome in patients treated with endovascular coiling for symptomatic and asymptomatic intracranial aneurism. Methods: We document symptoms, Hunt-Hess (HH) scale, risk factors and clinical outcome in 142 patient with intracranial aneurisms treated with endovascular coiling between 1998–2004, diagnosed and treated by the Neurosurgical Endovascular Team. All underwent angiography pre-embolization. Control angiography was realized in 123 patients (1 to 4 months from initial procedure). Results: A total 148 aneurysms where treated (n142). 3.5 % had multiple aneurisms (n5). Mean age was 46; 64 % female. 117 presented with SAH, and where treated with in acute stage, 17 where treated not in an acute stage, 8 asymptomatic with incidental aneurysm. The most frequent site of location was the anterior circulation (n121) (44 Anterior communicant artery (AcoA),49 Posterior communicant artery (PcoA), 12 Middle cerebral artery (MCA,6 ophthalmic,6 Anterior cerebral artery (ACA),4 bifurcation).27 posterior circulation (10 basilar TIP,10 vertebral,7 laterobasilar).85 % of patient had a H-H scale of 1–3, 10 % 4, 5 % 5. Total occlusion was obtained in 139 aneurisms, 9 had subtotal occlusion of 90 to 97 %. 137 had no complication (96.5 %). Our total complication rate was 3.5 % (n3 with intracranial embolism, n2 (1.4 %) with aneurysm rupture during the procedure).Control angiography was realized in 123 patients with a 2.4 % of recanalization (n3) 1 from ACA, basilar and MCA. Giant aneurysm where found in 5 patients. Conclusion: We recommend endovascular treatment for intracranial aneurysms as a safe procedural with less morbidity and mortality than conventional surgical techniques.

Moyamoya disease causes ischemic strokes in young adults. It is characterized by progressive bilateral intracranial arterial stenoses around the circle of Willis with formation of net-like collateral vessels. The simultaneous occurrence of multiple intracranial arterial stenosis and Grave’s disease is rare (nine previously published cases, all female). In September 2005 a 47-year-old woman was admitted to our stroke unit after acute onset of right sided hemiplegia and global aphasia. Physical examination at the time of admission additionally showed bilateral exophthalmos and a prominent goiter. Since the age of 13 she suffered from Grave’s disease with several antithyroid medications and recurrent thyrotoxic episodes during her life. She had mitral stenosis after rheumatic fever in her childhood and had undergone mitral valve dilatation in 1996, 2001 and 2005. Because of secondary atrial fibrillation she was treated with warfarin. Since the early 1990’s several transient ischemic attacks had occurred. Cranial CT at admission revealed an ischemic lesion in the left temporal and parietal lobe. Basal TSH value was slightly decreased, thyroid hormones were normal. TSH receptor antibody value was 20.13 IU/l (normal up to 1.5 IU/l). On the 4th day the patient’s clinical state deteriorated because of congestive heart failure and septicemia. She was transferred to the intensive care unit and artificially ventilated. Follow-up cranial CTs revealed infarction in both anterior and media territories. Cerebral angiography demonstrated bilateral occlusion of distal internal carotid arteries. Causative septic embolies were excluded by transoesophageal echocardiography. There was no evidence of infectious cerebritis, vasculitis or antiphospholipid-anticoagulans. Regarding all results we diagnosed moyamoya-syndrom in association with Grave’s disease. Under therapy with heparin, antibiotics, diuretics, perchlorate and corticoid the patient’s state stabilized at a low level, she now lives in a nursing home. As mentioned above, hereditary and immunogenic factors have been implicated in the underlying mechanisms of moyamoya disease. It is difficult to determine whether Grave’s disease and moyamoya disease are causally related or coincidental. The reported case did not meet all the diagnostic criteria for moyamoya disease, because there were no abnormal, net-like, collateral vessels. Similar observations in former case studies support a thyrotoxicosis related moyamoya variant.

P172 Auto-expandable stents in the treatment of intracranial symptomatic atherosclerotic stenosis A. Rangel-Guerra, A. Garcia de la Fuente Hospital Universitario (Monterrey, MEX); Hospital Christus-Muguerza (Monterrey, MEX)

P174 Viagra® (sildenafil) temporarily improves hemianopia after posterior infarction P. Schlindwein, M. Eicke, G. Vuckorevic, P. Stoeter, M. Dieterich Gutenberg University Hospital (Mainz, D); General Hospital (Idar Oberstein, D)

Background: 6–29 % of all ischemic strokes are related to stenotic lesions located in intracranial vessels, and an increased risk for stroke, heart disease, and death has been consistently observed [1–6]. Self expandable stents are the election treatment for other intracranial atherosclerotic stenosis. We present our experience using self expandable stents used by cardiologists. Patient 1: A 71 years old woman with a transient right hemiplegia had an MRI of the brain that showed an old left MCA infarction and the MRA demonstrated a left M1 stenosis. Balloon angioplasty, was perfomed with dissection of the veseel. Self expandable nitinol stent (Radius, Boston Scientific, Fremont CA) was used. The vessel recovered its normal diameter. Patient 2: A 73 year old man with history of transient right hemiparesis. The patient was admitted with quadriplegia and severe respiratory disturbances that required intubation. The MRI showed pontine infarctions and the angiography demonstrated right V3 occlusion with basilar collateral circulation through the anterior spinal artery. Left V4 stenosis, and also left V1 stenosis. Left supraclinoid carotid stenosis was present.A self expandable stent in the left V4 with balloon impaction, Balloon expanded stent was located in the left V1. 4.5 x 14 mm stent was positioned in the left supraclinoid carotid artery. The patient recuperated immediately his respiratory automatism. Patient 3: A 78 year old man has 3 day history of right hemiparesis and

In 2002 a 65-year-old man had a bilateral ischemic stroke of the posterior cerebral arteries (PCA), which was probably due to a cardiac embolization that also resulted in the occlusion of the proximal left vertebral artery. After partial recovery, he had persisting hemianopia to the right and less so to the left with some day-to-day fluctuations. In 2004 he experienced improvement of the heminaopia,every time he took 25 mg sildenafil.This effect started approximately 10 minutes after oral administration, reached its peak after 60–90 minutes, and lasted for at least 4–7 days. Since then he has taken 50–100 mg sildenafil regularly every 4–7 days. The improvement of scotomas and brightness of the visual field could be verified in visual field examinations (Humphrey and Goldmann). Functional MRI during a visual stimulation by horizontal optokinetic nystagmus showed significant differences in activations of the visual cortex (BA 17, 18, and 19) bilaterally between t-contrast images before and after the administration of 100 mg sildenafil. By overlaying the t-contrasts of the fMRI experiment on a high resolution T1-image of the patient, we located the new activations after medication mainly along the margins of the old bilateral posterior infarctions (lingual and fusiform gyri, cuneus bilaterally). Animal trials in rats with acute stroke showed improved neurological function with sildenafil (Zhang 2005). Although sildenafil had no effects on visual fields and intraocular pressure (Ermis 2004) in healthy human subjects, the pulsatile ocular blood flow was increased (Paris 2001). To date no data are available on its effect on patients with hemianopia due to stroke.

P173 Moyamoya disease associated with Grave’s disease S. Troll, W. Dietrich, M. Röbke, I. Bär, F. J. Erbguth Municipal Hospital (Nuremberg, D)

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This is the first report on objectively and reliably tested effects of sildenafil in a patient with bilateral hemianopia. Supported by DFG (German Research Foundation)

Clinical neurophysiology P175 Lambert-Eaton like myasthenic syndrome associated with non-autoimmune hypothyroidism N. Rodriguez-Espinosa, A. Moro, P. J. Pérez-Lorensu, J. C. de León Hospital Ntra. S [s] de Candelaria (Santa Cruz de Tenerife, E) Objectives: Clinical and neurophysiological characterization of reversible Lambert-Eaton syndrome as rare association with hypothyroidism. Methods: Sixty years old man with history of thyroidectomy for multinodular goiter, who had discontinued the hormonal replacement with tiroxine, presented a picture of fluctuating and progressive dysarthria, proximal weakness predominantly in the legs and dry mouth. The patient was evaluated with electromyography (EMG), including repetitive stimulation and blood determinations of TSH, T4, antithyroid and antineural antibodies. Results: The rapid repetitive nerve stimulation and the brief exercise test showed significative increment of compound muscle action potential (CMAP) compatible with presynaptic neuromuscular disorder. The blood determinations were compatible with hypothyroidism without the presence of antithyroid or antineural antibodies. After the hormonal replacement reintroduction the patient showed motor improvement. A second EMG did not show CMAP changes with repetitive stimulation. Conclusion: The carpal tunel syndrome, proximal myopathy and axonal sensorimotor neuropathy are recognised as neurological features of hipothyuroidism. The present report and literature references support the association between hypothyroidism and presynaptic myasthenic syndrome. P176 Early electromyography in acute focal weakness T. Jürgens, C. Puchner, W. Schulte-Mattler University of Regensburg (Regensburg, D) Introduction: Discharge rates of motor units tend to be decreased in lesions of the central nervous system. In contrast, increased discharge rates of motor units in concentric needle electromyography (EMG) indicate a loss of motor units and therefore a peripheral neurogenic lesion. It is not known whether increased discharge rates can be found immediately after a peripheral nerve lesion or after some time. Methods: Neurography and concentric needle EMG were done in 8 patients in whom acute peripheral nerve lesions were suspected upon clinical grounds. The studies were done within the first 72 hours after the weakness commenced. In at least one follow-up visit the kind and the severity of the lesions were further characterized. Results: In 6 patients increased (> 20Hz) discharge rates were found in all affected muscles weaker than MRC 4. During follow-up, the peripheral origin of the weakness was confirmed. In 2 patients discharge rates were well below 20 Hz despite severe muscular weakness. In these patients a lacunary ischemic stroke was identified as the underlying pathology. Conclusion: Recording of motor unit discharge rates can serve as a tool to differentiate between a central and a peripheral lesion immediately after the onset. However, it cannot differentiate between neurapraxia or axonotmesis. P177 Tethered spinal cord syndrome with diastematomyelia: interesting clinicalelectrophysiologic correlation I. Nestrasˇil, P. Kanovsk y´ Palacky University (Olomouc, CZ) Objectives: Tethered spinal cord syndrome (TCS) is a result of rostrocaudal traction on the conus medullaris. Tethering may also occur in the diastematomylia. It refers to the splitting of the spinal cord, conus medullaris, or filum terminale in the sagittal plane into two not necessarily equal halves. Patients with TCS may reach adulthood with their disease undiagnosed. The diagnosis may be assessed according to clinical findings and subsequent neuroimaging studies, particularly by MR imaging. Electrophysiological examination is helpful in its diagnostics. We report the interesting electro-

physiologic changes occuring in one patient with TCS demonstrating an asymmetric foot deformity. Methods: A 45-year-old woman was referred for bilateral pes excavatus. Except for the pain of the left foot she noted no sensory abnormalities. She underwent neurological and electrophysiological examination, which included somatosensory evoked potentials (SEP), nerve conduction studies (NCS) and electromyography. MR imaging (MRI) of the distal thoracic and lumbar spine was performed. Results: Neurological examination showed hypotrophy of the left lower extremity with hypoactive deep tendon reflexes and the absent ankle reflex. Ankle dorsiflexion and plantar flexion appeared to be slightly weak. Decreased touch, vibration and thermoalgic sensation was over the dorsum and sole of the left foot extending into the calf. No presence of sensory potentials of the left superficial peroneal and sural nerves with normal responses on the right side were in the sensory NCS. H-reflex was absent on the left side, the right H-response showed normal amplitude but shortened latency. The F responses were significantly prolonged on the left side. The slight to moderate inactive axonopathy was present in the muscles of myotomes L4–5, S1 bilaterally. The latency of the N22 lumbar potential was significantly delayed in the left posterior tibial nerve SEP recordings. Subsequent MRI of the distal thoracic and lumbar spine disclosed the caudally located conus medullaris and splitted into two asymmetric hemicords tethered from a thickened terminal filum. Conclusion: The TCS in the adult population is rare entity and its manifestation by club foot deformity is non-specific. The electrophysiological findings demonstrated that the nerve conduction studies and the posterior tibial nerve SEP may be a sensitive indicator of underlying pathology and neurophysiologic status in patiens with TCS. P178 A neurophysiological investigation of the motor system in two siblings with Canavan’s disease V. K. Kimiskidis, S. Papagiannopoulos, G. Vasiliadis, D. Zafeiriou, F. Zara, E. Tsatsari-Foroglou, Z. Kouvatsou, V. Kapina, D. Koutsonikolas, G. Anogiannakis, A. Kazis Aristotle University of Thessaloniki (Thessaloniki, GR); Evrodiagnosi Diagnostic Center (Thessaloniki, GR) Objectives: Canavan’s disease (CD) is a rare, autosomal recessive disorder due to aspartoacylase deficiency which results in accumulation of N-acetylaspartic acid (NAA) in the brain. Clinical manifestations of CD include macrocephaly and delayed motor and verbal development with death ensuing usually within the first decade of life. Neurophysiological studies of central motor pathways in CD have not been reported. Accordingly, the present study was designed to investigate the motor system of two non-Jewish sisters with CD, aged 14 and 12 years, notable for a relatively mild and protracted clinical course. Methods: Transcranial magnetic stimulation (TMS) of the motor cortex was performed with a circular coil centered over the vertex and responses were recorded with surface electrodes from FDI muscles. For lower limbs, a double cone coil was used (recording: AH). Cervical motor root stimulation was performed with a figure of 8 coil appropriately oriented so as to overly the C8-T1 roots. Upper and lower limb motor nerves were examined using standard techniques. Results: TMS at 100 % maximum stimulator output failed to produce facilitated or resting MEPs and silent periods (SPs) in upper and lower limbs. In contrast, cervical stimulation resulted in MEPs with normal latencies (14.06 ± 0.47 ms in patients vs. 13.84 ± 1.36 ms in 10 sex and age-matched controls). F-wave amplitudes in the CD patients were significantly increased compared to the control group. For instance, median nerve F-wave amplitudes were 0.48 ± 0.33 mV vs. 0.16 ± 0.09 mV in controls (Mann-Whitney test, p < 0.05). The remaining parameters (CMAP latencies and amplitudes, conduction velocities and F-wave latencies) were within normal limits. Conclusion: The principal findings of the present study are: a) absence of MEPs and SPs following TMS of the motor cortex and b) F-wave amplitude increase, most likely reflecting disinhibition of a-motoneurons from descending supraspinal pathways. These hitherto unreported findings provide evidence for significant upper motor pathway dysfunction in the late stages of CD.

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P179 Sweating disturbances and sympathetic skin response in Parkinson’s disease P. Schestatsky, J. Valls-Solé, J. Ehlers, C. de Mello Rieder, I. Gomes Hospital Clínic Barcelona (Barcelona, E); Hospital de Clínicas de Porto Alegre (Porto Alegre, BR) Objectives: Abnormalities in the sudomotor skin response (SSR) have been reported as an index of autonomic dysfunction in patients with idiopathic Parkinson’s disease (IPD). However, the relationship between SSR abnormalities and the clinical complaint of sweating disturbances is not known. We aimed to study the characteristics of the SSR in patients with sweating complaints to determine the possible relationship of SSR abnormalities and sweating disturbances in IPD. Methods: As part of a prospective analysis of autonomic dysfunctions carried out in our population of IPD patients, we selected 13 patients who complained of altered sweating, and 37 patients who did not report such complaint. We recorded the SSR of the palms of the hands to electrical stimulation of the median nerve and analyzed its onset latency, peak to peak amplitude and waveform. Results: Apart from excessive sweating,the two groups did not have other significant differences regarding symptoms and signs, type and degree of autonomic dysfunctions, or motor and sensory nerve conduction velocity. Excessive sweating involved mainly the face, head and trunk. We found that patients with hyperhidrosis had more often absent responses (c2 = 5.292; p = 0.021), their responses were of lower mean amplitude (ANOVA; F [2, 101]= 11.678; p < 0.001), and they had a reduced number of responses with a predominantly negative component (c2 = 8.493; p = 0.004) than patients who did not complain of sweating disturbances. Conclusions: Our results indicate that there is a marked decrease in sympathetic function over the palms of IPD patients with focal hyperhidrosis of face, head and trunk. This is in agreement with the notion of a compensatory sympathetic sweating disorder. We also found that the analysis of the shape of the SSR may contribute to the description of sudomotor abnormalities, in addition to absent responses and amplitude abnormalities in patients with IPD.

P180 An electrophysiologic consideration on the ‘Classification of disease stage of diabetic polyneuropathy’ O. Hasegawa, S. Kawasaki, S. Matsumoto Yokohama City University Medical Center (Yokohama, JP); Higashi-Matsudo Hospital (Matsudo, JP) Objectives: Diabetic polyneuropathy is understood as progressive nerve fiber loss on the pathological basis and clinically progresses from sensory, then autonomic and later to motor involvement. To simplify clinical evaluation of diabetic neuropathy Japanese Society of Considering Diabetic Neuropathy published on 2004 the ‘Classification of disease stage of diabetic polyneuropathy’. In this paper we studied the appropriateness of this classification from the aspect of nerve conduction, which is understood as a golden standard in the evaluation of neuropathy. Methods: Subjects were 188 patients with diabetes mellitus. In these patients we investigated from the bedside examination severity of paresthesia, Achilles tendon reflex (ATR), vibration sense and muscle volume of small foot muscles and classified them from 0 to 3 (normal). For the electrophysiological evaluation the polyneuropathy index-revised (PNI-R), a velocity index, and the sensory neuropathy index (SNI), an amplitude index were calculated. The disease stage was decided from clinical findings according to the classification. Results: The disease stage had a high coefficient of correlation (r > 0.6) with electrophysiological severity. All 4 clinical findings had a significant correlation (r > 0.4) with the disease stage or electrophysiological severity. The correlation of each clinical finding with the disease stage distribution showed that the ATR score decreased in the earlier stage, then the vibration sense, and the abnormality of muscle volume or paresthesia progressed relatively in the later stage. Conclusion: Those findings of earlier involvement such as ATR and vibration sense will fit for the diagnostic criteria, and paresthesia or muscle atrophy will be a suitable marker for the warning stage. This disease stage classification is composed concise and reasonably, and thought to be the roughly appropriate one. If possible an effort to clarify more the abnormal criteria of sensory, autonomic and motor involvement, and to insist upon the most important stage would be made. This disease stage classification was prepared for busy clinicians concerning diabetic management in evaluating easily severity of diabetic polyneuropathy in a short time, at the bedside without using special instruments. We hope that the evaluation of diabetic neuropa-

thy by physicians would be popularized, and for that purpose this staging classification could be useful and applicable. P181 The use of vestibular evoked myogenic potentials in the neurophysiologic study of basilar dolichoectasia S. Deftereos, G. Panagopoulos, I. Kapsalakis, D. Georgonikou, C. E. Karageorgiou Athens General Hospital,“G. Gennimatas” (Athens, GR) Objectives: Dolichoectasia of the basilar artery (BAD) may exert mechanical pressure on brainstem structures, causing relevant clinical signs. Radiology investigation of BAD includes Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA). Neurophysiologic investigation of brainstem function, on the other hand, can help determine the extent of neural dysfuction caused by mechanical pressure. The former usually comprises Somatosensory Evoked Potentials (SEPs), Myogenic Evoked Potentials (MEPs), Brainstem Auditory Evoked Responses (BAERs) and the Blink Reflex (BR). These methods evaluate the integrity of the somatosensory and motor pathways and that of the medulla and the upper pons. However, they cannot evaluate the integrity of the lower lateral pons. We describe for the first time the use of Vestibular Evoked Myogenic Potentials (VEMPs) for detecting lower lateral pontine dysfunction due to pressure by BAD, in patients with vertigo of sudden onset. Methods: We investigated 32 patients who were referred to our laboratory due to recurrent vertiginal crises, accompanied by horizontal nystagmus. None of the patients had additional clinical signs, while the ENT examination, basic laboratory investigations and brain CT scan were always normal. We further investigated our patients by means of BAERs, SEPs, MEPs and BR. We also obtained bilateral VEMPs recordings from the sternocleidomastoid muscles. Results: BAERs, SEPs, MEPs and BR were normal in all cases. The amplitude of the p13-n23 VEMPs wave was abnormally low unilaterally in 6 cases, in which we proceeded to brain MRI and MRA. In 3 of these cases MRI disclosed ischemic lesions of the lower lateral pons, ipsilaterally to the abnormal VEMPs. In 2 cases hemorrhagic lesions were revealed. In 1 case MRA disclosed BAD, which exerted pressure on the lower lateral pons, again ipsilaterally to the abnormal VEMPs. Conclusions: VEMPs are saccular responses to loud acoustic stimuli and are recordable from the sternocleidomastoid muscle ipsilaterally to the stimulated ear. Their reflex arc includes the ipsilateral vestibular nuclei, located at the limit of the lower pons and the upper medulla. Thus, they can detect neuronal dysfunction of this area, as opposed to the other aforementioned neurophysiological methods. Since BAD can selectively affect the lower lateral pons,VEMPs seem to be a useful addition to the techniques currently used for its evaluation.

Extrapyramidal disorders P182 BDNF haplotype tagging SNPs in Greek sporadic PD patients and patterns of linkage disequilibrium G. Xiromerisiou, V. Tsimourtou, V. Gourbali, K. Aggelakis, E. Dardiotis, M. Dardioti, G. Noulas, A. Papadimitriou, A. Singleton, G. Hadjigeorgiou University of Thessaly (Larissa, GR); NIA/NIH (Bethesda, USA) Objectives: To perform a genetic case-control association study of BDNF gene in Greek PD patients. Methods: Two hundred and seventeen Greek PD patients (87F, 130M; age at onset range 30–88) and 221 age-, gender-, and ethnicity-matched controls were studied using 8 haplotype tagging SNPs (htSNPs) selected through HapMap and five constructed haplotypes covering almost the whole gene locus. To assess the structure of this locus we have performed linkage disequilibrium (LD) analysis using these variants. Taqman® Assays-by-Design SM SNP Genotyping (Applied Biosystems) based assays were employed for allelic discrimination of the eight SNPs.Data was stored and manipulated for genetic analysis using the database GERON genotyping. Pair-wise D’, r2, and Hardy-Weinberg equilibrium (HWE) measurements were made using the program JLIN. Haplotype construction was performed using the Arlequin Ver. 2 program. Haplotype analysis for association was performed using the SHEsis program. Results: The selected SNPs captured a minimum of 95 % of the known common genetic variation across the gene. One apparent block of linkage disequilibrium was identified. All polymorphisms were in HWE for patients

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and controls. No statistically significant differences in genotype and allele frequencies were found between cases and controls. LD revealed a strong LD between all the markers.We identified five haplotypes with frequency > 0.02. Two haplotypes (TAGTTTCC and TAGCTATC) (p = 0.04 and p = 0.02) were associated with PD but since Bonferonni’s adjusted threshold for multiple comparisons was 0.01 (0.05/5) we consider all these associations as non-significant Conclusion: We showed that common genetic variability in BDNF is not associated with risk for PD in Greek population. P183 Dopamine receptor activity modulates the effect of N-methyl-norsalsolinol on serotonin metabolism in the rat caudate nucleus in vivo A. Thümen, A. Moser UKSH, Campus Lubeck (Lubeck, D) In the cerebrospinal fluid of L-dopa treated patients with Parkinson’s disease (PD) increased levels of the atypical dopamine metabolite N-methyl-norsalsolinol (2-methyl-6.7-dihydroxy-1.2,3.4-tetrahydro-isoquinoline, NMNSal) could be found. In former studies we could demonstrate that intraperitoneally administered NMNSal was able to pass through the blood brain barrier of the rat brain. Additionally, NMNSal was able to produce a long term effect on rat behavioural activity by alteration of the serotonin metabolism. In vivo microdialysis technique was applied to investigate the influence of dopamine (DA) agonists or antagonists on the long term mechanism by which NMNSal acts on both the behavioural activity and serotonin metabolism. Stereotaxic surgical procedures were used to implant guide cannulae aimed at the caudate nucleus of male wistar rats. Two days after implantation, artificial cerebrospinal fluid (aCSF) was perfused with a perfusion rate of 2 µl/min. After a 2 hour stabilization period, three 20 min samples were collected as basal values.NMNSal and DA agonists/antagonists were injected i. p. at time 0 and dialysate samples were further collected each 20 min. Furthermore, dopamine agonists or antagonists were injected i. p. 24 and 48 hours after starting the experiments. Serotonin metabolites [hydroxyindole acetic acid (HIAA), 5-hydroxytryptamine (5-HT)] were measured by HPLC/ECD analysis during the subsequent 180 min period as well as after 24 and 48 hours. 90 min after intraperitoneal injection of 40 mg/kg NMNSal, DA agonists or antagonists did not modulate serotonin levels or HIAA/5-HT ratios in the dialysate. After 24 and 48 hours, 5-HT levels continuously increased when compared to basal values. This effect was antagonised by the selective D1agonist dihydrexidine and D2-agonist bromocriptine. In the presence of the D2-antagonist sulpiride, enhancement of 5-HT levels was unchanged. In contrast to 5-HT, HIAA levels continuously decreased after NMNSal injection. This effect was diminished by co-administration of dihydrexidine and nearly completely antagonised by bromocriptine or sulpiride. Finally, the HIAA/5-HT ratio was significantly decreased after NMNSal injection. Coadministration of NMNSal with sulpiride, bromocriptine or dihydrexidine led to increased HIAA/5-HT ratios. These findings indicate that modulation of the dopamine receptor activity interferes with the effects of NMNSal on serotonin metabolism in the rat caudate nucleus in vivo. The author received an ENS stipend. P184 Effect of pallidal and thalamic deep brain stimulation on Holmes tremor caused by thalamic stroke D. Gruber, E. Lobsien, A. Kivi, T. Trottenberg, G. J. Jungehülsing, K. T. Hoffmann, G. H. Schneider, A. Kupsch University Medicine Berlin (Berlin, D) Objective: We present the effect of deep brain stimulation (DBS) of the ventral oral posterior nucleus (Vop) and the globus pallidus internus (GPi) on Holmes tremor secondary to a thalamic and subthalamic infarction. Thalamotomy and DBS of the ventrointermediate thalamic nucleus combined with Gpi- or with subthalamic nucleus lesions are known to alleviate symptoms of Holmes tremor secondary to midbrain lesions. Patient and methods: A right-handed 82-year-old female presented a medically intractable resting, postural and intention tremor of the right arm combined with involuntary ballistic movements in the proximal right upper extremity. The MRI showed a postischemic lesion of the dorsolateral thalamus extending to the subthalamic region. Clinical evaluation included: Tremor Rating Scale (TRS), disability scores: Activities-of-Daily-Livingscore (ADL) and Assessment of handicap and videotape. Quadripolar electrodes (model 3387) were inserted in the left Vop and GPi. Results: Postoperative MRI verified the correct electrode placement. We only documented a mild suppression of resting, postural and intention

tremor measured by TRS without improvement of ADL. No side effects following Vop DBS were evaluated. A bipolar stimulation was chosen: contact 0 positive; 1 negative; contacts 2, 3 and case off; the amplitude: 4.0 V, the frequency: 130 Hz and pulse width: 90 µs. In contrast there was no benefit of GPi-DBS after surgery. Therefore after one week Soletra only was implanted and connected to the Vop electrode. Discussion: The present case report shows that ventral oral thalamic deep brain stimulation ameliorates Holmes tremor in the upper extremity including resting, postural and intention components but in contrast to recent reports without improvement of activities of daily living. Furthermore we could not document any effects of GPi-DBS on Holmes tremor. P185 Association study of the –258T/G parkin gene promoter polymorphism in Parkinson’s disease and progressive supranuclear palsy J. Campdelacreu, M. Ezquerra, E. Muñoz, M. J. Marti, F. Valldeoriola, E. Tolosa Hospital Clinic (Barcelona, E) Objectives: Parkin gene mutations are responsible for the majority of cases of autosomal recessive juvenile parkinsonism. Several studies have hypothesized that loss of parkin expression due to mutations or functional polymorphisms of this gene could represent a risk factor for dopaminergic cell death and thus for sporadic Parkinson’s disease (PD). However, several association studies of parkin polymorphisms in PD have shown contradictory results. In addition, the fact that parkin is a ubiquitin ligase that could be involved in tau degradation gives the interest to investigate the role of parkin gene in diseases related to tau protein abnormal deposition. Recently, it has been described the case of a patient with pathologically confirmed progressive supranuclear palsy (PSP) which was a carrier of a parkin mutation. In this context, we have believed of interest to perform a case-control association study of the –258T/G parkin gene promoter polymorphism in order to assess whether it could represent a genetic risk factor in patients with PD and PSP. Methods: 158 patients meeting UKPDSBB criteria for PD, 16 patients with PD and dementia, 43 patients with probable PSP and 61 healthy controls were recruited. Genotyping was performed as previously described. Genotype and allele frequencies were compared with the chi-square test, using the SPSS 10.0 software for Windows. Results: No significant differences in the –258T/G parkin polymorphism genotype and allele frequencies were detected among patients with PD, PSP and controls. Conclusion: The –258T/G functional promoter polymorphism does not act as a risk factor for sporadic PD or PSP in the Spanish population. This does not rule out a role for parkin in PD or PSP because other single nucleotide polymorphisms alone or in combination with other genetic or environmental factors could favour neuronal degeneration in these diseases. P186 Dystonic antecollis: more than just a head drop! A clinical and electrophysiological study J. M. Flowers, M. H. Marion St George’s Hospital (London, UK) Background: Antecollis is a rare form of cervical dystonia. Despite the effective use of Botulinum toxin in the treatment of cervical dystonia, the antecollis subgroup is poorly understood and usually shows only a partial response to bilateral sterno-mastoid Botulinum toxin injections. Objectives: To make a clinical and electrophysiological study of dystonic antecollis in order to define specific protocols for its treatment with Botulinum toxin. Methods and Results: Here we describe three clinically distinct dystonic postures comprising antecollis. These are the “pseudo-head drop”(chin drop towards sternum), “goose neck” (forward projection of chin) and “double chin.” These three different forms of antecollis (3 cases of “double chin”, 2 cases of “goose neck” and 1 case of “pseudo-head drop”) will be described in terms of functional anatomy of the cervical spine and illustrated using photographic and video footage. Needle electromyography (EMG) recording of the cervical muscles was performed to characterize the muscles responsible for generating each dystonic posture in the 6 patients and two healthy volunteers (who were asked to mimic the three dystonic postures). “Pseudohead drop” was associated with initial activation of longus coli, and then both sterno-mastoid muscles.“Goose neck” was associated with synergistic contraction of both sterno-mastoids and both splenii.“Double chin” was associated with initial contraction of longus coli, and then contraction of the supra-hyoid muscles. Conclusion: This combined clinical and electrophysiological study has allowed us not only to define different clinical phenotypes of dystonic an-

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tecollis but also to formulate individual protocols for their treatment with Botulinum toxin.

P187 Abnormal somatosensory processing in clinically affected and non-affected PINK1 (PARK6)-mutation carriers assessed by quantitative sensory testing J. Ludwig, F. Lienau, R. Maag, K. Hedrich, G. Deuschl, C. Klein, R. Baron, C. Helmchen Universitätsklinikum Schleswig-Holstein (Lubeck, D) Introduction: Sensory symptoms are common in Parkinson’s disease (PD). It is unclear whether these symptoms are of primary origin or secondary due to pathophysiological changes occurring in PD. Recently, mutations of the PINK1 (PARK6) gene have been identified as one cause for the development of PD. Asymptomatic carriers of PINK1 mutations represent individuals at risk who can be identified prior to the development of PD by molecular genetic testing. Therefore, PINK1-associated PD may serve as a model to detect presymptomatic signs and sensory abnormalities before subjects show definite clinical signs of PD. This might shed light on the pathomechanisms related to sensory abnormalities in patients with the more frequent idiopathic PD. Methods: 14 family-members with PINK1 mutation (3 homozygous, 11 heterozygous) and 14 healthy controls were examined. A clinical examination, nerve conduction studies and a shortened form of the QST protocol of the German Research Network on Neuropathic Pain (DFNS) were performed. The QST protocol included perception thresholds for warm, cold, cold pain, heat pain, mechanical and painful mechanical stimuli, vibration and pain pressure. For evaluation, z-values were calculated and compared by the U-test. P < 0.05 was considered to be statistically significant. Results: The homozygous PINK1 mutation carriers were all symptomatic and had a definite PD. Despite the lack of symptoms for PD, five heterozygous PINK1 mutation carriers showed mild clinical signs for PD upon neurological examination. All individuals with parkinsonian signs upon neurological examination were considered “affected” (n = 8), family members without signs as “unaffected” (n = 6). Comparison of affected and unaffected PINK1 mutation carriers revealed significant lower z-values for mechanical detection (p < 0.0005) and vibration detection threshold (p < 0.01) in the affected PINK1 mutation carrier group. Both parameters correlated significantly negative with the UPDRS III. Conclusion: In contrast to patients suffering from idiopathic PD (Hägele et al. 2005), higher somatosensory thresholds seem to be a marker not only in affected, but also in unaffected PINK1 mutation carriers. Since neurography showed normal data, we hypothesize that sensory impairment is of primary origin, probably due to altered central somatosensory processing.

P188 Sequence analysis and gene expression of CRHR1 gene in progressive supranuclear palsy C. Gaig, M. Ezquerra, J. Campdelacreu, E. Muñoz, M. J. Martí, F. Valldeoriola, E. Tolosa Hospital Clínic Barcelona (Barcelona, E) Objectives: Several genes have been located in the chromosomical region 17q21 genetically associated with an increased risk for Progressive Supranuclear Palsy (PSP). The pathogenic role of this haplotype is not known, and it could act by modulating the function of tau protein or be in linkage disequilibrium with a potential causative neighbouring mutation in this region. Corticotropin releasing hormone receptor 1 (CRHR1) is a candidate gene included in this region. Corticotropin releasing hormone by its specific receptor subtype CRHR1 can protect neurons from different stress mechanism, such as beta-Amyloid toxicity in Alzheimer’s disease (AD) and ischemia in cerebrovascular disease (CVD). Consequently, it is possible that mutations or abnormalities in the gene expression pattern of CRHR1 gene could be involved as a primary event in the pathogenic mechanism in PSP. Methods: We sequenced directly the entire coding region of CRHR1 of two histopathologically confirmed PSP patients. We measured brain mRNA expression of this gene in frontal cortex and globus palidus using real-time PCR in 13 PSP, 6 controls, 10 AD and 5 CVD subjects. Results: We did not find any coding non-synonymous mutation in the patients analysed. Expression pattern of CRHR1 in globus pallidus was similar in all groups. There was an unexpected but significative reduction in CRHR1 expression in frontal cortex of PSP and CVD brains compared to controls. Conclusions: We have found changes in CRHR1 expression in frontal cortex of PSP patients, but this is not disease-specific. The normal findings

in globus pallidus do not support a causative role of CRHR1 gene in PSP pathogenesis. P189 Wilson’s disease – a genotype versus neurological phenotype correlation on the basis of the H1069Q mutation W. Hermann, P. Günther, A. Wagner, O. Sabri, J. Schneider, D. Huster, H. Kühn, G. Reichel, H. Barthel Paracelsus Klinik Zwickau (Zwickau, D); Universität Leipzig (Leipzig, D) Objective: Wilson’s disease is a rare hereditary disorder of hepatic copper transport leading to varying hepatic and neurological symptoms. The genetic defect is on the long arm of chromosome 13 encoding 1411 amino acids of the P-type 7B ATPase. Currently, about 250 causative mutations of the ATP 7B gene are known with H1069Q being the most frequent in Europe. The mutations might affect various functional parts of the ATP 7B protein leading to varying intracellular disturbances of ATPase 7B. On the basis of H1069Q mutation, a dysfunction in tertiary structure of the ATP 7B protein leads to a failed sensor function to copper level in the cytosole. The disturbed elimination of copper into the biliary tract is the common final result of possible different intracellular pathways. This study was initiated to search for a genotype vs. neurological phenotype correlation in Wilson’s disease. Methods: To elucidate a possible correlation in this study 40 patients with Wilson’s disease were subdivided into three groups according to the underlying mutation: homocygous H1069Q mutation (N = 16), compound heterocygous H1069Q mutation (N = 20), and other mutations (N = 4). A neurologic score was performed. Furthermore, in the patients, visual, acoustic, somatosensory and motor evoked potentials were analyzed, as well as fine motor movement (writing test), brain dopamine neurotransmission/glucose metabolism ( [123I]β-CIT and [123I]IBZM-SPECT, [18F]FDG-PET) and cerebral morphology (magnetic resonance imaging). Results: All three genotype groups show similar results concerning onset of symptoms (between 13.5 to 22 years), clinical findings with similar therapeutic response without any difference in sex of the patients. There were neither significant differences in the results of evoked potentials and fine motor skills nor in MRI and radiotracer brain imaging. Conclusion: Our results suggest that in Wilson’s disease – with regard to the neurological phenotype – the clinical presentation does not correlate with the underlying mutation. Thus, an influence of both genetic and epigenetic criteria on the course and phenotype of the disease is assumed without direct genotype vs. neurological phenotype correlation according to a decisive mutation.

General neurology P190 Use of potentially inappropriate pain-related medications in elderly patients with painful neuropathic disorders: a study using the UK general practice research database D. Leslie, A. Sadosky, D. Rowbotham, E. Dukes, K. Tai, M. Gore Yale School of Medicine (West Haven, USA); Pfizer, Inc. (New York, USA); University of Leicester (Leicester, UK); Avalon Health Solutions, Inc. (Philadelphia, USA) Objective: Polypharmacy is common in the elderly, resulting in an increased risk of inappropriate prescribing in these patients. Neuropathic pain is particularly difficult to treat and often requires the use of multiple medications, thereby compounding the potential of polypharmacy and inappropriate prescribing. Information on the extent of such prescribing in patients with painful neuropathic disorders (PNDs) is however lacking. Our goal was to assess the use of potentially inappropriate pain-related medications in elderly patients with PNDs. Methods: Using the UK general practice research database (GPRD) we identified 39.256 patients who were 65 years or older and had a diagnosis of a PND between 1998 and 2001. Use of potentially inappropriate pain-related medications in these patients was examined using the Beers 1997 criteria. Developed by a panel of experts in geriatrics and pharmacology, this is a comprehensive list of all medications “inappropriate” for use in the elderly. Results: On average patients were 74.6 (+ –6.8) years old (62 % women). Nearly one third (29.1 %) of PND patients had received one or more prescriptions for potentially inappropriate pain-related medications. Tertiary tricyclic antidepressants including amitriptyline (17.2 %) and benzodi-

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azepines (15.5 %) were the most common. Women were more likely than men to have received these medications (32.1 % vs. 24.2 %, p < 0.0001) and use increased with age (27.5 %, 30.4 %, and 32.5 % among those aged 65–74 years, 75–84 years, and ≥ 85 years, p < 0.0001). Among the different types of PNDs we examined, patients with postherpetic neuralgia (54.5 %) and phantom limb pain (53.2 %) were the most likely to receive potentially inappropriate pain related medications, p < 0.0001. Conclusions: Our results indicate that elderly patients with PNDs are often prescribed potentially inappropriate pain-related medications. The clinical significance of these data, is, as yet, unclear. While our results raise concern, further research is needed to evaluate the risks vs. benefits of such prescribing in these patients. Pfizer, Inc sponsored this study. P191 Use of amitriptyline in patients with painful neuropathic disorders in general practice settings in the United Kingdom D. Leslie, E. Dukes, D. Rowbotham, A. Sadosky, K. Tai, M. Gore Yale School of Medicine (West Haven, USA); Pfizer, Inc. (New York, USA); University of Leicester (Leicester, UK); Avalon Health Solutions, Inc. (Philadelphia, USA) Objective: Amitriptyline is a tricyclic antidepressant historically indicated and used to manage depression. More recently, due to clinical evidence demonstrating efficacy, it is often used to treat neuropathic pain. However, the amitriptyline label contains numerous preclusions (contraindications, warnings/precautions, drug interactions) for its use. Patients with painful neuropathic disorders (PNDs) tend to be older, suffer from other chronic comorbidities and are consequently more likely to have one or more of these preclusions. Our objective in this study was to measure the frequency of amitriptyline prescriptions in PND patients and assess whether any prescriptions were given to patients with preclusions listed in the product label. Methods: Using the UK General Practice Research Database we identified 13.546 patients (mean age 59 + –16.2 years; 66.7 % female) who had a diagnosis of a PND and received one or more prescriptions for amitriptyline between July 1998 and June 2001. We then examined the prevalence of preclusions in these patients. Results: Nearly half (46.7 %) of amitriptyline-prescribed PND patients had one or more preclusions: 3.5 % had one or more contraindications; 22 % had one or more warnings/precautions; and 33 % received one or more medications with a potential for drug interactions with amitriptyline. Pre-existing heart disease (8 %), and concurrent use of contraindicated analgesics (17.7 %), thyroid medications (6.6 %) and antiepileptics (6.1 %) were the most common preclusions. Preclusions were more likely in women (48.3 % vs. 43.4 %, p < 0.0001) and their incidence increased with age (42.8 %, 50.4 %, 55.1 %, 52.3 % among those aged < 65, 65–74, 75–84, and 85 + years, p < 0.0001). Conclusions: Results suggest that, in a significant number of cases, the existence of preclusions did not prevent the prescribing of amitriptyline. Prescribing of amitriptyline was also generally higher among the older and potentially more medically compromised patients. In theory, adverse outcomes may have been associated with this practice.While, we could not confirm this with this database analysis, caution on the part of prescribers is perhaps warranted. Pfizer, Inc sponsored this study. P192 Reversible magnetic resonance imaging lesions in a case of metronidazoleinduced central nervous system toxicity G. Moneger, F. Klapczynski, P. Beyroud, A. Ameri Meaux General Hospital (Meaux, F) Objective: To report a case of central nervous system toxicity associated with metronidazole therapy. Case report: A 56 year old women complained of subacute vertigo, nausea and vomiting, dysarthria, clumsiness of arms and paresthesia of the four extremities. Since three month and a half, she has been treated by metronidazole for a pseudomembranous Colitis with many complications and one recurrence. Neurological examination revealed dysarthria, ataxia, vertical nystagmus and peripheral neuropathy. Brain magnetic resonance imaging (MRI) showed high signal intensities in the cerebellar dentate nuclei bilaterally and splenium of corpus callosum on T2 and fluid attenuated inversion recovery (FLAIR), without contrast enhancement. Discontinuation of the metronidazole resulted in the improvement of the vertigo, dysarthria, ataxia and nystagmus within three days, whereas extremity pain persist five month later. A repeated brain MRI at 6 weeks showed complete resolution of abnormalities.

Discussion: Metronidazole is an agent widely used for the treatment of anaerobic and protozoal infection. Althougt the peripheral nervous side effects are classical, central nervous system toxicity of metronidazole is rare and unwell known. Reversible brain MRI lesions metronidazole-induced have only been described recently. Reversible abnormalities of the cerebellar dentate nuclei seems characteristic.The administered dose was within the recommended range, and toxicity seems to be associated with a high cumulated dose of metronidazole (more than 30 grammes). P193 Observations on carotid sinus hypersensitivity from 2 autonomic referral centres – implications for testing based on 373 subjects A. M. Humm, C. J. Mathias University Hospital (Berne, CH); Imperial College London at St Mary’s Hospital (London, UK) Objectives: To determine the frequency, age distribution and clinical presentation of carotid sinus hypersensitivity (CSH) among subjects referred to two national autonomic referral centres during a 10- year period, one a major teaching hospital and the other a specialist neurological hospital. Methods: Carotid sinus massage (CSM) was performed both supine and during 60° head-up tilt. Beat-to-beat blood pressure (BP) and heart rate (HR) were recorded using the Portapress II device, additionally a 3-lead ECG was recorded continuously. CSH was classified as cardioinhibitory (asystole ≥ 3sec), vasodepressor (systolic BP fall ≥ 50 mmHg) or mixed (combination of asystole ≥ 3sec and systolic BP fall ≥ 50 mmHg). All subjects additionally had autonomic screening tests (including tilt table testing) for orthostatic hypotension and autonomic failure (Mathias and Bannister 1999). Results: CSH was observed in 51 out of 373 subjects (13.7 %). The diagnostic yield of CSM was 0 % in subjects < 40 y (n = 32) and in those aged 40–49 y (n = 33), 2.4 % in subjects aged 50–59 y (n = 82), 9.1 % in the age group of 60–69 y (n = 77), 20.7 % in patients aged 70–79 y (n = 92) and 40.4 % in those over 80 years (n = 57). Syncope was the leading clinical symptom in 62.8 %; in more than half of these subjects without warning. In 27.4 % of subjects falls without definite loss of consciousness were the main clinical symptom; presyncopal episodes were reported by the remainder. Syncope or falls caused injury in 47 % of the subjects. Mild and mainly systolic orthostatic hypotension was recorded in 17.6 %; in none was there evidence of sympathetic or parasympathetic dysfunction. Conclusion: CSH was confirmed, and was likely to be the cause of syncope and falls, in subjects over the age of 50; the incidence increased with age. There were no subjects with CSH below the age of 50. Current European Society of Cardiology guidelines recommending testing for CSH in subjects over 40 years with syncope of unknown aetiology may need to be reconsidered. A. M. Humm was supported by a Swiss national grant for a fellowship in clinical neurophysiology (Grant 31–226). P194 Open trial to evaluate efficacy, safety and the dose-escalation of idebenone in patients with Friedreich’s ataxia J. Arpa, F. Domínguez, M. Moreno, F. Rodríguez-de-Rivera, M. Sarriá, S. Santiago, C. Pérez-Conde, R. López-Pajares, M. Blanco Hospital Universitario La Paz (Madrid, E) Objectives: To assess the efficiency of idebenone on cardiac hypertrophy in Friedreich’s ataxia. Material and methods: We studied 14 patients with FDRA. Annually, the dose of Idebenone was increased from 5 mg/kg/day during the first year, up to 20 mg/kg/day the third year. At each follow-up evaluation, all patients underwent clinical and neurological assessment and echocardiography. Results: The LVM index improved in 45.4 % of the patients after year 1 with Idebenone therapy (5 mg/kg/day), but it worsened in 54.5 % of them.At the end of the second year, the LVM index improved in 53.8 % of the patients with Idebenone therapy (10 mg/kg/day), but it worsened in 46.1 % of them. Finally, when the dose-escalation of Idebenone therapy had reached 20 mg/kg/day (third year follow-up), cardiac ultrasound indicated the normalization of LVM index in 75 % of the patients. In the other 25 % of them LVM index had remained normal. Conclusions: Idebenone could prevent or slow the cardiac hypertrophy in FDRA, although the same or higher dose than 20 mg/kg/day seems to be necessary. This study was supported by grant PI03/0971 from Fondo de Investigación Sanitaria (FIS)

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P195 Type A aortic dissection from the neurologist’s view W. Dietrich, C. Gaul, I. Friedrich, J. Sirch, F. J. Erbguth Municipal Hospital (Nuremberg, D); University Halle-Wittenberg (Halle, D) Background: Aortic dissection typically presents with severe chest or back pain. Neurological symptoms may occur due to occlusion of supplying vessels or general hypotension. Especially in painfree dissections diagnosis can be difficult and delayed. Methods: To assess the link between type A aortic dissection and neurological symptoms clinical records of 102 consecutive patients (62.7 % male, mean age 55.6 years) over 7.5 years were analyzed for medical history, preoperative clinical characteristics, treatment and outcome with main emphasis on neurological symptoms. Results: 30 patients showed initial neurological symptoms (29.4 %). Only two thirds of them reported chest pain, while most patients without initial neurological symptoms (94 %) experienced initial pain. Cerebral ischemia was the most common initial finding (16 %), more frequently hemispheric compared to vertebral-basilar and predominantly right sided. Other neurological symptoms were: spinal ischemia (1 %), ischemic neuropathy (11 %), hypoxic encephalopathy (2 %), syncope (6 %), and seizures (3 %). Half of the patients showed transient symptoms. Involvement of the supraaortic vessels was found in 43 % of all patients, most frequently affecting the innominate and carotid arteries. Only one fifth of these patients presented with preoperative stroke. In one third of patients with preoperative stroke, ischemia was not caused by supraaortic extension of dissection, but due to other mechanisms like thromboembolism or hypotension. Postoperative neurological symptoms were found in 47.5 % of all patients encompassing cerebral (14 %) or spinal ischemia (4 %), ischemic neuropathy (3 %), hypoxic encephalopathy (8 %), nerve compression (7 %), and temporary neurological dysfunction (15 %). Overall in-hospital mortality was 22.6 % and did not significantly differ in patients with and without initial neurological symptoms or complications. Conclusion: Aortic dissections with initial neurological symptoms occur in one third of patients without any pain.Additionally, in case of aphasia, unconsciousness or transient global amnesia patients can not report chest pain, thus complicating the correct diagnosis. Neurologists should be alert for aortic dissection in patients presenting unusual combinations of symptoms with involvement of central and peripheral nervous system. Presence of neurological symptoms, even severe, is not necessarily associated with increased mortality and does not warrant to withhold surgery to patients. P196 Intra-individual comparison of botulinum toxin type A and type B in patients with cervical dystonia and secondary non-response to botulinum toxin type A P. Bussfeld, M. Moll, U. Kahlen, M. Kurz, H. Hefter University of Dusseldorf (Dusseldorf, D) Objective: The efficacy of intramuscular injections of botulinum toxin type A (BTX-A) at the onset of therapy was compared to the clinical effect of injections of botulinum toxin type B (BTX-B) in patients with cervical dystonia who were treated the first time with BTX-B after a secondary non-response had occurred after several years of successful therapy with BTX-A. Methods: 33 patients with idiopathic cervical dystonia (CD) and secondary non-response to BTX-A were treated the first time with NeuBloc® (BTX-B). Secondary non-response was diagnosed when – inspite of previous good response to BTX-A – a continuous worsening of CD was found and documented by means of the TSUI-Score although the dose of BTX-A had systematically been escalated for at least 2 times. In 17 patients secondary non-response was confirmed by a positive mouse diaphragma test. The reduction of the TSUI-score after the first three injections of BTX-A was compared to the reduction of the TSUI-Score after the first three injections of BTX-B. Results: In this special group of patients with CD a reduction of the TSUI-score of 61 % was observed after the initial three injections of BTX-A and a reduction of 64 % after the first three injections with BTX-B. The mean TSUI-scores determined 3 months after each injection did not differ for BTX-A and BTX-B injections. The distributions of responses to BTX-injections were broad for both type-A and type B injections and did not differ. However, no correlation was found between the reduction of the TSUI-score after BTX-A and BTX-B injections. Conclusions: Interestingly, though as a group effect the response to BTXA and BTX-B was the same in our patient group, a correlation between the BTX-A and the BTX-B response was lacking. Thus, a patient responding well to BTX-A may not respond to BTX-B and vice versa. We conclude that the genetically determined decomposition of the snare complex at the muscle

end plats may considerably vary from patient to patient and may cause a difference in the response behaviour to BTX-A and BTX-B. P197 Copper deficiency associated reversible opticomyeloneuropathy I. Martínez-Torres, N. Muelas, S. Roig, M. Garcés, J. Vílchez Hospital La Fe (Valencia, E) Objective: To describe a patient with progressive bilateral optic neuropathy, myelopathy and neuropathy due to copper deficiency. Method: Description of the clinical features, ancillary testing (including spinal and brain MRI, electrophysiological studies and muscle biopsy), and response to treatment of one patient. Results: A 52-year old man came to our attention in May 2003 because of progressive visual and gait difficulties that evolved over the previous year. On examination he had diminished visual acuity and abnormalities confined to the lower limbs: spastic paraparesia, distal impaired sensation of proprioception and vibration, increased knee jerks, and bilateral extensor plantar responses. The patient was able to walk without support. The following studies were normal or negative: routine blood tests, iron studies, sedimentation rate, vitamin B12 and E, folate, angiotensin-converting enzyme, thyroid hormones and thyroid stimulating-hormone, inmunoelectrophoresis, tumoral markers, antinuclear antibody, antithyroid antibodies, organ specific antibodies, serum long chain fatty acids, serum lactate. CSF analysis was normal. Microbiological serum and CSF studies were negative, including Lyme, syphilis, Brucella, Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, Human T-cell lymphotropic virus type 1. Magnetic resonance of the spinal cord and brain were unremarkable. Somatosensory, visual and auditory evoked potential studies showed abnormal conductions. Electromyography and nerve conduction studies were consistent with lumbosacral multirradiculopathy. Muscle biopsy showed myopathic changes suggestive of mitochondrial myopathy. The patient slowly deteriorated, and after two years he could no longer walk without bilateral support. On June 2005 low serum copper and ceruloplasmine levels were detected. We started treatment with oral copper supplements, with progressive improvement. Seven months later the patient could walk without aid. Conclusion: Copper deficiency has recently been reported in patients with a clinical picture similar to subacute combined degeneration. Prompt recognition of this entity is important because replacement treatment may result in neurological improvement. Although rare, bilateral optic neuropathy may occur in these patients. Our muscle biopsy findings support the hypothesis of mitochondrial dysfunction in patients with copper deficiency.

Genetics P198 Association of vitamin D receptor gene polymorphism with reduced disability in multiple sclerosis G. Mamutse, J. A. Woolmore, J. Alldersea, M. Boggild, C. A. Young, A. A. Fryer, R. C. Strange, C. P. Hawkins University Hospital of N. Staffordshire (Stoke on Trent, UK); Walton Centre for Neurology and Neurosurgery (Liverpool, UK) Objective: Multiple sclerosis (MS) shows a latitude gradient of prevalence which may be related to exposure to ultraviolet radiation (UV). The effects of UV may be mediated through 1.25-dihydroxycholecalciferol which exerts its effects via the vitamin D receptor. We hypothesised that polymorphisms in the vitamin D receptor gene (VDR) are associated with disability in multiple sclerosis. Methods: We examined VDR Cdx2, g 0.3436G > C, g 0.3944A > G, g 0.20965C > T, g 0.30056C > T, FokI, g 0.48200C > T, and TaqI single nucleotide polymorphisms in 1040 patients with MS using pyrosequencing technology. Disability was assessed with the expanded disability status scale (EDSS) and was dichotomised into mild to moderate (EDSS < 6) and severe (EDSS ≥ 6) disability. Alleles, genotypes, and haplotypes at the 8 sites were analysed for association with disability in patients with disease duration > 10 years using logistic regression. Corrections were made for onset age, gender and disease duration which are independent predictors of disability in MS. Results: With disease duration > 10 years (mean 19.4 + –8.4 years), complete genotype data for all six markers were obtained in 512 patients (366 females/146 males; mean age 48.8 + –10 years). FokI ff genotype was significantly associated with reduced disability (EDSS < 6) (odds ratio: 0.37; 95 % confidence interval: 0.20–0.70; p = 0.002, Bonferroni corrected p = 0.048).

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There was also a trend for genotype combinations including FokI ff to be associated with reduced disability. Conclusions: We demonstrate association between a potentially functional VDR polymorphism with reduced disability in multiple sclerosis. Further confirmatory tests are planned in an independent cohort. P199 Increased Purkinje cells acid sphingomyelinase activity: an early pathogenetic event in a spinocerebellar ataxia type 1 mouse model S. Bonato, S. Falcone, N. Bresolin, L. Croci, G. P. Comi, G. Consalez, R. Magnoni, A. C. Turconi, M. Pandolfo, H. Orr, E. Clementi IRCCS Eugenio Medea (Bosisio Parini, I); San Raffaele Scientific Institute (Milan, I); IRCSS Fondazione Policlinico (Milan, I); Université Libre de Bruxelles (Brussels, B); University of Minnesota (Minneapolis, USA) Objective: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in SCA1 gene resulting in a polyglutamine-related disease. Several evidence suggest that a toxic gain of function of mutant ataxin-1 leads to Purkinje cells (PuC) degeneration. Transgenic mice overespressing a human mutant ataxin-1 allele with 82 CAG repeats show progressive ataxia and PuC death. Therefore, the disease time course in SCA1 [82Q] mice shows that PuC loss is negligible until well beyond ataxia onset. Thus the neurological manifestations are not the result of PuC death, at least until the intermediate stages of the disease. Acid sphingomyelinase (A-SMase) catalyzes the degradation of sphingomyelin to phosphorylcholine and ceramide, a second messenger of the sphingolipids pathway. Recent data show that ceramide play a relevant role in PuC cells survival and apoptosis. Moreover, A-SMase deficient mice (Niemann-Pick mouse model) shows ataxia and PuC degeneration. This study investigates the potential role of A-SMase activity in the pathogenesis of PuC cells degeneneration in SCA1 mouse model. Methods: We investigated the A-SMase pattern expression in the cerebellum of wild-type FVB/N mice by non radioactive in situ hybridization. We determined by radioactive assay, the A-SMase activity in whole cerebellum and cerebral hemispheres of wild-type (WT), heterozygous (HE) and homozygous (HO)SCA1 [82Q] mice at two, four and six months of age. Results: In control cerebella, A-SMase mRNA is only expressed by PuC. The cerebellar A-SMase activity in HE SCA1 [82Q] was significantly increased when compared to WT at two and four months of age, when ataxic symptoms likely correspond to PuC dysfunction, while it was decreased at six months, when PuC loss begins. In HO SCA1 [82Q], presenting an accelerated time course, showed a milder increase of A-SMase activity at two months, while it was decreased at the later stages associates with PuC death. On the contrary, in the cerebral hemispheres, where mutant ataxin-1 is not expressed, the A-SMase activity was the same as in WT, HE SCA1 [82Q], and HO SCA1 [82Q] mice at different ages. Conclusions: Our data suggest that an early increase in A-SMase activity participates in the cascade of events occurring within mutant SCA1 PuC before their death. P200 Mitochondrial DNA microarray resequencing in Leber’s hereditary optic neuropathy and other mitochondrial encephalomyopathies F. Saladino, R. Virgilio, I. Cifola, A. Bordoni, S. Galbiati, C. Battaglia, N. Bresolin, G. P. Comi University of Milan (Milan, I) Objectives: Mitochondrial encephalomyopathies (MEM) are heterogeneous disorders caused by respiratory chain dysfunction. Primary mitochondrial diseases are due either to defects in mitochondrial DNA (mtDNA), which are inherited according to the rules of mitochondrial genetics, or to defects in nuclear DNA, which are transmitted by mendelian inheritance. This double genetic control makes particularly complex the diagnostic process. Screening for mutations with resequencing microarray could simplify the MEM diagnosis. Furthermore the availability of the entire mtDNA sequence may be useful to define the role of mtDNA haplotypes in mitochondrial disorders. Methods: To identify mitochondrial mutations and sequence variations in patients with MEM, we applied the Mitochondrial Custom Seq Microarray developed by Affymetrix, version 1.0 (MitoChip). This is an array-based sequencing platform for rapid and high-throughput analysis of mtDNA, with oligonucleotide probes synthesized using standard photolithography and solid-phase synthesis, and should be able to sequence > 29kb of double stranded DNA in a single assay. We used 300 ng of genomic DNA to amplify the mitochondrial coding sequence in three overlapping long PCR fragments. We followed Affymetrix CustomSeq Resequencing protocol. Results: We analysed DNA extracted from muscle tissue of six patients

with MEM, according to clinical, histological and biochemical criteria, who were negative for common point mutations and multiple deletions, and DNA from patients affected with Leber Hereditary Optic Neuropathy (LHON, n: 3), MELAS and MERRF with known common mutations in mtDNA. These latter patients had the following mtDNA mutations: pt. 1 LHON G3460A; pt. 2: LHON G11778A and G13708A; pt. 3: LHON G13708A, pt. 4: MELAS A3243G, pt. 5: MERRF A8344G. We successfully assigned base calls only at 71 %–74 % of nucleotide positions. This result was not improved by loaded DNA or fragmentation protocol. Sequence analysis revealed 130 polymorphic changes within this group of patients. Among the known mutations, only 4 out of 6 could be identified by this method. Conclusions: MitoChip resequencing tool did not provide a complete sequence analysis in the investigated patients. The identified polymorphisms may be useful for haplotyping mtDNA of patients belonging to different disease categories. Since mutation detection proved to be incomplete, further experiments are needed to define if MitoChip might be used for rapid mtDNA screening.

P201 Clinical and genetic study of two Italian families with silver syndrome An. Orlacchio, C. Patrono, A. Borreca, C. Babalini, L. Dionisi, V. Moschella, Al. Orlacchio, G. Bernardi, T. Kawarai CERC-IRCCS S.Lucia (Rome, I); University of Perugia (Perugia, I); Hyogo Brain and Heart Center (Himeji city, JP) Objectives: Silver Syndrome (SS) is a particularly disabling type of autosomal dominant hereditary spastic paraplegia (ADHSP) characterised by amyotrophy and weakness of the intrinsic hand muscle in addition to lower limb spasticity. A recent genetic study has demonstrated that SS can be caused by mutations in the BSCL2 gene (seipin) on chromosome 11q12-q14 (SPG17). In this context, investigation of genotype-phenotype correlations is important to understand the mechanism(s) of the disease. In order to assess genotype-phenotype associations, we performed a clinical and genetic study of two large Italian families showing clinical features similar to SS. Methods: Neurological evaluations, neurophysiological and neuropsycological examinations, neuroimage 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. Linkage analyses at the currentknown ADHSP loci showed evidence of linkage to SPG4 in one family. Sequence analysis of SPG4 revealed a novel frameshift mutation in exon 6 (c 0.961insG) 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 cognitive dysfunction, decreased vibration sense in the upper limbs, pes cavus, and seizures, in addition to typical clinical manifestations of SS. Degree and age-at-onset of these additional neurological features were heterogeneous in the pedigree. Electrophysiological studies revealed involvement of lower motor neurons as well as upper motor neurons. The other family showed no evidence of linkage to the current-known ADHSP loci, although the clinical features of the family are very similar to those in SS. Conclusion: Our study demonstrates that SPG4-HSP may include clinical features observed in SS and widen the spectrum of genetic abnormalities of the disorder. The report also demonstrates evidence of further genetic heterogeneity in SS.

P202 Absence of mutations in TREM-2 coding region in patients with early onset dementia E. Venturelli, C. Fenoglio, D. Galimberti, L. Piccio, D. Scalabrini, P. Panina, C. Buonsanti, C. Lovati, P. Baron, G. Forloni, C. Mariani, N. Bresolin, E. Scarpini University of Milan, Ospedale Maggiore (Milan, I); Bioxell (Milan, I); University of Milan, Ospedale Luigi Sacco (Milan, I); Istituto di ricerche farmacologiche Mario Negri (Milan, I) Background: Triggering receptor expressed on myeloid cells (TREM)–2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). The early onset of dementia and the marked involvement of frontal regions are features characterizing either NHD or other types of neurodegenerative disorders, primarily Frontotemporal Lobar Degeneration (FTLD), but in some cases also Alzheimer’s disease (AD). To date, there are no information on a possible role of allelic variants in TREM-2 gene as susceptibility factors for FTD or AD. Four polymorphisms

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have been reported in TREM-2 coding region. Neither association nor functional studies have been carried out yet. Objective: To test a population of probable AD patients as well as FTLD patients for known variants of TREM2 in order to determine their possible role as susceptibility factors. To perform a mutation scanning of the coding sequence in a limited group of patients and controls to detect novel Single Nucleotide Polymorphisms (SNPs). Methods: One-hundred Italian AD patients as well as 56 patients with FTLD were genotyped for rs2234252, rs2234253, rs2234255, rs2234 256 by allelic discrimination using an ABI PRISM 7000 instrument (ABI). Direct sequencing of the coding reagion was performed by an ABI PRISM 3100 gene analyzer (ABI). Results: None of the SNPs analyzed by allelic discrimination on the overall population was present, either in patients or controls. Results were confirmed in a limited group of subjects by direct sequencing. Moreover, in order to further validate data obtained with allelic discrimination, a new PCR-Restriction Fragment Length Polymorphism (RFLP) method was developed for detecting rs2234 256 in exon 4. Lastly, mutation scanning of the five exons of TREM-2 failed to detect the presence of novel SNPs. Conclusions: According to these results, no allelic variants in TREM-2 coding region are present either in patients with AD and FTLD, or in control subjects. These data demonstrate that TREM-2 coding region is highly conserved, implying a crucial role of this receptor for the activation of the subsequent signaling pathway. Notably, a novel RFLP protocol to detect rs2234 256 has been developed. Further studies, including a functional analysis, are certainly required to clarify the role of TREM-2 in neurodegenerative processes. P203 Late onset genetic neurometabolic disorders in Israel S. Khoury, S. Korman, V. Barash, O. Abramsky, H. Rosenmann, A. Gal, J. Newman, Z. Argov, A. Lossos Hadassah University Hospital (Jerusalem, IL) Background: Genetic neurometabolic disorders of the central nervous system (CNS) typically manifest first symptoms in childhood and constitute important aspect of pediatric neurology practice. Although some of these disorders are increasingly recognized to initially present in adulthood, their spectrum in Israel is unknown. Objective: To describe the range of defined genetic neurometabolic disorders of the CNS presenting after the age of 18 years excluding disorders of mitochondrial or lysosomal function, Wilson disease and cerebrotendinous xanthomatosis. Design: Retrospective results of an established multidisciplinary neurometabolic framework at Hadassah Medical Center. Results: Three groups of disorders could be defined: 1). Hyperhomocysteinemia was identified in siblings from two unrelated families manifesting progressive cognitive decline and myelopathy of adult-onset successfully treated with betaine. In contrast to hyperhomocysteinemia of childhood, there were no ocular, skeletal or vascular complications. Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) due to a new mutation in the MTHFR gene was diagnosed in one family. The underlying cause in the second family is presumed to involve early stages of homocysteine metabolism. 2). Glycogen branching enzyme (GBE) deficiency was diagnosed in 15 patients with adult polyglucosan body disease manifesting late-onset myelopathy, mild cognitive decline, leukoencephalopathy, polyneuropathy and autonomic dysfunction. There was no myopathy or liver dysfunction, which are typical of type IV glycogen storage disease in childhood. Molecular analysis in the patients identified mutations in the GBE gene. 3). Isolated instances of ethylmalonic aciduria with progressive encephalopathy due to short-chain acyl-CoA dehydrogenase and of hyperlysinemia manifesting progressive myelopathy. Conclusions: Although relatively uncommon, several genetic neurometabolic disorders of the CNS may initially present in adulthood. The specific combination of clinical features is usually different from their earlyonset counterparts and may be confused with the primary degenerative diseases. The relatively high proportion of patients with adult polyglucosan body disease is unexpected and suggests that this disease may be more common than is currently known. High degree of suspicion followed by extensive neurometabolic workup may be worthwhile in selected adult patients with undiagnosed disorders of the CNS.

P204 Increased risk of migraine in Marfan syndrome S. Knudsen, M. B. Russell Glostrup University Hospital (Copenhagen, DK); Akershus University Hospital (Oslo, N) Objective: To study the prevalence of migraine in Marfan syndrome. Method: The patients were recruited from Landsforeningen for Marfan syndrome, a patient organization. A total of 46 persons were eligible for a validated semi-structured telephone interview by a physician trained in headache diagnostics. Results: The prevalence of migraine without aura was 13 % among men and 40 % among women. The prevalence of migraine with aura was 44 % among men and 37 % among women. The overall prevalence of migraine was 63 % with an equal sex ratio. This corresponds with a 3.6- and 2.0-fold significant increased risk among men and women, respectively, compared with the general population. Analysing the different migraine characteristics showed that unilateral pain location and pulsating quality were 33 % less frequent in those with Marfan syndrome compared with migraineurs from the general population. Otherwise the frequencies of the different migraine characteristics were similar in the two groups. The prevalence of tensiontype headache in Marfan syndrome was higher in men and lower in women than found in the general population. One man and a woman had postural headache a few days per year, and two men and three women complaint about pain in their temperomandibular joint when chewing, and one man and three women had had headache due to rhinosinusitis. Conclusion: The high prevalence and equal sex ratio of migraine is puzzling and likely to be secondary to Marfan syndrome. P205 Early onset X-linked Charcot-Marie-Tooth disease. Two novel mutations in the GJB1 gene one associated with abortion G. J. Braathen, J. C. Sand, G. Bukholm, M. B. Russell University of Oslo (Oslo, N); Akershus University Hospital (Oslo, N) X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene (GJB1). The gene encodes a polypeptide which is arranged in hexametric array and form gap junctions. We describe two novel mutations in the connexin32 gene in two Norwegian families. Family 1 had a 225delG which cause a frameshift and premature stop codon at position 247. This probably results in a polypeptide which is not arranged in a hexametric array due to the change in protein structure. This family had a female preponderance of X-linked CMT and several abortions were observed. Family 2 had a 536 G__A transition which cause a change of the highly conserved cysteine residue to tyrosine at amino acid position 179. One man had pathological VEP and three affected had markedly balance problems of probable central nervous system origin. The mean age at onset was in the first decade in both genders. Clinically the affected had symmetrical findings, while the neurophysiological examination revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected. We conclude that the two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations. P206 Charcot-Marie-Tooth syndrome. Two novel mutations in the myelin protein zero (MPZ) gene G. J. Braathen, J. C. Sand, G. Bukholm, M. B. Russell University of Oslo (Oslo, N); Akershus University Hospital (Oslo, N) Charcot-Marie-Tooth (CMT) disease is characterized by distal muscle wasting and weakness, sensory loss with reduced tendon reflexes and foot deformity. It is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 2.500. CMT is a heterogeneous disorder with respect to clinical features, neurophysiology, pathophysiology and genetics. The number of identified CMT genes is still expanding. So far the majority of the CMT genes encodes either neuronal or Schwann cell proteins. The myelin protein zero (MPZ) gene is expressed in the compact layer of the Schwann cells. We present two new mutations in the MPZ gene as well as the clinical features in the two affected Norwegian families

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P207 Interleukin 2 (+ 114) gene polymorphism and traumatic brain injury M. Dardioti, E. Dardiotis, K. Aggelakis, K. Paterakis, A. Komnos, A. Karantanas, A. Tasiou, G. Xiromerisiou, G. Hadjigeorgiou University of Thessaly (Larissa, GR); General Hospital (Larissa, GR); University of Crete (Heraklion, GR) Introduction: Traumatic brain injury (TBI) initiates a cascade of inflammatory processes the extent of which determines the degree of neuronal death and the patient’s clinical outcome. Genetic variants in susceptibility genes have been reported to influence clinical outcome in TBI patients. Recently, we reported that IL-1Ra allele 2 was associated with post-traumatic hemorrhagic events (Hadjigeorgiou et al. Neurology 2005). Interleukin 2 (IL-2) is a pro-inflammatory cytokine derived from helper T cells and it is involved mainly in cell-mediated immunity. IL-2 is strongly upregulated after experimental TBI. IL-2 (+ 114) gene polymorphism has been studied in various autoimmune diseases.We conduct a prospective study to test influence of IL2 (+ 114) gene polymorphism on patients’ clinical presentation at admission and 6-month outcome after TBI Methods: A total of 216 patients with TBI [mean age ± SD = 39, 8 ± 21, 11, females = 35 (16, 2 %)] successively admitted to the neurosurgical unit were evaluated. Initial neurological status was assessed using the Glascow Coma Scale (GCS), while we defined the patient’s 6-month outcome using the Modified Rankin Scale. IL-2 (+ 114) genotypes were determined from blood samples by standard PCR/RFLP method. Mann-Whitney U-test was used to study the differences in GCS at entrance between the genotypes. Odds ratios were calculated for the risk of favourable and unfavourable outcome. Results: The population was in H-W equilibrium. Distribution of IL-2 genotypes and alleles were similar in TBI patients with favourable and unfavourable outcome. However, G allele was overrepresented in patients with severe clinical presentation at admission (low GCS), (p = 0.026). Conclusion: Our findings show a genetic association of IL-2 (+ 114) G allele carriers with more severe neurological status, as expressed by the GCS at admission, after TBI. Further studies should be conducted to confirm and evaluate this association. P208 Genetics of Parkinson’s disease – age at onset and heredity K. Kollarova, M. Nevrly, P. Ressner, R. Herzig, P. Kanovsky University Hospital (Olomouc, CZ) Objectives: Parkinson disease (PD) is a common neurodegenerative age dependent disorder. PD affects approximetely 1 % of the population at the age of 65 years. The ratio of affected males to females is 3:2. PD is a complex, multifactorial syndrom of largely unknown etiology. Familial forms compose less than 10 % of all cases. Nowadays at least 5 genes have been shown to cause familial early onset parkinsonism. Genetic factors seem to be of predominant importance in early onset of PD, whereas the environmetal ones in late onset forms of the PD.Young age at PD onset has been linked to its familial occurence, because in several PD pedigrees probands frequently younger than 50 years were identified. However there are only few prospective studies supporting this hypothesi, also because of the rarity of large parkinsonian families, low heritability and heterogenity of PD. The aim of this study was to assess the participation of genetic factors in the young age of PD onset and the familial occurence of PD. Methods: 100 randomly asigned PD patients (50 males 47.86 ± 9.1 and 50 females 52.83 ± 12.4 years) were questionared. Age at PD onset, progression, familial occurence, the relation ship among afflicted kindreds, character and onset of the PD symptoms were the observed parameters. Results: Family history of PD was present in 13 (7 males, 6 females) out of the 100 PD patients (13 %). The mean PD onset age was 47.8 years in males with predominantly paternal heredity and 52.8 years in females with prevalent maternal heredity. Conclusion: This survey confirmed an asociation between the familial history and the younger age at PD onset. The presence of the phenomenon of the anticipation in the familial form of PD can be supposed in accordance with young age at disease onset found in PD patients descents.

Infection P209 Post infectious Bickerstaff ’s brainstem encephalitis without detectable antiganglioside antibodies G. Galassi, A. Magherini, A. Todeschini Institute of Neurosciences (Modena, I) Objective: To report a patient affected by post-infectious Bickerstaff ’s brain stem encephalitis (BBE). Methods: This 48 year-old woman fifteen days after respiratory tract infection experienced headache, diplopia, gait unsteadiness which worsened over next 2 days. Neurological examination on admission (day 3) showed drowsiness, dysarthria, dysphonia, internuclear ophthalmoplegia, spontaneous nystagmus in either directions, left sided facial weakness, tongue deviation towards left, trunk and limb cerebellar ataxia. Muscle strength was normal in upper and lower extremities. Deep jerks were brisk with an extensor plantar response. Sensation seemed unaffected. Results: Chest x-ray revealed basal pulmonary infiltration. Routine emato-urinary tests were negative, including search for Campylobacter Jejuni, Borrelia Burgdorferi. C-reactive protein was 4.88 mg/dl (normal < 0.80). Serum cold hemagglutinin titer was 1:512 on day 4. Serum sample for anti-ganglioside antibody assay (day 22) was negative and spinal fluid (day 6) normal. Electrophysiology (day 4) revealed normal findings, whereas on day 11 there were low amplitude of peroneal action potentials and delayed F waves. Visual evoked responses were slowed on day 11 and 24. EEG showed diffuse theta changes (day 5 and 11). Brain resonance imaging (MRI) on day 2 and 6 revealed hyperintense T2 weighted lesions involving white matter of mid-brain, cerebellar peduncles, forebrain and cerebellum with inhomogeneous enhancement after gadolinium. Since day 2, patient was treated with methylprednisolone (1 gr e. v. daily for 3 days, 500 mg for 2 days) with dramatic improvement. Steroids were slowly tapered to oral regimen and withdrawn within day 30. Patient steadily recovered within a month. In conclusion, this patient had a monophasic remitting illness preceded by pulmonary infection. The disease was characterized by central signs, such as altered cosciousness, hyperreflexia, cerebellar ataxia associated with mild electrophysiological changes in peripheral nerves. MRI revealed altered signal intensity in mid-brain and cerebellum. Based on whole features, which included EEG abnormalities, BBE was diagnosed. Previous reports outline the close similarity of BBE with Miller Fisher’s syndrome, as they could share the same autoantibody profile. However GQ1b antibody may lack in 44 % of patients with Bickerstaff ’s syndrome during the acute phase period. P210 Bone marrow-derived monocytes/macrophages migrate into the cental nervous system and differentiate to microglia after Streptococcus pneumoniae meningitis in mice M. Djukic, A. Mildner, H. Schmidt, D. Czesnik, W. Brück, J. Priller, R. Nau, M. Prinz Georg August University (Gottingen, D); Humboldt University Berlin (Berlin, D) Objectives: Previous studies have demonstrated a potential role of brain endogenous microglia and meningeal macrophages in inflammation and neuronal injury in bacterial meningitis. However, the contribution of postnatally invading hematopoietic microglia to this process is still unknown. Methods: To investigate the kinetics of microglial engraftment we used genetically labelled bone marrow-derived cells (BMC) from transgenic mice driving GFP under the beta chicken actin pomotor to deliver fluorescencelabelled microglia to the diseased brain. 8 weeks after transplantation, 104CFU of S. pneumoniae were injected into the lumbar cerebrospinal fluid. Results: The GFP-expressing microglial cells were present in different brain regions of all recipients analyzed at several time points. We showed phenotypic differentiation of BMC into tissue macrophages/microglia in experimental S.pneumoniae meningitis after intraspinal infection. Approximately 24 hours after infection, GFP-expressing parenchymal microglia changed their morphology to an activated phenotype and upregulated MHC class II molecules. Bacterial meningitis increased the engraftment of GFP + monocytes/macrophages and their differentiation to microglia during the postinflammatory period, but not during acute meningitis. As a consequence, the proportion of freshly blood-born microglia within the pool of parenchymal microglia in the central nervous system after inflammation was strongly enhanced. Conclusion: It is concluded that cells of the circulating pool of monocytes/macrophages enter the brain during the course of meningitis. Thus, hematopoietic monocytes/macrophages entering the CNS and differentiat-

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ing into microglia might provide a potential cellular target for the treatment of the tissue damage following meningitis via peripheral cell therapy. P211 Severe Epstein-Barr encephalopathy with a favourable outcome M. D. Reichhart, S. Jilek, M. Prella, P. Michel, C. Pollo, G. Pantaleo, J. Bogousslavsky, R. A. Du Pasquier Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Objective: The mechanism of the encephalopathy following Epstein-Barr virus (EBV) infection remains unclear. We report a patient with dramatic improvement after a very severe EBV encephalopathy. We wanted to determine whether this neurological condition is due to direct EBV infection of to aberrant immune response. Method: A 27 year-old man suffered from an infectious mononucleosis due to EBV, as documented by positive Monotest, anti-VCA EBV IgM + . Three weeks after its onset, he presented with a partial complex status epilepticus (SE). A head CT showed diffuse cerebral edema, a lumbar puncture disclosed an opening pressure at 31 cm H2O, 48 WBC/mcl, 1090 mg/L of proteins, normal glucose. PCR in the CSF were negative for S. pneumoniae, N. meningitides, H. influenzae, L. monocytogenes, HSV and Enterovirus. HIV testing was negative. Anti-myelin and anti-neuronal auto-antibodies were negative in the serum. The diagnosis of EBV-associated encephalopathy was established. His condition worsening and the intracranial pressure (ICP) rising (75 Torr), a hemicraniectomy was performed three days after neurological onset. He received penthotal 1000 mg/h to achieve burst suppression and methyprednisolone 500 mg/day. On day 4, a brain MRI showed massive brain edema but no T2-weighted or DWI lesions so that MP was discontinued.Attempts of withdrawal of penthotal were unsuccessful due to recurrence of SE until day 13 when extubation was finally possible. His clinical course improved gradually and he could resume his studies six months later. Results: To determine whether this encephalopathy was due to infectious or immune mechanisms, we performed serologies and PCR for EBV in the CSF. Both came back negative. Using ELISOPT and intra-cellular cytokine staining assays, we also compared the EBV- and myelin oligodendrocyte glycoprotein (MOG)-specific cellular immune response. We found that several epitopes of MOG elicited interferon-gamma and IL-2 secretion by CD4 + and CD8 + T cells. By contrast, there was only a weak IL-2 secretion by EBV-specific CD8 + T cells. Two months later, EBV-specific response had disappeared whereas MOG-specific response were diminished but still present. Conclusion: Our study suggests that this encephalopathy was not due to direct EBV infection of the brain, but rather to aberrant immune response, possibly mediated by MOG-specific T cells. This work was supported by grants from the Swiss National Foundation (FN 3200BO-104262 and PP00B-106716) to RADP P212 Proteolytic enzyme activity in human cerebrospinal fluid and blood: a new process marker of inflammation in the central nervous system? T. O. Kleine, S. Gronemeyer Clinical Chemistry, University Giessen-Marburg (Marburg, D) Objective: To study proteases, involved in disease processes of central nervous system (CNS), distinct enzyme proteins, usually, are quantified with specific antibodies neglecting actual proteolytic enzyme activity (PEA) which represents an active marker of tissue and cell destruction in body and CNS. Therefore, PEA was measured with a fluorophore casein substrate in fresh CSF and blood sample pairs of diverse patients and characterized with specific inhibitors. Methods: With control patients (I; n = 20) cellular and humoral parameters of paired lumbar CSF and plasma samples were within the normal range; patients with different forms of meningitis and other inflammatory CNS diseases (II; n = 15) had pleocytosis up to 2200 M/L leukocytes and < 500 M/L erythrocytes. Bloody CSF with complicated hemorrhages showed large pleocytosis (III; n = 15). Blood-brain barrier (bbb) disturbance (IV) was subdivided with Qalbumin into the ranges < 6.0, 6–10, 10.1–15, 15.1–30, > 30x10–3. Patients with systemic inflammation with leukocyte counts between 11 and 21 G/L (V; n = 20) were compared to those with < 10.5 G/L (VI; n = 30). Native PEA in 0.05 ml CSF, resp. 0.075 ml blood plasma, was measured with assays of 0.12 ml, resp. 0.18 ml total volume, incubated at body temperature with Tris-HCl buffer, pH 7.4, Cleland’s reagent, sodium azide, plus casein, resorufin-labeled (Roche Diagnostics). After 24 h incubation absorbance was measured at 578 nm in the supernatant. PEA (nmol/l/h) discrimination was done with protease activators (Ca2 +) or inhibitors (EDTA, elastatinal, calpain inhibitors I, II (Serva)).

Results: With controls (I) native PEA was higher in blood plasma than in CSF (on an average of 42/35 nmol/L/h), about one half being endogenously activated, the other half was activated by additive Ca2 + . PEA was discriminated mainly into calpain I and II. Elastase activity was low.All PEAs did not increase substantially with diverse CNS inflammatory processes (II) or different dimensions of bbb disturbance (IV); but PEAs were significantly elevated in CSF and plasma with bloody hemorrhages (III) and systemic leukocytosis (V). Conclusion: Native PEA and itemized PEAs as well, may indicate specific markers of inflammatory processes in CNS since PEA may grow up in CSF and blood only in the imbalanced process state, obviously as a result of inhibitor shortage; whereas in balanced state of inflammatory processes, PEAs were kept in check by diverse protease inhibitors in CSF and blood. P213 Cellular parameters of central nervous system infection in cerebrospinal fluid: assessment of laboratory assays with external pilot trials of Joint German Society of Clinical Chemistry & Laboratory Medicine (DGKL) T. O. Kleine, C. Löwer, T. C. Nebe, R. Lehmitz, D. Kunz, R. Kruse, W.-J. Geilenkeuser University Giessen-Marburg (Marburg, D); Clinicum Mannheim – University of Heidelberg (Mannheim, D); Centre of Nervous Diseases (Rostock, D); DRK Hospital (Neuwied, D); Reference Institute for Bioanalysis (Bonn, D); Reference Institute for Bioanalysis (Bonn, D) Objective: Cell counts of leukocytes (WBC), erythrocytes (RBC) and differential WBC count (dWBC) in cerebrospinal fluid (CSF) belong to the basic indices of CSF routine diagnosis in revealing infections of central nervous system. Therefore, external quality controls with standardized CSF samples of DGKL were carried out in routine laboratories to standardize and to improve CSF cell analysis. Methods: Two samples (A,B) of native WBC and erythrocytes in CSF medium were prepared from human blood and sent with two samples (C,D) of stabilized cells to laboratories to be analysed within 3 days after postage by different methods: Method I: manual counting of CSF cells, native or stained with vital dyes, in calibrated Fuchs-Rosenthal chamber, Method II: electronic cell counting and WBC differentiating with optical (laser) or impedance detection in hematology analyzers with CSF option, Method III: cytocentrifuge techniques of Shandon or Hettich with Pappenheim staining of cell pellet, Method IV: FACScan of CSF leukocytes with CD14, CD45, CD16. Method comparison was done evaluating relationship Y = b · X + a between two methods or analyzers X,Y (Bablok & Passing 1983). Results: Cell counting proved to be valid more with simple samples C,D; dWBC could be done only with native samples A,B. Method I with native unstained cells was selected for target values (X), because staining with Türk (gentian violet) and Samson (fuchsin) reagents in acid pH (Y) yielded lower WBC (and RBC). With method II WBC analysis was practicable; detection limits > 5000 M/L RBC was inaccurate: WBC (Y) in Abbott CD4000 or CD3500 were lower, in Sysmex XE2100 with impedance higher, but with laser option similar like target values (X); ADVIA 120 urine analyzer yielded similar WBC values (Y), but low RBC ranges were counted higher. FACS differentiation of native leukocytes (X) (method IV) was compared to dWBC with methods II (Abbott), III (Shandon, Hettich) (Y) exhibiting inconsistencies of monocyte (lower) and granulocyte values, but not with lymphocyte ones. Inconsistencies were lower with ADVIA120. Conclusion: For CSF cell analysis, manually counting of native leukocytes and erythrocytes with method I was recommended and mechanized counting of leukocytes only in Sysmex XE2100 with laser option (method II), or ADVIA 120 for all CSF cells. Manual and mechanized dWBC (method II, III) revealed lower monocyte values when compared to dWBC with FACS (method IV) besides some other inconsistencies. The study was kindly supported by a grant of Joint German Society of Clinical Chemistry & Laboratory Medcine (DGKL) P214 Humoral immune IgG antibody response against plasmodium falciparum in adult patients with cerebral malaria T-E. Sokrab, M. Shigidi, R. Hashim, M. Mukhtar, M. Idris Hamad Medical Corporation (Doha, QA); University of Khartoum (Khartoum, SD); Institute of Endemic Diseases (Khartoum, SD) Objectives: Although antibodies are essential mediators of immunity, high levels of IgG antibodies against a wide range of blood-stage antigens of P. falciparum are poor predictors of clinical protection. It is the qualitative and the functional specificity of the antibodies to malaria antigens that predict the development of a clinically potent protective immunity. In this study we investigated the profile pattern of the total and sub-class IgG (IgG1, 2, 3 and

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4) antibodies to the C-terminal fragment MSA-119 of P. falciparum in healthy and infected adult residents of a malaria-endemic area in Sudan. Methods: Total plasma IgG and IgG subclasses against the C-terminal region of the MSA-119 antigen of Plasmodium falciparum were measured by a quantitative enzyme-linked immunosorbent assay (ELISA) in 30 adult patients presenting to the emergency department with cerebral malaria (CM). The levels of IgG antibody profile in CM patients were compared with those in patients with uncomplicated acute malaria (n = 20) and in clinically healthy asymptomatic volunteers (n = 20). The control groups were age- and sex-matched and were residing in the same malaria endemic region. Results: Total plasma IgG level was significantly higher in CM patients. The level of the sub-class IgG1 antibody against MSA-119 was significantly lower in patients infected with P. falciparum; the lowest values being observed in CM patients and the highest values in the clinically healthy volunteers. Conclusion: It appears that low or defective IgG1 response may be associated with severe malaria in adults. P215 Incomplete Brown-Sequard syndrome as initial manifestation of neurosyphilis C. Pont-Sunyer, A. Rodriguez-Campello, E. Munteis, A. Gálvez, N. Segura, E. Cuadrado, G. Cucurella, J. Roquer Hospital del Mar (Barcelona, E) Objectives: In our setting, the rise of incidence in sexually transmitted diseases and human immunodeficiency virus (HIV) has been accompanied by resurgence in the incidence of neurosyphilis. Tertiary spinal cord manifestations are rare and only described in few cases. Meningovascular syphilis or tabes dorsalis are the most usual manifestations of tertiary syphilis, but it appears in older people.We report an unusual case of incomplete Brown-Sequard syndrome as initial manifestation of neurosyphilis in negative HIV patient. Methods: A 41-year-old man, homosexual, was admitted with a 4-month history of acute mild weakness in left lower limb with gait difficulty to go up the stairs. He had thermoalgesic sensory loss in right side with no alteration of vibratory or joint position sensibility. D9 sensitive level was found and abdominal reflexes were absent. He presented hyperreflexia and spontaneous clonus in left lower limb with occasional bladder disturbance. The patient didn’t present Argyll-Robertson pupil,previous genital or cutaneous lesions, psychiatric changes or other tertiary syphilitic frequent symptoms. Results: Spinal cord MRI (without contrast) showed hyperintense diffuse C2-C3, C5-C7 segments lesions and D2-D5, D7-D8 lateral lesions of spinal cord. Cranial and lumbar MRI were normal.Visual and auditory evoked potentials were normal, with alteration of somesthesic pathways of dorsal cord tract. The initial diagnosis of suspicion was a demyelinating disease, and CSF revealed high protein levels and lymphocitosis, with VRDL positive test suggesting syphilitic origin. Oligoclonal bands were positive in CSF. Blood serologic study was positive for IgG and IgM Treponema pallidum. Immunologic study, mycobacterium, HIV, HTLV1, HSV1–2 and Borrelia burgdorferi were negative. Final diagnosis was infectious myelitis. Treatment with high doses Penicillin G administered intravenously for 3 weeks was initiated, with partial improving of symptoms. A MRI was performed after three months and a new lumbar puncture with negative syphilitic study. Conclusion: Tertiary spinal cord affectation as initial manifestation of syphilis is rare, even in positive HIV patients. In our patient, a young man without HIV, the clinical onset of a tertiary form as an incomplete BrownSequard Syndrome is exceptional. We report our experience to take in account the neurosyphilis as a differential diagnosis of multiple sclerosis if isolated spinal cord affectation in young people appears. P216 The clinical features and the factors influencing outcome of tuberculous meningitis S. K. Park, S. R. Han, S. H. Ko, K. S. Lee The Catholic University of Korea (Suwon, KOR); The Catholic University of Korea (Seoul, KOR) Objectives: Central nervous system tuberculosis has various clinical spectrum and course but anti-tuberculous chemotherapy to CNS tuberculosis is not established (dose and the use of steroid). Here, we describe our cases of tuberculous meningitis, focusing on factors influencing clinical course and outcome. Methods: We reviewed the clinical course of the 40 patients and analyzed the factors influencing outcome by dividing 3 stages on admission. The diagnosis was performed considering clinical course, CSF findings, evidence of extra-CNS tuberculosis, and neuroradiologic evaluations.

Results: Patients with clinical stage 1 were 16, stage 2 was 21, and stage 3 was 3. 18.8 % of stage 1, 47.7 % of stage 2, and 100 % of stage 3 cases had developed radiculomyelopathy symptoms during anti-tuberculosis chemotherapy and steroid treatment. The radiculomyelopathy symptoms are developed 6 to 30days after start of treatment, and improved without sequelae at 18months of post-therapy follow up. But 5 cases expired during 6 to 45days, 100 % of stage 3 and 9.52 % of stage 2, and all of them had radiculomyelopathy. On the brain MRI, 37.5 % of stage 1, 57.1 % of stage 2, and 100 % of stage3 showed abnormal findings such as leptomeningeal enhancement, multiple nodules and infarctions, and hydrocephalus. On the CSF findings, protein level (stage 1.2,3) is 223, 293. 221 mg/dl; sugar ratio is 37.1, 30.4, 14 %; WBC count is 280, 218, and 270. ADA level is 12.7, 17.8, 21.3 mg/dl. 3 cases showed positive result on the PCR, all showed negative result on the CSF culture. Conclusion: The poor outcome is correlated with mental status at start of treatment, sugar ratio, ADA level, and the presence of lesion on the brain MRI.Although steroids may diminish neurological symptoms and improve outcome, radiculomyelopathy may appear during the course of anti-tuberculosis and steroid treatment. P217 Progressive multifocal leukencephalopathy – case report and review of therapeutic options N. P. Fehm, P. Prang, P. Erban, B. Vatankhah, N. Weidner, M. Schröder University of Regensburg (Regensburg, D) Progressive multifocal leukencephalopathy is deadly demyelinating disease of the central nervous system, caused by reactivation of the polyomavirus JC (JCV) in immunosuppressed individuals. Median survival time is 4–6 months, and due to the lack of appropriate treatment, patients are often significantly disabled with devastating neurological symptoms. We present the case of a 45year old male with a subacute onset of severe dysarthria, dysphagia and hemiataxia. Symptoms occurred 8 weeks prior to admission and were mild to moderate, with a significant worsening of symptoms few days prior to admission. Magnet resonance imaging of the brain showed multiple hyperintense lesions in T2-weighed images in both brain hemispheres and the cerebellum. There were severe signal hyperintensities of the left cerebellar hemisphere and the brainstem (pons and midbrain). Cerebral fluid diagnostics showed normal glucose, protein and cell count, whereas amplification of JC-virus-DNA with protein chain reaction (PCR) showed an increased JCV load. Thus, PML was diagnosed. The patient was treated with cidofovir, but nevertheless experienced severe worsening of symptoms soon after admission and died 9 weeks later due to pneumonia caused by aspiration. This case illustrates the typical subacute onset of symptoms with extraordinarily severe signal changes in the cerebellum and brain stem. Besides the presentation of this case report, we would also like to present a short review and update of therapeutic possibilities in diagnosed PML.

Multiple sclerosis P218 The p150 subunit of dynactin gene in multiple sclerosis C. Munch, R. Meyer, P. Linke, T. Meyer, A. C. Ludolph, J. Haas, B. Hemmer Jewish Hospital (Berlin, D); Charite Hospital (Berlin, D); University of Ulm (Ulm, D); Heinrich Heine University (Dusseldorf, D) Multiple sclerosis (MS) is a multifactorial disease in which mostly unidentified genetic factors in conjunction with environmental agents affect its clinical expression. Neurodegeneration has emerged as a significant contributor to CNS lesions in MS. Genetic susceptibility of the neuron may determine the degree of ensuing neurodegeneration after an inflammatory attack. We have recently described mutations in the p150 subunit of the molecular motor dynactin (DCTN1) in amyotrophic lateral slerosis (ALS) and frontotemporal dementia (FTD) that may predispose different neuron types to degeneration. Given the common features of neurodegeneration in MS, ALS and FTD, we raised the question whether genetic variants in the DCTN1 gene may constitute a risk factor for MS.We conducted a DCTN1 mutation analysis in 192 patients with MS (96 patients with relapsing-remitting MS and 96 with primary progressive MS) and the same number of unrelated controls. In MS, no mutations in the DCTN1 gene have been found. Three heterozygous mutations (R532L, T1249I, I196V) of the DTCN1 gene were detected in four controls. However, no significant genetic association of the three sequence alterations with the absence of MS has been found. We conclude that DCTN1 may not contribute to the genetic background of neurodegeneration

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in MS. Our findings support the notion that the DCTN1 gene is highly heterogeneous. DCTN1 mutations are also found under normal conditions and their pathogenetic relevance is far from being completely understood. This work was supported by the Deutsche Multiple Sklerose Gesellschaft (DMSG) P219 Oral CCR1 antagonist BX 471 increases ICAM-3 expression on RR-MS patients’ CD14 + myelomonocytic cells R. Reuß, V. Schreiber, A. Klein, K. Retzlaff, W. Pabst, P. Oschmann University Hospital Giessen and Marburg (Giessen, D) Objectives: Multiple sclerosis is associated with inflammatory chemokines and central nervous system infiltration by monocytes and T-lymphocytes expressing their receptors. In experimental allergic encephalomyelitis (EAE), chemokine ligand 3 (CCL3) as well as its receptor chemokine receptor 1 (CCR1) knockout mice exhibit a reduction in disease providing evidence for a role of CCR1 in EAE. Antibodies against CCL3, one of several CCR1 ligands, prevented infiltration of mononuclear cells into CNS. CCR1 has a specifity for B cells, T cells and monocytes. Here, we report on an immunological subgroup analysis to a randomized placebo-controlled multicenter phase II clinical trial of CCR1 competitive antagonist BX 471 in relapsing-remitting MS (RR-MS) patients. Intercellular adhesion molecules 1 and 3 (ICAM-1 and –3) act as counter receptors for the integrin leucocyte function-associated antigen-1 (LFA-1) and play an important role in the migration of activated T cells across the blood brain barrier. Methods: The efficacy of an oral administration of BX 471 (3*600 mg/day) over a period of 16 weeks was studied in 53 verum and 52 placebo patients. In a subgroup of 9 verum and 10 placebo patients, expression of ICAM-3 on CD14 + myelomonocytic cells was analyzed by flow cytometry at week 0 (baseline), week 4, week 16 and 4 weeks after end of treatment (W0,W4,W16 and W20).A two-way analysis of variance with repeated measures was performed. Results: In the verum group, ICAM-3 expression (means) was increased by 69 % at W4, by 74 % at W16 and unchanged at W20 (+ 3 %) compared to W0. In the placebo group, ICAM-3 expression was reduced at weeks 4 and 16. Overall, the verum and the placebo group significantly (p = 0.042) differed in ICAM-3 expression on CD14 + myelomonocytic cells. Conclusion: Administration of CCR1 antagonist BX 471 to RR-MS patients produces a biological effect, which might mean a therapy-induced reduced inflammatory activity. The expansion may be mediated by receptor cross talk and (autocrine) feedback mechanisms. Several chemokines are ligands to the same receptor and vice versa. Thus abrogation of signaling via CCR1 might enhance signaling of its ligands via other receptors that are known to enhance intercellular adhesion molecule expression, while engagement of monocyte ICAM-3 in turn is known to enhance chemokine expression. The immunological substudy was supported by Schering AG, Berlin. P220 MTR characteristics of lesions with differing intensity and/or morphological patterns M. G. Dwyer, S. Hussein, R. Chandrasekhar, N. Abdelrahman, N. Bergsland, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Larger T2 and T1 lesions have a tendency to coalesce and form confluent (CFL) lesions. These CFL lesions may represent subtly different underlying pathological processes not detectable in conventional spin-echo sequences. Magnetization transfer ratio (MTR) analysis provides a means of detecting these subtle differences via examination of local macromolecular concentrations. Objective: To compare the MTR characteristics of lesions with differing subtypes and/or morphological features in patients with multiple sclerosis (MS). Methods: We studied 314 MS patients (mean age 45.6 ± 9.7 years, mean disease duration 13.4 ± 9.3). Disease course was relapsing-remitting (RR) = 215, secondary-progressive (SP) = 99, with a mean EDSS of 3.3 ± 1.9. T2 lesion volume (LV) maps were created via a semi-automated method. A fully-automated program was then used to extract various morphological characteristics of the lesions including number, size, volume, concavity, surface factor, brightness, centroid, shape, and space orientation. Machine learning techniques were employed to classify the lesions as CFL or nonconfluent (NCFL) based on these characteristics. MTR analysis was then performed separately for total, CFL, and NCFL LVs. Results: Total T2- and T1-LV MTR values differed by 4.96 percent units (PU) (p < 0.001). Differences between CFL and NCFL T2 and T1 lesions were

smaller, but also highly significant: between CFL and NCFL T2, –0.45 PU (p < 0.001); between CFL and NCFL T1, –0.85 PU (p = 0.012). Conclusions: CFL lesions exhibit significantly decreased MTR values when compared to NCFL lesions of the same type, both for T2-and T1-LVs. This may provide additional insight in understanding the morphological and intrinsic pathological characteristics of CFL and NCFL T1- and T2 lesions. P221 Regional MRI measures and disability in multiple sclerosis M. G. Dwyer, R. H. B. Benedict, B. Srinivasaraghavan, D. A. Carone, V. Yella, N. Abdelrahman, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Region-by-region investigation of MRI parameters may provide additional insight into the relationship between MRI and clinical disability by increasing both sensitivity and specificity. Objective: To examine the relationship between conventional/non-conventional regional MRI measures and clinical disability in patients with multiple sclerosis (MS). Methods: We studied 108 patients with MS (age 46.3 8.9 years, disease duration 14.0 9.6 years). Disease course was relapsing-remitting (RR) = 65, secondary-progressive (SP) = 43. Mean EDSS was 3.6 1.9. Tissue segmentation (TS) and magnetization transfer ratio (MTR) maps were obtained via fullyautomated algorithms. T2 and T1 lesion volume (LV) maps were created using a semi-automated method. A semi-automated brain region extraction (SABRE) technique was then employed to create region-coding maps, which were overlaid with each of the calculation maps to create regional TS, T2, T1, and MTR maps. Regional TS maps were further processed to yield regional brain parenchymal fraction (RBPF) and grey matter fraction (RGMF) measures. The 26 regions identified were combined into larger frontal, parietal, temporal, occipital, and central regions to decrease the number of variables involved. Linear regression was used to examine the predictive value of these regional measures with regard to disability. Results: SP patients demonstrated significantly higher temporal T2-LV than RR subjects. All RBPF and RGMF were significantly different between RR and SP. All regional MTR values except occipital MTR were also significantly different. Temporal, frontal, and central regional measures showed the highest correlations with disability. In particular, temporal RBPF, RGMF and MTR, frontal T2-LV, and central T1-LV showed the highest correlations for regional BPF, GMF, MTR, T2-LV, and T1-LV, respectively. In regression models controlling for age, temporal RBPF accounted for the most variance in clinical disability, explaining 19.8 % of the variance in EDSS. In contrast, whole brain BPF explained only 16.7 % Conclusions: Regional MRI measures may potentially provide more sensitive and specific information than global measures in predicting clinical disability. P222 A longitudinal study of cortical atrophy in patients with relapsing-remitting multiple sclerosis over a 2-year period R. Zivadinov, O. Dolezal, C. I. Tekwe, D. Horakova, M. G. Dwyer, S. Balachandran, N. Bergsland, E. Havrdova Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Many short- and long- term studies have investigated the importance of brain atrophy development in patients with multiple sclerosis (MS). However, the evolution of cortical atrophy has not been investigated in patients with relapsing-remitting (RR) MS. Objective: To monitor the evolution of cortical atrophy in patients with RR MS over a 2-year period and determine the relationship cortical atrophy and clinical status. Methods: We followed 138 (110 females, 28 males) RR MS patients over a 24-month period. Mean baseline disease duration was 4.6yrs and mean baseline EDSS was 1.9. MRI scans were obtained on a bi-monthly basis for the first year, at month 18 and at the end of the two-year follow-up. The extent of cortical atrophy was determined at each time point on 3DSPGRT1 WI 1 mm thick slices with a fully automated segmentation program. T2-lesion volume (LV) was also calculated every 6 months using a semiautomated method. In addition, patients were assessed clinically (EDSS) every three months. Mixed effect modeling was used in the statistical analyses to account for cortical gray matter volume (CGMV) and disability changes at each time point. Results: CGMV changed by –2.79 % over two years (p < 0.001). No significant relationship was found between T2-LV and EDSS (p = 0.07). However, the mixed effect model analysis showed a strong relationship between CGMV loss and the development of disability (p < 0.008).

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Conclusions: A significant cortical atrophy development was detected over 2-year period in patients with early RR MS. The development of cortical atrophy predicted better disability development then accumulation of T2-LV.

P225 Subgroup analysis from users of complementary and alternative medicine in multiple sclerosis A. Apel, B. Greim, N. Koenig, U. K. Zettl University of Rostock (Rostock, D); Marianne-Strauss-Clinic (Berg, D)

P223 Glatiramer acetate mediated immunomodulation is driven by antigen presenting cells and is not T-cell antigen specific M. S. Weber, T Prod’homme, C. Rundle, L. Lee, O. Stueve, S. S. Zamvil University of California (San Francisco, USA); University of Texas Southwestern (Dallas, USA)

Objective: Up to 81 % of patients with multiple sclerosis (MS) are using complementary and alternative medicine (CAM), through the wide variety of CAM offered is difficult to encompass. Therefore it is not easy to categorize the different CAM used by MS patients. The aim of the study was to investigate if there are subgroups of CAM users who prefer certain therapies,for example vitamins,and how frequently they are used. Methods: 254 patients with a clinically definite MS (duration of illness: m = 8.3; SD = 6.7; EDSS: m = 4.3; SD = 2.1) were examined. Utilization of CAM was assessed in a 90 min semi-structured interview. Besides sociodemographic variables, patients were asked for aspects of their illness and the use of CAM. The frequencies of the different CAM reported were used to transform a hierarchical cluster analysis (Ward’s method). The characteristics of the generated clusters were described by frequency analysis for particular and overall used CAM. Results: 206 patients reported that since being diagnosed with MS they had utilised one or more CAM (m = 4.8; SD = 2.6). Best cluster solution was calculated for five clusters. Cluster 1 (n = 14) contained patients who used several CAM (m = 7.8; SD = 1.6) for example relaxation technique or homeopathy. Patients of cluster 2 (n = 25) can be characterized by the utilisation of various vitamins, minerals and different diets (m = 8.0; SD = 1.7). In cluster 3 (n = 55) CAM was less frequently used compared to the other clusters (m = 3.2; SD = 1.7). Vitamins were the mostly used therapy. Patients of cluster 4 (n = 34) prefered phytotherapy (m = 5.9; SD = 2.3). In cluster 5 (n = 78; m = 3.9; SD = 1.9) electrotherapy and massage were the most frequently used CAM. Differentiation between clusters was related to EDSS. Conclusion: The study shows clearly that many MS patients apply CAM, and that there are varieties within this group. Firstly, there are differences in frequency of overall used CAM, which means subgroups of MS patients use CAM less or more frequently. Secondly, the patients utilised different kinds of CAM; while one subgroup preferred electrotherapy, another focused on nutrition and dietary supplement and a small subgroup tested all sorts of therapies. Thirdly, patients of different clusters were unequally affected by MS. Future research should consider varieties and evaluate differences in attitude and personality within the group of CAM users.

Objective: To investigate the role of antigen presenting cells (APC) in causing T cell immunomodulation by glatiramer acetate (GA) in experimental autoimmune encephalomyelitis (EAE). Background: GA is thought to exert therapeutic benefit in multiple sclerosis by induction of GA-specific Th2 cells that cross-react with myelin antigen (Ag). Recent reports revealed that GA treatment alters APC activation and cytokine production.We investigated [1] whether these APC effects mediate the Th2 bias and induction of regulatory T cells (Treg), [2] whether GAtreated monocytes can adoptively transfer EAE protection and [3] whether T cell cross-reactivity between GA and myelin Ag is required for its therapeutic effect. Methods: MBP Ac1–11 immunized (PL/J x SJL/J)F1 mice were injected subcutaneously with 150 µg GA in PBS over 7 days starting day –9 (prevention) or when EAE was established (reversal). Splenic T cells were cultured with GA, MBP Ac1–11, MOG p35–55 or PLP 139–151. Monocytes from these mice or GA-treated RAG-1-deficient (-/-) mice were evaluated for cytokine secretion. In vivo GA-treated monocytes (7x150 µg qd) were co-cultured with naive T cells from MBP Ac1–11 TCR transgenic (Tg), MOG 35–55 TCR Tg or OVA 323–339 TCR Tg mice. Th differentiation and Treg induction were evaluated by cytokine secretion (IFN-g, IL-4) and CD4/CD25/FoxP3 tripleFACS staining, respectively. In vitro GA-treated (50 µg/ml) bone marrow derived monocytes were adoptively transferred into MOG p35–55 immunized C57BL/6 mice one day prior to EAE induction. Results: Daily GA administration without adjuvant prevented or reversed EAE. We did not observe T cell cross-reactivity between GA and myelin Ag in mice protected from EAE. GA treatment of (PL/J x SJL/J)F1 and RAG-1 -/- mice, which lack mature T cells, induced type II APC, secreting less TNF-a and IL-12 and more IL-10. These APC directed Th2 differentiation of naive myelin-reactive and OVA-specific T cells as well as induction of Treg. GA-treated type II monocytes could adoptively transfer EAE protection. Conclusions: Therapeutic benefit of GA in EAE does not require T cell cross-reactivity between GA and myelin Ag. GA treatment exerts immunomodulatory effects on APC without requirement of T cells or T cell-derived cytokines. GA-mediated APC immunomodulation drives Th2 polarization and Treg induction independent of T cell specificity and these APC can adoptively transfer EAE protection. P224 Intercellular adhesion molecule-1 (ICAM-1) gene polymorphism in Iranian patients with multiple sclerosis A. R. Moosavi, A. R. Nikseresht, N. Arandi, A. Borhani Haghighi, A. Ghaderi Shiraz University of Medical Sciences (Shiraz, IR) Objectives: Intercellular adhesion molecule-1 (ICAM-1) controls leukocyteendothelial cell interaction in several immunological and inflammatory reactions including lymphocyte migration and crossing of the blood-brain barrier in multiple sclerosis. This study was conducted to determine whether ICAM-1 gene polymorphism influences the risk of developing multiple sclerosis in an Iranian population. Methods: We studied 157 patients with definite multiple sclerosis (fulfilling McDonald criteria) and 156 ethnically-matched controls. The patients and controls were genotyped for ICAM-1 gene polymorphism at codons 241 (exon 4) and 469 (exon 6). The distribution of alleles and genotypes for each ICAM-1 polymorphism were determined and compared with controls. Results: Whereas G/R241 allele and genotype distribution did not show any significant difference between patient and control groups, the analysis with respect to subject’s gender showed significantly higher G/G than G/R genotype (OR = 3.34, 95 % CI: 1.26–8.88, p = 0.01) in female patients than in the homologous control group. In male subjects, these differences were not significant among patients and controls. Conclusion: We concluded that ICAM-1 gene G/R241 polymorphism may be a genetic factor involved in the pathogenesis of MS in women.

P226 Evolution of different brain atrophy measures in patients with relapsing-remitting multiple sclerosis over 2 years O. Dolezal, C. I. Tekwe, D. Horakova, E. Havrdova, S. Balachandran, N. Bergsland, M. G. Dwyer, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA); Department of Neurology (Prague, CZ) Background: Different brain atrophy measures have shown to be robust predictors of clinical worsening over time in patients with multiple sclerosis (MS). However, it has not yet been established which of these methods demonstrates superior predicitive capacity. Objective: To investigate the evolution of global and central brain atrophy measures in patients with relapsing-remitting (RR) MS over a 2-year period. To establish which brain atrophy measure is the best predictor of disability development in RR MS. Methods: 136 RR MS patients were included and followed over 24 months. At baseline, mean disease duration was 4.6 years and mean EDSS was 1.9. MRI scans were obtained bi-monthly for the first year, at month 18 and at the end of the two-year follow-up. Normalized grey matter volume (NGMV), normalized white matter volume (NWMV) and normalized brain volume (NBV) were measured at each time point. T2-lesion volume (LV), lateral ventricle volume (LVV) and third ventricle width (3VW) were also assessed every 6 months. Clinical examinations were performed every three months. Mixed effect modelling, accounting for MRI and disability changes at each time point, was used in the statistical analyses. Results: Over two years, changes for various MRI measures were as follows: T2-LV 33.9 %, LVV 24.1 %, 3VW 23 %, NGMV –2.6 %, NBV –1.52 % (all p < 0.0001) and NWMV –0.55 % (p = NS). In the mixed effect model, we observed a significant independent relationship between EDSS progression and the following MRI variables: LVV (p < 0.0001), 3VW (p = 0.0007) and NGMV (p = 0.0017). No relationship was observed between a decrease in NBV and NWMV, and an increase in T2-LV and disability progression. Conclusions: Development of central and grey matter atrophy is a more robust predictor of disability progression in patients with RR MS than the

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accumulation of T2-LV or the development of whole brain and white matter atrophy.

test to determine the loss of bioavailability of INFbeta also in clinical practice.

P227 Evolution of grey matter and central atrophy in early relapsing-remitting multiple sclerosis is most responsible for development of disability O. Dolezal, C. I. Tekwe, D. Horakova, Z. Seidl, E. Havrdova, S. Balachandran, N. Bergsland, M. G. Dwyer, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA)

P229 Comparing several simple models to predict the development of disability in individual multiple sclerosis patients from their disability history A. Neuhaus, M. Daumer, P. O’Connor SLCMSR (Munich, D); St Michael’s Hospital (Toronto, CAN)

Background: Recent studies suggest that brain atrophy plays a crucial role in multiple sclerosis (MS) pathogenesis. Objective: To investigate the evolution of brain atrophy in patients with relapsing-remitting (RR) MS. Methods: In the present study, two subgroups were recruited: 37 RR patients with a disease duration (DD) shorter than 18 months (early-ERR group) (mean DD 1.17yrs, mean EDSS 1.48) and 99 RR MS patients with DD longer than 18 months (longer-LRR group) (mean DD 6.32 yrs, mean EDSS 2.1). MRI scans were obtained bi-monthly for the first year, at month 18 and at the end of the 2-year follow-up. Normalized volumes (NV) of grey matter (GM), white matter (NWMV) and whole brain (NBV) were measured. T2-lesion volume (LV), lateral ventricle volume (LVV) and third ventricle width (3VW) were also calculated. Mixed effect modeling was used in the statistical analyses to account for MRI and disability changes at each time point. Results: Over a 2-year period, the following MRI changes were observed for the ERR and LRR groups, respectively: NGMV (–2.9 % vs. –2.5 %, p < 0.001), NBV (–1.8 % vs. –1.6 %, p < 0.001), 3VW (27.2 % vs. 21.9 %, p < 0.01), LVV (33 % vs. 20.6 %, p < 0.01) and NWMV (–0.4 % vs. –0.36 %, p = NS). NGMV loss over the first year was higher in the ERR group (–3.2 %) than in the LRR group (–2.3 %) (p = 0.05). The results were reversed in the second year, with a NGMV loss of –0.1 % in the ERR group and –0.8 % in the LRR group (p = 0.05). In mixed effect modeling, development of sustained disability was strongly predicted in the ERR group by a decrease in NGMV (p < 0.0017),) and an increase in LVV (p < 0.003). Conclusions: Significant GM and central atrophy occur in RR MS from the earliest stage of the disease and are most responsible for development of disability.

Objective: We investigated the ability of current disability level measured using the Expanded Disability Status Scale (EDSS) to predict subsequent EDSS scores over 1 and 2 years. Methods: Data from 892 MS patients were analysed from the Sylvia Lawry Centre database housed in Munich, Germany including 449 relapsing remitting (RRMS) and 443 secondary progressive MS (SPMS) individuals from the placebo arms of randomised clinical trials. Mean follow-up time was 2.4 years. Mean disease duration was 10.4 years (RRMS 7.1 ± 6.0, SPMS 13.7 ± 7.7) with baseline EDSS score of 4.0 points (RRMS 2.8 ± 1.4, SPMS 5.3 ± 1.1). Several linear and non-linear regression models and the ‘last observation carried forward’ method were compared in their ability to predict subsequent disability. Results: The average ± standard deviation EDSS change was 0.08 ± 1.04 (over 1 year) in the RRMS and 0.50 ± 0.92 (over 2 years) in the SPMS populations. In RRMS patients the most accurate prediction was obtained using the ‘last observation carried forward’ method with an average prediction accuracy of –0.04 ± 0.77. The proportion of predictions accurate to within 0.5 points in RRMS on the EDSS score at one year was greater than 60 %. In SPMS patients a linear regression model provides the most accurate prediction of EDSS score change over 2 years, with more than 70 % of predictions accurate to within 0.5 points. Exploratory analyses did not reveal obvious subgroups displaying different rates of EDSS change over the time course of the study. Conclusion: In RRMS the best 1 year-predictor of the EDSS score is the value at the beginning of the year. In contrast, mean EDSS score change over 2 years in SPMS is 0.5 and can be relatively accurately predicted using a simple linear equation.

P228 Assessment of INF-beta bioavailability in multiple sclerosis treated patients: MxA mRNA versus antibody-detecting assays C. Cordioli, R. Capra, A. Sottini, D. Monza, R. Bergamaschi, L. Imberti Multiple Sclerosis Centre (Brescia, I); Biotecnology Laboratory Spedali Civili (Brescia, I); Neurological Institute Mondino (Pavia, I)

P230 Expression of ferritin and S-100B in relation to nitric oxide metabolites in the cerebrospinal fluid of relapsing multiple sclerosis patients K. Rejdak, A. Petzold, H. Bartosik-Psujek, J. Kurzepa, Z. Stelmasiak, G. Giovannoni Medical University of Lublin (Lublin, PL); Institute of Neurology, UCL (London, UK)

Introduction/Objectives: In Multiple Sclerosis (MS) patients, anti INFbeta antibodies are related to the loss of INFbeta bioavailability. We investigated the reliability of two distinct laboratory methods in detecting the presence of anti INFbeta antibodies and their correlation to MxA mRNA induction. Matherials/Methods: 38 healthy controls and 96 MS INFbeta treated patients were investigated. Only patients with pre-treatment disease duration ≥ 18 months and treatment duration ≥ 24 months were selected. In our sample mean pre-treatment disease duration was 87 months (s. d. 60.9, range 18–294 months, while mean treatment duration was 53 months (d. s. 21.5, range 24–114 months). Real time (RT) PCR for MxA was standardized in order to avoid intra-assay variations (CV = 3 % for both MxA and for the house-keeping gene, GAPDH mRNA). Neutralizing antibodies (NAbs) were evaluated by cytopathic effect (CPE) assay, while binding antibodies (BAbs) were identified by radioimmunoprecipitation test (RIPA) after IFNbeta-1a radioiodination with chloramine-T method. Cut off values for MxA mRNA (Normalization Rate -NR-: 4.78) and BAbs (680 cpm) was established as mean + 3sd of values obtained in healthy controls, while samples were NAb positive at serum dilution > 1:20. Results: Mean NR for MxA mRNA was 1.04 in controls and in patient’s samples obtained before INFbeta injection, but increased to 25.4 in samples obtained 12 hours after IFNbeta administration. Anti INFbeta antibodies were detected by RIPA in 22.2 % of patients and 11 % of them also showed lack of MxA mRNA production. Negative correlation between MxA mRNA induction and anti INFbeta antibodies (p = 0.0001, R = –0.41) was found, with RIPA showing 100 % sensitivity and 90.4 % specificity. On the contrary, CPE assay correlation with MxA mRNA was lower both in terms of sensitivity and specificity. Furthermore, our data demonstrated that there were differences in the detection of NAbs and BAbs among MS patients. Conclusions: the presence of RIPA-detected anti INFbeta antibodies is well correlated with loss of MxA mRNA induction and, therefore, with INFbeta receptor binding in vivo. We consider this assay the most appropriate

Background: Acute relapse of multiple sclerosis is characterised by the activation of the complex immunological mechanisms involving blood-brain barrier damage and influx of peripheral blood T-cells and macrophages leading to local inflammation and acute lesion formation. Recently, we have demonstrated that nitric oxide metabolites levels are raised in CSF of relapsing MS patients and correlate with the volume of Gd enhancement on MRI. It is not clear what the relationship is between raised CSF NOx levels and the activation of residual glial cells in the CNS. This study investigated the CSF levels of ferritin and S-100, markers for microglia and astrocyte activation, in relation to concentrations of nitrate/nitrite (NOx) during acute relapse. Methods: Twenty seven MS patients (21 females and 6 males, median age 29 years [20–46]; disease duration 3 years [0–15]) presenting with acute clinical relapse (EDSS at presentation = 2.5 [1, 5–6, 5], median, range) and 10 controls (7 females and 3 males; median age 31 years [28–43]) without neurological disease were enrolled into the study. Patients were assessed using the EDSS and brain MRI, and underwent a diagnostic lumbar puncture. Levels of S100B and ferritin were analyzed using ELISA technique while nitrate/nitrite was measured with vanadium based colorimetric assay using the Griess reaction. Results: Relapsing MS patients had significantly higher NOx levels in CSF (9.1 uM [8, 5–12, 5] median, range; p = 0.0003) but not in serum (49.1 [44, 5–61, 2]; p > 0.05) compared to controls (2.2 [1, 5–5, 4], 46.2 [36, 1–52, 3], respectively). Concentrations of S100B (0.76 ng/mL [0, 6–1, 1]) and ferritin (5.7 ng/mL [4, 9–8, 7] in CSF did not differ comparing to control group (1.06 [0, 6–1, 3]; 4.4 [2, 5–6, 3], respectively). There was a significant correlation between CSF levels of S100B and ferritin (r = 0.5; p = 0.03) while CSF/serum ratio of NOx did not correlate with CSF levels of S100B and ferritin. Conclusions: Correlation between CSF levels of S100B and ferritin may reflect the direct interaction between activated astrocytes and microglia during the acute MS relapse. Raised CSF NOx levels detected during early

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phases of clinical relapse are likely to be a result of systemic compartment activation with less pronounced involvement of intrathecal NO production. P231 Alemtuzumab treatment in relapsing-remitting multiple sclerosis patients who have failed licensed beta-interferon treatment: one-year data E. Fox, L. Mayer University of Texas Medical Branch (Round Rock, USA); MS Clinic of Central Texas (Round Rock, USA) Objectives: This open-label,single-arm investigator-initiated study (IIS) was designed to assess alemtuzumab (CAMPATH®, MABCAMPATH®) safety and efficacy in patients (pts) with active relapsing-remitting MS (RRMS) who failed licensed interferon-beta (IFN-beta) therapies. This abstract reports 1-year data for a 2-year study. Methods: Data from 1 USA center, 15 pts. Key inclusion criteria: Expanded Disability Status Score (EDSS) 0–6; ≥ 2 physician-confirmed MS relapses during at least 6 months of IFN-beta treatment (tx) in the 2 yr before study. Alemtuzumab given IV 24 mg/day 5 days in a row (total = 120 mg), repeated at 1 yr for 3 days (72 mg) and followed for 2 yr. All pts were premedicated with methylprednisolone 1 gm IV daily the 1st 3 days of tx. Primary efficacy endpoint: proportion of relapse-free pts at 2 yr post-tx. Other efficacy endpoints include relapse rate (RR) and proportion relapse-free at 1 yr posttx. Safety assessments include adverse event (AE) analysis and changes in laboratory (lab) values. Results: A total of 15 pts (4 men, 11 women) were enrolled. All pts completed alemtuzumab tx without dose reductions or omissions, leading to effective lymphocyte depletion. Mean relapses in the 2 yr before study entry = 2.1 (range 1–3) and prestudy annualized RR (ARR) = 1.2. After the 1st cycle of tx, 3 pts relapsed (4 relapses total) on study; ARR at yr 1 = 0.27. The Kaplan-Meier 1 yr relapse-free rate is 78.6 %. No pts had sustained accumulation of disability or drug-related serious adverse events (SAEs). MRI-brain were performed pre-dosing and at 1 yr for 14/15 patients. Two pts had abnormally elevated platelet counts on study. No pts had low platelet counts or immune thrombocytopenic purpura (ITP). Several patients had abnormal thyroid values, but no pts developed clinically evident Graves’ disease. Nonserious drug-related AEs of severe intensity included laryngitis, rash, sinusitis, and swelling of the face, in 1 pt each. Acute infusion reactions including rash and fatigue were common and readily managed with acetaminophen and diphenhydramine. Conclusion: Year 1 clinical data suggest that alemtuzumab (CAMPATH®, MABCAMPATH®) tx is generally well tolerated and reduces RR in pts with RRMS who failed IFN-beta tx. AEs are mostly limited to readily manageable infusion reactions. All patients remain on study. Continued observation after 2nd alemtuzumab tx to study end will yield additional safety and efficacy data. This study has been financially supported by Genzyme Corporation. P232 Atorvastatin improves barrier function of cultured human brain endothelial cells at therapeutically relevant concentration M. Buttmann, A. Lorenz, A. Weishaupt, P. Rieckmann Julius-Maximilians-University (Wurzburg, D) Background: HMG-CoA reductase inhibitors (i. e. statins) are currently under clinical investigation for the treatment of CNS disorders including multiple sclerosis and ischemic stroke. The pathogenesis of these disorders critically involves disturbance of the blood brain barrier (BBB) which is mainly formed by specialised endothelial cells. Objective: To investigate whether statin treatment alters the barrier function of cultured human brain microvascular endothelial cells (HBMEC) under non-inflammatory and inflammatory conditions. Methods: Adhesion molecule, chemokine, and tight junction protein expression in cultured HMBEC was measured by FACS analysis, ELISA, immunocytochemistry, and Western blotting. Adhesion of activated T lymphocytes to HBMEC was tested by quantitative adhesion assays. Results: Treatment of immortalised HBMEC with Atorvastatin ranging from a therapeutically relevant concentration of 50 nM to 1 mcM dose-dependently decreased the basal expression of ICAM-1 and MCP-1/CCL2 without increasing HBMEC apoptosis at these concentrations. Atorvastatin pretreatment partially prevented an inflammatory upregulation of CCL2 but not of ICAM-1 expression by TNF-alpha and IL-1beta. Both inflammatory stimuli increased Claudin-3 expression while atorvastatin treatment had a contrary effect. ZO-1 and Occludin protein levels remained unaltered. The effects of Atorvastatin, Lovastatin, and Simvastatin on CCL2 expression were comparable at equimolar concentrations. Primary HBMEC also showed a reduction of basal and inducible

CCL2 expression upon Atorvastatin treatment. Atorvastatin pretreatment of primary HBMEC strongly and dose-dependently reduced adhesion of activated T lymphocytes and decreased lymphocyte adhesion induced by proinflammatory cytokines. Atorvastatin effects could partially be abolished by parallel Mevalonate treatment. Clear effects of Atorvastatin were already observed at the pharmacologically relevant concentration of 50 nM. Conclusion: Statins may decrease BBB permeability under non-inflammatory and inflammatory conditions by targeting human brain endothelial cells. Our results provide an additional rationale for the evaluation of prophylactic and acute statin treatment in diseases where transendothelial trafficking of immune cells at the blood brain interface plays a pathogenic role. P233 Haplotypes in IP-10 gene and multiple sclerosis: association and correlation with clinical course C. Fenoglio, D. Galimberti, D. Scalabrini, C. Comi, M. De Riz, E. Venturelli, C. Lovati, E. Brighina, C. Mariani, F. Monaco, N. Bresolin, E. Scarpini University of Milan, IRCCS Ospedale Maggiore (Milan, I); University of Eastern Piedmont (Novara, I); University of Milan, Ospedale Luigi Sacco (Milan, I) Background: Interferon-g-inducible Protein-10 (IP-10) was found to be upregulated in cerebrospinal fluid from Multiple Scerosis (MS) patients with symptomatic attacks of inflammatory demyelination, but no differences were found with controls during the stable phase of the disease. Gene polymorphisms in pathogenetic crucial molecules, including IP10, may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the severity of pathogenic processes or the response to drug treatment. Objective: To perform a case-control study for the known Single Nucleotide Polymorphisms (SNPs) reported in IP-10 coding sequence (rs3921 and rs8878 in exon 4), in order to determine whether the presence of these variants could influence the susceptibility or exert a protective effect on the development of the disease. To test possible influence of the polymorphisms on clinical variables. Methods: 226 patients with Multiple Sclerosis (MS) and 235 controls were genotyped for G® C and T® C SNPs in exon 4 by allelic discrimination using an ABI PRISM Ò7000 instrument (ABI). Haplotypes were tested for association by using the Fisher’s exact test. Mann-Whitney test was used to compare clinical variables in patients carrying different haplotypes. Results: none of the haploypes determined was associated with MS. However, GGTT wild type haplotype MS carriers had a Progression Index (PI) significantly lower than non carriers (P = 0.01). Considering SP-MS patients, the time occurred between the initial RR form and the subsequent worsening to SP was significantly longer in this group (P = 0.035). In patients who had a bout onset of the disease, the time occurred between onset and the second episode, which is considered a prognostic factor, was significantly longer in GGTT carriers (P = 0.001). Conclusion: The presence of the wild type GGTT haplotype in IP-10 gene does not confer an increased risk of developing MS, but is likely to influence the progression of the disease as demonstrated by a significantly lower PI in carriers compared with non carriers and acting as protective factor towards SP-MS in subjects affected by RR-MS. Moreover, the evidence that the interval between onset and the first episode was longer in wild type haplotype carriers further support this hyphotesis. Therefore, the GGTT haplotype of the IP-10 gene could be proposed as a disease modifying gene.

Neuro-oncology P234 Patterns of microvessel density and blood flow in low-grade gliomas.A PET study M. Wyss, S. Hofer, M. Hefti, E. Bärtschi, C. Uhlmann, U. Roelcke University Hospital (Zurich, CH); Cantonal Hospital Aarau (Aarau, CH) Objectives: Histopathological studies reveal patterns of microvessel density (MVD) as prognostic factor in ow-grade gliomas (LGG). We used positron emission tomography (PET) to study in vivo spatial characteristics of tumour blood flow (CBF) (O-15 H2O) and MVD (F-18 fluoro-ethyl-tyrosine, FET, as surrogate marker). These parameters may be critical for drug delivery. Methods: 13 patients with LGG WHO II were studied. ROI (region-of-interest) analysis was used to quantify tumor tracer uptake which was normalized to cerebellar uptake (T:C). Active tumor was defined at a 110 % cut-

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off of the cerebellar activity. This provided measures of active tumor volume, global and peak tumor CBF and FET uptake. Trace ROI across tumor created pixel-wise profiles of CBF and FET uptake (MVD). Standard MR sequences were used for spatial correlations. Results: Global and peak FET uptake corresponded to CBF increases (Spearman rank p < 0.05). Also the volumes of increased CBF and FET uptake were correlated (p < 0.01). Trace ROIs showed that irrespective of increased MVD at the tumor periphery, CBF increases were confined to the tumor center. Tumors with contact to, or infiltration of the corpus callosum showed reduced or even absent CBF and MVD in these particular regions. MVD and CBF patterns were not reflected in the MR appearence of the tumors which almost presented as homogeneous non-gadolinium enhancing lesions. Conclusion: LGG are heterogeneous tumors with regard to regional vessel densitiy and blood flow.At the tumor periphery where tumor infiltration of surrounding brain occurs blood flow may be low irrespective of increased vascular density. An ongoing study investigates the effect of chemotherapy on these measures. This work was supported by the Swiss Group for Clinical Cancer Research (SAKK) and by Essex Chemie AG, Luzern, Switzerland. P235 Low-dose continuous chemotherapy produces pronounced metabolic responses in MR stable disease patients with low-grade glioma M. Wyss, C. Uhlmann, E. Bärtschi, M. Bruehlmeier, S. Hofer, M. Hefti, U. Roelcke University Hospital (Zurich, CH); Cantonal Hospital Aarau (Aarau, CH) Objectives: Low-grade glioma (LGG) can respond to chemotherapy.We used positron emission tomography (PET) to investigate the effect of continuous low-dose temozolomide (TMZ) chemotherapy on tumor uptake of the amino acid F-18 fluoro-ethyl-tyrosine (FET). FET reflects tumor activity and represents a surrogate marker of microvascular density. We complemented our FET studies by PET measurements of tumor blood flow (CBF) using O15 labeled water. Methods: We prospectively enrolled 10 patients with progressive or recurrent LGG WHO II. 75 mg/m2 TMZ was administered 21q28d (= 1 cycle). MR and PET measurements were performed before, and three, six, and 12 months after initiation of chemotherapy. Region-of-interest analysis was used to quantify tumor tracer uptake which was normalized to cerebellar uptake (T:C). Active tumor was defined at a 110 % cut-off of the cerebellar activity. This provided measures of active tumor volume, global and peak tumor CBF and FET uptake. MR FLAIR sequences were used for calculation of the tumor volume. Results: A total of 97 TMZ cycles was administered. No patient showed tumor progression on MR or PET. Applying the Macdonald criteria the MR tumor volume remained stable until six months, at 12 months a partial response (> / = 50 % volume reduction) was achieved in two patients. The active tumor volume (FET uptake) was reduced by 31 % in one patient already at three months. At six and 12 months, mean reductions of 42 % and 61 % were observed. One patient showed complete tumor deactivation. Tumor FET uptake and CBF (T:C) showed similar trends. Conclusion: We demonstrate biochemical responders among patients otherwise classified as stable disease by MR. Reduced FET uptake due to chemotherapy may serve as an early marker more closely associated with tumor growth inhibition than MR FLAIR imaging. The relevance of CBF reductions with regard to drug delivery remains unclear and will be addressed during the follow-up period. This work was supported by the Swiss Group for Clinical Cancer Research (SAKK) and by Essex Chemie AG, Luzern, Switzerland. P236 Holmes-Adie pupils, myoclonic tremor, sensitive neuronopathy and autonomic neuropathy: small-cell lung cancer presentation E. Santos, A. Martins, F. Marques, J. Barros Hospital Geral Santo António (Oporto, P) Introduction: Paraneoplastic syndromes are rare manifestations of systemic cancer, frequently with severe and irreversible neurological symptoms. A few of this syndromes are well defined and when recognized, should be searched the neuronal auto-antibodies and the primary cancer. Case report: Thirty four years old woman, non-smoker, presented sequentially, in two months, with: anorexia, loss of weight, paresthesia and pain in the extremities, disequilibrium and tremor of the face and arms. On neurological examination she had Holmes-Adie pupils, exuberant myoclonic tremor of the face, predominantly peri-oral and tongue. Also in the arms associated with pseudoathetosis of the fingers. Hypotonia. Reduced

tendon reflexes in the arms and abolished in lower limbs. Poor limb coordination. Hyperesthesia bellow the knees, vibratory sensibility diminished bellow the hips. Proprioceptive loss, distally, in lower limbs. Sensory ataxic gait, only possible with bilateral aid. CSF showed 18 leuc/µL (13 MN), 1.66 g/L proteins and normal glucose. Platelet count was 818x109/L. Electrophysiological study was compatible with sensitive neuronopathy (absent action potential in all sensory nerves). Serum screening for neuronal auto-antibodies was positive for anti-Hu and thoracic CT scan showed a lesion in the left lung. Cytology of this lesion showed a small cell lung cancer. Treatment with IV immunoglobulins was started. During the admission she presented dysautonomia: vomiting, hypersudoresis, urinary retention, arterial hypertension and tachycardia. Sensitive symptoms worsened, ascending to the arms and being unable of standing. She initiated treatment of lung cancer with chemotherapy and radiotherapy and rehabilitation. There was a small improvement in the limb coordination, trunk equilibrium, becoming able of deambulation in wheel chair. Discussion: Paraneoplastic presentation of small lung cell cancer with some atypical aspects comparatively to the classical syndrome of sensitive neuronopathy and autonomic neuropathy: Holmes-Adie pupils and myoclonic tremor. Positive neuronal auto-antibodies anti-Hu and finding lung cancer permitted us to affirm the nature of the clinical picture.

P237 Anti-Hu-associated paraneoplastic sensory neuronopathy and bronchial carcinoid T. Afrantou, S. Tsounis, A. Triantafillou, I. Mavromatis, N. Grigoriadis, A. Angelou, V. Giantzi, M. Paschalidou, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: Paraneoplastic subacute sensory neuronopathy (SSN) with anti-Hu antibodies (Abs) is a severe disease. The diagnosis is more difficult when the lesions extend to the ventral horns. Case report: A 63-year old woman developed paresthesia with a glovestocking distribution in February 2002. She gradually became unable to stand up because of sensory ataxia and severe muscle weakness of her legs. The patient died of pulmonary failure in March 2005. When first admitted there was only deficit in pin and touch sensation in all four limbs with distal predominance. Gradually her pain and paresthesia became more severe. In September 2003 there was diffuse muscle weakness of her legs with predominance in the proximal muscles. Fasciculations were present in quadriceps and Babinski on the right. Reflexes were decreased in left lower limb. On all sensory modalities there were severe deficits in her legs and more mildly in her hands. Laboratory tests: Routine blood tests, urine analysis, B12, tumour markers were normal. Immunology tests were normal except anti-Hu Abs which were detected in three different serum samples. Oligoclonal bands were present in CSF. Brain and spinal cord MRIs, CT- scans of chest and abdomen were normal. Neurophysiologic tests: Motor nerve conduction velocities were decreased in lower and normal in upper limbs. Sensory nerve action potentials of sural nerve could not be elicited and the median nerve’s were mildly decreased. Needle electromyography revealed chronic neuropathic damage. Sural nerve biopsy showed loss of myelinated fibres. Scintigram with radiolabelled octreotide showed accumulation in the perihilar lymph nodes and somatostatin receptor-positive bronchial carcinoid was suspected. Hormonal examination of blood and urine showed serotonin 1120 (500–900 nmol/l), 5-HIAA 11.3 (0.7–8.2 mg/24h). Treatment: Steroids, IV Immunoglobulin, cyclophosphamide failed to demonstrate a clear benefit. When diagnosed with bronchial carcinoid she received Sandostatin LAR 30 mg/3 weeks but she died in third month of therapy from pulmomary failure. Conclusions: In patients with paraneoplastic SSN with anti-Hu Abs when the conventional radiological methods are negative for tumor detection, the whole-body 18FDG – PET is recommended. Nevertheless, this examination is not available in most neurological centers. We propose the use of somatostarin receptor scintigraphy in patients with paraneoplastic anti-Hu SSN.

P238 Detection of intrathecal synthesis of paraneoplastic antineuronal antibodies using recombinant immunoblot O. Stich, S. Jarius, C. Rasiah, B. Kleer, S. Rauer University of Freiburg (Freiburg, D); Ludwig Maximilians University (Munich, D); ravo Diagnostika GmbH (Freiburg, D) Background: Antineuronal antibodies are usually detected in serum of patients with paraneoplastic neurological disorders (PND), but in individual

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cases antibody titre is exceptionally higher in patient’s cerebrospinal fluid (CSF). Objective: To establish detection of specific intrathecal antibody synthesis using immunoblot. Methods: CSF/serum pairs of 21 patients with previously diagnosed PND (3 x anti-CV2-, 4 x anti-Ri-, 5 x anti-Yo-, 1 x anti-Amphiphysin-, 1 x antiMa2- and 7 x anti-Hu-associated PND) were investigated for intrathecal synthesis of antineuronal antibodies using a commercially available immunoblot (ravo PNS-blot®) employing recombinant antigens (HuD, Yo, Ri, CV2/CRMP5, Amphiphysin, Ma2). CSF/serum pairs were previously adjusted to equal amounts of total IgG. Patients were divided into three groups depending on their clinical symptoms: Group I: 11 patients with isolated PND of the central nervous system (CNS). Group II: 7 patients with PND affecting both the CNS and peripheral nervous system. Group III: 3 patients with isolated PND of the peripheral nervous system. As control, CSF/serum pairs of 10 patients with neuroborreliosis and multiple sclerosis were tested.Additionally, calculation of specific antibody index (AI) to quantify specific intrathecal synthesis was provided by ELISA employing recombinant antigens. AI > 1.3 indicates intrathecal synthesis. Results: In all CSF samples and in all but one serum specific antineuronal antibodies were detected. Positive specific antibody using ELISA as well as more intensive antigen specific bands (immunoblot) in CSF compared to the corresponding equilibrated serum were detected in 8/11 (group I) and in 6/7 (group II) patients, respectively. Only two CSF/serum pairs of patients with isolated affection of CNS (group I) reveal negative AI and stronger bands in the corresponding serum. All patients with isolated involvement of the peripheral nervous system (group III) were negative for specific intrathecal antibody synthesis. None of the 10 controls reveal any reactivity. There was a wide agreement between results of immunoblot and specific antibody index provided by ELISA. Conclusion: The immunoblot employing recombinant antigens allows a non quantitative estimation of specific intrathecal synthesis of paraneoplastic antibodies in the cases presented here. Furthermore, we demonstrate a rough correlation between specific intrathecal antibody synthesis and presence of symptoms of CNS. This data support the hypothesis of an autoimmune process in the pathogenesis of PND. P239 A case of anti-GAD positive encephalomyelitis with rigidity occurring in a patient with recently treated nasopharyngeal carcinoma A. Raman, S. A. Khan, S. Jaiser, T. Chang, Q. Chaudhri, A. Vincent, N. Bajaj Queens Medical Centre (Nottingham, UK); Weatherall Institute of Molecular Medicine (Oxford, UK) Antibodies to glutamic acid decarboxylase (GAD) are associated with a number of syndromes of increased muscular activity, the commonest being the stiff person syndrome (SPS) which is typically associated with continuous increased activity of thoraco-lumbar paraspinal, abdominal and proximal lower limb muscles. A related condition is progressive encephalomyelitis with rigidity (PER), which is associated with increased muscle activity of limb and axial muscles with a tendency to involve upper limb and cervical muscles. In addition patients with PER have other neurological signs, particularly of brainstem dysfunction. We describe the case of a 46-year-old male who developed a syndrome in keeping with PER three months after receiving radiotherapy and chemotherapy for nasopharyngeal carcinoma (NPC). The patient presented with severe cervical and upper limb rigidity associated with stimulus-sensitive spasms. Cranial nerve examination demonstrated dysconjugate eye movements and gaze-evoked nystagmus. Magnetic resonance imaging of brain and spinal cord were normal. Lumbar puncture revealed a CSF lymphocytosis with oligoclonal bands and both serum and CSF anti-GAD antibodies were significantly elevated. The diagnosis was supported by characteristic EMG findings of continuous activity in antagonistic muscles. His neurological symptoms initially improved with intravenous methylprednisolone and antispasmodic medication but later relapsed, and he was treated with IVIG with good response. To date no cases of PER have been described associated with NPC, and the timing of his symptoms would be against a paraneoplastic mechanism. Furthermore a search for occult tumour with CT body and fluoro-2-deoxy-D-glucose – Positron Emission Tomography has been negative. We discuss the entity of encephalomyelitis with rigidity in terms of its pathophysiology, relation to stiff person syndrome and its treatment.

P240 Primary non-Hodgkin large B cell lymphoma versus radicular or neuroborreliosis plexopathy L. Glosova, M. Bojar, E. Meluzinova, O. Hrusak, E. Mejstrikova, P. Urie Charles University (Prague, CZ) Objectives: To present the diagnostic pitfalls and the value of cerebrospinal fluid (CSF) cytology in the differential diagnosis between B-cell lymphoma,spondylogenous radiculopathy and nervous system (NS)infectious disorders(neuroborreliosis) in a young male patient,who was admitted for upper brachial plexopathy with C5.6 irritation and progressing fatigue palsy. Methods: CSF was obtained by lumbar puncture(LP). Cytospin technique with May-Grunwald staining was used for cytomorphology study.CSF lymphoid cells were further classified by flow cytometry. Gadolinium-enhanced MRI of the brain and spine were performed as well as bone marrow cytology, viral and bacterial CSF tests. Results: 1st LP revealed 816 cells/ul with atypical plasmacytoid features and 2.5 g/l of protein. MRI(brain, spine) was negative. After steroid treatment the suspected cells count decreased to 357/ul. Immunophenotyping confirmed the B cell lineage origin and distinct antigen expression from normal mature B cells which were completely absent. Cells were positive for CD10,CD45(low expression) and negative for kappa and lambda light chains.Viral and bacterial tests were negative. 3rd LP performed 2 months later disclosed 1533/ul large monomorphous cells with high nuclear/cytoplasmic ratio and bizzare polylobated nuclei.Repeated MRI found a mass lesion in hypothalamus region(13x10x10 mm) in the 3rd ventricle. Conclusion: Primary B-cell lymphoma was diagnosed by CSF cytology. When MRI is negative,atypical lymphoid cells may be difficult to distinguish from lymphoplasmocytes present in NS inflammatory diseases, especially in neuroborreliosis. Steroids might reduce the number of tumor cells and CSF protein concentration. In this case cytomorphology was well preserved but diagnostics could be hampered by steroids. Immunophenotyping and repeated LP helped to verify the malignant diagnosis.

P241 Paraneoplasic neurological manifestations P. Mihancea, C. Brisc, N. Havasi, M. Brisc Oradea University (Oradea, RO) Objective: Are to emphasize the neurological syndromes that accompanied the cases of oncology diseases hospitalized into our clinic, over a 20 years period. Method: The material consisted in the batch of 140 patients who had paraneoplasic neurological symptoms, gathered for 20 years form our hospital. Results: In the batch of 140 patients with paraneoplasiae, 88 of them were diagnosed with bronchi-pulmonary tumors(BPT), 16 of the esophagus, 10 of the stomach, 8 of the colon, 6 of the pancreas, 4 at the kidney, 2 in the uterus, 2 mammal, 2 presented the Hodgkin’s disease (HD) and 2 multiple myeloma(MM). The most frequent (21.4 %) paraneoplasia was the mixed motor-sensitive polineuropathy. It was present especially during bronchi-pulmonary cancer, but it was also noted while digestive tumors. The pure sensitive polineuropathy was noted at 20 patients (14.3 %), it being the stamp for the small-cell bronchi-pulmonary carcinoma. The pure motor polineuropathy appeared at 20 patients (14.3 %). The transverse myelitis was on the 4th place of the paraneoplasiae, found at 14 patients (10 %). This form of paraneoplasia was mostly found with gastric cancers. The cerebellar atrophy was found at 12 patients (8.6 %) ant it was associated with visceral cancers. In our batch there were 12 cases (8.6 %), all manifested as ischemic stroke in HD and BPT. It is described a form of paraneoplasia called the brachial paralytic neuritis. We had in the study 10 patients (7.1 %) with this diagnostic, and 4 of them were diagnosed with Pancoast-Tobias syndrome. We diagnosed 8 cases (5.7 %) of progressive multifocal leuko-encephalitic disease. At the beginning they were described as strokes or vascular dementia. The affection was more often present in malignant lymphoma. The paraneoplasic encephalitis was more frequent at elder male patients with BPT. We had 8 cases (5.7 %), the cancer affected organs being represented by lung and kidney. The myoclonic encephalitis was present at 6 patients (4.3 %) with BPT, breast cancer and MM. Conclusions: Neurological paraneoplasiae are not a consequence of the tumor local action and its metastases, but they are connected to the presence and developing of the malignant neoplasia. These paraneoplasias act like the second disease, which evolve simultaneously with the developing of the ma-

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lignant tumor. The clinic of neurological paraneoplasias is in connection to the location of the malignant tumor.

P242 Multiple paraneoplastic syndromes and recurrent limbic encephalitis as a manifestation of lung cancer with positive antineuronal-Hu antibodies K. Papadopoulos, A. Triantafillou, I. Milonas AHEPA University Hospital (Thessaloniki, GR) Objective: Paraneoplastic limbic encephalitis (PLE) is a neurological consequence of cancers, most commonly originating from lung, breast and testis. Its clinical manifestations include amnesia, depression, anxiety, seizures and personality changes. The onset of the PLE may precede the diagnosis of malignancy by a period of up to 2 years. We report a case of PLE with fluctuations of memory performance. Methods: A 64-year-old male was admitted to our clinic due to a epileptic episode and disturbance of memory performance, which occurred 20 days ago. The patient showed improvement after 12 days. He was admitted 1 month later, for the same clinical manifestations. He once again improved. 95 days later, he was admitted due to left hemiparesis, ataxia, numbness of the left arm and leg and deterioration of his consciousness level. The symptoms had an acute onset. After 1 week, he presented opsoclonus-myoclonus. The next day he died. Results: The patient’s neurological examination revealed loss of short memory function and left babinski sign.At his second admission he showed identical symptomatology. The brain magnetic imaging showed hyperintensity in the body of the right hippocampus on T2 images with enhancing of the paramagnetic substance on T1 images. The cerebrospinal fluid examination had oligoglonal bands. His electroencephalogram revealed right focal slowing and epileptiform activity. The rest laboratory examinations were unremarkable until his third admission. Then his neurological manifestations were severe left pyramidal weakness, cerebellar ataxia, and impairment of the cognitive functioning. Nerve conduction velocities showed mild sensiromotor polyneuropathy. Diagnosis was suggested by finding positive antineuronal antibodies (anti-Hu) and confirmed by biopsy of the mediastinal lymph nodes, which were revealed by computed tomography of the chest, at his third admission. The biopsy showed infiltration of malignant undifferentiated small cell cancer. He was treated with steroids intravenously during his 2 admissions and with gamma-globulin during his third one along with immediate initiation of chemotherapy. Conclusion: Paraneoplastic limbic encephalitis is a challenging neurological syndrome that demands joint management by neurologists, oncologists and the palliative care team. Early recognition of the syndrome is important as this will impose a thorough investigation for the responsible malignancy and consequently its early detection and management.

P243 Limbic encephalitis: association with ovarian teratoma and hippocampal neurophil antibodies J. L. López-Sendón, J. Masjuan, M. García-Cossío, M. Alonso de Leciñana, I. Corral, S. Estévez, M. García-Villanueva, J. Dalmau Ramón y Cajal Hospital (Madrid, E); Hospital of the University of Pennsylvania (Philadelphia, USA) Objectives: A disorder characterized by limbic encephalitis (LE) in association with ovarian teratoma (OT) and antibodies to the neuropil of the hippocampus has recently been reported. These patients are voltage-gated potassium channels (VGKC) antibodies negative and are often misdiagnosed. We report a young woman with LE associated with OT and hippocampal neuropil antibodies. Methods: Clinical case review. Immunohistochemistry with paraformaldehyde prefixed rat brain, and immunolabeling of live cultures of hippocampal neurons. Results: A 35-year-old woman was admitted because of rapidly progressive short-term memory loss and refractory status epilepticus that required sedation and prolonged respiratory support. MRI revealed bilateral medial temporal lobe FLAIR hyperintensities, without contrast enhancement. CSF showed 189 leukocytes/mm3; 68 mg/dl protein, and IgG oligoclonal bands. VGKC antibodies were negative by radioimmunoassay. CSF but not serum showed reactivity with antigens highly restricted to the neuropil of hippocampus and cell surface immunolabeling of neuronal cultures. Epileptic activity in the temporal lobes and diffuse slowing was demonstrated in multiple EEGs. CT and abdominal ultrasound revealed a benign ovarian cyst. The patient did not improve with corticosteroids, plasma exchange, or IVIg. Cyclophosphamide resulted in improvement of the CSF pleocytosis without a clinical response. The patient died 4 months after symptom presentation.

At autopsy, analysis of the cyst revealed an OT and neuropathological studies are pending. Conclusions: 1) OT-encephalitis should be suspected in young women with subacute development of short-term memory deficits, seizures, and hypoventilation; 2) The associated antibodies may only be detectable in CSF, and typically show high specificity for the neuropil of the hippocampus; 3) The benign imaging appearance of the OT can be misleading; 4) Recognition of the disorder is important because previous studies show that prompt therapy often results in recovery. P244 Limbic encephalitis: a case of definit paraneoplastic disorder A. Perli, S. Levtsuk North Estonia Regional Hospital (Tallinn, EST) Limbic encephalitis is considered to be one of classic paraneoplastic syndromes. Paraneoplastic neurological disorders (PND) are immunomediated neurological syndromes triggered by an underlying neoplasm which have may been formerly diagnosed or still unknown. Limbic encephalitis is characterized by subacute dementia, specific electroencephalographical changes and hyperintensivity in medial temporal lobes in T2 MRI images. Objectives: To establish the diagnosis of PND according to the definite criterias. Case report: A 60-year old man presented with 2 occasional epileptic seizures after he had developed a subacute progressive dementia. Neurological examination did not reveal evident neurological deficit, but he had a marked reduction of short-term memory and therefore he was completely confused in time, place and situation. His MMSE (mini-mental study examination) score was 14 of 30. The computered tomography of brain did not show visible changes. The positive anti-Hu antibodies in the cerebrospinal fluid and in blood were detected that led up to the diagnosis of possible paraneoplastic syndrome. The electroencephalogram (EEG) demonstrated slow backround activity in both temporal areas but no epileptic discharges. The diagnose was favored by the specific radiological findings on MRI – asymmetric hyperintensity in T2 and FLAIR sequences in the medial temporal lobes. Although there was no previous history of pulmonary problems and his x-ray of lungs was normal a tumor of lung seemed to be the most probable neoplasm considering that limbic encephalitis associated with anti-Hu antibodies indicates mainly to an intrathoracic tumor. The CT of lungs was performed. Radiological examination detected a slightly enlarged mediastinal lymphatic note. Biopsy of an abnormal area idendified a small cell lung cancer (SLCL). The response to oncological treatment turned out to be positive. One year later his MMSE score has improved up to 30 points, but he has still a mild cognitive deficit. Conclusions: The patient had a typical clinical course, including neuropsychological disorder with predominant short-memory loss and epileptic seizures as an initial symptom. The definit paraneoplastic disorder was proved by the typical clinical picture, the presence of positive anti-Hu antobodies and the finding of neoplasm. Cognitive abilities may improve markedly as a result to appropriate treatment. P245 Cerebellar degeneration and peripheral neuropathy in a patient with squamous cell lung carcinoma: two paraneoplastic disorders? A. Magherini, F. Barbieri, G. Ficarra, G. Galassi Institute of Neurosciences (Modena, I) Objective: Patients affected by cancer may develop signs due to damage of nervous system with variety of clinical syndromes. Combination of indolent tumours and progressive neurologic disability, in absence of metastases, may suggest antitumour immunity. Methods: This 78 year-old smoking woman was admitted after ten months of progressive paraesthesias in hands and feet, severe gait instability. Examination showed normal mental state, spontaneous nystagmus towards to left, scanned speech, severe limb, trunk ataxia. There were distal extremity weakness graded as 4 (Medical Research Council scale), areflexia, impaired sensation for touch, pin-prick, temperature position. Results: Electrophysiologically an axonal sensorimotor polineuropathy was diagnosed. Normal results included routine blood tests, neoplastic markers, viral, microbiological, autoimmune, rheumathological screenings. Antineuronal nuclear autoantibodies anti Hu (ANNA-1) and anti Ri (ANNA2) were positive in serum. Total body computed tomography and F-deoxyglucose positron emission scan revealed 13 mm lesion in right lung, diagnosed on biopsy as squamous cell carcinoma. Patient was treated with immunoglobulins intravenously (0.4 gr/kg of body weight for 5 days). A course of immunoglobulins was repeated monthly for 5 months with tran-

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sient improvement. Patient received combined chemotherapy with gemcitabine (1 gr/mq2 for 3 days every 4 weeks). The neurological disorder of our patient, mainly her ataxia progressed steadily. Conclusion: Paraneoplastic syndromes are rare conditions. Previous reports highlighted the association of remote tumour with peripheral neuropathy as well as with cerebellar degeneration proposing as immunological mechanism and crossed reactivity between cancer epitopes, cerebellar antigens and peripheral nerves. In our case, both clinical conditions could be considered as paraneoplastic and neurological symptoms related to production of antibodies against multiple tumoral antigens. On the other hand, the coexistence of multiple antibodies may further reflect targeting of multiple autoantigens related to intermolecular epitope spreading. P246 Anti-Hu antibodies associated paraneoplastic sensory neuropathy in a patient with ovarian cancer N. Vila-Chã, L. Sousa, P. Coutinho, A. Tuna Hospital de Sto António (Porto, P); Hospital de São Sebastião (Santa Maria da Feira, P) Introduction: Anti-Hu antibodies are considered to be a marker to paraneoplastic subacute sensory neuropathy. In most cases the primary tumor is identified as small cell lung cancer, reports of other tumor are rare. Case report: A 73 year old woman was admitted to the hospital with a 3 months history of hypoesthesia and paresthesia with a glove and stocking distribution. She was a non-smoker and had no relevant personal or family medical history. Neurological examination revealed generalized arreflexia, a stocking-glove sensory impairment of superficial sensation with normal deep sensation and normal gait. The CSF examination showed 49 mg/dL of protein, no cells and normal glucose. Brucella and syphilis CSF serologic tests and herpes virus PCR were negative. Sensory nerve conduction velocities were markedly decreased in median and sural nerves. Laboratory tests showed increased concentration of CA 125 46.9 U/mL (normal is below 35 U/ml); all other finding including hemogram, test for autoantibodies (ANA, RNP, ANCA, anti-dsDNA, Anti-SS-A, Anti-SS-B, RF, Anti-SM), folic acid, vitamin B12, thyroid gland function tests, and C-reactive protein were normal and HIV test was negative. Chest CT scan was normal. Ultrasonography assessment revealed a right ovarian mass. Serum anti-Hu antibodies were positive. Whole-body [18F]fluoro-2-deoxyglucose-PET showed only abnormal right pelvic region uptake. The patient subsequently underwent a right salpingo-oophorectomy and the histological examination revealed a poorly differentiated adenocarcinoma of the ovary. Discussion: Positive anti-Hu antibodies indicate the presence of a neoplasm with high specifity. In 80 % of cases, the primary tumor is identified as small cell lung cancer. Other tumors found in combination with anti-Hu antibodies were prostate carcinoma, breast carcinoma, melanoma, lymphoma, adrenal cancer, neuroblastoma and sarcoma. We report a subacute sensory neuropathy with anti-Hu antibodies in a patient with an ovarian cancer. To our knowledge, this is the first case in which this syndrome and this type of tumor occurred in combination. P247 Isolated hypoglossal nerve palsy due to glomus jugulare tumour – a case report H. Gotshal, T. Gurevich, V. E. Drory, Y. Segev, A. D. Korczyn Tel Aviv University (Tel Aviv, IL) Objectives: To describe an unusual case of tongue atrophy. Methods: Clinical examination, computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), electromyography (EMG), Tc99 bone scan, blood and cerebro-spinal fluid laboratory tests. Results: A 58 years old man presented with progressive speech disturbances, dysphagia and drooling from the right side of the mouth, with attacks of sudden sharp pain in the back of his neck radiating to the right side of the face over the preceding 2 months. Due to chronic sinusitis he underwent functional endoscopic sinus surgery (FESS) with normal biopsies 3 months previously. Neurological examination revealed dysarthria, unilateral right tongue atrophy and fasciculations, limitation of tongue movements to the right with deviation to the right on protrusion. Facial muscles strength, hearing, sensation and taste were normal. There was no bruit behind the ear or self-audible bruits or clicks. Head and neck CT and MRI were interpreted as normal, without any finding that can explain the patient’s clinical manifestations. Tc99 bone scan and laboratory results were normal. EMG showed complete denervation of the right hemitongue but no ab-

normality on the left and mild chronic neurogenic damage to the quadriceps bilaterally. Doppler of the carotid arteries was normal, excluding carotid dissection. A focused investigation using dynamic MRI demonstrated a hyperintense lesion that enhanced after injection of gadolinium, stretching from the jugular foramen up to the hypoglossal canal. The lesion appeared to be vascular and fed by many blood vessels, consistent with glomus jugulare tumor. Due to the tumor’s location, rich blood-supply, and the mild functional deficits, we decided against surgical intervention at present. The patient improved functionally (speech and swallowing) after speech therapy. Conclusion: Glomus jugulare tumors can present with isolated unilateral cranial nerve lesions (involvement of the right hypoglossal nerve in this case), which might not be revealed by conventional techniques of CT and MRI, but can be demonstrated using a special MRI method (dynamic MRI). We also would like to mention functional improvement after application of compensatory strategies. P248 Non-enhancing primary central nervous system lymphoma A. Koukoulis, M. Alonso, A. Iglesias, R. Fernández Martín Xeral-Cíes Hospital (Vigo, E); MEDTEC (Vigo, E) Primary CNS lymphoma (PCNSL) can affect normal as well as immunocompromised patients, causing general manifestations and focal neurological deficits which are indistinguishable from other CNS tumors. Diagnosis should be established pathologically by stereotactic biopsy of contrast-enhancing lesions previously to administration of corticosteroids. Recognizing PCNSL by its neuroimaging features is thus essential to avoid steroid medication and to facilitate attempts to biopsy. MRI typically shows lesions with intense homogeneous enhancement, although only a few immunocompetent patients have been reported with primarily non-enhancing PCNSL lesions. A 74 year old-man with past history of hyperuricemia and hypercholesterolemia presented with progressive walking and speech difficulties together with persistent headache, aggravated by cough, over the previous month. His initial neurological examination revealed right leg paresis, mild right dysmetria with bilateral dysdiadochokinesia and ataxic gait. MRI showed multiple bilateral lesions involving periventricular and subcortical white matter and basal ganglia, with surrounding edema. Lesions appeared hypointense on T1-weighted sequences and hyperintense on T2-weighted and FLAIR images, without contrast enhancement. After several days, the patient’s clinical situation worsened and corticosteroids were then administered with almost complete recovery. Extensive laboratory and imaging examinations, including CSF analysis, were inconclusive and the patient was discharged under steroid treatment.A week later he was readmitted because of progressive deterioration, dying after a few days. His final diagnosis at autopsy was PCNSL. We suggest that although typical MRI features of PCNSL are well known, this condition should also be suspected when unusual images are present, especially if the patient improves with steroid therapy. P249 Cauda equina tumour atypical presentation M. Gago, A. Mendes, C. Neves, J. Oliveira, E. Carneiro, P. Pereira, M. J. Rosas Hospital de S. João (Porto, P) Introduction: Cauda equina tumours account for around 1 % of all central nervous system tumours, of which ependymomas represent the most common type in adults. Cauda equine syndrome may manifest with flaccid weakness and sensory loss in lower extremities, saddle anaesthesia, radicular pain and sphincter disturbances. We present a clinical case of a cauda equine tumour with atypical neurological picture. Case Report: A seventyone years old female complained of one-year progressive walking difficulty associated with clumsiness, unsteadiness of gait and low back pain extending to the left leg. In this period kindred noticed some cognitive impairment, being house keeping less functional. In the last two months urinary incontinence was reported. She presented moderately distractible with sluggish global cognition but with preserved memory and language, suggesting subcortical dementia. Normal superficial and deep sensibilities. Normal deep tendon reflexes and flexor plantar reflex. Upper and lower extremities with normal strength. Left straight-leg-raising test positive at 30°. Gait with widened base, short-steps and stooped. No rigidity, tremor or ataxia. Cranial magnetic resonance imaging (MRI) revealed symmetric enlarged supratentorial ventricles with normal periventricular white matter signal. Normal cerebrospinal fluid (CSF) flow MRI study, without aqueduct flow void sign. Lumbar puncture revealed yellow CSF with 40 cells (59 % small lymphocytes), elevated proteins (4 g/dl), normal fluid pressure (110–120 cmH2O)

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and no evidence of CSF block at Queckenstedt test. Negative bacteriologic, serologic and virologic CSF study. Lumbar MRI detected an extensive L3 to S1 intraspinal and intradural sausage shaped mass with intense homogeneous enhancement, suggestive of a filum ependymoma. Conclusion: This patient presented with a clinical triad of gait disorder, cognitive decline and urinary incontinence suggestive of a communicating normal-pressure hydrocephalus. Nevertheless it lacked evidence of active normal-pressure hydrocephalus on MRI and there was no clinical improvement after CSF drainage. This case of cauda equina tumour gains interest as it presented with a secondary hydrocephalus clinic and it was the elevated protein content of CSF that led to a neoplasia study and diagnose. P250 Acute bilateral neurosensory hearing loss as the first manifestation of leptomeningeal carcinomatosis A. Angelou, A. Boutsi, T. Afrantou, N. Taskos, I. Milonas AHEPA Hospital (Thessaloniki, GR) Leptomeningeal carcinomatosis is a serious and quite usual neurological manifestation of systemic malignancy. The clinical sings include increased intracranial pressure, cranial nerves paresis, radiculopathies, syndromes that imitate ischemic strokes, seizures, and encephalopathy. Quite often the symptoms are not typical and differential diagnosis can be too difficult. Case report: A 53 year old woman with a history of breast cancer, treated with mastectomy two years before, was admitted to our department due to severe acute bilateral hearing loss and tinnitus. Two weeks later, she complained of headaches and blurred vision. Fundoscopy revealed pupillary edema with hemorrhages; audiometry showed neurosensory hearing loss. Brain MRI was negative for metastatic lesions as well as pathological meningeal enhancement. Magnetic venography did not reveal cerebral venous thrombosis. Finally, CSF cytologic analysis set the diagnosis of meningeal carcinomatosis. Course-Treatment: An intraventricular drainage valve was placed in order to reduce the elevated intracranial pressure. This lead to some improvement of the headaches and of the pupillary edema, while hearing ability remained unchanged. The patient was admitted to the oncological department. She was treated with chemotherapy. During the following six months her neurological and general condition gradually worsened. Conclusion: Acute bilateral hearing loss is rarely the first clinical manifestation of leptomeningeal carcinomatosis and can be the result of either direct infiltration of the auditory nerve or of ischemia due to compression of the vasa nervorum. P251 Neurologic complications following bone marrow transplantation M. Sahraian, M. Iravani, M. Motamedi, M. Nazari, S. Modaressi, S. Vazirian Tehran University of Medical science (Tehran, IR) Background: Bone marrow transplantation is increasingly used for both neoplastic and non-neoplastic diseases. Neurologic complications may be seen in transplanted patients especially during the first 3 months. These complications may adversely influence survival and careful monitoring is advised. Methods: We evaluated 546 bone marrow transplanted patients during 12 years. Data including identification, cause and type of transplantation, neurologic complications and outcomes were all registered. Statistical analysis conducted with SPSS software (version 11.5) using T-test and Chi-Square. Results: We studied 326 male and 220 female transplanted patients. The most common causes of transplantation were thalassemia (30 %), acute myelogenous leukemia (23 %), chronic myelogenous leukemia (12.5 %) and acute lymphocytic leukemia (10 %). 110 patients (20 %) had neurologic complications. Distal tremor (7.3 %), headache (6.8 %), impaired consciousness (4.2 %) and seizures(3.5 %) were the most common complications. Among the patients with these complications 92 % had allogeneic and 8 % had autologous transplantations. Graft versus host disease increased the frequency of such complications and they were associated with increased mortality. Conclusions: Neurlogic complications were significantly correlated to type of transplantation,GVHD and was associated with increased mortality. We could not find any correlation between age, sex, cause of transplantation and neurologic complications.

P252 Carcinomatous meningitis: an unusual complication of bladder cancer A. Camacho, C. Fernández García, I. Díaz Padilla, J. María Viguer GarcíaMoreno, R. Martínez Cabruja Hospital La Moraleja (Madrid, E); Clinica Ruber (Madrid, E); HistocitoMed (Madrid, E) Introduction: Carcinoma of the urinary bladder accounts for approximately 2 % of all malignant tumors. The frequency of neurologic complications is low and meningeal infiltration is extremely rare. We present a case of carcinomatous meningitis from a transitional cell carcinoma of the bladder. Case report: A 46-year-old woman was diagnosed of invasive bladder cancer with multiple bony metastases. After radical cystectomy she received 6 courses of systemic M-VAC (methotrexate, vinblastine, epirubicin and cisplatin) chemotherapy with good response. Three months later the patient complained of a 2-week history of intractable headache, blurred vision and vomiting. On neurological examination she had mild neck stiffness and swelling of the optic disc. Hemogram and routine laboratory analysis were unremarkable, but cranial CT scan showed slight hydrocephalus without any contrast enhancement. Two lumbar punctures were performed. The first one disclosed 25 cells (predominantly lymphocytes), protein 44.6 mg/dl and glucose 20.8 mg/dl. Four days later, CSF glucose got lower (10 mg/dl) and protein duplicated its previous value. All CSF bacteriology and viral serology were negative. Both citology samples showed large malignant cells with vacuolated cytoplasm and confirmed meningeal carcinomatosis. Despite antiedema treatment her neurologic status followed a fulminant course and she died 3 weeks after admission. Conclusions: Urothelial carcinoma of the bladder usually spreads through local invasion and hematogenous dissemination. Involvement of the nervous system is uncommon and only a few cases of carcinomatous meningitis in bladder carcinoma have been reported. The majority of these patients presented metastases and had been treated with a combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapies. It is possible that antineoplastic drugs may change blood-brain barrier permeability; this would allow the penetration of cancer cells, resulting in meningeal infiltration.

Poster session 2 Cerebrovascular disorders P253 Object-specific and “side inversed” palinopsia limited to the hemianopic field in occipital infarction R.J Metz, V. Pieri, N.J Diederich Centre Hospitalier Luxembourg (Luxembourg, LUX) Objective: Study of transient palinopsia (PA) in occipital infarction. PA is defined as the persistence or the delayed reappearance of previously perceived visual images. There have only been anecdotal reports of transient PA in ischemic infarction. Case report: 69-year old woman presenting with sudden onset of leftsided temporal homonymous hemianopsia, confirmed by perimetry, ipsilateral neglect and subtle paresis of the arm. The diagnostic work-up concluded to a bifocal cardioembolic infarcts due to atrial fibrillation. Detailed MRI imaging showed [1] ischemic stroke in the distal territory of the leptomeningeal branches of the right posterior cerebral artery along the optic radiations, and (b) borderzone millimetric infarct in the corona radiata between the territories of the anterior and middle cerebral arteries.Visual contrast sensitivity (Pelli-Robson, Vis-Tech tables) was reduced. Color discrimination and cognitive functions were normal. The EEG did not detect epileptic discharges. Results: From day 3 on the patient reported episodes of flash-like vision of colorful, repetitive, geometric figures, limited to the hemianopic field (HF). The personal drawings ad hoc during 2 days revealed the reality of the perceived objects: yellow curtain design; gray metallic tubes of the heating system etc. However, these objects were currently only visible in the intact right temporal visual field. The patient had not noticed this overlapping. She denied compensatory head movements as well as confusion of right and left visual fields. The PA phenomena disappeared after day 5. Conclusion: A predisposition of the right occipital area for PA as well as the limitation to the hemianopic field has been previously reported. PA may

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be due to transient postischemic hyperperfusion in the perilesional area or to functional disconnection from the primary visual cortex. To the best of our knowledge there has been no report of a “side inversed” PA content, with image origin from the intact contralateral visual field. We hypothesize that this phenomenon is suggestive of transhemispheric “dialogue” between specialized visual associative cortices in order to compensate fragmentary visual input information on one side. P254 Computer tomography perfusion of penumbra versus outcome in hypertensive intracranial haemorrhage undergoing conservative versus surgical management: a prospective study J. M. Abdullah, Z. Z. Abdul Ghani, N. A. Ahmad Alias, S. Jalaluddin, J. Tharakan, N. N. Naing, A. R.I Ghani Universiti Sains Malaysia (Kubang Kerian, Kelantan, MYS) Objective: This study aimed to find factors of abnormal perfusion in the perihaematoma regions of hypertensive ICH(HtICH) and factors affecting its clinical outcome. Materials and methods: Ten patients whom fulfilled the inclusion criteria and gave written informed consent were study for a period of 18 months from July 2004. NECT scan was done to confirm HtICH then CTP was performed. Haematoma volume and distance from skull were measured and four regions of interest were drawn based on CTP colour mapping. Each parameters of perfusion were produced by the GE perfusion software and were analyzed whether selected region had normal to severe ischaemic perfusion status. MBI was scored at presentation and 6 months. Statistical analysis: Fisher’s exact test was applied to investigate the effect of ischaemia around an intracranial haemorrhage on clinical outcome and radiological findings. Backward stepwise multiple logistic regression and Mc Nemar test was used to detect gliosis at region of interest (ROI) sub areas 1.2,3.4 with regard to whether the clot was removed. The level of significance was set at 0.05. Results: Baseline GCS was 8; median hematoma volume was 27.85 ml ± 24.12 SD. Site of ischemia (p = 0.500), whether surgery was performed (p = 0.500), age (p = 0.667), duration to CT scan (p = 0.708), GCS (p = 0.167), size of the clot (p = 0.500), ROI 1 (p = 0.240), ROI 2 (p = 0.585), ROI 3 (p = 0.533) and ROI 4 (p = 0.708) and type of ischemia (p = 0.708) (normal, moderate and severe) were found not to be associated with radiological outcome. Regarding MBI ‘none was significant and results are site of ischemia (p = 0.500), age (p = 0.500), duration to CTscan (p = 0.500), GCS (p = 0.262), clot size (p = 0.500), ROI 1 (p = 0.513), ROI 2 (p = 0.287), ROI 3 (p = 0.778), ROI 4 (p = 0.500) and type of ischemia (p = 0.500). Multiple logistic regression also showed no significant results. For gliotic areas surrounding the intracerebral clot, the variables investigated were gliosis at ROI 1.2,3.4 with the time internal of (less or more than 6 hours) and whether surgery was performed or not. No association was reported between gliosis in these four ROIs based on time interval with regard to whether surgery was performed or not. Conclusion: Despite presence of moderate to severe ischemia in the penumbra regions,conservative or surgical management did not effect outcome. This study supplements one CTP study by Fainardi E (J.Neuroradiol. 2005;32 [5]:333–6) and one MRI study by Kidwell CS study(Neurology 2001;57 [9]:1611–7) P255 Survival analysis and functional outcome at 6 months in surgical treatment of spontaneous supratentorial intracerebral haemorrhage J. M. Abdullah, J. Tharakan, A. R. I. Ghani, Z. Idris, S. Sayuthi, S. Awang, N. Abdul Wahab, M. Mohamad Ghazali, N. Murshid, F. Abdul Rashid Universiti Sains Malaysia (Kubang Kerian, Kelantan, MYS) Objective: A prospective cohort study, was conducted over a 13 month period, from February 2004 which consisted of studying hematoma evacuation with intracranial pressure monitoring regional cortical blood flow monitoring and microdialysis. Materials and methods: Cerebral autoregulation using transcranial Doppler sonography and the thigh cuff technique was performed in all subjects on admission to the ICU. Applanation tonometry assessing the central systemic haemodynamic by measuring the aortic augmentation index using the Pulse Wave Analysis. The end points were survival time and functional outcome at 6 months based on a dichotomized Glasgow Outcome Scale (GOS). Results: 36 patients were recruited into the study of whom 19 were males and 17 were females with ages ranging from 39 to 76 years and a mean age of 58.6 (± 10.1) years. 27 (75 %) patients had Glaslow Coma Score (GCS) be-

tween 5 to 8 on admission and 9 (25 %) were admitted with GCS of 9 on admission. The survival time ranged from 2 to 180 days with a mean survival time of 105.36 ± 76.4 days. At 6 months, 20 (55.6 %) patients had GOS 1, 1 (2.8 %) patient had GOS II, 10 (27.7 %) patients had GOS III and 5 (13.9 %) had GOS of IV. None of the patients in this study had GOS of V. The mortality rate at 6 months was 55 %. 86 % had a poor or unfavorable outcome (GOS I-III) and 14 % had good or favorable outcome (GOS IV-V) APOE å4 allele was not detected in all patients.A normal cerebral autoregulation was found in 27 (75 %) patients. In 7 patients where aortic augmentation index (AI) was measured, a high AI was observed. In the univariate analysis for the functional outcome shift (p = 0.009), regional cortical cerebral blood flow (rCoBF), (p = 0.034) and tracheostomy status (p = 0.047). The univariate analysis for survival function revealed that the regional cortical cerebral blood flow (rCoBF), (p = 0.0143), midline shift (p = 0.0064) and pupillary status on admission (p = 0.0016) were significant predictors of survival function. Conclusion: Pupillary status was sole significant predictor of survival function (HR = 2.298; 95 % CI 1.168–4.523; p = 0.016) in multivariate analysis. Patients with midline shift > 5 mm has almost 21 times higher chances of being associated with poor outcome (GOS I-III) and patients with abnormal pupil on admission has 2.3 times risk of mortality compared to patients with normal pupillary reaction on admission. P256 Risk factors and seasonal-diurinal variatons in lacunar infarctions M. Alemdar, P. Iseri, S. Kamaci, H. Efendi, F. Budak, S. Komsuoglu Kocaeli University, Faculty of Medicine (Kocaeli, TR) Objectives: Lacunar infarctions are deeply located ischaemic cerebral lesions smaller than 1.5 cm in diameter and mostly seen in elderly. In the present study, we investigated the risk factors and time of symptom-onset in patients with lacunar infarctions. Methods: The informations of the patients, who were hospitalized in our Neurology clinic inbetween the 2001 and 2005 and whose diagnoses were confirmed with neuroimaging studies, were analysed by screening of neurology inpatient registry database. The risk factors and time of symptomonset were re-asked by phone-calls with them or their primary relatives. Results: Eighty-one patients with the mean age of 64.6 were included. Forty-three of them (53 %) were femle. In 36 (44.4 %) of the patients, the lesion was in right cerebral hemisphere and in 45 (%55.6) of them, it was in left one. There was at least one vascular risk factor in 80 (98.8 %) patients and one cardiac risk factors in 6 patients (7.4 %). Sixty patients (80.2 %) had multiple vascular risk factors. There was hypertension in 68 (83.9 %) patients, dyslipidemia in 48 (59.2 %) patients, history of smoking in 26 (32.1 %) patients and diabetes mellitus in 22 (27.2 %) patients. Among the 16 patients with single risk factor, ten had hypertension and five had dyslipidemia. The symptoms had occurred during the night in 34 patients (41.9 %) (sleep period + first hour of awakeness) and during the day in 47 (58.1 %) patients. The disease was seen during the winter in 17 (21 %), during the spring in 22 (27.2 %), during the summer in 19 (23.4 %) and during the autmn in 23 (28.3 %)patients. Conclusions: The presence of patients with single risk factor revealed the importance of primary prophylaxis. The high frequency of patients with multiple risk factors underlined the needs for applying these prevention methods carefully and the addition of new strategies when needed in that group.After the analyses were corrected according to sex and age, we did not detect any seasonal or diurinal variation or side differences in this study population. P257 Reversible vasoconstriction of the basilar artery associated with thunderclap headache A. Basta, I. Markakis, E. Alexiou, G. Gekas General State Hospital of Piraeus (Nikaia, Piraeus, GR) Background: Reversible segmental cerebral vasoconstriction, also known as Call-Fleming syndrome, is a rare idiopathic disorder characterized by segmental vasospasm in one or more arteries of the brain, that typically reverts to normal in subsequent angiographic examinations. The major clinical feature on presentation is a sudden and very intense (thunderclap) headache, while focal neurological deficits may also develop during the course of the syndrome. Case history: A 46-year old female with a history of migraine attacks, experienced a sudden and severe occipital headache that radiated fast to include the entire cranium. The pain had a throbbing quality, was associated with nausea and vomiting and developed in the absence of physical activity. A brain MRI scan that was performed on admission showed no acute pathol-

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ogy. In order to exclude the possibility of subarachnoid haemorrhage, the patient underwent a lumbar puncture that did not reveal any abnormalities. Extracranial Doppler ultrasonography showed abnormal flow in both vertebral arteries. Cerebral angiography excluded the presence of aneurysm, but demonstrated a segmental narrowing in the distal part of the basilar artery. Autoantibody testing for connective tissue disorders, erythrocyte sedimentation rate, and Venereal Disease Research Laboratory were negative. EEG was also normal and there was no history of exposure to drugs or toxic agents. Four days after the onset of headache, the patient developed rightsided hemiparesis and homolateral hemianopia. Cerebral MRI demonstrated an acute subcortical infarct in the left parieto-occipital area. Following treatment with intravenous nimodipine, a marked clinical improvement was noticed, along with a complete reversal of cerebral vasoconstriction, as demonstrated by subsequent angiography. Conclusions: Idiopathic reversible cerebral vasospasm is a distinct clinical entity, whose diagnosis rests on the exclusion of secondary cerebral vasoconstriction (e. g. subarachnoid haemorrhage) and CNS vasculitis. It should be clearly distinguished from the above disorders, given that it follows a rather self-limiting course, has an excellent prognosis and requires a conservative therapeutic approach with calcium channel antagonists. P258 Point mutation A1020P in a sporadic case of CADASIL: pathogenic mutation or polymorphism? S. Castro, A. Mendes, M. Gago, C. Reis, J. Fonseca, M. J. Rosas, M. J. Sa Hospital de Sao Joao (Porto, P) Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a mid-adulthood disease characterized by subcortical ischemic infarcts, migraine-like events, dementia and mood disorders. The disease is caused by mutations of the Notch3 gene encoding a transmembranar receptor. Pathogenic described mutations remove or insert cystein residues. Case report: A 33 yr old woman, with an active life, presented an acute clinical picture of nauseas, vomiting and desiquilibrium to the right side. She also complained of migraine-like headaches without aura and depressed humour for the last 6 months. She had no history of cerebrovascular risk factors. At examinaton she revealed global cognitive decline suggestive of subcortical dementia and horizontal right third degree nystagmus. No motor or sensitive deficits were noticed. Familial history of cerebral strokes was negative. Brain MRI showed cortico-subcortical atrophy and bilateral lesions of high signal on the long TR images in the subcortical and periventricular white matter of both hemispheres, internal and external capsules, right thalamus, cerebellar peduncles and pons. Routine laboratorial analysis, homocysteine, serologic, immunologic studies were normal. Cerebrospinal fluid revealed a mild protein elevation and positive IgG oligoclonal bands. Cervical and transcranial duplex scan, echocardiogram, electrocardiogram were normal. Genetic test confirmed a Notch3 gene mutation in codon 1020, exon 19 (change of a prolin residue for alanin). Discussion: This case exemplifies the highly variable clinical expression of CADASIL which frequently leads to misdiagnosis mainly with demyelinating diseases or other cerebral vasculopathies. Dementia is usually seen in a late stage when white matter extensive lesions, particularly in the periventricular areas are seen. In opposite to typical CADASIL’s late dementia our patient had cognitive deterioration in the previous 6 months before the diagnosis which seems a severe and relatively rare form of presentation. Several mutations on Notch 3 have been described, mostly on exons 3 and 4, but also at 6, 11, 19 and others.We report a clinical case of CADASIL with a point mutation which doesn’t involve cystein residues in a patient without familial history. We hypothesize that it can be another pathogenic mutation of CADASIL. Although a polymorphism cannot be excluded. P259 Superficial siderosis of the central nervous system due to a bleeding lumbar ependymoma K. Spengos, G. Karachalios, G. Tsivgoulis, P. Toulas, D. Vassilopoulos University of Athens (Athens, GR); Encephalos Diagnostic Institute (Athens, GR) Background: Superficial siderosis (SS) of the central nervous system is an uncommon cerebrovascular disease caused by chronic subarachnoid hemorrhage that leads to hemosiderin deposition on the leptomenigeal layers of brain, cerebellum and spinal cord. It is characterized by cerebellar ataxia, sensoneuronal hearing loss and pyramidal tract signs of different severity. Diagnosis can be established, in vivo by means of T2* weighted magnetic resonance imaging that demonstrates impressively a black hemosiderin rim on the surface of the affected tissues. This way many reports of even asymp-

tomatic SS-cases were published in the international literature. However, in the majority of cases the source of bleeding remains uncertain. In such cases where no causal therapy is possible, corticosteroids may lead to some improvement. Case report: A 63-year-old man reported a since 5years persisting, however during the last 4 months dramatically progressing gait disorder. On conventional MRI no pathology was found. He also reported that his father had had similar problems, presented after the age of 60. Late-onset spinocerebellar atrophy was assumed and the patient was therefore admitted to our outpatients’ clinic for further evaluation. Clinical examination revealed extensive toes bilaterally, dysdiadochokinesia, dysmetria and intension tremor as well as inability to walk steady on toes and heels or on a line. Detailed questioning revealed an already diagnosed bilateral hearing impairment affecting high frequencies. Being familiar with the diagnosis of SS and paying attention to the combination of signs and symptoms, before starting an extensive diagnostic workup we just asked for T2* MRI of the brain and the cervical cord that verified our assumption and established the diagnosis of SS. Oral corticosteroids were initiated leading to a marked improvement within 3 weeks. Additional MRI of the thoracic and the lumbar spine was then performed and helped identifying a bleeding lumbar ependymoma as cause of SS. Conclusion: Neurologists should become familiar with the clinical entity of SS, which could be much more frequent that it is thought to be. It should also be included in the differential diagnosis of mixed atactic-pyramidal syndromes. As in the present case, including T2* sequences in the standard MRI protocol of such cases allows the identification of a dark number of possibly overseen SS cases, where an effective treatment might be possible. P260 Spontaneous spinal epidural haematomas in hypertensive patients K. Spengos, S. Vassilopoulou, A. Konstantinopoulou, G. Tsivgoulis, E. Manios, N. Zakopoulos, V. Zis University of Athens (Athens, GR) Introduction: Spontaneous spinal epidural hematoma is a rare vascular disease of mostly unknown cause. Uncontrolled hypertension can in some cases induce epidural hemorrhage leading to an acute or subacute spinal syndrome of variable severity. Case reports: We present the cases of two 65- (A)- and 75(B)-year-old insufficiently treated hypertensive women, who both experienced while resting sudden intensive lower neck pain and developed within 10 minutes (A) and 4 hours (B) variant Brown-Sequard syndromes. They were both initially transferred to an internistic emergency room. In both cases a CT brain scan excluded intracerebral or subarachnoid hemorrhage. They were then transferred to our neurological department with suspected ischemic stroke. Obviously sparing of the face and other focal signs were overseen. Detailed clinical examination revealed in case A left-side hemiparesis (2/5), bilateral pyramidal signs, right-side hemisensory deficit and bladder incontinence. In case B right-side hemiparesis (3/5) with diminished tendon reflexes on the right arm, left-side hemihypesthesia and right-side Horner-syndrome were documented.Assuming an acute space occupying process affecting the cervical spinal cord we performed in both cases MRI scans that demonstrated large extraspinal mass lesions with hematoma characteristics that critically compressed the left and right dorsolateral surface of the cervical medulla at the levels C4-C7 and C3-T2 respectively. Antiedematous treatment with dexamethasone was initiated leading to clinical improvement. Both patients were then transferred to the neurosurgical department. After selective spinal angiography that excluded any vascular malformation as bleeding source, they underwent laminectomy and complete hematoma evacuation. Their condition improved dramatically and they both left the hospital waking after a few days. Since both patients had presented extremely elevated admission blood pressure values, we assume in both cases acute epidural hemorrhage as a highly uncommon vascular accident caused by an episodic extreme elevation of blood pressure in poorly controlled hypertensive subjects. Conclusion: Although spontaneous epidural hematomas are rare, clinicians should be aware of them as possible vascular accidents occurring in poorly controlled hypertensive patients. Therefore not only the brain, but also the spinal cord should be considered as possible, albeit uncommon site of hypertension-induced nervous tissue damage.

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P261 Transcranial Doppler sonography and perfusion CT in patients with internal carotid artery stenosis P. Puz, Z. Kazibutowska Silesian Medical Academy (Katowice, PL)

P263 Ethnic differences in stroke characteristics of hospitalised patients in Mures county, Romania C. C. Szekeres, I. Szocs, S. Szatmári, J. A. Szász, A. Hojda, K. Orbán-Kis Mures County Hospital (Targu Mures, RO)

Objectives: Neurological events related to internal carotid artery (ICA) stenosis may be caused by intracranial blood flow disturbances and hypoperfusion of some of brain areas. Low cerebral perfusion may be helpful in identification of patients who will benefit from novel preventive approaches. Perfusion computed tomography (CT) allows the evaluation of cerebral perfusion by generating maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Transcranial Doppler sonography (TCD) is a method for noninvasively assessment of the effects of extracranial stenosis on intracranial hemodynamics. The aim of our study is to assess the results of perfusion CT and TCD findings in patients with carotid stenosis. Methods: Perfusion CT exams were perfomed in 30 patients with ICA stenosis (70–99 %) to calculate CBF, CBV, MTT values. The state of an ischemic tissue compartment was calculated as a relative perfusion score for CBV,CBF and MTT by using the contalateral hemisphere as reference. TCD and standard imaging techniques: conventional CT or magnetic resonance imaging (MRI) were performed to assess the flow parameters and areas of infarction and noninfarction of the brain tissue. Results: There was a signifficant difference between areas of stenotic and non-stenotic ICA territories for CBF, CBV and MTT. MTT assymetry (by 12–56 %) between ischemic and non – ischemic areas was the most sensitive indicator of ischemia. Changes in perfusion parameters ipsilateral to the stenosis were greater in symptomatic patients compared with asymptomatic patients and in patients with infarction in CT or MR imaging. Signifficant differences in CBF, CBV and MTT in the area of stenotic ICA, compared with those values on the contralateral hemisphere were correlated with the degree of stenosis. The mean blood flow velocity differences measured in the middle cerebral artery between areas of stenotic and non-stenotic ICA territories were greater in symptomatic patients (by 30 %) compared with asymptomatic patients (by 20 %). Differences of blood flow velocity in MCA are relevant to lower brain perfusion. Conclusion: Perfusion – related parameters can be used to describe cerebral ischemia. The extent of regional abnormalities on the perfusion maps was greatest with MTT, followed by CBF and CBV. TCD sudies may be helpful in detection of brain perfusion deficite in patients with ICA stenosis.

Objectives: our aim was to determine the local characteristics of stroke in hospitalized patients in three ethnic groups (Romanian, Hungarian and Roma-Gypsy), from Mures county, Romania. Methods: in a prospective epidemiological study we examined all stroke patients from Mures county admitted between 1st of November 2004 and 30th of October 2005 to Mures County Hospital in Neurology, Neurosurgery, Intensive Care Departments. For the statistical analysis we used the unpaired t-test, the Mann-Whitney Test and the chi-square test. Results: From 1478 patients (710 woman, 768 men) the mean age of men (66.5 ± 10.5 years) was significantly lower than the mean age of women (69.4 ± 11.0 years) (p < 0.0001), which reflects the worldwide characteristic feature in the incidence of stroke. The mean age of Roma subjects (mean age of woman: 64.2 ± 10.11 years, mean age of men: 61.7 ± 13.3 years) was significantly lower that the Romanian and Hungarian subjects age. The age of rural Romanian women (71.0 ± 9.2 years) was much higher that the age of urban Romanian women (65.0 ± 12.6 years) (p < 0.0001). This difference existed between the villager Romanian men (68.5 ± 9.8 years) and the urban Romanian men (64.9 ± 10.4 years) too (p < 0.0001). The frequency of hemorrhagic stroke was significantly higher in Romanian women than other subgroups. There were no ethnic or gender differences in case fatality during hospitalization. Conclusion: the mean age of the rural and urban people differed significantly in the Romanian population,which can suggest that the sedentary life style has a bigger impact as a risk factor on this population. The mean age of Roma subjects with stroke was much lower than the age of subjects from other nationalities, the possible explanation for this fact could be found in the poor health-education of this ethnic group, and the lack of identification and treatment in time of changeable stroke risk factors.

P262 Ophthalmic artery collateral pattern in patients with severe unilateral carotid stenosis P. W. Chung, Y. B. Kim, H. S. Moon, S. C. Hong Sungkyunkwan University (Seoul, KOR); Hanil Hospital (Seoul, KOR) Objective: Transcranial Doppler ultrasonography(TCD) is a non-invasive and easily applicable method to evaluate ophthalmic artery (OA) flow and cerebral hemodynamics. The aim of this study is to evaluate the significance of ophthalmic artery flow detected by TCD in cerebral hemodynamics of carotid artery occlusive disease. Methods: Eighty-five patients with unilateral internal carotid artery (ICA) occlusion or stenosis confirmed by cerebral angiography were enrolled in this study.We evaluated the patterns of OA flow by TCD, patterns of cerebral ischemic changes on MRI, and degree of ICA stenosis assessed by angiography. The flow direction of OA were compared with degree of ICA stenosis and patterns of ischemic changes. Results: OA signals were reversed in 17(77.3 %) out of 22 patients with ICA occlusion. Among the patients with 90–99 % ICA stenosis, OA signals were reversed in 20 patients(69 %). Only one out of 34 patients showed reversed OA signal in less than 90 % stenosis group. The frequency of reversal of OA flow was not significantly different between positive MRI lesion(presence of territorial infarction or borderzone infarction in ICA territory) group and negative MRI lesion(normal or small vessel change in ICA territory)group in both ICA occlusion (p = 0.498) and 90–99 % stenosis(p = 0.175) patients. Conclusion: Reversed OA flows on TCD indicate severe ICA stenosis of more than 90 %. But OA collateral flow has little significance in cerebral hemodynamic status in same degree of ICA stenosis.

P264 Characteristics of stroke in hospitalised young patients in Mures county, Romania L. Zoican, A. Hojda, I. Szocs, K. Orban-Kis, J. Szasz, S. Szatmari Mures County Hospital (Targu Mures, RO) Objective: Stroke represents the first cause of disability in young adults in Romania, so it would be necessary to prevent it by a correct treatment of risk factors. Methods: The present study evaluated the risk factors of stroke in young patients from Mures county, admitted for acute stroke to the Mures County Hospital between 1st November 2004–31st October 2005.We analyzed data of all adult patients with age of 50 years or below 50. We considered gender, provenance, nationality, risk factors on admission, primary prevention of stroke, subtypes of it and outcome. Results: Out of the 1478 patients admitted for stroke in this period, 106 were 50 or younger than 50. In the studied group 57.5 % were male (M), 42.5 % female (F); 55.67 % of urban provenance (F: 40.7 %, M: 59.3 %) and 44.3 % of rural (F: 44.7 %, M: 55.3 %). By nationality 47.2 % were Romanian, 46.2 % Hungarian, and 6.6 % Roma, reflecting demographic distribution of this county. In the studied group ischemic stroke (including 2 cases of transient ischemic attacks) had a prevalence of 73.6 %, hemorrhagic 19.9 %, and subarachnoid hemorrhage represented 6.6 %. Results: The most frequent risk factor was hypertension, detected in 59.4 % of cases on admission, (M: 52.4 % vs F: 47.6 %), followed by smoking (48.1 %), more frequent in male (62.7 % vs 37.3 %), obesity in 37.7 %, more common in female (57.5 % vs 42.5 %, p < 0.05), heart diseases in 26.4 %, history of stroke in family in 22.6 %, history of prior stroke in 16.9 %, alcohol abuse in 16 %, more frequent in male (M: 94.1 % vs F: 5.9 %), diabetes mellitus was present in 15.1 %, dyslipidemia in 12.3 %(male-female ratio 5.5:1, p < 0.05). We found no difference in risk factors, subtype of stroke, outcome, regarding nationality. Although the majority of patients had two or more known risk factors (80.18 %), primary prevention of stroke was performed only in 16.5 % cases. Hospital case fatality was 10.4 % (11 patients), out of which 4 were with ischemic stroke, 4 with hemorrhagic stroke, and 3 subarachnoid hemorrhages, respectively. Regarding disability among survivors at discharge, 58.5 % had a minor or no disability and 31.1 % had severe disability. Conclusion: Although our results may have been confounded buy the relatively small number of patients in the different subgroups, we conclude that risk factors are common and frequently neglected among young

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patients.There wasn’t any difference neither in risk factors on admission, subtype of stroke nor in outcome during hospital-care, regarding nationality.

study. Hospital mortality in our region is still higher than in developed countries, but it is much lower than in previous period.

P265 Outcome of stroke in mannitol-treated patients – a prospective, observational study performed during 1 year in Mures county hospital, Romania I. Szocs, C. Szekeres, K. Orban-Kis, A. Hojda, J. Szasz, S. Szatmari Mures County Hospital (Targu Mures, RO); University of Medicine and Pharmacy (Targu Mures, RO)

Clinical neurophysiology

Although no randomized clinical trials have been performed to decide whether the use of mannitol is justified or it should be restricted to certain subgroups of stroke,a vast part of stroke patients are traditionally treated with mannitol in our county. We evaluated 1478 patients consecutively admitted with stroke to our hospital between November 01, 2004 and October 31, 2005. We excluded those with subarachnoidal hemorrhage, transient ischemic attack and those with missing data, thus remaining 1423 patients. Diagnosis, level of consciousness (LOC), handicap and Scandinavian Stroke Score (SSS) on admission and discharge, case fatality during hospitalization were considered. Data analysis was performed by the Mann-Whitney test and chi-square. Out of the 1423 patients, 809 were given intravenous mannitol as part of their routine treatment.When we considered only those with altered LOC on admission (364 patients) we found that case fatality was higher in the treated group (32 % vs 28 %), but this difference was not statistically significant. The survivors of this group who received mannitol – compared to those who did not – had worse SSS and handicap both on admission and discharge (p < 0.001) and their improvement during hospitalization was lower (p = 0.04). Out of the 1170 ischemic patients, 578 got mannitol and 10 % of them died in hospital (vs 3 % fatality in the nontreated). The treated group showed worse SSS, LOC and handicap on admission and discharge, but the improvement of these factors was significantly better. There were 253 hemorrhages, 231 of them receiving mannitol. Case fatality was 24 % (vs 50 % in nontreated). Though there was a tendency for the treated group to have more altered parameters, we found no difference except for the LOC on admission of the treated group being more damaged. The patients with altered consciousness on admission when treated with mannitol, did not differ in case fatality from those not treated. Nevertheless, the mannitol-treated survivors showed a poorer recovery than those who did not receive the drug. Case fatality among the treated patients was higher in the ischemic, while it was lower in hemorrhage patients compared with those not treated. The mannitol treated ischemic patients showed a stronger improvement from a worse condition at admission than those not treated. These results may be biased by several factors, nonetheless they reflect a need of further evidence and suggest a refrain from uncontrolled mannitoluse.

P266 Characteristics of cerebrovascular diseases in the new millenium in Tuzla canton, Bosnia and Herzegovina D. Salihovic, D. Smajlovic, O. Sinanovic, M. Vidovic, L. Zonic University Clinical Centre Tuzla (Tuzla, BIH) Objectives: The aim of this study was to analyze the frequency and characteristics of cerebrovascular diseases (CVD) in the first years of new millennium, age and sex distribution, main risk factors and hospital mortality. Methods: In the study were enrolled 2968 patients with first-ever CVD admitted at the Department of Neurology Tuzla, Bosnia and Herzegovina in the period between January 1st 2000 and December 31st 2004. Results: Ishemic stroke (IS) had 2148 patients (72 %), intracerebral hemorrhage (ICH) 502 (17 %), subarachnoid hemorrhage (SAH) 124 (4 %) and 212 (7 %) patients had unknown stroke. Mean age was 65.87 years (SD 10.79) in males and 69.09 years (SD 10.52) in females. Out of total patients 1417 (47 %) were males and 1569 (53 %) females (P = 0.016). Females were overrepresented in all types of the CVD. Main risk factors were: hypertension in 2212 patients (74 %), heart diseases in 1203 (40 %), smoking in 859 (29 %), diabetes mellitus in 696 (23 %), atrial fibrillation in 464 (16 %), alcohol abuse in 251 (8 %) and hyperlipidemia in 165 (6 %) patients. Hospital mortality in the analyzing period was 32 % and it was lower comparing with the period 1996 to 2000 (38 %). Conclusion: In the new millennium, we find increased frequency of ischemic stroke and female dominance in all types of CVD. Hypertension, heart diseases, smoking and diabetes are the leading risk factors in our

P267 Electrophysiological diagnostic in syringomyelia F. Roser, C. Sixt, F. Riether, M. Liebsch, N. Kerting, M. Tatagiba University of Tubingen (Tubingen, D) Objective: The neurophysiological assessment of Syringomyelia has been unsatisfactory. Syringomyelia is characterized by a centromedullary syndrome with dissociative symptoms, where spinothalamic A-delta-fibers might first to be involved. Crossing spinothalamic fibers that convey pain and sensation are anatomically placed at highest risk to be compromised in the early stage of disease. The testing of cutaneus and mixed-nerve silent periods (CSP/MNSP) have been proven to be sensitive for detecting alterations in this pathway. Methods: Inclusion criteria for the study were a cervical Syringomyelia, no previous spinal operation, no intramedullary tumour and no history of meningitis. Out of a database of 120 patients with Syringomyelia 12 patients fulfilled the criteria: Routine electrophysiological measurements were applied including SEP and MEP recordings for all extremities. Additionally CSP, MNSP and cortical silent periods (CoSP) were derived. CSP were recorded from the pollicis brevis muscle and electrical stimuli were applied to the ipsilateral digiti II (single square pulses of 15-times the sensory threshold level). A CSP was defined “complete” when there was absence of EMG activity and as “incomplete” when the background ENG activity exceeded 100 mikroV during an otherwise clear suppression of voluntary activity relative to baseline. Ten healthy control persons with no history of spinal trauma or any neurological symptoms were recorded to receive a baseline value. The study was approved by the local ethic committee. Results: All control patients show normal CSP and MNSP in volitionally activated pollicis brevis muscle. In Syringomyelia patients the affected limb – hypaesthesia and hypothermaestehsia – demonstrate significant shortened or absent silent periods, despite normal values in SEP and MEP recordings. Conclusion: Upper extremity CSP/MNSP testing is a sensitive neurophysiological technique for the assessment of cervical Syringomyelia. They are highly associated with early dysfunction of thin myelinated spinothalamic tract fibers, when routine electrophysiological measurements for large diameter fibers still show normal values. Conduction abnormalities that selectively abolish CSP and later part of MNSP suggest a common central mechanism for both of these inhibitory responses. P268 Reaction of autonomic nervous system to vestibular stimulation T. Nedelka, J. Jerabek, R. Cerny Charles University (Prague, CZ) Objectives: The aim of our study was to investigate the autonomic reflex function during standard vestibular stimulation using warm water caloric stimuli (44 degrees) in 7 patients (18–52 years old, mean age = 33.43) suffering from unilateral vestibular lesion. The results were compared with findings in 7 healthy volunteers (23–28 years old, mean age = 25.26) Methods: Total number of five, 5-minutes long intervals with continuous short-term, frequency domain heart rate variability recording, was assessed in standard conditions.Initial orthostatic test containing supine rest, 90 degrees tilt and supine rest again, was followed by warm/44 degrees/water caloric tests.Function of vestibular system was recorded by means of standard ENG procedure. Caloric test was performed by using standard procedure 44, water for 20 sec.Manual systolic and diastolic blood pressure/BP/measurments were repeated every 30 seconds in the beginning and once again at the end of each of 5 intervals mentioned above. The subjects were instructed to keep breathing unchanged. Results: Systolic and diastolic blood pressure levels were comparable in controls and patients. We found decreased reactivity of autonomic nervous system response to ortosthatic test and calorisation in group of patients.HRV was compared after caloric stimulation of affected to the unaffected side. During calorisation of affected side, there was no response of vestibular system and results reflected the influence of the whole laboratory procedure, positioning, enviromental conditions, noise and sensoric sensation from the irrigated ear. During warm water caloric tests, the group of patients suffering from acute unilateral labyrinthine impairment showed defi-

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cient increase in total spectrum power/TSP/, LF power,LF power spectral density/LF PSD/and LF/HF ratio when compared to the 2nd supine rest sequence of orthostatic test. After caloric stimulation of healthy labyrinth, the increase of TSP,LF power, LF PSD values and LF/HF ratio was comparable to the results obtained in healthy controls. In healthy subjects, there was normal reactivity to the orthostatic test. Calorisation evoked signs of increase of absolute values mentioned above with no difference between both stimulated sides. Conclusions: In group of patients suffering from unilateral vestibulopathy significant decrease of power spectrum analysis parameters and lower reactivity of ANS to orthostatic test as well as caloric vestibular stimulation was found. Project supported by IGA MZd CR nr0.8439–3/2005

the non-affected side. SSR latencies were not different between sides regardless of the side stimulated. Amplitude of the SSR was asymmetric with significantly larger amplitudes in the paretic side with respect to the nonparetic side (multiple comparisons t-test; p < 0.01), except for the auditory stimulation. Our results indicate a reduced control of the spontaneous EDA and the stimulus-induced SSR in the paretic side after cerebral lesions, suggesting a compensatory liberation of activity in intracerebral sympathetic sudomotor circuits.

P269 The limits of high-frequency repetitive nerve stimulation for clinical diagnostics W. J. Z’Graggen, A. C. Nirkko University Hospital (Berne, CH)

Previous studies have clearly shown that corticospinal excitability is modulated during performance of imaginary actions. However, there is no evidence for the modulation of intracortical inhibition (ICI) during imaginary simple reaction time tasks (iSRT). Our aim was to use transcranial magnetic stimulation (TMS) to assess changes in corticospinal excitability and ICI in iSRT at different time intervals. Methods: In a simple reaction time task paradigm (SRT), 5 right-handed subjects were asked to perform a rapid isometric squeeze with their dominant hand as soon as possible after a visual imperative signal (IS). In the iSRT, subjects were given the same instruction but just imagining the task. Electromyograph (EMG) signals were recorded from first dorsal interosseus (FDI) muscle of the dominat hand. The mean SRT was calculated for each subject. TMS and paired-TMS (p-TMS) were applied at rest and at intervals of 25, 50, 75, 100 and 125 ms before the mean onset of EMG.We used the same intervals for both SRT and iSRT. The interstimulus interval for p-TMS was 2 ms. For each interval, eight trials were collected for TMS-rest, SICI-rest, SICIRT, TMS-iSRT, SICI-iSRT. The mean amplitude of MEPs were expressed as a percentage of the unconditioned responses in each condition. Result: MEPs during SRT were of larger amplitude in both SRT and iSRT in comparison to rest (p < 0.05), with significant differences at intervals of 25 and 50ms. There was a significant interaction between trial type and time interval (p = 0.01). SICI was reduced in SRT and iSRT in comparison to rest, with significant differences at the interval of 50ms (p = 0.05). There was not interaction between trial type and time interval. The reduction of SICI in iSRT was less pronounced than in SRT (p < 0.05). Conclusion: After the IS, there is an increase in corticospinal excitability and reduction of SICI beginning at about 50 ms before the time of expected onset of EMG in iSRT. These results indicate that imagining a motor act is enough to induce a reduction in cortical inhibition.

Objectives: High frequency nerve stimulation can be used to test for presynaptic dysfunction of the motor endplate and for metabolic muscle disease (McArdle). Frequencies up to 50 Hz are used for this purpose, but a drop in compound muscle action potential (CMAP) can be observed already in healthy subjects. The goal of this study was to derive normal values for 20 and 50 Hz nerve stimulation of the peroneal nerve and to determine the reason for the normal decrease of CMAP. Methods: The peroneal nerve was stimulated supramaximally at the capitulum fibulae. Surface recordings were obtained from the tibialis anterior muscle. Repetitive nerve stimulation was performed with a pulse rate of 20 and 50 Hz and a pulse train duration of 2 minutes. In addition, direct distal stimulation of the anterior tibial muscle with single supramaximal stimuli was performed during repetitive nerve stimulation to test for changes in muscle exitability. Results: 20 Hz stimulation of the peroneal nerve resulted in an initial small increase of the CMAP followed by an almost unchanged amplitude over a time period of 2 minutes. In contrast, 50 Hz nerve stimulation resulted in a drop of CMAP amplitude by more than 60 % of the initial amplitude size. Additional single supramaximal direct (post-synaptic) muscle stimuli during 50 Hz peroneal nerve stimulation resulted in equally reduced CMAP amplitudes. Conclusion: High frequency nerve stimulation of 50 Hz results in a large drop of CMAP amplitude over time, resulting from post-synaptic muscle membrane hypoexcitability with unchanged synaptic transmission at the neuromuscular endplate. Stimulation at 20 Hz may be more adequate for clinical purposes. Supported by the Swiss National Science Foundation (SNF grant 3200B0–107499/1). P270 Enhancement of sudomotor activity in the paretic side after medial cerebral artery infarcts J. Casanova, S. Fernández-Fernández, V. Obach, A. Chamorro, J. Valls-Solé Hospital Clínic (Barcelona, E) The control centers for sympathetic activity in the sudomotor circuits are poorly known. Neurophysiologically, it is possible to record oscillations of the galvanic skin resistence, known as the electrodermal activity (EDA), that occur apparently spontaneously at rest. They may reflect the activation of subcortical sudomotor centers with breathing, attentional shifts or emotional changes. Also, stimuli of various sensory modalities generate synchronized changes in the sympathetic sudomotor circuits, known as the sudomotor skin response(SSR). The level of EDA during a certain time window and the size of the SSR in response to controlled stimuli can reflect the excitability of the sympathetic sudomotor circuits. In this study, we determined the side to side differences in the excitability of sympathetic sudomotor circuits occurring after acute hemispheric vascular lesions. The study was carried out in 7 patients between 1 and 7 days after stroke. Four patients had a right medial cerebral artery infarct, and 3 had the infarct in the left side. We recorded EDA and SSR in the palms of both hands. EDA was analyzed during repeated epochs of 10 seconds, with the patient awake at rest. The SSR was obtained after electrical stimuli applied to the right and left median nerves and right and left supraorbital nerves, to unexpected acoustic stimuli of 130 dB, and to right and left focal transcranial magnetic stimulation (TMS). Mean level of EDA was significantly higher in the paretic side than in the non-affected side 1.38 ± 0.47 in the paretic side and 0.72 ± 0.24 in

P271 Modulation of corticospinal excitability and intracortical inhibition during imaginary simple reaction time task H. Kumru, J. Costa, J. Valls-Sole Hospital Clinic (Barcelona, E)

P272 Effects of water drinking on cardiovascular response to supine exercise and exercise-induced postural hypotension in patients with pure autonomic failure A. M. Humm, L. M. Mason, C. J. Mathias University Hospital (Berne, CH); National Hospital for Neurology and Neurosurgery (London, UK); Imperial College London at St Mary’s Hospital (London, UK) Objectives: In patients with pure autonomic failure (PAF), an abnormal fall in blood pressure (BP) to supine exercise and an enhancement of postural hypotension after exercise are observed. Water drinking increases seated BP and improves orthostatic hypotension in PAF by mechanisms that remain unclear. We studied the effects of water drinking on the cardiovascular response to supine exercise and on exercise-induced postural hypotension. Methods: 8 patients (5 female, age 63.9 ± 6.1 y) with PAF underwent a test protocol consisting of pre-exercise stand for 5 min, first supine rest for 10 min, supine exercise by pedalling a cycle ergometer at a workload of 25 W, 50 W and 75 W (each for 3 minutes), second supine rest for 10 min and postexercise stand for 5 min. The test protocol was done without water ingestion and on a second day with drinking of 480 ml distilled water just after the preexercise stand/before the first supine rest. Beat-to-beat cardiovascular indices were measured with the Portapress II device with subsequent Modelflow analysis. Results: In all patients, pre-exercise standing caused a marked fall in BP, which recovered immediately in the supine position. In the protocol including water drinking, a significant rise in BP was observed at 5 min into the first supine rest, which remained stable until exercise was started. Independent of water intake, there was a clear fall in BP with a modest rise in heart rate during supine exercise. BP recovered slowly during the second supine rest, but was at all times significantly higher in the protocol including water drinking. Without water ingestion, post-exercise orthostatic hypotension

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was more severe than pre-exercise. After water drinking, the fall in BP on postural challenge after exercise was less than pre-exercise and less than post-exercise in the protocol without water drinking. Conclusion: There was no change in the abnormal cardiovascular response to supine exercise. However, water drinking is beneficial in improving exercise-induced orthostatic hypotension. A. M. Humm was supported by a Swiss national grant for a fellowship in clinical neurophysiology (Grant 31–226).

P273 Usefulness of evoked potentials in exploring the pathophysiology of multiple sclerosis: diffuse versus focal damage L. Leocani, P. Annovazzi, L. Malciene, M. Riva, F. Martinelli Boneschi, M. Rovaris, V. Martinelli, U. Del Carro, G. Comi Hospital San Raffaele (Milan, I) Objectives: Pathophysiology of multiple sclerosis (MS) is far from being completely understood. Two main mechanisms may contribute to the accumulation of nervous damage: acute lesion-related myelin and axonal damage, and widespread damage at least partially depending upon a degenerative process. Lesion-related damage predominates in the relapsing phase of the disease, on the contrary the widespread damage characterizes the progressive forms of the disease. The aim of this study was to evaluate the role of evoked potentials (EPs) in exploring the pathophysiology of MS. Methods: We studied 153 patients of whom 109 relapsing – R (87 relapsing-remitting – RR; 22 clinically isolated syndrome – CIS) and 45 progressive – P (23 primary progressive – PP; 22 secondary progressive – SP).All patients underwent clinical examination with EDSS and Functional Systems (FS) scoring, and somatosensory (SEP) and motor (MEP) evoked potentials to the four limbs. For each modality, the severity of EPs abnormalities were scored using a conventional system in order to perform correlation with the corresponding FS. In addition, patients were classified as with diffuse damage when both sensory and motor lower limb EPs (of 3 of the 4 EPs) were abnormal; patients with other EPs abnormalities were classified as with focal/multifocal involvement. Results: The degree of EPs abnormality of both modalities significantly correlated with the corresponding FS (SEPs: r = 0.36, MEPs: r = 0.61; p < 0.0001). Disease course and disability were differently distributed among the three EPs groups (Chi-square, p < 0.0001). In particular, 77 % of P vs 34 % of R had ‘diffuse’ EPs damage, 9 % of P vs 25 % of R had focal/multifocal EPs, while 13 % of P vs 40 % of R had normal EPs. ANOVA showed a different EDSS distribution in the three EPs groups; R patients with ‘diffuse’ EPs had significantly higher EDSS than those with normal EPs (p = 0.0004), patients with focal/multifocal EPs had intermediate values, indicating that patients clinically classified as relapsing already show evidence of widespread, symmetrical nervous damage. Conclusion: As expected, SEPs and MEPs abnormalities correlated with clinical involvement of the corresponding pathway. The finding, in relapsing patients, of higher disability in patients with widespread, symmetrical nervous damage suggests that EPs assessment could be useful in early identification of relapsing patients at risk for developing a progressive form of the disease.

P274 Epilepsy and electroencephalographic characteristics of cerebral radiation necrosis A. Azevedo, J. P. Foreid, T. Pimentel, I. Costa IPO Lisbon (Lisbon, P) Introduction: Cerebral radiation necrosis is a potential long term complication of radiotherapy that occurs when the latter is directed to the central nervous system or to nearby structures. It consists in a focal structural lesion which can mimic tumor recurrence or a new primary brain tumor. It manifests as progressive neurological deficits and is usually associated with epilepsy. Case Reports: We report 11 cases of radiation necrosis, subdivided in 2 groups: 3 patients with primary brain tumors and 8 patients with other malignancies (head and neck tumors and brain metastasis of breast carcinoma). The radiation necrosis appeared 6 months to 4 years after the radiotherapy. In all cases the patients had simple or complex partial seizures, but there was never secondary generalization. We highlight 2 patients with musical seizures. On the electroencephalograms generally we found flattened slow waves (“in plateau”) and a reduction of the absolute energy values, particularly in alpha and beta range. Conclusion: Cerebral radiation necrosis is an entity known for decades, but its electroencephalographic characteristics have been poorly studied.

The E. E. G. findings now reported may have an important role in the dilemma of the differential diagnosis with tumor recurrence. P275 Somatosensory involvement in amyotrophic lateral sclerosis is related to delayed cortical activation during movement planning: an EEG study F. Cerri, E. Munerati, R. Fazio, N. Riva, P. Annovazzi, G. Comi, L. Leocani Hospital San Raffaele (Milan, I) Objectives: Although amyotrophic lateral sclerosis (ALS) is considered a neurodegenerative disorder of the upper and lower motor neurons, there is evidence that the disease can affect other systems such as the somatosensory. Event-related desynchronization (ERD) of the sensorimotor rhythms of the electroencephalogram is used to describe the spatial and temporal pattern of cortical activation during movement planning and execution. The aim of our study was to investigate the role of somatosensory involvement on movement planning in ALS. Methods: Twenty-six ALS patients (age 59.6 ± 11.3 years) and 16 righthanded healthy volunteers (age 55.25 ± 11.7 years) were included. Mu ERD to self-paced right thumb movement was studied on 32 channel EEG. Patients underwent standard clinical examination, disability scoring using the ALS Functional Rate Score (ALS-FRS) and somatosensory evoked potentials (SEPs) to the four limbs. Results: SEPs were abnormal in 13 patients. Patients with SEPs abnormalities had longer disease duration (36.76 + 33.58 vs 18.6 + 15.6) an ASL-FRS score lower (29.15 + 5.41 vs 33.15 + 2.5) than patients with normal SEPs. ERD onset latency over the contralateral sensorimotor region (C3 electrode) did not significantly differ between patients with normal SEPs and controls, while it was significantly delayed in ALS patients with abnormal SEPs compared to both groups (p < 0.02). No significant difference in onset latency over the ipsilateral sensorimotor region (C4 electrode) was found between both ALS and control groups. During movement execution, non signfiicant group difference were present in the amount of ERD. Conclusions: Delayed ERD onset over the primary sensorimotor region in ALS patients, with normal ERD amount during movement execution, suggests a dysfunction of cortical networks involved in movement planning rather than execution in these patients. This finding may indicate that patients with somatosensory involvement have a more widespread cortical impairment, thus involving also cortical circuitries related to motor planning. Another possible explanation is that the integrity of somatosensory afferences may play a specific, crucial role in maintaining the efficiency of sensorimotor circuits involved in programming of voluntary movement.

Dementia/Higher function disorders P276 The burden experienced by caregivers of patients with Alzheimer’s disease and related dementias E. Papastavrou, S. Papacostas Institute of Neurology and Genetics (Nicosia, CY) Objectives: The main purpose of this study is to assess the level of burden experienced by the families giving care to their relatives suffering from Alzheimer’s Disease (AD) and related dementias. It also aims to explore the risk factors of caregiver burden, to examine the consequences of care on the mental health of the primary family care giver and to identify the coping strategies used for moderating the stress of care. Another objective of the study is to test the hypothesis if the burden is relieved in the case that the demented patient is institutionalised. Methods: Four psychometric instruments were used: The Memory and Behavior Problem Check list to test the frequency of the patient’s problematic behaviour the Burden Interview (Zarit 1990), and the CES-Depression scale (Raddloff 1977) to examine the psychiatric morbidity of the care giver. The coping strategies that the primary care givers use to relieve the stress of care were explored with the Ways of Coping Questionnaire (Folkman & Lazarus1988). The sample was drawn from the Institute of Neurology and Genetics in Cyprus and the Psychiatric Community Health Centres. Two hundred patient-caregiver dyads were invited to participate and finally 172 accepted. Results: The results showed that the majority of primary care givers are suffering from high levels of burden and depression. There is an association between the problematic behaviour, care giver reaction to this behaviour, depression and perceived burden. The correlation analyses revealed that burden and depression are not changed in the case when the patient is nursed

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in an institution, which means that institutionalization does not reduce the burden of care. Multiple regression analyses show a strong correlation between burden and the strategies of avoidance and denial for coping with stress.The correlation between the two sexes confirmed increased levels of burden and depression among women and especially daughters. The most important demographic risk factors found for burden were the income and level of education of the primary caregiver, as well as the strategies used to cope with the stress of care giving. Conclusion: The results support the hypothesis that psychiatric morbidity in the form of burden and depression of care givers of demented patients is mainly related to the patient’s behavioural problems. The caregiver support needs to continue when they decide to place their relative in institutions. This research has been granted by the Research Promotion Foundation of the Republic of Cyprus. P277 Are normals entirely normal in tests of executive function? M. Senol, R. Togrol, H. Tekeli, E. Boylu, M. Saracoglu, O. Tanridag Gata Haydarpasa (Istanbul, TR) Objectives: Although they are the largest portion of the brain, and the executive functions are mostly located in the dorsolateral parts with its subcortical links,the frontal lobes are the most neglected.Somatic neurological examination and most commonly used mental state tests, including the Mini-Mental State Examination (MMSE),entirely neglect this area and testing these areas requires different methods.Common bedside tests specifically aiming these areas include go-no go tasks, visual grasp (antisaccade task),letter fluency,word generation tests,attention and concentration tests including digit span and letter span. Another method is the use of alternating sequences.In the Luria’s 3-step motor program for this evaluation,the patient is asked to sequentially copy 3 movements.There are many small variations of this test and no standard data on the action of normals is available The objective of this study was to evaluate the results from normal subjects on a standard performance of the test. Methods: 63 normal subjects(38 female 25 male) were included until now; the study is continuing.The average age is 32.3.All subjects had a normal somatic neurological examination and no history of mental or cognitive dysfunction.They were additionally evaluated with MMSE, Stroop test and alternating pattern sketches,another test of Luria’s,evaluating the dorsolateral cortex.Afterwards, the alternating pattern of three movements, alternating one hand between a flat hand,a fist and the side of the hand on the other palm was shown five times and then the patient was asked to repeat the sequence three times.After a distraction lasting about two minutes the patient was asked to repeat the sequence once again. Results: Of the subjects tested so far,9 (14 %) showed dysinhibition,i.e started the sequence before the examiner had stopped showing; 11 (17.5 %) missed one or more movements,7 (11 %) repeated a movement instead of going to the next,and 16 (25 %) mixed the movements and forgot the correct sequence at least once.After the two minutes almost all remembered the movements and only five (8 %) made mistakes. Conclusion: Our study is continuing but from our resuits so far, it seems that the bedside tests for evaluation of specific cognitive functions must be standardized with specific instructions and at least a 10 % of the normal population show minor deficits in the test but no major mistakes.Standardized, this test can become a more valuable tool in neurology practice. P278 Hashimoto’s encephalopathy in Mexico City J. I. Castro-Macias Instituto Nacional de Neurología (Mexico City, MEX) Introduction: In 1966 a patient was described with Hashimoto’s Disease and encephalopathy. During the last 35 years 105 patients have been reported with Hashimoto’s encephalopathy. There are two clinical types: vasculitic, with multiple stroke-like events, and diffuse progressive, characterized by a stepwise mental dysfunction. Both types can be associated with stupor or coma, tremor, seizures, and myoclonus. The diagnosis is based on the elevation of anti-thyroid antibodies and clinical data. The existence of this disorder has been questioned due to the high frequency of elevated anti-thyroid antibodies in asymptomatic persons. Objective: To report the diagnosed cases in the National Institute of Neurology and Neurosurgery in Mexico City in last 5 years based on the clinical and paraclinical criteria previously mentioned. Results: Case 1 27 yr woman. In June 2005 she presented with stepwise memory, executive and language functions deterioration. Clinically with hyperreflexia, bilateral Trömner and Hoffmann and distal fine tremor. Lumbar

puncture and brain MRI were normal. EEG showed generalized dysfunction. Thyroid function tests: free T4 64.1 pmol/L, FTI 26.4, free T3 14.0 pmol/L, TSH 0.0 µIU/mL, anti-TPO antibodies 26.6 IU/mL. Therapy: metimazol, prednisone and propranolol, observing slow improvement until she reached her basal status prior to disease onset. Case 2 46 yr woman. In August 2000 she presented with stepwise mental functions impairment mainly memory and temporospatial orientation, besides generalized epilepsy and distal upper extremities tremor. EEG showed generalized disorganization. Lumbar puncture and brain MRI were normal. Thyroid function tests were normal with positive anti-thyroglobulin and anti-peroxidase antibodies. Treatment: prednisone and propranolol with slow clinical improvement until she reached her basal status prior to disease onset. Last thyroid function tests: T3 1.2 ng/mL, T4 9.3 µg/dL, and TSH 3.66 µU/mL. The main follow-up was 24 months. Conclusions: We report these cases of well documented Hashimoto’s in Mexico City. We believe these are the first reported cases in Mexico with a follow-up long enough to describe the reversibility of the disease and the recovery of normal EEG pattern. P279 Pathogenesis of transient global amnesia – a psychological clinical study leads to a new hypothesis M. Fischer, T. Dressen, J. R. Jörg Helios Klinikum Wuppertal (Wuppertal, D) Objectives: Despite several new hypotheses concerning transient global amnesia (TGA) pathogenesis, especially a possible venous congestion in memory relevant structures due to insufficient jugular vein valves, there is no consensus about the origin.We performed a retrospective clinical study with TGA patients and TIA patients as control group to evaluate the hypothesis of special personality traits as predisposing factors for TGA. Methods: All TGA and TIA patients we treated in our hospital the last three years have been invited. 28 TGA (female 12, male 16) and 25 TIA patients (f:9, m:16) could be examined with standardised psychological test scales (among others: MINI-DIPS, nosologic diagnostic of psychiatric disturbances). Results: At 67.9 % of the patients with TGA we found indications for the prevalence of depressive disorders at the time of TGA onset, whereas only 12.5 % of TIA patients showed depressive disorders (highly significant p < 0.001).We found no difference in other psychiatric disorders between the groups. Conclusion: Our study indicates, that depressive disorders could be a predisposing factor to develop a TGA. We discuss, whether a dysbalance in hippocampal neurotransmitters could be the pathogenetic correlate causing or favouring the occurrence of a TGA. P280 Vitamin B12 and folate serum concentration in patient with presenile and senile dementia Alzheimer type W. Wierzba, G. Opala, S. Ochudlo, M. Smilowski, J. Siuda, M. Swiat Medical University of Silesia (Katowice, PL) Background: There are different opinion relating to the serum level of cobalamin and folate in dementia. Two forms of Alzheimer Disease were distinguished: Presenile Dementia Alzheimer Type; PSDAT – before the age of 65; and Senile Dementia Alzheimer Type; SDAT – after the age of 65. The aim o the study was to assess the serum level of cobalamine and folate in patients with PSDAT and SDAT in comparison to the control group, as well as the correlation between serum level of the vitamins and sex, age, degree of dementia, duration of the disease and morphological parameters. Methods: 43 patients (32 woman and 11 men) with Alzheimer disease were involved to the study. 38 patients without dementia symptoms were the control group. Results: Analyzing the average serum level of cobalamin in patients with PSDAT and SDAT, the lower serum level was observed in SDAT (273.73 pg/ml), in comparison to PSDAT (381.76 pg/ml); (p = 0.0391). Analyzing the serum level of folate, there was no difference between patients with PSDAT and SDAT. (SDAT –8.22 ng/ml, PSDAT –8.54 ng/ml, p = 0.26). Conclusions: The differences between serum level of Vitamin B12 in PSDAT and SDAT might suggest a different neurodegenerative patomechanism of PSDAT and SDAT.

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P281 Reversible cognitive impairment with confusional state as the predominant manifestation of hyperparathyroidism. Report of a clinical case C. Zuliani, P. Boni, A. Panico, C. Fattorello Salimbeni Operative Unit of Neurology (Mirano, I); Service of Neurology (Noale, I)

P283 An unusual but potentially treatable cause of cognitive impairment: relapsing polychondritis E. Karakoc, E. Tan, G. Gedikoglu, K. Selekler Hacettepe University (Ankara, TR)

Primary hyperparathyroidism (PHP) is a not uncommon disease in the elderly, and its incidence increases with age, with a reported prevalence of 3 % for women and 1 % for men in subjects aged 65 years and over. In the young subjects is instead certainly less considered and underestimated. Central and peripheral nervous system may be involved, and in literature are reported cases with a dementia like state. This report refers to a relatively young (58-year-old) hypertensive woman, admitted to our Operative Unit with a 2 months history of progressive cognitive impairment, accompanied during the last days by confusional state. Complete Neuropsychological assessment with Spinnler battery pointed out severe cognitive impairment, with temporal-spatial disorientation, deficit of attention, concentration and severe involvement of verbal, spatial and non verbal memory. Brain magnetic resonance images (MRIs), Cerebrospinal Fluid (CSF) examination and Densitometry evaluation of radius were normal, as CSF level of 14–3–3 protein detected by western blotting and Tau proteins determinated by ELISA, while EEG showed generalized abnormalities represented by subcontinuous theta-delta activity, above all on the fronto-temporal regions. Biochemical screening revealed more than once a significant hypercalcemia (3.34, 3.50 mmoli/L, with normal values ranging 2.15–2.50), associated with increased parathormone levels (237 pg/ml, with normal values ranging 12–65). Parathyroid scintigram was performed to confirm the diagnosis of PHP, showing the presence of a parathyroid adenoma. Patient underwent i. v. hydratation (2500 cc/die), Pamidromic acid and loop diuretics treatment, with a progressive normalization of calcium level and a dramatic improvement in mental status. Patient is in any case waiting for surgical treatment. Neuropsychologic retesting two weeks later showed her to be well oriented to time, place and person, with mild impairment of attention and concentration, and also EEG control normalized. Our case highlights the importance of considering PHP as the cause of onset of neuropsychiatric disorders also in non elderly patients. Because these disturbances can respond favourably to medical or surgical treatment, in our opinion the clinician must systematically look for PHP in patients of any age who exhibit symptoms of cognitive impairment.

Objectives: Relapsing polychondritis (RPC) is a rare multisystemic, episodic and progressive inflammatory disease affecting primarily cartilaginous (ear, nose, larynx, trachea, bronchi, and joints) and proteoglycan-rich structures (eyes, aorta, heart, and skin). The diagnosis of this potentially fatal disease of unknown etiology is based on the clinical criteria. Methods: A 56-year-old male patient, who was admitted to our center with a four-week history of acute onset encephalopathy, had been suffering from recurrent episodes of fever, headache, vertigo, nausea, vomiting together with redness and swelling in both auricles, and symmetrical swelling of the small joints of both hands for the last 10 months. Additionally, he experienced two brief attacks of difficulty in speech, numbness and myokymia on the left side of the face. On admission, he was in a delirious state manifesting with disorientation to time and place, alternating periods of stupor, psychomotor agitation or sometimes retardation, personality changes, uncontrolled inappropriate laughter or crying along with dysphasia, echolalia, frequent incontinence, symptoms of vestibular dysfunction and impaired hearing. Past medical history included pain-swelling-redness in knee joints 10 years ago and in small hand and wrist joints 4 years ago in addition to history of gastrointestinal system bleeding, hypertension, type 2 diabetes mellitus, hyperlipidemia. Laboratory investigations revealed increased sedimentation rate, hyperglycemia, glucosuria, and proteinuria. Cerebrospinal fluid examination revealed lymphocyte predominant cellular material, and slightly increased protein, glucose, and lactate levels. Other investigations including the neuro-imaging were unremarkable. However, bilateral mild sensory-neural hearing loss, moderate and widespread EEG abnormality characterized by slow waves, and inflammatory reaction demonstrated in the cartilage and connective tissues were the critical findings to support the clinical diagnosis of RPC. The clinical picture was resolved under cyclophosphamide and prednisolone treatment. Conclusion: The uncommon occurrence of this entity with variable clinical patterns, course and response to therapy adds up on the unknown etiopathogenesis of RPC. However, it is a well-known fact that the diagnosis of an unusual but potentially treatable (or lethal) cause of cognitive impairment may be available with the clinician’s physical examination.

P282 Brain diffusion tensor imaging and central motor conduction time studies in elucidating the pathological basis of fronto-temporal dementia A. Cifelli, N. Bajaj, D. Auer, P. Choudhary Queen’s Medical Centre (Nottingham, UK) Objective: We assessed the potential of brain DTI and CMCT studies for investigating the pathological basis of FTD in a single case. FTD is a condition with a variable histopathological basis. The clinical manifestations of the pathological changes, e. g. amyotrophy or parkinsonism, can take up to 2 years to appear after onset of dementia. DTI and CMCT are proving to be useful indicators of subclinical corticospinal tract involvement in cases of possible amyotrophic lateral sclerosis (ALS), but their utility in investigating the pathological substrate of FTD has not been explored yet. Methods: A 54-year-old gentleman presented with a 16 month history of dysarthria, dysphagia, forgetfulness, emotional lability, and personality change. There was no relevant past medical or family history. Clinical exam showed reduction in verbal fluency, concrete thinking and poor performance on Lurias fist-palm-side test. His tongue was not wasted but very slow. A pout reflex was present. Mild distal upper limb and proximal lower limb weakness were noted. Reflexes were pathologically brisk with extensor plantars. No fasiculations or limb wasting was seen. Results: Laboratory workup was normal. Neurophysiology revealed neurogenic changes in the limbs with normal tongue EMG. CMCT was delayed from the lower limbs. Conventional brain magnetic resonance imaging (MRI) showed moderate atrophy of temporo-polar and frontal cortices with right-sided predominance. On DTI there were marked reductions in fractional anisotropy in the subcortical and deep white matter of the temporopolar regions, and in the subcortical white matter along the motor cortex. Conclusions: While the potential of DTI and CMCT for an early diagnosis of ALS has been recognised, we believe this to be the first case described where DTI and CMCT have been employed in elucidating the pathological basis of a case of FTD.

P284 Reducing rightward bias of neglect patients by postural manipulation A. Saj, C. Richard, J. Honoré, T. Bernati, M. Rousseaux CHRU, Hopital Swynghedauw and EA 2691 (Lille, F); UMR 8061 CNRS, Université de Lille II (Lille, F) Background: The subjective straight ahead (SSA), a measure of the representation of body orientation, has been shown to be shifted to the lesion side in neglect patients. This deviation can be influenced by vestibular or somatosensory stimulation, but nothing is known about the influence of body positioning Objective: To investigate the influence of body posture changes in the sagittal plane. Methods: Twenty-one patients with right hemispheric lesion, of whom 12 had neglect, were compared to six healthy controls. We used an original method, requiring alignment of a luminous rod defining the SSA, to quantify both horizontal components of the SSA error, i. e. the lateral shift and rotation. Results: Neglect patients showed a significant rightward shift in sitting position, which was greatly reduced in supine position. No shift occurred in patients without neglect and controls. Rotation was absent in the three groups and was not influenced by positioning either. Conclusions: The results confirmed that translation but not rotation of the SSA is a frequent problem of neglect patients, and showed that this translation can be strongly reduced in supine position. Thus, body positioning seems to be a convenient tool to improve the representation of body midline position, and its influence could also be analyzed in daily living tasks.

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P285 The deviation of the subjective vertical of neglect patients is increased by hemianopia and in neglected space A. Saj, J. Honoré, T. Bernati, M. Rousseaux CHRU, Hopital Swynghedauw and EA 2691 (Lille, F); UMR 8061 CNRS, Université de Lille II (Lille, F) Background: The perception of the vertical is frequently impaired in patients with hemispheric lesions, and this is amplified in the case of spatial neglect. Objective: To analyse the influence of additional hemianopia and of egocentred space. Methods: Twenty-four patients with right hemispheric stroke were included. Fifteen had a left neglect according to their score in standard visuospatial tests, seven presented hemianopia (N + H +) and eight did not (N + H-). Control groups consisted of nine patients without neglect or hemianopia (N-H-) and eight healthy control subjects (C). The task consisted in adjusting a luminous rod to the vertical, whose rotation axis was located either in the median sagittal plane of the subject, or at 15 cm on the right or the left. Results: The three groups of patients showed a counter-clockwise deviation of the perception of the vertical, larger when neglect, and more so in hemianoptic ones. This deviation was significantly increased in the left space in neglect patients, with or without hemianopia. Furthermore, several patients with neglect and hemianopia also showed a reduction of the disorder in the right space. Conclusion: The influence of hemianopia and of egocentred space justifies taking them into account in the assessment of the deviation of the subjective vertical in neglect patients. P286 Involuntary emotional expression disorder in dementia patients R. Richter, B. Richter, A. Corman, U. Calef University of Oklahoma (Tulsa, USA); Tulsa Clinical Research, LLC (Tulsa, USA); Strategic Science Communications (Laguna Beach, USA) Background: Involuntary Emotional Expression Disorder (IEED) is characterized by episodes of disinhibited crying and/or laughing in patients with various neurological disorders. It has been referred to as pseudobulbar affect (PBA), emotional lability, pathological laughing and crying, and disinhibition syndrome. IEED in clinical practice is frequently overlooked. Pathophysiology: IEED involves lesions in the motor cortex and in the connections to the pyramidal system with the corticospinal area and corticopontine pathways. These lesions seem to “disinhibit” or “release” the laughter and crying centers of the brain. Prevalence: Prevalence data for IEED are limited and vary widely in Alzheimer’s disease (AD) and other dementias. The symptoms of the disorder are associated with certain stages (mainly later) of AD for example. IEED can also be observed in patients with ALS, MS, stroke, head trauma and Parkinsons’ disease. An association with neurotoxic syndromes after chemotherapy has also been observed. Clinical Experience: In our Clinical Research Center over a time period of 24 months we have carefully examined and treated 33 patients with IEED. Outbursts of crying or laughter or mixed episodes are generally inappropriate to context and can easily be misinterpreted or wrongly attributed to other conditions, such as depression or severe pain states. Although sometimes triggered by minor emotional issues/events, the threshold for response is considerably diminished. IEED in dementia is somewhat atypical relative to other neurological conditions, in that there is a broader loss of emotional regulation. In these patients, outbursts of irritability, frustration and anger are often intertwined with irresistible laughing/crying. Diagnosis can be facilitated by clinical observations and interviews. Validated measurement scales are also available. In dementia patients caregiver input can be of vital importance. Conclusion: IEED when thought of can frequently be observed in clinical practice, particularly in the context of dementias syndromes as well as certain other neurological illnesses. Clinicians should be aware of this debilitating and frequently overlooked pathological neurologic condition. Correct diagnosis of IEED is critical in view of promising novel treatments currently under investigation in clinical trials. Research support has been received from Avanir Phrmaceuticals.

P287 Isolate progressive visuospatial dysfunction: a new form of MCI? V. Navarra, C. Cupidi, T. Piccoli, F. Piccoli Neurology Unit (Palermo, I) Background: High order visuospatial deficit as onset of a neurodegenerative dementing disease has been reported. However, this initial focal symptom usually spreads to a more generalized cognitive impairment. Objective: To report on a patient with a six years long history of progressive visuospatial dysfunction that has remained clinically isolated. Case report: A 57-year-old right-handed man was referred to our hospital because he has experienced some difficulties in tasks requiring visuospatial information for 5 years. In particular he complained an impairment in calculating and in constructional abilities, as joinery or graphic works. At the same time he presented problems in spatial and topographical orientation and in retrieving past events. The symptoms had an insidious onset and a slow evolution during the years. After 3 years from onset, brain MRI showed atrophy in posterior cortical areas. Similarly brain SPECT showed hypoperfusion of the posterior parietal areas, particularly to the right.At admission, neurological examination was normal but the patient showed a cognitive impairment limited to visuospatial abilities. Biochemical workup and CSF analysis were normal. Neuropsychological examination demonstrated acalculia, constructional apraxia and deficits in visual attention, visuospatial memory, spatial perception and difficulty with time relationships. Other cognitive domains such as verbal memory and executive functions as well as visual perception, were normal. At 1-year follow-up, the patient reported an increasing inability in tasks requiring visuospatial manipulations, as to watch the clock and to tidy up the books in the bookcase. Cognitive pattern was similar except for a worsening of visuospatial functions and a mild impairment of lecture. However a normal level of functioning in social and occupational activities and in personal care excluded diagnosis of dementia according to DSM-IV criteria. Brain MRI and PET again showed a selective involvement of posterior parietal cortex, although the degree of atrophy and hypometabolism in these regions was larger than previous. Conclusions: We describe a patient with a non-dementing cognitive decline restricted to visuospatial functions due to a selective degeneration of parietal cortical areas. We suggest that this is an atypical form of MCI. P288 Emotional instability localised by FDG-PET in patients with multiple sclerosis J. Koehler, C. Büscher, H-G. Buchholz, M. Schreckenberger Johannes Gutenberg-Universität (Mainz, D) Introduction: Since 1881 different groups tried to allocate emotionality to one definite hemisphere. Gainotti found an increased emotionality in patients with left-sided hemispheric lesions. In contrast Sackheim attached positive emotion to the left and negative emotion to the right hemisphere. Our study focused on detecting an possible impairment of glucose metabolism by FDG-PET in 11 patients with newly diagnosed definite multiple sclerosis (MS) in correlation with the dimensions of the personality evaluated by the “Fribourg Personality Inventory” (FPI) Methods: Twelve dimensions of the personality were evaluated by the FPI in 11 patients with newly diagnosed definite MS. Within one month after diagnosis the glucose metabolism of the brain was investigated by FDG-PET. Afterwards the local cerebral glucose metabolism were correlated with the parameter-value of the dimensions by SPM99(Statistical Parametric Mapping). Results: SPM-analysis showed a significant negative correlation of the glucose metabolism at the insula (p = 0.01) with the dimension “emotionality”evaluated by FPI. Patients with high values in the FPI, which corresponds with emotional instability, increased sensitiveness and anxiety showed a reduction of the glucose metabolism in the cortex of the insula in both hemispheres with accentuation of the right.All other dimensions tested by the FPI showed no correlation with the FDG-PET. Discussion: The insula is known as an important part of the brain which is responsible for emotional processing. Therefore bilateral reduction of the glucose metabolism in these areas correlates with an increased emotional instability. Acceleration of the right hemisphere could be point to a partial lateralisation of the dimension “emotionality” in our patients. In contrast to previous studies we could found a reduction of glucose metabolism. Emotional instability in our patients could be triggered by emotional stress related to the newly diagnosed definite MS and lead to a local decrease of glucose metabolism.

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Objectives: Stroke is a commen cause of epileptic seizures in adulthood. To determine the risk profile of early epileptic seizures (EES, occuring within 14 days after acute stroke we looked for associated electroencephalografic, clinical and ct-morphological parameters. Methods: In a prospektive study we examined 173 patients with supratentorial stroke (and without epileptic seizures or further strokes in their former history.th On day 1 a brain computed tomography (CT) including cerebral angiography (CTA)and clinical examination were performed. Patients with an intracerbral haemorrhage (ICH) as well as with ischaemic infarction (II)were included. Electroencapholography (EEG) was performed within 48 hours after stroke-onset und brain magnetic resonance imaging (MRI) after 8 days. Results: 12 patients suffered from ICH, 151 from II.Early epileptic seizures occured in 7 patients:2 of them in ICH-, 5 in II-patients.In three of the II-patients with early epileptic seizures we found a stenosis or occlusion of the middle cerebral artery (MCA), whereas there were only seven findings of MCA-stenosis in the II-patients without early epileptic seizures. Conclusions: The total number of EES after stroke (as well II as ICH) in our collective fits to the results known from literature. The high number of MCA-Stenosis in the II-group with EES was a new finding, which hasn’t been described before. Maybe a locally decresased cerebral bood flow (CBF)may play a role in the development of seizures. Furthermore this mechanism could explain some of the seizures occuring before cerebral infarction, described by other authors and called “vascular precursor epilepsy) We thank the Paul Kuth Stiftung for supporting our project

both partial as well as independent generalized seizures. Patients received OXC as add-on therapy to 1–4 (mean 2) anticonvulsants.We compared mean seizure frequency for a 3-month period prior to and 12 months after introduction of OXC. All subjects had physical and neurological examinations, routine baseline hematological, biochemical, and urinary investigations at entry. Results: Two patients (10 %) became seizure free. Four patients (20 %) had seizure reduction by 75 % or greater. Two patients (10 %) had seizure reduction by 50–74 %. Seven patients (35 %) had no significant change from baseline and two patients (10 %) worsened. Oxcarbazepine was discontinued in 3 patients representing a withdrawal range of 15 %. Seizure free patients required an average of 1200 mg (range: 600–1800 mg) of OXC as daily adjunctive therapy. Maximum doses ranged from 600 to 2700 mg daily. The reason for discontinuation of OXC in all patients was lack of tolerability. An overall reduction of 32.4 % on the number of concomitant antiepileptics was achieved after the addition of OXC. Diplopia (15 %), dizziness/ataxia (15 %), rash (10 %), behavioral/psychiatric side effects (10 %), cognitive impairment (10 %) and numbness (10 %) were the most frequently reported side effects. Also noted (5 %) were weight changes, urinary frequency, elevated cholesterol levels, dysphagia, increased intraocular pressure, abdominal discomfort, headache and gelastic spells. No patient showed significant changes from baseline hematological and urinary parameters. Conclusion: Our results show that OXC was effective in focal epilepsy as demonstrated by significant reduction of seizures. A substantial rate of our population of pharmacoresistant cases became seizure free. The patient with both partial- onset and generalized seizures got worse after the addition of OXC. 40% of our patients with treatment resistant epilepsy experienced a reduction of 50 % or more in their seizure frequency with the addition of OXC. It was generally well tolerated by patients in all age groups, with only 15 % of patients discontinuing the study due to adverse drug reactions.

P290 Efficacy and safety of levetiracetam (Keppra) add-on treatment in an openlabel trial in adult patients with refractory epilepsy E. Auriel, V. Chistik, I. Blat, N. Margolin, M. Neufeld Tel Aviv Souraski Medical Center (Tel Aviv, IL); Sheeba Medical Center (Tel Aviv, IL)

P292 Vagus nerve stimulation therapy in a pharmacoresistant epileptic population in Cyprus P. Myrianthopoulou, A. Dietis, S. Papacostas The Cyprus Institute of Neurology & Genetics (Nicosia, CY); Nicosia General Hospital (Nicosia, CY)

Background: Levetiracetam, (LEV) is a new generation anti-epileptic drug, which has been approved as an add-on therapy for partial epilepsy. The mechanism of LEV is not yet completely understood. Aim: To evaluate the efficacy and tolerability of LEV in adult patients with refractory epilepsy. Methods: We report the results of 49 patients with refractory focal and generalized epilepsy who received LEV as an add-on treatment in an open uncontrolled trial, in two tertiary medical centers. There were 27 males, mean age 35.4 + 13 years. The average duration of epilepsy was 21 + 11 years, the average frequency rate was 31 + 30 seizures per month. The patients were treated with a mean of 2.6 AED before LEV was introduced. The patients were treated for 12.6 + 9.7 months with an average dose of 1964 + 1941 mg LEV. Results: Five (10 %) patients became seizure free, 12 (25 %) responded with seizure reduction more than 50 % following the introduction with LEV, 7 (14 %) responded with seizure reduction less than 50 %, no response to LEV was reported in 20 (41 %) and seizure aggravation was noted in 4 (8 %). No serious persistent adverse events were reported. The main side effect was drowsiness in 10 % of patients. Conclusion: From the results of our study, as well as previous studies, it is suggested that LEV is a well-tolerated new antiepileptic drug, and as an add-on therapy may effectively improve seizure control in patients with intractable focal and generalized epilepsy.

Objective: This retrospective study documents the outcome of intermittent vagal nerve stimulation (VNS) in 12 patients (pts) with medically intractable epilepsy. Method: Records of patients implanted for 1 year or longer were reviewed for changes in seizure frequency (SF). Length of the follow-up averaged 25.5 months (range 12 months – 3.3 years). The age range was 17–55 years. There were nine males and three females. Patients were divided into 2 categories (CAT): CAT1 (8pts) without change or/and decrease in antiepileptic drugs (AEDs) and CAT2 (4 pts) with AED dose titration or addition of another AED. Patients were further divided into 4 groups (G) regarding their response to VNS: G1: > 75 % seizure reduction (SR), G2: 50–74 % SR, G3: 25–49 % SR, G4: 0–24 % SR. Results: The percentage change in SF in both groups,from the time of implantation until the time of the study, was the following; G1: 1 pts, G2: 6 pts, G3: 2 pts, G4: 3 pts. 58 % of the patients had a 50 % or more decrease in SF. Changes in SF at 1 year of VNS therapy placed the patients of both categories into the following groups: G1: 0 pts, G2: 5 pts, G3: 2 pts, G4: 5 pts. Comparing the results of 1 year VNS therapy to those of the total follow-up time a progressive decrease in SF was noted. Results of the changes in SF of CAT1 patients at 1 year of VNS therapy were as follows: G1: 0 pts, G2: 4 pts, G3: 2 pts, G4: 2 pts. CAT2 results were the following: G1: 0 pts, G2: 1 pts, G3: 2 pts, G4: 1 pts. 43 % of CAT1 had a 50 % or more reduction in SF after one year of VNS therapy. The average decrease in SF in this group was 39 %. An average of 53 % decrease in SF was seen in CAT2 group patients after 1 year of VNS therapy. Comparing the results of the follow-up VNS therapy to those of 1 year VNS therapy, a progressive increase in the effectiveness of VNS therapy was noted over time for all patients. There was a 9 % increase in effectiveness for CAT1 patients and a 5 % increase for CAT2 patients. CAT2 included three of the most intractable patients in the study, which required AED manipulations. No patients in any group became seizure free. No patient’s SF worsened with VNS therapy. Conclusion: Our study showed a progressive increase of VNS therapy effectiveness over time for all patients. These results confirm those reported in other populations.

Epilepsy P289 Is stenosis of the middle cerebral artery associated with a higher risk of early epileptic seizures after cerebral infarction? C. Muhl, B. Böger, U. Kempkes, K. Klausa, E. Seidel, R. Zijderveldt, J. R. Jörg Helios Klinikum Wuppertal (Wuppertal, D)

P291 Efficacy and tolerability of oxcarbazepine during one-year follow-up as add-on therapy in patients with treatment-resistant epilepsy E. Kkolou, K. Kleopa, S. Papacostas The Cyprus Institute of Neurology and Genetics (Nicosia, CY) Objectives: To investigate the efficacy and tolerability of Oxcarbazepine (OXC) as add-on therapy in Cypriot patients with treatment- resistant seizures. Methods: Twenty patients, ages 12–71, were studied retrospectively for a 12 month period. All patients had partial onset epilepsy. One patient had

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P293 Early seizures after ischaemic stroke E. C. Mateiescu, D. Popoviciu, M. Schiopu, G. Iavorenciuc County Hospital Targu Mures (Targu Mures, RO) Objectives: To assess the incidence of early seizures (ES) after ischemic strokes (occuring within the first 48 hours after stroke onset) and correlations between ES and stroke location, gender, age, mean lenght of hospitalization, in-hospital mortality and laboratory data. Methods: Data of 1117 ischemic stroke patients admited consecutively at 2nd Department of Neurology County Hospital Tg-Mures Romania between January 1, 2004 and December 31, 2005, from registry of patients admissions – retrospective study. Subjects with hemorrhagic stroke or previous history of epilepsy were excluded. Seizure type was classified acording to International League Against Epilepsy (ILEA) criteria. Neurological exam, computer tomographyc scan (CT), electroencephalography (EEG), laboratory data (plasma ureea, creatinine, glucose, electrolyte levels) were performed. Demographic, neurological and neuroimaging variables in the seizure and nonseizure group were compared using the chitest. Results: ES were diagnosed in 17 patients (1.52 %). Of the 17 patients, 7 had generalized tonic-clonic apparently without a focal onset, one had secondary generalized partial, 7 patients had simple partial seizures, one had status epilepticus and in one, the type of seizures could not be defined. EEG was obtained within the first week after stroke in all patients with seizures. One EEG was normal. The other EEGs were abnormal. Showing mild nonspecific changes in 3 patients, focal showing in 13 (including 5 with irritative morphology). CT was performed in 1028 patients (92.03 %), in acute stage (first 48 hours). We founded middle cerebral artery teritorry lesions in 9 patients with ES and 412 without ES, vertebrobasilar territory lesions in 3 patients with ES and 95 without, and 6, respectively 496 patients, had no identificable lesions on CT scan. No one of 12 patients with anterior cerebral territory lesions presented seizures. ES were not significantly more frequent in men patients than women patients.The in – hospital mortality rate was 0 in seizure group and 5 % in the nonseizure group. Conclusions: Comparing the seizures group with nonseizures group we could not find any correlation between occurence of early seizures and stroke location, gender, age, mean lenght of hospitalization, in-hospital mortality or laboratory data. Much additional work is needed to better understand the epidemiology of postischemic stroke seizures for a good prevention and optimal management. P294 Television and computer screen stimulation and photosensitivity in EEG in juvenile myoclonic epilepsy G. Gelziniene, M. Endziniene, G. Jurkeviciene, N. Vaiciene Kaunas Medicine University Hospital (Kaunas, LT) Objective: The purpose of the study was to evaluate the seizure provocative factor of TV and computer screen stimulation and to compare it with photosensitivity registered on EEG in patients with juvenile myoclonic epilepsy (JME). Methods: 60 cases, 27 (38.3 %) boys and 37 (61.7 %) girls with diagnosis of JME were identified at the Child Neurology Unit, Kaunas University Hospital in 2003–2004 and were studied retrospectively. The mean age at seizure onset was 11.22 ± 3.6 years, and the mean age of patients at evaluation was 14.4 ± 2.45 years. We analyzed seizure precipitants reported by the patients as well as their EEG data. Intermittent light stimulation was done with Micromed computerized program with maximal frequency 24 Hz for 4 minutes. Eye opening-closure test was performed in addition. Statistical correlation between TV and/or computer screen stimulation and photosensitivity in EEG was evaluated using chi-square criterion. Results: Seizure precipitants were detected in 39 (65 %) cases: TV or computer screen stimulation precipitated seizures in 19 (31.7 %) cases, lack of sleep – in 15 (25 %), fatigue – in 11 (18.3 %), stress – in 10 (16.7 %), and 2 (3.3 %) patients had reported other precipitating factors such as hunger or sunbathe. During EEG registration photosensitivity to intermittent light stimulation was detected in 15 (25 %) cases. Generalized spikes or polyspikes during eye closure phase in eye opening-closure test were detected in 5 (8.3 %) cases.We found no correlation between provocative factor of TV or computer screen stimulation and photosensitivity to intermittent light stimulation or eye opening – closure test on EEG, while positive eye opening-closure test demonstrated significant correlation with photosensitivity during intermittent light stimulation. Provocative factor of TV or computer correlated with gender of patients and was more frequent in boys (p < 0.005). No gender correlations were found with photosensitivity on EEG. Conclusions: TV and/or computer screen stimulation was the most common seizure precipitating factor in young patients with JME. No correlation between TV and/or computer seizure precipitation and photosensitivity on

EEG was detected. Intermittent light stimulation longer than the usual 4 minutes and frequency up to 60Hz may be necessary to detect photosensitivity in patients with seizures precipitated by TV and/or computer screen stimulation. P295 The Corpus callosum in patients with interictal schizophrenia-like psychosis: a diffusion tensor imaging study D. Fluegel, M. Koepp, M. Cercignani, M. Symms, J. Foong Kantonsspital (St Gallen, CH); The National Hospital of Neurology and Neurosurgery (London, UK) Objectives: To explore the integrity of the corpus callosum in patients with interictal (schizophrenia-like) psychosis. Methods: DTI was performed in eighteen patients with temporal lobe epilepsy (TLE) and interictal psychosis and twenty TLE patients without psychosis. Regions of interests (ROI) of standard size (28 mm2) were outlined on the non-diffused weighted (b = 0) images in the splenium and genu of the corpus callosum showing maximal corpus callosum thickness. DTI images were coregistered with the b = 0 images and the ROIs were automatically transferred to the corresponding mean diffusivity (MD) and fractional anisotropy (FA) maps to obtain average values. Results: No significant differences of FA and MD neither in the genu nor in the splenium of the corpus callosum could be detected comparing the psychotic with the non psychotic group. Conclusion: While in patients with chronic schizophrenia reduced FA has been found in the splenium indicating disruption of the fibre tracts the corpus callosum seems to be unaffected in interictal psychosis. In spite of clinical and neuropsychological similarities of schizophrenia and interictal psychosis there might be different underlying structural abnormalities. This study was supported by the Big Lottery Fund (RG/1/010026026) P296 In vivo positron emission tomography study of the mutated a4b2 nicotinic receptors using [18F]-A-85380 in patients with autosomal dominant nocturnal frontal lobe epilepsy F. Picard, D. Bruel, D. Servent, D. Roumenov, E. Brodtkorb, S. Zuberi, A. Gambardella, B. Steinborn, A. Hufnagel, H. Valette, M. Bottlaender University Hospital of Geneva (Geneva, CH); Service Hospitalier Frédéric Joliot (Orsay, F); Laboratoire de Biochimie des Protéines (Saclay, F); St Olav’s Hospital Trondheim University Hospital (Trondheim, N); Royal Hospital for Sick Children (Glasgow, UK); University Magna Graecia (Catanzaro, I); University of Medical Sciences (Poznan, PL); University of Essen (Essen, D) Objectives: Mutations in the a4 or b2 nicotinic receptor subunits have now been identified in twelve families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Electrophysiological studies of the receptors carrying the different mutations identified a common alteration in their properties, corresponding to a gain of function. However the precise mechanisms leading to the frontal lobe epilepsy remain elusive. Studies of the distribution of the mutated a4b2 receptors in ADNFLE patients would constitute an important step in the understanding of ADNFLE pathogenesis. Methods: The distribution of a4b2 nicotinic receptors was studied in ADNFLE patients carrying a nicotinic receptor mutation, by a PET-scan using [18F]-F-A-85380, a ligand with a high affinity and specificity for a4b2 nicotinic receptors. Eight epileptic patients participated to the study. Causative mutations were: a4-S248F (four patients), a4-S252L (one patient), a4-T265I (one patient) and b2-V287L (two patients). Regional brain concentrations of the radiotracer in the ADNFLE patients were compared with those obtained in a group of seven control subjects. Parametric images of volume of distribution (Vd) were generated using the unchanged plasma input function. Results: The pattern of the brain distribution of the radiotracer was found clearly different in the ADNFLE patients when compared to the control subjects. The Vd calculated on several brain regions delineated on individual MRI of patients with ADNFLE and of control subjects revealed a significant increase (between 12 and 21 %, P < 0.05) in the patients in the mesencephalon, the pons and the cerebellum. Statistical parametric mapping (SPM) confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In 5 patients who underwent an additional [18F]-fluorodeoxyglucose PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. Conclusion: ADNFLE mutations of the nicotinic receptor subunits appear to modify the level and pattern of a4b2 nicotinic receptor expression in the living human brain. This finding might bring new insights in the under-

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standing of ADNFLE pathogenesis. In particular, we propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal. This work was supported by the Swiss National Foundation n°3100A0–104190/1, the DRRC Assistance Publique des Hôpitaux de Paris and Sanofi-Aventis. P297 Psychological evaluation of quality of life in seizure-free epileptic patients M. Coletti Moja, M. L. Genesia, S. Gasverde, A. Rovera, M. Agnesone, L. Ostacoli, P. M. Furlan, L. Durelli Ospedale S Luigi Gonzaga (Orbassano, I); University of Torino (Orbassano, I) Epilepsy is a neurological disease that has a great chronic impact on the life of affected. People affected by epilepsy are mostly young, the nature and the course of the disease is unpredictible, seizures can cause loss of consciousness and the diagnosis has sometimes a stigmatizing nature. In recent years there has been a growing interest in understanding how epilepsy and its treatment affect quality of life of patients. The Quality of Life (QoL), together with usual outcomes used in clinical practice, including type, severity, frequency of seizures and adverse effects, is recognised as an important concept to understand the distress of epilepsy patients, even when seizures are well controlled. The purpose of the study is to investigate, by quantitative and qualitative measures, the psychological, social and physical aspects of the health related quality of life in patients suffering from epilepsy seizures-free during the past year and to identify patients who have a risk to develop an adjustment disorder. Moreover, to correlate QoL and INTERMED identifying patients at risk of poor QoL and high complexity of care. 50 patients free from seizures during the past year, aged 18–60, without evident cognitive deficits and 50 age-matched controls are enrolled in the present study. The patients are invited by their neurologist to have a clinical interview, lead by a psychologist, about multidimensional domains of quality of life, with particular attention to psychological aspects.According to the biopsychosocial model of disease, for all patients will be used also the INTERMED interview, an instrument to assess biopsychosocial factors of risk. At the end of the interview, QoL is assessed and quantified using a self-completion questionnaire, the Quality of Life in Epilepsy – 31 (QOLIE-31), a reliable, valid and sensitive measure of the impact of the disease in the daily life. CES-D and Zung Anxiety Scale are completed by patients, in order to determine the contributions of depression and anxiety on health related quality of life in epilepsy. Preliminary results show a good correlation between QoL test scores and seizure control. In conclusion psycopathological assessment is crucial in evaluating anti epileptic drug therapy benefits in addition to standard neurological evaluation and seizure control. P298 Oxcarbazepine as first or second-line monotherapy in partial epilepsy M. Rascheva, N. Koleva Tzaritza Joanna University Hospital (Sofia, BG) Objective: To evaluate the efficacy and safety of oxcarbazepine (OXC) as first or second line monotherapy in patients with recently diagnosed partial epilepsy. Methods: A prospective open-label observational study compares effectiveness of OXC treatment in 39 patients with uncontrolled epileptic seizures from their first antiepileptic drug (second line OXC monotherapy) with those of 13 patients with first-line OXC monotherapy. The patients were followed up 9–27 months (mean 18, SD = 9). Results: A total of 52 patients, 28 male, age 16–62 years (mean 32.2, SD = 15.1) were enrolled, 29 with simple partial seizures (SP), 23 – with complex partial seizures (CP), 35 of them – with secondary generalized tonic clonic seizures (SGTCS). The frequency of seizures varied between 1 and 24 per month (mean 7, SD = 6). Reason for switching to OXC, mainly from carbamazepine (in 51.3 %) and valproate (in 25.6 %), were lack of efficacy (in 94.9 %) and lack of tolerability (in 10.3 %).A flexible 3 to 5 weeks conversion period was followed by 36 weeks of maintenance treatment. The dose of OXC were 900 to 1500 mg/day (mean 1001.0 mg, SD = 115.9). In 23 (56.4 %) out of the 39 patients first AED could be successfully discontinued and they remained at OXC monotherapy. Reduction of seizure frequency more than 50 % was established in 95.7 % of them and seizure freedom – in 1/3. The patients left on OXC adjunctive therapy demonstrated also a good efficacy – a reduction of seizure frequency more than 50 % was observed in 68.8 % with 12.5 % being seizure free. The results of patients on first line OXC monother-

apy were the best – all of them were responders with 61.5 % seizure free. The most common drug related adverse events (dizziness, somnolence, fatigue and hadache) were mild, observed mainly during the titration phase, and more frequent in patients at add-on therapy (in 25 %) than at monotherapy (in 13 %). Conclusion: The study provides support for high antiepileptic efficacy and safety of OXC as first and second-line treatment in adults with partial epilepsy. With slow titration OXC has not been associated with severe adverse events.

Extrapyramidal disorders P299 Pregabalin as add-on treatment to botulinum toxin in idiopathic hemifacial spasm P. Urban University of Mainz (Mainz, D) Introduction: Botulinum toxin is the medical therapy of choice in HSF. However, in some patients, especially those with a long history of HFS and extensive spasms, the therapeutic effect of botulinum toxin is insufficient, due to a small therapeutic window associated with side-effects or recurring spasms. I report the cases of two patients with HSF who responded favourably to the therapeutic combination of pregabalin and botulinum toxin. Patients: Both patients had a longstanding history of HFS and were treated with botulinum toxin over a period of several years. In the last two years of therapy the facial spasms also involved the perioral muscles and were never sufficiently relieved by botulinum toxin, due to the fact that higher doses of the substance lead to adverse effects. Both patinets declined to undergo a neurosurgical intervention. The EDB test showed a decrease in the CMAP amplitude of > 60 percent.Without changing the botulinum toxin regime, pregabalin up to 150 mg twice daily was added for a 1-month trial period. The HFS subsided gradually over a 3-week period. After discontinuation of the drug at the end of the trial period, the symptoms recurred after ~4 weeks. Rechallange with pregabalin alone at a dosage of 300 mg/d over 4 weeks improved HSF but did not prevent the development of spasms. Botulinum toxin therapy was therefore resumed, while pregabalin treatment was continued in parallel. The spasms began to disappear after approximately one week using the combination therapy. Discussion: Gabapentin and pregabalin are known to bind to the alphadelta-subunit of the voltage-dependent calcium channels, which are also present in the facial nerve. Furthermore, pregabalin has been shown to have a higher affinity to the calcium channels compared to gabapentin. Following the administration of botulinum toxin alone, both patients of the present study continued to develop spasms over a treatment period of at least one year. Only after the combined treatment with pregabalin and botulinum toxin, the complete and sustained cessation of HSF was achieved. The therapy with pregabalin alone alleviated the spasms, but did not prevent their occurrence. Therefore, we recommend pregabalin as a supplementary treatment option in those patients with facial spasms which can not be relieved sufficiently by botulinum toxin alone. P300 Sympathetic skin response study in Parkinson’s disease V. Shaygannejad, S. Khosravi, F. Ashtari Isfahan University (Isfahan, IR) Background: Parkinson disease (PD.) is one of the most Prevalent degenerative disease of the CNS.Its prevalence is a bout 360 per 100000 and increase with age. Beside the motor, cognition and emotional derangements, autonomic disturbances also are encountered, such as orthostatic hypotension, cool skin, constipation, hyperhydrosis, and Occasionally cardiac arrhythmia. The sympathetic skin response (SSR) was used to evaluate sympathetic sudomotor activity in P.D Methods: This cross sectional, case-control study was performed on 31 PD patients and 38 healthy controls, in 2004. We recorded SSRS to electric stimulation of median nerve at palm.We measured latency of SSRS and compare the results between two groups according to t-student test. Results: The mean age of two groups were matched at baseline. (P = 0.81) the mean latency of SSRs was 1.93(0.52) in case group and 1.50 (0.20) in healthy controlled group (P < 0.001). We also found that age of patients (P = 0.61), duration of affliction (P = 0.65) and intensity of rest tremor (P = 0.92) had not any influence on rate of abnormal SSR.

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In conclusion: The degenerative process in PD, involve the sudomotor system as reflected by increased latency of SSR without a correlation to PD symptom duration, tremor intensity and age of patients.

bling as a side effect of such a medication. Stopping or reducing pramipexole or similar drugs can lead to rapid normalization of the patient’s behavior.

P301 The “panda” sign in Wilson’s disease C. Balla, D. Parisis, S. Tsounis, N. Artemis, I. Milonas AHEPA Hospital (Thessaloniki, GR)

P303 Biological and clinical markers in the central nervous system degeneration H. Vranova, M. Nevrly, J. Mares, R. Herzig, P. Kanovsky University Hospital (Olomouc, CZ)

Introduction: Wilson’s disease is a disorder of copper metabolism that can present in young individuals with hepatic, neuropsychiatric disturbances or a combination of these. The disorder is caused by mutation affecting the ATP 7 B gene, which disrupts the metabolic pathway of copper in the hepatocyte. It is well established that the neuroradiological spectrum of Wilson’s disease is wide, and usually includes bilateral hyperintensities on T2-weighted images involving subcortical white matter, basal ganglia, thalami, midbrain and pons tegmentum. Furthermore there are occasional reports in the literature demonstrating an interesting imaging pattern of the disease, called the “panda” sign. Herein we describe a new case of this pattern. Patient- Methods: A 24-year-old man was admitted to our department because he developed over the last 2 years a mild coarse tremor which increased when the upper limps where outstretched.The neurological examination revealed a postural tremor in the arms and extrapyramidal rigidity mainly in the left arm with a concominant dystonic posturing. EEG and lumbar puncture did not show any abnormalities. Serum ceruloplasmin was severely reduced (4.15 mg/dl, normal > 22 mg/dl) whereas 24h urine collection showed significantly elevated copper values (540 µg/d, normal < 1.4 µg/d). Furthermore, slit-lamp examination indicated the presence of Kayser – Fleischer ring. Brain MRI demonstrated bilateral and confluent high signal abnormalities in the thalami, lenticular nuclei, midbrain and dorsal pons tegmentum and middle cerebellar peduncles on T2 and FLAIR-weighted images, whereas red nucleus, substantia nigra and superior colliculus showed relatively hypointensity, thus giving the appearance of a panda face. Blood tests and liver ultrasound revealed no abnormalities in hepatic function. The patient diagnosed as having Wilson’s disease and treatment with D-penicillamine 1 gr/d was initiated. Follow up examination one year later shows improvement of the movement disorder of the patient. No adverse effect of the drug where reported. Conclusion: The present case provides further evidence that Wilson’s desease may occasionally present with a distinctive pattern of neuroimaging abnormalities, namely the “face of panda”.Awareness of this association can be helpful for the early diagnosis of this treatable disorder.

Objectives: Selective neurodegenerative damage of certain neuronal subpopulations results in the specific clinical picture of the disease. The accumulation of abnormal proteins participates in the development of the disease. Both the influence of toxicity of protein inclusions and the loss of physiological function of damaged protein lead to the damage of neurons. The assessment of the level of these proteins in the cerebrospinal fluid (CSF) could be a valuable diagnostic criterion. The aim of our study was to assess the levels of tau protein, beta-amyloid [1–42] and cystatin C in the CSF in patients suffering from neurodegenerative diseases, and to assess their relationship to neurological and neuropsychological status. Methods: The laboratory assessment of tau protein, beta-amyloid [1–42] and cystatin C CSF levels was performed in 21 patients (13 males, 8 females; aged 29–77, mean 57.0 ± 13.5 years) suffering from a diagnosed neurodegenerative disease and treated at the Department of Neurology, University Hospital, Olomouc, Czech Republic. The neuropsychological examination was also performed in these patients and its results were classified according to the severity of cognitive deficit (CD) using the scale ranging from 0 (without CD) to 4 (severe CD). Results: Tau protein CSF level increase and beta-amyloid [1–42] CSF level decrease were found in patients suffering from Alzheimer disease (AD). Tau protein CSF level positively correlated with CD severity in AD patients. No correlation was found between the cystatin C CSF levels and both the diagnosis and the CD severity. Conclusion: The CSF tau protein levels could serve as a potential marker of AD.Further studies performed in larger sets of patients are needed to clarify the relationship between the levels of beta-amyloid [1–42], tau protein and cystatin C and the CD severity.

P302 Pathological gambling as a side effect of treatment with levodopa and pramipexole K. Spengos, G. Karachalios, G. Tsivgoulis, V. Masdrakis, G. Papadimitriou, M. Spengos University of Athens (Athens, GR) Background: Pathological gambling is an impulse control disorder that has been observed among patients with Parkinson’s disease (PD). PD is primary treated with drugs that restore or improve brain dopaminergic neurotransmission. Brain dopamine has been implicated in mediating the reward of gambling behavior. Almost thirty cases of pathological gambling in PD patients treated with dopamine agonists and especially pramipexole have been described in the recent international literature. A disproportionate phramacogenic stimulation of D3 receptor, mainly induced by pramepixole, is assumed as cause of this disorder. Case report: We present the case of a now 64-year old lady with history of PD since the age of 60. At the time of diagnosis medication with levodopa and pramipexole was initiated with a good clinical response. One year later the patient began to regularly visit the local casinos and gamble only on slot machines. During the last 16 months the frequency of those casino visits increased dramatically. Almost once a week the patient was leaving her house in the morning to return late in the evening, or even the day after. Gambling this way she practically stayed in the casino until she lost all the money she was carrying with. Since her behavior got out of any control their relatives searched for medical advice. Based on recent evidence suggesting stimulation of dopaminergic central pathways by dopamine agonists as cause of pathological gambling, pramipexole application was stopped and levodopa dosage mildly increased. Within two months of not taking pramipexole her habits and behavior returned to normal. Conclusion: Since dopamine agonists, including the highly selective D3 agonist pramipexole,are widely used in the treatment of PD,physicians dealing with such patients need to know and timely recognize pathological gam-

P304 In vivo imaging of nigrostriatal damage in schizophrenia K. Boelmans, R. Steinke, B. Schott, H. J. Heinze, L. Niehaus Otto-von-Guericke Universität (Magdeburg, D) There are a few histopathological studies indicating nigrostriatal degeneration in patients with chronic schizophrenia. However, pre-mortem differentiation between neuroleptic-induced parkinsonism and dopmaninergic nigrostriatal impairment in idiopathic Parkinson’s disease (IPD) has been difficult. We report a 63 year old patient with chronic schizophrenia who had developed a slowly progressive hypokinetic-rigid syndrome under neuroleptic medication over 15 years. To evaluate the nigrostriatal dopaminergic innervation transcranial brain parenchyma sonography (TCS) and dopamine transporter (DAT) imaging using I-123-FP-CIT SPECT was performed. TCS of the midbrain depicted a marked increased echogenicity in both substantia nigra (right: 28 mm§; left: 26 mm§) which is consistent with TCS findings in IPD. FP-CIT SPECT demonstrated a significant decrease of the striatal DAT on both sides (ROI ratios: 1.68 (right), 1.80 (left)). The finding of reduced presynaptic striatal DAT uptake exclude the possibility of a mere drug induced parkinsonism and indicates nigral neurodegeneration as seen in IPD. This case is the first to demonstrate coexistence of IPD and chronic schizophrenia using two in vivo imaging methods. These findings suggest that DAT-SPECT and TCS may provide a useful diagnostic tool to depict nigrostriatal degeneration in psychiatric patients with parkinsonian symptoms. In clinical practice, such patients will benefit from the in vivo detection of IPD by applying an optimal pharmacological replacement therapy or potentially deep brain stimulation. P305 Very late onset Friedreich’s ataxia with sphincter disturbances S. Fernández-Fernández, J. Casanova, M. Milà, E. Muñoz Hospital Clínic (Barcelona, E) Objectives: To describe a patient with very late onset Friedreich’s ataxia (VLOFA) with sphincter dysfunction mimicking multiple system atrophy. Background: Cases of Friedreich’s ataxia (FA) with age of onset > 40

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years (VLOFA) are infrequent. Usually, they tend to exhibit a milder disease with retained tendon reflexes and slight atrophy of the cerebellum and spinal cord in the MRI. In some instances, they can be misdiagnosed of the cerebellar variant of multiple system atrophy (MSA-c). However, contrary to MSA, sphincter disturbances have not been described in VLOFA. Patient: We present a 52-year-old man with ten years of progressive gait and limb ataxia, dysarthria, normal tendon reflexes, slight decreased vibration and temperature senses and pyramidal signs in the lower limbs. In the last year, the patient complained of urinary urgency and episodes of faecal incontinence. Family history did not show other members with a similar disease. Neither there parents were consanguinity. Results: MRI showed slight atrophy of the cerebellar vermix and cervical spinal cord. Genetic studies for autosomal dominant spinocerebellar ataxies were negative for SCA 1.2,3.6,7 and 8. The study of FRDA gene showed a homozygous GAA expansion (GAA 1:320 repeats). A neurophysiological study did not show abnormalities in the cardiac R-R’ variation. We could not perform a neurography study to investigate polyneuropathy because of patient low tolerance to the electrical stimuli. Conclusion: VLOFA can present with sphincter dysfunction. FA must be investigated in patients with late onset progressive cerebellar syndrome, especially if there is not prominent cerebellar or brainstem atrophy in the MRI, and independently of the presence or not of sphincter disturbances. P306 Cognitive disorders and depressive symptoms in Wilson’s disease P. Günther, W. Hermann, A. Wagner University of Leipzig (Leipzig, D) Objectives: Wilson’s disease is a rare autosomal recessive disorder of hepatic copper transport leading to a biliary excretion inhibition of copper. Overload of the metal mainly in liver and basal ganglia leads to hepatic but also to extrapyramidal motor as well as psychiatric clinical symptoms. Cognitive dysfunction is often complained and patients suffer from additional depressive symptoms. Methods: In this study, a cognitive impairment profile with SIDAM (SISCO) including mini mental state and Beck depression inventory (BDI) was performed in 38 patients with Wilson’s disease (26 patients with the neurological form, 12 patients with the non-neurological form) undergoing long-term medicamentous therapy. Results of cognitive testing and BDI score were correlated to results of clinical investigation and Electroencephalography (EEG). Results: The results of psychopathological investigation show slight cognitive impairment in the investigated patients with Wilson’s disease being on long-term treatment. Median results of SIDAM were 52.5 [35–55] in neurological form and 53 [49–55] points in non-neurological form. There is no statistical significance in correlation to the severity of neurological score nor EEG. However, there is a high incidence of depressive symptoms in patients with the neurological form of Wilson’ disease. Conclusion: Depressive symptoms and cognitive impairment in Wilson’s disease are frequently reported by patients beeing on long-term treatment. Since movement disorders often have improved with therapy additional observing of cognitive function and depressive disorders seems to be useful. Especially patients with a neurological form might have benefit of a antidepressive therapy. However, cognitive impairment occurs independently of the severity of neurological symptoms.

General neurology P307 Diffuse hyperhidrosis and acute pancreatitis as a primary manifestation of Shapiro syndrome F. Corea, V. Bignamini, N. Tambasco INSPE IRCCS S.Raffaele (Milan, I); University of Perugia (Perugia, I) We report on the medical treatment of a patient with the rare Shapiro syndrome. The leading symptom is recurrent episodes of diffuse hyperhidrosis and hypothermia (HH). Major anomalies were found in the central nervous system midline structures: subtotal agenesis of corpus callosum with persistence of the genu and enlargement of the posterior part of the lateral and third ventricles. Endocrinological examinations and electroencephalograms were found to be normal. The treatment of HH was with clonidine, an alpha 2-adrenoceptor agonist, together with a combination of fasting and fluids. Further medical options are discussed. In this patients the manifestations of the syndrome, first described by Shapiro and Plum in 1967, have

been interpreted as possible consequences of dopaminergic denervation of the hypothalamic thermoregulatory center. P308 Atypical presentation of Fahr’s disease: cerebellar mass E. Daglioglu, M. F. Ergüngör, H. G. Hatipoglu, G. Orhan, T. Ünal, E. Karakoc Ankara Numune Education & Research Hospital (Ankara, TR); Hacettepe University (Ankara, TR) Objectives: Fahr’s disease is characterized with symmetric calcifications of basal ganglia, cerebral or cerebellar hemispheres. Hypercalcemia, cognitive and behavioral abnormalities, and more recently cerebral tumors were proven to have association with this disease. Methods and Results: 26-year-old male patient was admitted to the emergency unit with complaints of vertigo and imbalance. He was noted to be severely disoriented. Neurological examination revealed bilateral nystagmus, clonus, Babinski positivity and gait ataxia on the right side. Emergent CT of the brain demonstrated triventricular hydrocephalus and cerebral edema which explained presenting symptoms of increased intracranial pressure. Further evaluation with MRI demonstrated cystic peripherally enhancing cerebellar and thalamic masses on the left side. Marked indentation of the fourth ventricle was noted due to the mass effect of the cerebellar lesion. Hyperdense calcium deposits at the basal ganglia, thalamus and cerebellar hemispheres bilaterally on CT scan were quite demonstrative for Fahr’s disease. Suboccipital craniectomy was performed and dark gray cystic and hemorrhagic mass was resected grossly as total. A mural nodule was also noted inside the cyst. Postoperative period was unremarkable. Prominent laboratory findings were decrease in serum ferritin, IgG levels and RF positivity with normal calcium or parathyroid hormone levels. Visual evoked potential studies were normal. Lumbar puncture was performed postoperatively and features normal protein and glucose levels. Histopathological examination revealed calcification of the vasculature, areas of demyelinization and gliosis. No sign of malignancy was detected. The patient was discharged three days after the operation. Postoperative follow-up CT showed successful decompression of the cerebellar mass. Most of the clinical symptoms improved after the operation. Conclusion: Fahr’s disease could be associated with astrocytoma as reported previously. Association of Fahr’s disease with cerebellar mass like lesions or signs of increased intracranial pressure were not reported. With regard to histopathology of the lesion, one could argue that the findings are compatible with leukoencephalopathy which was unpredicted. P309 Diagnostics and clinical management in syringomyelia F. Roser, T. Naegele, M. Tatagiba University of Tubingen (Tubingen, D) Objective: Minimal spinal trauma as the underlying cause of a Syringomyelia is commonly neglected in the management of this chronic disorder. Neurological deficits occurring late and are therefore most often not debated as the cause of syrinx development. However the restoration of adequate CSF-circulation can lead to cessation of disease progression. Methods and Results: All Syringomyelia patients transferred to our neurosurgical department undergo a standardized workup including neurological assessment with a meticulous history taking of the patient, to detect any spinal trauma occurred. Electrophysiological measurements include routine SEP and MEP for all extremities as well as cutaneus and mixed-nerve silent periods for detection of alteration in A? pain fibres. MRI diagnostic then comprised a central part of the diagnostic procedures: Beside routine acquisitions with FLAIR, T1-/T2 weighted images and contrast enhanced series we apply sagittal cardiac-gated sequences (CINE) for visualisation of CSF-pulsations and axial 3D -constructive interference in steady state (CISS) sequences, to detect focal arachnoid webs. If on MRI imaging a suspicious region is detected, axial postmyelographic CT scans are performed to obtain highest visibility of subarachnoid scar tissue formation. An indication for neurosurgical intervention emerges if a focal adhesion due to arachnopathic scar tissue is detected as the underlying cause of CSF-obstruction forming the Syringomyelia. The operation aims to decompress the subarachnoid space forming a new unobstructed CSF pathway, including an enlarging duroplasty. All treated patients show a collapse of the syrinx, some within days after surgery. Neurological symptoms do improve; however in most cases long-standing neurological deficits remain stable. Aggravation of deficits due to the natural history of the disease can be stopped. We demonstrate the diagnostic and operative management in these patients exemplarily, emphasize the necessity for meticulous spinal trauma detection. Conclusion: Syringomyelia should be seen as a symptom of an underlying arachnoid process,most often caused by a minor spinal trauma with sub-

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sequent arachnoid scar formation causing CSF flow obstruction. Neurosurgical detection and elimination of this obstruction lead to a free CSF passage and can stop the progredient course of the disease.

P310 Myelo-optico-neuropathy in copper deficiency M. Spinazzi, M. Armani, F. De Lazzari, C. Angelini, B. Tavolato University of Padua (Padua, I) Objective: to describe a new case of copper deficiency in a patient affected by myelo-optico-neuropathy mimicking subacute combined degeneration due to vitamin B12 deficiency. A history of partial or total gastrectomy was found in a relevant proportion of the few copper deficient patients affected by myeloneuropathy so far reported. However, the primary cause of copper deficiency has rarely been identified.We report here a new case of a 62-year-old woman who developed a severe sensory ataxia, spastic paraparesis, decreased visual acuity, hyposmia and anemia after significant weight loss resulting in copper deficiency, many years after a partial gastrectomy for gastric carcinoma. Methods: clinical, laboratory, electrophysiological and neuroimaging tests were performed. Ceruloplasmin and copper in plasma and liver were also measured and platelets were collected. Results: the neurological examination showed a severe sensory ataxia, associated with pyramidal features and sensory impairment with prominent vibratory and proprioceptive sensory loss in the lower extremities. Laboratory exams revealed mild normocytic anemia, decreased ceruloplasmin (0.13 gr/L; nv 0.22–0.60) and low copper in plasma (3.8 umol/L; nv 12.5–24.4) and liver. EMG showed diffuse axonal polyneuropathy. VEP and SEP were abnormal. MRI disclosed periventricular non enhancing lesions in periventricular regions and a longitudinal centrospinal lesion at the lower cervical level. CSF, folates, vitamin B12 and E, homocysteine, methylmalonic acid, VDRL, and paraneoplastic antibody panel were analysed and were found to be normal. Conclusions: some target organs, as bone marrow, central and peripheral nervous system, heart can be affected by this trace element deficiency. To our knowledge, the full phenotype of our patient characterized by bilateral optic neuropathy associated with myeloneuropathy has never been described before in copper deficiency. Previous gastric surgery, inadequate nutrition, or a malabsorption syndrome could be all predisposing risk factors. Prompt diagnosis and copper replacement therapy were important in preventing further neurological damage in our patient. We conclude by suggesting that copper status should be evaluated in all patients affected by unexplained non-inflammatory myeloneuropathy.

P311 Cerebellar ataxia associated with hereditary haemochromatosis M. P. Rutgers, A. Pielen, M. Gille Cliniques de l’Europe (Brussels, B) Objective: To report a patient who developed a progressive cerebellar syndrome probably due to Hereditary Haemochromatosis (HH). Case-report: A 72-year-old woman presented with a progressive cerebellar ataxia since 3 years. She had abnormal skin pigmentation with lower limb dysmetria, dysarthria, and lateral gaze evoked nystagmus. Brain Computerized Tomography (CT) and cerebro-spinal fluid examination were unremarkable. Brain Magnetic Resonance Imaging (MRI) revealed T1 and T2 low signals in the putaminal and dentate nuclei. High serum levels of ferritin (893ng/ml, normal 20–300) and iron (176µg/dl, normal 50–150) were associated with increased transferrine saturation (77 %, normal 20–55). Serum liver enzymes, thyroid hormons, and coeruloplasmin were normal. Anti-viral and anti-bacterial serologies were negative. Antinuclear, anti-gliadin, anti-endomysium, anti-GAD, andi-thyroid antibodies were absent. Total body Fluoro-Deoxy-Glucose Positron Emission Tomography did not reveal any occult neoplasia. Anti-Hu, anti-Yo, and anti-Ri antibodies were no detected. Abdominal CT showed a increased liver density consistent with iron overload. Genetic testing for spino-cerebellar ataxias types 1, 2, 3 and 6 was negative. Homozygosity for C282Y mutation in the HFE gene confirmed the diagnosis of HH. She was treated with phlebotomies (500 ml every week). The neurological manifestations were unchanged after 3 months of treatment. Discussion: Neurological involvements have been rarely reported in HH. They include cognitive decline and movement disorders, such as cerebellar ataxia, parkinsonism, action and postural tremor, dystonia, and myoclonus. They must be differentiated from HH-related hepatic encephalopathy or from other co-existing neurological disease. Brain iron overload in the basal ganglia has been suspected in some cases

of HH with neurological manifestations. Cellular accumulation of iron leads to lipid peroxydation with the consequence of cell damage and cell death. Conclusion: In our patient, the progressive cerebellar syndrome was probably related to abnormal iron accumulation in the dentate nuclei, well demonstrated as a local decreased signal on MRI. The absence of clinical improvement was probably due to the insidious long-during course of HH, with constitution of irreversible cerebral lesions. P312 Prognostic value of cerebral magnetic resonance imaging in coma within the first 6 to 36 hours after cardiac arrest: a pilot study S. Frigerio, L. Remonda, M. Arnold, M. Dahlqvist, H. P. Mattle, J. Takala, J. Slotboom, C. Kiefer, S. Jakob, C. Ozdoba, G. Schroth, H. U. Rothen University of Berne (Berne, CH) Background: Outcome in comatose patients with hypoxic-ischemic encephalopathy and preserved brain stem functions following cardiopulmonary resuscitation is difficult to predict. The objective of this study is to explore the prognostic value of early cerebral diffusion-weighted magnetic resonance imaging (DWI MR) in patients after cardiac arrest and successful resuscitation. Patients and methods: Pilot study to observe the outcome of patients with hypoxic ischemic encephalopathy after successful cardiopulmonary resuscitation in a single centre. In each patient a cerebral MR including DWI and perfusion-weighted imaging was performed according to a standardized protocol within 6 to 36 hours after cardiac arrest. Patient management, including blood glucose and cardiopulmonary control, was performed according to standard routine, and patients were assessed by a neurologist daily. Body core temperature was kept between 34.0°C – 37.0 °C during the first 24 hours after CPR. Results: From January 2005 to January 2006, 38 patients admitted to the ICU were eligible for the study. Of these, 14, (13 men and one woman, mean age 64.8 y), were included. 24 patients were not included because of contraindications to MR examination [8], rapid clinical improvement [8], missing consent of families [4] or death before the MR examination [4]. Twelve patients died within 5 days, and two were discharged from the hospital alive. The two survivors had normal MR findings. Nevertheless, they showed a severe amnestic syndrome 6 months later. Eight patients who died showed bilateral hyperintense signal on DWI MR in the basal ganglia and parietooccipital and mesiotemporal cortex. Four patients who died had a normal MR. MR angiography was normal in all patients. Conclusion: All 8 comatose patients with signal abnormalities on DWI MR after cardiac arrest and successful resuscitation died. Normal DWI MR was seen both in 2 survivors and 4 patients who died. Therefore, abnormal signal on DWI MR may have prognostic value and indicate adverse outcome. These findings have to be corroborated in a larger number of patients. Based on our results, we elaborate a protocol for a multicentre study in order to collect an adequate number of patients to answer this question. P313 Dictante dolore: Alphonse Daudet, Jean-Martin Charcot and neurosyphilis in Paris fin de siècle S. Dieguez, J. Bogousslavsky Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Objective: To describe an important cultural and scientific crosswalk for the history of neurology and to offer a subjective account of the mental effects of peripheral pain from an artist’s perspective. Background: In a poorly known notebook, French writer Alphonse Daudet made a frightening account of his painful experience of tabes dorsalis. La Doulou is the diary in which he describes his symptoms and treatments. From other sources, including Daudet’s elder son Léon, we learn crucial details on the medical personalities, discoveries and debates of the time. Methods: Literary review. Results: Charcot, friend and doctor of Daudet, obstinately denied any link between syphilis and tabes dorsalis. Daudet himself, however, was convinced of the sinful origin of his torments, especially as he was aware of Fournier’s work, another of his doctors. La Doulou is foremost a meticulous analysis of the varieties of peripheral pain. It also describes other symptoms like ataxia and body-schema instability, dissociative-like experiences, thought disorders and memory difficulties. However, higher function disorders were likely the effect of his dependency on morphine. Other treatments were the barbaric Seyre’s traction, imported from Russia by Charcot, and yearly stays at thermal baths. Conclusion: The first-person account of tabes from a penetrating writer such as Alphonse Daudet informs us like no other of the subjective experience and cognitive effects of excruciating pain.

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P314 Perfusion CT compared to conventional imaging modalities in mild to moderate head injury Z. Metting, L. Rodiger, J. H. A. De Keyser, M. Oudkerk, J. van der Naalt University Medical Center Groningen (Groningen, NL)

P316 Anti-MOG and anti-MBP antibodies predict the risk of multiple sclerosis after a clinically isolated syndrome I. Greeve, U. Walker, T. Lauterburg, K. M. Rösler, H. P. Mattle Inselspital (Berne, CH)

Objective: The most commonly used imaging technique in the acute phase of head injury is computed tomography (CT). It is used for the detection of intracranial haemorrhage, skull fractures, mass effect and oedema. It is the most relevant imaging procedure for the detection of lesions eligible for surgical intervention. Magnetic resonance imaging (MRI) is the technique of choice in the subacute phase of head injury and for follow-up of patients. MRI has shown to be more sensitive in detecting diffuse axonal injury and nonhaemorrhagic contusions compared to CT scanning. The aim of this study was to investigate the additive value of perfusion CT in patients with mild to moderate head injury compared to conventional imaging techniques as CT and MRI. Methods: a prospective trial was performed in patients with mild to moderate traumatic brain injury. Directly after admission to the emergency department of the University Medical Center Groningen a conventional CT and a perfusion CT were performed, during follow up a MRI scan was obtained. Results: 10 patients were included so far. Half of these patients had intracranial abnormalities on conventional CT; 4 showed contusions combined with the presence of subdural haematomas, 1 patient had a subdural haematoma only.All patients had an abnormal perfusion CT, predominantly with a pattern of hypoperfusion located in the frontal lobes. An MRI scan was obtained with a mean duration of 61 days after trauma. Post-traumatic intracranial abnormalities on MRI were seen in 7 patients, 5 of them had abnormal CT findings also. Most common abnormalities visible on MRI were contusions, followed by atrophy and diffuse axonal injury. Conclusions: In patients with mild to moderate traumatic brain injury, perfusion CT reveals more often abnormalities compared to conventional CT or MRI. These preliminary results could suggest that perfusion CT might be a more sensitive technique to visualise traumatic brain injury in this group of patients.

Objectives: Patients with multiple sclerosis (MS) initially present with a clinically isolated syndrome (CIS) due to an inflammatory demyelinating lesion of the central nervous system. The time-interval for conversion to clinically definite MS (CDMS) is highly variable ranging from a few months up to many years. Treatment with beta-interferon (b-IFN) extends the time to develop CDMS in high-risk patients by up to 1 year. Anti-MOG (myelin oligodendrocyte glycoprotein) and anti-MBP (myelin basic protein) antibodies have been shown to predict the spontaneous clinical course of CIS patients. In this study we investigated whether detection of anti-myelin antibodies predict early conversion to CDMS in CIS patients treated or not treated with b-IFN1a. Methods: We prospectively determined anti-MOG and anti-MBP IgM antibodies by western blotting in serum of 69 CIS patients from January 2004 until October 2005. A follow up of at least 6 months up to 20 months is available for 39 patients. Statistical analyses were performed using the SPSS statistics program. Results: Within the observation period, 22 of 39 patients developed CDMS. 19 patients had both anti-MOG and anti-MBP IgM antibodies, 11 patients had only IgM antibodies against either MOG or MBP, and 9 patients had no detectable IgM antibodies. None of these 9 patients developed CDMS within the observation period of 20 months. In the group of patients with detectable IgM antibodies, the mean time to CDMS within the observation period was 8.0 months for anti-MOG + /anti-MBP + patients (n = 14 out of 19) and 8.9 months for anti-MOG + /anti-MBP- patients (n = 8 out of 11). A subgroup analysis in anti-MOG + /anti-MBP + and anti-MOG + /anti-MBPpatients (n = 30) demonstrated that time to CDMS was 10.9 months in patients treated with b-IFN1a (n = 8) as compared to 7.4 months for untreated patients (n = 22) (Breslow generalized Wilcoxon test p = 0.01). Conclusions: Patients without anti-MOG and anti-MBP IgM antibodies represent a subset of CIS patients with a favourable short-term prognosis who potentially do not need immunomodulatory treatment immediately. In patients with detectable anti-MOG antibodies, b-IFN1a treatment delays the time to conversion to CDMS significantly as compared to untreated patients.

Multiple sclerosis P315 Elevated urinary excretion of aluminium and iron in multiple sclerosis C. Exley, G. Mamutse, O. Korchazhkina, E. Pye, S. Srekopytov, A. Polwart, C. P. Hawkins Keele University (Stoke on Trent, UK); University Hospital of N. Staffordshire (Stoke on Trent, UK); Leicester Royal Infirmary (Leicester, UK) Objective: Iron is deposited in the brain in multiple sclerosis (MS) and may contribute to the pathogenesis of the disease by promoting oxidative stress. This may cause selective oligodendrocyte cell death with consequent demyelination. Oxidative stress may also directly damage myelin through lipid peroxidation producing malondialdehyde (MDA). Aluminium- a pro-oxidant- could potentiate iron-induced oxidative damage. In this pilot study, we compared urinary excretion of aluminium, iron, thiobarbituric acid reactive substances and MDA in two groups of MS patients and a group of healthy volunteers. Methods: We studied 10 subjects with relapsing-remitting MS (RRMS), 10 with secondary progressive MS (SPMS) and a comparative group of 10 age- and sex-matched healthy volunteers. We used a battery of analytical techniques to determine the urinary excretion of (i) markers of oxidative damage- MDA and thiobarbituric acid reactive substances (TBARS) (ii) iron and the environmental toxin aluminium and its antagonist, silicon. Results: Urinary concentrations of MDA and TBARS were similar in the three groups. Urinary concentrations of iron were significantly increased in the SPMS group (p < 0.01) while those of aluminium were significantly increased in both the RRMS (p < 0.001) and SPMS (p < 0.05) groups relative to the control group. Silicon excretion was significantly reduced in the SPMS group (p < 0.05). Conclusion: We demonstrate increased urinary excretion of aluminium and iron in multiple sclerosis. Further studies to confirm and elucidate these findings are planned.

P317 Oligoclonal IgM bands in CSF do not correlate with the risk of relapse in patients with a primary demyelinating event R. Schneider, B. Euler, S. Rauer University of Freiburg (Freiburg, D) Objective: To study whether the presence of oligoclonal IgM bands (IgMOCB) in cerebrospinal fluid (CSF) from patients with a clinically isolated syndrome (CIS) anticipates the risk for a relapse which would lead to the diagnosis of a clinically definite multiple sclerosis (CDMS) as described earlier (Villar et al. Neurology, 2002 Aug 27;59 [4]:555–9.). Methods: Cerebrospinal fluid (CSF) and Sera from 36 patients with a (CIS) and positive intrathecal IgG-synthesis (CIS) were retrospectively tested for the presence of oligoclonal IgM bands in CSF. Isoelectric focussing of paired CSF and serum samples followed by high sensitivity immunoblotting was performed in all 36 cases. Clinical follow ups were estimated retrospectively by telephone interviews and documented neurological examination. The study period was 21 to 106 months (mean 60 ± 25). Results: We found IgM-OCB in 22 out of 36 patients (61 %). Those who developed CDMS during follow up showed intrathecal IgM-synthesis in 12 out of 21 cases (57 %), while patients, who did not have a relapse showed IgM-OCB in 10 out of 14 cases (71 %). There was one case of secondary progression, it didn’ show IgM-OCB. Using the Kaplan-Meier model there was no increased risk for developing a relapse (CDMS) in patients with intrathecal IgM-synthesis than compared to the negative ones. Conclusion: These findings do not confirm earlier results (Villar et al. Neurology, 2002 Aug 27;59 [4]:555–9.) which suggested that the presence of IgM-OCB is associated with an increased risk for developing CDMS during a defined time span.

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P318 Variable FOXP3, CTLA-4 and GITR gene expression of CD4 + CD25 + regulatory T-cells during relapses in relapsing-remitting multiple sclerosis patients N. Grigoriadis, I. Paspaltsis, D. Tsiadoulas, G. Deretzi, A. Dimakopoulou, D. Karussis, T. Sklaviadis, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR); Hadassah University Hospital (Jerusalem, IL) Objectives: Impairment in the immunological self-tolerance against myelin antigens may at least partly explain the autoimmune reactivity noticed in multiple sclerosis (MS). Self-reactive T cell activity may be down-regulated by regulatory T (TR) cells such as the CD25 + CD4 + subpopulation. Among the markers that may characterize the regulatory function of TR cells are FOXP3, CTLA-4 and GITR. The aim of the present study was to investigate the mRNA expression level of all three markers in peripheral blood CD4 + CD25 + T-cells in MS patients undergoing relapses, before, soon after and one month following corticosteroid treatment. Methods: CD4 + CD25 + T-cells were isolated from peripheral blood mononuclear cells, following CD4 + enrichment and the use of magnetic beads. The mRNA expression level was evaluated with real time – PCR analysis. Patients were evaluated clinically with EDSS at all time – points. Results: A heterogeneous FOXP3 expression in the CD4 + CD25 + T-cells among patients at the onset of the relapse, was noticed. Patients were subdivided into two groups according to their FOXP3 gene expression as compared to age- and sex- matched healthy controls: Group A patients exhibited a down-regulation of 20–80 % and group B an up-regulation varied between 20 % to more than 100 %. Corticosteroid treatment resulted in variable FOXP3 expression as measured six and thirty days after the corticosteroid administration in either group of patients. All but one patient in group A recovered completely one month after the end of the corticosteroid treatment. On the contrary, only one out of the six patients in group B had a good outcome whereas the rest recovered either poorly or not at all. Interestingly enough, one patient in group B had a new relapse 35 days after the corticosteroid treatment was accomplished. GITR and CTLA-4 expression levels varied and did not follow the changes noticed in FOXP3. In addition, no correlation to the corticosteroid response could be detected in either group of patients. Conclusion: FOXP3 has recently been reported to be expressed at lower levels in MS patients compared to healthy individuals. Our results indicate that at least during relapses, FOXP3 expression levels may be high in some MS cases. Presumably, there is an intrinsic mechanism in the immune system for more functional TR cell reinforcement in an attempt to control the exacerbating immune reaction. However, those patients had no benefit at all from corticosteroid treatment. P319 Mitoxantrone efficacy and safety in a cohort of multiple sclerosis patients F. Martinelli Boneschi, M. E. Rodegher, L. Moiola, M. Radaelli, M. Rocca, F. Esposito, F. Torrisi, A. Bellini, V. Martinelli, G. Comi Scientific Institute San Raffaele (Milan, I) Objective: To assess the efficacy and safety of treatment with Mitoxantrone (MX) in delaying the disease progression and in reducing gadolinium enhancing lesions in Multiple Sclerosis (MS) patients with “active” disease. Methods: 292 MS patients (188 females and 104 males) were treated in an open label protocol during the last three years. The dose regimens differed from 10 to 20 mg for single dose, administered monthly or every two-three months.A subpopulation of 165 patients (107 females and 58 males) who received at least 5 cycles, is the object of this analysis. The age ranged from 22 to 71 years (mean age 39 years). The median duration of treatment was 1.2 years and the median number of cycles were 6.0. Patients with a RR course were 34 (21 %), while 118 patients (71 %) had a SP MS and 13 patients (8 %) a PP MS. The patients were classified as non-responders if EDSS increased of at least 1.0 point during the period of treatment (if baseline EDSS was lower or equal to 5.5), and of 0.5 if baseline EDSS was higher than 5.5, and responders in all the other cases. A subgroup of 104 patients underwent brain MRI before and after treatment; 22 patients had a RR course, while 77 and 5 were respectively SP and PP. We defined as MRI responders the patients who switched from at least one enhancing lesion at the beginning of the treatment to no enhancing lesions at the end, or who had no enhancing lesions before and after the treatment. Results: Clinically responder patients were 111 (67.3 %): 30 (88 %) were RR MS patients, 75 (65 %) SP patients and 6 (46 %) PP patients. At the end of the treatment, the proportion of MS patients with at least one enhancing lesion dropped from 83 % to 33 % in RR, from 50 % to 15 % in SP, and from 20 % to 0 % in PP patients. As regards side effects, 16 % of female patients developed amenorrhea (12 % had persisting amennhorea for at least 6 months);

nausea and vomiting were reported by 34 % of patients, transient leukopenia by 22 %, urinary infections by 19 %, and other minor side effects by 9 %. None of the patients developed leukaemias, while 1 patient died for myocardial infarction with an echocardiography with a normal LVEF. Conclusion: MX treatment has a short-term efficacy both in delaying the progression of clinical disability and in reducing the MRI inflammatory activity. It is also safe at short-term evaluations.Additional data are needed for long-term safety and efficacy. P320 Multiple sclerosis in Iran: a demographic study of 5.000 patients J. Lotfi, H. Parsi, P. Zohrevand, K. Alikhani, M. Sahraian Tehran University of Medical Science (Tehran, IR); Iranian MS Society (Tehran, IR) Background: Multiple Sclerosis (MS) shows a wide range of clinical features and natural history in different geographical regions. This variation in prevalence and clinical pattern is probably due to ethnic and environmental factors and has been evidenced in various studies. Numerous studies tried to assess MS heterogeneous clinical spectrum with the hope of revealing the underlying cause of the disease. Here we report demographic characteristics of 5000 Iranian MS patients who have been registered in Iranian MS Society (IMSS) during 6 years (1998–2005). Methods: During 7years of activity, 5000 patients have been registered in IMSS. These cases were referred by neurologists and their MS diagnosis was determined by applying Poser (1998–2001) and McDonald Criteria (2001–2005).Registration has been accomplished by trained personnel.Both subjective (questionnaire) and objective data have been collected. Registry has been done at the time of patient’s first visit to the IMSS centers and was obviously independent from time of diagnosis of the disease or any other medical events. Records were reviewed for variables like age, gender, age at the onset of disease, time to diagnosis, presenting symptoms and family history. Results: Out of 5000 patients 3325 (66.5 %) were female and 1675 (33.5 %) were male. Female to male ratio was 1.98:1 Mean age of onset was 27 years, which was lower in female than male patients (26. ± 8.54 vs. 28.33 ± 8.82) Median time to diagnosis was 12 months but wide inter patient variation was seen. The most common presenting symptom were somatosensory (33 %), visual (29 %), motor (21 %), and brainstem/cerebellar problems (9.5 %).Among the patients 8.5 % mentioned a history of MS in their first degree relatives. Relapsing-remitting was the clinical course of the disease in 2460 (77.5 %) patients. 710 (22.5 %) patients had PPMS at the time of registration. Female/male ratio was significantly lower in PPMS than RRMS. Conclusions: Demographic characteristics reported in our study are not in sharp contrast with existing knowledge of MS which is mostly obtained from Western or other Asian populations. P321 Impact of spatial distribution of T2 and T1 lesion volume on disability and brain atrophy M. G. Dwyer, B. Weinstock-Guttman, F. E. Munschauer, S. Hussein, N. Abdelrahman, V. Yella, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Lesion volume (LV) measurement in multiple sclerosis (MS) has consistently demonstrated limited utility in predicting disability and brain atrophy. This may be due to the fact that volume measures alone do not adequately reflect the spatial distribution, yielding similar results for tightly clustered and widely dispersed lesions. Metrics incorporating spatial distribution (geometric size) may therefore be of use in quantitative characterization of lesion burden, and may provide more clinically relevant results. Objective: To examine the relationship between clinical disability, atrophy, and lesion measures incorporating volume and 3D spatial distribution information. Methods: We studied 301 patients with MS (age 46.8 10.1 years, disease duration 14.3 9.2 years, EDSS of 3.7 2.1). Brain parenchymal fraction (BPF) was obtained with an automated program. A semi-automated method was used to create voxel-wise lesion masks, and to determine T2/T1 LVs. From these masks, four distribution-based measures were calculated: spatial standard deviation (SSD), moment of inertia (MOI), Frobenius norm (FN), and centroid size (CS). Each of these measures, except SSD, incorporates both lesion volume and spatial distribution. Parametric and non-parametric correlations were used as appropriate to evaluate the relationship between these measures, EDSS, and BPF. Results: Except SSD, all measures showed significant correlations with EDSS. T2-CS showed a slightly stronger correlation with EDSS than LV alone

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(r = 0.272 for CS, r = 0.266 for LL), and all distribution measures except SSD showed a stronger correlation with BPF than LV alone (r = 0.458 for CS, r = 0.448 for LV). T1-LV alone was the best predictor of EDSS, but all T1 distribution measures, other than SSD, were more strongly correlated with BPF than T1-LV alone (r = –0.498 for CS, r = –0.487 for LV). Conclusions: While EDSS does not appear significantly more related to distribution than to LV alone, higher levels of spatial distribution are associated with more pronounced brain volume loss. Furthermore, CS appeared to be the most sensitive distribution measure. P322 Construct validity of potential multiple sclerosis clinical trial MRI outcome measures D. L. Cookfair, R. H. B. Benedict, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Factor analysis provides useful information regarding the degree of correlations among multiple related variables. It may also be used to reduce several variables to a smaller number of factors without losing information. Objective: To better understand the relationship and degree of correlation between 14 MRI parameters and reduce the 14 parameters to a smaller number of factors which: a) are comprised of related subsets of the larger set of MRI parameters; b) not measuring the same dimensions as other factors; and c) can be analyzed as individual variables themselves. Methods: 303 consecutively accrued MS patients were studied. Most had RR [206] or SP [75] disease. Median EDSS = 2.5; mean: DD = 12.3 ± 8.7 yrs, age 45.2 ± 9.6. MRIs were performed on a 1.5T scanner. Conventional MRI measures included T2-and T1-lesion volumes (LVs), fractions of brain parenchyma (BPF), grey matter (GMF) and white matter (WMF). Non-conventional MRI measures included magnetization transfer ratio (MTR) of T2-LV, normal appearing (NA) WM (NAWM), NAGM, NA brain tissue (NABT) whole brain (WB) and WB mean diffusivity (MD). WB entropy (ENT), third ventricular width (3VW) and lateral ventricular volume (LVV) were also measured in 185 patients. Results: Factor analysis yielded 3 factors explaining 78 % of variance in 11 MRI parameters (N = 303). F1 was defined primarily by NAGM, NAWM, NABT and WB-MTRs; F2 by T1- and T2-LVs, GMF and BPF; F3 by BPF alone. A more differentiated solution was obtained using 14 MRI parameters, explaining 80.6 % of variance (N = 185). F1b was defined by NAGM, NAWM, NABT and WB-MTRs; F2b by BPF, GMF, 3VW and LVV ENT, MD; F3b by T1and T2-LVs; and F4B by WMF. Data are presented showing the relationship between specific MRI factors and EDSS, DD, Tx and clinical course. Conclusions: Some of the 14 MRI variables studied may be measuring overlapping aspects of brain pathology. It is possible to reduce this number without sacrificing important information. P323 Correlation of morphological characteristics of T2 hyperintense lesions with neuropsychological testing in multiple sclerosis R. H. B. Benedict, A. Kilic, S. Hussein, M. G. Dwyer, N. Abdelrahman, B. Weinstock-Guttman, R. Zivadinov Buffalo Neuroimaging Analysis Center (Buffalo, USA) Background: Larger T2 lesions have a tendency to coalesce and form confluent lesions. In our previous work we developed a fully automated method for extracting morphological characteristics of the lesions. Objective: To determine the relative contribution of morphological characteristics of cerebral lesions to cognitive dysfunction in patients with multiple sclerosis (MS). Methods: We studied 67 MS patients (mean age 46.6 ± 8.8 years) using 1.5 T MRI. Disease course was RR = 44, SP = 22, RP = 1. Mean disease duration

Table to P324 Solifenacin in multiple sclerosis patients with overactive bladder – a prospective study Median frequency/day Median volume voided/void Median incontinence episodes/day Median no. pads used/day (IQD = interquartile distance)

was 12.7 ± 8.6. Mean EDSS was 3.4 ± 1.7. T2-lesion volume (LV) was calculated using a semi-automated method. A fully automated program was used to extract different morphological characteristics of the lesions including number, size, volume, concavity, surface factor, brightness, centroid, shape and their orientation respect to the x, y and z axes. Machine learning techniques were employed to classify the lesions as confluent (CFL) or non-confluent (N-CFL) based on lesion characteristics. NP testing included 5 variables derived from the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT), and the Brief Visuospatial Memory Test Revised (BVMTR). Depression was assessed using the Beck Depression Inventory Fast Screen. Results: T1LV explained 67 % of the variance in total T2LV, but only 17 % in CFL T2LV. T1LV was significantly correlated with poor NP performance on all tests (r ranged from BVMTR –0.38 to SDMT –0.46) and T2LV was significantly correlated with poor performance on 3 of 5 tests. While N-CFL T2LV was correlated with no NP measures, CFL T2LV was significantly correlated with all NP tests, with the highest r being for SDMT (r = –0.46). Conclusions: CFL T2LV was together with T1LV the best predictor of cognitive impairment. Advanced pathological substrate and morphological characteristics of lesions are contributing to more cognitive impairment in patients with MS. P324 Solifenacin in multiple sclerosis patients with overactive bladder – a prospective study F. van Rey, P. Jongen, J. Heesakkers University Medical Centre St Radboud (Nijmegen, NL); Multiple Sclerosis Centre Nijmegen (Nijmegen, NL) Introduction: The efficacy and safety of solifenacin, a once daily oral antimuscarinic agent, has already been demonstrated in a randomised, doubleblind placebo controlled study.As an underlying neurological disease was an exclusion criterion in the clinical studies performed until now, no decree can be made on its efficacy in a multiple sclerosis (MS) patient population. In this study the efficacy of Solifenacin was investigated in a MS patient population with complaints of an overactive bladder (OAB). Patients & methods: 30 Patients with MS and complaints of OAB were selected. Patients were treated with Solifenacin 5 mg for a period of 4 weeks after which they were given the choice to raise the dosage to 10 mg, in case of acceptable or no side effects.After a total treatment period of 8 weeks the efficacy of solifenacin was evaluated. Evaluation was done by means of a 72hour voiding diary and the MS QoL 54. Primary endpoints were defined as change from baseline in mean number of voids per 24 hours, mean voided volume per void and number of incontinence episodes per day and number of pads used per day. Change in quality of life (QoL) was a secondary endpoint. Results: 30 MS patients entered the study.After 4 weeks of treatment with Solifenacin 5 mg, 28 patients reported acceptable or no side effects. Of these patients 17 continued the study with the 10 mg dosage, 11 stayed on 5 mg. 2 patients withdrew from the study due to side effects. Evaluation after 8 weeks of treatment compared to baseline showed a decrease on all primary endpoints (see Table). 22 out of 28 patients chose to continue therapy after termination of the study. In spite of the fact that many patients reported a subjective improvement on QoL, this wasn’t apparent when analysing the MS QoL 54 (see Table). Conclusion: Solifenacin is effective in the treatment of MS patients with complaints of a neurogenic overactive bladder. We hypothesize that the little change in QoL is due to the small sample size combined with the fact that only one urological question is incorporated in the MS QoL 54.

Baseline (IQD) n = 30/

After 8 weeks of treatment (IQD) n = 28/

Wilcoxon Signed Ranks Test

11.67 (9.25–13.42)/ 121.93 (103.05–152.89)/ 1.33 (0.00–2.67)/ 2.00 (0.00–3.42)/

9.50 (6.92–10.92)/ 155.33 (103.08–198.16)/ 0.17 (0.00–1.67)/ 1.00 (0.00–2.00)/

p = 0.000 p = 0.000 p = 0.360 p = 0.010

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P325 Peripheral blood mononuclear cell phenotyping in multiple sclerosis patients – different effects of cyclophosphamide and new promising drug natalizumab E. Krasulova, E. Havrdova, H. Mareckova, Z. Vankova, I. Kovarova First School of Medicine (Prague, CZ) Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Our therapeutic possibilities are directed mainly against the inflammation and the efficacy is limited. Cyclophosphamide (CPA) represents a typical immunosupressive drug, which has been used in MS treatment for several decades. Natalizumab is a novel drug in MS treatment – a monoclonal antibody against adhesive molecule alfa4beta1 integrin expressed on lymphocytes. Due to natalizumab binding, integrine does not interact with VCAM-1 (vascular adhesion molecule) and thus lymphocyte is not migrating to the site of inflammation. The results of natalizumab 2-year-study showed 68 % drop in relapse rate. Aim of the study: To compare immunological effects of natalizumab and CPA on peripheral blood mononuclear cells in MS patients. Patients and methods: Peripheral blood was taken and immunophenotyping was performed in 19 MS pts after at least 6 months of open label safety natalizumab study (4 weeks after last administration of the drug), and 59 MS pts treated with monthly pulses of methylprednisolone and CPA, using flow cytometer FACSCalibur and monoclonal antibodies BD Bioscience (CD3, CD19, CD8 + , CCR5, IL2, TNF alfa and IL10 in CD14 + cells). Results: In natalizumab group significantly lower amounts of CD3 + and CD8 + lymphocytes (both p < 0.001), lower production of tumor necrosis factor alfa (TNFalfa, p < 0.001) and interleukin 2 (IL2, p < 0.001), and higher levels of interleukin 10 (IL10, p = 0.0003) were found. Th1 marker – chemokine receptor CCR5 was significantly less expressed on CD4 + lymphocytes in natalizumab group. Significantly lower amounts of CD19 + cells were found in CPA group. Conclusions: Natalizumab has been expected to decrease lymphocyte migration into the CNS. Further investigations suggest additional (immunomodulatory) mechanisms of action of this drug, primarily changing Th1/Th2 balance. CPA is known for its effect on B cells (CD19 +) but the numbers of B cells in natalizumab treated patients exceed even the numbers in normal controls. Further immunological studies may help to clarify not only the extent of natalizumab activities in vivo but also help to prevent possible side-effects.

with 22 or 44 mcg IFN beta-1a. Data from longitudinal analysis of the autoantibody occurrence during treatment compared to baseline will be presented. P327 Comparison of a biological (MxA protein level) and an MRI treatment response indicator for interferon beta therapy in multiple sclerosis G. Contessa, M. Clerico, P. Barbero, B. Ferrero, A. Ricci, E. Versino, G. Giuliani, E. Montanari, L. Durelli for the OPTIMS Study Group Objective: Predictivity analysis of serial MRI scans or MxA protein level increase as response indicators of interferon beta(IFNB) treatment. Background: Some 30–50 % patients do not fully respond to IFNB treatment and might require a dose adjustment or treatment change. The OPTimization of Interferon for MS (OPTIMS) trial is a multicenter trial involving 20 MS centers evaluating a new high (375 mcg every other day)(EOD) dose of IFNB-1b. Design/methods: MxA protein leukocyte production was determined by a two-site chemiluminescent sandwich assay in whole blood.We used as suboptimal treatment response indicators eitehr an active scan (with a new T2 or a gadolinium-enhancing lesion) or an increase of MxA protein level during a 6-month run-in phase where all patients were treated with 250 mcg EOD IFNB-1b patients. Primary outcome was the occurrence of either a clinical or an MRI suboptimal response (SR) during 18 months after run-in. Clinical SR: occurrence of a relapse or of sustained disease progression; MRI SR: at least one active scan. ROC analysis was used to assess sensitivity, specificity, and predictivity of the two response indicators. Results: In order to simulate clinical practice as closely as possible, subject of the main predictivity analysis were only the patients continuously treated with 250 mcg IFNB-1b (144 who received serial MRI scans and 66 whose whole blood samples were available for MxA level dosage). A single active scan or an increase of MxA levels below 3-fold baseline during the first 6 months of treatment predicted persistent clinical or MRI SR with a statistically significant specificity and positive predictivity (p < 0.05). Conclusion: Both indicators had a good positive predictivity. MxA test requires whole blood samples and only a minority of MS centers could contribute to the analysis. MRI scans were available from all 20 centers indicating that the use of MRI activity as treatment response indicator (with a good specificity and predictivity) can be easily done by any MS center. The study has been supported by Schering Italia S. p. A.

P326 The AUtoimmunity PRofile in INterferon beta (AUPRIN) study: occurrence of autimmune events during treatment with two different dosages of subcutaneous Interferon beta-1a (Rebif) L. Durelli, P. Barbero, M. Clerico, G. Contessa, A. Pipieri, L. Giordano for the AUPRIN Study Group

P328 Alpha and gamma enolase as possible biological markers in multiple sclerosis C. Maggiore, A. Cortini, S. Bembich, M. Zorzon, R. Marzari, A. Bosco, L. Locatelli, A. Bratina, M. Catalan, G. Pizzolato, P. Edomi University of Trieste – Ospedale di Cattinara (Trieste, I); University of Trieste (Trieste, I)

Background and objective: Immune response activation is particularly relevant for the treatment of a probable immune-mediated disease such as Multiple sclerosis (MS) reported that the frequency of autoimmune diseases is increased during interferon (IFN) beta treatment of MS patients; while others reported random, not statistically significant changes during the followup. To evaluate autoimmune events occurrence and autoantibody production in patients treated with 22 or 44 mcg IFN beta-1a subcutaneously, three times per week (TIW), in relapsing-remitting (RR) MS patients. Designs and methods: AUPRIN is a multicenter prospective observational study involving 30 MS centres. Patients with clinically definite RRMS, with an EDSS score between 1.0 and 5.0; and two clinically documented exacerbations during the preceding 2 years were included.All the patients were followed up for 12 months with clinical and laboratory assessments every 3 months.Autoantibody against the following antigens were studied: liver kidney microsomal, nuclear, smooth muscle, mitochondrial, gastric parietal cell, human thyroglobulin, and thyroid microsomal antigens. cross sectional and longitudinal analyses have been done. Results: 184 consecutive patients who started IFN beta-1a treatment between December 2000 and September 2003, were included in the study; 104 were treated with 22 IFN beta-1a mcg, and 80 with 44 IFN beta-1a mcg. Baseline demographics were similar in the two groups. Side effects occurrence showed no statistical differences in the two groups. The haematological parameters and the autoantibody production showed no statistical significant alterations of levels during the follow-up in the two groups. No autoimmune diseases occurred in both groups. Relapse rate showed statistical significant reduction if compared with the year before. Conclusions: 22 mcg and 44 mcg IFN beta-1a were well tolerated. The autoantibody production was not significantly different in the patients treated

Multiple sclerosis (MS) pathogenesis is attributed to immune mechanisms. This hypothesis is supported by analogies with the animal model experimental allergic encephalomyelitis (EAE). Several myelin specific autoantibodies have been identified, but until now no direct role in the pathogenesis of the disease has been established for any of them. To analyse the nature of global immune response in MS patient we used the phage display approach. Initially, we performed a global serological analysis of serum and CSF of MS patients by means of Western blot on bidimensional electrophoresis (2D-EF). Further on, the immune response of patient sera was evaluated in ELISA assays against known or potential autoantigens of MS, such as, MBP, MOG, alphaB cristallin, alpha-enolase, gamma-enolase, and ganglioside. Patients with more complex 2D-EF pattern of recognition and with more specific response against some antigens have been chosen to make phage display antibody libraries from peripheral blood lymphocytes (PBL). Because both IgG and IgM class antibodies have been associated with MS, we constructed phage display libraries for both classes of antibodies. Antibody libraries from PBL of relapsing-remitting and primary progressive patients were produced. In particular, our attention turned to alpha and gamma enolase that were recognized specifically by sera of patients from whom the antibody libraries were created. The enolase is a glycolitic enzyme belonging to a class of surface proteins and its role in autoimmunity was recently established. The IgG antibody phage libraries were selected through three cycles of binding, washing, and elution, on an immobilized recombinant human gamma-enolase. The positivity of recombinant antibodies was tested by means of ELISA. More than 80 % of clones were able to recognize the gamma-enolase.An isolated recombinant antibody was also able to recognize the gamma-enolase in Western blot on human tissue lysates.

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Based on these results, we analyzed MS patients sera by ELISA assays against alpha and gamma enolase, and by a two-site immunoluminometric assay (sandwich principle) for neuron-specific enolase (NSE) (quantitative determination). Finally, the potential of recombinant human gamma enolase to induce experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice was evaluated. Our data support the hypothesis that human enolase may be considered a potential biological marker of MS with the related diagnostic implications. P329 Cholesterol abnormalities in a cohort of Sicilian patients with multiple sclerosis R. Grimaldi, L. M. E. Grimaldi, B. Palmeri, G. Vitello, A. Gallo, P. Ragonese, G. Salemi, G. Savettieri Fondazione Ist. San Raffaele “G. Giglio (Cefalù, I); University of Palermo (Palermo, I); AUSL 2 (Caltanissetta, I) Objectives: To evaluate the levels total cholesterol (tot-chol), HDL cholesterol (HDL), LDL cholesterol (LDL) and triglyceride in multiple sclerosis (MS). Methods: Samples were collected between January 2001 and September 2005 from patients at different stages of the disease and followed in two Sicilian MS centres. Results were correlated to age, sex, disease duration, therapy, relapses and body mass index (BMI) and to blood lipid levels of a rural control population. We also determined the prevalence of familiarity for hypercholesterolemia. Patients with diabetes, hypotiroidism, hepatic and kidney diseases, and those in treatment with statins within three months before blood sample were excluded. Results: Among 215 patients studied, 142 were diagnosed as having the relapsing remitting form, 18 primary progressive; 50 secondary progressive; 5 progressive relapsing; mean age (± SD) of 40.01 ± 10.44 years (range 15–68), disease duration 10.59 ± 2.22 years, mean EDSS 3.6 ± 2.3 and mean BMI 24.9 ± 4.4. 136 patients were assuming MS specific drugs: 99 under immunomodulatory (IM) treatments (interferons beta1a and 1b,glatiramer acetate), 28 under immunosuppression (IS) (mitoxantrone, azatioprina, metotrexate) and 9 under a combined therapy. A significant increase of totchol (201.14 ± 47.92 mg/dl vs 192.2 ± 42.5 mg/dl; p < 0.02), was observed in MS patients with respect controls. In the group of MS patients between age 20–59, HDL was higher than controls (52.65 ± 14.08 mg/dl vs 44.3 ± 11.2 mg/dl; p < 0.001). An higher percentage of familial hypercholesterolemia was observed in male patients compared to controls (34 % vs 24 %). Interestingly we found a significant decrease of HDL among relapsefree patients compared to those with a relapse in the previous three months (50.2 mg/dl; n = 104 vs 59.6 mg/dl; n = 15; p = 0.02). Finally, HDL was significantly lower in patients under IM or IS therapy (49.88 ± 12.99; n = 114 vs 56.3 ± 14.53; n = 68; p = 0.001). Lower HDL levels were observed in patients under IFN beta 1a 22 mcg and 44 mcg three times a week. Conclusion: This study further suggests an involvement of lipids (especially of HDL) in patients with MS. Tot-chol and HDL levels are elevated in MS patients compared to controls. Interestingly, HDL increases in patients with a relapse not treated with steroids, and decreases in patients treated with IFN-beta, respect patients treated with IM drugs. It is unknown whether alteration of lipid methabolism is relevant to the clinical effects of immunotherapies. P330 The effect of interferon therapy on relapses and progression of disability in patients with clinically isolated syndromes suggestive of multiple sclerosis M. R. Motamed, N. Najimi, S. M. Fereshtehnejad Iran University of Medical Sciences (Tehran, IR) Objective: Multiple sclerosis(MS) is the most common demyelinative disease of the central nervous system among young adults.In 85 % of young adults with MS,onset is a subacute clinically isolated syndromes(CIS) of the optic nerves,brainstem or spinal-cord.The assessment and clinical approach of the patients who present with a CIS have been sought.Because a CIS is typically the earliest clinical expression of MS,it seems that disease-modifying treatments may prevent progression of disability and developed MS. Therefore, the aim of this study was to evaluate interferon’s impact on relapses and progression of disability in patients with a CIS. Methods: This prospective cohort study was conducted on 25 patients who were supposed to present a CIS suggestive of MS(after ruling out other causes).The patients were evaluated from October 2002 to March 2005 in two groups:11 patients under IFN therapy(groupA) and 14 patients without disease-modifying treatment(groupB).The used IFN in groupA was betaIFN1A(Rebif) administering subcutaneously three times a week.The progression of disability which was determined using Kurtzke Expanded

Disability Status Scale(EDSS) at the beginning,in regular follow-ups, at the end of study period and the number of relapses were recorded and analyzed using SPSSv 0.13 software.T-test,One way ANOVA,Repeated measurement and Linear regression model were used in analysis. Result: The mean age of patients was 25.12(SD = 6.36).Among the patients 8(32 %) were male and 17(68 %) were female. The most common CISs were optic neuritis(32 %),spinal-cord syndrome (28 %),brainstem syndrome(24 %) and cerebellar symptoms(16 %).The mean of number of new relapses during the study period were 0.68(SD = 0.80)and 1.79(SD = 1.05) in groups A and B, respectively.In addition, the mean of EDSS changes at the end of study were –1.09(SD = 0.49) and –0.64 (SD = 0.49) in groups A and B, respectively. Statistical analysis showed that disease-modifying treatment with beta-IFN1A may reduce relapses(P = 0.007) and prevent progressive disability(P = 0.034). Conclusion: Administration of disease-modifying treatment for the patients with a CIS is still controversial.On the other hand,as CIS is typically the earliest presentation of MS,disease-modifying treatment for CIS may lead to beneficial results.And also, our results show that beta-IFN significantly delayed progression to disability and incidence of new relapses.

Peripheral neuropathy P331 Myeloradiculoneuropathy of acute onset following gastric surgery M. R. G. de Freitas, O. J. M. Nascimento Federal Fluminense University (Niterói, BR) Polyneuropathy may follow gastric surgery for weight loss. Although vitamins deficiency seems to be a factor, in many cases no specific deficiencies are identified. The clinical picture is one of acute or sub acute sensory loss and weakness. We described a case with features of both sub acute polyneuropathy and myelopathy in a patient five weeks after gastric surgery for weight loss. A 31 year old age male was submitted to Capella’s reductive gastroplasty. He lost 21 kg in a month. Five weeks after the surgery, he presented paresthesias, pain and weakness (and) in the lower limbs. In seven days he was wheelchair-bound. Parenteral infusion of vitamins and methylprednisolone was given. Neurological examination showed lower limbs proximal muscular weakness, thermo-algesic hypoesthesia with a T10 sensory level and absent patellar and ankle reflexes. Electrophysiological examination showed abolished sensory nerve action potential, low motor amplitudes and denervation in all lower limbs muscle groups. CSF, blood analysis and a thoraciclumbar spine MRI were normal. One month afterward pain had subsided but a sensory level and a proximal lower limbs weakness persisted. Clinical and electrophysiologic findings in our case are in accordance with a sensory-motor axonopathy. The sensory level is indicative of simultaneously myelopathy, possibly related to the metabolic derangement due to a rapid weight loss. P332 Demyelinating neuropathies after TNF alpha blockers infusion P. Lozeron, C. Denier, D. Adams, C. Lacroix, G. Said Bicêtre Hospital (Kremlin Bicêtre, F) Tumour necrosis factor(TNF) alpha blockers are routinely used in the treatment of inflammatory disorders including rheumatoid arthritis (RA), ankylosing spondylitis, and Crohn disease. Neurological complications attributable to this treatment have been reported including essentially central nervous system-demyelinating disease. Concerning peripheral nervous system, to our knowledge, only two chronic inflammatory demyelinating polyneuropathy and one Guillain-Barre syndrome have been reported to date. We report herein three novel patients who developed demyelinating neuropathy resembling CIDP after initiation of TNF alpha blockers. They had been treated respectively for RA, psoriasic rheumatism and Verneuil disease. One patient presented a progressively worsening purely sensory neuropathy affecting all for extremities months after the last TNF alpha blockers infusion. Two patients presented a multifocal sensory motor neuropathy affecting only the upper limbs hours to weeks after the last TNF alpha blockers therapy. Electrophysiological analysis was performed between 1.5 and 6 months after symptoms onset. In the two patients with mainly motor deficit, conduction blocks with reduced motor conduction across the blocks were found in affected territories (median and ulnar nerves either at the forearm or at

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the arm). No motor conduction abnormality was found in non affected territories. Sensory responses were normal suggesting a radicular involvement in the sensory symptoms. In the third patient with pure sensory symptoms, electrophysiology found sensory motor demyelinating polyneuropathy with severely reduced conduction velocities and prolonged distal latencies and F waves. No conduction block was found. A nerve biopsy performed on this last patient confirmed the demylinating neuropathy. Contrarily to previous reports in which patients improved without any specific therapy, one of our patients with disabling multifocal motor neuropathy needed treatment. Unfortunately, intravenous immunoglobulins and plasmapheresis were given without benefit. This emphasize the possibility of poor prognosis of demyelinanting polyneuropathies occurring after TNF alpha blockers infusion. P333 Short- and long-term evaluation of liver transplantation in familial amyloid neuropathy with rare transthyretin variants (non Val30Met) H. Husson, V. Planté-Bordeneuve, C. Zaros, M. Misrahi, S. Dinanian, D. Adams, M. Slama, D. Samuel, G. Said CHU Bicètre, Centre d’étude des neuropathies amyloides familiales (Paris, F); CHU Antoine Béclère (Clamart, F); CH Paul Brousse (Villejuif, F) Transthyretin (TTR) amyloidosis is a severe autosomal dominant affection characterized by a sensori-motor and autonomic neuropathy associated with a cardiomyopathy. The disease progresses over 10 years in average. Since 1990, liver transplantation (LT) has allowed to improve the prognosis of the affection mainly in patients with the most frequently encountered Val30Met variant. Data remain scarce in cases who display other TTR mutations. Objective: to evaluate prospectively the short and long term effects of LT in patients with non Val30Met TTR variants. Methods: patients were evaluated 1 to 6 months preLT and every 6 months after the procedure. At each visit, a neurological examination was performed including a walking score. Functional abilities and vegetative symptoms were assessed through 2 questionnaires i. e. a modified Norris score and a newly designed compound autonomic dysfunction test (CADT) detailed elsewhere. From 1993 to 2005, 25 patients were included, with the following TTR variants Ser77Tyr (n = 8), Ser77Phe (n = 5), Thr49Ala (n = 3), Ser50Arg (n = 3), miscellaneous (n = 6). There were 16 men and 9 women. First symptoms occurred at a mean age of 51.5 ± 7.5 years. LT was performed in average 3.3 ± 1.8years after the disease onset.Virtually all patients (24 out of 25) had associated cardiac amyloidosis, including 14 who required a pace maker implantation. Results: After a mean follow up of 27 months [range 7–59 months], walking abilities remain stable in 80 % of patients who were able to walk unaided before. The functional score was unchanged in 87 % of patients who had a preLT scoring above 70 out of 81. The vegetative score remains stable in the majority of patients (80 %). It slightly deteriorated in the remaining cases (20 %). Overall, death occurred in 9 patients, including 7 within the 1st year postLT. Mortality was due to cardiovascular and hepatic complications in 4 and 3 cases, respectively. Conclusion: This study showed that LT might stop the neurological progression of TTR amyloidosis (non Val30Met variants) when performed very early in the course of the disease i. e. in patients able to walk unaided.A careful evaluation of the cardiac function is mandatory before LT, to reduce the high rate of cardiovascular death observed in this population. Supported by a grant from the French Ministry of Health for the study of Rares Disorders – Familial amyloid polyneuropathy P334 The cost effectiveness of duloxetine in the treatment of diabetic peripheral neuropathic pain in the UK S. Beard, L. McCrink, T. K. Le RTI Health Solutions (Manchester, UK); Eli Lilly (Indianapolis, USA) Objective: Diabetic peripheral neuropathic pain (DPNP) is a common complication of diabetes. The objective of this analysis was to evaluate the costeffectiveness of duloxetine as an additional step to standard DPNP treatment from the perspective of the United Kingdom (UK) health service. Methods: A decision model was used to represent sequential management of patients with DPNP. Treatment pathways were based on national clinical guidelines and expert opinion. Standard practice was represented as first-line tricyclic antidepressants (amitriptyline), second-line anticonvulsants (gabapentin) and lastly opioids (tramadol). The cost effectiveness of duloxetine, as an additional first, second or third-line therapy was evaluated over a 6-month time horizon for a cohort of 1000 patients. The model considered three levels of pain response based on an 11-point pain severity scale

(from no pain to worst possible pain): Full response (> = 50 % change from baseline); partial response (> = 30 to 49 %), and no response (< 30 %). The model was populated with efficacy and discontinuation data from placebocontrolled clinical trials of DPNP treatments, identified via Medline and internet searches. As there are no trials directly comparing treatment options for DPNP, indirect comparisons were made through relative effects to placebo. Direct costs were taken from national published sources at 2004 prices. Results: Duloxetine resulted in cost savings when introduced as first-line (≤ £34.791) and second-line (≤ £77.071) therapy. Both first and second-line treatment resulted in an additional 60–61 responders and 29 full responders for every 1000 treated patients. Additional quality-adjusted life years (QALYs) were 2.45 (second-line) and 1.88 (first-line). Therefore, duloxetine as a first or second-line therapy dominated standard treatment (i. e. was more effective and less expensive). Third-line duloxetine resulted in ≤ £4.338 additional cost and 1.61 additional QALYs, an incremental cost effectiveness ratio (ICER) of ≤ £2.698 per QALY compared to standard therapy. The results were robust to deterministic and stochastic sensitivity analyses, demonstrating an 80–95 % probability of cost saving when using duloxetine as an additional first or second-line treatment. Conclusion: This cost-effectiveness analysis shows that duloxetine, introduced as a first or second line option, is dominant in the treatment of DPNP when compared to standard treatment in the UK, and has an acceptable ICER as a third-line option. This study was jointly funded by Eli Lilly and Boehringer Ingelheim P335 Relapsing Guillain-Barré syndrome in beta-haemolytic group A streptococcal infection A. Alfaro, N. Diosdado, F. Pérez-Miralles, N. Muelas, J. C. Sánchez Hospital La Fe (Valencia, E) Objectives: There is mounting evidence of molecular mimicry in the pathogenesis of Guillain-Barré syndrome (GBS), especially regarding glycolipidic structures of Campylobacter yeyuni and Mycoplasma pneumoniae. There are old reports of GBS in scarlet fever and acute articular rheumatism, and hemolytic streptococcus has been isolated from two patients with the Miller Fisher syndrome (MFS). We report a patient with GBS, from whom beta-hemolytic group A streptococcus (BHGAS) was isolated during a relapse with acute pharyngitis. Methods: A 26-year-old man was admitted to the Hospital because of weakness of the upper extremities and unsteadiness of both legs that worsened over the past 2 weeks. An early EMG was normal. Neurologic examination showed global and symmetrical loss of strength in the arms and the flexor and extensor muscles of the hip. Muscle stretch reflexes other than mandibular and ankle jerk were absent. Treatment with intravenous immunoglobulins was followed by complete recovery and the patient was discharged asymptomatic 13 days after admission. Weakness reappeared 2 months later in a slighter but almost identical fashion, and was followed 7 days later by fever and odynophagia. Pharynx was hyperemic with no pus. Immunoglobulins were administered again with complete recovery. Results: First admission: Normal blood count. CK: 887 IU/l. IgA. 297, IgM: 103, IgG: 1260 mg/dl. ESR: 13 mm/hr. CRP: 1.9 mg/dl. ASO: 116 IU/l. Urine porphyrins negative. CSF: 3 cells/mm3 (mononuclear), total proteins: 64 mg/dl. EMG: important proximal blocking with preservation of peripheral motor and sensory conduction. Chronodispersion and low amplitudes of F responses. Increased latency and low amplitude of right H reflex. Bilateral trigeminofacial reflex and right sympathetic skin response were normal. MRI: discal protrusions at multiple cervical and dorsal levels. Second admission: Throat cultures: BHGAS, sensible to penicillin and rifampicin. Blood count: normal except 14.900 leucocytes/mm3, 92.8 % neutrophils. CK: 160.7 IU/l. CSF: 0 cells/mm3, total proteins: 52 mg/dl. EMG: similar results as the anterior study, without signs of acute denervation activity, i. e. proximal demyelination/blocking with scanty axonal degeneration. Conclusion: BHGAS should be investigated among other pathogens that cause sore throat in order to establish its possible role in the development and course of GBS. P336 Clinical features of neuropathy over 80 years: a retrospective study of 100 patients M. Suzuki, C. Lacroix, P. Lozeron, G. Said CHU de Bicetre (Le Kremlin Bicetre, F) Background: Peripheral neuropathy is an important cause of disability in the elderly. Objectives and methods: In order to refine our knowledge on the subject,

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we reviewed the clinical, electrophysiological and nerve biopsy findings in a series of 100 patients elder than 80 years referred for a disabling neuropathy, from July 1995 to November 2005. Results: One hundred patients were included in this study, 50 men and 50 women. The mean age was 82.8 years (range from 80 to 91). The mean interval from first symptoms to biopsy was 1.9 yrs. 22 sural nerve, 69 peroneal nerve, 3 radial nerve, one ulnar nerve, and 5 femoral nerve were biopsied. Thirty-two patients had different patterns of chronic inflammatory demyelinating polyneuropathy (CIDP); 18 patients had a vasculitic neuropathy. Of the 17 patients with monoclonal gammopathy, 10 had a chronic demyelinating polyneuropathy; one had a vasculitic neuropathy; 3 had an axonal neuropathy; 3 showed the normal nerve morphologically. Of the 8 diabetic patients, 3 had CIDP; 2 had a length-dependent diabetic neuropathy; one had a neuropathy associated with monoclonal gammopathy; one had an axonal inflammatory neuropathy; the nerve was normal morphologically in one. Ten out of the 18 patients with vasculitic neuropathy had a multifocal sensory-motor neuropathy, while the others had a distal symmetrical sensory-motor neuropathy. The other causes included a sequelae of cisplatin neuropathy, neuralgic amyotrophy, motor neuron disease and radicular metastasis. Thirteen patients had normal nerve biopsy findings in an affected territory, which is in favour of preganglionic radicular lesions, secondary suggest to that spinal spondylosis. Conclusion: CIDP and vasculitic neuropathy remain the most common treatable causes of neuropathy after the age of 80. Nerve biopsy is very useful for diagnosis. P337 An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy K. Toyooka, H. Fujimura, M. Funauchi Toneyama National Hospital (Toyonaka, JP); Osaka Medical Center for cancer and cardiovascular diseases (Osaka, JP) An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy was reported. Objectives: A 45-year-old Japanese man presented with progressive muscular weakness. In spite of steroid therapy, intravenous immunoglobulin treatment and plasma exchange, each resulting in transient improvement, his muscle wasting worsened. He died of respiratory failure at the age of 52. He also had IgM paraproteinemia. Methods: Brain, spinal cord, ventral and dorsal roots (VR, DR), dosal root ganglia (DRG), sympathetic ganglia (SyG), lumbar plexus (LuP), femoral nerve (FeN), sciatic nerve (ScN), common peroneal nerve (CoPN) and superficial peronel nerve (SuPN) were histopathologically investigated. Results: 1.Perivascular mononuclear cell infiltration, mainly in the epineurium (LuP > DRG > SyG, FeN, ScN > VR, SuPN > DR, CoPN). 2. Remarkable endoneurial edema with considerable focality among and within fascicles (LuP, ScN, VR > DRG, SyG, distal nerves). 3. Numerous onion bulb formations, with considerable focality among and within fascicles (VR > FeN, ScN > > distal nerves). 4. Moderate axonal loss, predominating on the distal part of the peripheral nerves. 5. Some neuronal loss in DRG, SyG and spinal anterior horn. 6. Degeneration in posterior columns of spinal cord. 7 Moderate to severe neurogenic atrophy of the muscle (peroneal brevis muscle > iliopsoas muscle). Conclusion: Neuropathological examination showed widespread multifocal inflammation, endoneurial edema and onion bulb formation, with remarkable difference among and within fascicles, accentuated axonal loss at the distal part of the peripheral nerves and severe degeneration in posterior columns of spinal cord. P338 Glycolipid antigens in patients with paraproteinaemia associated neuropathies or motor neuron disease K. Kilidireas, L. Muselimi, A. Politi, E. Karantoni, A. Anagnostopoulos, A. Dimitrakopoulos, D. Vassilopoulos, M. A. Dimopoulos University of Athens (Athens, GR) Objectives: Twenty-nine patients with paraproteinemia associated neuropathy or motor neuron disease were tested for glycolipid target antigens. Methods: The underlying disease was Waldenstrom’s Macroglobulinemia in 2 patients, MALT (Mucosa Associated Lymphoid Tumor) lymphoma in 2 patients, Multiple Myeloma in one patient, POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein band, Skin pigmentation/tethering) in 2 patients and MGUS (Monoclonal Gammopathy of Unknown Significance) in the remaining 23 (13 IgM, 4IgA, 6 IgG). The monoclonal paraprotein was IgM in 16 cases, IgA in 6 cases and IgG in 7 cases. Glycolipid target antigens were tested with Enzyme-Linked Im-

munoSorbent Assay (GM1, ASGM1, GD1a, GD1b, sulfatides) or Thin Layer Chromatography overlay with glycolipid extracts of Bovine Cauda Equina. Results: Twelve out of 16 IgM paraproteins recognised SGPG (sulfated glucuronic acid paragloboside), SGLPG (sulfated glucuronyl lactosaminyl paragloboside) and 2 of them also sulfatides. In eleven out of these 12 cases, the associated clinical syndrome was demyelinative sensory or sensorimotor neuropathy and axonal sensory neuropathy in the remaining 1 case. Two out of 16 IgM paraproteins had GM1 as target antigen (titers up to 12.800) and the associated disease was multifocal motor neuropathy with conduction block. In one of these 2 cases the monoclonal IgM recognised also ASGM1, but the other did not. In the remaining 2 out of 16 IgM paraproteins, target antigen was not identified (1 patient had chronic inflammatory demyelinative polyneuropathy and 1 had sensorimotor neuropathy). None of the IgG or IgA monoclonal paraproteins recognised glycolipid antigens and the associated clinical syndromes differed, as 6 patients had motor neuron disease (3 IgG, 3 IgA) and 7 patients had peripheral neuropathy (4 IgG and 3 IgA).On the contrary, the Western Blot assay with LAN-5 neuroblastoma cell line as source of antigen, revealed several proteins as target antigens of the monoclonal IgG and IgA immunoglobulins. Conclusion: IgM paraproteins tend to react with glycolipid antigens more than IgA or IgG and the related syndrome is neuropathy. IgG or IgA paraproteins relate to motor neuron disease more than IgM and recognise several protein antigens. P339 The incidence of carpal tunnel syndrome and other peripheral nerve abnormalities in upper extremities of iron-steel industry workers M. Gedizlioglu, E. Arpaci, D. Cevher, P. Ce, C. Kulan, I. Colak, B. Duzgun Izmir Research and Training Hospital (Izmir, TR); Aliaga Local Hospital (Izmir, TR) Objective: Work related recurrent twisting movements of the wrist constitutes an apparent risk for the development of carpal tunnel syndrome (CTS). There is general agreement on universally high risk of certain occupations like musicians (up to 20 %) or fish, poultry and meat processing industry. In this study we investigated the risk of development of CTS in iron-steel industry workers. Method: 80 subjects randomly assigned for the study among 650 workers of the steel factory. 53 healthy controls with occupations unrelated to heavy bodily work were enrolled. The inclusion criteria were to be 30–60 years age; minimum 10 years’ duration of work in steel industry; no history of drug or alcohol abuse; no history of systemic illnesses, particularly diabetes mellitus or thyroid dysfunction. All subjects were males. Informed consent of all subjects and approval of local ethical committee were obtained. The electrophysiologic evaluation involved median (1st and 3rd fingers) and ulnar (5th finger) sensory nerve conduction velocities (SNCVs) and sensory action potential (SNAP) amplitudes in both hands, median (both arms) and ulnar (right arm) distal motor latencies (DML), motor NCVs, and compound muscle action potential (CMAP) amplitudes. The findings were statistically analysed by Student’s t and chi square tests. Results: Worker and control subjects did not differ in terms of age, hand dominancy, and body mass indexes. One control subject had CTS electrophysiologically diagnosed, but none in the worker group. However, in the worker group all SNCVs and ulnar SNAP amplitudes in both hands and distal motor latencies (both median and right ulnar) including left median NCV were statistically meaningfully different from controls. Interestingly differencies were more remarkable in non-dominant hand and in ulnar nerves. Conclusion: In a group of heavy labourers without any risk factor,no case of CTS was detected. However electrophysiologic parameters, though within normal limits, were all different from controls, more significant in sensory nerves, in non-dominant hand and in ulnar nerves. Similar results are reported in forestry workers. The results point to a diffuse, but subclinical injury of peripheral nerves under heavy bodily work conditions, instead of a local affection like CTS. P340 Cranial and peripheral neuropathy due to leptomeningeal infiltration in patient with Waldenstrom’s macroglobulinaemia R. Sutter, C. Arber, A. Tichelli, A. J. Steck, A. Czaplinski University of Basel (Basel, CH) We present the case of a 70 year old male who was diagnosed with Waldenstrom’s macroglobulinemia (WM). Bone marrow infiltration at time of diagnosis was 40 %, the monoclonal IgM kappa in peripheral blood was

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11.5 g/L, and cryoglobulines were present. The patient responded well to the therapy with four cycles of R-CHOP and achieved a very good partial remission with only a residual bone marrow infiltration of 5–10 % and the monoclonal IgM kappa was 0.7 g/L. Six months later, the patient gradually developed nuchal rigidity, double vision, dysphagia and dysarthria. The clinical examination showed meningism and severe bulbar paralysis along with symptoms of sensori-motor polyneuropathy. Examination of CSF disclosed 106 cells/mm3, elevated protein level (3160 mg/l), and elevated beta-2-microglobulin (6.35 mg/L). Cytologic analyses revealed atypical lymphocytes and flow cytometry showed a kappa monoclonal CD19 positive B-cell population. Bone marrow examination showed a persistent multifocal infiltration (15 %) with lymphoplasmacytic lymphoma. The serum monoclonal IgM kappa was 0.4 g/l, cryoglobulines were low, and serum anti-MAG (myelin associated glycoprotein) antibodies were negative. The brain MRI showed a weak thickening of leptomeninges without tumour mass. In addition, nerve roots of the cauda equina were enlarged and enhanced after gadolinium administration. These findings were interpreted as cranial and peripheral neuropathy due to leptomeningeal and nerve root infiltration of lymphoplasmacytic lymphoma and a palliative radiation therapy of the brain and the cauda with simultaneous steroid therapy were established. The patient’s condition promptly improved with a clear decrease of bulbar and polyneuropathic symptoms. Sensori-motor neuropathy related to the antibody activity of the monoclonal IgM to the MAG is a well-known neurological complication of WM. However, affection of the peripheral nervous system due to leptomeningeal infiltration by neoplastic cells is very rare and has been reported in few cases only. Remarkably, in contrast to other lymphomas where meningeal involvement develops in the setting of progressive disease, in our patient meningeal infiltration occurred in a stable partial remission phase of the WM. In conclusion, we hypothesize that WM may progress in the nervous system without transformation into a more malignant B-cell-lymphoma (Richter’s syndrome) even if the initial chemotherapy leads to significant remission of the disease. P341 Peripheral nervous system impairment in patients with chronic renal failure K. Lipatov, A. Belova, V. Krupin, K. Beliakov Medical Academy (Nizhniy Novgorod, RUS); Regional Hospital (Nizhniy Novgorod, RUS) The aim of our research was to study the character and the reversibility of the peripheral nerves impairment in patients with chronic renal failure (CRF) depending on its duration and the method of correction. 63 patients (aged from 22 to 66, duration of CRF 1–12 years) hospitalized to the hemodialysis center passed a neurological and neurophysiologic (electromyography) examination. The peroneal, tibial and sural nerves were tested for nerve conduction velocity and action potentials. 30 healthy volunteers aged from 25 to 65 years made up the control group. Results: 21 patients were predialytic (group I); 28 patients were treated by hemodialysis (group II) and 14 patients survived kidney transplantation – group III. In the predialytic group more than the half of patients [12] had clinical symptoms and signs of sensory polyneuropathy (pain, paresthesia, sensation “stocking and glove” deficit pattern). Electromyography confirmed impairment of peripheral nerves in 18 cases in group I. The signs of axonal sensory fibers degeneration dominated, but the signs of demyelination and motor impairment were also present. One third of the patients with chronic hemodialysis treatment [10] had clinical polyneuropathy symptoms, the neurophysiologic signs of peripheral nerves pathology in group II were discovered in 22 cases. Electromyography pattern was the same as in group I. In group III only 2 patients (less than one sixth) had complaints and signs suggesting polyneuropathy,and electromyography abnormalities were discovered in 5 cases. Only the signs of axonal degeneration in sensory and motor fibers were present; conduction velocity was intact. Statistics analysis (Fisher Exact Method) revealed a significant difference (p < 0.05) between groups I and III, II and III in clinical manifestation and electrophysiology abnormalities incidence, but not between groups I – II. According to Spearmen ranks test, there was no significant correlation between the duration of CRF and the signs of peripheral nerves impairment (p > 0.05). Conclusion: Peripheral nerves impairment is common in patients with chronic renal failure.The electromyography signs of neuropathy may be present in cases where clinical manifestations are absent so far. The axonal degeneration of sensor fibres dominates. The treatment of chronic renal failure reduces the polyneuropathy signs; the patients with kidney transplantation demonstrated the most significant regress of pathological changes.

P342 Polyneuropathies in elderly patients E. Koutsouraki, D. Michmizos, N. Vlaikidis, V. Costa, S. J. Baloyannis Aristotelion University AHEPA Hospital (Thessaloniki, GR) We examined retrospectively twelve patients, at a mean age of 70 years and a male to female ratio of 11:1, who demonstrated neurophysiologicaly confirmed polyneuropathy. Most of these patients complained of weakness and numbness of their lower and, to a lesser extent, upper extrimities. The most common findings included loss of reflexes, distal symmetrical impairment of epidermal sensation, weakness in the distal parts of the limbs, as well as, significant diminution in vibratory sensation and nerve conduction velocities. Three of the patients (25 %) demonstrated a sensory form of polyneuropathy, one (8 %) a motor type and the rest (67 %) a sensorimotor type of polyneuropathy. Four of the patients (33 %) suffered from diabetes mellitus, threee (33 %) were alcoholic, whereas six (50 %) demonstrated anaemia due to vitamin B12 deficiency, two (17 %) were symptomatic of renal deficiency, five (41 %) of heart problems, one (8 %) of hyperthyroidism, one (8 %) of Ca (lung) and one patient (8 %) who expired during hospitalization due to intestinal perforation. In addition, one patient demonstrated both anaemia and positive Ra-test whereas another increased ani-nuclear antibodies. Our results indicate that sensorimotor polyneuropathy is the most common type of polyneuropathies in elderly patients, and it is usually associated with vitamin B12 (cobalamine) deficiency. P343 Unusual presentation of hereditary neuropathy with pressure palsies as diffuse symmetric demyelinating polyneuropathy S. Renaud, P. Fuhr, P. Zgraggen, C. Gobbi, J. Weis, M. Tolnay, A. J. Steck University Hospital Basel (Basel, CH); (Luzern, CH); University Hospital Aachen (Aachen, D) Background: The spectrum of phenotypic expression of hereditary peuropathy with pressure palsies (HNPP) is broad. However, most of the patients present with episodes of transient focal weakness. We report two patients whose first symptoms were a diffuse symmetric polyneuropathy. Case reports: Patient 1 was a 50 year old metal worker who noted three years prior to consultation a stocking like hypesthesia of both feet and paresthesias of both hands. The reason for the consultation was a transient weakness of his left arm after a fall. Extensive neurophysiological studies yielded a demyelinating polyneuropathy with a conduction block of the left median and ulnar nerve in the forearm. The protein in the CSF was slightly elevated with normal cell count. The sural nerve biopsy showed prominent, mostly axonal degeneration and absence of cellular infiltrates. Patient 2 was 56 years old and had been suffering since 3 years from progressive walking difficulties and frequent falls. On examination he had a symmetric sensorimotor polyneuropathy with gait ataxia and additional pyramidal signs. Electroneurography fulfilled criteria of a demyelinating polyneuropathy. CSF protein was slightly elevated. In the MRI of the head and the cervical spine there were multiple lesions without contrast enhancement. Nerve biopsy showed an active axonal degeneration, hypomyelinated fibres as well as a few tomacular swellings. Based on elevated CSF and nerve conduction studies CIDP was initially suspected in both patients. However, genetic testing revealed the1.4Mb deletion of chromosome 17p11.2–12 in both cases. Conclusion: Both cases of HNPP were unusual. Disease onset was late and patients presented with a diffuse symmetric demyelinating polyneuropathy. HNPP should be considered in patients presenting with a CIDP like neuropathy P344 Guillain-Barré syndrome after combined chemotherapy and rituximab in non-Hodgkin lymphoma F. Terenghi, G. Ardolino, C. Casellato, E. Nobile-Orazio Milan University, IRCCS Humanitas Clinical Institute (Rozzano, Milan, I) Different forms of neuropathy including Guillain-Barré syndrome (GBS) have been reported in patients with lymphoma and have been attributed to several pathogenetic mechanisms.We report on a 51 year old man with nonHodgkin’s lymphoma (NHL) who developed GBS three weeks after combined therapy with Rituximab and CHOP. In August 2005 the patients was first diagnosed non-Hodgkin’s B-cell lymphoma after biopsy of a symptomatic inguinal lymph node. After an initial course of CHOP the patient performed four courses of R-ICHOP (combined CHOP and Rituximab) at two weeks interval.After the first three courses the patient only complained mild finger paresthesias without motor impairment while three weeks after the fourth course (a two weeks after transient fever without additional symp-

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toms) he developed rapidly progressive flaccid tetra paresis. Neurological examination two days after onset of motor symptoms showed severe symmetrical predominantly distal weakness more pronounced in the legs, absent deep tendon reflexes and normal sensation. Routine laboratory tests were normal as were IgG anti-ganglioside antibodies. CSF proteins were increased (72 mg/dl) with normal cells. Nerve conduction studies were consistent with a demyelinating neuropathy. By the end of the first week the patient became bedridden despite 3 plasma exchanges. He was therefore treated with IVIg (0.5 g/kg) and intravenous methylprednisolone (500 mg) for four days with a moderate though transient improvement followed by the end of the second week by a rapid deterioration with respiratory insufficiency requiring assisted ventilation. The patient was treated again with IVIg (0.5 g/kg) and intravenous methylprednisolone (500 mg) for two days and gradually improved over the following three weeks when a slight worsening was treated again with the same regimen with further progressive improvement. One month later the patient was able to walk a few meters without support while NHL is in remission. Even if lymphoma itself or a possible antecedent infection suggested by the transient fever might be implicated in GBS in this patient, the close temporal relationship between onset of symptoms and combined CHOP and Rituximab therapy suggests their possible implication in the disease. In addition, since CHOP has been seldom associated with GBS it is possible that its combination with Rituximab had a relevant role in GBS pathogenesis.

lated hyperintense signal alteration of the occipitotemporal part (Meyer’s loop) of the optic radiation, that corresponded to the hypointense signal in the apparent diffusion coefficient (ADC) map and is therefore consistent with an ischemic infarction of the optic radiation. Doppler/duplexsonography revealed a hypoplasia of the right vertebral artery and a hyperperfused left vertebral artery. Transthoracal echocardiography disclosed a patent foramen ovale and an atrial septal aneurysm but was otherwise normal. However concomitant deep venous thrombosis was not found by duplex scanning. Hearth rhythm monitoring did not show cardiac arrhythmia. Because of the localisation of the infarction an embolic occlusion of branches of the middle cerebral artery, supplying the anterior part of the optic radiation, was assumed.A therapy with acetylsalicylic acid (100 mg daily) was initiated. Discussion: Meyer’s loop is the most anterior portion of the optic radiation, leaving the lateral geniculate body and looping around the lateral wall of the anterior temporal horn, before it turns backwards to end in the calcarine cortex. Meyer’s loop is supplied by branches of the middle cerebral artery. It transmits visual information from the contralateral upper field of both eyes, and damage of its fibres is one cause of a homonymous upper quadrantanopsia. Most common damage of Meyer’s loop is anterior temporal lobectomy performed for idiopathic temporal lobe epilepsy. However, isolated ischemic infarction of the Meyer’s loop, as presented above, is very rare.

Poster session 3

P347 Carotideal thrombus due to intravascular clotting activation in a patient with acute myeloid leukaemia F. Fluri, S. Engelter, A. Steck, P. Lyrer University Hospital (Basel, CH)

Cerebrovascular disorders P345 Natural course of carotid artery intima-media-thickness in healthy men F. Weber German Air Force Institute of Aviation (Furstenfeldbruck, D) 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. Methods: For a six years period (2000 until 2005) common carotid artery IMT was measured annually in 800 healthy volunteers. Additionally, bodymass-index (BMI), blood pressure, serum cholesterol level, erythrocyte sedimentation rate (ESR), cigarette smoking, and physical working capacity were recorded. Results: Mean IMT in this sample was 0.74 mm. Mean age was 47 yrs, mean BMI 25, mean cholesterol level 212 mg/100 ml, mean blood pressure 130/83 mmHg, mean ESR 5 mm in the first hour, mean PWC170 2.58 and mean cigarette consumption 3 cig/day (428 smokers). The repeated measures across time were compared with the use of a linear mixed effects model with a random effect for the patient and a fixed effect for age and the remaining predicting variables. Age, BMI, smoking status and ESR were significant determinants of IMT progression. Conclusion: In addition to traditional risk factors, IMT progression in the carotid artery is determined by ESR in healthy, physically active men. This is valid even if ESR is within the normal range. P346 Superior quadrantanopsia due to an infarction of the Meyer’s loop F. Fluri, C. Buitrago Tellez, R. Sutter, A. Steck, A. Czaplinski University Hospital (Basel, CH) Background: Isolated homonymous quadrantanopsia usually indicates infarction in the posterior circulation, affecting the lateral geniculate body, a part of the optic radiation and the lower bank of calcarine fissure. We now describe a case, showing that quadrantanopsia can also be caused by infarction within the carotideal circulation, damaging the anterior part (Meyer’s loop) of the optic radiation. Case report: A 76-year-old man with a history of hypertension and diabetes mellitus was admitted to our hospital because of an acute onset left visual field defect and vertigo for 1 day. Neurological examination was normal except of a left upper quadrantanopsia, which could be confirmed by perimetry. Occipital lobe infarction was assumed and brain MRI performed. Diffusion weighted imaging (DWI) sequences of the brain showed an iso-

Objective: We report on a patient with recurrent embolic cerebrovascular events due to intraluminal thrombus of the internal carotid artery (ICA). The assumed pathophysiology was intravascular clotting activation due to hematologic malignancy. Case report: A 52-year old ex-smoker with a history of acute myeloid leukemia (AML) was admitted to our hospital, suffering from an acute onset left sided facial palsy and weakness of the left upper extremity. One day prior to admission, two episodes of transient ischemic attack occurred lasting for 10 minutes. Neurological examination revealed a left sided brachiofacial hemiparesis. Acute middle cerebral artery stroke due to a steno-occlusive ICA- disease was assumed clinically. Diffusion-weighted imaging visualized multiple acute i lesions within the middle cerebral artery territory. Color coded duplex sonography revealed a right carotid thrombus, beginning in the distal common carotid artery and extending in the proximal ICA. The thrombus caused a high-grade stenosis, which was confirmed by MR angiography. Transthoracal echocardiography and 24-hour ECG showed no evidence of cardiac source for the thrombus. Intravenous treatment of heparin was initiated, followed by oral anticoagulation with phenprocoumon. Two months later, no further ischemic events have recurred. Follow-up duplex sonography showed partial resolution of the thrombus with organization of the remaining part. Hemodynamics of the right carotideal circulation were normalized. Discussion: The association between thromboembolism and neoplastic diseases is well recognized. It occurs in 3.2 % of all patients suffering from AML. A number of procoagulants can initiate intravascular clotting, including tissue factor, cancer procoagulants and interleukin-1. Abnormal platelet production and function contribute to the development of thrombosis in patients with myeloproliferative disorders. Especially in AML, intravascular clotting may also be induced by hyperleukocytosis. Furthermore a number of medications have thrombogenic potential, including corticosteroids and L-asparaginase. It remains to be determined, whether some patients with myeloproliferative disorders may benefit from prophylactic anticoagulation.

P348 A phosphodiesterase 4D polymorphism is not associated with ischaemic stroke in the Korean population M. K. Kim, E. J. Shon Chonnam National University Research Institute of Medical Science (Gwangju, KOR); Sangmoo Hospital (Gwangju, KOR) Background: In previous studies, a stroke susceptibility locus was mapped to chromosome 5q21 and the strongest association was found in PDE4D7 gene. However, the contribution of each variant in PDE4D7 gene as a risk factor for stroke is still in debates. Purpose: The aim of the present study was to explore the role of PDE4D7

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SNP41, existing near PDE4D exon1-D7a where the strongest association with stroke was found, in Korean population with ischemic stroke. Methods: A total of 205 consecutive ischemic stroke patients, including 92 large artery disease (LAD) and 113 small vessel disease (SVD) cases, and 170 unrelated controls were examined. Genomic DNA was extracted from the peripheral blood lymphocytes using a standard protocol and PDE4D7 SNP41 was genotyped. Results: Among control, the frequency of wild type homozygotes (CC) was 49.1 %, mutant heterozygotes (C/T), 42 %, and mutant homozygote (T/T), 8.9 %. There was no significant difference in the distribution of PDE4D7 SNP41 genotypes both between cases and controls and between LAD and SVD. Conclusion: This preliminary study suggests that PDE4D7 SNP41 mutant allele is not a major risk factor for ischaemic stroke in the Korean population.

P349 Prospective characterisation of time between stroke onset and hospital admission: results of a hospital-based study in Tbrgu Mures, Romania K. Orban-Kis, J. Szasz, Z. Bajko, I. Szocs, L. Zoican, S. Szatmari University of Medicine and Pharmacy (Targu Mures, RO) According to WHO statistics the incidence of stroke in certain Eastern-European countries is still rising. Furthermore there is a lack of data regarding the epidemiology of stroke and the prevalence of its risk factors in these countries. Knowing that for the outcome of stroke early diagnosis and therapy is crucial we studied the characteristics of stroke patients. Methods: Over 150 different data were prospectively collected for each patient admitted in Tβrgu Mures County Hospital with acute stroke diagnosis, over an one year period (1st April 2004 and 31st March 2005). In the present study we describe the clinical and therapeutic characteristics of patients as function of the time passed between the onset of stroke and the patient’s admission to the hospital, also dissecting the causes of late presentation. Results: In the above mentioned time period from 1473 patients admitted with acute stroke diagnosis 19.2 % were hemorrhagic and 80.8 % ischaemic. 7.5 % of all patients were admitted within the first hour from the onset of stroke, a further 23.5 % within 3 hours. 74.7 % of all patients admitted within the 3 hour time-window had ischaemic stroke. 41.2 % of hemorrhagic stroke patients were admitted within 3 hours but only 28.6 % of ischaemic stroke patients arrived in the same time frame (p < 0.01). These results correlate with the severity of stroke-subtypes. 80.3 % of all admitted stroke patients had severe or moderate neurological deficit. The time period from the onset of stroke to the moment of admission interestingly was not influenced significantly by the age, gender and social status of patients. We also studied the causes of lateness. The ambulance-service of Tβrgu Mures; is able to transport the patient to the hospital in 7–8 minutes even from the farest part of the city and around 30–40 minutes from the whole county, so the cause of late admission is the absence of the concept of high emergency in patients (54.3 %) or family doctors (24.6 %). This finding was not related to age or gender but partially was dependent on the place of residence, patients from rural areas were more frequently late.We also found that patients generally postpone contacting medical services in weekends and National Holidays (p = 0.049). Conclusions: Patients with more severe onset of the stroke ask for urgent transport more frequently. Early diagnosis and therapy can be improved after public education and training courses for both patients and general practitioners. This work was supported by grants from EMTE Sapientia 1467/2004.

P350 Microalbuminuria in acute ischaemic stroke N. Segura Bruna, A. Rodríguez-Campello, C. Pont-Sunyer, A. Ois, A. Gálvez, J. Roquer Hospital del Mar (Barcelona, E) Background: Microalbuminuria (MAL) is a marker of hypertensive and atherosclerotic damage in essential hypertension and has powerful prognostic value for cerebral and cardiovascular morbidity and mortality. Increased urine albumin excretion accompanies acute ischemic stroke and it is associated with worse outcome. The mechanism responsible for MAL in acute stroke patients remains unclear. The aim of our study is to investigate the prevalence of MAL in acute stroke and the relationship between MAL and outcome. Methods: Consecutive patients with acute ischemic stroke admitted between June to December 2005. MAL was defined as the daily urinary albu-

min excretion between 20 and 200 mg/L. We excluded patients with proteinuria, neoplasia, recent infection or chronic renal failure. Diabetic patients without macroalbuminuria were included. We analysed demographic data, vascular risk factors, stroke subtypes, clinical severity (NIHSS), recurrence, progression and outcome (modified Rankin Scale > 2 and in-hospital mortality). Results: 88 patients were admitted prospectively with acute stroke. We excluded 6 patients with proteinuria. MAL was found in 40 stroke patients (48.8 %). Patients with MAL were older (76.1 vs 71, p < 0.05). No differences were observed in gender (p = 0.25), smoking habit (p = 0.59), alcohol intake (p = 0.66), diabetes mellitus (p = 0.52), hypertension (p = 0.20), dyslipidemia (p = 0.45), ischemic cardiopathy (p = 0.68), previous stroke (p = 0.9) or peripheral arterial disease (p = 0.94). Lacunar strokes had less percentage of MAL than non lacunar infarction (29.2 vs 70.8, p < 0.03; OR 0.35). We found correlation between MAL levels and severity of neurological deficit on admission expressed by the NIHSS (r = 0.22, p < 0.05). Recurrence, progression and outcome were similar in both groups. Conclusion: MAL is detected in 48.8 % of consecutive patients with acute ischemic stroke. In this study factors associated with MAL in acute ischemic stroke were age, non lacunar stroke and initial clinical severity. No differences were found in outcome. Prospective large studies are necessary to establish this relation. P351 Effect of spirapril on brain perfusion in hypertensive patients O. Gulkevych, N. Makomela, E. Svyshchenko, L. Bezrodna Institute of Cardiology (Kiev, UKR) Objective: To assess the effect of spirapril (6 mg per day) on brain perfusion in hypertensive patients. Design and Methods: Twenty-five patients with mild to moderate essential hypertension (EH) (mean age 47.9.6.2 years; 15 males) treated by spirapril (6 mg per day) within 4 weeks and 33 healthy (normotensive) controls were studied.Both groups were matched for sex,age.Multimodal spiral computed tomography (MSCT) and 24 hour ambulatory blood pressure monitoring were performed at the end of wash-out period and after 4 weeks of treatment. We studied a cerebral blood flow in frontal and occipital lobes of both hemispheres. Statistical analysis was performed by pair variant method. Results: Spirapril significantly decreased systolic, diastolic and mean blood pressure. Before treatment brain MSCT revealed the decline of the cerebral blood flow in frontal lobes in pts with EH as compared to the control group (accordingly: 44.3?.0.7 vs 56.7.0.4 ml/min/100 g in the right frontal lobe, p < 0.05; 44.5.0.7 vs 56.8.0.6 ml/min/100 g in the left frontal lobe, p < 0.05). We observed the same changes in occipital lobes of both hemispheres (accordingly: 48.3.0.7 vs 63.6.0.3 ml/min/100 g in right occipital lobe, p < 0.05; 48.4.0.4 vs 64.3.0.4 ml/min/100 g in left occipital lobe, p < 0.05). After 4-weeks treatment by spirapril we observed the improvement of brain perfusion in both hemispheres. The cerebral blood flow in the both frontal lobes was increased to 48.4.0.8 ml/min/100 g on the right and to 48.4.0.8 ml/min/100 g on the left. The cerebral blood flow in the both occipital lobes was increased to 51.9.1.0 ml/min/100 g on the right and to 53.1.0.8 ml/min/100 g on the left. All distinctions were significant (p < 0.05). Conclusion: Our data suggest that patients with mild to moderate essential hypertension had significantly lower cerebral blood flow than healthy normotensive patients. Fosinopril (6 mg per day) significantly reduced blood pressure and improved brain perfusion.

Dementia/Higher function disorders P352 Efficacy of low-dose memantine in reducing behavioural symptoms in AD patients B. Corrà, D. Galimberti, I. Guidi, M. Tiriticco, L. Perego, A. Dobrea, P. Baron, N. Bresolin, E. Scarpini Ospedale Maggiore, University of Milan (Milan, I) Background: Memantine is indicated for the treatment of moderate to severe Alzheimer’s Disease (AD), but its effects on cognitive symptoms are still rather controversial. Conversely, this drug seems to improve the non-cognitive behavioural manifestations of the disease, such as mood disorders and anxiety, at the dose of 10 mg bid, and has excellent safety and tolerability in the clinical use. Objectives: To test the efficacy of memantine over a six-month treatment

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at the dose of 2.5 mg and 10 mg/day on memory and non-cognitive behavioural manifestations measured with MMSE and NPI, respectively. Methods: Thirty-eight patients with the diagnosis of “Probable” Alzheimer’s Disease were included. Cognitive functions were tested by MMSE, whereas behavioural symptoms were tested by NPI (12 item version) at baseline, three and six months from the beginning of the treatment. At baseline, memantine was administered at 2.5 mg and then increased within 15 days to the current dose of 10 mg bid in patients who tolerated the treatment. Non parametric Mann Withney test was used for comparisons. Results: Six patients with concomitant medication discontinued the treatment because of side effects (agitation and irritability). Eleven patients tolerated a 10 mg/day dose, whereas remainders were treated with a 2.5 mg/day dose over six months. No improvement of the MMSE score during the study period was observed in both groups. On the contrary, 46 % of patients treated with 2.5 mg/die and 54.5 % of those treated with 10 mg/die showed an improvement of NPI total score after the six-month treatment (53.5 % and 45.8 % decrease as compared with baseline, respectively). No significant differences were observed between the 10 mg and the 2.5 mg treatment groups. NPI improvement was already detectable after 3 months from the beginning of the therapy. Conclusions: Although effects on cognition cannot be evaluated with certainity considering the rating scale used, memantine seems to be non effective in improving memory, whereas behavioural manifestation seem to benefit from the treatment. Notably, the 2.5 mg/day dose is already effective at the same extent as the 10 mg/day dose in reducing the NPI score. Therefore, memantine at low doses could be proposed as an alternative treatment for neuropsychiatric symptoms associated with dementia, particularly in patients with cardiovascular risk factors in which the use of typical and nonconventional neuroleptics can be harmful. P353 A synthetic NCAM mimetic peptide, P2, facilitates recovery of cognitive and motor functions after traumatic brain injury B. Klementiev, T. Novikova, M. Penkowa, V. Berezin, E. Bock ENKAM Pharmaceuticals (Copenhagen, DK); Copenhagen University (Copenhagen, DK) Objectives: The neural cell adhesion molecule (NCAM) belongs to the immunoglobulin (Ig) superfamily and plays a pivotal role during development and regeneration of the nervous system, mediating neuronal differentiation, axonal outgrowth and fasciculation. NCAM also regulates synaptic plasticity, including such processes as learning and memory consolidation. NCAM is known to mediate cell-cell interactions by a homophilic and heterophilic binding mechanism. P2 is a 12 aminoacids peptide derived from the 2nd Ig module of the neuronal cell adhesion molecule NCAM. P2 is a potent NCAM agonist capable of strong induction of neuronal differentiation and of neuronal survival. Based on its in vitro profile, it is likely that P2 exerts in vivo activities promoting neuronal survival, and sprouting and regeneration of a variety of neuronal populations, leading to enhancement of cognitive functions (e. g. learning, memory, attention), as well as neuroprotection and neurorestoration. We here validated such hypothesis in vivo. Methods: P2 has been tested in a rat model of focal traumatic brain injury: the cryo-lesion model.Administration of P2 (5 mg/kg, subcutaneously) was started 2 hours post-injury and continued once every 24 hours until termination. The injury procedure induced significant cognitive and motor deficits in vehicle treated rats. P2 administration improved the functional outcome after traumatic brain injury, significantly ameliorating both cognition and motor performance. From the neuropathological point of view P2 administration significantly promoted wound healing and reactive neuritogenesis, which may represent the biological basis for its positive effects on functional outcome. P2 has been also tested in a model of short-term memory in intact rats, the social recognition test.After systemic (3.6 mg/kg, subcutaneous) administration P2 significantly enhanced short-term social memory. Further, systemic administration of P2 (3.6 mg/kg, subcutaneously) counteracted social amnesia induced by scopolamine. Conclusions: From these results we conclude that P2 has a promising profile as agent for restorative treatment of traumatic brain injury (TBI) and of its behavioural and psychological consequences. These studies were sponsored by ENKAM Pharmaceuticals

P354 Demographic and clinical characteristics of subcortical vascular dementia: an analysis of 101 patients B. Ku, J. J. Lee Kwandong University College of Medicine (Gyeonggi, KOR); Sejong General Hospital (Gyeonggi, KOR) Objectives: The unique pathophysiologic mechanism of subcortical vascular dementia (SVD)-lacunar infarction or chronic hypoperfusion- makes it a relatively distinct clinical entity among vascular dementia. Since the new research criteria for SVD was proposed by Erkinjuntti, no study has been reported on demographic and clinical findings of SVD that meets the new criteria. We report demographic and clinical findings of SVD patients who fulfill Erkinjuntti’s clinical and MRI criteria Methods: Of the 560 patients with vascular dementia from 1995 to 2005, we selected 101 SVD patients fulfilling Erkinjuntti clinical and MRI SVD criteria. We investigated demographic and clinical findings including neurologic signs. Regarding subtypes of SVD, we divided patients into three types according to MRI findings: lacunar type (L), white matter type (W), and a group of patients who met both the L and W types (LW). Results: Mean age was 68.44 years and male was predominant (67.3 %). Mean duration of SVD before diagnosed was 2.95 years, mean BMI was 23.7 and mean MMSE was 20.22. Major initial presenting symptoms were gait disturbance (34.7 %), dysarthria (23.8 %), memory impairment (20.8 %) in order of frequency. Most frequent risk factor for stroke was hypertension (77.2 %). but 14patients had no known stroke risk factors. Previous stroke event was present in 49 patients. Dysarthria (81.2 %) and gait disturbance (81.2 %) were most frequent neurologic symptoms. Bradykinesia (56.4 %), dysphagia (50.5 %), decreased facial expression (50.5 %), urinary incontinence (47.5 %) were also frequent. In contrast, sensory deficit (3 %) and tremor (4 %) were relatively rare. Pathologic laughing or crying was present in 20.8 %. Those who showed at least one of the parkinsonian symptoms accounted for 77.2 %. Common parkinsonian symptoms were bradykinesia and increased muscle tone while resting tremor was rare. SVD subtype analysis showed that LW type (55.4 %) was most common, which was followed by L type (29.8 %) and W type (14.9 %).After dividing the patients into lacunar (L) and nonlacunar (LW and W) types,we compared all the variables listed above, resulting in no differences. Conclusion: In our patients with SVD, male was overrepresented. Relatively large proportion of patients had no previous history of stroke and most of patients had parkinsonism. Demographic and clinical variables did not differ between the lacunar and non-lacunar type, a result suggesting that SVD is relatively a homogenous group. P355 Reduced thalamocortical connections in vascular dementia S. Singhal, C. Ojango, C. Bowler, P. Vesey, P. Morgan, N. Bajaj, D. Auer Queen’s Medical Centre (Nottingham, UK); University of Nottingham (Nottingham, UK); City Hospital (Nottingham, UK) Objectives: Frontotemporal dementia (FTD) refers to several neurodegenerative processes which differentially affect frontal and/or temporal lobes. Where frontal atrophy predominates, behavioural features are prominent. However, it can be difficult on clinicoradiological grounds to distinguish between this frontal variant (fv) FTD and vascular dementia (VD). Recently, diffusion tensor imaging (DTI) tractography has been used to reconstruct white matter tracts and assess connectivity between different brain areas non-invasively. DTI can measure fractional anisotropy (FA), which is thought to reflect integrity of brain tissue. The lower FA values in white matter tracts indicate the amount of less organised tissue, implying the possibility of disruption.We used DTI to investigate a 70 year old man presenting with symptoms and a cognitive profile typical of fvFTD. Surprisingly, MRI showed diffuse vascular disease involving frontal lobes and the thalamus, but only moderate and uniform brain atrophy. Our aim was to identify if disconnection of frontothalamic white matter tracts could be hypothesised as the cause for the clinical presentation. Methods: DTI was performed on the patient and three age-matched controls. Analysis was performed with FSL software (www.fmrib.ox.ac.uk/fsl). After correction for eddy current distortions the probabilistic tractography was performed. FA values along the projected tracts between the medial thalamus and frontal lobe were computed. Results: FA values of frontothalamic tracts were lower in the patient compared with controls (Right 0.28 vs 0.36; Left 0.33 vs 0.36). Conclusions: DTI identified reduced FA values in frontothalamic circuits in this patient implying disruption of white matter tracts. It is suggested the clinical picture of fvFTD may have been the result of a consequent vascular “disconnection syndrome”. To confirm this theory, future studies would have to demonstrate intact frontothalamic tracts in patients with fvFTD

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without vascular disease. DTI tractography may prove to be a useful technique for in vivo differentiation of “vascular” from “neurodegenerative” FTD.

P356 Emotional recognition in frontotemporal dementia and Alzheimer’s disease F. Girolami, F. Benuzzi, P. Nichelli University of Modena and Reggio Emilia (Modena, I) Objective: In frontotemporal dementia (FTD) and Alzheimer Disease (AD) neurodegenerative process comprises brain regions known to be involved in emotional processing. In addition, these pathologies are characterized by changes in emotional and social behavior, the principal symptoms of FDT and characteristics of the advanced stages of AD. Despite these data, research on dementias has focused primarily on cognitive deficits neglecting the processing of emotional cues. The aim of our study was to investigate the recognition of facial and prosodic expression of emotions in FTD and AD patients. Materials and Methods: We examined 14 patients (MMSE range = 16–24): 8 patients with probable AD and 6 patients with FTD. 17 healthy subject matched for age and educational level participated as controls. Two batteries were developed including task of visual recognition of facial expressions of emotion and of emotional prosody recognition. Five emotions were studied: happiness, sadness, fear, disgust and hungry. To exclude the presence of facial and prosodic deficits, control tests were included in the two batteries. Results: Visual tests: AD patients had poor results in all visual tasks but the difference did not reach the statistical significance; FTD patients had performances markedly worse in all the test of facial expression of emotion without a deficit in a specific emotion. Auditory tests: AD patients showed a general deficit in all prosody tasks, while FTD patients had a significant failure in the recognition of vocal emotions, in particular in the recognition of sadness. Discussion: The AD impairment in visual recognition tasks may be subordinate to a cognitive decline rather than to a primitive deficit of emotional processing. The failure in the in prosody recognition task with unimpaired performance in the emotional prosody tasks may be probably due to the memory deficit. In FTD the impaired performance in only one test may be ascribed to the exiguity of the group. Conclusions: The ability to identify facial emotion seems to be almost spared in AD, even in moderate stage, and may explain the well known experience that nonverbal communication often remains effective even in patients with severe dementia. In FTD, the emotion recognition impairments observed may contribute to the abnormal social behavior of this condition.

P357 Frontal lobes function in mild cognitive impairment L. A. Kartsaklis, I. Kapsalakis, T. Visviki, P. Zikos, M. Vikelis, D. Salli, N. Tsinia, N. Karpathiou, V. Kontogianni, J. Papatriantafyllou, C. E. Karageorgiou P. G. N. A. General Hospital of Athens (Holargos, GR) Objectives: To estimate through a frontal assessment battery (FAB) the frontal lobe function in Mild Cognitive Impairment (MCI) patients. Methods: From a pool of 313 individuals who were admitted to our outpatient memory clinic we processed the data of 257 patients whose Mini Mental State Examination (MMSE) score was above 18. The patients received a diagnosis according to the established criteria (NINCDS-ARDRA, Mckeith et al. NINDS-AIREN, Petersen et al. DSM-ÉV). 42: normal, 86: Dementia (Alzheimer disease, Frontotemporal dementia, Vascular dementia, Lewy Body and Parkinson Disease dementia), 32: Psychiatric disorders, 24: other miscellaneous disorders (MS, alcohol abuse, vasculitis, etc), 40: amnestic MCI, 24: multiple domain (... + executive) MCI, 6: multiple domain (... non executive) MCI, 3: single domain (non amnestic) MCI. We examined the cognitive status through a neuropsychological battery with the MMSE, Addenbrook’s Cognitive Examination, Digit Backwards, Clock DT, modified-Trails-B, Stroop test, Verbal and Design fluency tests, Geriatric Depression Scale, the NeuroPsychiatric Inventory and the FAB. Results: The statistical significance among the controls and the MCI patients, in terms of their FAB score, was lower than 0.001, indicating malfunction of frontal lobes early before the clinical onset of Dementia, even in the amnestic MCI group of patients. The same level of significance (lower than 0.001) was found among Dementia groups and the MCI sub-groups, indicating that Mild Cognitive Impairment could be assumed as a separate clinical entity. The tool (using the FAB total) seems to be insensitive when we ask to differentiate among the MCI sub-groups.

Conclusion: FAB is a useful tool to estimate frontal lobes’ function. There is a disorder of the frontal lobe function even for MCI patients. Statistical analysis of FAB scores suggests that Mild Cognitive Impairment could be considered as a separate clinical entity. P358 Vascular risk factors and intensity of cognitive dysfunction in MCI J. Siuda, A. Gorzkowska, G. Opala, S. Ochudlo Central University Hospital (Katowice, PL) Background: Patients with Mild Cognitive Impairment have a greater risk of developing dementia than general population. There are some data suggesting that vascular pathology has an influence on performance in neuropsychological tests of cognitive functions. Lots of evidence suggests that cardiovascular disorders appear more often in the MCI than in general population. The aim of this study was to evaluate association between vascular risk factors and intensity of cognitive impairment in the MCI group. Material/methods:24 MCI patients fulfilling Mayo Clinic Group Criteria were examined. Taking under consideration cardio-vascular risk factors: arterial hypertension, ischemic heart disease and diabetes mellitus – patients were divided into 2 groups: first group – 16 patients with MCI and vascular risk factors and second group of 8 patients with MCI without vascular pathology, mean education time were similar in both groups and it was respectively 13.81 and 15.25 years, everyone in those groups were retired. In the first group 10 patients (62.5 %) have arterial hypertension, 10 patients (62.5 %) have ischemic heart disease and 1 patient (6.25 %) has diabetes. Cognitive functions were assessed by neuropsychological tests battery including MMSE, Clock Drawing Test, Trail Making Test (TMT), Verbal Fluency Test with letters FAS, Auditory Verbal Learning Test (AVLT). Results: MMSE was comparable in both groups (I group – 26.69 ± 1.89, II group – 26.89 ± 1.36). In the MCI group with vascular risk factors we have found more distinct dysfunction of learning, recall and short-term memory than in MCI patients without vascular pathology assessed by Auditory Verbal Learning Test – I group – 26.63 ± 6.23 (total words), II group – 29.75 ± 4.23 (total words), after 30 minutes – I group – 4.37 ± 2.19 (words), II group – 5.63 ± 2.62 (words) and Trail Making Test part A – I group – 68.81 ± 18.48(seconds), II group – 61.25 ± 21.07 (seconds) and Trail Making Test part B – I group – 169 ± 53.51 (seconds), II group – 154.63 ± 57.31(seconds). Conclusions: In our MCI group with vascular risk factors more intensive dysfunction in learning ability, short-term memory, delay recall and operation memory was found then in the MCI group without vascular pathology. The presence of vascular risk factors in the MCI group has an influence on the results of neuropsychological tests. More distinct cognitive deficit may indicate higher risk of developing dementia. P359 Familial Alzheimer’s disease due to presenilin-1 Y115C mutation M. Doran, A. J. Larner Walton Centre (Liverpool, UK) Objective: To report a kindred with familial Alzheimer’s disease (AD) with three affected individuals in three generations, due to the presenilin-1 (PS1) Y115C mutation. Methods/Setting: Observational study, Cognitive Function Clinic Results: The proband developed memory problems in her mid 40s. Her mother was reported to have been similarly affected with a “depressive illness” in her early 40s, progressing to loss of activities of daily living prior to her death in her late 40s. The proband did not come to medical attention until she was mute and bed-bound in her mid 50s, dying shortly thereafter. Pathological examination of the brain confirmed definite AD. Neurogenetic testing revealed the Tyr115Cys (Y115C) mutation in exon 5 of the PS1 gene. The proband’s two asymptomatic daughters elected, after appropriate genetic counselling, to undergo predictive testing: one was found to carry the same mutation. Discussion/Conclusion: Three previous clinical reports of the PS1 Y115C mutation have been identified, two of which state age of onset (AAO), which overlapped with our family (early 40s). Of the two other mutations reported at this codon, Y115D and Y115H, AAO has only been reported for Y115H (mid 30s to mid 40s). It is possible that in this instance AAO may be mutation- or codon-specific.

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P360 Measuring behavioural disturbance in dementia: the utility of the Frontal Behavioural Inventory for Greek patients E. Aretouli, P. Ioannidis, M-H. Kosmidis, A. Aggelou, I. Milonas Aristotle University (Thessaloniki, GR); General Hospital AHEPA (Thessaloniki, GR) Background/Objectives: The Frontal Behavioural Inventory (FBI; Kertesz et al. 1997) was developed based on the Diagnostic Criteria for Frontotemporal Dementia (FTD) as a tool for diagnosing this disorder and differentiating it from other types of dementia. Unlike other types of dementia, the diagnosis of FTD depends mainly on the evaluation of behavioural and personality changes. Two main types of behaviour are measured: negative behaviours, such as apathy and emotional indifference, and behaviours resulting from disinhibition or excessive ‘normal’ behaviours, such as hyperorality and perseveration. Our main objective was to record the most frequent behavioural disturbances that occur in two different groups of patients with dementia, those with FTD and those with Alzheimer’s Disease (AD). Our second objective was to examine whether FBI is a reliable measure for the differential diagnosis of FTD for Greek patients. Methods: We administered the FBI to relatives/care-givers of patients diagnosed as suffering from FTD (n = 13) or AD (n = 14), without the patients’ presence. The duration of illness was estimated according to medical records and care-givers’ reports. The two groups of patients did not differ with respect to the duration of illness (p > 0.05). Results: FTD patients scored significantly higher on the FBI in comparison to AD patients (p = 0.000). The most frequently reported behavioural disturbances in FTD patients were both negative behaviours as well as behaviours resulting from disinhibition. Specifically, most prominent were perseverative behaviours (all FTD caregivers reported some kind of perseverative behaviour), followed by personal neglect (reported by 75 % of the care-givers) verbal apraxia (75 %) and hyperorality (75 %). The aforementioned behaviours differentiated the two patient groups. AD patients presented negative behaviours, such as aspontaneity and apathy (reported in varying degrees by all care-givers), more frequently than FTD patients, but this difference did not reach statistical significance. Conclusion: The present results highlight the importance of behavioural observations and care-givers’ reports in distinguishing between possible dementing conditions. FBI, based on care-givers’ reports, appears to be a useful inventory for differential diagnosis between AD and FTD. Finally, our preliminary data confirm the usefulness of FBI in recording behavioural disturbances in FTD patients in Greece. This study is still in progress. P361 Association between dementia and cancer I. Guidi, D. Galimberti, A. Dobrea, B. Corrà, M. Tiriticco, L. Perego, F. Bonino, N. Bresolin, E. Scarpini University of Milan, Ospedale Maggiore (Milan, I) Background: The relationship between cancer and dementia is still poorly understood. Recent studies showed that cancer survivors frequently experience short-term cognitive deficits, but it is unknown whether these deficits last or whether they worsen over time, as well as the cause of this association. Objectives: To evaluate whether patients with a diagnosis of dementia have a higher frequency of malignant neoplasia in their clinical history, and there is a correlation between cancer history and dementia subtype. Methods: Medical history of 470 consecutive subjects evaluated in our Centre for Cognitive Disturbances has been retrospectively examined to determine how many of them were cancer survivors. 200 had Alzheimer’s disease (AD), 89 Mild Cognitive Impairment (MCI), 49 vascular dementia (VaD), 25 tauopathies (21 Frontotemporal dementia, 3 Progressive Sopranuclear Palsy, 1 Corticobasal Degeneration), 28 other dementias. 79 subjects had neither cognitive impairment nor other neurological diseases. Frequency of cancer in these different groups has been compared by ChiSquare. Results: 59 out of 470 subjects were long-term survivors (cancer diagnosis more than 5 years before neurological diagnosis) and 6 were short-term survivors. A medical history of cancer was present in 12 healty subjects (15.1 %), 30 AD (15 %), 7 MCI (7.8 %), 7 VaD (14.2 %), 6 patients with tauopathies (24 %), 3 patients with other dementias (10.7 %). No significant differences in the frequency of cancer was observed between healthy aged and demented people. However, a trend towards an higher percentage of cancer history in patients affected by tauopathy compared with other dementias was observed. Stratifying by the type of malignant neoplasia, no significant differences were observed, as well as considering the age of occurrence of cancer. Notably, 6 of the 7 MCI patients were short-term survivors.

Conclusions: In our population, no significant association between dementia and cancer history was observed. Nevertheless, the higher prevalence of cancer hystory in patients with tauopathies needs to be further studied in larger populations. The possible biological mechanism underlying this association could be linked to microtubule and citoskeleton role in intracellular signaling, cell shape and replication. The higher prevalence of short-time survivors among MCI patients confirms the previous demonstration of a major risk of cognitive impairment in patients with cancer, possibly due to the therapy.

P362 Measures of medial temporal lobe structures in mild cognitive impairment B. Sawicka, W. Lojkowska, A. Bochynska, H. Sienkiewicz-Jarosz, W. Kuran, R. Boguslawska, R. Poniatowska, A. Makulec, R. Krawczyk, M. Gugala, P. Bienkowski, D. Ryglewicz Institute of Psychiatry and Neurology (Warsaw, PL) Mild Cognitive Impairment (MCI) is a risk factor for Alzheimer’s disease. Structural neuroimaging offers a potential tool in the clinical diagnosis of MCI. We hypothesized that dimensions of medial temporal lobe structures would be reduced in MCI and therefore measurements of their size could be used as a predictive value for progression from MCI to dementia. Method: Two groups of patients were examined: 51 patients with MCI deficits (mean age 67.3 ± 6.7), and control group (32 subjects, mean age 68.1 ± 6.7). The MCI diagnosis was established according to Petersen et al. (1997). MRI was used to measure the volumes of amygdala, hippocampus and parahippocampal gyrus. The respective volumes were assessed with two different methods: one, where the operator manually defines the borders of the relevant structures of the brain, and a second one, where dedicated software automatically detects the volume occupied by these structures.The second procedure delivers the cerebrospinal fluid/brain index (CFBI). Results: The volumes of above structures did not differ significantly between two groups of patients. However, patients with MCI displayed a slightly higher CFBI than the control group.A higher CFBI level is indicative of a more pronounced atrophy of hippocampus. Conclusions: The CFBI index is a more sensitive measure of hippocampal atrophy than simple assessment of its size. Its measurement is a promising tool for early diagnosis of MCI, but studies with larger groups of patients are needed to provide more conclusive answers.

P363 Proton magnetic resonance spectroscopy (1H-MRS): audit of pragmatic use in the cognitive function clinic A. J. Larner Walton Centre (Liverpool, UK) Objective: To assess the utility of proton magnetic resonance spectroscopy (1H-MRS) in the diagnosis of dementia. Methods/Setting: Observational study in a Cognitive Function Clinic. Single voxel 1H-MRS performed on GE Signa 1.5T Scanner (TE = 35 ms; TR = 1500 ms), measuring N-acetyl aspartate (NAA) and myoinositol (mI), with creatine (Cr) as reference, hence NAA:Cr and mI:Cr ratios. Results: Of 20 patients undergoing 1H-MRS, 11 were diagnosed with dementia (AD = 8, FTD = 3) and 9 were judged not demented. Comparing mean NAA:Cr and mI:Cr ratios in occipital and frontal voxels for demented vs. non-demented patients, the only difference reaching statistical significance was for increased mI:Cr in occipital voxels in demented patients (t = 4.60, df = 15, p < 0.001). There was a trend observed for decreased NAA:Cr in frontal voxels in demented patients (t = 1.86, df = 13, 0.05 < p < 0.1). Discussion/Conclusion: In this heterogeneous clinical practice population undergoing 1H-MRS, high occipital mI:Cr ratio was useful in differentiating demented from non-demented patients; low frontal NAA:Cr may also be suggestive of dementia. However, such aggregate data may obscure the utility of 1H-MRS in individual cases. Longitudinal studies with 1H-MRS may also be useful, rising occipital mI:Cr and falling NAA:Cr over time being suggestive of progressive disease. 1H-MRS may therefore be of use in a non-research setting.

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P364 Digit span index: a new diagnostic tool to differential diagnosis between Alzheimer’s disease and frontotemporal dementia D. A. Perez-Martinez, J. Porta-Etessam, B. Anaya, A. I. Puente-Muñoz Hospital Cruz Roja (Madrid, E) Objective: This study compares the performance of patients with Frontotemporal dementia (FTD), Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) on forward digit span (FDS), backward digit span (BDS) and digit span index (DSI). Methods: DSI is calculated like FDS minus BDS. Subjects were 9 patients with FTD, 26 patients with AD, 20 patients with amnestic form of MCI (aMCI), 13 patients with multi-domain form of MCI (md-MCI), and 11 patients without cognitive impairment on evaluation. Groups were comparable in terms of age, sex and education. FTD diagnosis was made clinically using the consensus criteria of Neary et al. AD diagnosis was made using NINCDS-ADRDA criteria. MCI diagnosis was made using criteria of Peterson et al. Results: Both the AD and MCI groups were significantly (p < 0.05) impaired relative to control group on FDS and BDS, but no differences were on DSI. Subjects with FTD performed similar score on FDS compared with control group, but they were significantly (p < 0.05) impaired on BDS, too. However, specifically, FTD patients exhibited significantly (p < 0.05) greater score on DSI relative to AD patients (3.22 vs 2.22), a-MCI patients (3.22 vs 1.85), md-MCI patients (3.22 vs 2.08) and control subjects (3.22 vs 1.91). Conclusions: These findings suggest that this new diagnostic tool DSI may be useful in differential diagnosis of FTD versus AD, MCI or control subjects. Working memory is a type of short-term memory and there is a well-established relationship between the prefrontal cortex function and this type of memory. Previous studies suggest that FDS is a measure of general attention; on the other hand, BDS has a relationship with verbal working memory. However, there is a weak association between BDS and frontal dysfunction on clinical practice. Usually, AD and MCI groups are impaired on attentional function, so FDS and BDS are impaired with relative normal DSI. Nevertheless, FTD is associated with a different profile. This group is impaired on BDS with relative normal FDS. Then, this subjects exhibit greater score on DSI. In conclusion, DSI could be a better index of working memory and prefrontal function on clinical practice. P365 The role of parietal lobes in memory encoding: an fMRI study in Alzheimer’s disease D. Bonnet, S. Kinkingnehum, K. Andrade, L. de Souza, F. Antonelli, V. HahnBarma, S. Lehericy, B. Dubois Hôpital Pitié-Salpétrière (Paris, F) Objective: Episodic memory impairment is the clinical hallmark of Alzheimer’s disease (AD). Amnesic symptoms are usually considered as resulting from hippocampal degeneration. However, for long term memory disorders, particularly for encoding troubles, other structures, lesioned during AD, may also be implicated. Methods: To demonstrate the neuronal network supporting this process and the nature of memory impairment in AD, we studied the neuronal brain activation with functional Magnetic Resonance Imaging (fMRI) during encoding of visual information in 7 healthy normal controls (mean age = 72 yrs; education = 6 yrs; Mini Mental State Examination (MMSE) score 27.9) and 7 early AD patients (mean age = 71 yrs; education = 5.2 yrs; MMSE score = 24). Subjects viewed a serial of black and white pictures, which they have to encode spontaneously in order to recognize them among distractors, immediatly and after delay (24 hours).This test condition was compared with a baseline condition consisting in staring at a blurred screen. Data were analysed using whole-brain statistical parametric mapping for intergroup analysis. Significatives areas at p < 0.01 were considered. Results: The AD group showed a significantly lower activation of posterior associative regions – specially the left angular gyrus and the precuneusduring memory encoding when compared with control subjects. This result suggests an impairment of spontaneous semantic processing of episodic informations. Otherwise, a non significant trend for a decreased activation of the right hippocampus and of the left parahippocampal gyrus was found in AD subjects. Conclusion: These fMRI findings demonstrated the role of parietal lobes in memory encoding and suggest that the functional study of this stage of memory process could be a useful diagnostic instrument in early AD.

Extrapyramidal disorders P366 A case of mastocytosis with chorea and hyperglycaemia S. Palao, F. Navacerrada, M. Calvo, R. Toledano, L. Escribano, J. M. Gobernado Ramon y Cajal Hospital (Madrid, E) Objectives: Systemic Mastocytosis(SM)is a non frequent disease characterized by an abnormal excess of mast cells in various organs. Neurological manifestations include headache, dizziness,and seizures. The association between chorea and SM is extremely rare with unknown phisiology. We report a case of a 75 year old male with SM who developed a transient hemichorea triggered by a hyperglycaemia crisis. Methods: A 75 year old male with hypertension, Diabetes Mellitus(DM)and SM was admitted to hospital because of an acute involuntary movements of the upper left extremity and fonatory muscles during the previous 2 weeks. He was treated with hydrea, disodium cromoglycate, Ranitidine, and Corticosteroids. No previous systemic,motor or paresthesia symptoms. General physical examination revealed hepatomegaly, icterus and urticary pigmentosum. Neurological examination showed choreic movements involving the upper left extremity,trunk ipsilateral lower extremity, and orofaciolingual muscles that interfered with speech and walking. Loss of vibration and decreased tendon deep reflexes in lower extremities. No other abnormalities. Results: Analitical examinations showed non ketosic hyperglycemia of 450 mg/dl, AST/ALT 116/120 U/L, LDH 123 U/L, haemoglobin 10.1 g/dL. Tryptase 329 micrg/l. The rest of the routine blood test, including immnulogical, serologies and mycrobiological test were normal. No drugs in blood or urine. Brain Computer Tomography (CT) showed increased density in bilateral ganglia basal, with high signal intensity on T1-weighted Resonance Magnetic (RM) images. Electromyography showed a sensitive-motor mixed polyneuropathy in lower extremities. The patient was asymptomatic after insulin therapy was performed. Conclusion: The findings in CT and RM in our case have been described in transient chorea associated with non ketotic hyperglycemia in DM, whereas they were normal in other reported cases of SM and chorea. Few of the large population with DM develop this movement disorder. The possible pathophysiological explanation could be an unrecognised underlying pathology as responsible for the vascular damage, and not only the metabolic disorder. SM is an enough cause of neurological symptoms, and could be also a predisposing factor for the “high signal intensity and non ketotic hyperglycaemia syndrome related to chorea”. P367 Plasma homocysteine levels in Parkinson’s disease patients – the effect of levodopa and entacapone treatment. Pilot study M. Nevrly, P. Ressner, I. Nestrasil, H. Vranova, R. Herzig, P. Kanovsky University Hospital of Palacky University (Olomouc, CZ) Objective: Homocystein (Hcy) is a risk factor for vascular diseases, dementia, and cognitive impairment. Elevated plasma Hcy levels were found in Parkinson disease (PD) patients treated with levodopa. This has been verified by several retrospective studies. The object of this study was to compare levels of Hcy in regular levodopa treatment and in combined levodopa and inhibitor catechol-O-methyltransferase (COMT) treatment. Methods: From the available COMT inhibitors only entacapone (Comtan®, Stalevo®) was used in the study. Patients indicated for levodopa and entacapone treatment were divided into 3 groups: 1) PD patients long-term treated by levodopa, in whom Comtan® was added to the treatment (16 patients, aged 56–81, mean 69.5 ± 7.0 years); 2) levodopa-naive PD patients, in whom levodopa treatment was started and Comtan® or Stalevo® was added later (after 4 weeks of treatment) (6 patients, aged 64–74, mean 69.0 ± 4.2 years); 3) control group (CG) subjects whom Hcy levels were assessed in the same intervals as in patients taking levodopa and entacapone (21 patients, aged 38–78, mean 51.7 ± 11.1 years). CG subjects did not suffer from any disease affecting Hcy levels. All patients underwent visits at week 0, 1, 4, and 8 with UPDRS, blood count, basic biochemical screening and plasma Hcy levels controls. Results: The following Hcy plasma levels were found in the particular groups – mean ± SD (min – max) (umol/l): 20.0 ± 7.5 (13.3–44.4) and with added entacapone 18.5 ± 6.1 (11.9–31.1) in Group 1; 13.6 ± 3.4 (8.5–18.1) and at week 8 of concurrent levodopa and entacapone treatment 15.7 ± 4.2 (10.6–22.1) in Group 2; 9.7 ± 2.8 (6.6–16.5) in CG. Conclusion: Results of this pilot study confirm the presence of elevated

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plasma Hcy concentrations in patients with long-term levodopa treatment. Combinated levodopa and entacapone treatment apparently decreases plasma Hcy levels. P368 Delayed continuous bruxism with Olivary hypertrophy after top of basilar syndrome Y. K. Minn, S. J. Cho, K. H. Kwon Hallym University (Seoul, KOR) Objective: There are many specific symptoms in top of basilar syndrome. However, delayed continuous bruxism with olivary hypertrophy is not reported yet. Symptomatic bruxism with supra tentorial lesion may improve with L-dopa. Case: A 49-years man present with quadriplegia and opthalmoplegia. He had been diagnosed of sick sinus syndrome but did not take specific treatment. Brain MRI and MR angiogram one day after the onset showed acute brain infarction in bilateral midbrain, right median thalamus and superior cerebellum with occlusion of distal basilar artery. One month later, patient started bruxism (about 80 Hz)and this symptom persisted during sleep. Ldopa treatment was not effective. Palatal myoclonus was not observed. Follow up MRI taken 4 moth later showed bilateral olivary hypertrophy Eight month later, bruxism and olivary hypertrophy were persistence. Bruxism ceased 2 years after. Conclusion: Olivary hypertrophy can occur without palatal myoclonus. Central pacemaker of bruxism which is not related dopaminergic system may locate in inferior olivary neucleus. P369 Novel heterozygous mutation in 5’UTR region of the GTP-cyclohydrolase-1 gene V. Amaral, P. J. Lorenzoni, H. A. G. Teive, R. H. Scola, L. C. Werneck, C. Carducci, T. Giovanniello Universidade Federal do Paraná (Curitiba, BR); University of Rome “La Sapienza” (Rome, I) Dopa-responsive dystonia (DRD) is caused by the heterozygote abnormalities of the gene the enzyme guanosine-5-triphosphate cyclohydrolase-1 (GCH1). We report a girl with progressive diffuse limb dystonia and myoclonic jerks affected muscle upper limbs and trunks. She had a compound heterozygote for two mutations in GCH1 gene: P23L (c68C > T) of maternal origin and Q182E (c 0.544C > G) of paternal origin. The characteristics of the DRD with the new molecular genetic analysis are discussed. P370 Sympathetic skin response in Parkinson’s disease before and after mental stress E. Gkiza, S. Bostantjopoulou, Z. Katsarou, G. Georgiadis University of Thessaloniki (Thessaloniki, GR) Purpose: The purpose of this study was to evaluate sympathetic sudomotor activity in Parkinson’s disease (PD) by means of the sympathetic skin response (SSR) and explore its possible change due to mental stress. Material-Method: Sudomotor function was evaluated using SSR in 29 patients with PD (Hoehn and Yahr stage I-IV) without clinical evidence of autonomic (A. N. S.) dysfunction. Twenty five healthy matched controls were also evaluated. SSR was elicited by electrical stimulation of the right median nerve and simultaneously recorded on the palms of both hands. Arithmetic mental stress was evoked by means of the WAIS-R arithmetic subscale. Latency and amplitude of SSR were evaluated before and after arithmetic mental stress. Results: The SSR was present in all patients and controls. There was no significant difference in the mean latency and amplitude values between patients and controls. Mental stress had no effect on SSR parameters in both groups. Within group comparisons of mean SSR values showed that by separating PD patients in two groups, according to the severity of the stage, there was a significant difference in SSR amplitude only. Conclusions: SSR parameters in PD without autonomic dysfunction were comparable to matched controls. Although PD patients are sensitive to mental stress, the arithmetic task had no effect on SSR parameters. Consequently, SSR as a method of evaluation of sympathetic sudomotor function, in order to be used for exploration of subclinical A. N. S. dysfunction in PD, but must be combined with other tests of A. N. S.

P371 Continuous dopaminergic stimulation in Parkinson’s disease: clinical experience with lisuride F. Stocchi, L. Vacca, S. Ruggieri, W. Olanow, H. Bliesath, D. Palla, R. Horowski University of Rome (Rome, I); IRCCS NEUROMED (Pozzilli, I); Mount Sinai School of Medicine (New York, USA); NeuroBiotec (Berlin, D) Objective: Continuous dopaminergic stimulation (CDS) is expected to improve the therapy of Parkinson’s disease (PD) as oral therapies so far have not proved very successful (sustained release, frequent intake, long acting but weak compounds) in part due to first pass metabolism resulting in high variation of bioavailability. Methods: We have used the potent dopamine agonist lisuride (LIS), an isoergoline derivative, for both s. c. infusion [Stocchi et al, , Brain, 2002] and as a transdermal form in advanced PD [Poewe et al, submitted]. Results: Continuous s. c. LIS infusion in selected patients with motor fluctuations (up to now, some of them are treated for more than 10 yrs continuously) has resulted in substantially improved motor control and a possible disease stabilisation, with good longterm safety (including no change in echocardiography in a subgroup which confirms the absence of valvulopathy reported in the PMS documentations of oral LIS). It is of importance to select and instruct patients properly for this kind of technically demanding treatment in order to obtain therapeutically satisfactory longterm results. A more patient – friendly CDS therapy is a transdermal application continuously releasing LIS into the systemic circulation. In a recent study in advanced PD, transdermal LIS every other evening showed relevant efficacy already after 2 weeks without the need for dose titration. The application was easy and comfortable for the patient and resulted in good systemic tolerability. Conclusion: Our LIS data support the potential of CDS with these galenical formulations for an improved therapy of PD. P372 Genetic polymorphism of the 5.10-methylenetetrahydrofolate reductase (MTHFR), plasma homocysteine, folate and vitamin B12 in patients treated with Parkinson’s disease J. Lin, K. Yueh, C. Liu, S. Wu, J. Lin Chu Shang Hospital (Taipei, TW); Chushang Show-Chwan Hospital (Nantou, TW); Changhua Christian Hospital (Changhua, TW) Objective: Patients with Parkinson’s disease (PD) may have elevated serum homocysteine levels, resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, and often go along with low normal plasma folate and vitamin B12. Homozygote for the C677T mutation in the gene for the 5.10-methylenetetrahydrofolate reductase gene (MTHFR) is frequently associated with hyperhomocysteinemia. The present study was initiated to evaluate a possible relationship between hyperhomocysteinenemia, age and duration of patients with PD and to find out a possible relationship between the genetic polymorphism of the MTHFR and the development of hyperhomocysteinenemia in PD patients living in Taiwan. Methods: This study included 95 PD patients treated with L-dopa and 146 controls of a similar ethnic origin, matched by sex and gender. The C/T polymorphism of the MTHFR was identified by conventional polymerase chain reaction. Level of serum homocysteine was measured in the laboratory by ELISA method, and the folate and vitamin B12 were by RIA. Results: The mean age at onset of PD and duration of the disease was 61.3 ± 12 and 6.3 ± 5.1 years, respectively. All the PD patients received the Ldopa treatment with duration of 5.0 ± 4.3 years. There was a trend of increasing serum concentration of homocysteine in both older PD patients and controls. The mean total homocysteine was significantly (p = 0.001) elevated in PD (13.6 ± 4.7 µgmol/l) compared to controls (11.7 ± 3.9 µgmol/l). Meanwhile, there was going along with significantly low normal serum folate (7.7 ± 2.6 ng/ml) and vitamin B12 (574.7 ± 295.0 pg/ml) concentration in PD compared to controls (11.2 ± 4.2 ng/ml and 648.0 ± 308.3 pg/ml, respectively; p < 0.001 and p = 0.006, respectively). Comparison of these chemicals with the MTHFR polymorphism revealed that PD patients with homozygote MTHFR-CC genotype presented with significantly higher serum homocysteine (p = 0.003), lower folate (p < 0.001) and lower vitamin B12 (p = 0.037) concentrations in comparison to PD patients with either MTHFR-TT or MTHFR-CT genotypes. Conclusions: MTHFR-CC genotype is a significant factor for hyperhomocysteinemia along with deficiency of the serum folate and vitamin B12 concentration in L-dopa treated PD patients living in Taiwan. We advise MTHFR should be determined in PD patients since hyperhomocysteinemia contributes to increased cardiovascular disease and stroke in PD patients.

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P373 Dopamine derived from exogenously administered L-DOPA in rats with nigro-striatal dopaminergic denervation T. Maeda, K. Nagata, Y. Yoshida, K. Kannari RI for Brain and Blood Vessels (Akita, JP); Hirosaki University (Hirosaki, JP) We previously reported the dopamine immuno-reactivity induced by exogenously administered L-DOPA in the raphe-striatal serotonergic neurons of rats with nigro-striatal dopaminergic denervation. The aim of this study is to examine whether astroglias in the striatum of rats with dopaminergic denervation are induced to contain dopamine by exogenous L-DOPA administration. Unilateral nigro-striatal dopaminergic denervation was induced by stereotaxic microinjection of 6-hydroxydopamine into the right medial forebrain bundle and confirmed by anticlockwise rotational behavior in apomorphine challenge test. These rats were divided into two groups, either with or without intraperitoneal injection of L-DOPA and a peripheral decarboxylase inhibitor. Double-labeling immunofluorescence method was performed on the rat brain sections. Immuno-positive area was detected by a confocal laser microscope and measured quantitatively by image analyzing system. Dopamine immuno-positive area was extremely decreased in the lesioned striatum and the substantia nigra pars compacta. Serotonin immuno-positive area was significantly increased in the denervated striatum. In rats without L-DOPA injection, no dopamine immuno-positive area was observed in the striatal serotonergic terminals and cell bodies in the raphe nuclei, whereas in rats with L-DOPA injection, dopamine immuno-positive area was induced to be localized in serotonergic terminals of the lesioned striatum as markedly as the intact striatum and cell bodies in the raphe nuclei. Glial fibrillary acidic protein (GFAP) immuno-positive area was increased in the dopaminergic denervated striatum, while no dopamine immuno-reactivity was induced in GFAP immuno-positive cells by L-DOPA injection. These findings suggest that GFAP immuno-positive cells in the dopaminergic denervated striatum can not compensate for the lost function of dopaminergic neurons. P374 Clinical outcome and complications after deep brain stimulation: description of a series I. Martínez-Torres, N. Muelas, M. Boscá, J. Burguera Hospital La Fe (Valencia, E) Objective: To describe a series of patients treated with deep brain stimulation (DBS), and the appearance of clinical complications, long term functioning of device, and adjustment of stimulation parameters. Methods: Surgery procedure was done in another institution in all patients, and referred to our centre for follow-up. Clinical periodical evaluations were done, including clinical rating scales and adjustment of stimulation parameters. Results: Forty patients were treated with DBS between 1994–2005. Surgery procedure was done in another institutions located within our city in 60 % of the patients and in another Spanish city in the rest of them. Thirty two patients had Parkinson’s disease (PD), 4 essential tremor, and 4 dystonia. In PD group the surgical targets were Globus Pallidus internus (GPi) in 57 % of patients (years 1994–2001) or subthalamicus nucleus (STN) in 40 % of patients (years 1998–2005). The mean Hoehn and Yahr scale before the surgery was 3.36 for patient with GPi electrodes, and 3 for patients with NTS electrodes. Follow up and complications: the median follow-up after the procedure was 7 years [1–12]. Six patients died because of diseases unrelated with their neurological disorder or DBS. Eight patients developed cognitive impairment (as compared with patients without cognitive impairment, these patients were older and with longer mean disease duration). Adverse events occurred in 15 patients, and included: 1) Events related to the procedure: hemiparesis due to intracerebral hemorrage in 1 patient with GPi electrodes, 1 patient with insufficient stimulation effect due to misplacement of STN electrodes; 2) Events related to device: 3 patients with disconnection of the neurostimulator, 4 patients with infection of the device that required removal of the subcutaneous extension lead and/or pulse generator; 3) events related to stimulation: 3 patients with eyelid-opening apraxia (2 with STN and 1 with GPi electrodes), 1 with tetanic muscle contractions (GPi), hypophonia and dysphagia in 1 (STN), dysarthria in 1 (STN). Eight patients required battery replacement after a median period of 4 years [3–7] Conslusions: Disabling complications of DBS are not uncommon and they are seldom life threatening. Because surgery procedure is usually performed in small number of reference centres, availability of experienced clinicians in DBS more easily accessible to the patient is important for early recognition and treatment of potentially severe complications

Infection P375 Central and peripheral demyelination associated with hepatitis C virus infection T. Mestre, J. de Sá, J. Pimentel Hospital Santa Maria (Lisbon, P) Introduction: Hepatitis C (HCV) viral infection is occasionally associated with neurological manifestations, most frequently affecting the peripheral nervous system (PNS) in the form of a sensory axonal polyneuropathy. Anecdotal isolated central nervous system (CNS) involvement or with concomitant PNS involvement have been documented. Generally associated with essential mixed cryoglobulinaemia and vasculitis, the absence of cryoglobulinaemia have been documented but only for isolated PNS or isolated CNS presentations. Clinical case: a 43-year old patient, with past IV drug abuse history was admitted for delirium and flaccid tetraparesis. Two months earlier, a neuropathological diagnosis of a pseudo-tumoral form acute demyelinating leukoencephalopathy had been obtained in a brain biopsy sample conducted after MRi studies revealed a right parieto-occipital pseudo-tumoral lesion concomitantly with an intramedullary dorsal spinal cord lesion, in the sequence of acute complaints of numbness and decreased muscle strength to the left hemibody. Following clinical evolution during admission, a chronic inflammatory demyelinating polyneuropathy (CIDP) diagnosis was obtained as documented by electromyographic studies and an isolated elevated cerebral spinal fluid (CSF) protein level. Sural nerve biopsy revealed a primarily myelinic degeneration in the presence of macrophages, without perivascular inflammation. A HCV infection with active viral replication was diagnosed in the persistent absence of cryoglobulinaemia and with a normal complement study. The investigation for other viral or bacterial infections, autoimmune disease or specific intrathecal immunoglobulin synthesis was negative. The use of prednisolone and IV human immunoglobulin did not halt progression of CIDP to a flaccid tetraplegia. Clinical stabilisation with mild improvement in upper limbs muscular strength with undetectable viral load and normalising CSF parameters was warranted after combined ribavirin and pegylated interferon alpha-2b therapy was initiated within two month of admission. Discussion: a first case of a multifocal demyelinating process involving both CNS and PNS is presented in a patient with active HCV infection without cryoglobulinaemia or vasculitis.A direct viral cytopathic effect or an immunological mechanism distinct from vasculitis might be implicated. Therapeutic options were scarce and of marginal effectiveness. Combined anti-viral therapy might be considered. P376 Role of complement receptor 3 in a mouse model of pneumococcal meningitis B. Obermaier, R. Paul, M. Klein, B. Angele, B. Popp, H. W. Pfister, U. Koedel Ludwig-Maximilians-University (Munich, D) Objectives: The complement system is assumed to play a significant role in the host defense against pneumococcal infections. Recently, our group showed that, in a mouse model of pneumococcal meningitis, deficiency in complement factor C3 was associated with increased cerebellar bacterial titers and a dramatic reduction of the innate immune response as evidenced by lower leukocyte counts in the cerebrospinal fluid (CSF) and reduced expression of proinflammatory mediators. The latter was paralleled by reduced intracranial complications. In order to find out whether these effects were due to inhibited opsonophagocytosis mediated via complement receptor (CR) 3, in this study, we used mice with a targeted deletion of CR3 (kindly provided by Leusen JH, University Medical Center Utrecht, Netherlands). Methods: A well established mouse model of pneumococcal meningitis was used. Meningitis was induced by intracisternal injection of Streptococcus (S.) pneumoniae type 2 (D39, kindly provided by Oggioni MR, University of Siena, Italy). The following parameters were evaluated: clinical score, cerebellar and blood bacterial titers, CSF leukocyte counts and intracranial pressure (ICP). Results: At 24 hours after infection, cerebellar bacterial titers in CR3 deficient animals were significantly increased compared to wild type controls (7.46 vs. 5.69 log cfu/homogenate, p < 0.01). CR3 deficient animals exhibited an aggravation of disease associated with significantly increased clinical scores, increased weight reduction and reduced body temperatures. One out of six CR3 deficient mice died within 24 hours of infection, whereas none of the nine wild type mice did not survive the disease. Worsening of disease might be due to more severe bacteremia observed in CR3 deficient animals since CR3 deficiency was associated with an attenuated inflammatory re-

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sponse in the central nervous system (CNS) (e. g. reduced CSF leukocyte counts) and reduced intracranial complications (e. g. reduced ICP). Influence of CR3 deficiency on other intracranial complications, like blood-brain barrier disruption, and expression of proinflammatory mediators are under investigation. Conclusions: Taken together, these results show that CR3 might be involved in complement mediated bacterial phagocytosis and that it plays an important role in controlling host immune response to S. pneumoniae within the CNS. P377 A retrospective survey for cerebral hydatidosis in children C. A. Sirbu, R. Nitulescu, O. Sirbu, M. T. Vasile, T. Lupescu, R. Gheorghe-Dane, A. V. Chirtes, A. Drugea, D. Constantin Central Military Clinical Emergency Hospital (Bucharest, RO); Emergency District Hospital (Ploiesti, RO); Agrippa Ionescu Hospital (Bucharest, RO) Objectives: Data from the literature suggested that the rupture of hydatid cyst during surgery predicts a poor prognostic. We try to evaluated the prognosis of children operated for cerebral hydatidosis, after 5 years of follow-up. Methods: Epidemiological descriptive research as the “series of cases” type, amoung children with cerebral hydatid cyst, under medical observation in hospital between 1 of January 1990 and 31 of December 2000 in three hospitals in Bucharest. The following variables were recorded: 1) sex and age at presentation; 2) epidemiological data; 3) number, size, localization and rate of growth of cysts; 4) clinical features; 5) surgical approaches and medical therapy; and 6) relapses and sequelae. The processing of data was made with EPI INFO, version no. 6 and EXCEL – PC programs. Results: 26 children between 3–16 years old were analised, (mean 9.4 yr, 12 female, 14 male)0.92 % presented only one cyst, 8 % more than one cyst. The cysts diameters were in the range of 4–15 cm (mean 7.85). In 38.46 % cases cyst rupture occurred during surgery. The average time of survey was 5 years. 43.3 % presented sequelles. 15 % presented recurrences because rupture of the cysts during surgery. 11 % died of intracranial hypertension or meningoencefalitis. Conclusions: The prognosis is better defined by cyst size than by rupture during surgery (p < 0.05). Prompt evaluation and diagnosis followed by surgical treatment with pre-and post -chimiotheraphy will give a better prognosis. Chimiotheraphy given before surgery reduces the size of chists.

Conclusion: Quinacrine was the potentially effective treatments for CJD, but our trial found effectiveness only decrease of amount of myoclonusas and facial expression using modified Unified MSARS‡U. Neuropathologic scales fail to show significant effect. The survival term of treated patients was slightly longer than that of untreated patients. P379 Neuroborreliosis in the South West of England J. K. Lovett, N. Gutowski Southampton General Hospital (Southampton, UK); Peninsula Medical School (Exeter, UK) Objectives: Lyme Disease is becoming more commonly diagnosed in the UK. However, anecdotal reports and media coverage has suggested that cases are frequently missed or the diagnosis is delayed. In Europe, the commonest complications of Lyme disease are neurological. Previous UK studies, which have included mostly New Forest cases, suggest that 15 % have neurological manifestations, although this proportion may vary across the UK as it does across the world. Therefore, we studied serologically confirmed cases in the South West of England, the UK region with the second highest prevalence of Lyme Disease. Our aims were to study the frequency and nature of neurological complications, and to investigate the delays before appropriate treatment was given. Methods: We reviewed hospital and GP notes of all patients in the Royal Devon and Exeter Hospital region with positive borrelia serology during a five-year period (2000–2004). Results: There were 90 cases, of which 64 % reported insect bites. The commonest symptoms were erythema migrans (64 %) and arthralgia or myalgia (27 %). Headache was reported by 16 patients (18 %). However, 22 (24 %) had neurological symptoms other than headache. Of these, 14 had facial palsy (3 bilaterally), 8 had confusion or drowsiness, 4 had meningism, 5 had radiculopathy, 2 had other cranial nerve palsies, and 2 had other peripheral neuropathies. Of the 22 neuroborreliosis cases, only 10 reported tick bites, and 8 reported rashes. Length, dose, route and type of antibiotic treatment for neuroborreliosis was highly variable and it was often delayed (median 26 days). Conclusion: The proportion of Lyme patients with serologically confirmed neuroborreliosis was higher than in previous UK Lyme studies, and most worldwide studies. Identification and treatment of neuroborreliosis is frequently delayed. This could be partly because symptoms are diverse and most patients do not recall a characteristic tick bite or rash.

P378 Clinical, neuropathological analysis of administration of quinacrine in Creutzfeldt-Jakob disease K. Satoh, S. Shirabe, K. Eguchi Nagasaki University (Nagasaki, JP)

P380 Spinal cord lesion in secondary syphilis V. Matijosaitis, A. Vaitkus, V. Pauza, L. Malciene, R. Balnyte Kaunas University of Medicine (Kaunas, LT)

Ojectives: Quinacrine has been reported as an anti-prion drug and was administrated as the Creutzfeldt-Jakob disease patients. In Europa quinacrine did not have the significant effect for CJD patients, but in Japan patients, insensible before treatment, had integrative responses such as eye contact or voluntary movement in response to verbal and/or visual stimuli restored.We want to re-analyze for quinacrine effects as using many clinical scales, neuropathological aspects and the survival time. Methods: We studied the first 10 patients with CJD admitted to our hospital between 2002 and 2005. The clinical diagnosis of CJD was made according to standard criteria. According to Master’s criteria,10 patients showed 4 definite cases and 6 probable cases.We analyzed clinical courses of ten patients by many scales of other neurodegenerative diseases. Among these scales, Unified Multiple System Atrophy Rating Scales (MSARS_U) was most adaptable scale to have the influence on patients’ condition. According to Nagasaki University protocol in Japan, all patients received orally a loading dose of 100 mg three times a day with verparmil(120 mg/day) and cimetidine(800 mg/day). Disease progression was evaluated every 30 days based on Modified Unified MSARS‡U. Blood cell count and transaminase level were controlled after every 4 days of treatment. The neurolopathological study was performed after fixation of the brain Formalin-fixed paraffin-embedded brain sections were subjected to histological analyses including hematoxylin-eosin staining and PrP immunohistochemistry of 3F4 monoclonal antibody. Results: The duration between the onset and initiation of the treatment was 3.2 months (mean; range to 1 to 5 months) for 10 patients with CJD. Treatment duration was 28 days (1 to 36 days) for the patients with CJD. The survival terms of treated patients were 20 months in averrage and that of untreated patients was 17.1 months. Our neuropathological analysis of 13 selected lesions in CJD’s brain has no remarkable difference between 4 patients treated with quinacrine and 2 patients without treatment.

Introduction: WHO estimates 12 million new cases annually, and approximately 150000 deaths due to syphilis. The CNS becomes involved in up to 40 % of patients as a result of seeding during the stage of secondary syphilis. In many cases syphilis can be asymptomatic. Spinal cord lesions appear to be very rear in secondary syphilis. Case report: A 38 year-old man was admitted to the hospital because of shooting low back pain, radiating to the legs, legs weakness, numbness and retained urination with constipation. Symptoms appeared four months before the admission to the hospital and deteriorated. The patient declared having sexual contact about one and a half year before. On neurological examination lower limbs motor function was graded 3/5 proximally and distally. Knee jerks were brisk and ankle jerks were diminished bilaterally. Abdominal reflexes were absent. Pinprick and thermal sensations were absent below the costal margins. Joint-position sense and vibratory sensation were absent in the legs. Pathological Babinski signs were observed in both feet. The patient couldn’t walk unsupported. A small scar on the dorsal surface of the penis and Condylomata lata in anal region were noticed. Cerebrospinal fluid analysis showed pleocytosis (18 cells in mm≥) with domination of lymphocytes and elevated protein level (0.88 g/l). Serologic tests for syphilis were positive: RPR 1:128, TPHA 4 + , ELISA and VDRL in CSF 1:16. HIV test was negative. Spine MRI disclosed a T2 hypersignal lesion intramedularly in the ventral part at T6–7 level, accumulating contrast material in T1 regime. Penicillin 4 million IU five times/day for 20 days together with prednisolone starting at 30 mg/day allowed partial clinical and serological improvement. Discussion: This spinal lesion had to be excluded from neoplastic, vasculitic, demyelinating and other reasons. Skin lesions and history of sexual contact may often be neglected, but it has a great value to come to a hypothesis of possible infectious cause of spinal lesion. Cases like this as well as all unclear cases should be investigated in order to exclude neurosyphilis and serological tests should be done.As morbidity of syphilis in Lithuania is con-

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stantly decreasing, cases of neurosyphilis are of great clinical and scientifical importance as a rare infectious disease which can be complicated with neurosyphilis in any stage. Further surveillance with repeated serological tests and symptoms of recurrence is obligatory.

Motor neuron disease P381 SERPINA3 signal region A/T polymorphism and risk of sporadic amyotrophic lateral sclerosis in a Polish population D. Partyka, B. Tomik, A. Slowik, J. Pera, T. Dziedzic, A. Szczudlik Jagiellonian University (Cracow, PL) Introduction: Genetic factors involved in the pathogenesis of sporadic amyotrophic lateral sclerosis (sALS) still remain unknown. One of the candidate genes is SERPINA3, a serine protease inhibitor. SERPINA3 signal region A/T polymorphism influences SERPINA3 protein expression with the highest levels in T allele carriers. It has been shown that imbalance of serine proteases and internalized serpins may play a role in the pathogenesis of sALS (Chou SM, J N Sci 1998). The aim of the study. To check a possible association between SERPINA3 signal region A/T polymorphism and the risk of sALS as compared to healthy controls in Polish population. Material and methods: We have included 165 patients with sALS and 404 healthy controls matched for age and sex. The definite or probable diagnosis of sALS was established according to El Escorial Criteria (1998). The familial ALS (fALS) cases were excluded based on positive ALS family history. The polymorphisms were studied by PCR and restricted enzyme digestion. Results: The distribution of SERPINA3 signal region A/T polymorphism did not differ between cases and controls (cases, n = 165: AA – 38 [23 %]; AT – 84 [51 %]; TT – 43 [26 %], controls, n = 404: AA – 106 [26, 2 %],AT – 193 [47, 8 %], TT – 105 [26 %]). However, when bulbar and limb sALS onset cases were studied separately, the SERPINA3 A/T polymorphism influenced only the risk of bulbar sALS onset (genotype distribution in the cases, n = 52: AA – 8 [15, 5 %], AT – 24 [46 %], TT – 20 [38, 5 %], genotype distribution in the controls, n = 404: AA – 106 [26, 2 %], AT – 193 [47, 8 %], TT – 105 [26 %], p = 0.058), (allele distribution in the cases: A-40 [38, 5 %], T-64 [61, 5 %] vs. the controls: A-405 [50, 1 %]; T-403 [49, 9 %], p = 0.025). Conclusion: We found that T allele of SERPINA3 gene may influence the risk of bulbar onset of sALS in a Polish population. P382 Epidemiology of ALS in Cuba: a pilot study in Havana T. Zaldivar, J. Gutierrez, G. Lara, O. Hardiman, R. Mustelier Institute of Neurology (Havana, CUB); Beaumont Hospital (Dublin, IRL) Background: The incidence and prevalence of ALS has been considered to be uniform throughout the world, with the notable exceptions of Guam and the Kii peninsula in Japan. However, most population based studies have been conducted in Europe and North America, and have captured mainly those of European Caucasian origin. The lower incidence of ALS in non-European countries, and the lower incidence of ALS in African-Americans may have been confounded by reduced ascertainment. Full disease ascertainment of neurological disease is possible in Cuba, as medical care is available to all, and there is a well developed network of neurological care. We have previously demonstrated a striking difference in the incidence of spinal muscular atrophy, a childhood onset form of motor neuron disease, in different ethnic groups in Cuba. We have similarly noted a reduced incidence of ALS in those who report their ethnicity as “Black” and “Mulatto” compared to those who report their ethnicity as “White”. Aim: To ascertain all cases of ALS in the Havana Province, and to determine the incidence, prevalence and clinical features of the disease within 3 defined groups – “White”,“Mulatto” and “Black”. Methods: All Havana-based Neurologists and Neurophysiologists have agreed to participate in this study, and ethical approval has been obtained from the Institute of Neurology in Havana. All cases of ALS are classified by the El Escorial criteria. Clinical details are collected and stored on a password protected database held at the Institute of Neurology. Results: Preliminary findings indicate an increased incidence of ALS in those self-reporting to be European descent, and a reduced incidence of those of African ancestry. Conclusions: This is the first detailed population based epidemiologic study of ALS in a population of mixed ethnicity. Our findings will determine the relative importance of ethnic origin in the pathogenesis of ALS.

P383 Pilotstudy of thalidomide in amyotrophic lateral sclerosis T. Meyer, J. Dullinger, C. Munch, S. Ohlraun, P. Linke Charite University Hospital (Berlin, D); Jüdisches Krankenhaus (Berlin, D); Koordinierungszentrum für klinische Studien (Berlin, D) Background: Neuroinflammation has recently observed in both sporadic and familial amyotrophic lateral sclerosis (ALS) and in the ALS superoxide dismutase 1 (SOD1) transgenic mouse model. They include an accumulation of large numbers of activated microglia and astrocytes.Proinflammatory cytokines, such as tumor necrosis factor (TNF-alpha), are robustly upregulated in ALS. TNF acts as a principal driver for neuroinflammation in ALS.We initiated an investigational therapy of ALS with oral administration of thalidomide (THL) based on the anti-inflammatory properties of THL through the modulation of inflammatory cytokines such as TNF. Methods: 40 patients will be enrolled and randomly assigned to either Group 1 (100 mg thalidomide, dose escalation to 400 mg + riluzole 100 mg) or Group 2 (riluzole 100 mg). The patients are treated over a 24 week treatment period. The primary aim of the trial is to determine whether treatment with THL is safe and well tolerated in conjunction with riluzole and whether patients with ALS can tolerate daily doses of up to 400 mg. We to compare the total number of adverse events (AE), the rate of functional decline measured by the ALS Functional Rating Scale-revised (ALS-FRS-R); 2) and the effects of THL on the forced vital capacity. We evaluate the sleep quality and somnolence using the Epworth Sleeping Scale and the frequency and severity of sensory neuropathy. Results: We show preliminary data on safety and tolerability of THL in conjunction with riluzole in 40 ALS patients. Conclusion: The small sample size and limited duration of the THL trials render it premature to draw conclusions regarding efficacy. However, secondary endpoints of the investigational therapy will evaluate clinical effects of thalidomide on ALS progression. The trial is designed as feasibility study in planning for a larger phase IIb/III trial of efficacy. ClinicalTrials.gov Identifier: NCT00231140 Supported by a grant of the Immendorff Fonds for ALS research and the Pharmion Germany GmbH P384 Elevated serum angiogenin levels in spinal-onset amyotrophic lateral sclerosis S. Cronin, M. Greenway, J. Prehn, O. Hardiman Beaumont Hospital (Dublin, IRL); National Centre for Medical Genetics (Dublin, IRL); The Royal College of Surgeons in Ireland (Dublin, IRL) Background: An allelic association and a series of novel mutations in the angiogenin gene suggest a role for angiogenin in the pathogenesis of amyotrophic lateral sclerosis (ALS) [1]. However the patterns of serum angiogenin (ANG) expression among ALS patients have not previously been assessed. Objective: The aim of this study was to investigate whether serum angiogenin levels were altered in ALS patients. Patients and methods: Serum angiogenin levels were measured in 61 patients with definite or probable ALS by the El Escorial criteria, and in 45 healthy control subjects. Among ALS patients, 46 presented with spinal onset symptoms and 15 with bulbar symptoms. Blood was drawn at diagnosis, and follow-up 15 month sera were available in 10 cases. Serum ANG levels were assayed using a quantitative sandwich enzyme-linked immunosorbent assay. Results: ANG serum levels were significantly elevated in spinal-onset ALS when compared to controls (p = 0.03). No significant difference in ANG serum levels was detected for the overall ALS group (p = 0.06) or the bulbaronset group (p = 0.59) when compared to controls. No significant difference was detected between levels at 15 months when compared to baseline. Conclusions: These data suggest a modest elevation in serum ANG in spinal-onset ALS. Further investigation will be required to assess the utility of serum ANG as a biomarker for ALS and as a predictor of disease progression. Supported by the Charitable Infirmary Charitable Foundation Reference 1. Greenway MJ, Alexander MD, Ennis S, Traynor BJ, Corr B, Frost E, Green A, Hardiman O (2004) A novel candidate region for ALS on chromosome 14q11.2. Neurology 63 [10]:1936–1938

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P385 Primary lateral sclerosis presenting with progressive pseudobulbar syndrome A. Becker, M. Hardmeier, A. Steck, A. Czaplinski University of Basel (Basel, CH) Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with slowly progressive spinobulbar spasticity. The diagnosis can usually be made clinically according to proposed diagnostic criteria. Here, we report a patient with probable PLS presenting with progressive pseudobulbar syndrome in absence of signs of a tetrapyramidal syndrome. A 60-year old male developed gradually (within few months) slurring of speech and had consequently lost his clear speech. He also noticed slowly progressive dysphagia and emotional lability. The family history was negative. Neurological examination showed a severe pseudobulbar syndrome with dysarthria, strained and nasal voice, reduced amplitude and speed of lingual movements without atrophy or fasciculations, swallowing-difficulties and emotional lability. There were no clinical signs of a tetrapyramidal syndrome (spasticity, hyperreflexia) and no signs of lower motor neuron (LMN) involvement. Higher cognitive functions were preserved. Serum chemistry was normal. Tests for syphilis, Lyme disease, HTLV and HIV were negative. CSF was negative for oligoclonal bands. There were no relevant lesions or atrophy on brain MRI. Spinal MRI showed no compressive lesion of cervical spine or foramen magnum but a thoracic syrinx. Needle EMG of bulbar, cervical, thoracic and lumbosacral muscles showed no signs of an acute denervation process. MEP showed abnormal central motor conduction to the legs but not to the arms. According to the diagnostic criteria proposed by Pringle, the diagnosis of PLS requires the presence of slowly progressive, nearly symmetrical, bilateral pyramidal involvement including the face in absence of family history. In our case the clinical features were limited to pseudobulbar symptoms without any clinical upper motor neuron (UMN) signs in the arms and legs. However, we hypothesize that our patient had developed a form of PLS with exclusive pseudobulbar involvement. Further clinical follow-up will show whether our patient will develop a tetrapyramidal syndrome and fulfil the diagnostic criteria of “classical” PLS or gradually present LMN features and fulfil the ALS criteria. We believe that PLS is probably not a discrete nosological entity but represents a part of the range of motor neuron diseases with predominant UMN involvement. However, recognizing the PLS phenotype is important because it offers a much better prognosis than the ALS phenotype. P386 Movement-related cortical potentials in amyotrophic lateral sclerosis E. Ortu, G. Sau, I. Aiello University of Sassary (Sassari, I) Objectives: To evaluate the preparation and execution of self-paced voluntary movements in amyotrophic lateral sclerosis (ALS) by means of movement-related cortical potentials (MRCPs) recording. Methods: MRCPs preceding brisk voluntary flexion of right thumb were studied in 10 right-handed ALS patients (6 men and 4 women, mean age 57 ± 5.8 years, mean illness duration 8.2 ± 3.1 months, mean illness severity 74 ± 6.0 according to the Norris Score) and compared with those recorded in 10 age-matched healthy subjects (5 men and 5 women, mean age 56.8 ± 7.7 years). Electroencephalograms (EEGs) were recorded from 3 electrodes placed over the scalp (C3, Cz, and C4) according to the International 10–20 System. The electromyographic (EMG) activity, used as trigger signal for the EEG acquisition, was recorded from the thenar muscles. Onset, amplitude, area and duration of the two principal MRCPs components, the bereitschaftspotential (BP) and the negative slope (NS’) were measured. Results: MRCPs were recorded in 9 out of the 10 ALS patients. Duration of MRCPs, onset of BP and onset of NS’ was significantly reduced in all three recording positions (p < 0.05). Amplitude, area and duration were increased for BP and decreased for NS’, though not significantly. Conclusions: Reduced MRCPs duration and BP and NS’ onset were reported with our study. This is in agreement with ALS pathophysiology driven by motor cortical neuronal loss. BP originates from bilateral activity of supplementary (SMA) and cingulated (CMA) motor areas, while NS’ is generated by the activation of the contralateral primary motor area (M1). Should an increased BP amplitude, area and duration, and a reduction of the same parameters for NS’ be confirmed with a larger sampled study, this could point to a compensatory increased activity of cortical areas involved in motor planning, beside the reduced activity of the primary motor area due to the neuronal loss in ALS. These findings would be in agreement with fMRI studies. We acknowledge Regione Autonoma della Sardegna (Assessorato dell’Igiene, Sanità ed Assistenza Sociale)

P387 Risk of ALS in Irish marathon runners C. Sheehan, O. O’Toole, B. J. Traynor, O. Hardiman Beaumont Hospital (Dublin, IRL); NIH (Bethesda, USA) Background: Recent epidemiological evidence suggests that vigorous, sustained exercise may be a risk factor for developing ALS.Training for and running in marathons represents one of the most extreme aerobic sports commonly undertaken by non-professional athletes in today’s society. The Dublin City Marathon began in 1980 with 1.420 entrants rising to 8.700 entrants in 2000. Objectives: The authors sought to determine if the incidence of ALS was higher among Irish individuals who completed the Dublin City Marathon. Methods: The names and nationality of individuals who completed the Irish marathon for the years 1980 to 2002 were identified from publicly available published lists. These names were cross-referenced with the names of individuals diagnosed with ALS listed on the Irish ALS Register. The Irish ALS Registry has full case ascertainment for all patients diagnosed with ALS in the Republic of Ireland since 1995. Results: 59.604 individuals completed the Dublin City Marathon during the study period. Full names were available for 59.594 individuals, of whom 14.443 were omitted because they were not Irish. 676 Irish patients were diagnosed with ALS in Ireland between June 1993 and June 2002. Comparison between the 45.151 Irish marathon runners and the 661 Irish ALS patients revealed 151 patients with the same name. Of these, 22 were listed as having symptom onset before the date of the marathon and were omitted. A further 5 patients had different ages and were discounted. One subject had a different address and was omitted. Follow-up of the 123 patients is ongoing to determine if they have completed a marathon in the past. Conclusions: This represents the first epidemiological study to determine the risk of ALS among a large cohort of individuals engaging in nonprofessional vigorous exercise. P388 Signs of sensory dysfunction in patients with amyotrophic lateral sclerosis I. Artmonov, V. E. Drory Tel-Aviv Sourasky Medical Center (Tel-Aviv, IL) Background: Patients with amyotrophic lateral sclerosis (ALS) report sometimes symptoms related to sensory system dysfunction. The incidence of sensory symptoms and signs in ALS is thought to be very low, but recent epidemiological data are not available. Methods: From clinic records we determined the existence of sensory symptoms and signs in 360 patients with ALS (55 % males, aged 59 ± 13 years). Results: Subjective sensory symptoms were reported by 38 patients (10.5 %). 32 of them (9 %) had confirmatory signs of sensory dysfunction at the neurological examination. Among those 5 had diabetes and distal sensory involvement, compatible with a diabetic sensory polyneuropathy, one of those had also a superimposed carpal tunnel syndrome, and two had a cervical myelopathy. One had a distal symmetric polyneuropathy possibly related to severe peripheral vascular disease. Ten patients had unrelated focal peripheral nerve injuries: electrical injury in one, leg trauma in one, bilateral carpal tunnel syndrome in one, Brown-Sequard syndrome due to an intramedullary cyst in the conus medularis in one, one patient with a rheumatologic disorder and multiple ischemic nerve lesions, five had cervical or lumbar disc protrusions with significant root compression. Six patients had previous strokes with hemihypoesthesia. In ten patients (3 %) no reason for the sensory dysfunction was found, in spite of extensive diagnostic work-up. Seven had a distal symmetric pattern of involvement compatible with cryptogenic polyneuropathy, two had a hemisensory syndrome and one had lower body hypoesthesia with a thoracic border. Conclusion: Signs of sensory dysfunction in ALS are mostly explained by other neurologic conditions, but may be part of the ALS symptom complex in up to 3 % of cases. P389 Increased risk of type II diabetes mellitus in post-polio syndrome: understanding the link J. Phukan, M. Hatunic, O. O’Toole, D. Gasparro, J. Nolan, O. Hardiman Beaumont Hospital (Dublin, IRL); St James’s Hospital (Dublin, IRL) Background: The last reported case of poliovirus in Ireland was in 1965. Post-poliomyelitis syndrome (PPS) is characterised by new progressive weakness, fatigue, and pain. A disruption in insulin-like growth factor has been reported in PPS. There have been few studies to determine whether pa-

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tients with PPS have altered responsiveness to insulin. Studies to date have also not yet explored possible mechanisms for altered insulin responsiveness, should this exist. Objectives: To determine the prevalence of Type II diabetes in a clinicbased cohort of patients with PPS, and to compare these with age and sex matched controls. To determine underlying mechanisms for altered insulin responsiveness in post polio syndrome, should this link be established. Methods: Patients between 18 and 80 with a prior history of poliomyelitis and registered with the Post Polio Support Group were invited to attend the National Post Polio Clinic. Exclusion criteria included the presence of other chronic neurological conditions, secondary causes of diabetes and a pre-existing diagnosis of type I diabetes. 34 patients underwent history and physical examination. Fasting lipids and a standard two-hour glucose tolerance test were performed in 31. Data from the PPS population were compared with controls from a recently compiled normative Irish database. For the first time in the study of post polio syndrome, the Oral Glucose Insulin Sensitivity (OGIS) model was used to calculate insulin sensitivity. Results: 3 patients were excluded from glucose tolerance testing as they had a prior diagnosis of diabetes. 34 patients were studied. Over one third were found to have altered insulin responsiveness. Calculations using the OGIS method confirmed inherent changes in insulin sensitivity. 4 (12 %) were diabetic, and 7 (22.6 %) were found to have impaired glucose regulation (normative population rate: 4.9 %). Twenty-four (77 %) had dyslipidemia (normative population rate: 49 %). 57 % had cholesterol values of over 5 mmol/L, 87 % had an LDL value over 2.5 mmol/L. 19 (61 %)were overweight and 4 (12 %) were obese (similar to normative Irish population rate). The findings of increased risk of diabetes mellitus were independent of increased BMI. Secondary causes of diabetes were also excluded. Conclusion: Patients with PPS are at increased risk of developing type II diabetes and dyslipidemia. This risk may be related to altered insulin signalling in chronically denervated muscle. P390 Progressive motor neuron disease in two patients with human immunodeficiency virus (HIV-1) infection: a causal relationship? A. Ariatti, G. Tassone, F. Girolami, G. Galassi Institute of Neurosciences (Modena, I) Objective: Clinical pattern of human immunodeficiency virus (HIV) associated motor neuron diseases may mirror those of progressive spinal muscular atrophy or of segmental forms such as brachial amyotrophic diplegia (BAD). BAD results in weakness and atrophy of upper extremities usually in absence of bulbar, lower limb involvement, pyramidal signs, sphincter dysfunctions, sensory loss. Methods: We describe two HIV-1-seropositive patients affected by a motor neuron disorder which could be defined as BAD in case 1, whereas in case 2 a clinical phenotype similar to BAD was associated to external eye and bulbar muscle involvement. This 50 year-old man noticed progressive symmetric weakness and wasting of shoulders and arms. On examination, patient exhibited a peculiar posture of both hands hanging loosely at his sides with visible fasciculations. Reflexes were absent in upper extremities, but normal in the lower. Case 2, aged 51 years, presented with diplopia, dysarthria, dysphagia, similar symmetric weakness and profound atrophy of upper extremities. Neurological examination showed also paresis of the right 6th, right 7th, 9th, right 12th cranial nerves and tongue atrophy. Patient could walk and stand normally. Results: In both cases routine blood tests, search for antibodies to gangliosides were negative in serum. In Case 1 creatin kinase was elevated (361mU/ml, n. v. below 195). The test for HIV-1 was positive with RNA level of 144.920 copies/ml and CD4 count equal to 403/mm3. In case 2 test for HIV1 was also positive with RNA level of 25.357 copies/ml. CD4 count was 90/mm3; HIV viral load was 58.093 copies/ml. Spinal fluid of case 2 showed increased protein content (181 mg/dl, n. v. below 45) and 15 polymorphonuclear cells/mm3. Electrophysiology showed in case 1 low amplitude of muscle action potentials, slowed motor conduction velocity in upper extremities without evidence of conduction block. Motor conduction velocity in case 2 was normal. On EMG, there were acute and chronic neurogenic changes in upper and lower limbs of both. Patient disability remained stable over two years under retroviral therapy. Conclusion: Although there is no proof of definite causal relations between HIV infection and motor neuron disorders it is necessary to outline such occurrence. The disorder of our patients may represent the end of the broad spectrum of motor neuron diseases occurring in association with HIV-1 infection.

Multiple sclerosis P391 The design of the CLARITY study (CLAdRIbine tablets Treating multiple sclerosis orallY) G. Giovannoni, S. Cook, P. Rieckmann, P. Vermersch, P. Soelberg-Sorensen, G. Comi, P. Chang, M. Lopez-Bresnahan, R. Kim Institute of Neurology (London, UK); University of Medicine and Dentistry (Newark, USA); Bayerische Julius-Maximilians-Universität (Wurzburg, D); Hôpital R Salengro (Lille, F); Rigshospitalet (Copenhagen, DK); Università Vita-Salute San Raffaele (Milan, I); Serono Laboratories Inc (Rockland, USA) Objective: To compare the efficacy and safety of cladribine tablets versus placebo for treating relapsing-remitting multiple sclerosis (MS). Background: Cladribine, a purine nucleoside analogue, preferentially targets certain lymphocyte populations. Since its 1993 FDA approval to treat hairy cell leukaemia, cladribine has been approved in Europe and most of the world for the treatment of hairy cell and chronic lymphocytic leukaemias, non-Hodgkins lymphoma and Waldenström’s macroglobulinaemia. Preferential targeting of lymphocytes makes cladribine a good candidate to target inflammatory autoimmune diseases such as MS. Based on promising results with parenteral cladribine in relapsing and progressive MS and the development of an oral tablet formulation delivering comparable pharmacological exposure to parenteral cladribine, a randomised trial testing the tablet formulation in relapsing-remitting forms of MS has started. Design/Methods: 1290 subjects will be randomised to cladribine-tablet low-dose, high-dose, or placebo groups. Patients receiving cladribine tablets will receive five consecutive daily treatments each month for two or four months per year (low- and high-dose groups, respectively). All patients receiving cladribine in the first year will receive the low dose in the second year. Key eligibility criteria include: diagnosis of definite MS (McDonald criteria); EDSS score 0–5.5; one or more relapses in the previous 12 months; magnetic resonance image (MRI) consistent with MS (Fazekas criteria). Neurological evaluations will be by independent blinded evaluating physician; a separate treating physician will monitor safety assessments. Results: Primary endpoint: reduction in relapse-rate at 96 weeks. Secondary endpoints include: proportion of subjects relapse-free, disability progression, MRI, quality of life, safety and pharmacokinetic assessments. Conclusions/Relevance: Despite all the currently approved disease-modifying MS drugs that are given parenterally, there is still an unmet need for new treatments. Cladribine tablets may provide a more convenient alternative and the infrequent oral dosing may enhance adherence with therapy. Study supported by Serono International SA.

P392 Analysing the psychological reactions (grief reactions) in multiple sclerosis patients after awareness of their diseases M. Nabavi, V. Shariatpanahi, B. Barzegar Shahed University (Tehran, IR); Azad University (Tehran, IR) Objective: Multiple sclerosis(MS) as a common chronic demyelinating disabling disorder of central nervous system could raise psychological grief reactions after diagnosis for all patients. In this study we evaluated the presence of: Denial, Anger, Bargain, Depression, Acceptance and Hopefullness as common grief reactions to chronic disease. Methods: 36 definite MS patients after at least 6 months after the diagnosis of MS participated in this study and answered to the questiones that abstracte and planned from some standard questoinares such as Beck depression inventory (BDI), SCID, . . Results: 30 % of the patients experienced denial period, 50 % anger, 83.4 % bargain, 52.4 % depression and 86 % acceptance, 61.2 % of patients pretended to be cured successfully, 30.5 % said they will be cured but incompeletly and finally 8.3 % caimed they wont have any cure. Conclusion: This study revealed that MS patients experience the steps of grief reactions as other chronic disabling disorders but in comparison to another similar diseases MS patients have a great hope to be successfully cured.

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P393 Oligoclonal IgG patterns in multiple sclerosis J. C. Alvarez-Cermeño, M. Espiño, J. Gomez-Rial, N. Garcia-Barragan, M. Diaz-Sanchez, M. C. Sadaba, J. Masjuan, P. Gonzalez-Porque, L. M. Villar Ramon y Cajal Hospital (Madrid, E) Objective: To explore the oligoclonal band patterns of IgG(OCGB) found in multiple sclerosis (MS) cerebrospinal fluid (CSF) Methods: OCGB were studied in 201 clinically definite MS patients (McDonald criteria) and 100 patients with other non inflammatory diseases of the central nervous system (OND). Paired CSF and serum proteins adjusted for equal amounts of IgG in either sample were separated by isoelectric focusing and transferred to nitrocellulose membranes. IgG was detected by a new method of western blot with specific antibodies labelled with alkaline phosphatase. Results: Four distinct patterns were observed in the IgG response in patients; I: Absence of bands. II: Identical bands in serum and CSF (mirror pattern). III: Bands in serum with additional bands in CSF. IV: IgG bands exclusively in CSF. OND patients showed pattern I. Pattern III was predominantly found in primary-progressive MS patients while pattern IV was observed in relapsing-remitting ones (p < 0.0001) Conclusion: Different patterns of OCGB may be found in MS. They may reflect distinct pathogenic mechanisms. P394 High-dose (375 mcg) interferon beta-1b treatment of multiple sclerosis and neutralising antibodies. Long-term follow-up L. Durelli, A. Ricci, P. Bergui, A. Pipieri, A. Cucci, B. Festa, A. Rovera, G. Contessa, M. Bergui, E. Versino, M. Clerico for the OPTIMS NAb Sub-Study group Background: Neutralising anti-interferon beta (IFNb) antibodies (NAbs) seem to have a detrimental effect on treatment response. Increasing IFNb dose could reduce their occurrence. The OPTimization of Interferon for MS (OPTIMS) study was a multicenter prospective trial investigating clinical and magnetic resonance imaging (MRI) outcomes with a new high dose of IFNb-1b(375 µg every other day). Objective: Frequency and effect of NAb on clinical and MRI response during the OPTIMS trial and subsequent long-term (4 years) follow-up using two different statistical approaches (cross-sectional and longitudinal analyses). Methods: At the end of a 6-month run-in phase, where RR MS patients were treated with the standard approved dose of IFN beta-1b (250 mcg EOD), subobtimal responder patients were randomized to continue treatment with 250 mcg, or to increase to 375 mcg. A suboptimal response was defined either by at least one active scan or a relapse or EDSS confirmed progression. An active scan was any scan with either a new PD/T2 or enhancing lesion. NAb were tested using the MxA protein production neutralization assay in a lung carcinoma cell line. NAb titer was expressed as the highest dilution of serum which neutralizes a 10 IU/mL IFN-beta activity to an apparent 1 IU/mL activity. The activities were determined by an IFN-beta standard curve without any antiserum added. Sera with a titer ≥ 20 NU/mL were considered positive. Cross-sectional and longitudinal analyses of treatment response according to NAb + or NAb – status were made. Results: 145 patients from 14 NAb frequency was only negatively associated with MRI treatment response and no detrimental effect of NAb on the clinical signs of treatment response was observed. NAb + patients treated with the higher dose of IFNb-1b had a significantly greater probability of having their NAb disappear (hazard ratio: 1.5; 95 % CI: 1.04–2.15; p = 0.02) and an over five-fold lower risk of having persistent MRI activity during treatment compared with patients treated with the standard approved IFNβ–1b dose (RR = 5.41; 95 % CI: 1.67–17.84; p = 0.001). Results of the two statistical approaches were similar. Conclusion: The use of a dose of IFNb-1b higher than the currently approved 250 µg dose improves treatment response and induces an earlier disappearance of NAbs. B cell tolerance induction by a high antigen dose might explain the decrease of NAb frequency in patients treated with IFN beta-1b 375 mcg. The study was supported by Schering,AG, Berlin, Germany, and Schering Italia, S. p. A., Milano, Italy

P395 A long-term open-label trial of safety and efficacy of Sativex®, a cannabis based medicine, in central neuropathic pain due to multiple sclerosis D. J. Rog, T. J. Nurmikko, N. S. Sarantis, C. A. Young Walton Centre for Neurology and Neurosurgery (Liverpool, UK); Pain Research Institute (Liverpool, UK); GW Pharmaceuticals (Salisbury, UK) Objective: To investigate the long-term safety and efficacy of Sativex, an oromucosal- whole plant cannabis based medicine in patients with multiple sclerosis (MS) and central neuropathic pain (CP). Methods: The efficacy and tolerability of Sativex was investigated in a randomised trial of 66 MS patients with CP. Each spray contained 2.7 mg delta-9 tetrahydrocannabinol and 2.5 mg cannabidiol, Sixty-four patients (97 %) completed the study (5 weeks), and 63 (96 %) entered the open-label extension. Patients self-titrated their daily dosage up to a maximum of 48 sprays and maintained their existing analgesia. Results: In the randomised trial, Sativex achieved significant improvements in pain (Numerical Rating Scale (NRS)–11, p = 0.005 and Neuropathic Pain Scale p = 0.044) and sleep disturbance (NRS-11, p = 0.003) compared to placebo. The mean NRS-11 pain scores at baseline and in the last week were: Sativex 6.5 and 3.8 and placebo 6.4 and 4.9, respectively. The mean duration of open-label Sativex treatment was 463 days (median 638, range 3–917, SD 378).Thirty-four patients (54 %) were treated for more than one year; their neuropathic pain improving to 2.8 (0–8, 2.0) a mean decrease of 3.6 (0.14–7, 1.9) from the end of randomised treatment. The mean number of sprays remained stable from 7.7 (2.1–16.9, 4.3) early in open-label treatment to 7.5 (1.3–21.9, 5.7) at a year, whilst the mean intoxication visual analogue scale reduced from 5.9 (0–47, 12.7) to 1.8 (0–49, 8.8). Patient’s sleep quality was maintained and 26 patients (76 %) had no, or only one, awakening per night after a year of treatment. Fifty eight patients (92 %) experienced a treatmentrelated adverse event (AE), which were rated in 47 patients (75 %) as mild, moderate in 49 (78 %) and severe in 32 (51 %). The commonest AEs were dizziness (27 %), nausea (18 %) and feeling drunk (11 %). Two serious adverse events, ventricular bigeminy and circulatory collapse occurred, both in the same patient and resolved completely. Eleven patients (17 %) experienced oral discomfort; in four this was persistent. Regular oral examinations revealed seven patients (11 %) with white and two (3 %) red buccal mucosal patches; all were rated as mild. All patients perceived benefit of Sativex after a year of treatment, rated by themselves and the Investigator. Conclusion: Sativex is well tolerated and efficacious as a treatment for CP due to MS for at least 12 months with no evidence of tolerance. Study designed and sponsored by GW Pharmaceuticals P396 Clinical experiences with mitoxantron therapy in secondary progressive multiple sclerosis in the years 2001–2005 A. Barcikova, M. Zahonova, L. Prochazkova Comenius University (Bratislava, SVK) Introduction: Mitoxantron (MTX) is a synthetic anthracenedione agent with antineoplastic, immunosuppressive and immunomodulatory effect. Its beneficial effect in multiple sclerosis (MS) patients has been established in many trials. MTX effectively decrease the number of relapses, moderate clinical progress and decrease MRI activity in MS patients. The aim of this study was to describe efficacy and tolerability of MTX treatment in the group of secondary progressive MS (SP-MS) patients in routine clinical practice. Methods: In our retrospective study we analyzed 20 SP-MS patients (8 males, 12 females, mean age in the beginning of the therapy 42.6 years, mean duration of the disease in the beginning of the therapy 11.45 years, mean EDSS in the beginning 5.925 points [4, 5–7, 0]) who received 12 mg/m2 of body surface i. v. mitoxantron every 3 months up till total dose 140 mg/m2 of body surface. Each patient underwent the set of laboratory tests, electrocardiography and clinical examination with evaluation of Expanded Disability Status Scale (EDSS) before and after the treatment. Results: During observation period from 1 August 2001 to 31 December 2005 the patients received 83 cures of mitoxantron in total, 1–6 cures per patient, the mean EDSS in the end of the therapy was 5.875 points. In 10 % of the patients the improvement by 0.5 points was registered and in 90 % of the patients clinical status remained stable. The adverse reactions were registered in 2 patients (10 %) (in 1 case thrombophlebitis of left lower extremity and in 1 case myelosupression), which were the reason to discontinue further therapy. Conclusion: Mitoxantron is effective treatment in improving and stabilizing the disease course in SP-MS patients with a worsening disease course. MTX in dose of 12 mg/m2 every 3 months was well tolerated. The severe adverse reactions were rare. Our experiences with MTX therapy are positive.

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P397 Prevention of relapse with intravenous immunoglobulin study: initial results of a dose-finding trial in relapsing-remitting multiple sclerosis F. Fazekas, M. S. Freedman, H. P. Hartung, D. Li, F. Lublin, P. Rieckmann, P. Soelberg-Sørensen, M. Maas-Enriquez, B. Sommerauer, M. Anderesi Medical University Graz (Graz, A); The Ottawa Hospital (Ottawa, CAN); Heinrich-Heine-Universität (Dusseldorf, D); University of British Columbia and UBC Hospital (Vancouver, CAN); The Mount Sinai Medical Center (New York, USA); Neurol. Universitätsklinik (Wurzburg, D); Copenhagen University Hospital Rigshospitalet (Copenhagen, DK); Bayer HealthCare AG (Leverkusen, D); Bayer Vital GmbH (Leverkusen, D) Objective: Several studies have demonstrated a beneficial effect of intravenous immunoglbulin (IVIG) on relapse reduction in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of the Prevention of Relapse with IntraVenous ImmunoGlobulin (PRIVIG) study was to assess the safety and efficacy of two different doses of IVIG-C, 10 % compared with placebo (Pl). Methods: 127 patients fulfilling McDonald criteria for definite MS with an RRMS disease course were enrolled in this multinational, multicentre, randomised, placebo-controlled, double-blind clinical trial. 44 and 42 patients were randomised to receive treatment with 0.2 g/kg and 0.4 g/kg IVIGC, 10 %, respectively, and 41 patients to placebo (0.1 % albumin) every 4 weeks for 48 weeks. Frequent MRI evaluations were performed every 6 weeks and clinical evaluations every 3 months. Informed consent was obtained for all study patients prior to the initiation of any study-related procedures. The primary endpoint was the proportion of relapse-free patients at 48 weeks. Secondary and exploratory endpoints included MRI lesion activity, lesion and brain volumes, relapse rate, time to first relapse, change in Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC). Results: The proportion of patients remaining relapse free did not differ between the 3 groups (0.2 g/kg, 57 %; 0.4 g/kg, 60 %; Pl, 68 %). There was also no difference between the groups with the main secondary endpoint, the cumulative number of unique newly active MRI lesions (median, 0.2 g/kg, 8.0; 0.4 g/kg, 5.0; Pl, 7.2) nor any of the other endpoints except for reduction in brain volume at 48 weeks (median, 0.2 g/kg, 0.79 %; 0.4 g/kg, 0.35 %; Pl, 0.98 %; p = 0.02 0.4 g/kg vs Pl). There were no significant differences in the rates of adverse events between groups. Conclusion: This study could not substantiate a beneficial effect of IVIG. While the IVIG groups had a proportion of relapse-free patients similar to that previously reported in successful IVIG trials in RRMS, the placebo group performed equally well.Whether the placebo group behaved similarly to natural history controls with the same baseline characteristics would be of interest in trying to understand these results relative to those observed in previous RRMS IVIG studies. PRIVIG Study Group and UBC MS/MRI Research Group This study was supported by Bayer HealthCare AG.

P398 Clinical outcome 6 years after autologous haematopoietic stem cell transplantation in multiple sclerosis Y. Blanco, J. Berenguer, M. Gómez-Choco, E. Carreras, T. Arbizu, F. Graus, A. Saiz Hospital Clínic (Barcelona, E); Hospital de Bellvitge (Barcelona, E) Introduction/objectives: We previously reported that the 3-year actuarial probability of progression-free survival of 14 patients with severe MS treated with autologous hematopoietic stem cell transplantation (AHSCT) was 85 % (Neurology 2004;62:282). Here we describe the outcome after a median follow-up of 6 years (range, 4.5 to 7.5), the longest ever published after AHSCT. Methods: Fourteen MS patients (9 SP, and 5 RR), with a median age: 31 years [22–45], median EDSS: 6.0 (4.5–6.5), median relapse: 3 [1–7], median worsening of the EDSS in the previous year of 1.0 (0.5–4.5) and median percentile MSSS of 9, were treated with an AHSCT procedure that included Cy, BCNU, ATG and T-cell depletion by CD34 + selection. Results: At 4.5 years the progression-free survival was 71 %, and the disease activity-free survival (includes any measurable disease activity) was 29 %. The 6-year actuarial probability of progression-free survival was 51 % (95 % CI: 20–81 %). The median MSSS at last follow-up decreased to the percentile 8. In other words, the last median EDSS of 6.3 was 1.0 point lower than that predicted by using MSSS (choosing the best EDSS score).Only 5 patients presented relapses (63.5 % of patients were free of relapses at 6 years), with a reduction from baseline 3.43 relapses/patient-year to 0.14 relapses/patient-year. In 4 of them immunomodulatory therapy was restarted. Only 2 patients presented enhanced T1 lesions during the MRI follow-up (at + 24

and + 67 months, respectively). No long-term complications related to the procedure were observed. Conclusions: The 71 % of progression-free survival achieved by our AHSCT regimen at 4.5 years is higher than that observed by other disease-modifying agents that are currently available. Furthermore, our procedure reduced the probability of progression of disability by one-half at 6 years in this population of rapidly worsening MS patients. Whether this clinical outcome associated with low toxicity can be improved by a higher immunoablative therapy is presently unknown.

P399 Development and validation of novel cell-based anti-interferon beta neutralising antibody assay R. A. Farrell, G. Giovannoni University College London (London, UK) Background: Interferon-beta is well established as first line therapy in Relapsing Multiple Sclerosis. The occurrence of neutralising (Nabs) and binding (Babs) antibodies to IFN-beta has been widely reported. Subjects with Nabs have shown reduced response to treatment with IFN-b, having higher relapse rates, increased MRI activity and a higher risk of disease progression. The frequency and titre of Nabs varies depending on preparation used, dose and frequency of administration and also the assay used to quantify them. Existing assays utilise either the anti-viral effect of IFN-beta (the cytopathic effect assay) or measure the IFN-beta induced gene products (Myxovirus resistance protein or mRNA). These assays are time consuming and expensive and show variability between laboratories. Objectives: To develop a bioassay which is easy to perform and reliable and utilises commercially available products. Methods: Human fibrosarcoma cell line HT-1080 was obtained from the ATCC. This was stably transfected with the firefly luciferase gene, which is linked to the Interferon Stimulated Response Element (ISRE). When interferon binds to its receptor, the reporter cassette is activated by the JAK/STAT intracellular signalling mechanism and Luciferase is expressed within a few hours. Serum samples from subjects treated with IFN-beta are pre-incubated with a known amount of IFN-beta. This is added in serial dilutions to the cells and further incubated for 5 hours. Luciferase expression is then quantified by measuring luminescent counts per second in a Wallac Luminometer. Nab titre is calculated using the Kawade technique. Results: Luciferase expression in response to stimulation with IFN-beta was found to be linear in the range of 0–100 U/ml. The percentage inhibition of luciferase expression, in response to stimulation by 10 U/ml of commercial IFN-beta 1a, by subjects’ serum was calculated. The assay was shown to be robust in relation to cell density and incubation time. The intra-assay variability ranged from 0 to 20 % depending on titre. Titres were comparable to those obtained with the MxA assay with inter-assay variability of 0–10 %. Conclusions: This new assay has significant advantages over existing assays. It is simple, efficient and cost effective and could be used in the clinical setting to monitor patients on IFN-b therapy for the presence of Nabs. This research was supported by an unrestricted grant from TEVA in support of the Department of Health Risk Sharing Scheme

P400 Interferon beta-1b: incidence of neutralising antibodies over time J. Oger, M. Cantillon Neuroimmunology Laboratories and Multiple Sclerosis Clinic UBC (Vancouver, CAN); University of Medicine and Dentistry New Jersey (Morristown, USA) Objective: To better understand the relevance of neutralising antibodies (NAb) to interferon beta (IFNB)–1b (Betaferon(r)) therapy for multiple sclerosis (MS) by examining their evolution over time. Methods: Serum samples were collected regularly from patients with relapsing-remitting (RR) MS during the 3-year original pivotal North American IFNB-1b trial. Samples were tested using the myxovirus protein A assay and titres ≥ 20 were considered positive. Results: The evolution of NAb was analysed in all patients who were NAb-positive at any point during the study (n = 52/124 patients studied). The proportion of patients with a positive NAb titre gradually increased from Day 1 (2/46, 4.3 %) to Day 540 (approximately 18 months; 41/49, 83.7 %), when the highest median titre of 48 (range: 0–2247) was observed. After Day 540, the median NAb titre decreased as the proportion of patients with a positive titre also decreased. By Day 1170, only 45.9 % of this subgroup of patients who eventually became NAb-positive remained positive. High NAb titres (≥ 400) were not observed until after 6 months of treatment and

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the proportion of patients with a high titre remained low throughout the study (range: 1.9–14.6 % of patients who eventually became NAb-positive). Conclusions: NAb develop with all current immunomodulatory treatments for MS, including IFNB-1a and glatiramer acetate. However, there is controversy over the clinical relevance of NAb to IFNB-1b. This subgroup analysis of NAb data from the pivotal North American IFNB-1b RRMS trial demonstrated that the incidence of NAb positivity had peaked by 18 months, before declining over the second half of the study; similarly, the median NAb titre peaked at around 18 months. These findings support previous observations that a considerable proportion of patients treated with IFNB-1b revert to NAb negativity within 3 years of starting therapy. The incidence of high NAb titres remained low similar to that observed in other IFNB-1b trials. Study supported by Schering AG, Germany, Berlin and Berlex Laboratories Inc., Montville, NJ, USA. P401 The final results of the interferon beta-1b 16-year long-term follow-up study G. Ebers, A. Traboulsee, D. Langdon, A. Reder, C. Miltenburger, C. Wolf, A. Konieczny Radcliffe Infirmary (Oxford, UK); University of British Columbia (Vancouver, CAN); Royal Holloway University of London (Egham, UK); University of Chicago (Illinois, USA); Schering AG (Berlin, D) Objectives: To evaluate the impact of treatment with interferon beta-1b (INFB-1b) on long-term outcomes in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: The 16-Year Long-Term Follow-up (LTF) study is a multicenter, open-label, observational study that evaluates cross-sectional data that has been collected from patients with RRMS who participated in the pivotal North American IFNB-1b trial. Assessments include a neurological examination (Functional Systems and Expanded Disability Status Scale scores), MS functional composite, magnetic resonance imaging, a battery of neuropsychological tests to assess cognitive function, quality of life measures and reports of any specific adverse events. Results: Almost 90 % of the original 372 patients who participated in the original pivotal IFNB-1b trial have been identified.All of the 11 original centers in North America have contributed to this trial, some of which have been able to follow 100 % of their pivotal trial patients. Of the patients identified, 35/329 (10.6 %) are deceased, of which the majority was treated in the placebo group during the randomised, double-blind pivotal trial. Results of the final analysis will be presented at the meeting. Conclusion: Within a short period of time, the original 11 North American centers have identified almost 90 % of the patients who participated in the original IFNB-1b trial in RRMS. The final analysis of the data from the 16-Year LTF study will allow clinicians to evaluate the long-term safety and tolerability of IFNB-1b and its effect on a wide range of clinical and paraclinical outcome variables. Study supported by: Schering AG, Germany, Berlin and Berlex Laboratories Inc., Montville, NJ, USA. P402 Glatiramer acetate induces a CD4 + CD25 + T regulatory cell subset that is associated with low level alpha4beta1 (a4b1) expression ex vivo S. Haque, D. Gondek, L. Kasper Dartmouth Medical School (Lebanon, USA) Objective: To evaluate the effect of Glatiramer Acetate (GA) on the induction of a4b1 (VLA-4) T cells with regulatory properties and the production of cytokine in experimental autoimmune encephalomyelitis (EAE). Background: a4b1 expressing CD4 + T cells are paramount to the effector phase of EAE. T regulatory cells (CD4 + CD25 +) impact both EAE and MS (Multiple Sclerosis). GA is an approved drug for RR (Relapse Remitting) MS that can induce a Th2 polarization. The importance of a4b1 by GA elicited regulatory cell population is unknown. Design and Methods: The phenotypic expression of regulatory T cell was determined both by an intracellular marker Foxp3, a specific marker for Treg and CD4 + CD25 + T cells. In vivo treatment with GA in EAE induced mice significantly increased the level CD4 + T cells that express Foxp3 expression in CD4 + cells in EAE mice compared to untreated control mice. Magnetic bead separated CD4 + CD25 + populations were cultured at varying ratios in the presence of plate-bound anti-CD3 and proliferation measured by 3H-thymidine. A decreased response consistent with T regs in the CD4 + CD25 + was unaffected by exposure to anti-a4b1 (PS/2) antibody. A 50 % dose depended suppression of effector CD25- T cells proliferation by CD4 + CD25 + T cells was observed at a 1:1 CD25 + /CD25- cell ratio com-

pared to T cells isolated from non-GA treated mice. T cells isolated from GA primed mice secreted increased IL-10 and decreased IFNg whereas only IFNg was measured in T cells from control mice. This observation was further confirmed by RT-PCR. Blockade of either IL-10 or IL-4 but not IFNg resulted in a decrease in Foxp3 expression. No significant difference in the low level of a4b1 expression of surface molecules was observed on T reg obtained from GA immunized mice compared to control mice ex vivo or in vitro although there was an increase of CD3 + ,CD4 + ,CD8 + T cells from GA primed mice compared to naïve controls. Further studies to explore the migration and trafficking of these low a4b1 expressing regulatory cells into the CNS is currently underway. Conclusion: T reg cells have been shown to be of increasing importance in the control of autoimmunity. These observations suggest that GA may influence the conditioning of the T reg response by suppressing T cell effector function that may not be affected by a4b1 expression and will lead to better control of the disease. This work was supported by a grant from TEVA Neuroscience and NIH AI61938 P403 Efficacy, safety and tolerability of 500 mcg versus 250 mcg interferon beta1b versus glatiramer acetate in patients with relapsing-remitting multiple sclerosis (the BEYOND study): baseline patient characteristics P. O’Connor, B. G. W. Arnason, G. Comi, S. Cook, D. S. Goodin, H. P. Hartung, D. R. Jeffery, L. Kappos, V. Filipov, C. Kraus, I. Tornus, T. Bogumil St Michael’s Hospital (Toronto, CAN); Surgery Brain Research Institutes (Chicago, USA); San Raffaele Hospital (Milan, I); UMDNJ New Jersey Medical School (Newark, USA); University of California San Francisco (San Francisco, USA); Heinrich Heine University (Dusseldorf, D); Wake Forest University School of Medicine (Winston-Salem, USA); University Hospital (Basel, CH); Schering AG (Berlin, D) Objectives: To present the study design and the baseline characteristics of the patients with relapsing-remitting multiple sclerosis (RRMS) who have enrolled in the BEYOND (Betaferon(r)/Betaseron(r) Efficacy Yielding Outcomes of a New Dose) study. Methods: The BEYOND study is a Phase III, multicentre, randomised, parallel-group study that compares the efficacy, safety and tolerability of interferon beta-1b (IFNB-1b; Betaferon(r)) 500 mcg versus IFNB-1b 250 mcg versus glatiramer acetate over a treatment period of at least 2 years. Treatment-naive patients aged 18–55 years with McDonald criteria confirmed RRMS and an Expanded Disability Status Scale (EDSS) score of 0–5.0 were recruited into the study. Patients also needed to have had one or more relapse in the 12 months prior to study entry. Patients were randomised to receive IFNB-1b 500 mcg subcutaneously (sc) every other day (eod) or IFNB1b 250 mcg sc eod (double-blind) or glatiramer acetate 20 mg sc once daily (evaluator-blinded) using an allocation ratio of 2:2:1. The primary outcome variable will be the risk of recurrent relapses. Other relapse-related measures, EDSS and MS functional composite changes, magnetic resonance imaging outcomes and alterations in quality-of-life will also be assessed. Results: Enrolment into the study has now been completed and 2244 patients have been randomised at 198 sites in 26 countries world-wide. Baseline data for the study population will be presented. Conclusion: The BEYOND Phase III study will show whether using a higher dose (500 mcg sc eod) than the currently approved 250 mcg dose of IFNB-1b results in greater efficacy in patients with RRMS, while still achieving an acceptable safety and tolerability profile. In addition, the BEYOND study will provide important comparative data on the efficacy of IFNB-1b and glatiramer acetate in patients with RRMS. Study supported by Schering AG, Germany, Berlin and Berlex Laboratories Inc., Montville, NJ, USA. P404 Impact of beta-interferon on disability progression in relapsing-remitting multiple sclerosis: a Bayesian analysis K. O’Rourke, C. Walsh, M. Hutchinson St.Vincent’s University Hospital (Dublin, IRL); Trinity College (Dublin, IRL) Objective: Bayesian analysis enables multiple estimates based on unique data without statistical correction. The study used Bayesian analysis to determine whether beta-interferon (IFNb) therapy for relapsing-remitting multiple sclerosis (RRMS) in clinical practice attenuates the rate of disability progression in treated patients relative to matched historical control subjects. Methods: 175 RRMS patients treated with IFNb were followed at 12 monthly intervals for a median of 5 years. An Expanded Disability Status Scale (EDSS) measurement was performed at the start of IFNb therapy and

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yearly thereafter. Progression was defined as a one-point increase in the pretreatment EDSS sustained for 6 months. The liklihood function for the odds ratio (OR) of progression after 2 and 4 years of IFNb was calculated by comparison with the progression rate in a matched group of 185 historical controls from the Sylvia Lawry Centre for MS Research; this was adjusted for an estimated 30 % observational over-precision (variance inflation) and positive bias (bias correction). Prior probability distributions (priors) for the OR of progression after 2 years of IFNb were derived from a meta-analysis of pivotal trials; the PRISMS-4 trial was used to derive a prior for the OR of progression after 4 years. The prior and likelihood functions were integrated to yield a posterior 95 % credible interval (CI) for the OR of progression after 2 and 4 years of IFNb. Results: After 2 years, the OR (95 % CI) of progression for the unmodified likelihood function was 0.18 (0.09, 0.34), for the variance-inflated likelihood function 0.18 (0.08, 0.40), and for the variance-inflated and positive bias-corrected likelihood function 0.23 (0.10, 0.53). After 4 years, the unmodified, variance inflated, and variance inflated and positive bias-corrected likelihood functions yielded an OR (95 % CI) for progression of 0.25 (0.10, 0.64), 0.25 (0.08, 0.72) and 0.32 (0.11, 0.94) respectively. The 2-year standard, likely, enthusiastic, and sceptical posterior 95 % CIs for the variance-inflated and positive bias-corrected data were 0.60 (0.44, 0.81), 0.70 (0.52, 0.94), 0.29 (0.15, 0.55), and 0.43 (0.22, 0.83) respectively. The 4-year likelihood functions had negligible effects on the 4-year prior for the OR of progression. Conclusion: Disability progression is attenuated after 2 years of IFNb therapy for RRMS in clinical practice. No effect is evident after 4 years. P405 Atorvastatin prevents and reverses experimental autoimmune encephalomyelitis independent of STAT6-mediated Th2 differentiation M. S. Weber, T. Prod’homme, S. Youssef, C. Rundle, L. Steinman, S. S. Zamvil University of California (San Francisco, USA); Stanford University (Stanford, USA) Objective: To investigate whether experimental autoimmune encephalomyelitis (EAE) protection by atorvastatin (AT) requires STAT6-mediated Th2 differentiation. Background: AT has been shown to prevent and reverse EAE and is currently tested for multiple sclerosis (MS) treatment in clinical trials. Several EAE studies reported a Th2 differentiation of myelin reactive T cells under AT treatment with an upregulation of STAT6 signaling. The STAT6 pathway controls differentiation of T cells into a Th2 phenotype. Using STAT6-knockout (-/-) mice we investigated whether Th2 differentiation is required for immunomodulation of EAE by AT. We further investigated whether AT might exert a preferential inhibition on proliferation of differentiated Th1 or Th2 cells causing overall Th2 deviation by default. Methods: C57Bl/6 STAT6 -/- mice were immunized with MOG p35–55 and fed orally with 1 or 10 mg/kg/d AT starting either 2 days prior to EAE induction (prevention) or after EAE was established (reversal). Splenic T cells isolated from mice treated for EAE prevention (10 mg/kg/d) were cultured in the presence of MOG p35–55 and evaluated for proliferation and cytokine secretion. Naïve T cells isolated from B10.PL IL-4-GFP reporter mice (4GET) were cultured in the presence of 50 µg/ml anti-IFN-g antibody (Ab; 50 µg/ml) and IL-4 (50 ng/ml) or anti-IL-4 Ab (20 µg/ml) and IL-12 (5 ng/ml) to induce Th2 or Th1 differentiation, respectively. T cell differentiation was analysed by evaluation of IL4-GFP reporting using FACS. Mature resting Th1 and Th2 cells were stimulated with anti-CD3 and anti-CD28 in the presence of atorvastatin (1 and 10 µM) and evaluated for proliferation. Results: AT treatment could effectively prevent and reverse EAE in STAT6 -/- mice comparable to its treatment effect in C57BL/6 wild-type mice. MOG p35–55-specific proliferation was inhibited and secretion of IFN-g, TNF-a and IL-12 was reduced in T cells from STAT6-/- mice treated with 10 mg/kg/d AT. In vitro, AT inhibited proliferation of both mature Th1 and Th2 cells in a dose-dependent manner. Conclusions: Our data indicate that AT can prevent and reverse EAE independent of STAT6-mediated Th2 differentiation. Other mechanisms besides Th2 differentiation, including the inhibitory effect on T cell proliferation reported here significantly contribute to the therapeutic effect of AT in treatment of EAE.

P406 Betaferon® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): subgroup analyses C. H. Polman, L. Kappos, M. S. Freedman, G. Edan, H. P. Hartung, D. Miller, X. Montalban, F. Barkhof, L. Bauer, S. Dahms, C. Pohl, R. Sandbrink on behalf of the BENEFIT Study Group Objectives: To investigate the treatment effect of interferon beta-1b (IFNB1b; Betaferon®) 250 mcg subcutaneously (sc) every other day (eod) in BENEFIT subgroups dichotomised for important patient baseline characteristics (age, gender, mono/multifocal clinical presentation, T2-lesions, and Gadolinium-enhancing [Gd +] T1-lesions on brain magnetic resonance imaging [MRI] scans); to determine the impact of such factors on the development of clinically definite multiple sclerosis (CDMS). Methods: Patients with a first clinical event and at least two clinically silent brain MRI lesions were treated with 250 mcg IFNB-1b (n = 292) or placebo (n = 176) until CDMS was diagnosed or they had been followed for 24 months. Results: IFNB-1b had a statistically significant effect on time to CDMS in all subgroups analysed. Treatment effects were more pronounced in patients with monofocal presentation, in patients without Gd + T1-lesions and in patients with fewer than 9 T2-lesions at screening (hazard ratios [HR]: 0.45; 0.43; 0.40) as compared with multifocal presentation, at least 1 Gd + T1-lesion or at least 9 T2-lesions (HR: 0.63; 0.57; 0.62). Treatment effects were very similar in subgroups of different age (< 30 versus > = 30 years), and gender. The risk for CDMS within the observation period increased with a higher number of T2 and Gd + lesions and decreased with age of onset. Neither gender nor mono/multifocal clinical presentation affected the risk for CDMS. Conclusions: BENEFIT demonstrated that IFNB-1b 250 mcg sc, eod has a beneficial treatment effect in patients with a first clinically demyelinating event and an MRI scan suggestive of MS. The effect of 250 mcg IFNB-1b sc, eod was robust and compelling across all subgroups in the BENEFIT study. Of note, treatment effects were more pronounced in patients with less disseminated and active disease at screening, although, as known from other studies, these patients had a lower risk for conversion to CDMS within the observation period of two years. Study supported by Schering AG, Germany P407 Impact of the T-1237C and T-1486C polymorphisms in the toll-like receptor 9 gene on multiple sclerosis B. Rosche, L. Hamann, R. R. Schumann, C. Meisel, F. Zipp, K.-P. Wandinger Humboldt-University (Berlin, D) Objectives: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). Although research regarding autoimmune diseases in the past mainly focused on adaptive immunity, innate immunity also seems to pay a critical role in the initiation and perpetuation of autoimmune disorders. Toll-like receptors (TLR) have recently been identified as key components of the pathogen recognition machinery of mammals mediating inflammatory responses brought about by microbes. In this context, an increased risk for asthma among European Americans with a C allel at position –1237 vs controls in the TLR-9 is shown. Methods: We investigated the frequency of T-1237C as well as T-1486C polymorphisms by Real Time PCR in the TLR-9 receptor in 265 patients with multiple sclerosis vs 118 healthy controls.In a second step we determined the surface expression of TLR-9 on B cells between MS patients and controlls. Results: We did not find differences in the frequency of the polymorphisms or surface expression of the receptor between MS patients and controls. Conclusion: Overall, our findings do not support a role of the investigated TLR-9 promotor polymorphisms in the development of MS.

Muscle disorders P408 From mountain-racing to implantable cardioverter-defibrillator in a new laminopathy phenotype M. Dunand, G. Gremion, P. Y. Jeannet, X. Jeanrenaud, R. Ben Yaou, G. Bonne, T. Kuntzer Centre Hospitalier Universitaire Vaudois (Lausanne, CH); Hôpital Orthopédique (Lausanne, CH); G. H. Pitié-Salpêtrière (Paris, F) Objectives: To describe a new phenotype in a family with limb girdle muscular dystrophy (LGMD) and to point out the importance to screen for po-

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tential carriers of this disorder, as sudden death has been recently described in mutation of lamin A/C (LMNA) gene. Methods: Our index patient, a 37 yo sportive man, was referred by the Sports Medicine Unit for investigation of exercise intolerance while participating to a Swiss Alps race, La Patrouille des glaciers. Familial history revealed that his father suffered from a unknown myopathy with pacemaker implantation, and that his paternal grandmother had also pacemaker; his brother, a 39 yo, was known for cardiac problems. Results: Clinical examination of the 3 patients revealed a slight limb girdle muscle weakness; all 3 had rigid spine, but elbow and knee contractures were evident only in the father. Cardiac investigations revealed fascicular blocks with ventricular and supra-ventricular extrasystolia in the 2 brothers; heart failure and ventricular tachycardia were reported in the father, that lead to cardiac arrest and reanimation despite a pacemaker, just before diagnostic procedures were finalized in the family. In the index patient, muscle biopsy showed an abnormally distributed muscle fiber type as the sole changes. In the father’s muscle the same findings were observed, and no dystrophic pattern were seen. Multiplex westernblot analysis was normal. Based on the associated muscle weakness and cardiac involvement, an autosomic dominant laminopathy was suspected. We found indeed an already described R377H mutation on exon 6 of the LMNA gene. Thirty-three other family members were systematically screened over 3 generations; 26 were healthy; we still have 7 patients to screen. Conclusion: The members of this family present still another phenotype among the already known diverse phenotypes of LGMD type 1b (LMNA gene mutation), as they suffer from rigid spine together with a limb girdle muscle weakness and cardiac involvement. Our experience with the father of our 2 patients parallels what was recently underlined by Meune et al. (NEJM 354; January 12, 2006) who recommend early implantable cardioverter-defibrillator in order to prevent sudden death in LGMD1b patients.

Two patients underwent to muscle biopsies resulting in unspecific myopathic findings, with normal expression of the dystrophin-glycoprotein complex, dysferlin and calpain-3. The molecular analysis for SMN gene deletion, Calpain3 and FKRP gene mutation was negative. Genomic DNA was extracted from blood leukocytes of patients and unaffected family members. All exons of the UDP-N-acetylglucosamine 2epimerase/N-acetylmannosamine kinase (GNE) gene were amplified by PCR, using specific sets of primers, and directly sequenced. Results: Affected individuals were diagnosed as having hereditary Inclusion Body Myopathy (hIBM) based on the results of GNE gene analysis. The patients are compound heterozygous for two GNE mutations: a c 0.5A > G resulting in a Glu2Gly amino acid change, and a c 0.1105G > A resulting in a Gly351Ser change. Both the mutations have not been observed so far in hIBM patients and are located within the epimerase domain of the protein. Conclusions: hIBM constitutes a heterogeneous group of neuromuscular disorders characterised by adult-onset slowly progressive distal and proximal weakness. The autosomal recessive form (AR-hIBM) is due to mutations of GNE gene. GNE is a bifunctional enzyme known to be rate-limiting in the sialic acid biosynthetic pathway, although the specific ones associated with AR-hIBM remain to be clarified. The described family summarizes some of the controversies linked to the diagnosis of AR-hIBM due to GNE gene mutations: 1) muscle biopsy specific findings may be absent, 2) pattern of muscle involvement may be variable within a given family; 3) quadriceps may also be variably affected.

P409 Myasthenia gravis: reasons for unsatisfactory outcome revealed by a prospective study M. Dunand, F. X. Borruat, S. A. Botez, P. Roux-Lombard, T. Kuntzer Centre Hospitalier Universitaire Vaudois (Lausanne, CH); Hôpital Ophtalmique Jules-Gonin (Lausanne, CH); HUG (Geneva, CH)

Background and objectives: Duchenne Muscular Dystrophy (DMD) is a fatal recessive X-linked muscular disease caused by the absence of dystrophin. Dystrophin isoforms are also expressed in the cerebral neocortex and in the cerebellum. The presence of mental retardation in DMD patients is wellrecognised since 1992 (Emery), 1/3 of DMD children show a reduction of Intelligence Quotient (IQ),associated with lower scores in Verbal rather than Performance IQ. The cognitive impairment is not progressive and not correlated with the severity of muscle disease. The present study investigated cognitive, linguistic and narrative abilities in a group of Italian DMD children. Patients and methods: All DMD patients were diagnosed according to international standard criteria. They were aged from 5 to 12 years. Intellectual level was assessed by means of age-appropriate Wechsler Intelligence Scales (WISC-R, WPPSI). Visual attention, visual/verbal cross-modal memory and verbal learning were assessed administering specific subtests of the NEPSY (Developmental Neuropsychological Assessment). Their general linguistic abilities were analysed administering the Battery for linguistic assessment of children from 4 to 12 years and the Test of Morpho-Syntactic Development. Narrative abilities were analysed administering a picture description task. Results: The patients showed mildly reduced full IQ, with lower Verbal than Performance IQ. Visual attention and short-term memory were mildly affected. At the linguistic assessment, neither receptive (word comprehension) nor expressive (naming tasks and fluency) lexical abilities resulted impaired. However, their narrative skills were qualitatively inferior with respect to those produced by a group of age-matched control children. Their speech samples were characterised by the presence of few verbs and reduced production of complete sentences. Conclusion: Since the lack of dystrophin is assumed to produce effects on the maturation of the brain and particularly the cerebellum, these findings may support the hypothesis of the existence of a cerebellar-cortical circuit specialized in verb and sentence production.

Objective: To study 41 patients with autoimmune myasthenia gravis (MG) in order to know the percentage and the reasons of unsatisfactory outcome. Methods: Patients were initially diagnosed with MG, and referred lately to our Nerve-Muscle Unit. Outcome was then rated repetitively according to the Myasthenia Gravis Foundation of America Postintervention Status. The Complete Stable remission, Pharmacologic Remission, Minimal Manifestations and Improved Status were considered as satisfactory outcome. Patients scoring Unchanged (U), Worse (W) or Exacerbated (E) during follow-up were all taken into account and the reasons leading to unsatisfactory responsiveness were analysed. Results: Unsatisfactory outcome rate was 19.5 % (8/41) with 4 patients scoring U, 3 W and 1 E at the last visit, but during the follow-up, 22 patients (54 %) were U (3/22), W (8/22) or E (11/22). They were related to insufficient medication (36 %), infectious diseases (23 %) and no compliance (28 %). Conclusion: This study points out that more than 50 % (22/41) of our MG patients had an unsatisfactory outcome during follow-up. Part (60 %) of this unsatisfactory outcome could be prevented by tailoring adequate treatments during regular appointments by interested specialists in myology. P410 Autosomal recessive myopathy without inclusion bodies caused by GNE gene mutations R. Del Bo, M. Guglieri, M. G. D’Angelo, S. Ghezzi, F. Magri, L. Napoli, A. Prelle, A. C. Turconi, M. Moggio, N. Bresolin, G. P. Comi University of Milan (Milan, I); I. R. C. C.S. E. Medea (Bosisio Parini, I) Objective: To describe the clinical and genetic features of five brothers belonging to an Italian family affected with a long lasting history of progressive distal and proximal muscle weakness, mixed neurogenic and myogenic signs at the EMG, without specific muscle biopsy findings. Methods: Five brothers (4 males and 1 female) of a generation of nine individuals born from non consanguineous parents presented with a slowly progressive proximal upper limb and proximal and distal lower limb weakness, beginning from the ages of 25 to 40 years. The affected individuals were initially classified as axonal Charcot Marie Tooth disease. CPK levels were moderately increase in all patients.EMG demonstrated a chronic neurogenic pattern in two patients, and a mixed myogenic/neurogenic pattern in one.

P411 Evaluation of linguistic abilities in a group of Italian children affected by Duchenne muscular dystrophy F. Civati, M. G. D’Angelo, M. L. Lorusso, A. Marini, M. Guglieri, A. C. Turconi, F. Fabbro, N. Bresolin IRCCS E. Medea (Bosisio Parini, I); IRCCS E. Medea (San Vito al Tagliamento, I); University of Milan (Milan, I)

P412 Modified maximal thymectomy in patients with myasthenia gravis. Biologic and therapeutic implications S. Salakou, A. Tsamandas, E. Tsibri, E. Apostolakis, D. Bonikos, T. Papapetropoulos, D. Dougenis University of Patras School of Medicine (Patras, GR) Objectives: In this study the clinicopathologic features of 46 patients with myasthenia gravis (MG) who underwent modified maximal thymectomy (MMT), for therapeutic purposes, were investigated and correlated with patients’ outcome after thymectomy. Methods: The study included 46 patients

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(17 males, 29 females; mean age 36.60 ± 16.09 years) with MG who underwent MMT for therapeutic reasons. Osserman classification, before thymectomy, showed: stage I in five, IIA in 21, IIB in 17 and III in 3 patients. Microscopic examination of thymus revealed: thymic hyperplasia (n = 26), atrophy (n = 8), thymoma (n = 9), thymic carcinoma (n = 3). Patients were followed up for 39–166 (median 86) months. At the end of the follow-up period, according to MGFA criteria (Jaretzki A et al. Neurology 55:16, 2000) patients were classified as having complete stable remission, pharmacological remission, minimal manifestations, improvement, deterioration. Results: Followup data were available on 39/46 patients; 37/39 (95 %) patients showed improvement and 2 deterioration. More specifically, 13 patients showed complete stable remission, 2 pharmacological remission, 17 minimal manifestations, 5 improvement and 2 deterioration. ANOVA revealed that the clinical factors correlated with more frequent presence of complete stable remission were: younger age of the patients (less than 40 years-p = 0.036), shorter interval time between disease onset and thymectomy (less than a year-p = 0.009) and earlier stage of the disease (I + IIA vs. IIB + III-p = 0.013). Thymus pathology did not correlate with patients’ outcome. Cox regression analysis revealed that only the shorter interval time between disease onset and thymectomy (less than a year) and the earlier stage of the disease (I + IIA vs. IIB + III), constitute independent prognostic factors (95 % CI:0.043–6.50, p = 0.01 and 95 % CI:1.023–4.529, p = 0.043, respectively). Conclusion: This study shows that a) patients with MG who underwent MMT for treatment, developed improvement in 95 % of the cases and b) independent prognostic factors for therapeutic response after thymectomy are: the shorter time interval between disease onset and thymectomy, and the earlier stage of the disease. P413 Novel missense mutation in the caveolin-3 gene in a case of rippling muscle disease P. J. Lorenzoni, A. L. M. Carsten, N. Vieira, M. Vainzof, M. Zatz, R. H. Scola, L. C. Werneck Universidade Federal do Paraná (Curitiba, BR) Hereditary rippling muscle disease is a rare autosomal dominant myopathy, with symptoms and signs of muscular hyperexcitability. We describe a 17years-old patient, first and sporadic affected daughter of consanguineous parents, who presented with generalized muscular hypertrophy evident since the age of 6 month. In the childhood she had muscle stiffness, cramps and pain unrelated to exercise, as well as proximal muscle weakness in the lower limbs. On neurological examination, muscle percussion provoked myoedema like phenomenon, persistent muscle contraction with involuntarily rolling muscle contractions, characteristic of rippling phenomenon. The investigation showed increased serum muscle enzymes; needle electromyography at rest presented with fibrillation potentials, on voluntary contraction a myopathic pattern and electrically silent in rippling phenomenon area provoked by muscle percussion; muscle biopsy disclosed myopathic characteristics and protein imunohistochemical analysis showed deficiency of caveolin-3 (CAV-3), but with scattered partially labeled fibers. The genetics analysis reveals a novel missense point mutation (A140C) in CAV-3 gene. Only a few cases of RMD with recessive inheritance have been described worldwide, thus the characteristic of disease, especially clinical and genetics manifestations, laboratorial and electromyography changes, as well as, the study of the pattern of inheritance for genetic counseling are discussed. P414 Congenital myasthenic syndromes B. L. Gervini, P. J. Lorenzoni, C. S. K. Kay, R. H. Scola, L. C. Werneck Universidade Federal do Paraná (Curitiba, BR) Objective: To describe characteristic of the congenital myasthenic syndromes (CMS) and to evaluate the electrodiagnostic study contribution to the differential diagnosis of these disorders. Methods: Data of 17 patients with CMS were reviewed. Motor and sensitive nerve conduction, low and high frequency repetitive nerve stimulation and needle electromyography results were evaluated. Clinical and laboratorial findings, and muscle biopsy results were also reviewed. Results: Low frequency repetitive nerve stimulation showed decremental compound muscle action potential (CMAP) in 13 patients. One patient presented with low amplitude CMAP and 20Hz stimulation showed increment up to 878 %, confirming the diagnosis of the presynaptic subtype Eaton-Lambert like. In 3 cases motor nerve conduction study showed repetitive CMAP, suggesting the diagnosis of acetylcholinesterase deficiency or slow channel syndrome. In 2 of these patients the clinical features of asymmetrical and distal muscle weakness or the clinical improvement with fluoxetine characterized the diagnosis of slow channel syndrome.

Conclusion: Electrophysiological study is essential in investigation of patients with CMS and can contribute to identify the specific subtype. P415 Presynaptic congenital myasthenic syndrome P. J. Lorenzoni, B. L. Gervini, C. S. K. Kay, R. H. Scola, L. C. Werneck Universidade Federal do Paraná (Curitiba, BR) Congenital myasthenic syndromes are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The presynaptic failure of neurotransmission is a rare form of these syndromes attributed possibly a presynaptic defect in acetylcholine resynthesis or vesicular filling. This is a case report of 2-years-old girl was born at term, the fourth child of consanguineous parents (first cousins), presented with markedly reduced spontaneous motor activity and difficulty in sucking or swallowing since birth. Motor nerve conduction showed compound muscle action potencial (CMAP) with reduced amplitude in median, ulnar, deep peroneal and posterior tibial nerves. The repetitive stimulation of the median, deep peroneal and posterior tibial nerves at 3 Hz showed a decrement greater that 10 % in CMAP amplitude. The repetitive stimulation in medium, ulnar, deep peroneal and posterior tibial nerves showed increment of the 522 %, 378 %, 225 % and 878 % of the CMAP amplitude, respectively, after 100 stimulations at 20 Hz. Needle electromyography revealed “miopathic pattern”. The biopsy of the quadriceps and biceps brachii muscles showed muscle fiber atrophy of the type 2. The patient received piridostigmine with mild improvement of muscular weakness. The clinical and genetics characteristic of disease, as well as, neurophysiological, microphysiological studies and motor nerve conduction changes of presynaptic congenital myasthenic syndrome are discussed. P416 Myotonic dystrophy type 2 with calf hypertrophy and no myotonia M. Milone Mayo Clinic College of Medicine (Rochester, USA) Objective: To identify the molecular basis of a predominantly proximal myopathy with calf hypertrophy and normal creatine kinase (CK). Methods: EMG studies; muscle biopsy; standard 12-lead EKG; echocardiogram; direct testing of CCTG repeat expansion in intron 1 of the zinc finger protein 9 gene associated with Myotonic Dystrophy type 2 (DM2) by [1] PCR-based repeat detection assay and [2] genomic DNA Southern blot hybridized with a DM2 specific probe. Results: The patient is a 73-year-old man with 3-year history of progressive proximal limb weakness, more pronounced in the lower extremities. He has no myalgia or muscle stiffness.He had normal motor milestones and was physically very active until he had a knee replacement four years prior to the onset of the weakness. Neurological examination revealed mild to moderate proximal weakness in the upper and lower extremities (MRC grade 4/3.5), and mild distal leg weakness (MRC grade 4). He had no clinical myotonia. He has marked calf hypertrophy. EMG showed myopathic motor unit potentials and fibrillation potentials, but no electrical myotonia. Serum CK measurements were normal in multiple occasions. His known hypothyroidism was well controlled on hormonal replacement. Muscle biopsy of the right triceps showed muscle fiber-size variability, marked increase in internal nuclei, fiber splitting, few regenerating fibers and rare vacuolated fibers. EKG showed first degree AV block, right bundle branch block and premature ventricular complexes. Echocardiogram revealed no findings suggestive of cardiomyopathy. The patient refused the slit-lamp examination. Genetic analysis detected the CCTG repeat expansion associated with DM2. Conclusion: [1] To my knowledge this is the first report of genetically proved DM2 presenting with muscle weakness, calf hypertrophy, normal CK and no clinical or electrical myotonia. [2] This patient expands the clinical spectrum of DM2. [3] In patients with predominantly proximal weakness and calf hypertrophy, DM2 should be considered in the differential diagnosis. P417 Central nervous system involvement in myotonic dystrophy type 2 K. Spengos, G. Tsivgoulis, E. Gotsis, P. Toulas, E. Gialafos, G. Papadimas, T. Zambelis, P. Manta University of Athens (Athens, GR); Encephalos Diagnostic Institute (Athens, GR) Background: Myotonic dystrophy type 2 (MD2) and type 1 (MD1) are autosomal-dominant multisystemic diseases with an expansion of an unstable repeat sequence in a noncoding part of different chromosomes as molecu-

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lar basis. Both share common clinical, histological and electrophysiological features.Notable differences include age of onset,absence of congenital MD2 cases and pattern of muscle weakness. There is also limited evidence for central nervous system (CNS) involvement in MD2, whereas hypersomnia, cognitive changes and white matter (WM) lesions are well established signs of CNS involvement in MD1. Recently, diffuse microstructural changes affecting the normal-appearing WM and also neurochemical alterations have also been demonstrated by means of Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (MRS) in cases with MD1. However until now, there is no evidence of such changes in MD2 patients. Case presentation: A 60-years-old woman with over 25 years persisting difficulties in climbing stairs and standing up from the sitting position, noted two years ago an also proximal weakness of both arms. She had a twelve-year history of bilateral cataracts, while her father had presented similar symptoms after the age of 60. On examination slight facial and neck flexion weakness were also found. Percussion myotonia was absent, while needle electromyography revealed mild myopathic findings and diffuse myotonic discharges. There were no clinical signs of CNS involvement. Molecular testing excluded MD1 [7/24 CTG repeats] and established the diagnosis of MD2 [23/580–1500 CCTG repeats]. Conventional MRI was unremarkable, while DTI revealed increased anisotropy of both corticospinal tracts beginning at the level of the internal capsule and reaching the pons. MRS revealed decreased N-acetylaspartate concentrations and N-acetylaspartate/Creatine-ratios in all examined hemispheric, both cortical and subcortical, regions, suggesting neuronal loss, especially in the right frontal WM and the left hippocampus. Elevated choline and myoinositole concentration indicative of beginning gliosis was also found in the right frontal WM. Conclusion: The present case clearly proves a clinically silent CNS involvement in a MD2 patient and suggests that microstructural and neurochemical cerebral changes might be further common features of MD1 and MD2. Our finding remains to be verified and further elucidated by similar imaging evaluation of larger MD2 case series. P418 The potential role of bcl-2, bax, bax/bcl-2 ratio and ki67 expression in patients with myasthenia gravis S. Salakou, A. Tsamandas, E. Tsibri, E. Apostolakis, D. Bonikos, T. Papapetropoulos, D. Dougenis University of Patras School of Medicine (Patras, GR) Objectives: In this study, bcl-2, bax (apoptotic oncoproteins) and Ki67 (cell proliferation marker) expression in thymus from patients with MG were investigated and correlated with patients’ outcome after thymectomy. Methods: The study included 46 patients (17M/29F; mean age 36.60 ± 16.09 years) with MG who underwent thymectomy. Osserman classification, before thymectomy, showed: stage I in 5, IIA in 21, IIB in 17 and III in 3 cases. Microscopic examination of thymus revealed: thymic hyperplasia(n = 26), atrophy(n = 8), thymoma (n = 9), thymic carcinoma (n = 3). Paraffin sections were subjected to a) immunohistochemistry (bcl-2, bax and Ki67 protein), b) in-situ hybridization (bcl-2, bax mRNA) and c) TUNEL method (apoptotic index-ABI). The bax/bcl-2 ratio was determined for each sample by dividing %bax (+) cells by % bcl-2 (+) cells.Patients were followed up for 39–166 (median 86) months. At the end of the follow-up period, according to MGFA criteria (Jaretzki A et al. Neurology 55:16, 2000) patients were classified as follows: group-A: complete stable remission, group-B: pharmacological remission + minimal manifestations + improvement + deterioration. Results: Follow-up data were available on 39/46 patients; 13/39 patients belonged to group-A and 26 to group-B. Bcl-2 expression was higher in hyperplasia and thymoma cases, compared to thymic carcinomas (p < 0.001). Higher expression in carcinomas, compared to hyperplasia and thymomas, was observed for bax, Ki67, ABI and bax/bcl-2 ratio values (p < 0.001 in each case). In addition these markers showed higher expression towards advanced stages of the disease (p < 0.001 in each case).All cases of group A had a bax/bcl-2 ratio < 1, and all cases of group B > 1. Statistical analysis showed: positive correlation between %Ki67(+) and %bax(+) cells (p < 0.05). Cox regression analysis revealed that bax/bcl-2 ratio constituted independent prognostic factor (95 % CI:1.078–44.073, p = 0.041). Conclusion: In patients with MG who underwent thymectomy, expression of the several molecular markers of this study (bcl-2, bax, Ki67) correlates positively or reversibly with thymus’ microscopic features. Increased apoptosis and proliferation accompany advanced disease stage. Bax/bcl-2 ratio constitutes an independent prognostic factor. More extensive studies are needed in order to use these markers in the design and selection of the proper therapeutic modality in such cases.

P419 Stabilsation of myasthenia gravis following plasma exchange: combined treatment with rituximab and mycophenolate mofetil A. Berthele, I. Hahntow, T. Sprenger, J. Lutz, U. Heemann, B. Conrad Technical University Munich (Munich, D) Objective: Patients in myasthenic crisis benefit from plasma exchange (PE). Relapses after PE are nevertheless common and maintenance therapy may turn out difficult. Mycophenolate mofetil (MMF) and rituximab are discussed as new therapeutic options in myasthenia gravis (MG). Whereas MMF suppresses both T and B cell proliferation, the CD20 specific monoclonal antibody rituximab is especially attractive since it targets B cell activation and differentiation to plasma cells. Methods: We present 3 adult male patients with acetylcholine receptor (AChR) antibody-positive MG necessitating plasma exchange (PE) treated with rituximab and MMF as maintenance therapy. Results: In patient 1 (81 years) generalized MG was diagnosed in 08/2003. AChR antibody titer was 34 nmol/l. Despite steroids, he deteriorated rapidly. Crisis was successfully treated with 5 courses of PE; steroids were reinstalled and azathioprine started. In 10/2003 symptoms worsened again; his antibody titer was 62.3 nmol/l. Immunoglobulins (IvIg) were of no effect; 3 courses of PE were again necessary. Thereafter, a single dose of rituximab was administered and MMF (2 g/d) started. A second dose of rituximab was given in 02/2004. The AChR antibody titer, 24.5 nmol/l in 11/2003, decreased to 11.3 nmol/l in 06/2004 and remained stable. Up to now, the patient is doing well. – Patient 2, a 60 years old male with bladder cancer and a history of ocular MG for 3 years, was referred to our clinic (09/2005) due to generalization of MG following dexamethasone, which was given during chemotherapy. IvIg were not effective.After 3 courses of PE and a single dose of rituximab, the patient stabilized. Under MMF, subsequent chemotherapy regimens including single high doses of steroids were well tolerated. – Patient 3 (82 years) suffered from bulbar weakness since 2 months (10/2005). Under pyridostigmine and prednisolone (5 mg/d) he developed severe dyspnea. After 3 courses of PE, the patient recovered. After rituximab followed by MMF, the patient is still stable. The antibody titer, initially reduced from 60 to 22 nmol/l by PE, has not changed during follow-up. – Thymoma was ruled out in all three patients. Instead, all suffered from bladder cancer: patient 3 was surgically cured in 1991 and patient 1 was diagnosed in 03/2004. Conclusions: From our observations it can be reasoned that rituximab, at least when combined with MMF, is able to maintain stabilization induced by PE in patients with acute deterioration of MG. P420 Long exercise test: a diagnostic tool in the differential diagnosis of myotonic dystrophies versus skeletal muscle channelopathies E. Soulaeva, M. Sterlicchio, V. Sansone, E. Mancinelli, G. Meola Policlinico San Donato – University of Milan (Milan, I) Objective: To study whether the long exercise test may guide towards the diagnosis of myotonic dystrophy type 1 (DM1), type 2 (DM2), or towards a skeletal muscle channelopathy. Methods: Eight patients with DM1 (mean age 35.5 ± 14.7; CTGn repeats 600–800) and 6 patients with genetically determined DM2 (mean age 58 ± 9.2); 10 patients with skeletal muscle channelopathies (5 CACN1A; 1 SCN4A; 1 ClC-1; 1 Kir2.1; mean age: 32 ± 10.1) and 10 age-, sex-matched healthy controls were subjected to the McManis exercise test procedure: after the patients or controls had rested for 5 minutes, supramaximal stimulation of the ulnar nerve to the wrist of the dominant hand was performed. Recording of compound muscle action potential (CMAP) every 60 seconds before the exercise test for 5 minutes to obtain baseline; during the 3-minute exercise test (repetitive contraction of the hypothenar muscles) every minute; after the exercise test every minute until baseline (mean 20.9 ± minutes; skin temperature maintained between 30°–34°C). Percent increase in amplitude and area were calculated using the following formulas:(greatest amplitude/area after exercise minus baseline amplitude/area before exercise) divided by amplitude/area before exercise x 100 and percent decrease were calculated as (greatest amplitude/area after exercise minus smallest amplitude/area after exercise) divided by greatest amplitude/area after exercise x 100. Results were compared between all groups and controls. Results: No significant difference was observed in amplitude increase and decrease in CMAP for all groups. A significant difference in area decrease after the exercise test was observed in patients with myotonic dystrophies (mean area decrease 18.94 ± 11.30) compared to channelopathies (mean area decrease 14.23 ± 7.18, p = 0.01) and between myotonic dystrophies and controls (mean area decrease 21.16 ± 8.24, p = 0.0001). Conclusions: Although preliminary and on a small sample size, our data suggest CMAP area after the long exercise test in myotonic dystrophies may show a typical pattern of decrease compared to channelopathies and con-

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trols. Further investigations are needed on a larger sample size to target further diagnostic screening, in particular for the differential diagnosis of myotonic dystrophies and non-dystrophic myotonias; additional studies are in progress to verify whether the long exercise test may be an early diagnostic tool in these disorders. P421 Combined immunosuppressive treatment after myasthenic crisis – effects on the long-term outcome C. Rozsa, G. Panczel, F. Krupai, Z. Kaposzta, S. Komoly Jahn Ferenc Hospital (Budapest, HUN); Péterfy Hospital (Budapest, HUN); Pécs University Faculty of Medicine (Pécs, HUN) Objective: Myasthenic “crisis” (MC), the most severe complication of myasthenia gravis (MG) is defined by respiratory failure requiring intubation and ventilatory assistance. Crisis occurs in approximately 12 to 20 % of patients, with a mortality rate of 4 %. The accepted treatment of the MC is plasmapheresis/intravenous immunoglobulin (IVIg), steroids, and supportive treatment in the intensive care unit (ICU), however, the long-term survival and outcome depends on the long-term treatment. The efficacy of the combined azathioprine (AZA) and prednisolone (PR) treatment was proven in a double-blind placebo-controlled study. In our former study we have analysed the safety and adverse effects of long-term combined immunosuppressive treatment in 163 myasthenic patients. The goal of the present study was to analyse the frequency of recurrent MCs in a patient population on AZA + PR treatment, which was introduced during the first MC. Patients and methods: In this study we analysed retrospectively 41 MC of 30 MG patients (mean age 61y, range 27–91 y, 15 male and 15 female) treated in our hospital from January 1997 until December 2000. A prospective post-crisis follow-up was conducted until December 2005. All patients were treated by plasmapheresis during the crisis, and combined treatment with PR and AZA was initiated during the crisis. Results: A second MC developed in 6 pts (20 %). All of the recurrent MCs happened within the first 3 months of treatment (within 4.3 weeks in average). None of the patients who remained continuously on treatment developed any other MC during the follow-up (mean: 6 years). The decrease of the incidence of MC at 3 months and at 1 year of treatment was highly significant (p < 0.001). Conclusion: In our patient cohort the combined AZA + PR treatment introduced during the first MC prevented the recurrence of MCs on the longterm.

We conclude that DM1 may affect brain and suggest that patients with DM1 having signs or symptoms of brain involvement should undergo MRI. These changes are probably with vascular etiology, and they are part from a wide spectrum of multisystemic disorders in DM1. P423 Potential clinical applications of muscle BOLD functional magnetic resonance imaging A. C. Nirkko, J. Slotboom, W. J. Z’Graggen, C. Kiefer University Hospital (Berne, CH) Objectives: We applied functional magnetic resonance imaging (fMRI) using blood oxygenation level dependent (BOLD) endogenous contrast to assess the response of human skeletal muscle to exercise, and it’s nerve innervation pattern. Methods: Supramaximal repetitive (50 Hz) electrical stimulation of the peroneal or ulnar nerve was applied during 2 minutes. Series of BOLD echo planar images (EPI) of the corresponding muscles were acquired before, during and after stimulation. Results: A selective T2* lengthening was observed in the contracting muscles. After cessation of stimulation, the BOLD signal further increased up to 80 % above baseline. Non-contracting control muscles showed no signal changes. Partial (sub-maximal) nerve stimulation resulted in a somatotopically reduced responding muscle area, not in a submaximal response in the whole innervation region. In a patient with neuropathy but structurally still normal anterior tibial muscle, no fuctional response was obtained. Innervation anomalies (median-ulnar forearm anastomosis) could be demonstrated through visualization of the response pattern, as verified by electrophysiology. Conclusion: The vascular response of skeletal muscle is strictly confined to the exercised areas. The signal change is much larger than with brain fMRI. This is due to the low resting metabolism and its large increase during excercise, as compared with the continuous high metabolic demands of the brain. A diseased muscle can yield an abnormal response, and innervation anomalies can be visualized. Clinical applications in neuropathies and myopathies are envisaged. Supported by the Swiss National Science Foundation (SNF grant 3200B0–107499/1).

Peripheral neuropathy P422 A case of myotonic dystrophy type 1 with MRI white matter abnormalities of the brain I. Barbov, S. Vlaski-Jekik, S. Lazarova Clinical Center Skopje (Skopje, MK) Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system (CNS), caused by CTG repeat expansion on the chromosome 19q. CNS white matter abnormalities are described in DM2 (proximal myotonic myopathy-PROMM), with clinical symptoms included mental changes, hypersomnia, stroke-like episodes and seizures. The causative relationship of these clinical features with the magnetic resonance imaging (MRI) white matter abnormalities remains to be established. We report a 50 years old women with familiar history for DM1, manifesting temporal, ocular and bulbar muscle weakness, slight flexor neck, distal limb weakness, mild intermittent myotonia, bilateral cataract and sterility. Deep tendon reflexes were absent. She suffered a stroke-like episode, followed by right hemiparesis, six months ago. CK level was 274 U/l. Generalized myotonia and myopathic changes in EMG. Skeletal muscle biopsy shows myopathic changes: varied fiber size, endomysial connective tissue mildly increased, type I fiber predominance. MRI of the brain: bilateral multifocal white matter changes, periventricular and in brain steam, hyperintense on T2-weighted and proton density-weighted images and hypointense on T1-weighted scans. MRI of cervical spinal cord was normal. MRI cerebral angiography was also normal. Cerebrospinal fluid (CSF) was normal with no evidence of immunological activity. Electoencephalography and evoked potentials were also normal. Neuropsychological testing shows mild cognitive impairment We found definite MRI abnormalities in patient with DM1. Examination of the CSF gave no evidence of an inflammatory process. The morphology underlying this leukoencephalopathy is unknown.The MRI pattern suggests a process affecting the perivascular spaces or small pial vessels. Microangiopathy is another possible mechanism.

P424 Familial amyloidotic neuropathy: an epidemiological and genetic study T. Kyriakides, L. Koutsou, E. Papanicolaou, F. Vonta, A. Kladi, D. Vasilopoulos, K. Christodoulou Cyprus Institute of Neurology and Geneti (Nicosia, CY); University of Cyprus (Nicosia, CY); Universitry of Athens (Athens, GR) Objectives:
Define the incidence and prevalence of Familial Amyloidotic Neuropathy Portugese type(FAP) on the island of Cyprus and to estimate the total number of carriers with the FAP mutation.
Define the phenotype in the Cypriot population and establish the penetrance of the disease.
Study acquired and genetic modifier factors of disease expression. Methods: The clinical and neurogenetic databases were used to identify probands with FAP and family trees were established. Possible carriers of the mutation were assessed clinically and epidemiological information and DNA collected. Genetic analysis for ApoE, Transthyretin, serum amyloid P and complement C1q was carried out and correlated with phenotype. Results: The incidence of FAP is 0.69/100000/year and the prevalence on 1/12/03 is 5.2/100000. Penetrance is estimated to be 35 %. Mean age of onset 46 years, mean time to diagnosis is 2 years. The phenotype observed is the classical one. There were no atypical presentations. There was no correlation between age of onset and ApoE alleles. Several new polymorphisms were discovered in the other genes and will be presented. Conclusions: FAP is relatively prevalent in Cyprus compared to other European populations. Understanding the biological factors that determine penetrance could potentially lead to therapeutic advances. Supported by Research Promotion Foundation of Cyprus

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P425 Prevalence of diabetic peripheral neuropathy and associated pain in French adults E. Q. Wu, J. Borton, E. Kahn, G. Said, T. K. Le, A. Garcia-Cebrian, B. Monz Analysis Group Inc (Boston, USA); TNS Healthcare (Owings Mills, USA); Hôpital le Kremlin Bicetre (Paris, F); Eli Lilly and Company (Indianapolis, USA); Eli Lilly and Company (Surrey, UK); Boehringer Ingelheim GmbH (Ingelheim, D) Objective: Diabetic Peripheral Neuropathy (DPN) is the most common complication associated with long term diabetes and patients with DPN often experience neuropathic pain. Although several studies in the literature described the prevalence of DPN in France, none have reported the prevalence of painful Diabetic Peripheral Neuropathy (pDPN). Due to the chronic nature of these complications and the likelihood of diabetes prevalence increasing, reliable estimates of prevalence rates of DPN and pDPN among diabetes patients will lead to improved estimates of the economic and social impacts of diabetes care in France. This study estimated the point prevalence of DPN and pDPN in French adults with diabetes. Methods: The patient-administered part of the Michigan Neuropathy Screening Instrument (MNSI) and selected items of the Brief Pain Inventory (BPI) formed part of a computer-aided telephone survey to a representative, random sample of French households from March 1, 2005 to April 30, 2005. Questions from the MNSI and the BPI were used to assess the point prevalence of DPN and pDPN in French adults with self-reported diabetes. Results: The prevalence of DPN in French adults with diabetes was 11 %. Compared to other regions in France, Paris district had the highest prevalence rate (13 %). Seventy-eight percent of study participants with DPN experienced pDPN, of which 35 % classified their pain as severe, 49 % as moderate, and 17 % as mild. The prevalence of DPN was higher in participants with type I (14 %) than those with type II diabetes (9 %). However, the prevalence of pDPN was similar between DPN patients with type I (82 %) and type II diabetes (78 %). Sixty-seven percent of the participants with DPN and 64 % of the participants with pDPN were females. Conclusions: This study concluded that 11 % of participants with diabetes in France had DPN and the majority of them experienced pDPN. The prevalence rates of DPN and pDPN varied by type of diabetes, geographic region, and gender. Research was funded by an unrestricted research grant from Eli Lilly and Company and Boehringer Ingelheim International GmbH. P426 Indirect meta-analysis of duloxetine versus pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain S. Quilici, J. Chancellor, M. Lothgren, D. Simon, G. Said, T. K. Le, A. Garcia-Cebrian, B. Monz, D. Kajdasz Innovus Research UK Ltd (Uxbridge, UK); Hopital de la Pitie (Paris, F); Hopital le Kremlin Bicetre (Paris, F); Eli Lilly and Company (Indianapolis, USA); Eli Lilly and Company (Windlesham, UK); Boehringer Ingelheim GmbH (Ingelheim, D) Objective: To perform an indirect comparison of the efficacy and tolerability of duloxetine (DLX) with pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP). Methods: We searched PubMed, Ovid, CENTRAL databases and regulatory websites for reports of randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs) assessing DLX, PGB and GBP in DPNP. Only study arms using approved dosages (DLX: 60–120 mg/day, PGB 150–600 mg/day, GBP: 900–3600 mg/day) with assessments after 5–13 weeks were eligible. Efficacy criteria were: reduction in 24hour pain severity (24hPS, 11-point Likert scale) for all three drugs, and response rate (> 50 % pain reduction) and Patient’s Global Impression of Improvement/Change (PGI-I/C) for DLX and PGB only. Tolerability criteria were: discontinuation rates due to AEs,lack of efficacy and other reasons and incidence of diarrhoea, dizziness, headache, nausea and somnolence. Pooled fixed- and random-effects analyses were conducted on endpoints reported in at least two studies of each drug. Each drug was compared with placebo. DLX was compared indirectly with PGB and GBP by meta-regression. Results: Three studies of DLX, 6 of PGB and 2 of GBP were eligible. Between-study heterogeneity was not significant. In random-effects analyses, all drugs were superior to placebo for all efficacy parameters. Effects (è) favouring drug over placebo, and differences (ä) favouring DLX over PGB or GBP, take a negative sign for 24hPS, PGI-I/C and tolerability and positive sign for response. For 24hPS, è (95 % CIs) were DLX: –1.13 (–1.36; –0.89), PGB: –0.90 (–1.23; –0.57), GBP: –1.44 (–2.21; –0.66). Corresponding è values for response rate were DLX: 0.86 (0.63; 1.09), PGB: 0.84 (0.52; 1.16); and for PGI-I/C were DLX: –0.76 (–1.00; –0.51), PGB: –1.29 (–1.72; –0.86). Mean effect differences ä (95 % CIs) for DLX vs. PGB for 24hPS were: –0.25 (–0.67;

0.16), for response rate 0.03 (–0.39; 0.45) and for PGI-I/C 0.54 (0.02; 1.06), the latter just reaching significance. For 24hPS, ä (95 % CI) for DLX vs. GBP was 0.27 (–0.47; 1.02). Dizziness was the only tolerability criterion to reach significance: ä (95 % CI) = –1.08 (–1.90; –0.32). Conclusions: From the few studies available for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine provides an important treatment option for this disabling condition. This research was supported in full by a grant from Eli Lilly and Company P427 A compound test for assessment of autonomic and sensory-motor dysfunction in familial amyloid polyneuropathy C. Denier, V. Planté-Bordeneuve, H. Husson, P. Lozeron, D. Adams, G. Said CHU de Bicêtre, Centre d’étude des neuropathies amyloides familiales (Paris, F) Background: Reproducible quantitative evaluation of signs and symptoms are necessary for the assessment of treatment efficacy. Familial amyloid polyneuropathy(FAP) patients manifest progressive sensory-motor length dependent neuropathy and severe autonomic dysfunction, which lead to death within 10 yrs after first symptoms. In this setting the autonomic manifestations include mainly nausea and vomiting, diarrhoea and constipation, postural hypotension, sphincter disturbances and erectile dysfunction. Objective: to determine the reliability of a new compound test cumulating evaluation of autonomic (CADT) and sensory-motor dysfunction (modified Norris score) in FAP. Methods: CADT is a new questionnaire including 4 items to evaluate the main symptoms of autonomic dysfunction observed in FAP. In male patients a fifth item evaluates the erectile function. Each item precisely defined, is noted from 0 (severe impairment) to 4 (normal), making a total normal score of 16 in women and 20 in men. A separate functional questionnaire, based on the Norris test previously validated in amyotrophic lateral sclerosis and used in CIDP, assesses the disability due to the sensory-motor deficit. The modified Norris test (MNT) includes 25 questions on activities of the daily life. Each question is noted from 0 (unable to perform the item) to 3 (normal), with a total maximum score of 75. The compound test takes approximately 5–10 minutes to perform. In this prospective study, we intend to evaluate 50 FAP patients to test interexaminer reliability i. e. both questionnaires rated independently by 2 examiners at the same visit. We also evaluate both tests comparing results at initial visit with testing by phone call. Finally, we will perform a follow up scoring by the same examiner 3 to 6 months after initial evaluation. Preliminary results: To date, 47 FAP patients have been included (20 women and 27 men). For both questionnaires, interexaminer reliability tested on 22 patients is high (13 men vs 9 women). Mean independent MNT scores were 59.9 ± 17.6 vs 60.0 ± 17.6 with a mean difference of 1.7 ± 1.9 points between the 2 examiners. Concerning CADT, mean independent scores were 15.4 ± 4.4 vs 15.4 ± 4.1 with a mean difference of 0.9 ± 0.9 points for men (n = 13), and 11.7 ± 2.1 vs 11.8 ± 3.1 with a mean difference of 1.0 ± 1.2 points for women (n = 9) (not significant difference). Testing by phone gave similar results (n = 23). Intraexaminer variability appears negligible since identical scoring is found in our patients for the CADT and the MNT. Conclusion: Preliminary results show that the newly designed brief compound test of autonomic and sensory-motor dysfunction in FAP patients has a good inter and intra investigators reliability, which will be useful for assessment of treatments in this condition. Supported by a grant from the French Ministry of Health for the study of Rares Disorders – Familial amyloid polyneuropathy P428 Pathophysiology of pes cavus in Charcot-Marie-Tooth disease type 1A (CMT-1A) duplication: a transversal clinico-MRI study J. Berciano, E. Gallardo, A. García, O. Combarros University Hospital Marqués Valdecilla (Santander, E) Objectives: To describe clinical and MRI patterns of leg and foot amyotrophy in CMT-1A duplication patients, with either pure foot semeiology or with at most moderate peroneal weakness, paying special attention to its correlation with the presence of foot deformities. Methods: A total of 10 secondary CMT-1A patients and one patient with de novo mutation were prospectively evaluated.Ages of patients varied from 8 to 61 years (median, 24). Disease severity was established using a ninepoint disability scale (FDS) and CMT neuropathy score (CMTNS). Muscle strength of flexo-extensor ankle and toe muscles was assessed manually

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with the standard MRC scale. In all 11 patients, leg MRI study included T1and T2-weighted spin-echo sequences in coronal and axial planes. In seven patients both feet were simultaneously studied in coronal and axial planes. Results: Six patients had pes cavus, an FDS score of 0 (normal), mild CMTNS and normal mucle power of foot flexo-extensors. In these six patients, MRI showed fatty infiltration of intrinsic foot muscles mainly involving the lumbricals, all four leg compartments being preserved. The remaining five patients had pes cavus, FDS scores 1 (cramps or fatigability) to 3 (walking difficult), mild to moderate CMTNS and variable weakness of peroneal musculature. In these five patients MRI showed, besides intrinsic foot muscle involvement, variable and distally accentuated fatty infiltration of the lateral, anterior and superficial posterior leg muscle compartments and, to a lesser degree, of the deep posterior compartment. Conclusions: Clinical-MRI patterns of lower limb muscle atrophy varied with evolution of semeiology. Selective involvement of intrinsic foot muscles with predominant wasting of the lumbricals occurred in CMT-1A patients with minimal disease signs, such a finding giving support to the notion of their pathogenetic role in initiating forefoot cavus deformities. Our findings suggest that leg muscle imbalance is a later pathogenetic mechanism of pes cavus. P429 Post-infectious hand weakness as mild Guillain-Barrè syndrome variant F. Girolami, A. Ariatti, M. Pugnaghi, G. Tassone, G. Galassi Institute of Neurosciences (Modena, I) Objective: Usually Guillain Barrè syndrome (GBS) is characterized by ascending limb weakness, progressing to trunk and cranial regions. However, regional variants are recognized with weakness confined to limited regions. Methods: Three patients presented with post infectious hand weakness which remained confined to the distal muscles of upper extremities during whole course of their illness. A 68 year-old man (case 1) was admitted because of right anterior interosseus syndrome with onset six days after gastrointestinal infection. Case 2, aged 48 years, experienced after a flu-like episode bilateral hand paraesthesias with inability to extend wrist, fingers and to abduct the right thumb. The third patient, aged 43 years, was admitted because of bilateral hand muscle weakness developed six days after an influenza-like episode. Results: Extensive emato-urinary tests, B12, folate level, creatine kinase, microbiological, viral screenings were negative, including herpes, human immunodeficiency, epstein bar and cytomegalo viruses. Search for Campylobacter Jejuni and Borrelia Burgdorferi were negative as well for Toxoplasma Gondii. Tests in serum for antiganglioside IgG antibodies in all patients were negative. Spinal tap in case 2 (day 5) showed increased protein content (62 mg/dl, normal below 45). Electrophysiology revealed in case 1 (day 5) signs of demyelination, in case 2 (day 13) axonal features, in case 3 (day 3 and 9) normal maximal velocity in upper and lower extremities. Case 1 and 3 recovered spontaneously within day 150 and 540. Case 2 had benefit from high dose of immunoglobulins (0.4 gr/kg of body weight). In conclusion, these patients were affected by a benign, post-infectious neurological illness with a monophasic course. GBS may onset with hand weakness; the unpredictability of course of GBS makes difficult to determine whether patient’s conditions will worse and progress to legs. Limited regional forms of GBS characterized by unusual focal signs or symptoms mimicking other illnesses such as compression neuropathies in upper limbs have been previously described, suggesting that the pathologic and immunologic processes in GBS can be localized and selective. It has to be kept in mind that small hand muscle weakness may remain as a main symptom throughout the disease. P430 Diagnostic validity of skin biopsy, utilising intra- and subepidermal nerve fibre densities in painful sensory neuropathies E. Moravcova, J. Bednarik, L. Dusek, K. V. Toyka, C. Sommer University Hospital Brno (Brno, CZ); Masaryk University Brno (Brno, CZ); Julius-Maximilians University (Wurzburg, D) Objectives: To evaluate the diagnostic efficacy of several measures of skin innervation in painful sensory neuropathies and to assess their correlation with clinical, neurophysiological and psychophysical examination. Methods: Skin punch biopsies from the distal calf were performed in 99 consecutively recruited patients with clinical symptoms of a painful sensory neuropathy and with abnormal thermal thresholds on quantitative sensory testing (QST), and in 37 age-matched healthy volunteers. Intra- and subepidermal nerve fiber densities (IENFD and SENFD) were quantified using PGP 9.5-immunostaining. Epidermal thickness and size and shape of dermal papillae and the number and morphological changes of Langerhans

cells (LC) were evaluated. IENFD and SENFD were correlated with sensory thresholds as determined by QST, with measures of pain (visual analogue scale, VAS), with items on the Michigan Neuropathy Screening Instrument Questionnaire (MNSI), and with nerve conduction studies. Results: IENFD and SENFD were reduced to 50 % in neuropathy patients compared with controls. Using both these parameters, the sensitivity of the skin biopsy for sensory neuropathy reached 92 %, the specificity 88 %. Elevated warm detection thresholds correlated with IENFD, nerve conduction study parameters correlated better with SENFD. There was an inverse correlation between IENFD and pain intensity as assessed by VAS. Specific items in the MNSI questionnaire, like trophic skin changes, prickling, and numbness, were associated with low IENFD values. Epidermal thickness was slightly reduced, and the Langerhans cell shape was more irregular in neuropathy patients compared to controls. Conclusions: A high diagnostic validity for both the IENFD and SENFD examination in patients with painful sensory neuropathy was demonstrated. These parameters are complementary, and the use of both of them further increases the sensitivity and specificity of the skin biopsy examination. The weak correlation between the evaluated skin biopsy parameters and thermal thresholds indicates that function and morphology are not in accordance in all patients,thus both IENFD and QST are independently supportive of small fiber disease. The VAS scale and the MNSI questionnaire are useful in the evaluation of patients suffering from painful sensory neuropathy. Besides the changes in innervation, epidermal thinning and increased irregularity of Langerhans cells can be found in painful neuropathies. The study was supported by the Czech Ministry of Education Research Plan No. MSM0021622404, E. Moravcova was supported by a Fellowship of the European Neurological Society (ENS). P431 Use of potentially inappropriate pain-related medications in elderly patients with diabetic neuropathy in general practice settings M. Gore, E. Dukes, D. Rowbotham, A. Sadosky, K. Tai, D. Leslie Avalon Health Solutions, Inc. (Philadelphia, USA); Pfizer, Inc. (New York, USA); University of Leicester (Leicester, UK); Yale School of Medicine (West Haven, USA) Objective: Diabetic neuropathy (DN), a frequent complication of diabetes, often results in substantial persistent neuropathic pain that can be difficult to treat and may require the use of multiple medications. Some medications commonly used to treat neuropathic pain have significant side effects. Since aging affects an individual’s ability to absorb, metabolize, and eliminate drugs from the body, side effects of medications are especially acute in the elderly. Accordingly, several recent guidelines have focused on developing lists of medications “potentially inappropriate” for use in elderly patients. Our goal was to assess the use of potentially inappropriate pain-related medications in elderly patients with DN. Methods: Using the UK General Practice Research Database (GPRD), we identified 875 patients (≥ 65 years) with a diagnosis of DN between 1998 and 2001. Use of potentially inappropriate pain-related medications was examined based on the Beers 1997 list. Developed by a panel of experts in geriatrics and pharmacology, this is a comprehensive list of all medications “inappropriate” for use in the elderly. Results: On average, patients were 73.4 (± 6.2) years old; 46 % female. A substantial number had other chronic pain-related (40.5 %) and non-pain related (42.5 %) comorbidities. Over a third (35.3 %) of DN patients received at least one prescription for a potentially inappropriate pain-related medication during the study period. Tertiary tricyclic antidepressants, including amitriptyline (30.3 %) and benzodiazepines (9 %), were the most common. Women were more likely than men to have received these medications (39.4 % vs. 31.8 %, p < 0.05). Use of inappropriate medications did not vary with age (36.7 %, 33.2 %, and 32.7 % among those aged 65–74 years, 75–84 years, and ≥ 85 years, respectively; p = 0.5546). Conclusion: Results suggest that elderly patients with DN often receive potentially inappropriate pain-related medications. Since DN patients also had other chronic comorbidities requiring treatment, in theory, the inappropriate prescribing we noted may have further increased the risk of adverse outcomes in these patients. However, due to database limitations, we could not confirm whether adverse outcomes occurred. While our results raise concern, some of these medications can indeed be used successfully for the treatment of neuropathic pain. Further research is needed to evaluate the risks and benefits of prescribing such medications for these patients. Pfizer, Inc sponsored this study.

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P432 Recurrent Miller Fisher’s syndrome G. Galassi, R. Suozzi, A. Ariatti, S. Facchini, F. Girolami Institute of Neurosciences (Modena, I) Objective: To report a patient with recurrent Miller Fisher’s syndrome (MFS). Methods: This 34 year-old woman experienced five months after delivery of her first child, twelve days after febrile cystitis, inconstant diplopia, gait unsteadiness, tingling paresthesias, distal numbness. Her unsteadiness, worsened over next 2 days. Neurological examination (day 3) showed restricted external eye movements, normal force except for mild loss of strength in hand muscles. There was tremor, both postural and intentional and ataxia on heel to shin test. Deep jerks were absent throughout.Vibration and position were moderately impaired distally in upper extremities, whereas light touch, pin-prick and temperature were normal. Results: Cerebro-spinal fluid (day 4) revealed normal findings. Extensive emato-urinary tests, B12, folate level, creatin kinase, microbiological, viral screenings were negative, including herpes, cytomegalovirus and EpsteinBarr viruses. Search for Campylobacter Jejuni and Borrelia Burgdorferi were negative as well for Toxoplasma Gondii. Serum sample for anti-ganglioside antibody assay (day 4) was unremarkable. Brain computed tomography and enhanced magnetic resonance imaging did not show lesions. Electrophysiology (day 4) revealed an axonal neuropathy. Patient did not receive immunotherapy as she experienced gradual improvement. In November 2000, six months after her second delivery, ten days after viral febrile episode, patient experienced diplopia in either directions and unsteady gait. Enhanced brain scans as well as anti-ganglioside antibody assay remained negative. Her ataxia ultimately disappeared within day 90. In conclusion, this patient exhibited an acute post-infectious benign neurological illness, which developed in both occasions 10 to 12 days after febrile episode during late post partum. Ataxia and tremor did not correlate with weakness and loss of proprioception which were mild. Electrophysiology suggested an axonal neuropathy, mainly involving upper limb.Anti-ganglioside antibodies were absent in sera obtained during both acute phases. Clinical findings were compatible with features of MFS, whose immunological marker is IgG anti-GQ 1b antibody, not detected during the two relapses of our case. Precipitating factors in recurrent MFS remain unknown; immunogenetic factors related to serological human leukocyte antigen may play a role. P433 Influence of the neuropeptides vasoactive intestinal peptide and substance P on sudomotor functions T. Schlereth, B. Seewald, F. Birklein Johannes-Gutenberg-University Mainz (Mainz, D) Neuropeptides are the mediators of neurogenic inflammation. Some neuropathic pain states, e. g. complex regional pain syndromes, are characterized by increased neurogenic inflammation and by exaggerated sudomotor function. We have shown that the neuropeptide calcitonin gene related peptide (CGRP), which is enhanced in complex regional pain syndrome, enhances the sweating reaction (Schlereth 2004). The aim of the present study was to explore, whether the neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP), which are involved in neurogenic inflammation, influence human sweating. VIP was found in neurons associated with human sweat glands (Vaalasti 1985). In previous studies VIP and SP reduced cholinergic induces sweating (Kumazawa 1994, Berg 1995). We investigated the effects of different concentrations of VIP and SP on acetylcholine (ACh) induced axon-reflex sweating in healthy subjects (n = 6, age: 26 ± 1; 3 female, 3 male), n = 4 were tested with each concentration of VIP and SP. All substances were applied via dermal microdialysis using fibers with a cut-off of 3000 kDalton.With this technique all substances were applied without time related skin trauma. For measuring of the sweating response two sweat capsules were attached to the skin of the lower leg surrounded by two microdialysis membranes each, which were either perfused with ACh alone or ACh combined with VIP or SP in various concentrations. Acetylcholine 10–2 M always elicited a sweating response, the neuropeptides VIP or SP alone did not.VIP at any concentration had no significant effect on axon reflex sweating (absolute humidity with 1.4 ± 0.4 g/m≥ and without VIP 1.2 ± 0.3 g/m≥, p = 0.4; sweat amount: 188 ± 52 AUC vs. 122 ± 29 AUC, p = 0.2; duration of sweating response: 538 ± 52 s vs. 472 ± 73 s, p = 0.3). SP reduced only the duration of the sweating response significantly (499 ± 150 s vs. 704 ± 170 s, p < 0.01), whereas the amount of sweat was not significantly affected (absolute humidity with 0.69 ± 0.16 g/m≥ and without SP 0.73 ± 0.17 g/m≥, p = 0.8; sweat amount 78 ± 28 AUC vs. 105 ± 37 AUC, p = 0.2), indicating reduced sweating with SP.Accordingly ACh-induced skin blood flow was not affected by VIP and SP.

The results indicate that the neuropeptide VIP in contrast to CGRP has no effect on axon-reflex sweating, whereas substance P shows a tendency to reduce axon-reflex sweating. Supported by DFG Bi 579–1/1–3 P434 Successful treatment of piriformis syndrome with botulinum toxin A A. Stenner, G. Reichel, W. Hermann Paracelsusklinik Zwickau (Zwickau, D) Objectives: Piriformis syndrome (PS), an compression syndrome of the ischiadic nerve, occasionally also of the inferior gluteal nerve, in the infrapiriform foramen was first described 75 years ago. According to literature, it represents 6–8 % of all lower back pain syndromes. As of now, clinical signs published include a moderate outward rotation of the foot, expressing shortening of the piriform muscle on the affected side, and pain in the piriformis muscle during palpation. Methods: We compared the incidence of the above mentioned clinical signs in a test developed in our clinic, in which permanent muscular tension of the piriform muscle on the affected side lead to increased pain, when the patient was doing scissor-like movements with stretched legs in a supine position. We tested 80 patients with PS, and 50 patients with diverse back and bottom pains, and called it JAGAS-Test.Afterwards, all patients were injected with Botulinum toxin A into the piriform muscle with CT-support, and treatment was controlled clinically. Results: Average age of the predominantly female patients [74] was 43 [14–72]. Half of them complained about increasing problems when sitting hard surfaces. In clinical diagnostics the following findings were the most reliable (decreasing in importance): typical pressure point – Jagas test, Freiberg’s test and Pace’s test. Laseguè’s sign is also positive in PS, as well as during radicular stimulation; although it is typical for PS that the pain eases off during outward rotation of the leg after reaching the pain spot. The neurophysiologic FAIR test rarely showed latency prolongation; decreased amplitude of the H-reflex potential was more likely. One third of the cases presented with slight atrophy and/or weakness of the gluteal muscle (passage of inferior gluteal nerve through infrapiriform foramen).The average diameter of the piriformis muscle was 12 [3–23] mm in CT. CT-supported injection of 2.0 ml (200 U) Botulinum toxin A lead to permanent painlessness for 71 of 80 patients after a single administration. In 8 cases there had to be 2 to 5 injections. One female patient has been treated 8 times so far; her pain ceased for 4 months after each injection. Conclusion: Clinical identification of piriformis syndrome is becoming safer with the newly developed Jagas test. CT-support injection into the piriform muscle is an efficient technique; in the most of cases a single administration leads to long-term improvement. P435 Symptomatic Charcot-Marie-Tooth, a pair of concordant monozygotic twins G. J. Braathen, J. C. Sand, M. B. Russell University of Oslo (Oslo, N); Akershus University Hospital (Oslo, N) A pair of monozygotic twin brothers was referred due to hereditary peripheral neuropathy. The clinic and neurophysiology was compatible with Charcot-Marie-Tooth disease with late onset. Molecular genetic analysis excluded mutations in PMP22, connexin32 and MPZ. The twins were employed in PVC production and developed symptoms after 14 years of massive exposure. We conclude that the monozygotic twin pair have symptomatic CMT, i. e. a phenocopy, since it is primarily caused by environmental and not by genetic factors. Phenocopies occur, but it is extraordinary that the two patients in a family do have a symptomatic rather than the hereditary form of CMT. This illustrates the importance of an occupational history even in the molecular genetic era. P436 Isolated unilateral hypoglossal nerve palsy – report of five patients M. Boban, V. V. Brinar, M. Habek, M. Rados University Hospital Center (Zagreb, HR) Hypoglossal nerve palsy (HNP) is not an uncommon finding in neurological diseases. However, when isolated, HNP can represent a diagnostic challenge in everyday clinical work and is limited to isolated case reports and few small case series. Thorough patients’ history accompanied with good knowledge of hypoglossal nerve anatomy as well as careful and rational selection of diagnostic tests is necessary for making the diagnosis. We report five patients with HNP as the sole neurological manifestation,

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without simultaneous involvement of other cranial nerves or long-tract signs. The most common cause proved to be metastatic disease at the base of the skull in three patients. The remaining two causes were internal carotid artery dissection (ICAD) in one patient and acute disseminated encephalomyelitis (ADEM) in another. In cases suspected on brain skull metastasis (clinically presented with positive meningeal signs and/or pain in the neck) contrast-enhanced CT scan of the skull base was primary and usually definitive diagnostic tool. Additionally, histopathologic confirmation of the metastasis has to be obtained. In cases of ADEM and ICAD, MRI was the diagnostic procedure of first choice for the localizing the lesion. MR angiography, CT angiography or digital subtraction angiography might be good additional tests in patients with suspected ICAD. Additional work-up (such as CSF finding and visual evoked potentials) are needed for diagnosis of demyelinating disease. P437 Presentation of the CMT-TRIAAL study protocol (multicentre placebo-controlled randomised trial of ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A) D. Pareyson, A. Schenone, N. Rizzuto, G. M. Fabrizi, F. Gemignani, L. Padua, L. Santoro, A. Quattrone, G. Vita, F. Visioli, D. Calabrese, A. Solari on behalf of the CMT-TRIAAL Group Objectives: To present the study protocol of the CMT-TRIAAL (CharcotMarie-Tooth disease TRial Italian with Ascorbic Acid Long term). Background. Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a duplication of the peripheral myelin protein 22 (PMP22) gene. To date there are no pharmacological treatments for CMT1A patients. Treatment with ascorbic acid (AA) has been shown to be effective in transgenic mice overexpressing PMP22, a model of the human disease. Treated animals had much less severe neuropathy as compared to untreated controls as shown by clinical and histological findings. Some clinical parameters even improved during treatment. PMP22 expression reduction occurred in CMT1A mice after treatment. A clinical trial evaluating the efficacy of AA treatment in CMT1A is feasible and warranted, as AA is a well tolerated and easily available treatment. Methods: Design and setting: Phase III prospective, randomised, double blind, placebo-controlled study involving eight Italian centres. Participants: at least 202 genetically-confirmed CMT1A adults, with CMT Neuropathy Score (CMTNS) between 1, excluding electrophysiology, and 35 [1]. Treatment: Oral therapy with AA (1500 mg/day) or placebo in two divided doses, for two years. Primary efficacy endpoint: Improvement in CMTNS overall score. Secondary efficacy endpoints: Changes in electrophysiological parameters, and in the following clinical scales: distal arm and leg strength (measured by maximum voluntary isometric contraction); 10 metre timed walking; 9-hole-peg test; Overall Neuropathy Limitations Scale; Visual analogue scale for pain and fatigue; health-related quality of life (assessed with the 36 item Short Form questionnaire, SF-36). Clinical and electrophysiological assessment will be performed at baseline and every 6 months thereafter. In a subset of patients skin biopsy will be performed to evaluate PMP22 expression at baseline and study-end. Serum AA concentration and anti-oxidant activity will be assessed at 6-month intervals. Conclusion: Study aims are: To assess efficacy and safety of long-term AA treatment in CMT1A. To develop and validate an evaluation protocol suitable for future trials in CMT. To better define the natural history of the disease (placebo arm). [1] Shy et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 2005;64:1209–14. Funded by Telethon-UILDM grants GUP04002 and GUP05007 P438 Nerve conduction abnormalities in myotonic dystrophy: primary involvement of nerve? Or incidental coexistence? S.M Go, J. S. Bae, S. S. Park, M. U. Jang, M. Kim Seoul Medical Center (Seoul, KOR) Background: Involvement of peripheral nerves in myotonic dystrophy (MD) is still controversial and the features of neuropathies are not well known. Purpose: The aim of the study is to access the frequencies of abnormal nerve conduction findings and electrophysiological characteristics of peripheral neuropathy in MD. Methods: We analyzed medical recordings and nerve conduction studies (NCS) of 18 patients with MD and 30 healthy subjects. The early changes in NCS were determined using a sural/ulnar SNAP amplitude ratio (SUAR). To correlate the neuropathic changes with cardiac abnormality, we compared corrected QT interval (QTc) with the NCS parameters. Results: Eight patients out of 18 showed abnormal NCS. Of these,

abnormal peroneal motor NCS and H-reflex abnormalities were most common. Only one patient complained sensory symptoms and showed abnormal sensory and motor NCS compatible with sensorimotor axonal polyneuropathy. There was no significant correlation between SUAR and disease duration, age, CTG repeats or QTc. Presence of diabetes mellitus was not related with the presence of abnormal NCS or SUAR. Conclusions: Comparing with previous reports, frequency of peripheral neuropathy or abnormal NCS in MD was low in our study. Our conclusion from this study is that abnormal NCS findings in MD seems to be resulted rather from myopathic changes or coincidental neuropathies or radiculopathies than primary involvement of nerve by MD. P439 Subacute polyneuropathy and inappropriate secretion of antidiuretic hormone (SIADH): two paraneoplastic disorders in the same patient? P. Guaraldi, G. Calandra Bonaura, G. Ficarra, G. Galassi Institute of Neurosciences (Modena, I) Objective: We report a patient with inappropriate secretion of antidiuretic hormone (SIADH) associated with subacute axonal and demyelinating polyneuropathy predating the diagnosis of a remote tumour. Methods: This 73-year-old woman was admitted because of delirium, lower limb weakness, frequent falls. Routine laboratory tests were normal, except for decreased serum sodium concentration (119 mEq/l, normal 136–145). Sodium urinary excretion was normal. Patient was diagnosed having SIADH and treated successfully with hypertonic saline combined with furosemide. By day 15, patient developed areflectic paraplegia, distal upper weakness, sensory loss for touch and pin-prick. Results: Serum concentration of immunoglobulins was within normal as well as tumour marker titer. Anti-ganglioside antibodies (day 50) could not be detected. Viral screening for HIV, hepatitis, vasculopaties were negative. Cerebrospinal fluid examined on day 60 revealed increased protein (561 mg/dl, normal below 45 mg/dl). On electrophysiology, a severe mixed axonal and demyelinating sensorimotor neuropathy was diagnosed in upper and lower extremities. Total body computed tomography (CT) and exhaustive searches for remote tumour did not reveal malignancies. Brain CT and magnetic resonance imaging were negative. Treatment with high dose of immunoglobulins (0.4 gr/kg/day for 5 days) was administered combined to steroid therapy Three months after admission patient could only sit in a wheelchair with aid. Her sensorimotor neuropathy had no improvement, but it further deteriorated on clinical follow up. Neck CT scan one year after onset of signs and symptoms revealed a mass lesion in the right pharynx diagnosed as a poorly differentiated squamous cell carcinoma. Conclusions: SIADH may result from various central nervous system disorders; it can occur also in association with acute polyradiculopathy, acute sensory neuropathy and paraneoplastic sensorimotor neuropathy. The pathogenetic mechanism of SIADH in neuropathies is yet undetermined. Peripheral neuropathy may represent the first appearance of malignant tumours occult at time of neurological onset. In our case, despite the absence of antibodies to onconeural antigens on repeated tests, both conditions, SIADH and neuropathy could be possibly considered as paraneoplastic disorders.Cross reacted immune responses generated against the tumour may underlie such condition.

Poster session 4 Cerebrovascular disorders P440 EMAP II: a potential biomarker for discriminating traumatic versus ischaemic brain injury C. Yao, A. Williams, M. Lu, R. Chen, Z. Liao, R. Connors, K. Wang, R. Hayes, F. Tortella, J. Dave Walter Reed Army Insitute of Research (Silver Spring, USA); McKnight Brain Institute, University of Florida (Gainesville, USA) Objective: Recent attention has focused on the development of protein biomarkers for the diagnosis and treatment of brain injury. In previous studies, using a high throughput immunoblotting (HTPI) technique, we reported changes in 30 out of 998 proteins following acute focal injuries to the rat brain. Importantly, we discovered that one protein, endothelial monocyte-

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activating polypeptide II (EMAP II) was differentially expressed between two models of brain injury (traumatic vs. ischemic). EMAP II is a known inflammatory cytokine involved in apoptotic signaling. Our current objective is to verify the changes in EMAPII expression and to evaluate the potentially important mechanistic implication that the differential regulation of this protein has on injury development. Method: Rat serum and brain tissues were collected at 24 h following either a right frontal penetrating ballistic-like brain injury (PBBI) or a transient middle cerebral artery occlusion (MCAo). Changes in protein expression were assessed by Western Blot analysis. Results: Preliminary results confirm previous data, indicating EMAP II in brain and serum are significantly increased 1.7–1.8 fold following PBBI, but decreased 2.1–2.3 fold after MCAo injury compared to the relative shams. Conclusion: The differential expression of EMAPII may be used as an injury-specific biomarker for diagnosis of traumatic vs. ischemic brain injury and provide valuable information for directing injury-specific therapeutics. Further studies are ongoing to explore the functional mechanism and/or the site of action of EMAPII following brain injury. P441 Immediate anticoagulation of ischaemic stroke of presumed cardioembolic origin L. Correia Guedes, J. M. Ferro Hospital de Santa Maria (Lisbon, P) Objectives: Immediate anticoagulation of ischaemic stroke of presumed cardioembolic origin is still controversial. It can prevent early recurrence but may induce major bleeding. The objective of this reveiw is to evaluate the efficacy and safety of anticoagulation in the first 48 hours of ischaemic stroke of presumed cardioembolic origin. Methods: We conducted a systematic review of all available randomized controlled trials (RCT) of anticoagulation in the first 48 hours of ischaemic stroke of presumed cardioembolic origin. Search strategy: we searched Cochrane reviews, recent guidelines, MEDLINE, bibliography of related papers and personal files.When needed, authors were contacted to provide additional information. Selection criteria: RCT comparing anticoagulants vs placebo or aspirin, within the first 48 hours after an ischaemic stroke of presumed cardioembolic origin. Data collection and analysis: two reviewers independently selected studies for inclusion, assessed trial quality, extracted and analyzed data. Outcomes: Symptomatic and asymptomatic cerebral haemorrhages, recurrent ischaemic strokes, vascular death, death and disability at follow-up and favorable outcome at 3 months. Main results: Seven trials, involving 4473 patients, were included. Two trials compared unfractionated heparin vs placebo or aspirin, four trials compared LMWH vs placebo or aspirin and one trial heparinoid vs placebo. The only trial that was specifically conducted on cardioembolic stroke patients was prematurely terminated. One trial included patients with atrial fibrillation. All other trials allowed subgroup analysis of patients with ischemic stroke of presumed cardioembolic origin. Five trials excluded patients that, according to the treating physician, had clinical indication for anticoagulation. Allocation to anticoagulation was associated with a significant reduction in the odds of recurrent ischaemic stroke (Peto odds ratio 0.70, 95 % CI 0.52–0.94) but also with a clear tendency to an increased rate of intracerebral haemorrhages (Peto odds ratio 1.47, 95 % CI 0.98–2.22). Comparing anticoagulation vs no anticoagulation or aspirin, the NNT was 67 for prevention of a single recurrence and the NNH was 125 for symptomatic haemorrhage. Conclusions: Despite the methodological limitations of CRT, our review does not support the routine use of immediate anticoagulation in acute ischaemic stroke of presumed cardioembolic origin. A new pragmatic RCT is warranted. P442 Cerebral ischaemia: correlation of patients’s clinical status with cell adhesion molecules’ levels and proinflammatory cytokines M. Arnaoutoglou, G. P. Spanos, S. A. Kapsali, V. Kosta, G. Andriopoulou, K. Kozetzidou, K. Dutsu, A. Arnaoutoglou, C. Aggouridaki, S. J. Baloyannis AHEPA Hospital (Thessaloniki, GR) Background: Implications have been recently made about the role of adhesion molecules in atherosclerosis and cerebral ischeamia. Objective: The purpose of our study was to measure the plasma levels of soluble ICAM and VICAM-1 adhesion molecules in patients with acute cerebral ischeamia and to correlate our findings with other mediators of inflammation (proinflammatory cytokines) and the patients’ clinical status. Methods: The levels of TNFa, IL-1a, IL-2, ICAM and VICAM-1 adhesion

molecules have been measured during the first 24 hours after cerebral ischeamia and also on the 4th and on the 16th day of admition. Ten normal individuals of the same age group were used as normal controls. The patients have been evaluated according to the NIH scale on the 1st and on the 16th day and neuroimaging was performed. Results: No statistically important difference was found between the serum levels of IL-1a, IL2, and the normal controls. TNFa was raised (both in the initial and in the subsequent measurements) in patients with significant brain damage, whereas no statistically important elevation of the TNFa was detected in strokes of limited clinical manifestation (lacunar strokes, TIA). The ICAM/VICAM-1 levels were significantly elevated in stroke patients compared to normal controls. Nevertheless, no correlation was detected between those levels and the severity of the clinical status. Conclusion: TNFa can be used as a prognostic tool of stroke outcome whereas the raise ICAM and VICAM-1 only indicate of the involvement of immunity in cerebral ischeamia. P443 A composite score consisting of the ASPECT-score of the admission CTscan, clinical findings and the protein S-100 serum concentration can predict stroke outcome J. J. Schwarze, A. Liebert, C. Almendinger, M. Federbusch, J. Klingelhoefer Chemnitz Medical Center (Chemnitz, D) Background: Predicting the patient’s prognosis at an early stage of the disease is essential for therapeu-tic decision-making, especially as new and increasingly invasive therapeutic strategies emerge. Physical examination is a useful measure but of little help if patients are unconscious. Imaging studies are precise in determining the infarct volume, but impractical as serial measures. It has been suggested that surro-gate markers like the S-100 protein may be of assistance, but they do not reflect the patient’s situation entirely. Hence, it was the aim of this study to investigate the predictive value of a composite score that comprises of the protein S-100 serum concentration (S-100), clinical and imaging findings. Methods: Patients were included if they showed symptoms of acute cerebral ischemia, the exact time of onset was known, and intracranial bleeding could be ruled out. Upon admission the clinical findings were determined as score on the mRS. Early signs of ischemia on CT-scan were quantitatively assessed as AS-PECTS-score. The S-100 was measured on admission (mean = 2.5 h after symptom onset), 6, 9, 12, 15, 18, 24, 48, 72 and 96 hours after symptom onset. Infarct volume on day 3–7 and clinical outcome 90 days after symptom onset were also determined. Results: There were twenty-seven patients with a mean age of 66.5 years. The median infarct volume was 20 ml (0.5–512 ml). Median baseline S-100 concentration was 0.11 (0.05–0.22) µg/ml. Twelve hours after symptom onset the value was 0.16 (0.04–0.41) µg/ml. In patients with large infarct volumes (> 20 ml) the serum S-100 concentration increased significantly as early as 12 hours after symptom on-set. The median ASPECTS-score on the admission CT-scan was 5 [3–10]. The median mRS-score was 3 [2–5] on admission and 3.5 [0–6] 90 days later. There was a statistically significant correlation between the composite score and the final infarct volume (r2 = 0.91, p < 0.05) and the clinical outcome 90 days after symptom onset (r2 = 0.80, p < 0.05). Conclusions: The results of our study suggest that a composite score consisting of clinical and imaging findings as well as the protein S-100 serum concentration correlates well with the final infarct volume and the clinical outcome 90 days after symptom onset. In addition it is suggested that the composite score has a predictive value early as 12 hours after symptom onset, and may aid therapeutic decisions substan-tially. P444 A non-invasive standard protocol for early acute stroke treatment impacts long-term disability F. F. A. Figueira, V. S. Santos, F. C. Silva, A. C. Marques Hospital da Penitencia (Rio de Janeiro, BR) Background: Time-dependent sequence of events renders stroke a medical emergency. Potentially salvageable tissue, the ischemic penumbra region, targets clinical efforts to reduce necrosis and so, long-term disability. In our country, first care of stroke sufferers is usually provided by an internist at Emergency Room (ER). In this setting, we standardized a protocol for diagnosis and clinical treatment of stroke on an as early as possible basis. Sample: Consecutive and non-selected 2185 patients entering our ER with admission diagnosis, made by internist, of clinically probable stroke. Sample was stratified according to pathophysiologic criteria as well as estimates of time to start therapy from the beginning of symptoms. A control group was formed by 113 patients attended in the year prior to protocol.

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Results: Primary diagnosis proved to be correct in 1928 patients (88.23 %). Disability scores, measured by Barthel index at 90th day from acute event, were significantly better among sample when compared to control and this difference was directly related to early start of therapy. Among groups, cardioembolism and small vessel disease did better than large vessel disease, and this difference was greater when they were admitted on first 6 hour interval. Proportion of good outcomers was related to early start of therapy, and, again, this difference was significantly greater among cardioembolism and small vessel disease patients. Conclusion: A standard protocol for early clinical care in stroke was feasible to be applied by a non-specialist. It proved established effective for patients attended on first 6 hours from onset, probably effective between 6 and 12 hours but had no benefit when patients were admitted after 12 hours from beginning of symptoms. P445 Long-term effect of tibial nerve neurotomy in stroke patients with lower limb spasticity M. Rousseaux, N. Buisset, O. Kozlowski, W. Daveluy, S. Blond CHRU, Hopital Swynghedauw and EA 2691 (Lille, F); CHRU, Hopital Salengro (Lille, F) Background: The efficacy of tibial nerve neurotomy has been evaluated in recent studies, with variable results. Nevertheless, no work has analysed the late evolution of efficacy, and the predictability of this improvement. Objective: To investigate these two points. Methods: Fifty four hemiplegic patients (mean age: 51 years) were recruited at the late phase (mean delay: 45 months) following a first-ever hemispheric stroke. All showed disabling spasticity at the lower limb. Neurotomy was performed on motor branches of the posterior tibial nerve, selected according to clinical examination (equinus, varus, clawing toes). Patients were regularly assessed following treatment (M3, M6, and Y1 for all patients): spasticity, motor control, range of active and passive movements, balance, walk (FAC), gait parameters (10m walk), Rivermead Motor Assessment, subjective improvement in daily living and satisfaction. Results: Neurotomy resulted in a severe (p < 0.01) drop of spasticity of the ankle plantar flexors, increase in passive and active range of movement in dorsiflexion and eversion, and considerable improvement of foot position in upright situation (equinus, varus, clawing toes, heel-ground distance). There was also a decrease in active plantar flexion and eversion. We also found improvement in upright balance, walk (FAC mainly barefoot; step length), and Rivermead Motor Assessment. The effect on gait velocity was small. Patients also reported important subjective benefit. Discrete recurrence of spasticity was found between at Y1 and Y2, but functional parameters still showed regular improvement at that time. The progression (Y1-J1; Y2-J1) in functional parameters was more important in patients with more severe initial deficits. Conclusion: At a distance from a stroke event, tibial nerve neurotomy severely reduces spasticity, improves motor control of the antagonists and functional use of the lower limb. It is also associated with fair improvement in daily living situations and patient satisfaction. A discrete recurrence of contracture can be observed in some patients. P446 Age-related white matter lesions: analysis according to a simple visual scale in a one-year follow-up study M. Viana-Baptista, C. Jordão, A. Ferreira, O. Ribeiro, J. Cortez, J. A. Esperança Pina, J. M. Ferro Hospital de Egas Moniz (Lisbon, P) Background: The natural course of white matter lesions (WML) is difficult to characterize on account of several factors, including gathering patients with substantially different degrees of lesion. Objectives: To compare clinical and imagiological features of patients with differente degrees of WML and to describe their evolution at one year. Methods: 30 patients aged > 65 years (mean 72.5) with WML identified on CT-Scan and no/or mild disability (Instrumental Activities of Daily Living – IADL),were assessed at baseline and at one year with a clinical and MRI protocol. Patients were classified according to the Fazekas scale in two groups: WML2-Moderate/Severe (n = 15, mean age 73.6 years) and WML1Mild (n = 15, mean age 71.5 years) Results: At baseline (t0) and at one year (t1) WML2 compared with WML1: had a wider extent of lesion (ARWMC-11.9vs4.8, p < 0.001; 14.0vs5.9, p < 0.001); performed worse on functional (IADL 90.7vs99.2, p = 0.023; 86.4vs96.7*), motor (SPPB-9.87vs10.3*; 9.54vs10.5, p = 0.058) cognitive (MMS-25.7vs27.2*; 27.5vs28.2*) and mood (Cornell-6.7vs3.5, p = 0.037; 6.2vs4.5*) tests.

Analysing the evolution profile from t0 to t1 of each group (WML2 and WML1), we observed: an increase in the extent of lesion in both (ARWMC 12.0vs14.0, p = 0.007; 4.8vs5.9, p = 0.006); a tendency to a worse functional performance (IADL 90.0vs86.4*; 99.1vs96.7*); a tendency to a worse motor performance only in the Moderate/Severe group (SPPB 9.8vs9.5*; 10.3vs10.5*); different tendencies of variation in cognitive tests: worsening in both groups (Digit Cancelling-17.4vs17.5*; 16.9vs19.9, p = 0.036), improvement in both groups (MMS 25.7vs27.5, p = 0.031; 27.5vs28.2*; Rey Complex Fig. 9.2vs11.2*; 8.3vs14.3, p = 0.045; Digit-Sybol substitution 23.9vs20.2, p = 0.04; 21.4vs 23.1*)*p < 0.05 Discussion: Increasing WML severity is associated at baseline and at one year with worse functional performances. WML progression at one year related to preexistent amount of lesion. One year seems to be a short period of time to detect clear-cut influence on functional status. Cerebrovascular Disease Research Grant from Brystol Myer Squibb Portugal P447 Ipsilateral embolisation in stent-PTA of extracranial brain artery stenosis K. Niederkorn, S. Horner, G. E. Klein, I. Brcic, D. Thaler, M. Augustin, G. Pichler Medizinischen Universität (Graz, A) The aim of the present study is to evaluate the incidence of stent-PTA relat ed delayed embolisation by one-day postprocedural TCD-monitoring and diffusi on-weighted(DWI) MRI in comparison with clinical findings. Patients: 112 patients (male 82, mean age 72 years, range 44–84), 61 % with previous stroke/TIA. Arteries treated: ICA 89, CCA 10,Vertebral Artery 11, Innominate Artery 2 Methods: Bilateral TCD monitoring (DWL,Germany, Multidop X-7;MCA 101 patients, PCA 11 patients)one day pre and post stent-PTA; montoring time one hour per vessel; occurrence of embolic signals pre/post-procedural, side of occur rence, embolic count;DWI-MRI one day pre/post-procedural (1.5 T Philips, The Netherlands),occurrence of DWIsignals pre/postprocedural, side of occurren ce,vascular distribution of lesions. Results: Signs of ipsilateral embolisati on on TCD: preprocedural 6/112 (5.4 %), postprocedural 8/112(7.1 %); With neurological deficit 3/8 (37.5 %); Signs of ipsilateral embolisation on DWI MRI: preprocedural 11/112(9.8 %), postprocedural 29/112(25.9 %), vascular area of art ery treated 28/29 (96.5 %); With neurological deficit 3/29 (10.3 %) Conclusion: Signs of one-day postprocedural embolisation were present on TCD in 7 % and on DWI-MRI in 26 %. Of the 4/112 patients with postprocedural neurological deficits 2 were positive on TCD and 3 on DWI MRI.Postprocedural monitoring can b e limited to patients with new clinical symptoms following stent-PTA of brain supplying arteries. P448 Unusual rapid progression with fatal outcome in biopsy-proven cerebral amyloid angiopathy M. Nordmann, M. Tröger, U. Buettner Kantonsspital Aarau (Aarau, CH) Introduction: Cerebral amyloid angiopathy (CAA) is one of the most common causes of intracerebral hemorrhage (ICH). Little is known about the prognosis of CAA. We present a case with an unusual rapid progressive course and fatal outcome. Case report: A 73-year old Italian lady with a history of arterial hypertension and heavy smoking (75 pack years) presented to our emergency department with an acute palsy of her right leg. She had no overweight and no family history of cerebro- or cardiovascular events. Her husband reported a mild cognitive impairment and weight loss over the past year. On physical examination the patient’s right leg dropped within five seconds and a moderate weakness in muscle testing was detected. She had sensory loss and impaired proprioception in that leg. The babinski sign was positive on the right. The cranial nerves were normal and there were no apparent neuropsychological deficits. The initial cranial CT showed two cerebral hemorrhages in the parietal lobes, one on the left and another smaller lesion on the right side. The MRI showed a perifocal edema around the left parietal leasion. Routine blood cell count, electrolytes, kidney- and liver function tests, lipid status and the infectious parameters were normal. Tumor screening done because of anorexia and weight loss revealed no neoplasm. The patient was released for neurologic rehabilitation and a MRI was scheduled two months later. She returned on the same day because of a secondary generalized seizure. The CCT showed three new small lesions bifrontally, the MRI revealed multiple cerebral hemorrhages of different age in both hemispheres.

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The cerebrospinal fluid showed a massive impairment of the blood-brain barrier but no inflammation. Septic emboli were excluded by transesophageal echocardiography. A cerebral angiography showed normal arteries of the brain and no signs of vasculitis. Finally we performed a brain biopsy of one of the lesions that confirmed the clinical suspected diagnosis of a CAA. The patient was dismissed with no specific therapy and palliative care. She died three months after onset of the disease as consequence of a recurrent hemorrhage. Conclusions: Hypertension and CAA are the most common causes of spontaneous ICH in the elderly patient. Our case illustrates that it is often difficult to make a definite diagnosis of CAA without biopsy. Our patient showed a very rapid progression and fatal outcome within three months after onset of the disease. P449 Stroke analysis in a Greek general army veterans hospital R. M. Psaras, C. Bairaktaris, G. Nasis, V. Papachronopoulou, M. Kallikourdi, M. Panagopoulou, I. Papanastasiou 417 N. I. M. T.S. Army Share Fund Hospital (Athens, GR) Objectives: The analysis of stroke according to type, age, sex, seasonal variation and mortality. Methods: We studied 205 patients diagnosed with stroke, hospitalized in our department between August 2003 and August 2005, analyzing them according to age, sex, month of admission and stroke type. A follow-up was performed, 3 months after admission. Results: The 205 patients with stroke were the 1.04 % of all the patients admitted to the emergency unit. There were 111 men (54.15 %) and 94 women (45.85 %). The stroke percentage was 1.22 % in male population and 0.88 % in female. The mean age was 76.7 (SD 10.6) in all stroke patients, 75.2 in men (SD 10.1) and 78.5 in women (SD 10.9). There were 168 ischemic strokes (81.95 %) and 37 hemorrhagic (18.05 %). In men, 89 were ischemic (80.18 %) and 22 hemorrhagic (19.82 %), while in women, 79 were ischemic (84.04 %) and 15 hemorrhagic (15.96 %). The mean age of ischemic stroke patients was 76.74 (SD 10.48) and that of hemorrhagic, 76.54 (SD 11.33). The months with the higher stroke admission were December (1.35 % of all patients in emergency unit) and January (1.33 %), while August and September presented the lower percentage (0.77 %). Mortality was 28.78 %, 3 months after the stroke (20.72 % in men and 38.3 % in women). It was 27.38 % in ischemic and 35.14 % in hemorrhagic strokes. In men, it was 16.85 % in ischemic and 36.37 % in hemorrhagic, while in women, 39.24 % in ischemic and 33.33 % in hemorrhagic strokes Conclusion: There was a male predominance. The predominance of ischemic strokes was higher in women, while the mean age was the same in ischemic and hemorrhagic strokes. An increase of strokes during the first months of winter was observed. There was a higher mortality in women. The mortality was higher in hemorrhagic strokes, generally, and in men, while in women, ischemic strokes presented higher mortality. P450 Intracerebral haemorrhage associated with sildenafil use: a case report M. H. Alpsan, N. Bebek, F. D. Ciftci, O. Coban, S. Bahar, R. Tuncay Istanbul University (Istanbul, TR) Objectives: Drug induced intracerebral hemorrhages occur mostly due to anticoagulants, thrombolytics, and sympathomimetic drug use. Here, we report a case of intracerebral hemorrhage, possibly due to sildenafil use.As far as we know, this is the third reported case. Case: The patient is a 62 year old, right handed male. He admitted to the Emergency Service, with left sided weakness and numbness. He reported that he had taken a 50 mg of Sildenafil two hours ago and realized numbness and weakness in his left arm and leg, an hour after taking the drug. On his admission,he had left hemiparesis,hemihypoesthesia and hemihypoalgesia. He had mild hypertension and hypercholesterolemia. Cranial CT scan and MRI showed hemorrhage in the right thalamus and the posterior limb of internal capsule.Intracranial and extracranial MRA were normal.At discharge he did not have a neurological deficit apart from mild clumsiness of the left hand. Results: Sildenafil, used in the treatment of erectile dysfunction is an inhibitor of phosphodiesterase-5 (PDE-5). Many neurological side effects of the drug were reported including headache, migraine, transient ischemic attacks, and visual disturbances, which suggest that the drug has an effect on brain microvasculature regulation. Studies show that sildenafil may act on PDEs like PDE-1 and 2, which are involved in the control of cerebral vasculature. It may also inhibit platelet activation and aggregation by nitric oxideguanosine 3.5’-cyclic monophosphate pathway. These effects may be the

cause of cerebral vasodilation, and combined with reduced platelet function, may have resulted in intracranial bleeding. Conclusion: Our findings indicate that sildenafil may be the cause of the intracranial bleeding in our patient. This case, with the two previous ones, brings the issue of using this drug with caution especially by the people who have vascular risk factors. P451 Stroke associated with type 3 odontoid fracture: a peculiar case M. F. Ergüngör, E. Daglioglu, H. G. Hatipoglu, E. Karakoc Ankara Numune Education & Research Hospital (Ankara, TR); Hacettepe University (Ankara, TR) Objectives: Upper cervical trauma is less frequent among cervical trauma classification. Although most of the cases are asymptommatic, vertebral artery dissection is a well known complication of cervical trauma with an incidence around 10 %. Methods and Results: 43-year-old man suffered from a traffic accident with symptoms of vomitting and nuchal pain. Neurological examination was completely normal except a decreased gag reflex prominent on the right side. The patient also suffered from dysphagia and refused to take oral fluids so he was fed with N/G tube for several days. Laboratory findings were unremarkable except a moderate increase of blood glucose level. Direct Xray revealed odontoid fracture line involving the neck and basis (Type 3 odontoid fracture) which was better demonstrated on routine and 3D-CT scans. MRI showed fracture and edematous signal of odontoid process. There was also acute right inferior cerebellar and tonsillar infarct in the posterior inferior cerebellar artery (PICA) distribution. Contour irregularity of the right vertebral artery was noted on MRI images. The patient was put on halo traction and alignment of the odontoid process was controlled by Xray. Conclusion: Association of isolated odontoid fracture (Type 3) and infarction within the PICA distribution on the same site of the trauma origin has been defined only in a few case reports previously. A reasonable explanation is that posttraumatic vertebral artery dissection predisposed to an infarction in the cerebellum. P452 Ipsilateral ventriculomegaly in unilateral carotid stenosis S. C. Hong, P. W. Chung Hanil Hospital (Seoul, KOR); Kang Buk Samsung Hospital (Seoul, KOR) Chronic cerebral hypoperfusion alone may produce cerebral atrophy even in the absence of apparent ischemic changes or infarcts. To test this hypothesis, we studied 24 subjects with unilateral proximal carotid stenosis (right:14, left;10) more than 70 % (NASCET method) but without infarcts on MRI in the cerebral hemisphere, and 27 age- and sex-matched controls. Cerebral atrophy was assumed if ventriculomegaly was present without a cortical sulci effacement. The lateral ventricle volume was measured and then the laterality index (LI: left – right/left + right x 100) was computed (+ value represents larger left ventricle). LI of patients and controls showed normal distribution (Shapiro-Wilk, p > 0.05) and their mean values were 3.56 + 4.59 in the control, 8.30 + 6.62 in the left carotid, and 1.49 + 7.39 in the right carotid groups. LI of control differed from that of left (p = 0.019) or right carotid group (p = 0.01). Our results suggest a unilateral carotid stenosis can produce ipsilateral cerebral atrophy even without an apparent infarcts or ischemic changes.

General neurology P453 Central cord syndrome in a 20-year-old male secondary to cervical hyperextension A. Angelou, S. Tsounis, T. Afrantou, M. Paschalidou, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Introduction: The central cord syndrome is characterized by greater weakness in the arms than the legs, with sparing of sacral sensation.Although the majority of cases has been observed in older persons with cervical spondylosis/stenosis, there is a small number of reports in young patients after cervical hyperextension. Case report: A 20-year-old male was admitted to our department in order to be investigated for weakness and numbness on his upper extremities

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for a presumed demyelinating disorder. The patient reported that his symptoms presented after a fall on the ground and subsequent mild head injury with cervical hyperextension. An obvious external injury was not observed. On neurological examination there was a moderate muscle weakness and a diffuse diminished superficial sensation exclusively at the upper limbs while vibration and position sense were slightly impaired on all extremities. All tendon reflexes were mildly increased even though plantar responses were flexor. The bladder function was normal. Computed tomography of the cervical spine did not reveal cord compression and the anteroposterior diameter of the spinal canal was normal. T2-weighted images in cervical MRI demonstrated an abnormal high-signal intensity lesion which expanded from C3 to C4, mainly in the central part of the spinal cord. T1-weighted images were normal. Nevertheless MRI showed no changes in ligamentum flavum, displaced vertebral bodies, disc herniations or findings of cervical spondylosis. Somatosensory evoked potentials were normal. Course and treatment: The patient received 1 gr methylprednisolone (IV) daily for a period of 5 days.An excellent recovery was noticed after completion of the above treatment and all clinical signs and symptoms disappeared. Conclusions-discussion: This case demonstrates that central cord syndrome may appear some times in young individuals in absence of predisposed risk factors (cervical spondylosis, vertebral and ligamental injuries) after cervical hyperextension which must be questioned and recognized when the clinical history has been taken. Relatively to the histopathological background of our case we estimate that the direct improvement of the clinical picture after the administration of corticoids indicates the diagnosis of pure spinal cord edema of traumatic etiology as the most possible. This hypothesis is amplified by the fact that the pathological findings in cervical spine MRI totally vanished during corticotherapy. P454 Cerebral sinus thrombosis associated with adult celiac disease: a case report S. Vlaski-Jekic, G. Zografski, I. Barbov, M. Krstevski Medical Faculty (Skopje, MK) Cerebrovascular events are not described in association with celiac disease (CD). We report a case of left lateral sinus thrombosis in a patient with untreated active adult CD. The patient was 30-years old man, suffering for several years of intermittent diarrhea and abdominal pain, abdominal distension, flatulence, weight loss, chronic fatigue, as well as iron deficiency (2.7umol/l) mild anemia (RBC 3.04x106 mm3; HGB 9.7 g/dl; HCT 24.0 %), thrombocytosis (1211x103/mm3), hypoproteinemia (58 g/l), prolonged protrombin time (25 sek), and mildly elevated alkaline phosphatase (217 U/l), liver enzyme (AST 63 U/l, ALT 46 U/l, CK 213 U/l), serum alpha-amylase (270 U/l), and antiphospholipid antibody levels. The patient was admitted to our Clinic because of headache and medical history for sudden appearance of recurrent transient attacks of right hemiparesis and sensory-motor dysphasia. Neurological examination revealed right hemiparesis, dysgraphia, dyslexia, bilateral increased deep tendon reflexes, and bilateral flexor plantar responses. Brain CT and MRI showed multiple bilateral basal ganglia and white matter parietal and paraventricular ischemic lesions, as well as left parietal cortex gyri enhancement. MRI angiography, EKG and ECHO cardiography findings were normal. Rheumathological serology was negative.There was increased thrombophoesis on sternal punction. Abdominal ultrasonography and abdominal CT revealed intestinal luminal dilatation with fluid and gas, diffuse thickening of the small intestine wall, retroperitoneal lymphadenopathy. Duodenal biopsy showed intestinal villi flattening, intestinal crypts lengthening, intraepithelial lymphocytic infiltrates. We treated this condition with low molecular weight heparin and antiplatelet therapy. Neurological clinical improvement was complete in ten days, when follow-up CT and MRI studies demonstrated marked regression of parenchymal cerebral abnormalities. MR venography,realized at the same time, registered partial recanalization of previously occured left lateral sinus thrombosis, and increased collateral venous circulation. CD was treated with gluten-free diet and supplemet therapy. Clinical improvement appeared in a few week time. Cerebral sinus thrombosis may be part of extraintestinal pathological spectrum of untreated, late diagnosed adult CD. Association with thrombocytosis is suggestive for hypercoagulability, as an extraintestinal manifestation of CD, which could provoke cerebral thrombotic phenomena.

P455 Pseudomigraine with lymphocytic pleocytosis: clinical implications and risk of misdiagnosis G. Nuzzaco, M. Spinelli, F. Fumagalli, F. Corea, A. Faggi, V. Martinelli, G. Comi, M. Sessa IRCCS S.Raffaele (Milan, I) We describe three patients admitted to our unit in the last two years, for the sudden onset of focal neurological deficits associated with headache. All patients were young men. The most common dysfunctions were sensory right hemibody symptoms plus aphasia, lasting from minutes to one day. All the episodes had a favorable outcome. One of our patients, evaluated within three hours from onset, received intravenous t-PA therapy. Transient episodes of migraine-like headache with neurological dysfunction lasting more than one hour may sometimes occur in young patients and be mistaken for a seizure or a stroke. In such cases, the cerebrospinal fluid (CSF) may show a lymphocytic pleocytosis and increased protein content. Conclusions: Pseudomigraine with lymphocytic pleocytosis seems to be an emerging syndrome, which has to be taken into consideration in the differential diagnosis of young patients with acute onset of focal neurological symptoms. P456 Breathing pattern at rest and during rhythmical movements in hemispastic patients D. Ebert, P. Bussfeld, H. Hefter University of Dusseldorf (Dusseldorf, D) Objectives: Coordination between breathing and limb movements, the physiological phase locking, seems to depend on the degree of automatisation of movements, especially when breathing and limb movements have been trained simultaneously. Alterations of breathing movements during rhythmical limb movements and at rest have been investigated in various neurological diseases. However, in hemispasticity, though being a severe motor disturbance, coordination between active and passive limb movements and breathing movements has not be studied so far. The aim of the present study was to analyze, whether spasticity also affects the breathing motor system. Methods: We investigated breathing movements in patients with hemispasticity at rest as well as during rhythmical spontaneous and passive movements of both the affected and not affected limbs with small amplitudes inside the frequency range of spontaneous breathing rates (0.2–0.5 Hz). Breathing was recorded by means of a RESPITRACE® setup. Breathing parameters and phase relations between breathing and limb movements were calculated. A group of 15 patients suffering from upper motor neuron disease (UMND) was compared to an age and sex-matched group of 15 healthy subjects. Results: Breathing at rest was faster (p < 0.01) and more irregular (p < 0.01) in the patients. Spontaneous voluntary movement tempo was much slower in the patients, while their breathing rates during these movements were faster than in the controls. During both, passive and active extremity movements of the patients the breathing rhythm was kept constant without coupling to the extremity movements. Conclusions: We interprete the findings for breathing at rest to be the result of an increased internal vegetative stress, the vegetative balance may be tuned towards an increased sympathetic tone. The lack of phase locking between movements and breathing may be considered as the result of an increased voluntary effort for the limb movements which have not been trained previously, especially not in parallel to breathing. P457 Effects of age, gender, bolus volume and bolus consistency on swallowing parameters and on temporal coordination of breathing and swallowing in normal adults P. Urban, M. Zahn, S. Schranz, R. Rolke, O. Glassl, P. Pittermann University of Mainz (Mainz, D) Background: The temporal coordination of respiration and swallowing is provided by an extended pontomedullary neuronal network. However, it is not well known which factors influence swallowing parameters and the breathing pattern during swallowing. Methods: The study included 60 healthy subjects, median age 49y. A 2channel computer assisted system was used to obtain concurrent respiratory and submental surface electromyographic signals. Subjects were seated in an upright position and asked to swallow a bolus of 5.10.25 ml water and 5 ml applesauce presented in random order. Eight swallows of each bolus volume and viscosity were recorded. For each swallow, the [1]latency between the onset of swallowing and swallowing apnea (SA), [2] duration of

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swallowing, [3] duration of SA, and [4] pattern of breathing after each SA were evaluated. Results: In healthy subjects a total of 3.360 swallows were performed. The main finding was a significant prolongation of all swallowing parameters (latency between the onset of swallowing and SA, duration of swallowing and duration of SA) (ANOVA, p < 0.0001) with age in all bolus volumes of water but not with a higher bolus consistency. Increasing bolus volumes led to a significant increase of the duration of swallowing and SA (ANOVA, p < 0.01). Gender influenced none of the parameters. Inspiration after SA occured in 1.9 % of all swallows and was not significantly affected by age, gender and bolus variables. Conclusion: Our study demonstrated a strong influence of age and bolus volume on all swallowing parameters when swallowing water. However, age, gender and all bolus variables did not influence the temporal coordination of breathing and swallowing, which is relevant for airway protection from aspiration during swallowing. Supported by MAIFOR. P458 Neurosarcoidosis treated with mycophenolate mofetil: first report of two cases A. Chaussenot, V. Bourg, S. Chanalet, J. Fornari, M. Chatel, C. Lebrun Hopital Pasteur (Nice, F); Cadrans Solaires (Vence, F) Objective: To evaluate the efficacy of mycophenolate mofetil (MMF) in patients resistant to a standard schedule of treatment for sarcoidosis. To quantify clinical and radiological responses on 2 patients which have progressive neurological disease after the association of corticosteroids and a first-line of immunosuppressive drugs (methotrexate and cyclophosphamide). Methods/patients: Two symptomatic patients (14 and 27 years-old women), known for a neurosarcoidosis were proposed for a second-line of immunosuppressive therapy. The two patients had observed a corticotherapy regimen and a first-line of immunosuppressive drug with progressive disease on brain MRI and symptoms. A second-line of treatment with MMF (2 g/d) was instaured. Results: A significant and dramatic efficacy was observed on brain MRI (mean delay of radiological response 1 month). Radiological response was correlated with symptoms improvement. After 1 year of follow-up, the two patients are still in complete response without corticosteroids. No hematoor digestive toxicities were reported. Discussion: Neurosarcoidosis is often resistant to corticosteroids and standard immunosuppressive drugs i.e cyclophosphamide, cyclosporine, aziathioprine, or methotrexate. These treatments present many counter-indications, side-effects and cumulated toxicity. MMF is already proposed for many neurological diseases with success. Resistant neurosarcoidosis could be another indication to evaluate. Conclusion: The MMF seems to be an interesting drug in resistant neurosarcoidosis. Prospective studies are mandatory to assess tolerance and efficacy on large cohort of patients P459 Tentorial herniation in ADEM requiring craniectomy P. Shanahan, S. Omer St Georges Hospital (London, UK) Objective: We report a case of sudden, severe deterioration following an initial reponse to steroid treatment for ADEM, necessitating surgical decompression. Methods: We describe the case of a 62 year old woman who presented with loss of proprioception in her left arm and leg two weeks after an upper respiratory tract infection, with laboratory and imaging findings supportive of a diagnosis of ADEM. Following an initial improvement with IV methylprednisolone,she abruptly deteriorated,with new,acutely oedematous white matter lesions and developed tentorial herniation. She was commenced on dexamethasone, underwent a decompressive frontal craniectomy and was subsequently given a course of intravenous immunoglobulin. Results: Following surgery and IVIG there was a slow clinical improvement and resolution of much of the white matter oedema on MRI. Since then she has regained abilty to obey commands and communicate verbally, and is currently undergoing neuro-rehabilitation. Conclusion: Acute disseminated encephalomyelitis (ADEM) is generally considered to have a favourable outcome in the majority of cases. In the acute phase, however, the neurological consequences may be severe. We discuss the management of ADEM and the potential for acute, life-threatening deterioration.

P460 Valproate-induced hyperammonaemic encephalopathy revealing adult onset ornithine transcarbamylase deficiency: about an unusual case M. Ragé, M. Nassogne, P. Laloux, M. Ossemann Cliniques Universitaires de Mont-Godinne (Yvoir, B); Cliniques Universitaires St-Luc (Brussels, B) Background: Ornithine transcarbamylase (OTC) deficiency is the most common inherited defect of the urea cycle. Late onset cases have been rarely described most of them in a context of valproate-induced hyperammonaemic encephalopathy. We report a case of late onset OTC deficiency admitted for altered state of consciousness and a history of energy drinks abuse. Case report: A 30-year-old woman with a history of excessive energy drinks intake (> 20 cans/day) was transferred to our institution for a progressive stuporous state of consciousness of unknown origin. She was admitted three days before in a regional hospital for unusual drowsiness, ataxia and frontal dysfunction features.Neurological examination showed no other abnormalities. Initial work-up revealed hyperthyroidism (TSH 0.09 mU/L). Toxicological screening, CSF examination and brain MRI were normal. EEG showed global slowing and generalised, irregular large amplitude activities intermixed with sharp components. A misdiagnosis of partial complex status epilepticus was made and she was treated with IV sodium valproate and phenytoin. She deteriorated and was transferred to our hospital on day 4. Complementary work-up demonstrated a generalised delta slowing on EEG and a hyperammonaemia (211 mcmol/L). Anticonvulsants were stopped. Urinary orotate and uracile were significantly increased and blood amino acid profile showed raised glutamine and glutamic acid. These results were consistent with an OTC deficiency. A low protein regimen and oral carnitine was started. She recovered a normal state of consciousness and was discharged on day 13. Further questioning revealed a difficult scholarship and episodic consciousness and behavioural disturbances during childhood. She avoided excessive protein intakes spontaneously. Discussion: This new case of encephalopathy due to unrecognised OTC deficiency at adult age was probably caused by an important intake of energy drinks. The administration of sodium valproate enhanced the clinical picture and allowed the diagnosis of hyperammonaemic encephalopathy. Patients admitted for an acute encephalopathy and a history of energy drinks abuse, known to be rich in amino acids, should be screened for a hyperammonaemia and, if positive, disorders of the urea cycle. P461 The spectrum of Avellis’ syndrome M. Habek, V. V. Brinar, Z. Mubrin Zagreb School of Medicine (Zagreb, HR) Introdution: Avellis syndrome was described in 1891 by Georg Avellis. It is characterized with a paralysis of the soft palate and vocal cord on one side, and hemiparesis or loss of pain and temperature sensation on the other side. This is a rare condition that almost exclusively occurs in association with infarction of the medulla oblongata. Patients: Recently we have observed two patients who presented with the symptoms of Avellis syndrome and were thought to have a stroke. The first patient is a 19-years-old girl, who on brain magnetic resonace imaging (MRI) had a demyelinating lesion in the medulla which later spread to the middle cerebellar peduncle and whose cerebrospinal fluid (CSF) and electrophysiological findings were consistent with the diagnosis of acute disseminated encephalomyelitis. The intravenous corticosteroid treatment was initiated and a very good recovery achieved. The second patient is a 67-years old man, who, six months after Borrelia burgdorferi infection presenting as a left peripheral facial palsy, developed Avellis syndrome. His MRI showing band-shaped lesion in the right medulla oblongata and intrathecal synthesis of IgG Borrelia burgdorfery antibodies (confirmed with ELISA and Western blott) were consistent with the diagnosis of Neuroborreliosis. The treatment with ceftriaxon was initiated, and good recovery ensued. Discussion: The clinical presentation in both of our patients was dysphonia with palatal palsy on one side and altered exteroceptive sensation or hemiparesis on the other side. However, young age and not so abrupt symptoms development prompted us to seek a more common pathological process than stroke due to atherosclerosis, in the first patient.After thorough work-up it proved to be a rare, brainstem delineated, case of acute disseminated encephalomyelitis. In the second patient, medical history of Borrelia burgdoreri infection was a clue which led to the CSF examination. Although there are many false negative results when dealing with Borrelia antibodies, CSF IgG antibodies were tested with two methods, what is a current standard. As well intratecal synthesis in the CSF in the absence of IgM antibodies is consistent with the late stage (stage 3) Borrelia burgdorferi infection. Conclusion: With presentation of these patients we wanted to emphasise how etiology of Avellis syndrome is not solely consequence of atherosclero-

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sis, but other aetiologies may play a role, bringing different treatment implications into light. P462 An extradural cervicothoracic arachnoid cyst causing spinal cord compression in an elder patient M. Vikelis, M. Xifaras, K. Belis, G. Gekas General Hospital of Nikea (Nikea, GR) Background: Symptomatic arachnoid cysts of the spine are uncommon and have only rarely been reported to occur extradurally. Most of such reported cases refer to children or young adults. The etiology of spinal extradural arachnoid cysts is uncertain. They may develop from arachnoidal herniation through a congenital defect of the spinal dura. Progressive enlargement of the cyst is presumed to be due to fluid transport, active or passive. Case report: We present the case of a 70-year-old man who presented with complaints of progressive right leg weakness and numbness. The symptom was initially noticed by the patient two months before admission. His past medical history was unremarkable. Neurological examination revealed mild right arm and leg weakness graded at 4/5. Babinski sign was present on the right. Cranial nerves and sensory system were normal. There was no deficit in bowel or bladder functions. The patient’s routine blood examination, chest x-ray, ECG and carotid Doppler studies were normal. A CT brain scan showed findings compatible with mild microangiopathy. Magnetic resonance imaging of the cervical and thoracic spine revealed an extradural arachnoid cystic lesion extending from the C-6 to T-7 levels in the cervicothoracic region, located dorsally and causing compression of the spinal cord, especially at the level of the T2-T3 where atrophy of the spinal cord was also noted. The signal intensity of the lesion was similar to that of the cerebrospinal fluid on all pulse sequences. The patient was subsequently referred for neurosurgical consultation. Based on patient’s personal decision, no operation was decided. Conclusion: Only a few patients with symptomatic spinal extradural arachnoid cysts have been reported, most of them being children or young adults. Our case indicates the possibility of such a cyst as the cause of spinal cord compression even in elder patients. P463 Natural history of syringomyelia. A health status survey F. Roser, F. Riether, C. Sixt, M. Tatagiba University of Tubingen (Tubingen, D) Objective: The assessment of the natural history of patients with Syringomyelia has not been performed in a satisfactory way. Syringomyelia is characterized by a centromedullary syndrome with dissociative symptoms. Most patients undergo a slow but steady progression of subtle neurological symptoms. Psychological alterations are not infrequent. Methods: Life quality of patients with Syringomyelia was assessed through standardized questionnaires like the SF-36, cervical spine disability index and an individualized questionnaire for Syringomyelia. 59 patients with Syringomyelia could be analysed with a complete set of data: 32 females and 27 males had a mean age of 50 years (range 17–78). The underlying pathology for the Syringomyelia was spinal trauma (37 %), Arnold-Chiarimalformation (33 %), intramedullary tumour (15 %), scoliosis (11 %) and meningitis (4 %). Results: Related to the normal healthy population the physical component score (PCS) in Syringomyelia is lower than in any other chronic disease including heart failure and diabetes. Especially the physical functioning score (49 % vs. 85 %), bodily pain (47.3 % vs. 79 %), health perception (44 % vs. 68 %), social functioning (63 % vs. 88 %) and emotional role (74 % vs. 90 %) were low. More than 50 % of patients experience a chronic deterioration of physical function whereas only 10 % describe a stabilisation of disease within five years of follow-up. Leading causes of deterioration is increasing neuropathic pain and loss of protopathic sensibility. Conclusion: Syringomyelia has long been underestimated concerning the severity of symptoms. This study for the first time shows that the physical performance in Syringomyelia ranks among patients with severe chronic diseases. There is a noticeable discrepancy between physical and psychological performance. Early detection and consequent physical and psychological support of Syringomyelia-patients is essential to avoid chronification of the disease.

P464 Seasonal variation in the occurrence of cerebral vein and dural sinus thrombosis M. Saadatnia, M. Zare, M. Mojarrad Isfahan University of Medical Science (Isfahan, IR) Objectives: Several investigations described the chronobiology of different stroke types, but such information is rare and has discrepancies in different geographical areas for cerebral vein and dural sinus thrombosis (CVST). The aim of this study was to investigate whether a seasonal variation exists for CVST in Iran or not. Methods: We analyzed the seasonal distribution of disease onset in an Iranian cohort of 122 consecutive CVST patients treated in two neurological centers from 2001 to 2004. In all cases, diagnosis was confirmed either by conventional angiography or magnetic resonance imaging and MR angiography. Patients with septic CVST were excluded.We evaluated the number of new CVST cases per month and compared the distribution of new cases during the annual seasons. The total sample was divided into subgroups by gender. For statistical analysis, the distribution of symptom onset was tested for uniformity by the chi 2 test. Results: Seasonal analysis showed (spring 27, summer 22, autumn 43, winter 30) a significantly reduced frequency of CVST events in summer and increased in autumn and winter, for the total population, men and women (p < 0.05), with two peaks in September and December. Conclusion: This study showed the existence of a highly significant seasonal variation in the occurrence of CVST, characterized by autumn and winter peak. Thus, colder months and relative hypercoagulability can be considered as a supplementary high risk condition when prescribing an anticoagulant regimen.

Immunology P465 Comparison of circulating antibodies directed against tryptophan derivatives, no- and no 2-modified antigens in amyotrophic lateral sclerosis, Alzheimer syndrome and multiple sclerosis S. Duleu, C. Van Der Velden, D. Bodet, F. Poulletier de Gannes, M. P. Dabadie, M. Geffard GEMAC BIO (Cenon, F); PIOM, ENSCPB-EPHE (Pessac, F) The first objective of this study was to identify specific circulating antibodies directed against tryptophan derivatives (TD), NO and NO2- modified amino acid residues in patient sera of amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), remitting relapsing multiple sclerosis form (RRMS) and secondary progressive form (SP-MS). The second objective was to determine immunoglobulin classes of identified circulating antibodies. For the antibody evaluation, we synthesized TD conjugates, NO- and NO2-conjugates in order to mimic metabolites induced during the pathogenic processes. The TD antigens were: tryptophan, kynurenin, 3OHkynurenin, kynurenic acid, picolinic acid, xanthurenic acid, anthranilic acid, 3OH-anthranilic acid, quinolinic acid and quinaldic acid, linked to bovine serum albumin (BSA) using carbodiimide coupling reaction. Then, conjugates were purified and the coupling ratios were evaluated. NO- and NO2conjugates were the following amino acid residues: nitrotyrosine, tyrosine, phenylalanine, citrulline, tryptophan, asparagine, creatin, cysteine, methionine, histidine, arginine, linked to BSA via glutaraldehyde reaction. After a reduction step and purification, a nitrosylation with NaNO2 was done, except for nitrotyrosine conjugate.All conjugates were coated on well plates for identification of circulating antibodies. High levels of circulating antibodies to TD conjugates, NO- and NO2-conjugates were found in ALS, AD, RR-MS, SP-MS in comparison of healthy control sera, using ELISA assays. Immunodetection of IgG, IgM and IgA classes directed against TD conjugates, NOand NO2- amino acid residue conjugates was done. These studies shown that: 1) specific circulating antibodies directed against TD, NO- and NO2- modified components were found for each pathology with a specific pattern. The identification of specific antibodies indirectly reveals the stimulation of enzymatic and immunologic mechanism disorders associated with these diseases; 2) specific profiles of immunoglobulins were also observed for each disease. The identification of differential isotype classes to these neoantigens opens new perspectives for a better understanding of these autoimmune and neurodegenerative processes. This work has been supported by Institut pour le Developpement de la Recherche en Pathologie Humaine et Therapeutique (IDRPHT) (Talence, France).

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P466 Multiple sclerosis: glatiramer acetate inhibits IL-2 and TNF-alpha production of naive, memory and effector CD4 + T-cells independently of T-cell specificity S. Kantengwa, M. S. Weber, C. Juillard, A. Paunier-Doret, B. Fellay, S. S. Zamvil, M. Gougeon, M. Chofflon, P. Lalive University of Geneva (Geneva, CH); University of California (San Francisco, USA); University of Fribourg (Fribourg, CH); Institut Pasteur (Paris, F) Objectives: Immunomodulatory drugs available to treat RRMS include GA, a combination of 4 amino acid copolymers. The main mechanism of GA has been identified as a bystander Th2 deviation, although it is unclear which cytokine and what CD4 + T cell subset are involved in Th1 suppression. The goal of the study is to evaluate the regulation of Th1 cytokines IL-2 and TNF-alpha on naive, memory and effectors CD4 + T cells of Glatiramer acetate (GA)-treated relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We analyzed by a five-color flow cytometry staining the effect of GA-treated RRMS patients on intracellular production of IL-2 and TNFalpha cytokines of naive, memory and effector CD4 + T cells. PMBC from 14 healthy controls, 11 untreated RRMS and 7 GA-treated RRMS age-gender matched patients were isolated and stimulated 16h with PMA/ionomycin before analysis. PBMC were gated on CD4 + CD45RA + CD27 + (naive), CD4 + CD45RA-CD27 + (memory) and CD4 + CD45RA-CD27- (effector) T cells, then intracellular Th1 cytokine was analyzed. P values < 0.05 were considered as significant (Mann Whitney test). Results: We found that, compared to healthy controls, IL-2 was significantly increased in effector CD4 + cells of non-treated RRMS patients (p < 0.05), whereas TNF-alpha was significantly increased in memory CD4 + cells of non-treated RRMS patients (p < 0.05). Compared to nontreated RRMS patients, IL2 was significantly decreased in all CD4 + cell subtypes of GA-treated patients (p < 0.05), whereas TNF-alpha was decreased in naive and effector CD4 + cell subsets (p < 0.05). Conclusion: Our ex-vivo results indicate that GA exerts not only an immunomodulation on differentiated antigen-primed T cells but also on naive T cells. Thus, GA appears to exert its beneficial effects by restraining the proliferation of both Ag-activated and non-activated T cells independently of the T cell specificity. P467 Brain-derived neurotrophic factor: a neuroprotective effect for interferonbeta treatment? S. Kantengwa, C. Juillard, M. Chofflon, P. Lalive University of Geneva (Geneva, CH) Objectives: It is believed that interferon-beta achieve its beneficial effect on MS progress via anti-inflammatory properties. A neuroprotective effect has been recently suggested through the increase of nerve growth factor in PMBC of IFN-beta-treated MS patients. On the contrary, the effect of IFNbeta on the expression of BDNF in PBMC has not been confirmed yet. The goal of the study is to evaluate the impact of interferon-beta (IFNbeta) treatment on the expression of brain-derived neurotrophic factor (BDNF) in peripheral blood mononuclear cells (PBMC) from patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Up to now, five RR-MS patients included in the study were treated with IFN-beta1a 44 microg subcutaneously three times weekly. Controls consisted in 5 healthy donors and 5 non-treated RR-MS patients. PBMC were isolated, by standard Ficoll gradient centrifugation. Proteins from whole cell lysates were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE). The mature bioactive form of BDNF (14 kDa) was detected by western blot using a rabbit anti-human BDNF polyclonal antibody. The volume of immunoreactive band was determined by optical densitometry (Arbitrary Unit (A. U.)). In parallel, BDNF was measured in the sera from the same patients by ELISA kit. Results: Densitometry analysis showed higher levels of BDNF in PBMC from IFN-beta-treated patients (A. U. mean + SD = 9.84 + 2.1) in comparison with non-treated patients (A. U. mean + SD = 3.06 + 1.6) (p < 0.0004) or healthy donors (A. U. mean + SD = 6.65 + 1.4) (p < 0.02). On the contrary, serum levels of BDNF, were similar in all groups (p = ns). Conclusion: By increasing BDNF production in PBMC, IFN-beta may participate in neuroprotective mechanisms in RR-MS. Since no differences were observed in serum BDNF levels between the groups, we hypothesize that the increased intracellular BDNF secondary to IFN-beta treatment is not released in the periphery and is specifically delivered in targeted organs like CNS.

P468 Qualitative evidence of anti-Ri specific IgG synthesis in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes S. Jarius, O. Stich, R. Voltz, C. Rasiah, S. Rauer Ludwig Maximilians University (Munich, D); Albert Ludwigs University (Freiburg, D); University of Cologne (Cologne, D) Background: Intrathecal anti-Ri specific antibody synthesis in patients with paraneoplastic syndromes (PNS) has been shown by semiquantitative methods. However, the oligoclonal IgG bands were not shown to be specific for Ri antigen. Objective: To investigate the presence of Ri-specific oligoclonal IgG bands in the CSF of patients with anti-Ri associated PND. Patients and methods: Five anti-Ri-positive patients and six controls (3 x anti-CV2-, 2 x anti-Yo-, and 1 x anti-Hu-associated PND; evidence of intrathecal Ig synthesis in all controls) were included in our study. Associated tumours were small cell lung cancer in 2/5, a carcinoid tumor of the lung, and breast cancer. In one patient no tumour has been detected so far. All patients presented with symptoms compatible with anti-Ri associated PND. Oligoclonal bands were detected by isoelectric focusing. Ri-specific affinity blotting was used to assess Ri-specific bands in serum and CSF. Results: In 4/5 CSF samples reactivity of IgG bands with recombinant Ri antigen was found. In one patient with absence of oligoclonal bands of total IgG in CSF, anti-Ri-specific oligoclonal bands were detected with the same sample indicating a higher sensitivity of Ri-specific affinity blotting as compared to affinity blotting with anti-human IgG antibodies. Conclusion: Our findings provide further arguments that anti-Ri-specific antibodies are produced by B-cell clones in the central nervous system of patients with PNS and support the hypothesis of an intrathecal immune reaction being responsible for anti-Ri associated paraneoplastic neurological syndromes. P469 CSF findings in patients with voltage-gated potassium channel antibody associated limbic encephalitis S. Jarius, L. Clover, A. Vincent, R. Voltz John Radcliffe Hospital – University of Oxford (Oxford, UK); University of Cologne (Cologne, D) Background: Recently, a new subtype of limbic encephalitis (LE) has been described, serologically characterized by the presence of antibodies against voltage gated potassium channels (VGKC, to be called VGKC-LE). Discrimination of “classical”LE and VGKC-LE is important as many of the latter cases are non-paraneoplastic, and symptoms respond well to immunotherapies. In “classical” LE, CSF analysis frequently reveals oligoclonal bands as well as other signs of CNS inflammation. However, little is known about CSF findings in VGKC-LE. Objective: To assess whether CSF analysis may contribute to the discrimination of “classical” LE and VGKC-LE. Methods: The results of 29 CSF examinations in 17 patients with VGKCLE were analysed retrospectively. Results: Intrathecal immunoglobulin (Ig) synthesis – as defined by the presence of CSF-specific oligoclonal IgG bands, an increased IgG index, or an elevated IgG, IgA, or IgM ratio – was undetectable in all 29 samples. A slight pleocytosis, mainly consisting of lymphocytes and monocytes, and/or elevated total protein concentrations were present in 41 and 47 %, respectively. Dysfunction of the blood-CSF barrier was found in 35 %. CSF findings were normal in 23 %. Conclusion: Our data demonstrates, that normal CSF findings, particularly a lack of intrathecal Ig synthesis, are frequent in VGKC-LE and do not rule out the diagnosis. It is therefore strongly recommended to assess VGKCAb also in patients with signs of LE and normal CSF findings. A. Vincent’s department receives payments and royalties for VGKC antibody assays. P470 Involvement of PKC-alpha, delta and zeta in Abeta 1–42 induced T-cell activation in Alzheimer’s disease F. Ciccocioppo, P. Lanuti, A. Bascelli, A. R. Gaspari, M. Paludi, L. Velluto, M. Marchisio, D. Genovesi, G. Ausili Cèfaro, S. Miscia, D. Gambi Università G.d’Annunzio (Chieti, I) Objectives: Protein kinases C (PKC) are critical regulators of transmembrane signal transduction in most cell types. [1]. There is considerable evidence demonstrating altered activity of the major isoforms of PKC (PKC-alpha, PKC-delta, PKC-zeta) in the neurons of Alzheimer disease (AD) brains, but little is know about the activity and/or level of the different PKC isoforms

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involved in the intracellular signaling of peripherals T cell in AD [2–3]. The aim of this study is to characterize the different involvement of PKC-alpha, PKC-delta, PKC-zeta, their phosphorylated forms and T cell receptor helper 2 (CRTh2) levels in the events regulating the activation of Abeta1–42-reactive T cells in middle-aged and elderly healthy subjects, and in patients with AD. Methods: The “split-well culture system” [4] and flow cytometry have provided the chance to correlate the behaviour of PKC-alpha, PKC-delta, PKC-zeta and their phosphorylated forms with the expression of CRTh2 or Th2 surface levels [5]. Results: The level of Th2 + cell percentage in elderly healthy subjects before immunization with Abeta1–42 was lower than that from healthy adults while AD patients disclosed a higher level of Th2 cell percentage; further, an expansion of Th2 + subset after Abeta1–42 immunization was evidenced. Measurements of PKC levels after Abeta1–42-specific activation revealed that PKC-alpha levels, PKC-delta and PKC-zeta expression and phosphorylation were significantly modulated in AD T cells compared to T lymphocytes from healthy adults and elderly subjects. Conclusion: These data suggest a possible involvement of different PKC isoforms in the abnormal signalling mechanisms characterizing peripheral T cells in the AD patients. References 1. 2. 3. 4. 5.

Marchisio M, et al. (2005) J Cell Phys 205:32–36 Bard F, et al. (2000) Nat Med 6:916–919 Town T, et al. (2002) J Neuroimmun 132:49–59 Monsonego A, et al. (2003) J Clin Inv 112:415–422 Marchisio M, et al. (2006) Int J Immunopathol Pharmacol (In Press)

P471 Immunological involvement in the pathogenesis of Parkinson’s disease M. Reale, D. Gambi, M. Onofrj, M. Salvatore, A. Thomas, C. Iarlori University G. d ‘Annunzio (Chieti, I); Fao (Rome, I) Objectives: Parkinson disease (PD) is a neurodegenerative disorder characterized by a massive and selective loss of dopaminergic neurons in the substantia nigra. The pathogenesis of neuronal degeneration in PD remain unknows, although the immune reaction-related inflammation may be proposed. Peripheral T cells can infiltrate the blood-brain barrier and may be important for to promote the immune response in the brain parenchyma. Immunological alterations are present in peripheral blood of PD patients in which the cytokine network may be deranged, leading to an altered immunoregulation. To elucidate peripheral immunologic alteration in PD we studied cytokine production in 20 patients with idiopathic PD (10 men and 10 women, the mean age ± SD was 69 ± 7.0 years) and 15 healthy controls, matched to the sex and age. None of the 20 patients had a history of infectious, immune, or any other neurodegenerative disorders. Methods: Heparinized peripheral venous blood samples were collected and Elispot assays was performed to detect the production of a typical Th1 cytokine (IFNgamma) and a typical Th2 cytokine (IL-4). PBMC (2 x 105 cells/well for the IFNgamma and 4 x 105 for the IL-4 Elispot assay) were cultured for 18 h at 37°C and 5 % CO2. For each subject, quadruplicate wells were exposed or not to PHA, plates were read with an automated imaging system and the images were analysed with appropriate computer software (Zeiss, Jena, Germany). Results: Background responses (number of ELISPOTs ± SD) in the absence of stimulation were 42 ± 29 for IFNgamma, 9 ± 0.9 for IL-4 in PD and 36 ± 21 for IFNgamma and 17 ± 7 for IL-4. The IFNgamma and IL-4 Elispot detected a response to PHA in PBMC from patients as well as from control donors. The frequency of cytokine-producing, PHA-stimulated cells was 335 ± 105 for IFNgamma, 26 ± 8 for IL-4 in PD and 240 ± 115 for IFNgamma, 76 ± 13 for IL-4 in HC. Conclusions: The results of our study provide additional evidence that a peripheral immunologic alterations exist in patients with PD. An increased IFNgamma secretion and IL-4 decreased secretion in PD patients (P < 0.05) when compared healthy control, indicates that the peripheral immune system is shifted toward the Th1-type immune response. We hypothized that the immune response in the peripheral blood of PD patients may reflect the immune reaction-associated inflammatory process seen in the brain of patients with PD.

P472 Prevalence of anti-nuclear antibodies and anti-cardiolipin antibodies in patients with ischaemic stroke, cerebral haemorrhage and other neurological diseases T. Afrantou, O. Kanta, A. Angelou, M. Krommyda, E. Sidiropoulou, N. Artemis, M. Paschalidou, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Objectives: To determine the prevalence of autoantibodies-antinuclear (ANA) and anticardiolipin antibodies (aCL)-in patients suffering from acute ischemic stroke, cerebral hemorrhage and other neurological diseases and to evaluate the significance of these antibodies in each of them. Methods: 138 internal stroke patients (mean age 55 yrs) and 156 patients with a variety of neurological disorders (mean age 51 yrs) of the 2nd Neurology Department of AHEPA hospital in Thessaloniki were included in the study. These patients underwent complete immunological control in order to clarify the possible autoimmune background of their disease. ANA were detected by indirect immunofluorescence technique on fixed Hep2 cells. IgG and IgM aCL antibodies were measured using ELISA and they were considered positive if they were ≥ 15 U GPL and ≥ 7 U GPL respectively. Results: Stroke patients: ANA ≥ 1:80 (21 %), IgG aCL positive (2 %), IgM aCL positive (25 %). Cerebral hemorrhage (n = 14): ANA ≥ 1:80 (50 %), IgG aCL positive (7 %), IgM aCL positive (42 %). Other neurological diseases (n = 142): ANA ≥ 1:80 (21 %), IgG aCL positive (2.1 %), IgM aCL positive (40 %). Conclusions: In general, high titers of ANA and aCL are related to systemic immunological disorders, vasculitides and antiphospholipid syndrome which may lead to ischemic episodes. Although the prevalence of ANA in stroke patients did not differ significantly from that in other neurological patients, it is obviously higher than the one observed in general population (2–5 % in subjects younger than 60 yrs). Similarly the presence of positive aCL was not found in a large proportion of the stroke sample in comparison to the other categories of the study. Nevertheless titers of ANA ≥ 1:80 indicate an underlying autoimmune disorder, which cannot be easily interpreted. The detection of high titers of ANA and aCL in patients with cerebral hemorrhage implies a severe autoimmune process, especially if we take into consideration the low mean age of these patients (50 yrs). For the detailed evaluation of the above mentioned results further investigation is needed. P473 Recurrent transverse myelitis – symptom of the smouldering systemic lupus erythematosus R. Opavsky, R. Herzig, P. Kanovsky University Hospital (Olomouc, CZ) Objectives: Transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory and autonomic dysfunction. The estimation of its incidence varies from 1 to 5 per million population. TM can affect people of all ages with peak incidences between the ages of 15 and 35 years of age. Viral and bacterial pathogens are often involved in the pathogenesis of TM. TM can also be an uncommon manifestation of autoimmune diseases: sarcoidosis, Sjögren’s syndrome or systemic lupus erythematosus (SLE). Although TM is usually a monophasic disorder, in some cases its course is recurrent. The evaluation of patients with TM is based on gadolinium enhanced MRI of the spinal cord, examination of CSF and serology. Case report: A case of a young woman with recurrent attacks of TM is presented. The patient had two autoimmune disorders in her previous medical history. Clinical picture of the first attack evolved during 6 days. It consisted of incomplete Brown-Sequard syndrome with ascending right-sided sensory deficit and left sided central hemiparesis with acral maximum. This attack was preceded by respiratory tract infection. MRI of cervical spine revealed intramedullar expansion within C2-C7 segments with heterogenous gadolinium enhancement at the level C4–5 with profound perifocal swelling. CSF showed lymfocyte pleocytosis, elevated protein level and IgG index. Serology examination verified acute infection with Mycoplasma pneumoniae, which can be a potential cause of TM. Further tests showed increased ANA, ds DNA and antinucleosomal antibodies, decreased levels of complement. After thorough examination no other cause of myelitis and no other sign of SLE disclosed. In the next course patient experienced two more attacks of cervical TM with left and then right sided central hemiparesis and different sensory symptoms. Positive laboratory markers of SLE persisted. These attacks appeared after excessive exhaustion and non-compliance in long-term medication (prednisone, azathioprine). There was always a very good effect of intravenous methylprednisolone, oral doxycykline (first attack) and physiotherapy. After 3 years follow-up SLE activity in no other organ system detected.

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Conclusion: SLE is an uncommon cause of TM. TM with a rare recurrent course can be the first sign of the connective tissue disease, which does not meet all the criteria for the diagnosis of SLE. P474 Prevalence of anti-nuclear antibodies, anti-cardiolipin antibodies and antismooth muscle antibodies in inpatients with multiple sclerosis and other neurological disorders A. Angelou, T. Afrantou, O. Kanta, M. Krommyda, E. Sidiropoulou, M. Paschalidou, I. Milonas Aristotle University of Thessaloniki (Thessaloniki, GR) Objectives: To determine the prevalence of autoantibodies-antinuclear (ANA), anticardiolipin (aCL) and antismooth muscle antibodies (ASMA)-in patients suffering from multiple sclerosis (MS) and other neurological diseases and to evaluate a possible role of these antibodies. Methods: 65 MS patients in relapse (mean age 36 yrs) and 107 patients (mean age 51 yrs) with other neurological disorders (degenerative disease (DD), myopathies-neuropathies, CNS tumours) of the 2nd Neurology Department of AHEPA hospital in Thessaloniki were included in the study. These patients underwent complete immunological control in order to clarify the possible significance of the specific rheumatoid autoimmune markers in the background of MS compared to other neurological diseases. ANA were detected by indirect immunofluorescence technique on fixed Hep2 cells. IgG and IgM aCL antibodies were measured using ELISA and were considered positive if they were ≥ 15 U GPL and ≥ 7 U GPL respectively. ASMA were detected by indirect immunofluorescence technique using rat liver, kidney and stomach tissues. Results: MS patients: ANA ≥ 1:80 (21 %), ASMA positive (12 %), IgG aCL positive (0 %), IgM aCL positive (36 %). DD (n = 40, mean age 57yrs): ANA ≥ 1:80 (10 %), ASMA (27 %), IgG aCL positive (0 %), IgM aCL positive (42 %). Myopathies-Neuropathies (n = 54, mean age47): ANA ≥ 1:80 (25 %), ASMA (14 %), IgG aCL positive (1.8 %), IgM aCL positive (38 %). CNS tumors (n = 13, mean age 51): ANA ≥ 1:80 (0 %), ASMA (0 %), IgG aCL positive (0 %), IgM aCL positive (30 %). Conclusions: Patients with MS, myopathies and neuropathies showed elevated titers of ANA in comparison to the general population. The high titers in DD and tumors were observed in a small percentage relatively to MS. Prevelance of aCL was within the normal range in all groups and the antiphospholipid syndrome was not diagnosed in any case. In all disease categories ASMA were frequently detected especially in patients with DD in contrast to their prevelance in normal population (2 %). The presence of autoantibodies in neurological disorders could be accidental, as an epiphenomenon. Nevertheless the absence or low incidence of autoantibodies in non inflammatory conditions like tumors and DD are a matter of concern. Increased titers of ANA in MS and neuromyopathies may result from the inflammatory autoimmune process of these disorders. Moreover, elevated ASMA levels seem to appear more frequently in chronic neurological conditions. P475 Sneddon’s syndrome, marantic endocarditis and lung cancer: a paraneoplastic phenomenon S. Murphy, M. Keogan, M. Farrell, J. Moroney Beaumont Hospital (Dublin, IRL) Objective and Methods: To report the observation that clinical features consistent with Sneddon’s syndrome may suggest a paraneoplastic phenomenon and predate the diagnosis of an underlying malignancy. Sneddon’s syndrome is characterised by stroke with livedo reticularis. The neuropathological mechanism and the best treatment are unknown. Some reports suggest that it is caused by a non-inflammatory arteriopathy of cerebral vessels, while others implicate an associated vasculitis. Diagnosis is based on clinical features, and brain biopsy may be required to look for associated vasculitis.While previous reports have documented the association of atrial myxoma with Sneddon’s syndrome, there has only been one case report of an underlying cancer and the authors proposed a role for vascular proliferation. Results: A 53 year-old woman presented with a major dominant hemispheral stroke syndrome due to infarction in the left middle cerebral artery (MCA) territory. She was a lifelong smoker. Transoesophageal echocardiogram, holter monitor, thrombophilia and vasculitic screens and formal cerebral angiography did not reveal a mechanism. She represented 19 days later with recurrent infarction in the right MCA and posterior cerebral artery territories. She now had an erythematous serpiginous rash typical of localised livedo reticularis and skin biopsy revealed transmural immune complex and

complement deposition. Repeat four-vessel cerebral angiography showed features characteristic of vasculitis. A clinical diagnosis of inflammatory Sneddon’s syndrome was made and she was commenced on treatment with high dose intravenous steroids, pulsed cyclophosphamide and anticoagulation. She deteriorated with recurrent strokes and focal seizures, and died three months after initial presentation. Autopsy showed marantic endocarditis with widespread thromboemboli throughout cerebral, splenic and coronary vessels as well as pulmonary hypertension from recurrent pulmonary emboli. There was also evidence of metastatic adenocarcinoma in a subcarinal lymph node and a small peripheral lung primary was found. Conclusions: Ours is the first report of Sneddon’s syndrome in association with marantic endocarditis. We suggest that the underlying pathophysiology was a paraneoplastic phenomenon due to a combination of marantic endocarditis and an immune complex vasculitis. Aggressive disease course and lack of response to appropriate therapy should suggest an alternative cause of the syndrome. P476 Expression of CD95 molecule on peripheral blood T-lymphocytes in patients with relapsing-remitting, primary and secondary progressive multiple sclerosis Z. Petelin, N. Zurak, V. V. Brinar, D. Milat, M. Golemovic, D. Batinic University of Zagreb (Zagreb, HR); Polyclinic Sunce (Zadar, HR) Objectives: The aim of this study was to analyse the expression of CD95 molecule (cell surface receptor by which the apoptotic process is mediated) on peripheral blood (PB) CD4 + and CD8 + T lymphocytes in patients with relapsing-remitting (RRMS), primary progressive (PPMS) and secondary progressive multiple sclerosis (SPMS), immediately before and after pulse corticosteroid therapy (PCT), and 6 months after the beginning of investigation, when RRMS patients were in the remission. Methods:The prospective study included 50 patients with multiple sclerosis diagnosed by McDonald’s criteria: 27 RRMS patients (4M,23F), age from 20 to 51 years, the average expanded disability status scale (EDSS) 3.24 ± 1.18; 10 PPMS patients (5M,5F), age from 24 to 57 years, the average EDSS 5 ± 1.55;13 SPMS patients (4M,9F), age from 30 to 53 years,the average EDSS 5.62 ± 1.24. PCT consisted of intravenous methylprednisolone 1000 mg/day in 250 ml physiological saline in short infusions during 5 days. The proportions of CD95 + T lymphocyte subsets were analysed by the use of monoclonal antibodies (anti-CD4-PE/Cy5, anti-CD8-FITC and antiCD95-PE, DAKO) and flow cytometry (FACSscan cytometer and CellQuest software, Becton Dickinson). The results were presented by mean ± SD. For statistical analysis Two-way ANOVA for repeated-measures with post hoc Sheffe’s test was used. The p values < 0.05 were considered as statistically significant. Results: The proportion of CD4 + CD95 + T lymphocytes significantly decreased after therapy in RRMS patients (46.91 ± 7.79 vs. 39.5 ± 5.67, p < 0.01), PPMS patients (46.16 ± 5.9 vs. 40.02 ± 7.22, p < 0.01) and SPMS patients (51.26 ± 6.56 vs. 44.68 ± 7.75, p < 0.01). After 6 months the same proportion significantly increased in PPMS patients (40.02 ± 7.22 vs. 46.1 ± 5.95, p < 0.01) and SPMS patients (44.68 ± 7.75 vs. 50.99 ± 6.46, p < 0.01), while in RRMS patients the same proportion further significantly decreased (39.5 ± 5.67 vs 0.36.1 ± 4.62, p < 0.01). The proportion of CD8 + CD95 + T lymphocytes significantly decreased after therapy in RRMS patients (26.71 ± 5.21 vs. 18.89 ± 5.05, p < 0.01) and SPMS patients (21.25 ± 4.35 vs. 17.17 ± 5.83, p < 0.05). After 6 months the same proportion significantly increased only in SPMS patients (17.17 ± 5.83 vs. 21.21 ± 4.59, p < 0.05). Conclusion: The differences in dynamics of stated laboratory parameters, indicators of T lymphocyte apoptosis, point to the different patophysiologic events in RRMS patients compared to the PPMS and SPMS patients. This study is an integral part of the project of the Ministry of Science and Technology of the Republic of Croatia entitled “Apoptosis and neuronal growth factors in multiple sclerosis” (code: 0108296).

Motor neuron disease P477 Familial amyotrophic lateral sclerosis with L126S mutation of Cu/Zn superoxide dismutase gene. Pathological study of two cases K. Inoue, H. Fujimura, K. Toyooka, Y. Yamamoto, S. Sakoda Toneyama National Hospital (Osaka, JP); University of Osaka (Osaka, JP) Background: Previous report of familial amyotrophic lateral sclerosis (FALS) with L126S mutation of superoxide dismutase (SOD1) gene shows

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that mild clinical course, lack of upper motor neuron signs, and formation of Lewy body-like hyaline inclusions (LBHI). On the other hand, there are clinical and pathological variations within/among families of FALS patients with same SOD1 gene mutation. Objectives and Methods: To describe clinical, genetic and pathological features of two patients of FALS with L126S mutation of SOD1 gene. Results: Case 1: A 62-year-old Japanese woman revealed progressive weakness of lower extremities and gait disturbance. At the age of 67 she developed weakness and muscle wasting of upper and lower extremities. Neurological examination revealed quadriparesis and fasciculation while there was no upper motor neuron sign. Nine years later from onset, she showed bulbar palsy and died of respiratory failure at the age of 71. Case 2: The second son of case 1. A 38-years-old man developed muscle weakness and wasting of lower limbs. He showed upper and lower motor neuron signs of bilateral lower extremities. He died of respiratory failure after 8 years illness. They were diagnosed as familial ALS by gene analysis of SOD1 gene. Autopsy was performed on both of two cases. Microscopic examination revealed depletion of the lower motor neuron in the spinal cord and brainstem, associated with mild demyelination of pyramidal tract and posterior column, in both cases. Neuronal loss in the primary motor cortex was mild. Characteristic features were numerous intracytoplasmic hyaline inclusions in the resting motor neurons, which were weakly positive for anti-SMI31, SOD-1, ubiquitin antibodies, and partially positive with Gallyas-Braak stain. Immunohistochemical features of the inclusions were somewhat different between two cases. LBHI presented rarely in both cases. Conclusion: The clinical features of FALS with L126S are onset on lower limbs, and lower motor symptoms predominance. Pathologically, formation of intracytoplasmic hyaline inclusions, mainly observed in the resting motor neurons, was the most prominent feature, while the immunohistochemical characteristics of the inclusions were somewhat different between cases. P478 Involvement of the pyramidal fibres of Onuf ’s nucleus in ALS: a transcranial magnetic stimulation study N. Karandreas, T. Zambelis, P. Piperos, E. Kararizou, P. Kokotis University of Athens (Athens, GR) Objectives: To investigate the extend of involvement of the corticospinal fibers projecting to Onuf ’s nucleus(ON) in patients with amyotrophic lateral sclerosis (ALS)and to compare it to that of the fibers projecting to the contiguous motor neuron pool of the flexor hallucis brevis (FHB) muscle and to the electromyographic findings from the bulbocavernosus (BC) and FHB muscles. Methods: Needle electromyography (EMG) was performed in the above muscles of 26 male patients with definite sporadic form of ALS, without any symptoms indicative of lower urinary tract dysfunction. The electrophysiologically recorded bulbocavernosus reflex (BCR)was also used to investigate the motor and sensory fibers of the pudendal nerves and sacral roots.The corresponding corticospinal fibers were investigated using transcranial magnetic stimulation (TMS). Results: EMG showed severe denervation in the majority of FHB, but only minimal morphological changes of the motor unit potentials (MUAP) of BC in half of the cases and MUAP instability in 4 more patients. Peripheral motor conduction time (PMCT) of FHB was significantly delayed compared to normal values in contrast to that of BC. Conversely, central motor conduction times (CMCT) to FHB and BC did not differ statistically, being abnormal to almost the same degree, 56 % versus 60.9 %, respectively, either in the form of prolonged CMCT or of non-elicited MEPs. Conclusion: Our findings show that corticospinal fibers to ON are involved to the same degree as those projecting to limb muscle motor neurons, despite the lack of overt abnormality of the pelvic musculature. It is postulated that the lack of corresponding symptoms could be due to the relative sparing of the ON neurons and to the fact that micturition and urinary continence per se are controlled by involuntary mechanisms and organized at the level of the homonymous centers of the pons. Our findings are consistent with the hypothesis of a primary corticomotoneuron dysfunction in ALS and a subsequent transneural degeneration of the particularly susceptible to glutamatergic toxicity motor neurons with the exception of those of the external ocular and perineal muscles.

P479 Tau expression in transgenic mouse models of amyotrophic lateral sclerosis and Alzheimer’s disease M. Kuzma, B. Kazmierczak, E. Usarek, B. Gajewska, C. Muench, A. C. Ludolph, A. Baranczyk-Kuzma Medical University of Warsaw (Warsaw, PL); Jewish Hospital (Berlin, D); University of Ulm (Ulm, D) Objective: Tau is a member of microtubule-associated proteins involved in stabilization of microtubules, axonal transport and dendrites outgrowth. Beside classical tauopathies, including fronto-tempotal dementia, Alzheimer’s disease (AD) and progressive supranuclear palsy, the hyperfosforylated tau protein was also found in naurofibrillary tangles of amyotrophic lateral sclerosis of Guam (G-ALS). The aim of this study was to establish the tau expression profile in transgenic mouse models of ALS and AD. Methods: Competitive RT-PCR and Western blotting of tau protein were performed on the brain frontal cortex and cerebellum of symptomatic transgenic B6SJL mice with the ALS associated human SOD1 G93A mutation and the age-matched presymptomatic C57BL/6J transgenic mice expressing human APP751 cDNA with the Swedish double mutation, associated with AD. Age- and genetic background-matched wild type animals were used as controls. Results: The total tau expression on both RNA and protein level was slightly decreased (by 15 %) in the brain cortex of ALS model compared to wild type controls. In the age-matched AD animals the tau protein expression was however 2-fold increased, compared to controls, with only minor differences detected on the RNA level (3.9 and 3.7 respectively). Interestingly, the concentration of the tau protein was found to be 2.5-fold lower in cerebellum of ALS, despite a slight increase in RNA expression (5.6 and 4.0; respectively) when compared to the wild type animals. The tau protein concentration in cerebellum of AD mice was increased by 200 % at the presence of minor decrease in RNA level (1.8 vs 2.2). Conclusion: The study shows that the G93A mutation causes alterations of tau expression in cerebellum. A different mechanism seems to be responsible for tau alterations in ALS and AD, suggesting an impairment of protein translation or increased degradation in ALS, rather than decreased protein cleavage and accumulation observed in AD. The study was supported by the Ministry of Scientific Research and Information Technology of Poland, grant no. K053/P05/2003 and the German Ministry of Science and Technology, Polish-German Cooperation in Neuroscience grant no. 01GZ0313. P480 Erythropoietin is neuroprotective in motor neuronal cells expressing mutated Cu/Zn superoxide dismutase J. Y. Cho, J. K. Park, H. J. Kim, K. W. Lee Ilsan Paik Hospital (Goyang-si, KOR); Seoul National University Hospital (Seoul, KOR) Background: Erythropoietin as a tissue-protective cytokine in addition to its crucial hormonal role in red cell production. Nonerythropoietic actions of erythropoietin include a critical role in the development, maintenance, protection and repair of the nervous system. The purpose of this study is to investigate the possible protective effects of erythropoietin in motor neuronal cell line expressing mutant Cu/Zn superoxide dismutase (SOD-1). Methods: To test the effect of erythropoietin on cell proliferation, erythropoietin was treated in motor neuronal cells expressing wild type (WT) or mutant (G93A) SOD-1 and the viability was determined by 3-(4.5-dimethylthiazol-2-yl)- 2.5-diphenyltetrazolium bromide (MTT) assay. To investigate activation of survival pathway by erythropoietin, each cell groups were co-incubated with phosphatidylinositol 3-kinase (PI3K) inhibitor or mitogen-activated protein kinase (MAPK) inhibitor during the treatment of erythropoietin. To determinate neuroprotective effect of erythropoietin, cells were pre-incubated with erythropoietin, and then treated with exogenous nitric oxide (S-nitrosoglutathione; GSNO) or homocysteine for 24 hours. Bax expression and PARP cleavage were also analyzed. Results: Erythropoietin increased viability of G93A cell lines. Increase of viability by erythropoietin was inhibited by PI3K inhibitor or MAPK inhibitor. In addition, erythropoietin attenuates mutant cell death by GSNO. After treatment of GSNO, increased Bax and PARP cleavages were also decreased by erythropoietin. Conclusions: Our data suggest that erythropoietin may contribute to the reduction of degeneration of motoneuron with the SOD-1 mutation through activation of survival signal pathways or action as an anti-apoptotic agent. Therefore, it may provide a potentially useful treatment in patients with familial amyothrophic lateral sclerosis.

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P481 Melatonin is detrimental to survival in a transgenic mouse model of familial ALS T. Kyriakides, G. Rizki, B. Marquez, A. Hadjisavvas, F. Vonta, S. Malas, K. Kyriacou Cyprus Institute of Neurology and Geneti (Nicosia, CY); University of Cyprus (Nicosia, CY) Objectives: Melatonin is an endogenous neurohormone with well recognized anti oxidant and anti apoptotic properties. In amyotrophic lateral sclerosis (ALS) there is convincing experimental and human data that reactive oxygen species (ROS) and apoptosis are involved in the pathogenesis of disease onset and propagation. Melatonin has been proposed as a candidate compound for neuroprotection in ALS and a high tolerability of the oral drug has been demonstrated in these patients. The aim of the current study was to asses the effect of melatonin on disease phenotype in the G93A transgenic mouse model of ALS. Methods: BS6JL-TgN (SOD1-G93A) carrying the human disease causing G93A Copper/Zinc superoxide dismutase (Cu/Zn SOD) mutation were imported from the Jackson Laboratory and bred under specific pathogen free conditions. Five groups of 10 animals each were used as follows; four groups were injected 0 mg/kg, 0.5 mg/kg, 2.5 mg/kg and 50 mg/kg of melatonin intraperitoneally from age 40 days and the last group fed on water. The end points were disease onset, survival, rotorod performance and morphometry of lumbar cord motor neurons. Results: There was no statistically significant difference in disease onset between the five groups although there was a tendency for the 2.5 mg/kg dose to delay onset. Survival was significantly reduced (P < 0.05, two tailed ttest) with the 0.5 mg/kg and 50 mg/kg and tended to be reduced with the 2.5 mg/kg dose. Conclusion: Melatonin reduces survival in the G93A mouse model of ALS despite its known anti oxidant and anti apoptotic properties. This phenomenon is probably explained by the known effect of melatonin to up regulate gene expression of anti oxidative enzymes, including, in the G93A transgenic mice, the mutated and toxic Cu/Zn SOD. This proved to override any of its beneficial effects of scavenging ROS. Supported by a MDA (Cyprus) Telethon Grant P482 Decreased serum levels of prolyl hydroxylase in amyotrophic lateral sclerosis S. Ono, T. Irie, T. Yamazaki, Y. Nakamura, M. Suzuki Teikyo University School of Medicine (Ichihara, JP) Objectives: Recent studies of skin collagen in amyotrophic lateral sclerosis (ALS) have shown several abnormalities including decreased diameter, increased solubility of collagen, alterations of cross-linking of collagen, and decreased type IV collagen. Prolyl hydroxylase (PH) activity in a number of experimental and clinical states have indicated that this enzyme activity is usually increased in conditions associated with an enhanced rate of collagen formation. The changes in serum PH levels are thought to reflect changes in this enzyme occurring tissues. However, there has been no study concerning serum PH in ALS. Methods: For the measurement of collagen contents of skin, two 3-mm biopsy specimens of skin overlying the left biceps were obtained from 15 ALS patients and 15 diseased control subjects. Approximately 0.5 mg of each sample was hydrolyzed with 6N HCl in vacuo for 24h at 115°C after flushing with N2. An aliquot of the hydrolysates was analyzed for its hydroxyproline content on a liquid chromatograph configured as an amino acid analyzer, using ninhydrin with color development at 135°C. For the measurement of serum PH levels, blood samples were obtained from 28 ALS patients, 20 diseased control subjects and 21 healthy control subjects. Serum PH levels were measured with a sandwich enzyme immunoassay (EIA) kit that uses a mouse monoclonal antibody against the beta subunit of human PH. Results: The collagen content per dry weight of skin in ALS patients (0.77 ± 0.28 nmol/mg) was significantly smaller (p < 0.001) than in diseased control subjects (1.69 ± 0.20 nmol/mg). The collagen content in ALS showed a progressive decrease in relation to duration of illness. This negative correlation was highly significant (r = –0.75, p < 0.01). Serum PH levels were significantly smaller (p < 0.001 and p < 0.001) in ALS patients than in disease and healthy control subjects. There was a significant negative correlation (r = –0.91, p < 0.001) between serum PH levels and duration of illness in ALS patients. In addition, there was a significant positive relationship (r = 0.61, p < 0.02) between serum PH concentrations and the collagen content of skin in ALS patients. Conclusion: These data suggest that decreased serum PH levels reflect decreased collagen content of skin in ALS patients, and that serum PH may

be useful in examining the relationship between the formation and the degradation in skin in ALS. P483 Protective effect of vitamin E and riluzole on glutamate-induced cell death in the NSC34 neuroblastoma x spinal cord cell line J. G. Lim, S. S. Jang, W. K. Baek, B. Lim, D. K. Song Keimyung University (Daegu, KOR) Objectives: Neuroblastoma x spinal cord (NSC) hybrid cell lines resemble developing motor neurons, which are degenerative in amyotrophic lateral sclerosis. Moreover, modification of the growth conditions of NSC-34 by serum depletion promotes the expression of functional glutamate receptors. We have compared antioxidative effect of vitamin E and riluzole on hydrogen peroxide (H2O2-) and glutamate-induced cellular apoptosis with the NSC-34 cell line cultured at serum-containing (10 %) or serum-depleting (0.1 %) media, respectively. Methods: Cell survival was estimated by cell count. The apoptosis was analyzed by FACS analysis. Results: After 30 min treatment of H2O2, drugs were applied 6 h later and then incubated for 48 h, at which cell counting was performed. Cell number was reduced to 40 % of control and cells in sub-G1 phase were greatly increased by 0.5 mM H2O2 compared with cells not exposed to H2O2. However, the reduction of cell number was significantly ameliorated by treatment with vitamin E (200 microM) or riluzole (1 microM) by 20 % and 30 %, respectively. Differentiated cells cultured at serum-free condition exhibited glutamate sensitivity showing that 48 h treatment with 1 mM glutamate cotreated with glycine and cyclothiazide reduced the cell number by 30 %. Vitamin E and riluzole recovered the cell death by 15 %. Conclusion: These results may suggest that vitamin E and riluzole have protective effect to recover cell damage after glutamate-induced oxidative insult in motor neurons. NSC-34 cell line is a good tool to investigate glutamate-induced neurotoxicity. Acknowledgements: Authors thank Professor Neil Cashman for the gift of the NSC-34 cells. P484 Alterations in IGF bioavailability during progression of amyotrophic lateral sclerosis S. Hosback, P. Jakeman, C. Nolan, M. Doyle, O. O’Toole, G. Gorman, C. Lynch, O. Hardiman University of Limerick (Limerick, IRL); University College Dublin (Dublin, IRL); Beaumont Hospital (Dublin, IRL) Objective: To assess whether alterations in Insulin-like Growth Factors (IGFs) and regulatory binding proteins (IGFBPs) occur in Amyotrophic Lateral Sclerosis (ALS); and to assess whether changes in IGF are associated with disease progression as monitored using the Revised ALS Functional Rating Scale (ALSFRS-R). Methods: 28 patients with Definite or Probable ALS and 28 healthy controls individually matched for sex, age (± 3y), and BMI (± 2.5 kg.m-2) were recruited. Blood samples were drawn and ALSFRS-R questionnaire completed at entry to the study and every 3 months for up to 24 months. The concentration (ng/ml) of serum IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and acid-labile subunit was determined by immunoradiometric assay (IRMA). Data was analysed by Student t-test paired sample means. Results: Two contrasting subgroups were identified: a) Surviving patients (SP n = 10) who had disease duration of > 3 years, and remained alive at the end of the study; b) Patients who died during the study, in whom the final IGF sample was taken less 30 days prior to death, termed pre-agonal (PA) patients (n = 11). Surviving patients demonstrated a 36 % (p = 0.032) increase in IGF-I and a 58 % (p = 0.02) reduction in IGFBP-1 compared to controls. Additionally, the IGFTOTAL to IGFBP-3 ratio demonstrated an 18 % (p < 0.009) reduction in IGF binding capacity in SP patients compared to controls. This suggests an increase in IGF bioavailability in SPs. Pre-agonal patients had IGF/IGFBP concentration and binding capacity similar to controls. Conclusions: IGFs promote the survival of motor neurons and support existing neuromuscular junctions. Surviving ALS patients mount a compensatory response to disease by increasing IGF bioavailability, while ALS patients in the pre-agonal stage of the disease lose this ability and IGF bioavailability reverts to normal. IGF bioavailability may be a predictor of survival in ALS. This study was supported by an unrestricted research grant from Serono Pharmaceuticals.

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P485 Diffusion tensor tractography in amyotrophic lateral sclerosis patients E. Pagani, B. Benedetti, D. Caputo, M. Perini, M. Filippi Scientific Institute and University Ospedale San Raffaele (Milan, I); Fondazione Don Gnocchi (Milan, I); Ospedale di Gallarate (Gallarate, I)

CSF analysis and, in addition, confirm the sensitivity and refine the specificity of a positive MRZ reaction for MS. However, though MRZ reaction positivity renders MS likely, a negative MRZ reaction does not rule out the diagnosis of MS.

Objectives: In amyotrophic lateral sclerosis (ALS) the progressive accumulation of severe locomotor disability is the result of a progressive involvement of the pyramidal tracts (PYT). Aim of this work was to assess weather the study of the PYT by diffusion tensor (DT) magnetic resonance imaging (MRI) could provide us with relevant information about the mechanisms underlying disability in this condition. Methods: We studied 14 ALS patients (M/F = 8/6, age: 54 ± 13 years) and 13 healthy volunteers (M/F = 6/7, age: 44 ± 16 years), by deriving indices of mean diffusivity (MD) and fractional anisotropy (FA) from DT-MRI and averaging them over two regions of the PYT, the pons and the mesencephalon up to the internal capsule. The entire PYT was first segmented using a tractography algorithm and then partitioned into the two regions using anatomical landmarks. After normalization into a stereotaxic space, the volume of each PYT region was calculated and included in the analysis as an index of atrophy. The ALS Functional Rating Scale (ALSFRS) evaluating the patient’s degree of functional impairment was also assessed. A Mann-Whitney U non-parametric test was performed to assess differences in MD, FA and volumes of the PYT between patients and controls and the Spearman correlation coefficient was calculated between MRI-derived variables and clinical parameters. Results: Compared to controls, patients had significantly higher MD and lower FA in both regions of the PYT, whereas no significant differences were found in volumes. FA was significantly correlated with ALSFRS (r = 0.63, p = 0.02) in the mesencephalon only and after correcting for age. Conclusions: The approach described here allows the pathological involvement of the PYT to be revealed. The alteration of indices of MD and FA and the normality of the volume of the PYT are likely to reflect a modification of the microscopic structural characteristics compatible with a reduced axonal density and the presence of reactive gliosis.

P487 MRZ reaction is a useful tool in the diagnostic workup of patients with suspected neuromyelitis optica (Devic’s syndrome) S. Jarius, R. Bergamaschi, D. Franciotta, S. Rauer, K. P. Wandinger, H. F. Petereit, M. Mäurer, H. Tumani, B. Wildemann, R. Voltz Ludwig Maximilians University (Munich, D); University of Pavia (Pavia, I); University of Freiburg (Freiburg, D); Charite University Hospital (Berlin, D); University of Cologne (Cologne, D); Julius-Maximilians University (Wurzburg, D); University of Ulm (Ulm, D); University of Heidelberg (Heidelberg, D)

Multiple sclerosis

Background: Neuromyelitis optica (NNO, Devic’s syndrome) is a rare inflammatory demyelinating disorder of the central nervous system. NMO may mimic multiple sclerosis (MS) with regard to clinical presentation, time course, MRI and laboratory findings. In both diseases mild pleocytosis, CSFspecific oligoclonal bands, an increased IgG index, and mild alterations of the blood-CSF barrier may be present, making discrimination by means of CSF analysis difficult. The presence of an intrathecal immune response to neurotropic viruses such as measles, rubella, and varicella zoster virus (MRZ reaction; as seen in about 90 % of MS patients), has not previously been evaluated in NMO patients. Objectives: To assess, whether MRZR is capable of discriminating between MS and NMO. Methods: Twenty NMO and 42 MS patients were included. Antibody levels were quantified by ELISA. The intrathecal synthesis of antibodies to measles, rubella, and varicella zoster were detected by calculation of their respective antibody specificity indices (AI). Results: A positive MRZ reaction as defined by a combination of at least two positive AIs was found in only 1/20 NMO patients, but in 37/42 MS patients. Mean AI values differed significantly between both groups (p < 0.001).A sensitivity of 88 %, a specificity of 95 %, and a positive and negative likelihood ratio of 17.6 and 0.1, respectively, were calculated. Conclusion: Our results facilitate the discrimination of MS and NMO by CSF analysis and, in addition, confirm the sensitivity and refine the specificity of a positive MRZ reaction for MS.

P486 Intrathecal polyspecific immune response against neurotropic viruses discriminates between multiple sclerosis and acute demyelinating encephalomyelitis S. Jarius, D. Franciotta, E. Marchioni, R. Hohlfeld, B. Wildemann, R. Voltz Ludwig Maximilians University (Munich, D); University of Pavia (Pavia, I); University of Heidelberg (Heidelberg, D); University of Cologne (Cologne, D)

P488 Comparing the 2005 and 2001 McDonald criteria for the diagnosis of multiple sclerosis in clinically isolated syndrome patients J. K. Swanton, K. T. M. Fernando, C. M. Dalton, K. A. Miszkiel, A. J. Thompson, G. T. Plant, D. H. Miller Institute of Neurology (London, UK); National Hospital for Neurology and Neurosurgery (London, UK); Moorfields Eye Hospital (London, UK)

Acute demyelinating encephalomyelitis (ADEM) may mimic MS at onset with regard to clinical presentation, MRI and laboratory findings. In both diseases mild pleocytosis, oligoclonal bands, an increased IgG index, and mild alterations of the blood-CSF barrier may be present, making discrimination between MS and ADEM by means of CSF analysis difficult. However, ADEM is usually characterized by a monophasic course, not calling for a sustained immunomodulatory treatment, whereas MS mostly follows a relapsing-remitting course demanding long-term therapy. Moreover, early treatment has been demonstrated to influence significantly the long-term clinical outcome in patients with MS. Early discrimination of ADEM and MS is therefore of utmost importance. The presence of an intrathecal immune response to neurotropic viruses like measles, rubella, and varicella zoster virus (MRZ reaction, MRZR), as seen in about 90 % of MS patients, has not been evaluated in ADEM patients. Objectives: To assess, whether MRZR might be capable of discriminating between MS and ADEM. Methods: 12 ADEM patients (relapse-free follow-up > 3 years) and 42 MS patients were included in our study. Antibody levels were quantified by ELISA. The intrathecal synthesis of antibodies to measles, rubella, and varicella zoster virus was detected by calculation of the respective antibody indices (AI). AI values > 1.5 were considered positive. Results: A positive MRZ reaction as defined by a combination of at least two positive AIs was found in only 1/12 ADEM patients, but in 37/42 MS patients. MRZR was already positive at time of first attack in 9/9 MS patients. Mean AI values differed significantly between both groups (p < 0.001). Based on our data, a sensitivity of 88 %, a specificity of 91 %, and a positive and negative likelihood ratio of 7.6 and 0.1 was calculated. Conclusion: Our results facilitate the discrimination of MS and ADEM by

Aims: The McDonald criteria were introduced in 2001 and allowed multiple sclerosis (MS) to be diagnosed in patients presenting with a clinically isolated syndrome (CIS) characteristic of MS where there was MRI evidence of dissemination in time and space (DIT and DIS) in the absence of clinical evidence. The criteria are highly specific for the development of clinically definite MS but have limited sensitivity. It was noted by Dalton et al. (2003)that the sensitivity could be improved by allowing a new T2 lesion on a follow up scan as evidence of DIT, rather than a Gadolinium-enhancing lesion, without affecting specificity. In 2005 the criteria were modified to this effect, allowing a new T2 lesion on a follow up scan as evidence of DIT as long as the baseline scan had been performed more than 30 days from CIS onset. We set out to assess the performance of the modified criteria in our cohort of CIS patients. Methodology: MRI was performed on 81 prospectively recruited CIS patients (32 male, 49 female, median age at onset 32 years) between 30 days and 3 months of symptom onset and repeated 3 months after the first (T2weighted and gadolinium enhanced T1-weighted brain MRI on both occasions, plus cord at baseline). The patients were followed up for 3 years or until the development of CDMS. The sensitivity, specificity and accuracy of the 2001 and 2005 McDonald criteria were calculated. Results: 65 patients had optic neuritis, 9 brainstem, 6 spinal cord and one optic tract syndrome. 46 % developed CDMS during the 3 year follow up (median time to CDMS 8 months). Both 2001 and 2005 criteria were 93 % specific for the development of CDMS, but the 2005 criteria were more sensitive (59 % compared with 41 %) and therefore more accurate (78 % compared with 69 %). Conclusion: The 2005 criteria are more sensitive than the 2001 criteria but maintain specificity of 93 %.

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The NMR research unit and prospective follow up CIS study is funded by the MS society of Great Britain and Northern Ireland P489 mRNA levels of cytokines, chemokines and chemokine receptors as indicator of treatment response in multiple sclerosis patients treated with interferon-beta 1b A. Cucci, G. Contessa, M. Clerico, P. Barbero, A. Pipieri, B. Ferrero, M. L. Genesia, E. Festa, A. Rovera, A. Tavella, L. Durelli for the OPTIMS Study Group Objective: MS is a putative T helper 1(Th-1) mediated disorder of central nervous system, and cytokines and chemokines produced by these cells appear to be involved in the pathogenesis of the inflammatory demyelination. We quantify the mRNA levels of cytokines, chemokines and chemokine receptors in different group of patients with relapsing remitting (RR) multiple sclerosis (MS) with a different response to treatment. Methods: Quantification of mRNA levels of 23 molecules (Chemokines: CCL3, CCL5, CXCL10, MCP-1; chemokine receptors: CCR1, CCR5, CXCR3; cytokines: IFN-b, IFN-g, IL10, IL12a, IL12b, IL18, IL1-b, IL4, IL5, IL8, TNF-a, TGF-b; IL1- receptor antagonist; MMP9; TIMP1; VLA4) by real time RT-PCR (Taqman, ABI PRISMTM 7900 Sequence detection system) in whole blood of 38 patients with RR MS. Patients with a suboptimal treatment response were defined on the basis of persisting MRI activity on serial MRI scans or by the occurrence of clinical relapses during the first 6 months of interferon(IFN) beta-1b treatment (250 mcg, every other day). Results: Eighteen patients had a good response, without any clinical or MRI sign of disease activity. In suboptimal responders (20 patients), compared to responders, we found, after 3 months of treatment, a significant increase of mRNA levels of both IL18 (p = 0.02) and IFN-g (p = 0.03), CXCL10 (p = 0.05), TNF-a (p = 0.03) and a significant decrease of mRNA level of IL10 (p = 0.05) and TGF-b (p = 0.05). The observed changes persisted thereafter. Conclusion: Only the patients with a good treatment response to IFN beta had decreased level of proinflammatory cytokines and increased level of immunosuppressive cytokines. On the contrary, in patients with a suboptimal response to IFN beta, we observed that the mRNA level of proinflammatory cytokines and chemokines (IL18; IFN-g; TNF-a;CXCL10) increased and that of the immunosuppressive cytokines (IL-10;TGF-b) decreased. Testing mRNA cytokine level during IFN beta treatment may lead to identification of putative peripheral markers of disease activity in MS patients. The study was partially supported by Schering S. p. A., Milano, Italy P490 Balo’s concentric sclerosis: multimodal MRI reveals dynamics of different pathophysiological processes S. Lindquist, N. Bodammer, J. Kaufmann, F. König, H. J. Heinze, W. Brück, M. Sailer Otto-von-Guericke-University (Magdeburg, D); University of Göttingen (Göttingen, D) Defining tools in magnetic resonance imaging, which represent specific changes in tissue pathology, is needed to better understand the complex relationship between inflammation, myelin breakdown, axonal injury and clinical symptoms in multiple sclerosis and its variants. Here, we describe a case of histologically defined multiple sclerosis, in which the radiological appearance of the lesion, the pathological characterization as a demyelinating lesion with apoptosis of oligodendrocytes (pattern III), and the clinical course support the diagnosis of Balo’s concentric sclerosis. Serial magnetic resonance examinations including magnetization transfer, diffusion tensor imaging and 1H-magnetic resonance spectroscopy from 14 days to 13 months after biopsy show that these different magnetic resonance-based parameters have partially non-overlapping pathological correlates. In our case acute changes are not only monitored by T2-weighted imaging, but sensitively traced by early loss of fractional anisotropy and increased lactate in magnetic resonance spectroscopy. Subsequent decrease of the magnetization transfer ratio in combination with the increase of the apparent diffusion coefficient represent the increasing loss of tissue through demyelination and axonal transsection seen in the histological sample. The delay from the peak of symptoms in a dramatic clinical course to the maximum tissue destruction indicated through magnetic resonance imaging suggests that compromise of axonal function due to extensive conduction blocks and edema may be decisive for the acute clinical situation. To our knowledge, this is the first report comparing 1H-magnetic resonance spectroscopy, magnetization transfer and diffusion tensor imaging with histopathology in a patient with Balo’s concentric sclerosis. This work was supported by a Centre of Advanced Imaging award by the BMBF, Germany, to H. J. H.

P491 Efficacy of immunosuppression in relapsing neuromyelitis optica P. Cabre, M. Bonnan, S. Olindo, A. Signate, D. Smadja Pierre Zobda Quitman Hospital (Martinique, F) Objectives: Although immunosuppressants (IS) are recommended in relapsing neuromyelitis optica (RNMO), it’s still unknown whether IS are effective for relapse prevention and disease progression. Only one very small case series reported that 4 of 5 patients with RNMO experienced disease stabilization after mitoxantrone (MTX) therapy. As part of a multicentric RNMO survey in French Antilles (Martinique and Guadaloupe) and French Guyana, we investigated effect of IS in a larger patient sample. Methods: Thirty-three patients (32 women, one men; mean age at onset, 29.5 years) fulfilled diagnostic criteria of RNMO (Wingerchük et al. 1999). Seventeen patients had been treated by IS (IS RNMO group) while 16 patients did not receive any IS (NIS RNMO group). IS RNMO and NIS RNMO groups did not differ in terms of early events of RNMO ie median time from initial symptom to combined optic neuritis and spinal cord involvement, median time from onset to EDSS 3.0, and early attack rate. Disease progression, survival, and relapse rate were evaluated retrospectively. Results: All RNMO patients but one were given IS before they required aid for walking. Mean follow up after initiation of IS was 5 years in the IS RNMO group (range 2–10). IS RNMO group had slower functional deterioration than NIS RNMO group (aid- requiring walking: 3.1 vs 7.0 years, p < 0.0001; bedridden state: 6.9 vs 12.4 years, p = 0.0009) and showed longer survival (11.7 vs 15 years, p = 0.007). In IS RNMO group, mean attack rate declined from 2.4 attack/patient/year to 0.5 attack/patient/year (p = 0.003). Thirteen patients were treated by MTX and 4 patients were treated by cyclophosphamide. In 9 RNMO patients treated by MTX, mean time between initiation of treatment and first relapse was 19.1 months (range 1–61). One patient treated by MTX developed myelolastic acute leukaemia 33 months after first infusion of MTX. Conclusion: Our study shows IS are efficient to alter natural history of RNMO. IS should be given as soon as diagnosis of RNMO is done to prevent early disability an even death. P492 Sample size estimations to detect treatment effects in relapsing-remitting multiple sclerosis based on brain atrophy measurements from serial MRI V. M. Anderson, N. C. Fox, L. Fisniku, G. R. Davies, W. Rashid, D. H. Miller University College London (London, UK) Objective: Brain atrophy measured on serial MRI may be an effective marker of disease progression in multiple sclerosis (MS). Disease-modifying drugs currently available for MS, e. g. beta-interferon, have been shown to decrease the frequency and severity of clinical relapses but their effect on disease progression is unclear. With the advent of potential neuroprotective agents, it is vital that clinical trials using brain atrophy as a marker of progression are of sufficient power to detect treatment effects. Our aim was to evaluate brain atrophy rates on MRI using two methods in relapsing remitting MS (RRMS) subjects over 1 and 2 year intervals, and subsequently estimate and compare sample sizes required to show treatment effects of varying magnitude. Methods: Twenty-four RRMS subjects (19 F:5 M, age 37.1) and 12 controls (5 F: 7 M, age 35.6) had T1-weighted volumetric MRI at baseline and approximately 1 and 2 years later. Brain atrophy was quantified over these periods using the brain boundary shift integral (BBSI) and SIENA. Both methods required registration of serial scans before automatic atrophy quantification. Individual rates were corrected for scan interval and mean (SD) 1 and 2 year rates were determined in controls and RRMS. These values were used to estimate sample sizes assuming a treatment effect of various magnitudes and based on 90 % power to detect a drug effect. Estimates also assumed 10 % subject drop-out and 10 % unusable scans. Results: Mean (SD) atrophy rates over 1 year using SIENA and BBSI respectively were –0.08 % yr-1 and –0.004 % yr-1 in controls and –0.74 % yr-1 and –0.64 % yr-1 in RRMS. BBSI and SIENA yielded similar sample sizes. Over 1 year a drug with an anticipated ability to reduce atrophy rate by 20 % required 471 patients in each treatment arm based on SIENA measurements and 503 based on BBSI measures. A treatment effect of 50 % would require 77 (SIENA) and 82 (BBSI) patients per arm, whilst an 80 % treatment effect would require 31 (SIENA) and 32 (BBSI) per arm. Over 2 years sample sizes were reduced; based on a 20 %, 50 % and 80 % treatment effect respectively sample sizes were 293, 48 and 20 with SIENA and 307, 51 and 20 with BBSI. Conclusion: The method chosen to measure brain atrophy in MS should ideally be sensitive, reproducible and allow treatment effects to be seen in reasonably small samples. This study has shown that two registration-based measures of atrophy provide sample sizes within the context of a traditional phase 3 trial.

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P493 The international development of patient-reported outcome indices for multiple sclerosis L. Doward, S. McKenna, D. Meads, A. Jovell, J. Fisk, B. Eckert Galen Research (Manchester, UK); University Autonoma of Barcelona (Barcelona, E); Dalhousie University (Halifax, CAN); Novartis Pharmaceuticals Corp. (East Hanover, USA) Objectives: To develop patient reported outcome indices for multiple sclerosis (MS) (PRIMUS). The PRIMUS consists of 3 scales; symptoms, activities and quality of life (QoL). Symptoms and activities scales were designed to complement existing clinical measures. The QoL scale assesses overall impact of MS and its treatment on patients. The PRIMUS is being developed in the UK, France, Germany, Italy, Spain, Sweden, USA and Canada (French and English). Methods: Content was derived via qualitative interviews with UK MS patients. Theoretical basis for QoL scale was the needs model. The PRIMUS was assessed by clinical experts to check coverage and field-tested for face & content validity with UK MS patients. The PRIMUS was translated using the dual-panel process. The initial translation was produced by a “professional” panel of people fluent in both source (UK) & target languages. A group of people of average education (lay panel) in the target country ensured that the translations represented everyday language. Only the lay panel was required for US and Canadian English versions. Results: Interview sample: n = 35 (15 males/20 females) aged 31–75 (mean 50; SD 13.2), MS duration 2–58 (mean 17.7; SD 14.2) years. Predominant MS-types: relapsing-remitting (31.4 %), secondary-progressive (28.6 %). Field-test sample: n = 15 (6 males/9 females) aged 32–73 (mean 48; SD 12.9), MS duration 2–41 (mean 14.9; SD 12.3) years Predominant MStypes: relapsing-remitting (40 %), primary-progressive (33.3 %). Key symptoms reported were: fatigue, pain, incontinence and mood problems. Key activity impact related to: physical incapacity, activities of daily living, personal care, social functioning. QoL impact related to intimate and social relationships, self-esteem, loss of identity, personal fulfilment, fear of the future. Draft scales used interviewee’s own words where possible to maximize immediacy. Draft PRIMUS consisted of; symptoms (38-items), activities (20items) and QoL (47-items). Minor changes were made following assessment by clinical experts (2 items removed, 2 added, 2 amended). UK patients found the measure clear & relevant. The scales were successfully translated for all languages. Conclusion: The PRIMUS will allow assessment of effectiveness of MS treatments from the patient’s perspective. The draft scales are currently being assessed for face & content validity in remaining countries. Psychometric and scaling properties for all language versions will then be assessed. This study was funded by Novartis Pharmaceuticals P494 Evaluation of GEMSP effects on the central nervous system of the Lewis 1a rats in a chronic EAE model A. Mangas, R. Coveñas, D. Bodet, M. de Leòn, M. Geffard, M. P. Dabadie Gemacbio, SA (Cenon, F); INCYL (Salamanca, E); ENSCPB-EPHE (Pessac, F) In order to evaluate the effects of a new potential therapy in Multiple Sclerosis, we used a chronic Experimental Autoimmune Encephalomyelitis (EAE) model induced with a mixture of Myelin Oligodendrocyte Protein and Mycobacterium tuberculosis in 10 weeks old Lewis 1A female rats.A potential drug (GEMSP), was constituted of fatty acids linked to poly-lysine (PL), antioxidants linked to PL, scavengers linked to PL and amino acids linked to PL. Experiments were conducted on three groups: 1) rats with an EAE treated with GEMSP (40 mg/kg/day); 2) rats with an EAE treated with NaCl (positive control); 3) rats without EAE (negative control) and treated with NaCl. The three groups were treated under the same conditions; it means that all the groups received two subcutaneous injections per day of 250µl of its respective solutions (six days a week, starting 9 days after induction of EAE). The usual clinical score [0–4] was evaluated six days a week from the first day until the day of perfusion (both included). Crises and the clinical scores were completely abolished by this potential therapy drug (GEMSP). Moreover, indirect immunocytochemical techniques were applied to evaluate leucocyte infiltration and demyelination in the rat CNS of the three groups mentioned above. Thus, the panleucocytic marker CD 45 shows a very large infiltration in the animals perfused belonging to the positive control group in the first crises; but at the end of the experiment (two months later) animals remained with clinical signs but in general no large infiltrations were found,since only some animals of the positive control group presented large infiltrations in some spinal cord levels and in the cerebellum. The anti-Myelin Basic Protein antibodies showed a lower immunoreactivity in the positive control group than in the other two

groups (GEMSP and negative control). Moreover, data reported from histological techniques (Luxol Fast Blue) showed a disorganization in some levels of the spinal cord white matter only in the positive control group. Our studies clearly show that: 1) GEMSP was very active on leucocyte infiltration; 2) GEMSP may be effective on blood brain barrier rendering this less permeable to leucocyte infiltration, decreasing the leucocyte infiltration per se, and could play an immunomodulator role; 3) GEMSP abolish EAE crisis; 4) GEMSP seems to have a myelin protection. 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) (Talance, France). P495 Presence of oligoclonal IgG bands in Sardinians with multiple sclerosis are influenced by carriage of different HLA DRB1-DQB1 haplotypes E. Cocco, C. Sardu, E. Mamusa, R. Murru, J. Frau, L. Lorefice, R. Aste, M. Solla, M. G. Marrosu Centro Sclerosi Multipla (Cagliari, I); Public Health Department (Cagliari, I) Background: Involvement of human leukocyte antigen (HLA) class II alleles in multiple sclerosis (MS) susceptibility has been firmly established, but the contribution of these molecules on phenotype has not been definitively clarified. In Japan has been recently reported an association between HLA DR4 and a subpopulation of MS patients who not presented oligoclonal bands (OCBs) in the CSF at the contrary in the same population DRB1*1501 seemed to increase the presence of OCBs. Similar results have also been obtained in a set of Swedish MS patients. The purpose of this study was to verify the influence of genetic background on the presence of OCBs in Sardinian MS patient. In Sardinia, an insular Italian population characterized by a highly homogeneous genetic background, and very high prevalence of MS, the disease is associated with five DRB1-DQB1 haplotypes, (namely DRB1*0405-DQB1*0301 and DRB1*0301-DQB1*0201, DRB1*1303-DQB1*0301 DRB1*1501-DQB1*0602 and DRB1*0405-DQB1*0302). Methods: A group of 825 (554 women and 271 men) Sardinian MS patients were typed at the DRB1*DQB1 loci, and underwent lumbar puncture for diagnostic purpose. OCBs in the CSF were detected by isoelettrofocusing and immunoblot analysis. Effect of age at onset, MS course and DRB1*DQB1 predisposing and not predisposing haplotypes were evaluated by a multivariate analysis in MS patients grouped on the basis of presence (two or more OCBs) or absence of OCB (one or none OCBs). Results: OCBs were identified in 604 (73.2 %) MS patients, while were absent in 203 (24.6 %) and 18 (2.2 %) exhibited only one band. Multivariate analysis showed no effect of age at onset and MS course on OCBs status, while it was influenced by HLA DRB1*DQB1 carriage, in particular DRB1*1501-DQB1*0602 increased the risk of OCB presence (OR of 3.1; p = 0.034) whereas DRB1*0405-DQB1*0301 conferred a lower risk of OCBs (OR = 0.61; p = 0.028). In conclusion, our results are in line with previous studies performed in other Populations, suggesting that OCBs positive and negative patients are two different MS subtypes,associated with distinct genetic background.Further immunological studies are required to elucidate the observed phenomenon. P496 Delayed effect of age at onset on disability progression in multiple sclerosis E. Cocco, C. Sardu, M. Deriu, P. Solla, E. Mamusa, A. Sirca, J. Frau, L. Lorefice, V. Barletta, P. Contu, M. G. Marrosu Centro Sclerosi Multipla (Cagliari, I); Public Health Department (Cagliari, I) Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system causing high disability in young adults. At the present time,factors conditioning disability risk in each individual are elusive. The most important factor in determining MS severity is the progressive course, while other factors (gender, age at onset, high rate of relapses) have been claimed as severity influencing variables, however, their burden and role on disability has not been definitely clarified. We attempted to validate a model of disability determinants, which take into account major variables (course, age at onset, duration of the disease) influencing disability progression. Methods: Disability was assessed in 207 MS patients, with a disease duration of at least 15 years, utilizing the Expanded Disability Status Score (EDSS) starting from onset and successively every 5 years (at 5, 10 and 15 years from onset). Patients were categorized on the basis of the course in two groups:183 were bout onset (BO) and 24 primary progressive (PP). The joint

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effect on progression of disability of age at onset (considered as continuous variable) and duration of the disease was examined individually for both BO and PP groups using repeated measures ANOVA. Statistical analysis was performed using SPSS software. Results: In the BO group, about the 42 % (p < 0.001) of progression could be explained by disease duration, furthermore an adjunctive 2 % could be due by the significative interaction (p = 0.01) between age at onset and disease duration. EDSS score, for a given year of disease duration, differs between subjects and it is function of age at onset (increasing with age at onset). The EDSS variation increases regularly (0.003, 0.01, 0.03 and 0.04 respectively at onset, at 5, at 10 and at 15 years of diseases duration) and the effect of age at onset achieves a level of significance after 10 years (p = 0.05 at 10 years) of disease duration. Age at onset does not exerts any effect in the PP group and duration of the disease explains the larger part of disability progression. Conclusions: Results of this study support the opinion that age at MS onset could exert a delayed effect on disability progression in BO course of the disease. P497 Hip bone mineral density is correlated with EDSS in patients with multiple sclerosis C. Hotermans, D. Dive, C. Rinkin, M. Leroy, M. Malaise, G. Moonen, N. Franchimont CHU Liège (Liège, B) Objective: Patients with Multiple Sclerosis (MS) have an increased risk of bone loss due to exposure of glucocorticoids (GCs) or other treatments and to lack of mobility. However, the exact relevance of each of these factors on cortical and trabecular bone mass density (BMD) is still poorly documented. Method: In this cross-sectional study, we measured lumbar spine (LS), total hip (H) and femoral neck (FN) BMD in 71 patients, 43 women and 28 men (age ranging from 23 to 77 years; mean ± SD: 43.8 ± 11.9) with relapsing remitting MS. A multiple regression analysis was performed between BMD and BMI (BMI mean ± SD: 23.7 ± 4.85), the EDSS score (EDSS mean ± SD: 4.35 ± 2.09), the use of interferon beta (IFN, 41 % of users), the cumulative doses of GCs (46.5 % had received at least 15 g IV) and the use of GCs (41 % of patients) or not (59 %) during the year preceding BMD measure. All patients who had received GCs had benefited from a supplementation in calcium and vitamin D concomitantly. Results: In the whole population, multiple regression analysis of LS BMD was only correlated with BMI whereas H and FN BMD were correlated positively with BMI and negatively with the EDSS score. No statistically significant correlation was found between LS, H or FN BMD and GCs use or IFN intake. Fifty five percent of the patients had a z-score > –1.0 (i. e. at least 1 SD below age-matched controls) either at the LS, at the H or at the FN. When comparing these group of patients (n = 39) to the group of patients with a zscore > –1 (n = 32), a statistical difference was only observed for the variables BMI (p < 0.0001) and EDSS (p < 0.031). Again, no difference in GCs or IFN use was observed between the 2 groups. Conclusion: These data confirm that MS patients are at risk of bone loss even at a young age. Hip BMD (H and FN) was significantly correlated with the EDSS score, underlining the role of disability and biomechanical loading on cortical bone mass. Conversely, no significant influence of GCs or IFN treatments on trabecular or cortical bone mass was shown in this population. P498 The multifactorial prognostic index: a new compound clinical and CSF index to predict multiple sclerosis evolution J. Mandrioli, P. Sola, R. Bedin, P. Nichelli, E. Merelli Clinica Neurologica (Modena, I) Objectives: The ability to predict the future progression of multiple sclerosis (MS) represents a key issue for the neurologist. The aim of this study was to individuate a multifactorial prognostic index providing the probability of a severe course of MS at diagnosis, based on clinical and immunological CSF parameters. Methods: 64 clinically definite relapsing-remitting MS (38 benign MS, 26 severe MS) followed up for at least 10 years, were included in the study. Clinical and demographic details, EDSS after five and ten years, progression index, relapse number and rate, and time to a second relapse were assessed. CSF and serum samples collected at diagnosis were examined for CSF oligoclonal (OC) IgM and IgG and quantitative IgM and IgG determination. Results: The presence of CSF OCIgM was the most significant prognostic factor for MS course (76.92 % in severe MS, 26.31 % in benign MS,

p = 0.0002). Examining two groups on the basis of the presence or absence of OCIgM, OCIgM + compared to OCIgM- patients showed significantly higher EDSS scores (1.97 vs 2.88 after 5 years, p = 0.0389; 2.26 vs 4.27 after 10 years, p = 0.0004), progression rate (0.20 vs 0.39, p = 0.0016), relapse number (3.29 vs 5.27, p = 0.0250) and relapse rate (0.24 vs 0.40, p = 0.0440). The role of OCIgM as predictors of a MS worse evolution was confirmed also by logistic regression (p = 0.0003). Kaplan-Meier analysis showed that this parameter was the most important factor to reach EDSS 3 (p < 0.001), and the unique significant factor for EDSS 4 (p < 0.001). To improve the accuracy of our prognosis, with the logistic regression we elaborated a multifactorial prognostic index (MPI), composed by the contribution of all the significant prognostic factors available at diagnosis (pyramidal and sensory symptoms, months to the second episode, and OCIgM presence/absence), giving the probability of developing a severe MS course. Conclusion: for the first time we elaborated a MPI, using clinical and biological markers of prognosis to predict the clinical course of MS. This index can support the clinician in patients’ counselling, therapeutic choices, as well as in patients selection criteria for clinical trial. P499 Test-retest reliability of QMA fatigue testing in an Italian cohort M. Robotti, E. Mancinelli, S. Canella, A. Gelfi, V. Torri Clerici, G. Meola University of Milan (Milan, I); Policlinico San Donato (San Donato Milanese, I) Objective: Fatigue is an important and disabling symptom related to multiple sclerosis (MS) and other neurological diseases. Objective quantification of fatigue is still an intriguing question due to its multi factorial nature, and a reliable fatigue index is extremely important to monitor drug or exercise efficacy in clinical practice and in therapeutic trials. Methods: We used computer assisted, quantitative fixed myometry technique, i. e. quantitative muscle assessment (QMA), to measure maximal isometric voluntary contraction (MIVC), static (SF) and dynamic fatigue (DF) in a 20 to 60 years old population of 30 healthy subjects (15 male and 15 female). Fatigue severity scale (FSS), Fatigue impact scale (FIS), Becks depression inventory (BDI) and Epworth sleepiness scale (ESS) were firstly administered to all subjects to confirm the absence of self-reported fatigue and of depression or sleep disorders that can influence fatigue and motor performance. In 2 identical testing session separated by 2 days we tested MIVC and SF during a 30 sec isometric contraction of 6 different dominant and non dominant muscle groups: elbow extensor and flexor, ankle dorsiflexor, knee flexor and extensor and hand grip, where DF was also measured. For each muscle tested, we calculate 2 different fatigue indexes (FI) established in previous studies by Schwid et al. in 1997 and Surakka et al. in 2004 (FI1 and FI2), based on the calculated area under the force versus time curve. Intraclass correlation coefficients (ICC), as estimated from a one-way random effect analysis of variance model was used to test reliability of MIVC, FI1 and FI2. Results: ICC of MIVC were very good varying from 0.84 to0.94. ICC of FI1 were very good in each district, varying from 0.84 to 0.95, as well as for ICC of FI2. No statistically significant difference between dominant and non dominant muscle tested was found for MIVC, FI1 or FI2.ICC of dynamic fatigue was 0.65. MIVC correlate with FI1 of elbow extensor and flexor and hand grip (p > 0.05). Conclusion: QMA is a reliable method to test muscular fatigue,is well tolerated and has a good compliance in all subjects. Thus, could be considered as a useful tool, together with self reported fatigue tests, to objectively quantify fatigue and we should consider to use it in clinical trials to better estimate the different and overlapping components of fatigue. P500 First demyelination and cognition in multiple sclerosis – a descriptive study J. H. Faiss, A. Apel, K. Baum, F. Hoffmann, W. Köhler, A. Kunkel, M. Sailer, D. Schulz, U. K. Zettl Landesklinik Teupitz (Teupitz, D); Universität Rostock (Rostock, D); Oberhavel Kliniken GmbH (Hennigsdorf, D); Städtisches Krankenhaus MarthaMaria (Halle, D); Sächsisches Krankenhaus Hubertusburg (Wermsdorf, D); Otto-von-Guericke-Universitätsklinikum (Magdeburg, D) Objectives: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It is known that cognitive functions are often impaired by MS in the later course of the disease and occur in approximately 50 % of all MS-patients. Domains commonly affected are memory (22–31 %), attention (22–25 %) and executive functions (12–19 %). Only little is known about cognitive deficits in the early course of MS. The aim of

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the present study is to evaluate cognition in a very early stage of the disease and to correlate cognitive functions with measures of magnetic resonance imaging (MRI). At this point we present neuropsychological data on specific patterns of cognitive dysfunction in 30 patients assessed directly after the first clinical presentation. Methods: MS-patients were recruited in MS-centers. We included 30 patients (12 male, 18 female, age M = 28.86 ± 9.00) as defined by the McDonald criteria or with a clinically isolated syndrome (CIS). All were included at the onset of first neurological symptoms and with an Expanded Disability Status Scale (EDSS) lower than 5.0 (Mdn = 1.5, range 0.0–4.5). The neuropsychological assessment was confirmed 90 up to 180 days after the first neurological examination and included tests to measure verbal and figural memory, attention (alertness, divided attention, flexibility) and executive functions. 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 applied. Results: Test scores that declined below two standard deviations of the normative sample were considered to reflect impaired performance. Analysis of the cognitive tests revealed specific deficits: the study-cohort demonstrated in 5–14 % an increased slowed reaction time for simple and focused attention, in 25 % impaired figural learning function and in 14–29 % executive dysfunction as measured by word fluency tasks. Only two patients (10 %) showed evidence of clinical depression in their scores. Intellectual capabilities were not affected (T-norm M = 48.24 ± 5.36). Conclusions: Even at the time of confirmed diagnosis of MS, specific cognitive deficits in the form of reduced speed of information processing, disturbed figural learning function and impaired executive functions can be shown. P501 Detection of the peptides leptin, adiponectin, resistin, and ghrelin in human cerebrospinal fluid: first indication of a pathognomonic role in multiple sclerosis U. Meier, T. O. Kleine, A. M. Gressner, M. Hollenhorst Technical University Aachen (Aachen, D); University Giessen-Marburg (Marburg, D); University Giessen-Marburg (Giessen, D) Objectives: The peptide hormones leptin, adiponectin, resistin, mainly produced by adipocytes, and active ghrelin, produced in stomach cells, have important roles in energy homeostasis of the body, besides other still unknown functions in central nervous system (CNS). They may affect CNS cells by transferring blood-brain barrier (bbb) or blood-CSF barrier via cerebrospinal fluid (CSF), thus regulating processes under normal and diseased conditions in CNS and the body. Therefore, concentrations of the peptides in CSF and blood serum of multiple sclerosis (MS) patients in comparison to controls were studied here to throw new light into pathomechanisms of MS. Methods: Lumbar CSF and serum pairs from 30 MS (Poser’s classification) and 15 control patients with vertigo or headache were assayed for laboratory routine parameters which were in normal range with controls. The human peptide contents were determined with ELISA (sensitivity): leptin (0.5 ng/ml), its soluble receptor (0.4 U/ml), resistin (0.2 ng/ml) from Biovendor, active ghrelin (3.4 pg/ml) from DRG Instruments, adiponectin (0.3 ng/ml) from R&D Systems; coefficients of variation with interassay precision ranged from 4 % to 10 %. Differences between controls and MS values were tested with median test or t-test. Results: Comparing peptide contents, leptin, a satiety hormone, was distinctly lower and its soluble receptor higher in CSF of MS with respect to controls, indicating reduced synthesis in CNS or increased binding in CSF of MS patients, because there were no such differences in blood; adiponectin was higher in CSF with respect to blood, resistin and active ghrelin did not show such large differences. CSF/blood differences of the peptides were not caused by bbb disturbances, because Qalbumin was < 6x10–3 with MS and controls. Conclusion: First evidence for a role of the peptide hormones in CNS, which are mainly synthesized in adipocytes or stomach cells, came from the detection of differing concentrations in lumbar CSF of MS and control patients: leptin and its soluble receptor in CSF may regulate neuroendocrine pathways that regulate sympathetic nervous system activity; adiponectin may inhibit inflammatory pathways in CNS of MS patients. Resistin, also having a possible role in inflammatory processes of CNS and the body, and active ghrelin, which may enhance immune responses in CNS, appeared to be not altered in CSF and serum of MS and controls,indicating balanced axes CNS – body and body – CNS.

P502 A Cochrane review on immunomodulatory treatments in clinically isolated syndromes at risk of converting to multiple sclerosis M. Clerico, M. Tintoré Subirana, J. Palace, G. Rice, F. Faggiano, L. Durelli Universita’ di Torino (Orbassano, I); Vall d’Hebròn University Hospital (Barcelona, E); University of Oxford Radcliffe Infirmary (Oxford, UK); University of Western Ontario (London, CAN); University “A.Avogadro” (Novara, I) Objective: Interferon (IFN) beta (IFN beta 1a or IFN beta 1b) or Glatiramer acetate are the approved immunomodulatory treatment for MS. A Cochrane meta-analysis showed a limited efficacy in reducing disease activity. In all studies treatment started in patients with an established disease often with a long disease history. It is, therefore, important to assess the efficacy of early immunomodulatory treatments in Clinically Isolated Syndromes (CIS) patients in reducing the risk of conversion to clinically defined Multiple Sclerosis (CDMS). Design/method: Inclusion criteria (types of studies, types of participants, type of interventions, types of outcome measures) and the search strategies (medical literature, data bases, abstracts books) followed the Cochrane methodology. Results: 454 papers identified; 430 not eligible; 6 of adequate quality all referred to two studies, CHAMPS and ETOMS, both using once-weekly lowdose IFN beta 1a. Since the two studies had different outcomes (occurrence of a second clinical episode or of disease progression in CHAMPS; occurrence of a second clinical episode in ETOMS) has not been possible to merge data in a metanalysis. The studies have been analysed separately according to both the “per protocol”as well as to the “Intention to Treat” (ITT) analyses. Sensitivity analyses(“best”, “worst” and “likely” scenarios) have been done. Per protocol analyses showed that IFN beta treatment significantly prevented the outcome. Results of CHAMPS study were not stastistically 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 at 1 year; not significant in worst scenario at 2 years. Conclusion: The efficacy of early IFN beta treatment in preventing conversion to MS was modest at 1 year. The efficacy was not confirmed by all analyses at 2 years in one study and it was not possible to conduct a quantitative analysis beyond 1 year in the other. The review provided no firm evidence that once-weekly low-dose IFN beta prevent conversion to MS beyond 1 year.

Neurobiology P503 A novel neuroprotective compound, NNZ-2566, attenuated Caspase 3 activity induced by penetrating ballistic-like brain injury in rats M. Lu, C. Yao, H. Wei, Z. Liao, F. Tortella, J. Dave Walter Reed Army Institute of Research (Silver Spring, USA) Objective: Glypromate is a byproduct cleaved from Insulin-like growth factor-1 (IGF-1) in the brain and is reported to be neuroprotective against hypoxic-ischaemic brain injury in experimental animals. The mechanistic action of Glypromate appears to be independent of IGF-1 because it does not interact with IGF receptors. However, evidence suggests that it inhibits caspase 3 mediated apoptosis and attenuates injury-induced activation of microglial cells. NNZ-2566 is an analogue of Glypromate developed by Neuren Pharmaceuticals Inc. Recently, we tested NNZ-2566 in a newly developed rat model of penetrating ballistic-like brain injury (PBBI) and identified its optimal neuroprotective dose to promote functional recovery and, similar to Glypromate, to attenuate PBBI-induced activation of microglial cells. In this study we further investigated the ability of NNZ-2566 to inhibit caspase 3 activity as a mechanism of its neuroprotection in the rat PBBI model. Method: Experiment I. Each rat received 10 % right frontal PBBI (Williams et al. J. Neurotrauma, 2005). The control rats received craniotomy with or without probe insertion. Brain tissue was collected through the core lesion site at 1, 2, 4, 6, 15, and 24h post injury and analyzed for caspase 3 activity using colorimetric activity assay. Experiment II. In separate groups of animals, immediately after PBBI injury, the rat received either NNZ-2566 treatment at a dose of 3 mg/kg/h i. v. infusion for 4h or equal volume of saline infusion. The brain tissue of each rat was collected at 4h post injury (the time of peak increase in caspase activity after PBBI observed in Experiment I) and analyzed for caspase 3 activity. Results: Compared to sham injury control brains, caspase 3 activity was significantly increased at each time point with a peak elevation of greater

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than 4 fold measured at 4h post injury. Treatment of NNZ-2566 for 4h significantly attenuated the caspase 3 activity by 48 %. Conclusion: Activation of caspase 3 after acute brain injury has been well recognized as a detrimental mediator of apoptosis. Not surprisingly this culprit was also detected in our new rat PBBI model. Although to what extend the activation of caspase 3 is involved in the development of secondary injury after PBBI remains unclear, attenuation of caspase 3 activation by NNZ2566 appears to be consistent with its neuroprotective efficacy observed previously and suggests a mechanistic of action targeting delayed cell death. This study was supported in part by Neuren Pharmaceuticals and USAMRMC P504 3T magnetic resonance imaging of the hypothalamus R. J. Mills, C. A. Young, T. Smith Walton Centre for Neurology and Neurosurgery (Liverpool, UK) The hypothalamus is a small but inordinately important part of the brain. Homeostasis is co-ordinated here by marshalling the autonomic nervous system, endocrine systems and behavioural responses. There is both direct and indirect communication with virtually all other brain areas. It also has a pivotal rôle in modulation of the immune system. Standard, 2D MRI at 1.5T of this structure does not reveal much of its complex anatomy. The objective was to demonstrate the normal anatomy and blood supply of the hypothalamus, in vivo, using high resolution 3D MRI at 3T. Five normal female subjects (age range 42–44yrs) were scanned on a Siemens 3T machine. T2 TSE, T2 FLAIR and T1 IR, 3D sequences of contiguous, 1 mm slices with in plane resolution of up to 0.5 mm by 0.5 mm were obtained, pre and post contrast, and images reconstructed in three orthogonal planes. The images demonstrated clearly the principal white matter tracts in the hypothalamus viz the fornix, mammillary body and mammillothalamic tract. The main hypothalamic arteries were visible including the plexus of vessels within the hypothalamus. The paraventricular and supraoptic nuclei could be assessed on the post contrast scans by virtue of their extremely high capillary density. An understanding of the three dimensional shape of the hypothalamus and its relation to the rest of the diencephalic and mesencephalic anatomy was facilitated by the multiplanar views. Example images are given. To the authors’ knowledge, this is the first, specific demonstration of hypothalamic anatomy, in vivo, using high resolution MRI at 3T. P505 Modulation of dopamine and GABA outflow by glucose reduction is mediated by ATP-sensitive potassium channels in the rat caudate nucleus H. Fuellgraf, M. Steinkamp, M. Kolbe, A. Moser University of Lubeck (Lubeck, D) ATP-sensitive potassium (K(ATP)) channels couple the bioenergetic metabolism of the cell to membrane excitability. They have been demonstrated to play an important role in the release of neurotransmitters in the rat caudate nucleus and the substantia nigra. The main input to the caudate nucleus from the substantia nigra is dopaminergic whereas the efferent output is GABAergic. Dopamine (DA) outflow in the caudate nucleus is known to be modulated by GABA via presynaptic inhibitory GABA(A) receptors. The aim of this study was to examine this functional network at different glucose concentrations. Slices of the rat caudate nucleus were incubated in superfusion chambers and DA and GABA concentrations were measured by HPLC with ECD. The results showed that after glucose reduction from 10 to 7 mM, DA outflow increased to 125 % of basal values, while GABA concentrations decreased from 6.7 ± 2.0 to 3.2 ± 1.6 nM. When the KATP channel blocker glibenclamide (Glb 10 µM) was added to glucose 7 mM, modulations of both DA and GABA outflow were abolished. In conclusion these results demonstrate that in the neuronal network of the rat caudate nucleus reduction of extracellular glucose generates desinhibition of DAergic outflow due to decreased GABAergic activity. Since the K(ATP) channel blocker and sulfonyl urea receptor agonist glibenclamide was able to primarily antagonize glucose effect on GABAergic neurons, these effects imply [1] glucose effects mediated by K(ATP) channels and [2] different types of K(ATP) channels with low ATP affinity on inhibitory GABAergic and high affinity on excitatory DAergic neurons.

P506 The effect of the Na + /K + -ATPase inhibitor ouabain on dopamine outflow in the rat caudate nucleus in vitro H. Fuellgraf, M. Steinkamp, A. Moser University of Lubeck (Lubeck, D) The Na + /K + -ATPase plays an important role in the cell membran potential and function. In this study, we examined the effect of the Na + /K + -ATPase-inhibitor ouabain on dopamine (DA) outflow at different glucose concentrations. We used slices of the rat caudate nucleus, containing afferent dopaminergic neurons from the substantia nigra as the main input. Slices were incubated in superfusion chambers and DA concentrations were measured by HPLC with ECD. Under basal conditions with 10 mM glucose concentration in the superfusion medium (artificial cerebrospinal fluid, aCSF) addition of the Na + /K + -ATPase inhibitor ouabain (10 or 100 µM) did not modulate DA outflow. At 8 mM glucose, DA outflow decreased to 89 % in presence of ouabain (10 or 100 µM) compared to control.When glucose concentration was reduced to 4 mM, addition of 100 µM ouabain induced an increase of DA outflow to 126 %. Under these conditions, DA concentrations in presence of 10 µM ouabain were comparable to control. In conlusion, these results demonstrate that under different glucose concentrations blockade of the Na + /K + -ATPase by ouabain has probably contrary effects on DA outflow, implying that these effects show no direct association between the Na + /K + -ATPase and dopaminergic activity depending from glucose as the main energy and ATP resource. Thus, we suppose further mechanisms that couple the energy state of neurons with their functional activity. P507 Mesenchymal stem cells and 6-hydroxydopamine-induced neuronal lesion: preliminary results of an in vitro and vivo study F. Blandini, E. Zennaro, M. T. Armentero, L. Cova, P. Bossolasco, C. Calzarossa, G. Levandis, D. Soligo, G. Lambertenghi Deliliers, E. Polli, V. Silani IRCCS Fondazione Istituto Neurologico C. Mondino (Pavia, I); IRCCS Istituto Auxologico Italiano (Milan, I); Fondazione Matarelli (Milan, I); Ospedale Maggiore IRCCS (Milan, I) Objectives: The purpose of the study was to verify adult human mesenchymal stem cells (hMSC) potential to support dopamine neurons survival after unilateral intrastriatal 6-hydroxydopamine-induced (6-OHDA) lesion in rats, a procedure that causes a progressive and retrograde degeneration of the nigrostriatal pathway. Methods: Commercial hMSCs were expanded and, after normal karyotype confirmation,were characterized for the expression of stem (as nestin, CD133) and neuro-glial (i. e. GFAP and NFM) genes (by RT-PCR) or proteins (both by Facs or immunochemistry). In addition, we tested the hMSCs behaviour after acute or chronic exposition to two different 6-OHDA concentrations (50 and 320 µM) for 12 days. Several parameters, such as cellular morphology, viability (through Ki67 staining), and apoptosis (by TUNEL analysis) were taken in account. Thereafter male Sprague Dawley rats received a stereotaxic injection of 6-OHDA in the right striatum and, five days later, a Hoechst 33258 labelled hMSCs implant in the same region, both in the presence or absence of immunosuppressive treatment (cyclosporine A). Animals were tested for behavioural response (rotation) to systemic injection of apomorphine and sacrificed 12 or 28 days after 6-OHDA lesion. Immunochemical stainings in combination with FISH analysis defined the proliferation state of endogenous or transplanted cells (Ki67) and the host astroglial/microglial response (GFAP/CD11). Results: In vitro hMSCs characterization revealed stromal specific markers presence in conjunction with a reduced percentage of neuro-glial antigens while no tyrosine hydroxylase or dopamine transporter expressions were detected. 6-OHDA treatment was ineffective on hMSCs proliferation or morphology and no apoptotic features were shown. Our in vivo results showed that hMSCs could be detected along the lesion at both time points, although no overall behaviour improvement could be observed. Endogenous and hMSCs proliferation was concentrated 1 week after transplantation in and around the lesion site while reactive astrogliosis and microglial activation were stably maintained around the implanted area. Conclusion: hMSCs can resist to 6-OHDA insult in vitro, can be maintained and stably integrated in 6-OHDA treated striatum in vivo, even in the absence of immunosuppressive treatment. Our preliminary results demonstrate hMSCs homing capability and sustain their future use for cellular network reconstitution and physical recovery in PD therapy.

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Pain and headache P508 Serum nerve growth factor levels are increased in acute complex regional pain syndrome S. Leis, R. Hellweg, P. Hasbak, F. Birklein University of Erlangen-Nuremberg (Erlangen, D); Charite University of Berlin (Berlin, D); Hvidovre Hospital, University of Copenhagen (Hvidovre, DK); University of Mainz (Mainz, D) Objectives: Complex regional pain syndrome (CRPS) is characterized by oedema, increased skin temperature, skin reddening and pain or hyperalgesia. In acute CRPS facilitated neurogenic inflammation with the release of neuropeptides such as calcitonin gene-related peptide (CGRP) was shown. The neurotrophin nerve growth factor (NGF) is involved in the regulation of neuropeptide synthesis and inflammatory pain. The aim of this study was to further investigate the contribution of neuropeptides to the pathophysiology of CRPS. Methods: In addition to physical examination, NGF concentrations in blood sera drawn from the cubital vein were measured using a fluorometric enzyme immunoassay in 25 patients with acute CRPS (14 female, 52.7 ± 1.9 years) and in 24 age and sex matched healthy controls (13 female, 52.0 ± 2.7 years). Besides, serum CGRP concentrations were measured using a radioimmunoassay in 12 of these patients. Results: NGF levels were significantly increased in CRPS patients (116.9 ± 33.0 pg/ml; controls 38.5 ± 3.7 pg/ml; p < 0.03, unpaired t-test) and increased NGF levels were correlated to CGRP levels (r = 0.55, p < 0.05, Pearson’s correlation). However, no correlation was found to CRPS type, duration of symptoms and clinical signs like oedema, increased skin temperature, skin reddening and spontaneous pain (German McGill pain questionnaire) or hyperalgesia. Conclusion: Our results of increased systemic NGF levels in patients with acute CRPS and the correlation to CGRP levels confirm a pivotal role of neuropeptide release and neurogenic inflammation as one pathophysiologic mechanism in acute CRPS. This study was supported by the German Research Foundation (DFG, SFB353), the ELAN Fund of the University of Erlangen-Nuremberg and the Johannes and Frieda Marohn-Foundation. P509 Headache prevalence among medical students in a Kaunas medical university A. Vaitkus, K. Petrikonis, J. Janusauskaite, L. Paulauskaite Kaunas University of Medicine (Kaunas, LT) Objectives: To perform a descriptive epidemiological study of headache among medical students at Kaunas Medical University. Methods: Random student sample was asked to fill in the unique questionnaire, designed according to the International Headache Society (IHS) criteria. Demographic data, lifetime headache characteristics, coexistent complaints, patterns, concerning work productivity loss, family headache history, susceptibility to stress, means of coping with pain were evaluated. Results: The questionnaire was completed by 250 students, 80 % female and 20 % male. Medium age of respondents was 21.9. 90.8 % of respondents complained of headache, 67.8 % of them stated having it more often than once a month. The estimated prevalence of migraine and TTH was 15.9 % and 61.2 %, respectively. No significant differences in headache prevalence were estimated between sexes. 77.1 % of headache sufferers used medication in order to relieve pain. 22.3 % of those suffering headache noted to have consulted doctor and 3.1 % of them had been hospitalised because of headache. Consultation rates (p < 0.001) and medication usage (p = 0.046) were significantly higher in migraineurs than in TTH sufferers. 30.8 % of respondents pointed their headache to interfere with work productivity. Median count of days per year with reduced productivity due to headache was 2, with significant difference in those suffering from migraine and TTH (15 vs. 1, p = 0.02). Respondents, who noted to be undergoing stress every day, were more likely to have daily headaches (p = 0.039).A significant correlation was found to link migraine with the frequency of stress. Migraine type of headache was more prevalent among students, suffering stress every day (p = 0.001). The most conspicuous provoking factors were alterations in normal sleep regimen (85 %), physical or emotional exertion (43.6 %), insufficient nutrition (36.6 %) and alcohol (33.9 %). Conclusions: The study reveals that headache is highly prevalent among medical students of Kaunas Medical University. Analgesic overuse is likely in this population as most of the students choose this way of coping with

pain while doctor consultations are not commonly chosen. The study confirms the profound impact of headache (especially migraine) on students’ daily performance. The most conspicuous provocative factors for headache in this population appear to be alterations in sleep regimen and stress which both can hardly be avoided in medical studies. P510 Migraine prevention: a cross-sectional survey in Thai neurologists K. Phanthumchinda, K. Wongjaima, W. Dandamrongrak for the Headache Study Group, Neurological Association of Thailand Objectives: Migraine is a chronic disabling and possible a progressive disease. Preventive consideration is crucial for migraine management.As a prelude to developing migraine education among Thai neurologists, current status of migraine prevention is very important. A cross-sectional survey probing migraine prevention patterns was performed. Methods: A cross-sectional survey was performed. Participants were practicing neurologists recruited from an academic neurological meeting. Self administrated questionnaires were developed to assess baseline data of the neurologists and their patients, previous treatments from general practitioners (GPs) and strategies of migraine preventions. Results: 80 neurologists participated in this survey and the average duration of their practice was 9.0 years. 68.2 % of migraineurs in neurologic clinics were referred cases from GPs. Patients’ age ranged from 21–40 years in 63.4 %. Male:Female ratio was 1:3. Only 59.8 % of Migraineurs were correctly diagnosed by GPs. 60.6 % of migraineurs received only acute symptomatic treatments from their GPs and 40.1 % of patients were suspected to have drug-abused headache. 59.9 % of cases did not receive appropriate preventive medications from their GPs. 75.9 % of migraineurs in neurologic clinics fulfilled indications for migraine prophylaxis. The most common indications for prophylaxis were headache frequency, acute treatment failure, contraindications for acute treatments, drug-abused headache, chronic migraine, uncommon migraine and impact on activity of daily living. The obstacles for prevention were adverse drug reactions, drug interactions, economical problems and poor compliance. Prophylactic medications were calcium channel blockers 21 %, Beta-blockers 19 %, tricyclic antidepressants 19 %, topiramate 16 %, sodium valproate 14 %, gabapentin 4 % and others 7 %. Conclusion: Migraine was underdiagnosed and migraine prophylaxis was underused among GPs. A significant number of patients had drugabused headache. Thai neurologists considered prophylactic treatment in most of migraine sufferers. Anticonvulsants were increasingly used among Thai neurologists. This survey study was funded by Janssen-Cilag Thailand P511 Late-onset migraine with aura secondary to meningioma A. Villarejo, A. Camacho, R. García-Ramos, A. Martínez-Salio, T. MorenoRamos Hospital Universitario Doce de Octubre (Madrid, E); Hospital La Moraleja (Madrid, E) Introduction: Some patients who seem to have a primary headache may have a secondary origin. It is important to know when to suspect these cases. On the other hand, secondary cases help us to understand the pathophysiology of headaches. Case reports: Case 1.A 40 year-old woman, with a 20 year history of sporadic right-side migraine without aura (3–4/month). In the last two years, she felt visual and sensory disturbances 15–30 minutes before headache onset. They started with photopsia and then paresthesias in the left face that gradually spread to left hand, arm and leg. Neurological examination disclosed a mild left central facial palsy. A brain MRI showed a large frontoparietal mass with homogeneous contrast enhancement.After complete resection, histological diagnosis revealed a highly differenciated meningioma. Seven moths after the operation, she has had no migraine attacks or aura symptoms. Case 2. A 45 year-old woman with a long history of migraine without aura, started to experience photopsias and cloudy vision that slowly progressed to blindness and disappeared in 30–45 minutes to be followed by one of her typical migraines. Rizatriptan relieved the pain. On neurological examination she had a left inferior homonymous hemianopia. A brain MRI showed a right parieto-occipital tumour that was surgically removed, with the histological diagnosis of fibroblastic meningioma. One year after surgery the patients is migraine free, but the visual field defect persists. Conclusions: Our cases fulfilled IHS diagnosis criteria for migraine with aura, but had several characteristics of a symptomatic origin: side-locked migraine, late-onset auras and neurological signs on examination. The as-

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sociation with meningioma, previously reported, is supported by aura type and disappearance of attacks after surgery. The pathophysiology of episodic migraine in these cases is unclear. P512 The efficacy and tolerability of cinnarizine in migraine prophylaxis M. Togha, M. Rahmat, K. Nilavari, H. Ashrafian Tehran University of Medical Scienses (Tehran, IR) Objectives: Calcium-antagonists (CA) are heterogeneous group of drugs with different efficacy in migraine prophylaxis. Several studies have firmly demonstrated flunarizine (FLU), and verapamil as the proven calcium-antagonists for migraine prophylaxis. Cinnarizine (CIN), is not only a Calcium-antagonist with less complications but also with antihistaminic action. There is very few studies to show the effect of this drug on migraine. The current study evaluates the efficacy and safety of Cinnarizine on migraine in comparison to Sodium Valproate, an acceptable drug in migraine prophylaxis. Methods: The current study is a randomized double blind clinical trial on 132 participants with intractable migraine headache. The patients who had experienced three or more severe attacks per month with history of inadequate response to beta blockers and tricyclic antidepressants were eligible for the study and received either daily 75 mg Cinnarizine or 600 mg Sodium Valproate blindly. We evaluated the effect and complications of Cinnarizine in comparison to Sodium valproate during 14 weeks of study via 4 times out patient visits. The data was collected and analyzed by SPSS software. Results: The mean age of cases was 34 ± 11 years. Both groups of patients, who were on Sodium Valproate and those on Cinnarizine, showed significant improvement in headache attacks frequency, duration and severity. There was no significant difference between mean decrease headache frequency in two groups, 61 % in Cinnarizine group and 51 % in Sodium Valproate users. Mean severity of headache attacks decreased by 47 % in Cinnarizine users, in compare with 32 % in valproate group (p = 0.034). Although Cinnarizine was more effective in mean decrease attack duration, no significant difference was noted between two groups. No significant difference was detected in drug’s complication led to discontinuation of treatment, 3 % in Cinnarizine group in respect to 5.2 % in valproate users. Conclusion: Cinnarizine as Sodium valproate is an effective and safe drug in migraine prophylaxis even in intractable headache. P513 Management of nontraumatic headache in the emergency department: a survey in an Italian province G. Relja, A. Granato, Z. Bisin, G. Nider, M. Zorzon, M. Catalan, C. Maggiore, G. Pizzolato University of Trieste (Trieste, I) Background: Nontraumatic headache (NTH) is one of the most frequent presenting symptom to the Emergency Department (ED), accounting for 0.6–4.5 % of all visits. Guidelines for therapy of headache in the ED setting are lacking. Objective: To study the therapies employed in patients (P) presenting to the ED with a chief compliant of headache in order to provide therapeutic guidelines to ED physicians and improve the cost-to-benefit management of such patients. Methods: A retrospective analysis of the records of all P presenting in a six-month period (01. 01. 2004–30. 06. 2004) with nontraumatic headache (NTH) to the ED of the University Hospital of Trieste was performed. Demographic and clinical information, therapies administered, time spent in ED were obtained. The data were processed and analysed using the Statistical Package for the Social Sciences (SPSS 12.0). Results: Of 38238 P screened, 300 (0.8 %) presented with NTH, 61 % F and 39 % M with a mean age of 45 (SD 19) years. P were classified as having secondary headache, 41.3 %, primary headache, 24.3 %, and headache of no obvious source (NOS),34.4 %.56.6 % of P were treated with mono- or poli-therapy (56.7 % with NSAIDs, 13.4 % with benzodiazepines, 10.7 % with antiemetics, 6.2 % with antihypertensives, 1.5 % with triptans, and 11.5 % with other drugs). 40 of 50 P with migraine, received pharmacologic treatment, 90 % with NSAIDs and 10 % with triptans. The mean time spent in ED was 225 [SD 285] minutes, without differences between primary, secondary and NOS headaches. A significant difference in the length of stay in the ED between migraineurs to whom triptans were administered (112 minutes [SD 25]) and migraineurs treated with NSAIDs (265 minutes [SD 282], p = 0.02) was found. Conclusions: The frequency of patients with NTH presenting to the ED was similar to other studies. Most used drugs were NSAIDs, first of all ke-

torolac and indometacin. The administration of triptans in patients with migraine significantly reduced the length of stay in ED. Patients in which triptans were used did not need other drugs. Notwithstanding this, only 10 % of migraineurs received triptans, despite the recommendation to use triptans as first-line drugs for moderate and severe migraine attacks. Only 33 % of patients with cluster headache received sumatriptan. Guidelines to the ED physicians are needed to improve diagnostic specificity and therapeutic interventions. P514 Plane landing headache H. D’Onofrio, H. Videla, J. Maegli Deutsches Hospital (C Madero, RA); Borda Hospital (Cap Federal, RA); Pinero Hospital (Cap Federal, RA) Objective: To describe a form of crash repeated primary headache (PH), with paroxysmal onset during landing of plane flight. Background: Several trigger factors (TF) have been reported associated to known PH but plane landing repeatedly acting as TF during the debut of severe or complicated PH, in patients with no headache history does not conforms to usual descriptions. Design/Methods: 4 patients (3 M, 32–48 y.o,) (1 F, 52 y.o) evaluated between 1998–2005 reported episodes of crash hemicrania with sharp and stabbing quality specially severe behind the orbit beginning during plane landing maneuver (cabin altitude lower than 3000 ft.).Sensory or autonomic symptoms/signs were not associated. Episodes lasted 3–5 hours. No prior headache history was reported. Results: Evaluations and images performed in male patients showed normal results. The woman was assisted after the 3rd headache episode appearing during flight plane landings. No focal deficits were found but she had developed excessive mystic ideas in her speech and behavior disorder. Her brain MRI showed a deep infarction (left middle cerebral artery topography). AngioMRI, CSF, laboratory, and cardiologic tests were normal. No other than tobacco smoking risk factor for cerebrovascular disease was found. No new data appeared in her follow up. Neither Cluster headache or Migraine could be diagnosed in these patients because INH diagnosis criterions were not fulfilled. Trigger factors such as changes in blood viscosity, plane cabin pressurization and head position, abrupt fluid shifts in vascular and extravascular spaces, exposure to low cabin air quality, body acceleration/deceleration, can be considered as source of head pain and brain infarction. Conclusions/Relevance: Primary headache only provoked by plane landing is unusual.More unusual is repeated severe headache that begins during plane landing presenting as a complicated one.The workup should include images to exclude organic disorders. Trigger factors for air travel headache may be shared by different known headache phenotypes but these stressors affected these described patients with no need of prior symptoms that point to the existence of a known underlying phenotype. P515 Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders S. Santos, E. Lopez, J. López del Val, L. F. Pascual, G. Piñol, C. Pérez, C. Iñiguez University Clinical Hospital Lozano Ble (Zaragoza, E) Background: Prophylactic treatments of migraine and chronic daily headache are far from satisfactory because of lack of good efficacy, side effects and drugs interactions. Botulinum toxin type A (BTX-A) is an emerging treatment for such patients whose headaches are poorly controlled with currently prophylactic pharmacotherapy. Patients and methods: This is a retrospective review of all patients who received BTX-A for the treatment of headache during the last two years. Patients were injected 100 U of BTX-A into multiple sites of pericranial muscles. The primary outcomes were the reduction in headache days HD one and three months following injection. Patients were diagnosed according to IHS criteria and classified into these categories: chronic daily headache (CDH; more than 15 headache days per month) and episodic migraine (EM). Results: The mean age of the 19 patients studied was 43.63 years (SD, 9.55); 15 patients (78.9 %) were women. CDH (100 % with acute overuse medication) accounted for 12 patients (63.2 %) while EM was present in 7 patients (36.8 %). BTX-A treatment significantly reduced the number of HD per month from 18.68 (SD, 10.04) to 10.42 (first month; SD, 7.82; p = 0.002), to 11.16 (third month; SD, 8.74; p = 0.007). That means a 44.2 % and 40.2 % of reduction respectively. Significant reduction in HD frequency was also observed in the CDH-group from 24.75 (SD,7.26) to 13.08 (first month,SD,8.65; p = 0.003) to 14.17 (third month; SD, 9.72; p = 0.014). That means a 47.15 %

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and a 42.74 % of reduction respectively. In the EM-group the improvement was not significant. No adverse events were reported. Conclusions: These results suggest that BTX-A may be an effective and safe prophylactic treatment for a variety of moderate to severe chronic headache types.

P518 Do migraine patients have cognitive dysfunction? Evaluation by detailed neuropsychological tests G. Acar, L. S. Bir, T. Çabuk, F. Özdemir Esmeli Pamukkale University Faculty of Medicine (Denizli, TR)

Background: Pattern-reversal visual evoked potentials (PRVEPs) in migraine showed variable results, but Flash visual evoked potentials (FVEPs) in migraine showed usually in the increased amplitude. We have tried to ascertain whether the amplitude of FVEPs increase and the other abnormality of FVEP present. Methods: FVEPs were recorded in 25 patients with migraine with aura, 23 patients with migraine without aura during interictal period without specific medications associated with migaine and 48 normal subjects. The migraine groups consisted of 11 men and 14 women in migraine with aura patients aged 20 to 71 years (mean age; 49 years), and 12men and 11 women in migraine without aura patients aged 27 to 70 years (mean age; 57 years). The normal control group consisted of 23 men and 25 women in healthy volunteers aged 28 to 71 years (mean age; 54 years) Results: The amplitude of FVEPs in migraine showed significant increase (p < 0.001) compared to normal subject, and only A1(N1-P1) amplitude in migraine without aura showed significant increase (P < 0.05) compared to migraine with aura. Conclusion: The increased amplitude of FVEPs compared to PRVEPs results in other study suggest that migraine brain is more excitable in flash stimulation associated Y-system than pattern stimulation associated with Xsystem.These findings are explained by specific cortical distribution of serotonin and noradrenaline in X,Y-system of the visual cortex.

Objective: The current literature addressing the neuropsychological consequences of migraine has been far from to be conclusive and the reports of cognitive testing in adult migraineurs and controls have yielded inconsistent results. Therefore, this study was designed to determine the neuropsychological alterations in migraine patients by comparing age, sex and educational level matched headache free control subjects. Methods: The participants were 30 patients with migraine and 30 age, sex and educational level matched healty induviduals. Patients with other systemic disease, substance abuse, learning disability, central nervous system disease and depression were not included to the study. Neuropsychological tests included Verbal Memory Processing Test, Wisconsin Card Sorting Test, Wechsler Memory Scale-Revised and its visual reproduction sub-category, Trail Making Test, Stroop test. Parametric data obtained from different neuropsychological tests were compared between groups by student t test. Mann-Whitney test was used in order to compare the data of two subgroups of migraine (with and without aura). Results: The results revealed that there was no statistically meaningful difference in cognitive performance between migraineurs and normal controls in majority of the tests, but the scores of long term memory of visual reproduction sub-category of Wechsler memory scale (p = 0.001), Stroop reading (p = 0.01), conceptual responses (p = 0.034) and number of cathegories (p = 0.011) in Wisconsin Card Sorting Test were worse in migraine patients. No significant difference was found between patients with and without aura in none of the tests. Conclusion: Our results are important in confirming the general concept of subtle cognitive impairment limited to specific areas in migraine.We suggest that neuropsychological tests of visual perceptual processing should be included in subsequent studies.

P517 Treatment of migraine associated with medication overuse E. Nikolakaki, N. Kouroumalos, E. Kalamafkianaki, V. Christoforakis, G. Georgakakis General Hospital of Chania (Chania, GR)

P519 Spontaneous intracranial hypoptension with cerebral sinus venus thrombosis: a case report O. Kanta, J. Harushukuri, D. Karakostas, N. Taskos, I. Milonas AHEPA Hospital (Thessaloniki, GR)

Objectives: A great proportion of patients visiting headache special practices suffer from chronic daily headache (CDH) associated with medication overuse (MO). Some of those patients were initially suffering from migraine attacks of variable frequency, which over time, due to MO, gave rise to CDH. According to International Headache Society’s classification of 1988, headache should be present for more than 15 days a month for a period of at least 6 months. Methods: In a retrospective study of the files of patients being followed up at the headache special practice of the General Hospital of Chania, we examined the files of those suffering from migraine associated with MO (n = 38). The patients were divided into three groups according to the medication administered to treat their CDH: one composed of patients treated with Tricyclic Antidepressants (TCAs), another one made of patients treated with Serotonin Specific Reuptake Inhibitors (SSRIs), and a third one consisting of those treated with specific anti-migraine medication (such as Bblockers or calcium- channel blockers). More specifically: 9 patients were given only amitriptyline, 5 patients amitriptyline and SSRIs, 9 patients only SSRIs and 15 patients took specific anti-migraine medication (β-blockers or calcium- channel blockers). Furthermore, the response to treatment between the three groups was compared. Results: Using the criterion of general improvement, this being relief from CDH as well as interruption of MO, we found that there was no significant difference between the three different groups with respect to the number of patients who were successfully treated from CDH. The number of responders was almost the same among those treated with either TCAs, SSRIs or specific anti-migraine medication (β-blockers or calcium-channel blockers). Conclusion: The problem of CDH associated with MO seems of great importance although results arising from different special headache practices range from 20 % to 73 %. TCAs, SSRIs, β-blockers as well as calcium-channel blockers, are all medication used in the treatment of CDH. Among those, none was found in our study to be of greater efficacy when compared to the others with respect to patients’ response. In bibliography, some studies show SSRIs to be more effective than TCAs in the management of CDH with the exact reason for this being unknown, whereas others show no difference in the efficacy of either category.

Background: Intracranial hypotension is determined by a cerebrospinal fluid (CSF) pressure of 60 mm H2O or less. The main symptom is postural headache, which may be associated with other symptoms, such as nausea, vomiting and dizziness, tinnitus, hearing distortion, neck pain, horizontal diplopia, blurred vision, and visual field defects. SIH may be complicated by persistence of headache, subdural hemorrhage and, rarely, cerebral sinus thrombosis (CST). Methods: A 42-year-old male with hypercholesterolemia was admitted to our clinic, complaining of postural headache, nausea and horizontal diplopia that had begun 20 days before. Physical and neurological examination was completely normal. Results: MRI of the brain showed diffuse thickening of the pachymeninx with gadolinium enhancement. CSF pressure was 20 mm H2O. Analysis of the CSF showed increased protein concentration, normal glucose levels and 0–1 cells. Spinal MR imaging was normal. A few days after his admission, his headache became permanent and lost its orthostatic component. The patient presented a grand mal seizure. Brain CT showed scattered small hemorrhages. Brain MRI and MR cerebral venography revealed a thrombosis in the upper saggital sinus. Complementary screening studies for infections, immunological, hematological, neoplastic or systemic disorders did not disclose any conventional cause of CSVT. Intravenous heparin was started, followed by oral anti-coagulation. The headache improved and the patient remains without any other symptoms. Conclusion: Our patient had a typical intracranial hypotension syndrome and a month later developed CSVT without any apparent cause. Based on the pathophysiology of SIH, it could be possible that SIH causes an extreme ingurgitation and stasis of the dural venous system leading to thrombosis. Few cases have been reported in the literature with CSVT after spinal tap, myelograghy or epidural injection, supporting this theoretical possibility. Most of them had contributing risk factors, including a hypercoagulate state. Only 4 case reports describe CSVT after spontaneous CSF leaks and 2 of them were without any apparent cause.

P516 Flash visual-evoked potentials in migraine patient J. H. Han, D. E. Kim Seoul Veterans Hospital (Seoul, KOR)

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P520 Radicular leg pain: deep or superficial pain causes worse function? K. Petrikonis, A. Sciupokas, A. Vaitkus, L. Malciene, R. Balnyte University Hospital of Kaunas University (Kaunas, LT) Background: typically, patients with radicular pain due to lumbar disc herniation or stenosis will present with a shooting, lancinating or electric quality pain radiating below the knee. The pain is dermatomal and localized, “band-like”, whereas referred pain typically is a dull, deep ache or pressure like. Radicular leg pain (RLG) and referred pain are not mutually exclusive. They can co-exist. Failure to distinguish referred from radicular pain is still persisting pitfalls in everyday neurological practice. Superficial and deep pain determines different pain matrix activation and particular influence to function of the patient. Objective: the current study sought to identify clinical utility of RLP parameters and correlation with subjectively reported functional capacity. Methods: 196, 52 % male and 48 % female patients, mean age 44.6 ± 11.6 year with radiologicaly identified specific degenerative spinal etiology of RLG and clinically confirmed lumbosacral radiculopathy participated in the study. 120 patients had acute (till 3 month) and 76 chronic (above 3 month) course of disease. We evaluated the intensity and pain quality in the leg using Neuropathic pain scale (NPS), disability due to leg pain with modified version of Roland-Moriss questionnaire (RMQ). Results: pain intensity scores for acute and chronic RLP were respectively 5.54 ± 2, 48 and 5.99 ± 2, 18 (p = 0.224). Ratings of sharp, hot, cold, itch and deep pain qualities were significantly higher in chronic pain group. Factorial (principal component) analysis of NPS divided acute RLP into deep, superficial and dull (included 65.6 % of variance) but in chronic stage RLP was deep and superficial (59.8 % of variance). RMQ value 12 ± 6, 1 (max 24) in chronic pain stage against 9.76 ± 5.8 in acute pain indicate consistent worse disability of foremost due to leg pain (p < 0.01). Strongest deep leg pain had significant correlation with higher value of RMQ disability score (r = 0.513, p < 0.001), but superficial leg pain intensity had moderate connection with RMQ (r = 0.337, p < 0.001. Conclusions: the prominence of deep pain component in RLP is useful clinical symptom with leaning to chronification and worse function comparing with superficial (typical dermatomal) pain. P521 Pseudotumour Cerebri: is it really an idiopathic pathology? L. Martinez, S. Santos, G. Piñol, T. Corbalán, L. García, C. Iñiguez, L. F. Pascual, E. Mostacero Clinical Hospital of Zaragoza (Zaragoza, E) Objective: Pseudotumor cerebri (PC) is a complex syndrome characterized by increased intracranial pressure in the absence of any space occupying lesion, usually self-limiting, but often relapsing. When the aetiology is unknown this clinical condition is known as idiopathic intracranial hypertension. In the last years some authors had researched the relationship between venous sinus disease and PC and they suggested that it must be excluded by magnetic resonance venography (MRV) before diagnosing this pathology as idiopathic. Our aim is to determine the frequency of venous sinus disease and the necessity of MRV in these patients. Methods: We have studied 26 patients admitted between 1998 and 2005 in the Neurology department of University Clinical Hospital “Lozano Blesa” (Zaragoza; Spain) whose were diagnosed of PC. We have reviewed the epidemiological and clinical features. MRVs were reviewed and their appearances rated for focal narrowing and signal gaps. Results: Ten of these 26 patients (three man, seven women) underwent a MRV. Demographic details of these group were analyzed. Three patients had strong uniformal signal in both lateral and transverse sinus and their image was considered as normal. The other seven patients (70 %) showed filling defects on the transverse sinus (focal unilateral narrowing in three cases, one or more signal gaps in four cases). Conclusions: MRV in patients with idiopathic intracranial hypertension commonly presents a pattern of uni or bilateral lateral sinus defect (focal narrowings and signal gaps). For this reason we concluded that MRV should be done in all patients with PC looking for a possible aetiology. P522 Headache and pseudotumour cerebri G. Piñol, C. Iñiguez, S. Santos, I. Beltran, O. Alberti, L. Martinez, E. Mostacero Clinical Hospital (Zaragoza, E) Introduction: Pseudotumor cerebri (PC) is a complex syndrome characterized by increased intracranial pressure in the absence of any space occupying lesion, usually self-limiting, but often relapsing. Diagnosis is based on a

record of intracranial pressure of over a limit of 25 cmH2O. Morbidity is basically due to possible loss of vision associated with atrophy of the optic nerve. When the aetiology is unknown this clinical condition is defined as idiopathic intracranial hypertension. Subjects and methods: It is a descriptive and retrospective study that includes 26 patients which were admitted to the Department of Neurology of Clinic Hospital to Zaragoza between January 1997 and October 2005. Results: Mean age: 30.04 years (DE 12.31;Interval 14–66).26 patients were admitted with the diagnosis of PC (23 women and 3 men). Obesity was present in 54 % of cases. In 22 patients the disorder was presented with headache, with or without associated symptoms of disorders of vision. The headache was holocranial, continuos and well-tolerated in 86 % of patients and alternatively uni or bilateral, pulsatile, moderate, with or without photophobia or nausea and vomiting in 14 % of patients. In 3 cases, headache worsen with Valsalva’s manoeuvres. Bilateral papilloedema was seen in all patients. In two cases there were also bilateral and unilateral falcial palsy and neck rigidity. Disorders of vision: loss of visual agudity (27 %), transient darkening of visual field (23 %), diplopia (15 %), fotopsia (8 %), escothoma (4 %). In seven cases visual field measurement were abnormal (inferonasal escotoma, bilateral concentric reduction). Progress was poor in only one case. Conclusions: In spite of being theorically benign, and with many forms of treatment, PC may cause considerable morbidity of vision. Therefore, early diagnosis and close follow-up attention is essential.

Sleep disorders P523 Carotid artery stenosis and sleep-related breathing Z. Sˇonkova, K. Svátova, M. Kalina, P. Sˇebesta, K. Sˇonka Hospital Na Homolce (Prague, CZ); Charles University (Prague, CZ) Sleep-related breathing disturbances (SBD) are closely related to cardiovascular morbidity. SBD are a risk factor for atherogenesis and for stroke. According to some studies, however, impaired cerebral perfusion can induce sleep apnea. This inspired our study of patients before endarterectomy. Ten consecutive patients (4 women, 6 men, mean age 65.0 + SD = 10.9 years) indicated for endarterectomy because of major carotid stenosis were examined clinically and by means of limited sleep polygraphy (respiratory flow, chest and abdomen respiratory movements, oxygen saturation, respiratory noises and leg movements). 6 patients had suffered a transitory ischemic attack (at least 5 weeks before polygraphy), 3 had no history of neurological symptoms, and one had had a stroke without any sequels in the past. The mean Apnoea/Hypopnoea Index (AHI) was 13.6 + 14.6, mean Oxygen Desaturation Index (ODI – number of oxygen saturation drops of 3 % and more) 20.0 + 18.6 and basal oxygen saturation 94.0 10.7 %. Mean time of saturation below 90 % was 7.4 18 %. Seven patients (70 %) had AHI > 5. Two experienced SBD mainly in the supine position, central apnoeas were found in one patient. The large number of patients meeting the sleep apnea syndrome criteria (AHI > 5) suggests a relationship between SBD and carotid artery stenosis. This requires elucidation in more detailed studies. Supported by grants ME 701 and VZ 0021620816. P524 A study of snoring history in patients with ischaemic stroke A. Pashapour Imam Khomeini Hospital (Tehran, IR) Background and purpose: Several studies have propounded snoring as an independent risk factor for incidence of ischemic stroke. It also has been showed that snoring is related to ischemic brain infarctions that occur during sleep or the first 0.5 hour after awakening and not ischemic stroke occurring at other times of the day. So we performed this study to assess the relationship between snoring and ischemic stroke. The purpose of this study was to determine the frequency and severity of snoring in patients with ischemic strokes occurring during sleep or up to 0.5 hour after awakening compared with strokes occurring at the other times of the day. Subjects and methods: This is a case-control study that has 50 patients of case group including patients with ischemic stroke who have been occurred during sleep or at the first 0.5 hour after awakening, compared with a control group including 50 patients with strokes occurred at the other daytimes.

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Frequency of other important risk factors of stroke (ie: smoking, diabetes, hypertension, hyperlipidemia ‘history of heart diseases,age and gender) have been compared between two groups. The diagnosis of subjects were confirmed by a neurologic examination and brain imaging, however patients with hemorrhagic stroke were excluded of the study. Results: In case group, 10 patients had not any history of snoring, while 29 patients had habitual and 11 patients had occasional snoring. In control group 22 patients had not any history of snoring while 14 patients had habitual and 14 patients had occasional snoring (P = 0.006). So the difference between two groups about history of snoring was significant. In their age, gender, and other risk factors, there was no significant difference between two groups and about the heart diseases 10 patients of case group and 19 cases of control group had history of this risk factor. Conclusion: Total snoring (specially habitual snoring) is more common in ischemic strokes that occurred during sleep or 0.5 hour after awakening than the strokes occurred at the other daytimes. So snoring is considered as an independent risk factor for ischemic stroke. frequency of other risk factors are the same. contrary to expectation, frequency of heart diseases were more common in control group. P525 Excessive daytime sleepiness and sleep architecture in obstructive sleep apnoea syndrome Ö. Kayim, E. Yüksekkaya, G. Akhan Atatürk Education and Research Hospital (Izmir, TR) Objectives: This prospective study was designed to evaluate excessive daytime sleepiness (EDS) using the Epworth sleepiness scale (ESS) in untreated patients with different levels of obstructive sleep apnea syndrome (OSAS) and comparing with healthy controls. Another purpose was to elucidate the possible connections between the severity of OSAS, changes of sleep architecture and the extent of EDS. Methods: Patients with complaints of OSAS were evaluated at Atatürk Education and Research Hospital between May 2004 and June 2005. The patients underwent a nocturnal polysomnogram (PSG); fifty-eight eligible patients were diagnosed as OSAS and formed the study group. The study group was classified as suffering from mild, moderate and severe subgroups according to apnea-hypopnea index (AHI). The control group was formed by 43 age and sex-matched subjects. ESS was administered to all of the patients and controls, a score of ≥ 10 was considered as EDS. The control subjects also underwent a nocturnal PSG. All data were systematically monitored using a computerized sleep system and manually analyzed by a single investigator according to the standard Rechtschaffen and Kales criteria. Results: The mean ESS score of the OSAS group was higher than of the control group (p < 0.05). Also, the mean ESS score of the severe OSAS subgroup was higher than of the moderate and mild subgroups (p < 0.05). There was a positive correlation between AHI and ESS scores. In the OSAS group, ESS score was negatively correlated with the minimal and mean oxygen saturations. The mean slow wave sleep (SWS) amount of the OSAS group was lower than of the control group (p < 0.05).Also, the mean SWS amount of the severe OSAS subgroup was lower than of the mild and moderate subgroups (p < 0.05). The rapid eye movement sleep (REM) amount of the moderate OSAS subgroup was lower than of the mild subgroup (p < 0.05). There were no differences between the OSAS and control groups, or among the OSAS subgroups regarding sleep efficiency or REM latency (p > 0.05). In the OSAS group, the SWS amount was negatively correlated with ESS score and AHI. Conclusion: EDS assessed by ESS in OSAS was positively correlated with the severity of the disorder. ESS could be used to detect EDS in OSAS and to prioritize severe OSAS patients for PSG. Because there was no difference regarding sleep efficiency, EDS in OSAS could be a consequence of disturbed sleep and reduced SWS stage percentage rather than altered sleep quantity. P526 Prevalence of restless legs syndrome in patients treated with antidepressants M. Sieminski, A. Nitka-Sieminska, A. Lesnicka, W. Nyka Medical University of Gdansk (Gdansk, PL) Objective: Restless legs syndrome (RLS) is a common sleep and movement disorder. Its secondary forms can be caused by various drugs, including antidepressants. The aim of this study was to assess the prevalence of RLS among patients treated due to depression. Methods: We have used a screening questionaire for RLS based upon diagnostic criteria of RLS created by International Restless Legs Syndrome Study Group. The questionnaire was used in face-to-face interviews with patients hospitalised in Department of Psychiatry because of depression. We have also collected data upon patients’ therapy. We have divided thee used

drugs into three categories: tricyclic antidepressants (TADs), non-tricyclic antidepressants (NTADs) and neuroleptics (NLPs). Results: We have examined 128 patients (33 males, 95 females, mean age 47.4 years). RLS was found in 24 patients (18.7 %). In the RLS-positive group the following groups of drugs were used: TADs in 45.8 %; NTADs in 41.6 % and NLPs in 33.3 % of the patients. In the RLS-negative group 44.2 % of the subjects were treated with TADs; 52.9 % with NTADs and 26 % with NLPs. Conclusion: The fact that neuroleptics and tricyclic antidepressants were used more frequently in the RLS – positive group than in the RLS-negative group suggests that therapy with these two groups of drugs may lead to development of secondary RLS. It can be also concluded that antidepressants other than tricyclics are possible therapeutic options for treatment of depression in patients with restless legs syndrome. P527 Prevalence of insomnia in post-stroke patients M. Sieminski, A. Gojska, A. Nitka-Sieminska, W. Nyka Medical University of Gdansk (Gdansk, PL) Objectives: The aim of this study was to assess the prevalence and intensity of insomnia in post stroke patients. We also wanted to analyse the relation between insomnia, depression and patients’ functional outcome in various domains of life. Methods: We have used following scales: Soldatos Insomnia Scale (SIS), Beck’s Depression Index (BDI) and Nottingham Health Profile (NHP). NHP is a tool assessing patient’s well-being in 6 following domains: Energy Level(EL), Pain(P), Emotional Reactions(ER), Sleep(S), Social Isolation(SI) and Physical Activity(PA) – higher score in each of the domains means better condition of the patient. We have sent sets of scales to patients hospitalised in Department of Adults’ Neurology, Medical Univeristy of Gdañsk, Poland, because of ischaemic stroke. Results: We have received 38 fully answered sets of scales (18 males and 19 females). The mean age of the group was 68.3 years. The mean score in SIS was 16.8 points and in BDI 15.5. Symptoms of isomnia were found in 86.8 % and depression in 57.9 % of the subjects. 52.6 % of the subjects suffered from insomnia and depression and 34.2 % of them suffered only from insomnia. The intensity of insomnia measured with SIS was negatively correlated with scores in following domains of NHP: EL (coefficient of correlation: –0.53); P(–0.51); ER(–0.23); S [–0, 48]. There was not such correlation in SI and PA domains. Conclusion: The prevalence of insomnia in post-stroke patients is very high nad probably underestimated in everyday practice. This sleep disorder may influence various domains of patients’ life thus requiring more detailed attention of physicians. P528 REM sleep regulation in narcoleptics and normal controls E. Werth, R. Poryazova, R. Khatami, C. L. Bassetti University Hospital Zurich (Zurich, CH) Introduction: REM sleep (REM) propensity is known to be high in the early morning. REM duration, REM latency and number of interventions to prevent REM are major markers to explore REM regulation. In the present study we attempted to specify the role of REM regulation in narcoleptics and healthy controls by studying daytime sleep under varying sleep pressure (SP). Methods: 5 narcoleptics with cataplexy (NC, age: 28.2y ± 3.2 (SEM) and 4 healthy controls (C, age: 31.8 ± 4.2) underwent a four session crossover balanced sleep protocol with 2 sessions with a night of sleep deprivation to increase SP and 2 sessions with a 4h night time sleep episode (23:00–3:00h) to reduce SP, followed by daytime sleep (DS, 7:00–15:00h). In 2 sessions (one with high and one with low SP) subjects were repeatedly awakened during the first 4h of the DS episode to prevent REM. DS was undisturbed in the other 2 sessions. Results: The number of interventions to prevent REM was significantly increased in NC (25.6 ± 7.2) compared to C (8.8 ± 2.3), p < 0.001), whereas different SP did not (in NC: 26.8 (high SP) vs. 24.4 (low SP) interventions, in C: 7.5 (high) vs. 10.3 (low). The amount of accumulated REM (within the first 4h) in the undisturbed DS with low SP was significantly increased by 70 % compared to the high SP condition in C (p < 0.03). Chances in NC were minor (23 %, p > 0.34). Additionally, a low SP shortened REM latency in C (low SP) 63 ± 20 min, high SP: 119: ± 8 min, p < 0.07). Conclusion: Our preliminary results suggest that markers of REM regulation (i. e., number of interventions during its deprivation and accumulated REM duration) may behave different in respect of its regulation and between NC and C. Supported by the SNF

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P529 Strictly unilateral restless legs syndrome. A series of three cases P. Valko, E. Werth, M. M. Siccoli, C. L. Bassetti University Hospital Zurich (Zurich, CH) Background: Restless legs syndrome (RLS) is a clinically pleomorphic syndrome, that usually is localized in the lower extremities, but may affect virtually every part of the body. Although RLS complaints may show considerable asymmetry, cases with strictly unilateral long-term manifestation have not yet been reported. Objective: To describe the clinical und electrophysiological characteristics of three RLS patients with exclusively unilateral symptoms. Patients and Methods: The clinical histories, polysomnographic (PSG) findings and pharmacological responses are reviewed. All essential RLS criteria were fulfilled in each patient. Structural lesions were excluded by neuroimaging and electrophysiological studies. Results: Patient 1 is a 21-year-old man with a 5-year history of pressing pains in the right calf and sole, appearing at rest in the evening, with improvement by movement. Family history was positive for RLS. PSG shows predominantly right-sided PLMS (23/h resp. 13/h). No improvement was obtained with dopaminergics, antiepileptics, benzodiazepines and opioids. Patient 2 is a 52-year-old man with a 2-year history of painful sensations in the right lower leg, appearing only at rest in the evening, associated with an urge to move and relieved by walking. PLMS-index was 21/h on his right and 0/h on his left. With ropinirol 1.5 mg daily symptoms subsided. Patient 3 is a 68year-old man with a 30-year history of burning sensation in his right lower abdomen, groin, gluteal region and leg. Symptoms appeared only at rest, were initially restricted to night-time and improved by movement. Periodic limb movements in sleep (PLMS)-index was 99/h on his right and 7/h on his left. Treatment response to dopaminergics, opioids and antiepileptics was unsatisfactory. Conclusions: Our observations suggest the existence of unilateral RLS with predominantly homolateral PLMS and less favourable treatment response as a (so-far unrecognized) variant of “classical” RLS. P530 CSF prostaglandin D synthase levels are reduced in patients with excessive daytime sleepiness C. Baumann, M. Hersberger, C. L. Bassetti University Hospital (Zurich, CH) Objective: Lipocalin-type prostaglandin D synthase (L-PGDS) is a brain enzyme, which catalyzes to production of prostaglandin D2, an endogenous somnogen. A reduction of serum L-PGDS has been described in humans after sleep deprivation. The aim of this study was to compare cerebrospinal fluid (CSF) L-PGDS levels in patients with EDS secondary to narcolepsy, other neurological disorders, and chronic sleep deprivation, to levels in a healthy control group without neurological or sleep disorders. Methods: CSF L-PGDS levels were determined by immunonephelometric assay in 30 consecutive patients with excessive daytime sleepiness due to narcolepsy and other neurological disorders, in four patients with chronic sleep deprivation, and in 22 healthy controls. Results: Cerebrospinal fluid L-PGDS levels were significantly decreased in excessive daytime sleepiness secondary to narcolepsy, other neurological disorders, and chronic sleep deprivation, when compared to healthy controls. Conclusions: L-PGDS is the first neurochemical measure of excessive daytime sleepiness. This study, however, does not allow elucidating the role of L-PGDS in the pathophysiology of EDS. P531 Magnetic resonance imaging of the brain in familial narcolepsy M. A. Durka-Kesy, J. Staszewski, A. Sepien 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 are frequently associated with narcolepsy. The exact causes of narcolepsy are unknown however there is evidence for genetic predisposition for this disorder. Several familial cases have been described, but most cases are sporadic (95 %). There are reports concerning the relationship between symptoms of narcolepsy and dysfunction of dopaminergic system. Magnetic resonance imaging (MRI) studies conducted among the patients with idiopathic narcoleptic syndrome have led to conflicting findings concerning the presence of structural brain stem lesions. Objective: This report describes high incidence of the neurodegenerative changes of substantia nigra in case of familial narcolepsy.

Methods: MRI studies of the narcoleptic probants were carried out in a large family with several affected members. From 60 members of this family 11 persons with the sleep disturbances were distinguished by a phone survey. Among those 11 patients were 5 men and 6 women with a mean age of 41 years (5–78 years). Patients were assessed in Epworth scale of daytime sleepiness. All patients underwent MRI of the brain, overnight polysomnography and Multiple Sleep Latency Tests (MSLT).We define symptomatic narcolepsy as those cases that meet the International Classification of Sleep Disorders (ICSD) criteria. Results: Consistent with ICSD classification 9 from 11 probants of the analised family met the diagnostic criteria of narcolepsy. Another 2 patients showed excessive sleepiness however they didn’t meet ICSD criteria. MR images of 6 patients with diagnosed narcolepsy showed bilateral T2 hyperintensities in the substantia nigra. Among 2 remaining studied probants without all features of narcolepsy MRI revealed changes in substantia nigra in one case. Conclusions: This is the first study reporting lesions in substantia nigra on magnetic resonance imaging in patients with familial narcolepsy. Further investigations are necessary to explain the relationship between patophysiology of familial narcolepsy and neurodegenerative lesions in substantia nigra which were found very often among members of described family. P532 Prevalence of restless legs syndrome and REM sleep behaviour disorder in multiple sclerosis patients M. Gómez-Choco, Y. Blanco, A. Iranzo, J. Santamaria, F. Graus, A. Saiz Hospital Clínic i Provincial (Barcelona, E) Introduction/objectives: Restless legs syndrome(RLS) and REM sleep behaviour disorder(RBD) may be related to spinal cord or brainstem lesions, respectively. Because lesions in both areas are frequently present in multiple sclerosis (MS) patients, the prevalence of both disorders might be higher in MS than in healthy subjects. Patients/Methods: One-hundred twenty four consecutive definite MS patients from our outpatient MS clinic were asked for symptoms suggestive of RLS or RBD using a standardized questionnaire. The questionnaire was based on RLS and RBD diagnostic criteria, and RBD questions needed a “sleep witness” to be answered. Patients with symptoms suggestive of RLS or RBD were re-evaluated by a Sleep disorders specialist. Polisomnography (PSG) was performed in all patients with RBD symptoms. The demographic and clinical data collected were: age, gender, age at MS, RLS and RBD onset, type of MS, disease duration, expanded disability status scale (EDSS) score, history of past brainstem or spinal cord relapse, anemia, antidepressants intake, and MRI lesion location. Sixty-six age and sex-matched unrelated healthy controls were included as controls. Chi square test was used for comparisons between groups. Results: Patients were 74 women and 50 men, with a mean age of 43 ± 12 years. Seventy six per cent were relapsing-remitting, 14.5 % secondary progressive and 8.9 % primary progressive MS. Seventeen patients fulfilled criteria for RLS (13.7 %) and three for RBD (2.4 %), although only two of them were definitively diagnosed as RBD after PSG. No significant differences were found for any of the studied variables between patients with or without RLS or RBD.Although spinal cord lesions were more frequent in patients with RLS (89 % vs 68 %, respectively), the difference did not reach statistical significance. A similar result was found for the presence of anemia. The frequency of RLS and RBD in the control group (12 % and 1.5 %, respectively) was similar to that found in the MS population. Conclusion: The frequency of RLS and RBD in our MS patients is not different from that observed in the general population. The presence of spinal cord lesions is higher although no significant in those MS patients with RLS. P533 Parallel changes in resting muscle sympathetic nerve activity and blood pressure in a hypertensive obstructive sleep apnoea syndrome patient demonstrate treatment efficacy V. Donadio, P. Montagna, R. Vetrugno, M. Elam, F. Falzone, A. Baruzzi, R. Liguori University of Bologna (Bologna, I); University of Goteborg (Goteborg, S) Objectives: Studies comparing the efficacy of continuous positive airway pressure (CPAP) versus surgery in correcting cardiovascular abnormalities in Obstructive Sleep Apnea (OSA) syndrome are lacking. This case gave us the opportunity to compare the efficacy of both therapies in correcting daytime cardiovascular dysfunctions. Methods: We describe an OSA patient with hypertension who refused to continue CPAP and instead chose to undergo uvulopalatopharyngoplasty (UPPP) surgery. We evaluated the patient at baseline, in absence of therapy,

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after two months of CPAP treatment and three months after surgery. Patient underwent to a polysomnographic (PSG) study, daytime standardized cuff measurements of blood pressure (BP) and microneurographic recording of sympathetic activity from peroneal nerve. The Epworth Sleepiness Scale (ESS) measuring subjective daytime sleepiness was also applied before and after therapy. Results: At baseline PSG showed severe OSAS with apnoea-hypopnoea index of 31 and mean SaO2 of 89 ± 1 %, muscle sympathetic nerve activity (MSNA) was 44 ± 1 bursts/min and 82 ± 2 bursts/100HB (n. v. 29 ± 3 and 54 ± 4), BP 148/98 mmHg (systolic and diastolic respectively) and ESS was 14 (n. v. < 12). CPAP treatment markedly lowered ESS [5], MSNA (31 ± 1 bursts/min and 63 ± 2 bursts/100 HB) and BP (133/90 mmHg) whereas findings after UPPP were comparable to pre-treatment baseline (ESS: 13; MSNA: 45 ± 1 bursts/min and 89 ± 1 bursts/100 HB; BP: 140/95 mmHg). Conclusion: The most important observations in this case are the treatment-related parallel changes in MSNA and blood pressure, which support the concept that OSA-related hypertension may be neurogenic to a large extent. Our findings even highlight the need for evaluation of cardiovascular outcome after surgery aimed at correcting OSA.

Poster session 5 Cerebrovascular disorders P534 Risk factors in hospitalised stroke patients in Mures county, Romania A. Hojda, L. Zoican, I. Szocs, K. Orban-Kis, J. A. Szasz, S. Szatmari Mures County Hospital (Targu Mures, RO) Objectives: Stroke is a major problem of community health. Early diagnosis and correct treatment of risk factors would decrease the frequency and outcome of stroke. The objectives of our study were to analyse the correlation between the risk factors recorded on admission and discharge of patients, to see if risk factors, unknown on admission are identified and if there are any differences regarding the gender or the provenance of the patients. Methods: We performed a prospective study, enrolling 1478 patients from Mures county, hospitalized for stroke in Mures County Hospital between 1st November 2004–31th October 2005. For all patients we considered age, gender, provenance, risk factors known on admission and risk factors recorded at discharge. Statistical analysis was performed with chi-square test. Excluding subarachnoid hemorrhage and fatal cases we obtained a database for 1305 patients. Results: In the studied sample mean age was 68 ± 11 years, male:female ratio was 1.1:1, the rate of urban patients was 40.7 % and that of rurals’ 59.3 %, respectively. Regarding stroke subtype 85.7 % were ischemic, 14.3 % were hemorrhagic.The most commonly detected risk factor was hypertension, recorded in 76.8 % of cases on admission and 94.6 % at discharge. Among 233 newly identified hypertension cases, there were more rural patients than urban (64.8 % vs 35.2 %), and more men than women(67 % vs 33 %). Diabetes mellitus was known in 12.2 % cases on admission and confirmed in 20.7 % at discharge. Newly detected diabetes was significantly more frequent in rural patients(p < 0.001). Out of cardiac diseases, the rate of atrial fibrillation was 12.6 % on admission and 19.8 % at release. The largest number of newly discovered cases was recorded as regards dyslipidemia. There were 9.7 % cases on admission and 44.75 % at discharge. From 457 newly identified cases, were significantly more in rural patients than in urban (p < 0.001). Obesity was found in 29.3 % of cases, more frequent among women and rural patients. History of prior stroke was present in 25.6 % of patients. Alcohol abuse was mainly present in males and rural patients, respectively. Cigarette smoking was declared in 24.1 % of patients, mainly by men. Conclusion: This study proves that the screening of diseases with high impact on the morbidity of stroke is far from being satisfactory. As rural patients had poorer knowledge about risk factors, so health education programs and improving addressability to physicians are necessary especially for this category of patients.

P535 Level of consciousness as a conditioning factor of F wave generation in stroke patients G. Katsoulas, A. Argyriou, P. Polychronopoulos, E. Chroni University Hospital of Patras (Rion-Patras, GR) Objective: The current study sought to investigate whether the level of consciousness influenced, as an independent factor, the F wave generation. Methods: Forty three patients with acute stroke were divided according to their level of consciousness in two groups, to those with Glasgow scale (GCS) score 3–7 indicating coma (group I) and those with GCS score 8–15 (group II). A series of 40 electrical stimuli were delivered to the ulnar nerve bilaterally in order to obtain F waves. The following variables were estimated and then compared between groups: F persistence, F wave latency, amplitude and duration. All studies were performed within 3 days from stroke symptoms’ onset. Results: The main finding to emerge was the significantly reduced F wave persistence in the group of patients with low GCS score as opposed to patients allocated in the group with GCS score 8–15. This result is referred to F waves obtained from both the affected and unaffected limb. F wave minimum latency was also prolonged in the group with low GCS score, whilst the comparison of all other F wave variables revealed no significant differences between groups I and II. F wave persistence measurements did not differ between the affected and unaffected sides. Stroke location and type (ischemic or hemorrhagic) were not associated with alterations of F wave measurements. Conclusion: The generation of F waves, expressed by the F wave persistence, is associated with the level of consciousness, irrespective of the motor performance of the examined limb. F wave study may be useful, as an objective measure in documenting the severity of consciousness impairment. P536 Early vital and functional outcome of acute ischaemic stroke patients: influence of deep vein thrombosis prevention with pneumatic compression devices M. Spinelli, F. Corea, V. Bignamini, G. Nuzzaco, C. Ghidinelli, V. Martinelli, G. Comi, M. Sessa IRCCS S.Raffaele (Milan, I) Background: Venous thromboembolism (VTE) is a well recognized complication of acute ischemic stroke, with a mortality rate up to 25 %. The effectiveness of pneumatic compression stockings to reduce the risk of VTE and thereby stroke mortality has not been clearly stated in consecutive patients. Objective: objective of our study was to assess the influence on early vital and functional outcome of automatic compression stockings: Venaflow® (AIRCAST) devices. Methods: by means of a standardized prospective protocol with a monocentric, randomized design we assigned consecutively the patients either to LMWH (enoxaparine 4.000 UI s. c.) or LMWH in association with bilateral pneumatic compression stockings,. Results: over 800 patients screened 93 (58 females and 35 males) were eligible for the study. All of them were randomized within 48 hrs from stroke onset (85 % within 24 hrs). Reason for non eligibility were mainly the presence of brain hemorrage (or other diseases contraindicating the LMWH use), slight lower limb paresis (3/5 MRC was requested), and, in two cases, the presence of surgical wounds. Two outcome events (OE) were recorded (1 DVT, 1 PE) over the study population during the observation period. The mortality rate was 18 % (8/44) in the Venaflow® arm vs 12 % (6/49) and mainly due to infective complications. According to the bivariate analysis the use of pneumatic devices was associated to a more severe disability at admission (94 % vs 68 % p < 0.05) while no association was found with death or disability at discharge (RM < 3 19 vs 33 p = 0.08). Conclusions: The use of pneumatic compression devices did not influence the mortality rate or the functional outcome. P537 Aggressive behaviour and posterior cerebral artery stroke S. A. Botez, E. Carrera, P. Maeder, J. Bogousslavsky Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Objective: To describe and discuss the mechanisms leading to an aggressive behaviour among patients with acute posterior cerebral artery stroke. Methods: We prospectively included all patients with posterior artery stroke who had occipital involvement, violent behaviour and were admitted to our Department from 2003 to 2004. Patients with hemorrhagic stroke, history of stroke, other brain lesion or prior history of psychiatric disease were

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excluded. Other causes of confusion such as metabolic, endocrine, electrolyte disorders, or alcoholic withdrawal, were systematically excluded. Results: Aggressive behavior, defined as an attack on another person, was found in three patients (three men, age 68, 74, and 83). Two patients had occipito-temporal and thalamic involvement. One patient had isolated occipital stroke. In addition to a controlateral homonymous hemianopsia, the patients, physically and emotionally balanced before the stroke, presented an acute unusual aggressive behaviour. The patients became agitated and aggressive when they were stimulated by environment, and responded to solicitations by their relatives or by medical personnel by shouting insanities, hitting and biting others. In all three cases temporary physical restraint was necessary and neuroleptics were administered. However, these patients never showed spontaneous violent verbal or physical signs when not exposed to external stimulation. This unusual behavioural pattern resolved within two weeks after stroke. Conclusion: Aggressive behaviour is a rare presentation of acute posterior cerebral artery stroke which may be difficult to diagnose in patients presenting with hemianopsia as only concomitant neurological sign. Mechanisms probably involve a dysfunction of the limbic or of the serotoninergic system. P538 A biphasic signalling pathway endows the hippocampal dentate gyrus with an early neuroprotective effect against global ischaemia P. Blanquet, J. Mariani, B. Fournier Université P. & M. Curie, CNRS-UPMC (Paris, F) Dentate gyrus is usually assumed to be resistant to ischemia. However, the mechanisms underlying this functional plasticity are not fully understood. Herein, we aimed at identifying a neuroprotective mechanism in the dentate gyrus of the adult rat after global ischemia. Cyclic AMP response element (CRE)-binding protein (CREB), brain-derived neurotrophic factor (BDNF) and calcium/calmodulin-dependent protein kinase IV (CaMKIV) are known to be mediators of neuronal survival and plasticity. Involvement of CaMKIV, BDNF and CREB in ischemic resistance was therefore examined using intracerebroventricular injections of pharmacological agents such as inhibitors, antibodies and consensus oligonucleotides followed by immunohistochemical and Western blot analysis. We provide evidence that ischemia triggers activation of a biphasic pathway during the resistance period of dentate neurons: [1] CaMKIV mediates the early phosphorylation of CREB which drives a prominent synthesis of BDNF; [2] this BDNF synthesis, in turn, induces a second peak of CREB phosphorylation which is required for the maintenance of BDNF synthesis. In addition, we show that: [1] impairment of these transduction signals by the pharmacological agents causes tissular damages and apoptotic deaths in the post-ischemic dentate gyrus; [2] some similar disturbances also occur beyond the resistance period in the dentate gyrus of untreated ischemic rats; [3] these disturbing effects are mainly observed in the suprapyramidal dentate subfield. Collectively, the present results suggest that activation of the CaMKIV/CREB/BDNF pathway plays principally an early protective role in the suprapyramidal subfield of the dentate gyrus. P539 Sudden deafness associated with infarction in the territory of the non-anterior inferior cerebellar artery H. Lee, S-I. Sohn, Y-W Cho, J-G. Lim, S-D Yi Keimyung University School of Medicine (Deagu, KOR) Background: It is well known that the most commonly infarcted territory on brain MRI associated with the sudden deafness was in the anterior inferior cerebellar artery (AICA). Until now, there have been few reports regarding the sudden deafness associated with non-AICA territory ischemic stroke. Objectives: The aim of this study was to document the frequency of sudden deafness associated with the non-AICA territory infarct(s) and to describe the vascular topographical patterns of ischemic lesion associated with sudden deafness based on data collected from a prospectively acute stroke registry. Methods: We defined the sudden deafness of vascular causes as follows: [1] the patients noted a definite change in hearing at the time of posterior circulation infarction; [2] pure tone audiometry also documented new onset of the sensorineural hearing loss; and [3] brain MRI showed acute infarct in the posterior fossa. According to the above criteria, 42 patients were identified as having sudden deafness as a symptom of VBI. Results: Among 42 patients with sudden deafness, 35 (83 %) had infarct(s) in the territory of the AICA, and 7 (17 %) in non-AICA territory. Five patients with sudden deafness had infarct in the territory of the posterior inferior cerebellar artery (PICA) and other 2 in brainstem. In all patients ex-

cept two, the unilateral hearing loss was on the side of infarct, as shown on brain MRI. Five of 7 patients with non-AICA territory infarct had vertigo as an associated symptom. Three patients had canal paresis to caloric stimulation ipsilaterally. Conclusion: Sudden deafness due to non-AICA territory infarction mostly associated with infarct in the territory of the PICA. This phenomenon may be due to variations of known vascular anatomy of AICA. P540 Isolated small infarction in posterior circulation territory: magnetic resonance imaging and magnetic resonance angiography study P. W. Chung, S. C. Hong Sungkyunkwan University (Seoul, KOR); Han-il Hopsital (Seoul, KOR) Objectives: There has been few reports concerning isolated small infarction in posterior circulation territory. We performed this study to investigate the relation of infarct location and vascular patterns of small infarction in posterior circulation territory. Methods: Patients with acute posterior circulation infarction were enrolled in this study. We included patients with isolated small infarction with a diameter < 1.5 cm. Patients with large infarction, branch atheromatous type infarction and multi-focal infarction were excluded. All patients underwent brain MRI with diffusion image, time-of-flight magnetic resonance angiography (TOF-MRA), contrast enhanced MRA, EKG, transthoracic echocardiography, 24 hour EKG Holter monitoring and standard blood tests. Patients were grouped according to infarct location on diffusion MRI. Vascular stenosis pattern in MRA and risk factor profiles were compared among groups. Results: Total of 46 patients were enrolled in this study. Medullary infarctions were most common (n = 15, 32.6 %), followed by pontine infarctions (n = 14, 30.4 %) and thalamic infarctions (n = 11, 23.9 %), midbrain infarctions (n = 5, 10.9 %). Cerebellar infarction was observed in only 1 patient. Basilar artery (BA) stenoses were observed in 5 patients (10.9 %) and vertebral artery (VA) stenoses were observed in 26 patients (56.5 %). BA stenosis was not significantly different among infarct locations. VA stenosis was frequently observed in medullary infarction, and less frequently observed in middle and distal territories (86.7 % in medullary infarctions, 50 % in pontine infarctions, 40 % in midbrain infarctions, 36.4 % in thalamic infarctions; p < 0.01).Among VA segments,V4 segment stenosis was most common. Risk factor profile was not significantly different among infarct locations. No patient showed definite cardioembolic source. Conclusion: Small isolated infarctions are relatively evenly developed in all posterior circulation terriotories excluding cebelleum and occipito-temporal cortex. But etiology of small isolated infarction may be different among infarct locations. P541 Impact of peripheral arterial disease on ischaemic stroke A. Galvez, A. Ois, A. Rodriguez-Campello, N. Segura, C. Pont-Sunyer, E. Cuadrado, G. Cucurella, J. Roquer Hospital del Mar (Barcelona, E) Objectives: Ischemic stroke, myocardial infarction and peripheral arterial disease are the clinical expression of a single underlying pathology. The aim of our study is to determine percentage of patients with peripheral arterial disease (PAD) in a consecutive cohort of patients with acute ischemic stroke and to evaluate the relationship between PAD and clinical severity and outcome. Methods: Between 2003 and 2005, all patients admitted with acute ischemic stroke into the emergency room in relation to PAD were evaluated. The presence of PAD was established using the medical history. The following variables were analysed: age, sex, alcohol consumption, smoking habit, vascular risk factors, antithrombotic pretreatment, presence of coronary heart disease (CHD), atrial fibrillation, initial stroke severity by NIHSS, significant symptomatic carotid or intracranial atherosclerosis (SA), recurrent stroke. Outcome was evaluated with the functional situation (modified Rankin Scale) and mortality at three months after the stroke. Results: We analysed prospectively 971 patients with acute ischemic stroke. The mean age was 73.69 years (SD 12.10). 111 patients (11.5 %) had PAD. Univariate study showed the following results: age (p = 0.762), male sex (p < 0.001), arterial hypertension (p = 0.173), dyslipidemia (p = 0.003), diabetes mellitus (p = 0.113), heavy alcohol intake (> 60 g/day) (p < 0.001), current smoking (p < 0.001), atrial fibrillation (p = 0.770), previous stroke (p = 0.018), previous CHD (p < 0.001), antithrombotic pre-treatment (p < 0.001), SA (p < 0.001), stroke recurrence (p = 0.153), mortality at 3 months (p = 0.053) and dependence (p = 0.92). Logistic regression showed independent association with: male sex OR = 4.02, 95 %CI (2.30–7.03), cur-

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rent smoking OR = 2.53, 95 %CI (1.50–4.24), heavy alcohol intake (> 60 gr/day) OR = 2.10, 95 %CI (1.10–3.99), SA OR = 1.73, 95 %CI (1.06–2.84), antithrombotic pretreatment OR = 4.42, 95 %CI (2.75–7.09) and mortality OR = 2.11, 95 %CI (1.19–3.75). Conclusion: 1. In our setting, 11.5 % of patients with acute ischemic stroke had previous diagnostic of PAD; 2. There were many differences between patients with and without PAD, mainly related to gender, toxic habits and vascular risk factors; 3. Patients with PAD had more serious strokes and a worse outcome; 4.This antecedent could indicate the importance of an exhaustive arterial study and aggressive therapeutic treatment. P542 Long-term effect of intra-arterial thrombolytic therapy in acute stroke K. Nedeltchev, U. Fischer, M. Arnold, L. Kappeler, T. Haefeli, C. Brekenfeld, L. Remonda, G. Schroth, H. P. Mattle University of Berne (Berne, CH) Background: Thrombolysis has been shown to improve the 3-months outcome of patients with acute ischemic stroke. Knowledge regarding the longterm effects of thrombolysis in stroke is limited. Patients and Methods: Monocenter, retrospective study comparing the long-term outcome of patients who were treated with intra-arterial urokinase (IAT) with that of patients receiving aspirin or heparin only (non-IAT). The long-term outcome was assessed using the modified Rankin scale (mRS). 173 IAT and 261 non-IAT patients from the Bernese Stroke Registry were eligible for the study. A matching algorithm that took into account patients’ age and initial stroke severity (as measured by the National Institute of Health Stroke Scale, NIHSS) was used to assemble a IAT and a non-IAT group. Matching was blinded for clinical outcome. Results: 144 IAT patients (mean age 63 years, 50 % women) and 147 nonIAT patients (mean age 62 years, 45 % women) were included in the comparative analysis. The median NIHSS was 14 in each group. At 2 years, 57 % of the IAT patients and 45 % of the non-IAT had a favourable outcome when defined as mRS 0 to 2 (p = 0.037), or 41 % and 26 %, when favourable outcome was defined as mRS 0 to 1 (p = 0.008). Mortality was 23 % in the IAT and 24 % in the non-IAT group. Conclusion: The present study provides evidence for a sustained effect of IAT when assessed 2 years after the stroke. The results support the more widespread use of IAT for treatment of acute stroke. P543 Predominantly verbal deficit of encoding with stroke limited to the left posterior hippocampus F. Scacchi, A. Carota, J. Morier, J. Bogousslavsky Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Background: The exact role of the hippocampus is still a matter of debate, because of discrepant findings in functional neuroimaging research in healthy subjects. Besides, a first-ever acute stroke limited to the hippocampal region is an extremely rare event. Case report: a 41 years old right handed man, without known cerebrovascular risk factors, was admitted because of abrupt onset of an amnestic syndrome, with the patient repeatedly asking the same questions, resembling transient global amnesia (TGA) except for the presence of “amnestic aphasia”. MRI (DWI) showed acute infarction of the posterior region of the left hippocampus (FIG). Acute neuropsychological examination showed an amnestic syndrome, which notably improved within 24–48 hours, followed by a severe deficit of episodic long-term memory (strongly prominent in the verbal modality) with features that are considered typical for dysfunction of the medial temporal lobe (default of encoding, semantic intrusions). Partial recognition was possible by familiarity processing in metamemory tasks. Conclusion: stroke limited to the posterior region of the hippocampus (posterior choroidal artery territory) is a very rare event. The initial TGAlike picture in our patient is a further element to suggest the role of the posterior hippocampal region in TGA. Our findings also point to a role of this region for lexical retrieval, familiarity processing. They provide further evidence to the specialisation of the left hippocampus for verbal material encoding.

P544 Combined CT imaging protocol for acute stroke patients in current clinical practice: feasibility and influence on decision making for thrombolysis D. Vondráèková, K. Seltenreichová, J. Weichet, Z. Sˇonková, L. Janousˇková, M. Kalina Hospital Na Homolce (Prague, CZ) Objectives: Perfusion CT (PCT) has been shown to be more sensitive than noncontrast CT (NCCT) to early ischemic changes and can describe the salvageable cerebral tissue. Combined with CT angiography (CTA), it can give more information about stroke etiology and increase the number of patients treated with thrombolysis. Based on these data, we introduced a new CT imaging protocol in stroke patients. We analyze the duration and feasibility of this protocol in clinical practice and present 2 cases with unknown onset of symptoms where PCT data helped to decide for thrombolysis. Methods: NCCT, dynamic PCT and CTA were examined in 39 patients. All patients presented with symptoms of acute stroke.We measured the time between patient arrival to the beginning of CT scanning, total imaging duration and the time between patient arrival to possible acute intervention. The feasibility of CT protocol, adverse events and promptness of data interpretation were also studied. We elaborated a new decision making protocol for thrombolysis based on PCT data that selected patients with tissue at risk for possible treatment independently of time, and excluded patients with irreversible ischemia from aggressive treatment. Results: Mean door-to-CT time was 22.6 [11–45] minutes, mean CT duration was 13.9 [8–40] minutes, and mean time of patient arrival to possible acute intervention was 58.2 [35–80] minutes. Most delays occurred due to the analysis of blood coagulation parameters and initially due to technical problems at the CT suite. NCCT/PCT and CTA were obtained in all patients. Three (7.6 %) PCT interpretations were obscured by motion artifacts. Two patients (5.1 %) received intraarterial thrombolysis and 4 (10.2 %) patients were successfully treated with intravenous thrombolysis. Two of these 4 patients had unknown onset of stroke, but were thrombolysed on the basis of our PCT protocol. Conclusion: Despite its limitations, NCCT/PCT/CTA should be implemented in the routine clinical practice. Our results support previous data about advantages of this imaging protocol in the stroke treatment based on tissue viability. Whether this patient triage is really more accurate and effective must be proved in larger studies. P545 Intracerebral haemorrhage: multifactor analysis and outcome in a 7-year study E. Mamaloukas, N. Artemis, O. Koutoula, D. Karakostas, I. Milonas AHEPA Hospital (Thessaloniki, GR) Background: Primary intracerebral hemorrhage (ICH) is one of the common vascular insults with a relatively high rate of mortality. The aim of the current study was to determine the mortality rate and to evaluate the influence of co-existing intraventricular hemorrhage (IVH) and other risk factors on the mortality of patients with intracerebral hemorrhage (ICH). Demographic characteristics along with clinical features and neuroimaging information on 236 patients with primary ICH admitted to the 2nd Dept of Neurology of AHEPA hospital between 1999–2005 were assessed by multivariate analysis. Results: Of 236 patients diagnosed with ICH, 140 were men and 96 were women. The mean age of all subjects was 63 years. The frequency of localization of the hematomas was lobar 50 %, basal ganglia 28.4 %, brainstem 4.6 %, cerebellum 10.3 % and lone IVH 6.9 %. Our data showed that 51.7 % of the patients with a poor outcome (death) had a combination of ICH with IVH or IVH alone, whereas only a 27.6 % of all participants presented with the same condition. A history of hypertension was the primary cause of ICH in 67.2 % of participants and it was found more frequently compared to other cardiovascular risk factors such as diabetes mellitus (27.5 %), cigarette smoking (12.9 %) and alcohol consumption (6.9 %).The overall mortality rate among ICH patients admitted to the hospital was 13.5 %. Conclusion: Higher rate of mortality was observed in patients who had ICH combined with IVH or had IVH alone. The presence of intraventricular bleeding appears to be an independent negative prognostic factor in cases of ICH. Early detection and treatment of the complications of IVH such as hydrocephalus may help improve prognosis.

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Objectives: Studies suggest that the increased common carotid artery intima-media thickness (CCA-IMT) is a risk factor for stroke. However stroke is a heterogeneous disease that comprises several subtypes with different etiologies.In this study we are exploring the association of the CCA-IMT and the severity of ischaemic stroke in symptomatic carotid stenosis. Methods: Sixty-one patients (mean age 66.6 ± 7.3) with recent, acute and first-ever ischaemic attack underwent a carotid ultrasound examination to quantify the degree of stenosis. We included patients with symptomatic carotid stenosis of 50–99 %. Lacunar infarcts were excluded.All subjects had an IMT measurement at the far wall of both CCAs. Stroke severity was assessed according to definitions, procedures and scoring system of National Institutes of Health Stroke Scale (NIHSS) and of Barthel Activities of Daily Living Index (BI). The NIHSS was assessed on hospital admission and BI at discharge. Results: Multiple regression analysis showed that CCA-IMT was positively related with NIHSS (p = 0.02, β = 50.3) and reversely related with BI (p = 0.04, β = –52.9), after adjustment for age. Conclusion: The increased IMT is considered to reflect generalized atherosclerosis and related with advancing atherosclerosis which is a precursor of atherothrombotic infarction. We found that the CCA-IMT is correlated with admission NIHSS score that actually reflects the severity of neurological impairment and the functional outcome at discharge as measured by the B I. We conclude that CCA-IMT as measured by ultrasonography could be considered as a determinant for ischaemic stroke severity in symptomatic carotid stenosis.

prepared. Aim: The aim of the study was to analyze the prevalence and control of CVD risk factors among subjects with history of stroke from small Polish towns. Methods: The objective of the P400CP is CV diseases prevention for the years 2004–2006. The project concerns the citizens of small Polish towns [418] with population under 8 thousand. In 2004, in 123 towns, 36696 subjects, aged 18–98 years underwent medical examination and series of tests (blood pressure measurements (BP), anthropometrical measurements and laboratory tests (total cholesterol and glycaemia strip tests)). The prevalence of stroke and CV risk factors were analyzed by filling in a questionnaire by the subjects. The assessment of AH control was based on the mean of two BP measurements taken during one visit (< 140/90 mmHg), Control of hipercholesterolemia (HCH < 190 mg/dl) and glycaemia disorders (fasting glucose < 100 mg/dl) were based on strip tests values. Results: A history of stroke was declared by 471 subjects (1.28 %; W 1 % vs. M 1.8 %; p < 0.001), aged 45–91 years (Women, W 66.5 ± 9.4 vs Men, M 64 ± 8.9; p < 0.001). In this group 75.6 % had BMI ≥ 25, in 72.4 % abdominal obesity was diagnosed. 89 % of the subjects after stroke had a history of AH or newly increased BP detected during the first visit. Only 12.7 % of the subjects with AH had BP < 140/90 mmHg and in 33 % BP was < 160/95 mmHg.A history of HCH or newly increased total cholesterol values were detected in 75 % of the subjects after stroke. A good control of HCH (< 190 mg/dl) was observed in 25 % of examined with previously detected HCH. Fasting glucose ≥ 100 mg/dl (newly or earlier detected) was found in 28 %. Only 5.6 % of subjects with history of stroke and glycaemia disorders had fasting glucose < 100 mg/dl. 12.1 % of the subjects admitted to smoking. Concusion: The experience of the PPCP has proved that – considering the number of undetected cases requiring treatment in secondary prevention after stroke – there’s currently an urgent need for educational and interventional projects to be run across small town and village communities in Poland. Supported by the Ministry of Health, Poland

P547 A comparison of radiosurgical treatment outcomes in embolised and nonembolised brain AVMs in Canadian patients: a Propensity Score approach K. R. Burton, G. Tomlinson University of Calgary (Calgary, CAN); University of Toronto (Toronto, CAN)

P549 Is there any effect of Ramadan on occurrence of cerebral vein and sinus thrombosis? M. Saadatnia, E. Asgari Moghadam Isfahan University of Medical Science (Isfahan, IR)

Background and Purpose: Due to a lack of randomized controlled trials, little information exists about the relative benefit of multimodal therapy (embolization plus radiosurgery) compared to unimodal therapy (radiosurgery) alone for arteriovenous malformations (AVMs). The objective of this study was to assess whether multimodal therapy is associated with a higher rate of cure of AVMs in a large observational database. Methods: AVM patients admitted to hospitals cooperating within the Toronto Brain Arteriovenous Malformation group between June 1991 and January 2004 were included. Patients treated with multimodal therapy and patients receiving unimodal therapy were allocated propensity scores. Survival analysis with adjustment for the propensity score quintile compared AVM cure and AVM cure or shrinkage rates between therapy groups over a 24 month follow-up. Results: A total of 158 AVM patients met the inclusion criteria for this study. Of these, 51 patients (32 %) were treated with multimodal and 107 (68 %) were treated with unimodal therapy. Over 24 months, 23 (14.6 %) patients experienced AVM cure and 43 (27.2 %) patients experienced AVM cure or shrinkage. Time to 24-month cure was similar in multimodal and unimodal treatment patients (HR, 0.46; 95 % CI, 0.15–1.40). Likewise, time to 24month cure or cure or shrinkage was similar in multimodal and unimodal treatment patients (HR 0.75; 95 % CI: 0.38–1.50). Conclusion: There may be no difference between AVM treatment outcomes when AVM patients are treated with unimodal versus multimodal therapy.

Objectives: Over one billion of Muslims fast worldwide during the month of Ramadan.Fasting during Ramadan is essentially a radical change in life style for the period of lunar month. However a few studies showed fasting during Ramadan has no affect on stroke, but there are no report about venous form of stoke and Ramadan. Our objective is to investigate whether hospital admissions of cerebral vein and sinus thrombosis (CVST) differ during Ramadan compared to other months. Methods: All patients (n = 107) with CVST admitted to two neurological centers from 2001 to 2004 in the Isfahan Province were included in this study. Patients were divided into 2 groups according to the month of onset of stroke. The first group included patients with CVST that occurred in Ramadan (n = 22) and the second group formed by CVST patients with onset in other months (n = 85).We evaluated the number of CVST cases per month and compared ages, sex and the distribution of new cases during Ramadan and others months. Results: The mean number of patients for 1 month of Ramadan and other months were 5.5 and 1.93, respectively. The analysis showed a significantly increased frequency of CVST events in Ramadan compared to other months (P = 0.006). The studied groups were not significantly different with respect to age (37.1 ± 10.9, 35.7 ± 12.5, p = 0.64) and sex (p = 0.32). Conclusion: We concluded that fasting during Ramadan affects CVST occurrence. This can be explained by the hypothesis that the daily fasting period of Ramadan, which includes a no-drinking and no-eating period of at least 12 hours,makes patients prone to dehydration,and coexistence of other risk factor with dehydration in fasted patients during Ramadan can be the reason for an increased susceptibility to CVST.

P546 Common carotid artery intima-media thickness and ischaemic stroke severity I. Heliopoulos, T. Hatzidounas, M. Papaioakim, K. Vadikolias, A. Terzoudi, D. Artemis, C. Piperidou University General Hospital (Alexandroupoli, GR)

P548 Urgent need of educational and interventional projects for subjects with history of stroke. Polish 400 Cities Project results K. Chwojnicki, T. Zdrojewski, L. Wierucki, A. Czlonkowska, D. Ryglewicz, B. Wyrzykowski, W. M. Nyka Medical University (Gdansk, PL); Institute of Psychiatry and Neurology (Warsaw, PL)

P550 Heart impairment in the antiphospholipid syndrome and stroke A. Bartkova, R. Opavsky, M. Hutyra, D. Sanak, I. Vlachova, B. Krupka, R. Herzig, E. Sovova, P. Kanovsky University Hospital (Olomouc, CZ)

Introduction: Epidemiological data show that citizens of small towns and villages represent worse trends in cardiovascular (CV) mortality and poor control of CV risk factors during political transformation in Poland than citizens of large towns. To try to eliminate these inequalities the Polish 400 Cities Project (P400CP), large educational and interventional project was

Introduction: The antiphospholipid syndrome (APS) is defined by the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), venous or aterial thrombosis and recurrent pregnancy loss. The association with echocardiographic abnormalities and APS has been increasingly recognized. Valvular abnormalities develop in about a

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third of patients with primary APS. Valvulopathy includes thickening, nonbacterial vegetations. The mitral and aortic valves are most commonly affected. The predominant functional abnormality is regurgitation, stenosis is rare. Thrombotic vegetations may be difficult to distinguish from bacterial endocarditis. Antiphospholipid antibodies have also been incriminated in intracardial thrombi, pericardiac effusion, cardiomyopathy and premature restenosis of vein grafts for coronary bypass. Case report: In three young patients, with embolic cerebral infarct, was found the mitral valve large mass in the transesophageal echocardiography (TEE). One of them, 40 years old man, had myocarditis with global systolic dysfunction and tachyfibrillation, electrical cardioversion was needed. Subsequently, the diagnosis of primary antiphospholipid syndrome was made. Permanent anticoagulantion therapy was effective in all cases. Control TEE shows full resolution of mitral valve vegetation. Conclusion: TEE plays an important role in the assessment of patients with cerebral embolic events. In patients with APS is incidence of cardiac lesions high. The presence of antiphospholipid antiodies seems to increase risk for thromboembolic complications, mainly cerebrovascular, posed by cardiac impairment. The determination of cardiac impairment in this patient is important for short and long term management, especially for the possibility of causal therapeutic impact. P551 Recombinant factor VIIa (Novoseven) in hyperacute intracerebral haemorrhage R. M. Sivakumar Cerebrovascular and Vasculitis Research (Chennai, IND) Background: Intracerebral haemorrhage (ICH), is the deadliest form of stroke. We have the first effective treatment, in the form of NovoSeven® (recombinant Factor VIIa, rFVIIa), which has been shown to reduce bleeding and have a positive impact on disabilities associated with ICH when administered early after ICH onset (3–6 Hours). One of the strongest predictors of mortality and morbidity in ICH is haematoma volume and rFVIIa has the potential to improve neurological outcome and survival for people with ICH, by preventing the growth of ICH, by its unique hemostatic effects. Objective: To evaluate the efficacy and safety of rFVIIa in preventing early haematoma growth in acute ICH Methods and Materials: 12 patients who presented with ICH within 6 hours of onset were administered 20–40 µg/kg of rFactor VIIa. CT scans of brain were done at baseline, after 3 hours and after 72 hours. The Primary end points was Efficacy: Percentage change in ICH volume and the Secondary endpoints were Patients’ survival and/or functional status at 90 days after treatment. Results: There were 9 men and 3 woman. Median age was 61.78 years, Median NIHSS 7.44, Barthel Index at one week 76 and mRS 3.16. 3 patients with massive ICH expired. No serious adverse events like Cerebral infarction, Deep Vein Thrombosis or Pulmonary Thromboembolism were seen. Conclusions: RFactor VIIa given within 3–6 hours from onset of ICH improves the morbilty and prevents expansion of volume of ICH. Further large multicenter studies are necessary to confirm the above preliminary findings.

Child neurology P552 Cherry red spot – myoclonus syndrome M. T. Mendonça, M. Santos, F. Santos, L. Lacerda, C. Barbot, S. Gonçalves, I. Carrilho Hospital de Crianças Maria Pia (Porto, P); Instituto de Genetica Medica Jacinto Magalhães (Porto, P) The typical bilateral cherry red spot occurs in several of the lysosomal storage disorders but when associated with punctate opacities of the lens is suggestive of Sialidosis. Sialidosis type I, also known as cherry red spot-myoclonus syndrome, is a relatively milder, late onset, nondysmorphic type of the disorder. Patients usually present on the second or the third decade of life and develop gait abnormalities, a myoclonus syndrome and gradual visual failure. Ataxia and seizures have also been reported. We present a case of Sialidosis type I in a 13-year-old boy. He has a personal history of involuntary movements suggestive of action tremor in the upper limbs for the last 2 years. In Mars 2005 he had a first generalized seizure during sleep and started sodium valproate. Four months late his fam-

ily notice gait abnormalities and leg tremor, worse in the morning after waking up and when climbing stairs. The parents also notice exuberant sleep myoclonus. In October he had a second seizure while asleep, followed by worsening of the involuntary movements of the legs and walking difficulty. During follow-up a progressive walk difficulty associated with involuntary movements was seen, predominately in the legs and exacerbated in stress situations. Clinically it was difficult to classify the movements as action tremor or action myoclonus. He had no other systems complains including visual ones. He has no family history of movement disorders or consanguinity. He has a normal neurological examination except action tremor of the hands and gait instability with mild ataxia and sometimes visible involuntary jerks movements in legs and trunk. During investigation, the ophthalmologic examination showed a cherry red spot at the center of the macula and punctate opacities of the lens bilaterally, directing the investigation to the possibility of Sialidoses type I. Abnormal pattern and amount of urinary sialyloligosaccharides and glycopeptides were detected by thin-layer chromatography. Combined deficiency of neuraminidase and B-galactosidase (galactosialidosis) was excluded by determination of normal B-galactosidase activity. The clinical picture and the deficiency of neuraminidase activity in cultured skin fibroblasts confirmed the diagnosis of Sialidosis type I (MIM256550), an autossomal recessive lysosomal storage disorder. The authors highlight the importance of a good ophthalmologic examination. P553 Structural cerebellar abnormalities associated with developmental stuttering B. Benedetti, S. Davis, P. Howell, K. Watkins University of Oxford – FMRIB (Oxford, UK); University College London (London, UK) Objectives: Developmental stuttering is a disorder affecting the fluency of speech, characterized by repetitions, prolongations or difficulties with initiation of sounds. It affects approximately 1 % of the adult population and 4 % of children. People who stutter (PWS) are otherwise neurologically, psychiatrically and cognitively unimpaired. Only a few studies have investigated brain anatomy in PWS, revealing both structural and functional abnormalities. One functional abnormality characteristic of the brains of PWS is overactivity in the cerebellum during speech. Here, we tested the hypothesis that developmental stuttering also has a structural correlate in the cerebellum. We compared grey and white matter volumes of the anterior and posterior lobes and the vermis in a group of young PWS and controls. Methods: Whole-head T1-weighted MRI scans were obtained at 1.5 T in 18 PWS (12M:6F; aged 14–27 years, avg. 18 y) and 12 age- and sex-matched controls (7M:5F; aged 14–27 years, avg. 17.8 y). The images were linearly transformed into standard space to normalize for total brain volume. Using FSLview, which allows us to view coronal, axial and sagittal slices of the brain simultaneously, we manually demarcated the following regions of the cerebellum: left and right anterior and posterior lobes and the vermis. Using FAST (FMRIB’s Automatic Segmentation Tool) we calculated partial volume estimates for two tissue classes, grey and white matter and, thereby, obtained grey and white matter volumes for each region. Analysis of variance was used to compare volumes between PWS and controls examining the factors of hemispheric side, lobe and tissue type. Results: The volume of the cerebellum was significantly smaller in PWS compared to controls (p = 0.043); the mean volume for the PWS was 92 % of the mean control volume. There was a significant interaction between lobe and group (p = 0.034), which was due to reduced volume of the posterior lobe rather than the anterior one in PWS compared to controls; this effect was particularly striking for grey matter (p = 0.07). No significant differences were observed between PWS and controls in the volume of the vermis. Conclusion: This study indicated the existence of anatomical abnormalities in the cerebellum of PWS, suggesting the possibility that the functional abnormality may be related to a structural one. It also supports the possibility that the cerebellum plays an important role in the pathophysiology of developmental stuttering. P554 The HexB gene is up-regulated during the brain development: effect for GM2 gangliosidosis therapy S. Martino, R. Tiribuzi, I. di Girolamo, R. Guadalupi, F. D’Angelo, G. Makrypidi, AN. Orlacchio, G. Bernardi, AL. Orlacchio University of Perugia (Perugia, I); CERC-IRCCS Santa Lucia (Rome, I) Objectives: Therapy for genetic lysosomal disorder with neurological involvement, GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases), requires

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an active Hexosaminidase (Hex) A and B production in the central nervous system and a therapeutic approach whose effect velocity could be faster than human disease progression. In this contest, it is crucial the identification of the best time of treatment. Using a Tay-Sachs (TS) disease mouse model we are developing a combined gene/cell based-therapy.We are exploiting the efficacy of the gene transfer strategy by using a viral vector carrying the HEXA gene to restore the missing Hex A activity and the potential of stem cells to repair the damaged brain. Here we report evidences showing that the best time of treatment corresponds to the postnatal mouse age. Methods: Tay-Sachs and C57/BL6 (WT) mice were sacrificed at different ages (embryonic vs. adult) and the brain analyzed for Hex isoenzymes activities and for genes expression. We evaluated the Hex A and Hex B production by DEAE-cellulose chromatography and by enzyme activity assays with two substrates: MUG (hydrolyzed by both alpha- and beta- subunit) and MUGS (hydrolyzed by alpha-subunit). We evaluated the expression of hexa and hexb genes and the 18S rRNA by RT-Real Time PCR. Results: RT-Real Time PCR analysis of the expression of Hex genes in WT and TS mice brains at different ages (embryonic, postnatal and adult) revealed the up-regulation of the hexb gene in the adult vs. the embryo mouse brain, while, at the same age, the hexa gene had a constant expression. Notable, we found a similar hexb gene behavior in the developed TS mouse brain. As consequence of the hexb gene up-regulation, we found a big increase of Hex activity in adult and postnatal wild-type mice with respect to the mice at embryonic stage. Particularly we observed a Hex B-like isoenzyme, in both WT and TS mice that corresponded to 40–45 % of the total Hex activity. Conclusion: Our data for the first time, showed the regulation at transcriptional level of the hexb gene during the brain development, and, revealed the presence of the Hex B-like isoenzyme that could be involved on the alternative ganglioside metabolic pathway observed in TS mice. Furthermore, our results suggest that, to be effective, the time of treatment must prevent the up-regulation of the Hex activity, then, must carried out at the post-natal age. P555 Impaired neural progenitor cells in extremely preterm infants may affect cortical development and function K. Deguchi, S. Takashima, D. Armstrong, K. Inoue Deguchi Pediatric Clinic (Nagasaki, JP); Yanagawa Institute for Developmental Disabilities (Fukuoka, JP); Baylor College of Medicine (Houston, USA); National Institute of Neuroscience NCNP (Tokyo, JP) Extremely preterm infants (EPIs) are at risk for brain damages such as periventricular white matter injury (PVWI) and create an increasing population with cognitive dysfunction, the most common neurological complication in EPIs, however its exact pathogenesis remain unknown. At the time of birth for EPIs, active neurogenesis and gliogenesis is occurring in ventricular and subventricular zones (VZ and SVZ) where neural progenitor and precursor cells proliferate and migrate toward their destination.We thus hypothesized that PVWI in EPIs may disrupt VZ/SVZ and concomitantly affect neural progenitor and precursor cells, thereby interrupting subsequent brain development and contributing to cortical dysfunction. We examined a series of 45 autopsy brains from EPI with PVWI in comparison with a developmental series of 40 control brains. Standard histological evaluation, immunohistochemistry of neural progenitor markers including Musashi1and Nestin, and a layer-specific marker Calbindin, and examination of apoptotic markers were performed in the VS/SVZ and cerebral cortex. We observed prominent disorganization in the VZ/SVZ, regardless of pathologic features of PVWI, gestational weeks at birth and length of survival before death. Musashi1 and Nestin-positive neural progenitors and precursors were significantly reduced in number in all cases. Residual neural progenitors in the VZ/SVZ of short-term survivors revealed TUNEL and Caspase3-reactivity, suggesting an involvement of apoptosis in the neural progenitor injury. Accordingly, an examination in long-term survivors showed a loss of postnatal neural progenitor cell lineage, i. e., ependyma cells and adult neural stem cells. In the examination of cortex, we observed scattered TUNEL- and Caspase3-positive neurons in the short-term survivors, indicating a partial neuronal loss in the early stage of disease process. In the long-term survivors, we found abnormally located Calbindin-positive neurons in layer V in addition to normally populated neurons in layer II, suggesting either delay in the maturation or displacement of the cortical neuron, either of which can be associated with retardation of cortical development. Together, our observations suggest that the injuries to the neural progenitors and precursors in VZ/SVZ are common in EPIs with PVWI and may be associated with delayed cortical development, which possibly contribute to cognitive dysfunction in EPIs

P556 Neuronal differentiation of neuroblastoma triggered nitric oxide production M. Evangelopoulos, J. Weis, A. Kruttgen University of Berne (Berne, CH); RWTH Aachen (Aachen, D) Neuroblastoma is a frequent malignant pediatric neoplasm. This tumour is remarkable regarding its potential to spontaneously differentiate and regress. The mechanisms leading to neuroblastoma differentiation are poorly understood. NB cell lines are commonly used as models to study neuronal differentiation because they retain the capacity to differentiate into a neuronal-like phenotype. Studies in other experimental systems have established that nitric oxide (NO) is an important signalling molecule triggering differentiation of neuronal cell lines and stem cells. As a model, we studied the neuroblastoma cell line Neuro2a and differentiation was induced by serum withdrawal or treatment with statins. To address whether neuronal differentiation of neuroblastoma involved production of NO, we first established by immunoblotting that Neuro2a cells express the neuronal isoform of NO synthase (nNOS). NO was detected in differentiated Neuro2a cells after serum withdrawal or after statin treatment for 24 h or, but not in proliferated cells grown under full serum conditions. The morphological differentiation of neuroblastoma cells was associated with the upregulation of the neuronal marker NeuN, the upregulation of nNOS and the rapid and sustained increases in phosphorylation of key signaling proteins including PKB (Akt). To ascertain whether NO was necessary for differentiation, cells were treated with the nitric oxide synthetase inhibitor L-NAME. L-NAME decreased PKB phosphorylation and potently blocked differentiation in a dose dependent manner. Our results indicate that differentiation of Neuro2a cells by serum withdrawal or treatment with statins triggered NO production. Supported by Stiftung Papavramides, Ehmann-Stiftung and Stiftung zur Krebsbekämpfung, Switzerland

Extrapyramidal disorders P557 Sleep and Parkinson’s disease: preliminary results N. Klepac, M. Relja Medical School, University of Zagreb (Zagreb, HR) Background: The sleep disturbance occurs frequently in Parkinson’ disease (PD). The cause of sleep disorders in PD is multifactorial, including the neurodegenerative changes affecting sleep centres and persistence of PD symptoms at night. Objective: The aim of present study was to evaluate the characteristics of sleep problems and different subtypes of PD. Patients and Methods: A consecutive series of eighty-three PD patients (39 men, 44 women) with a mean age of 61.2 ± 9.2 years, PD duration of 5.3 ± 5.4 years, mean Hoehn & Yahr stage of 2.2 ± 0.5 who fulfilled the criteria for idiopathic PD were included the study. Motor performance was evaluated using the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS). The severity of insomnia was assessed using the Pittsburgh sleep quality index (PSQI). Daytime sleepiness was evaluated with Epworth sleepiness scale (ESS). Patients were divided according to akinesia and tremor score on UPDRS in group of akinetic rigid subtype or tremor subtype. The tremor dominant subtype of PD was defined as patients with a ratio of tremor to bradykinesia score of 0.5 or more, and the akinetic rigid subtype as patients with a ratio of < 0.05. Results: Fifty-four (65 %) patients belonged to akinetic rigid subtype and 29 (34.9 %) patients to tremor subtype. There were no significant differences between groups regarding the age and duration of disease (Mann Whitney, p > 0.05). Patients with predominance of akinetic-rigid features had worse quality of sleep than tremor dominant patients (13.6 ± 3.7, 8.5 ± 3.8; Mann Whitney, p < 0.05) according to PSQI. This was evident in several different domains; subjective sleep quality, sleeps duration, sleeps latency and sleep disturbances. There was no difference in daytime sleepiness according to scores obtained on ESS. Conclusion: Our preliminary results suggest that the akinetic subtype of PD is associated with more sleep disturbances. This could be due to nocturnal immobility that interferes with normal sleep architecture. Clinician should pain attention on this group of patients regarding sleep quality.

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P558 Bipallidal lesions induce delayed and progressive parkinsonism A. Thomas, L. Bonanni, A. Luciano, K. Armellino, F. Anzellotti, S. Varanese, A. D’Andreagiovanni, M. Onofrj University G.D’Annunzio Chieti-Pescara (Pescara, I) The degeneration of nigrostriatal pathway is the principal lesion in Parkinson’s Disease and the abnormal inhibitori output from globus pallidus (GP) to the thalamus and brainstem contributes mostly to motor symptoms like rigidity and bradykinesia. In literature several cases described akatisia, restlessness, behavioural disturbances, dystonia and parkinsonism following vascular lesions of the globus pallidus or intoxications like carbon monoxide poisoning and cyanide poisoning of the globus pallidus. We describe 3 more cases of patients with pure vascolar/hypoxic bilateral lacunar lesions of the GP who developed parkinsonian features. Patient 1, 68 year old woman, presented as onset symptoms, moving toes without pain. She was treated with low dose of Gabapentin (900 mg/day) and involuntary movements disappeared and sleeping hours increased to 7–8 hours per night in two weeks. After 5 years she developed parkinsonism characterized by bradykinesia and axial dystonia. UPDRS motor subscale score was 18. MRI T2 weighted image showe bilateral pallidal lucencies. Patients 2 a 63 old woman, following a sever atrial fibrillation the patient presented bilateral pallidal lesions with high haemoglobine contents due to hemorrhagic infarction. First the patient developed tremor of the head and postural tremor of the upper limbs than she developed progressivly alien limb phenomenon, apraxia, eyelid retraction, bleating voice, upper limb dystonia, postural instability with falls, bradyphrenia, freezing of gait. Patiente 3 a 64 old woman, presente REM sleep behaviour disorder, she was treated with clonazepam, 5 years later she developed parkinsonian features MRI evidenced bilateral lucencies of the pallidum. All patients were treated with L-Dopa and/or dopamineagonist, but the response to treatment was poor or transient. We hypothesize that pallidal firing rate has become “noisy” by the lesion, likely due to a complete lesion of the external GP which lead to the disinhibitaion of subthalamic nucleus, resembling parkinsonian features, and partial lesioning of the internal GP which produce restlessness, akatesia and dystonia. The lack of response to dopaminemimetic therapy is probably based on the “post-synaptic-lesional” origin of these parkinsonian features. Progressive worsening, despite obvious vascular origine of lesions adds further informations on the pathophysiology of basal ganglia lesions. P559 Efficacy and tolerability of ropinirole in routine treatment of Parkinson’s disease patients Z. Rackova, A. Barcikova, K. Gmitterova, J. Benetin Comenius University (Bratislava, SVK) Ropinirole has been proved to be effective in early and advanced Parkinson’s disease (PD) patients by several controlled clinical trials.We performed clinical prospective study to evaluate its efficacy and tolerability in routine clinical practice. 106 patients with early PD and 162 patients with advanced PD were followed up in 48 outpatient departments after introduction of ropinirol to their PD therapy. Efficacy of ropinirole was evaluated by Unified Parkinson’s Disease Rating Scale III (UPDRS III) and Schwab-England (Sch – E) scales. During the study adverse reactions were recorded as well as doses of ropinirole and levodopa and other antiparkinsonian medication. Mean age of this PD population was 69 [43–86]. Mean duration of follow up period was 35 [4–52] weeks. Mean dose of levodopa at the beginning of follow up was 521 mg/day, at the end of was 364 mg/day. Improvement of UPDRS III was from 18, 28 up to 11, 8 in early PD patients and from 30, 7 up to 20, 9 in advanced PD patients. Improvement of Sch – E scale was 15 %. Adverse reactions were overall rare. The most common were gastrointestinal complains 9 %, somnolence 3 %, insomnia 0, 7 %, hallucinations 2, 9 %. In advanced PD patients was dystonia present before introduction of ropinirole in 31 % of patients. Under stable ropinirole dose a reduction of levodopa dyskinesias decreases in 24 % of patients and increases in 5 %. Only in 8 cases was ropinirole withdrawn due to adverse reactions and another 4 patients preliminary stopped follow up because of insufficient collaboration. Conclusions: Study suggested that ropinirole is effective and valuable medication in early PD patient in monotherapy as well as in advanced Parkinson’s disease as add-on therapy to levodopa. Ropinirole was well tolerated. Overall frequency of adverse reactions reported by neurologists in outpatient departments was markedly lower than the one reported in phase III controlled clinical trials. Low incidence of dyskinesias in advanced PD patient can bee explained by generally low dose of levodopa at the beginning of ropinirole add – on and frequent combination of levodopa with entacapone.

P560 Gender-related differences of the subthalamic action potentials in Parkinson’s disease S. Mrakic-Sposta, S. Marceglia, F. Cogiamanian, M. Egidi, E. Caputo, F. Tamma, E. Accolla, S. Barbieri, A. Priori IRCCS Ospedale Maggiore Policlinico (Milano, I); Università di Milano (Milano, I); Azienda Ospedaliera San Paolo (Milano, I) Objectives: The human brain displays several gender-related differences, including morphological, neurophysiological and hormonal specificities. In this study we sought possible gender-related differences in the electrical activity by studying neuronal action potentials in the subthalamic (STN) area during DBS surgery. Methods: Single-units were recorded during the microelectrode-guided stereotactic procedure for localizing the STN in 15 patients (9 male-M- and 6 female-F-) affected by PD. Neuronal activity was recorded through a concentric bipolar microelectrode (0.7–1 MOhm; at 1 MHz), from the subthalamic nucleus (STN) and the substantia nigra (SN). We measured the spike amplitude [micro, V], spike area [micro, V*ms], spike duration [ms], rise time [ms], and average firing rate [Hz]. We characterized 142 M and 78 F single-units in the STN, 57 M and 11 F in the SN. Results: We found significantly higher STN cell amplitude and area in males than in females (amplitude: 41.97 ± 32.74 vs 26.19 ± 19.73 micro;V, p < 0.0001; area: 31.77 ± 26.43 vs 12.98 ± 10.56 micro;Vmsec, p < 0.001), whereas the average firing rate was lower in males than in females (64.11 ± 50.51 vs 82.74 ± 49.61 Hz, p = 0.001). In SNr the variables measured did not differ between the two genders. Conclusions: Our data demonstrate the existence of gender-related differences in the action potentials from the human STN area in Parkinson’s disease. P561 Altered cortical activation of patients with blepharospasm during repetitive forearm contraction: an fMRI study M. Obermann, O. Yaldizli, A. DeGreiff, M. L. Lachenmayer, F. Tumszak, A. R. Buhl, J. Vollmer-Haase, E. R. Gizewski, H. C. Diener, M. Maschke University of Duisburg-Essen (Essen, D); Knappschafts-Krankenhaus (Recklinghausen, D) Background: Idiopathic blepharospasm is a common focal dystonia characterized by involuntary eyelid closure. Etiology appears to be multifactorial, including the influence of a genetic background and a possible environmental trigger. Genetics may play a role in reduced brain inhibition leading to increased brain plasticity. Objective: To determine whether cortical activation of patients with blepharospasm compared to healthy controls is altered during a repetitive forearm contraction task using fMRI. Methods: Eleven patients (mean age 52.45 ± 10.82 SD; male 4 female 7) with blepharospasm were compared to seven (mean age 49.33 ± 12.48 SD; male 3 female 4) healthy controls using high-resolution fMRI. Both groups were scanned (Siemens symphony scanner, 1.5 Tesla) while contracting either the right or left hand (frequency 1 Hz) in an alternating block design including a rest condition (each condition presented 30 s). All patients were under treatment with botulinum toxin A with a mean duration of illness of 5.55 ± 4.25 SD years. For statistical analysis we performed an ANOVA using SPM2. Results: Patients with blepharospasm showed an increased activation in the contralateral primary sensorimotor and premotor areas (global maxima: right (x,y,z): –30,–30.72 mm, Z = 4.95, p < 0.001; left: 44,–12, 58 mm, Z = 5.24, p < 0.001), the cingulum, ipsilateral cerebellar hemisphere and vermis compared to healthy controls. Conclusion: The increase of movement associated cortical activation in patients with blepharospasm points towards an altered sensorimotor integration in focal dystonia. Results of the present study are in line with behavioural studies of our group and others that revealed an impaired sensorimotor integration in focal dystonia, e. g. impaired discrimination and detection of passive movements. Moreover, our results confirm studies in focal hand dystonia, which also showed an abnormal recruitment of cortical areas involved in the control of voluntary movement P562 Safety aspects of high-dose xeomin therapy D. Dressler, F. Adib Saberi Rostock University (Rostock, D); Klinikum Nord.Heidberg (Hamburg, D) Recently, Xeomin® (Merz Pharmaceuticals, Frankfurt/M, Germany), a novel therapeutic preparation of botulinum toxin (BT) type A, was introduced. It

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differs from conventional therapeutic BT preparations, since all complexing proteins of the BT component could be removed, thus reducing its molecular size to 150kD as compared to 900kD of the conventional BT type A preparations. The purpose of this study was to evaluate whether the reduced molecular size of Xeomin® alters its tissue diffusion and thus its adverse effect profile. For this 37 blinded patients (age 49.3 ± 17.4 years, 22 females, 15 males) were included in this study. 13 patients suffered form cervical dystonia (BT dose 341.5 ± 57.4MU, min 300MU, max 460MU, number of target muscles 7.5 ± 1.8, BT dose per target muscle 48.7 ± 17.8MU), 9 from arm spasticity (mean dose 397.8. ± 90.8MU, min 300MU, max 580MU, number of target muscles 3.7 ± 1.3, BT dose per target muscle 114.8 ± 23.5MU), 9 from arm and leg spasticity (BT dose 590.0 ± 14.4MU, min 440MU, max 840MU, number of target muscles 6.6 ± 1.3, BT dose per target muscle 91.0 ± 14.4MU) and 6 from generalised spasticity (BT dose 643.3 ± 195.3MU, min 300MU, max 840MU, number of target muscles 7.0 ± 3.3, BT dose per target muscle 126.8 ± 93.4MU). Patients had been treated with BT type A (Botox®, Allergan, Irvine, CA, USA, 100MU/2.5 ml 0.9 %NaCl/H20) for 3.2 ± 1.9 years before they received Xeomin® (100MU/2.5 ml 0.9 %NaCl/H2O). The minimum Botox® pre-treatment time allowed was 1 year.All patients had stable Botox® treatment results without complaining of adverse effects. Patients were selected for this study in order to construct a Xeomin® dose escalation scheme. None of the patients complained of local, regional or systemic adverse effects when they received Xeomin®. Shortness of breath, fatigue, accommodation difficulties, constipation, heart burn, dryness of eye or mouth were explicitly denied. None of the patients reported differences between Xeomin® and Botox® with respect to intensity and duration of the therapeutic effect. These data show that [1] BT type A preparations can be safely used in doses of up to 840MU, [2] Xeomin® and Botox® can be converted by a 1:1 conversion ratio and [3] Botox® and Xeomin® have identical adverse effect profiles even when high doses are applied, suggesting that the influence of the complexing proteins on the tissue diffusion of BT preparations is limited. DD has been consultant to Allergan Inc, Ipsen Ltd, Elan Plc and Merz Pharmaceuticals

Multiple sclerosis P563 Apolipoprotein E genotype does not associate with disease severity measured by Multiple Sclerosis Severity Score A. L. Guerrero, E. Laherran, F. Gutiérrez, J. Martín-Polo, C. Alcázar, J. Peralta, P. Rostami, M. Rodríguez-Gallego Hospital Rio Carrion (Palencia, E) Objectives: During last years, association between Apolipoprotein E (APOE) polymorphism and disease susceptibility and severity in Multiple Sclerosis (MS) has been studied with conflicting results. Due to a considerable individual variation in the clinical course of MS, there is no consensus method for measuring progression using single assessments of disability. Recently, the Multiple Sclerosis Severity Score (MSSS) has been proposed as a powerful method for compare disease progression using single data. MSSS corrects Expanded Disability Status Scale (EDSS) for duration, comparing an individual’s disability with the distribution of scores in patients with equivalent disease duration. We pretend to evaluate in our population if there is any correlation between APOE genotype and severity according to MSSS. Methods: We considered 82 patients (62 female/20 male) followed in our Neurology Unit throughout the year 2005,due to a diagnosis of multiple sclerosis, and with disease duration of at least two years. We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, EDSS score and total number of relapses. When reached, we determined the latency to EDSS scores of 4.0 and 6.0. We calculated the Progression Index (EDSS/time from onset in years) and the Relapse Rate (number of relapses/time from onset in years). We ascertained MSSS for our patients in the global MSSS table. The APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient’s subgroups with allele E2 or E4 and the mentioned variables were tested using the t test or the U Mann Whitney test when appropriate. A p value less than 0.05 was considered statistically significant. Results: We found 4 patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4.

Relapse Rate (p: 0.017 with IC 95 %: 0.005–0.57), and Progression Index (p: 0.016 with IC 95 %: 0.004–0.38) were significantly lower in E4 carriers. MSSS scores were not associated with carriership of E2 or E4. Conclusion: Our results show no effect of the APOE genotype on the severity of Multiple Sclerosis measured by MSSS. In our population, using of Global MSSS seems to correct contradictory results that indicate an association of the E4 allele with a less severe course of the disease measured with Progression Index. P564 Serum uric acid levels variation in multiple sclerosis during relapses and immunomodulatory treatment A. L. Guerrero, E. Laherrán, J. Martín-Polo, F. Gutiérrez, M. Rodríguez-Gallego, A. Gurruchaga, C. Alcázar, J. Peralta Hospital Rio Carrion (Palencia, E) Objectives: Uric acid (UA), a product of purine metabolism, is an antioxidant, and a scavenger of peroxynitrite, which is the product of nitric oxide and superoxide. Peroxynitrite exerts a toxic effect on neurons, axons, and glia cells and increases the blood-central nervous system-barrier permeability. Patients with gout have a reduced incidence of Multiple Sclerosis (MS). A number of studies found that patients with MS have low serum levels of UA, although it has not been established whether this represents a primary deficit or a secondary effect. UA has also been proposed as a marker of disease activity, as some authors have shown that UA levels are lower during clinical or magnetic resonance imaging (MRI) activity than in remission. UA levels increase after high-dose methylprednisolone relapse therapy and during treatment with Glatiramer Acetate. Methods: We retrospectively reviewed 83 Relapsing-Remitting or Secondary Progressive MS patients (64 females and 19 males) followed in our Neurology Unit. We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, Expanded Disability Status Scale (EDSS) score and total number of relapses. We considered UA levels in three different situations: during a relapse, during remission period and during remission period under immunomodulatory treatment (Interferon beta or Glatiramer Acetate). A paired-mean analysis was carried out to determine differences between groups. A p value less than 0.05 was considered statistically significant. Results: In 33 patients we were able to compare at least one UA value obtained during a relapse with at least one when remission without treatment. Mean serum UA levels were significantly lower when measured during a relapse. (r: 0.39, p: 0.024) In 27 cases we compared at least one remission value without treatment with at least one obtained during remission and immunomodulatory treatment. Mean serum UA levels significantly increased when determined during Interferon beta or Glatiramer Acetate therapy (r: 0.84, p < 0.001) Conclusion: Our data show that UA levels increase during immunomodulatory treatment. This study also suggests that serum UA might serve as a possible marker of disease activity in MS. P565 Value of cytokine gene polymorphisms as prognostic markers of efficacy of interferon beta-1b (Betaferon®) in relapsing-remitting multiple sclerosis A. L. Guerrero, E. Arranz, D. Pérez, J. A. Garrote, A. Mendoza, J. T. López-Alburquerque, A. B. Caminero, J. C. Morán. GENPROCLEM Group Objectives: The response to immunomodulatory agents used in the treatment of Multiple Sclerosis (MS) is highly variable. The genetic heterogeneity characterizing the disease may contribute to this variability. Cytokinecoding genes might be possible prognostic factors of response to treatment. An open, multicentric, prospective, longitudinal, case-control observational study is being conducted, in which 11 hospitals with neurology specialists belonging to the Public Health Network SACYL (Castilla y León Autonomous Community, Spain) participate. The main goal is to assess whether certain cytokine-coding genes might have a prognostic value as markers of response to treatment with Interferon beta-1b (BETAFERON®). Methods: A total of 25 MS patients, in whom treatment with Betaferon® was initiated previously to inclusion (following prescription by each investigator, based on clinical criteria and further approval by the “Advisory Committee for the Treatment of MS” that regulates the use of immunomodulatory agents in our Community) will be recruited. Patients previously treated with other immunomodulatory agents are excluded. The following polymorphisms are determined by PCR-SSP: TNFalpha (G-A transition in position –308 of its promoter), LTalpha (transition G-A in position + 249 of its first intron), TGFbeta (transition T-C in codon 10 and C-G in codon 25), IL6 (transition C-G in position –174 of its promoter), IL-10 (transitions A-G in

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position –1082, T-C in position –819 and A-C in position –592 of its promoter), IFNgamma (transition T-A in position + 874 of intron 1), CTLA-4 (transition A-G in position + 49,exon 1) and IL-1 receptor antagonist (VNTR detected minisatallites). Results: Included patients sign an Informed Consent. Information is handled anonymously after double encrypting: the clinician has only access to personal and clinical data of his patients; the geneticist has only access to genetic data; and a third party will create a database with clinical and genetic data at the end of the study, including no sensitive personal data. Demographic and clinical data from each patient are collected on the basal visit. Clinical follow-up will be conducted for 2 years, including the relapse rate and the EDSS score every 6 months. Conclusion: Correlations between the cytokine gene polymorphisms in each patient and his/her condition as Responder or Non-Responder to treatment with Betaferon® will be analyzed at the end of the 2-years follow-up period. This study is supported by Schering España S. A. P566 Factors influencing interruption of disease-modifying agents in multiple sclerosis V. Nociti, L. Padua, M. Mirabella, A. K. Patanella, C. Sancricca, M. Caggiula, G. Frisullo, F. Angelucci, P. A. Tonali, A. P. Batocchi Catholic University (Rome, I) Objective: In order to identify factors influencing interruption of disease modifying agents and to investigate reasons for stopping and switching therapy, we analysed clinical data of 212 MS patients attending our Multiple Sclerosis centre from January 2000 to May 2005. Methods: The study was a retrospective chart review of 212 patients (62 men and 150 women) with clinical definite MS. One hundred and eighty patients were affected by relapsing-remitting MS and 32 by secondary-progressive MS. A neurological examination was performed at the first observation and every three months thereafter (as sooner if relapse occurred); at each visit the number of intercurrent relapses, Expanded Disability Status Scale (EDSS) and type and severity of side effects were recorded; the principal haematological variables (complete blood count, liver and kidney function) were evaluated at the same time. Statistical analyses were carried out using two multiple regression analyses for each group of patients (we classify patients on the ground of therapy). Results: Age of patients and number of years of therapy before the shift are the main predictive variables (p < 0.01) for changing therapy followed by number of relapses before the beginning of therapy and worsening of EDSS from baseline (p < 0.05). The highest proportion of interruptions occurred in the first year (40/180 patients –22 %-). 70 patients stopped therapy: 30/79 patients (38 %) treated with IFN beta1a IM (27 for lack of efficacy, 2 for liver test abnormality, 1 for ‘flu-like syndrome’); 21/56 (37 %) patients treated with IFNbeta-1a 22 mcg SC (18 for lack of efficacy, 2 for ‘Flu-like syndrome’ and 1 for liver test abnormality); 6/10 (60 %) patients treated with IFNbeta-1a 44 mcg SC (3 for lack of efficacy, 1 for leucopoenia, 2 for liver test abnormality); 11/49 (22 %) patients treated with IFNbeta-1b SC (10 for lack of efficacy and 1 for liver test abnormality); 2/15 (13 %) patients treated with glatiramer acetate for dizziness. Conclusions: Age, number of years before shift therapy, number of relapses and EDSS before the beginning of therapy were the main predictive variables influencing drug interruption. The critical period for stopping drug was the first year of treatment. The main reasons for stopping and switching therapy were the lack of efficacy followed by side effects.

Four patients have multiple affected family members. Demographic and clinical features of the cases with familial recurrence of MS (age at disease onset, symptoms at manifestation, initial relapse rate and course of disease) were compared with those of the sporadic cases. In cases from multiplex families age at onset was significantly lower (30 vs. 33.1years; p = 0.04) than in sporadic cases. Cases with affected parents had the lowest disease onset age (mean 24.4 yrs) and showed first symptoms significantly earlier than their parent. There was a substantial excess of optic neuritis as initial symptom in the familial cases (36 vs 25 %, p = 0.02). Male to female ratio [1:2, 4] was greater than in the sporadic cases [1:2, 7]. No difference between familial and sporadic cases was found regarding mean age at present (47.5 vs 47.9 years) and mean duration of disease (16.9 vs 15.1 years). The groups closely resembled each other in parameters of disease course (initial relapse rate, time to second relapse, proportions of disease types) and outcome (EDSS after 5 and 10 years). The data suggest that type of presenting symptom, especially optic neuritis, as well as age at disease onset may be under genetic control. Regarding concordant parent-child pairs there might be an anticipating effect in disease manifestation, but earlier diagnosis due to more awareness of symptoms and improved diagnostic tools in the following generation should be taken into account. This work was supported by BIOGEN GmbH, Schering GmbH, Serono Pharma GmbH and TEVA Pharma GmbH/Aventis P568 A primary study on familial morbidity of multiple sclerosis in Chania, Crete N. Kouroumalos, E. Nikolakaki, K. Giouzepas, E. Kalamafkianaki, V. Christoforakis, A. Bellou, G. Georgakakis General Hospital of Chania (Chania, GR) Objectives: Prevalence in Chania according to data of MS reference center in Chania Crete, on September 2005, seems significantly higher (87.1/100.000 or 131 patients/150.387 population) compared to both the outcome of the previous epidemiological study (pr: 16.68/100.000 – Kylindireas 1985) as well as the value range for Southern Europe (except Sardinia). Given this discrepancy we formulated a hypothesis that familial incidence of MS would appear high, in accordance to the high prevalence. Methods: In a retrospective study, files of patients hospitalized in our clinic, from 1990 to 2004(n = 131) were examined and records of 1st, 2nd and higher degree relatives who suffered from MS, were formed. Correlations were carried out between several parameters, such as age, gender, type of MS and disease onset among patient with or without familial incidence of MS as well as relatives. Results: Among the total number of patients with MS, 15.5 % (20/131), have a relative also suffering from MS. Specifically, 11.36 % (15/131), of patients have a 1st degree relative suffering from MS. Among those 5 are children and patients, and 10 are siblings. The other 5 are higher than 1st degree relatives. Mean value of age of disease onset is significantly smaller for patients with familial incidence of MS compared to those without (t(0.032) [129]= 1.914). Female to male ratio was found higher among patients with familial incidence of MS than among those without. Conclusion: Our hypothesis is confirmed in that a high number of familial cases are noted in accordance to high prevalence. The percentage of familial incidence lies within the higher values (15–20 %) of the range reported in bibliography.

P567 Clinical features of familial multiple sclerosis – data from a populationbased case register at Erfurt, Germany P. Fasbender, H. W. Kölmel HELIOS-Klinikum Erfurt (Erfurt, D)

P569 Design of a randomised, placebo-controlled study of oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis L. Kappos, P. Calabresi, R. Hohlfeld, P. O’Connor, C. Polman, S. Aradhye University Hospital (Basel, CH); Johns Hopkins Hospital (Baltimore, USA); Ludwig Maximilians University (Munich, D); St. Michael’s Hospital (Toronto, CAN); Free University Hospital (Amsterdam, NL); Novartis Pharmaceuticals Corporation (New Jersey, USA)

Studying familial cases of multiple sclerosis (MS) gives clues to weighing risk factors for familial recurrence and the impact of genes on different disease parameters. Concordance studies in multiple sclerosis suggest that age at disease onset might be to some extent under genetic control. The risk of siblings to develop MS was found to increase with lower age of disease onset of the index patient. 1998 a population based MS register was established in Erfurt, the capital of Thuringia, Germany, assembling 841 consecutive cases by now. Seventy-two patients (8.6 %) were found to have a relative with MS. Classified by type of relative these are: concordant siblings (41 %), affected parent or child (38.5 %) and more distant relatives with multiple sclerosis (20.5 %).

Objectives: Fingolimod, an oral sphingosine-1-phosphate receptor modulator, limits the egress of T cells from peripheral lymph nodes, thereby reducing inflammatory cells recirculating to the central nervous system. In a 6month Phase II study, fingolimod reduced inflammatory activity on frequent MRI by up to 80 % and relapse rates by more than 50 %, compared with placebo. A large randomised, double-blind, placebo-controlled Phase III study (Protocol 2301) has been initiated to further evaluate efficacy and safety of fingolimod in patients with RRMS. Methods: Inclusion criteria: diagnosis of RRMS with ≥ 1 documented relapse during the past year or two relapses in the past 2 years, age 18–55, an Expanded Disability Status Scale (EDSS) score of 0–5.5, and no evidence of

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relapse for 30 days prior to screening. Approximately 1.100 patients from more than 100 centres worldwide are being randomised in a 1:1:1 ratio to once-daily fingolimod 1.25 mg, fingolimod 0.5 mg, or placebo, for up to 24 months. Ethical considerations relating to placebo use have been addressed by: fully apprising participants of current treatments, including patients if they formally decline available therapies; obtaining a well-informed, formal re-consent whenever a relapse or progression of disability occurs. The primary outcome measure is relapse rate at 24 months. Secondary outcome measures include disability progression as measured by EDSS; time to first relapse; proportion of relapse-free patients at 12 and 24 months; MRI measures including change from baseline in volume of T2 lesions at months 12 and 24, and change from baseline in volume of T1-hypointense lesions at month 24. Relapse severity, corticosteroid use, hospitalisations and quality of life measures will also be assessed. Safety assessments include physical exams, vital signs, laboratory analyses, ECGs, chest X-rays, pulmonary function tests and ophthalmic examinations. Assuming a 15 % dropout rate, a sample size of 1100 patients provides a power of > 90 % to detect a ≥ 40 % reduction in relapse rates between fingolimod and placebo groups.All efficacy analyses will be based on the intent-to-treat population. Statistical methods will be discussed. Results: Recruitment started in January 2006. Results are expected in 2009. Conclusion: This study will help in defining the role of fingolimod as a new oral treatment option for RRMS. This study was supported by Novartis Pharma AG

P570 Results of a randomised, double-blind, parallel-group study assessing safety and efficacy of 40 mg vs. 20 mg of glatiramer acetate on MRI-measured disease activity in relapsing-remitting multiple sclerosis M. Rovaris, J. Cohen, A. Goodman, G. Comi, M. Filippi on behalf of the 9006 Study Group Objectives: Twenty mg GA (Copaxone®) is an approved therapy for relapsing-remitting multiple sclerosis (RRMS). Its safety and efficacy are supported by three pivotal trials and over a decade of experience. We evaluated safety and efficacy of 40 mg of glatiramer acetate (GA) given subcutaneously every day for 9 months vs. those of the approved drug formulation (20 mg) in RRMS patients. Design/Methods: Key eligibility criteria included clinically definite MS with a relapse in the prior year, EDSS score 0–5.0, no prior use of GA and at least one gadolinium (Gd)-enhancing lesion on a screening MRI. Subjects underwent MRI scans at baseline and at months 3, 7, 8 and 9. Neurological examinations were performed at baseline and at months 3, 6 and 9. Suspected on-trial relapses were confirmed at an unscheduled visit. The primary efficacy endpoint was the total number of Gd-enhancing lesions at months 7, 8 and 9. The difference between the two treatment arms was assessed using a Poisson regression model accounting for study site and baseline Gd-enhancing lesion counts. Results: Of 229 screened subjects 90 were eligible. The two treatment groups were well-matched for age, disease duration, EDSS, pre-study annual relapse rate and number of Gd-enhancing lesions at baseline. A 38 % greater reduction (relative risk = 0.62, 95 % CI = 0.36–1.08, p = 0.0898) in favour of 40 mg vs. 20 mg in the mean cumulative number of Gd-enhancing lesions at months 7, 8 and 9 was observed (mean per scan = 0.79 vs. 1.32 lesions for the 40 and 20 mg groups, respectively). This difference emerged as early as month 3 (mean number of lesions was 1.33 and 2.61 for the 40 and 20 mg groups; p = 0.005). When compared to baseline, the risk of having enhancement in the 40 mg group at months 7, 8 and 9 was reduced by 75 % (relative risk = 0.25, 95 % CI = 0.15–0.40, p < 0.0001) and by 65 % in the 20 mg group (relative risk = 0.35, 95 % CI = 0.24–0.53, p < 0.0001). Mean relapse rate during the study period was 0.34 in the 40 mg and 0.57 in the 20 mg group. In the 20 % of subjects who experienced a relapse during the trial, time to the first relapse was delayed from 80 days in the 20 mg group to 213 days in the 40 mg group (p = 0.0367). GA 40 mg was well-tolerated with a safety profile similar to the 20 mg dose. Conclusions: Over a nine-month period of observation, GA 40 mg is safe, well-tolerated and more effective than the currently approved 20 mg dose in reducing MRI activity and relapse rate in patients with RRMS. This study was supported by TEVA Pharmaceutical Industries

P571 Alemtuzumab and craniotomy for severe acute demyelinating illness K. M. Gormley, J. P. Zajicek Derriford Hospital (Plymouth, UK) A 37-year-old female in the immediate puerperal period presented with an acute severe demyelinating illness, which did not respond to high doses of intravenous steroids, immunoglobulin or plasma exchange. In keeping with a Marburg variant or tumefactive demyelinating disease, the clinical course indicated a space demanding process as well as a demyelinating one. At her worst, the patient was aphasic and unable to move any limb. Failure of conventional therapy necessitated decompressive craniotomy to alleviate brainstem compression as a neurosurgical emergency, at which point a biopsy was also performed. This was followed by intravenous alemtuzumab. From a virtually moribund condition, the patient improved to the point of returning to her normal life, with minimal language problems. Although emergency craniotomy has been reported once before in this situation, this is the first time such a successful combined neurosurgical and medical approach has been reported to treat malignant demyelinating disease, with good results up to 12 months after initial presentation. P572 Prevalence of multiple sclerosis in Isfahan, Iran V. Shaygannejad, F. Ashtari, M. Etemadifar Isfahan University (Isfahan, IR) Background: The prevalence of multiple sclerosis (MS) has a considerable variability all over the world. According to Kurtzke, Iran is considered to have low prevalence. Objective: To estimate the period prevalence and risk factors of MS in Isfahan, central part of Iran. Methods: A cross-sectional case register study conducted from 2004 to 2005. In the province of the Isfahan, Iran, all patients known to have definite multiple sclerosis during 2004 to 2005 and alive and resident within the Isfahan and were member of Isfahan MS Association were included in the study. Demographic and case-related information was recorded. 1391 definite MS patients (308 men and 1083 women) from Isfahan MS Association, Iran have been identified. The disease was confirmed according to clinical information and magnetic resonance imaging findings by a neurologist and radiologist. The patients were evaluated by interview and a questionnaire. The mean (SD) age of participants was 32.5 (9.3) years with a mean (SD) duration of disease of 6.4 (5.1) years for men and 6.9 (5.3) years for females. Results: The period prevalence of MS was 35.5 per 100.000 [95 % confidence interval (CI) 33, 6, 37, 3] in a population of 3.923.255, with higher rate in women than men (54.5 (95 % CI: 51.1, 57.8) women and 14.9 (95 % CI: 13.3, 16.6) men). The female/male ratio was 3.6 (95 % CI: 3.2 to 4.1). MS rates were highest among 30–39 year olds and decrease with increasing age. Sensory and visual disturbance were the most common initial presentation with a prevalence of 51.1 % (95 % CI: 48.4, 53.7) and 47 % (95 % CI: 44.4, 49.7) respectively Conclusion: The Isfahan could be considered as an area of medium-high risk. This is in sharp contrast with the gradient hypothesis. P573 Safety of a novel oral single-agent fumarate, BG00012, in patients with relapsing-remitting multiple sclerosis: results of a phase 2 study R. Gold, E. Havrdova, L. Kappos, V. Limmroth, D. Miller, C. Polman, M. Yang, M. Eraksoy, E. Meluzinova, I. Rektor, G. N. O’Neill University Clinic Gottingen (Gottingen, D); General Teaching Hospital (Prague, CZ); University Hospital Basel (Basel, CH); City Hospital of Cologne (Cologne, D); University College London (London, UK); VU Medical Centre (Amsterdam, NL); Biogen Idec (Cambridge, USA); University of Istanbul (Istanbul, TR); Faculty Hospital V Motole (Prague, CZ); Masaryk University (Brno, CZ) Objective: To determine the safety and tolerability of BG00012, a novel oral fumarate preparation, in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: This was a randomised, double-blind, placebo-controlled, phase 2 clinical trial conducted at 45 clinical centres in Europe. Men and women 18 to 55 years of age were eligible for the study if they had a diagnosis of RRMS and an Expanded Disability Status Scale score between 0.0 and 5.0. Patients also must have had either ≥ 1 relapse within 12 months prior to randomisation with lesions on cranial magnetic resonance imaging (MRI) consistent with MS, or had gadolinium-enhancing (Gd +) lesions on cranial MRI within 6 weeks of randomisation. Patients were assigned to four treat-

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ment groups and received BG00012 capsules 120 mg by mouth (PO) once daily (120 mg/day), 120 mg three times daily (360 mg/day), 240 mg three times daily (720 mg/day), or placebo. The study consisted of two phases: a 24-week, double-blind, placebo-controlled treatment phase, followed by a 24-week, dose-blinded, safety-extension phase in which all patients received BG00012. Patients received physical exams and had haematological assessments and urinalysis during both phases. All adverse events (AEs) were reported, regardless of severity or relationship to study drug. Results of the treatment phase are reported and data are pooled among BG00012 dose groups. Results: Of 257 patients enrolled, 176 (92 %) BG00012 patients and 59 (91 %) placebo patients completed the 24-week treatment phase. The most common AEs were flushing, headache, nasopharyngitis, and nausea. The overall incidence of infection was similar in patients treated with BG00012 and patients treated with placebo. Conclusion: BG00012 was safe and well tolerated in RRMS patients over 24 weeks of treatment. This study was sponsored by Biogen Idec and Fumapharm AG. P574 Cognitive impairment in early multiple sclerosis: an independent predictor of burden? S. Simioni, J.-M. Annoni, L. Bruggimann, C. Ruffieux, J. Bogousslavsky, M. Schluep Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Objective: Cognitive impairment occurs during multiple sclerosis (MS) and contributes actively to the burden of the disease. Its effect in the initial phase of MS still needs to be determined as heterogeneous criteria have often been used considering MS phenotype,duration and handicap.We propose to evaluate cognition and the consequences of deficits in a uniform group of early MS patients. Methods: We enrolled 106 patients with a diagnosis of confirmed MS (61 with relapsing-remitting [RR] MS and 14 with a single relapse but dissemination in time and space demonstrated by magnetic resonance imaging [MRI]) or possible MS (9 with a monosymptomatic, 22 with a multisymptomatic isolated relapse, positive oligoclonal bands in the cerebrospinal fluid and positive MRI at the time of diagnosis) according to McDonald’s criteria. Mean disease duration was 2.4 years and mean Expanded Disability Status Scale (EDSS) score was 1.7 (range 0–2.5). They were tested for long-term memory, executive functions and attention, as well as for fatigue, mood disorders, handicap and quality of life (QoL). Parametric and non parametric tests were used for statistical analysis. Results: Twenty-nine patients (27.4 %) were cognitively impaired: 20.8 % had learning deficits, 11.3 % attentional and 5.7 % executive impairment. The prevalence of cognitive impairment only showed a trend to a difference between confirmed and possible MS (32 % vs. 16 %; p = 0.1), and between patients with RRMS, a monosymptomatic or a multisymptomatic isolated relapse (33 % vs. 12 % vs. 25 %; p = 0.2). It was independent of MS duration (p = 0.8) and EDSS score (p = 0.2). In the possible MS group, 3 out of 7 (43 %) patients who confirmed MS by a second relapse during follow-up (range 4–21 months) had cognitive deficits. Cognitive dysfunction was associated with depression (p = 0.006) but not with anxiety, fatigue, handicap or QoL. Conclusion: We confirmed that mild cognitive deficits occur in early MS. They were significantly associated with depression, but had no impact on handicap and QoL at this stage. Their comparable frequency in possible and confirmed MS questions their weight as a parameter reflecting MS initial severity. A longitudinal evaluation would help to determine whether cognitive impairment represents an independent factor for predicting MS burden of disease, and whether the course of MS differs between patients with and without cognitive deficits. P575 Foxp3 and T-bet expression in circulating mononuclear cells of relapsingremitting multiple sclerosis patients: correlation with disease activity G. Frisullo, M. Mirabella, F. Angelucci, M. Caggiula, C. Sancricca, A. K. Patanella, V. Nociti, R. Iorio, P. A. Tonali, A. P. Batocchi Catholic University (Rome, I); Catholic University – Fondazione Don Carlo Gnocchi (Rome, I) Objectives: To evaluate the expression of Foxp3 and T-bet in peripheral blood mononuclear cells of patients affected by Relapsing- remitting multiple sclerosis (RRMS) in different phases of disease activity (relapse-remission) and healthy subjects. Methods: We studied 20 RRMS patients, 10 in relapse and 10 in remission, and 10 age and sex matched healthy subjects. Isolated PBMC were incubated with specific PC5-conjugated anti-CD4, CD8 and CD25 antibody.

For Foxp3 and T-bet detection, PBMC were fixed, permeabilized and then incubated for 30 min with the specific PE-conjugated antibody. After incubation, cells were washed again and resuspended in PBS for flow cytometry (FCM). Results: CD4 + CD25 + T cells were present with the same frequency in peripheral blood of healthy subjects and RRMS patients in relapse and in remission. There was no difference among the three groups in the frequency of circulating CD4 + T cells expressing high levels of CD25 (CD4 + CD25h). We did not find any significant difference in mean Foxp3 expression in CD4 + CD25 + T cells and in CD4 + CD25 + Foxp3 + T cells count between RRMS patients and controls.When we divided the patients according to disease activity we found that the mean expression of Foxp3 was higher in CD4 + CD25 + T cells of remitting than relapsing RRMS. Moreover Foxp3 expression in CD4 + CD25 + T cells was higher in remitting RRMS patients than in controls though not reaching significant difference. The mean expression of T-bet was higher in RRMS patients in relapse than in patients in remission or in controls both in CD4 + and CD8 + T cells. Conclusion: We observed an inverse correlation between Foxp3 and Tbet expression in PBMC of RRMS patients in different phases of disease activity. The up-regulation of T-bet expression in circulating CD4 + and CD8 + T cells of RRMS patients in relapse was associated with a down-regulation of Foxp3 expression on CD4 + CD25 + T cells; on the contrary in patients in remission we found high levels of Foxp3 in CD4 + CD25 + T cells and low levels of T-bet in CD4 + and CD8 + T cells. This work was supported by grants from Fondazione Italiana Sclerosi Multipla(FISM 2003) and Italian Ministry of Health (Finalizzato 2003) P576 The neuroprotective potential of immune cells: the role of gender, age and multiple sclerosis M. Caggiula, A. P. Batocchi, G. Frisullo, F. Angelucci, V. Nociti, A. K. Patanella, C. Sancricca, P. A. Tonali, M. Mirabella Catholic University – Fondazione Don Carlo Gnocchi (Rome, I); Catholic University (Rome, I) Inflammatory reactions in the central nervous system are usually considered detrimental, but recent evidence suggests that they can also be beneficial and even have neuroprotective effects. Those effects are, at least in part, mediated by the release of neurotrophic factors. In multiple sclerosis (MS) the beneficial effect of inflammation seems to be greater in younger patients and in the ones with a shorter disease duration. Few data are, to date, available about neurotrophin production in healthy people. Objective: The aim of this study was to compare brain-derived neurotrophic factor (BDNF) production by peripheral blood mononuclear cells (PBMCs) in healthy subjects with its levels in a large group of relapsing-remitting (RR) MS patients. Methods: We determined BDNF production by unstimulated PBMCs derived from 43 healthy subjects (23 females and 20 males) and 77 patients with RR MS (53 females and 24 males). Mean age of controls was 43.9 ± 14.8 years (43.7 ± 14.7 as to females and 44.15 ± 15.4 as to males); nine females were postmenopausal. Mean age of RRMS patients was 31.3 ± 9.5 years; mean disease duration was 4.8 ± 5.9 years. All patients were in stable phase of disease. The last relapse or steroid administration had occurred at least 3 months before blood sample. None of our patients had ever been treated with any immunomodulatory drugs except corticosteroids. Spontaneous BDNF production was measured in duplicate by enzymelinked immunoabsorbent assay (ELISA) in supernatants of PBMCs. Results: In healthy subjects we found that PBMCs derived from females produced higher levels of BDNF as compared with PBMCs from males. Besides, we observed an inverse correlation between age and BDNF production by PBMCs. Also among MS patients we detected higher BDNF levels in females than in males. Moreover, BDNF production seems to decline during the course of the disease. Relapse rate in the year before and EDSS score seemed not to influence BDNF production by PBMCs. We also found that PBMCs from healthy subjects produced higher levels of BDNF than PBMCs from MS patients in stable phase of disease. Conclusions: These data demonstrate that BDNF production by immune cells is more effective in females than in males both in MS patients and controls. It declines with age in healthy subjects and seems to be reduced in MS where it is inversely correlated with disease duration.

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P577 Haemorrhagic ADEM or possibly acute haemorrhagic leukoencephalopathy and subsequent progression to multiple sclerosis – A case report M. J. Stone, M. B. Davies, C. P. Hawkins University Hospital of North Staffordshire (Stoke-on-Trent, UK) We report the case of a 32 year old woman was admitted to the University Hospital of North Staffordshire in 1996 with sudden onset occipital headache, right sided hemiplegia and encephalopathy. Her magnetic resonance imaging (MRI) revealed multiple areas of abnormal high T2 signal in both cerebral hemispheres with evidence of haemorrhage with a lesion in the right parietal lobe. Magnetic resonance angiogram was normal. Cerebrospinal fluid (CSF) analysis showed 130 red blood cells x10^6/litre, a lymphocytic pleocytosis (31 x10^6/litre white blood cells), a CSF protein of 0.56 g/dl and a glucose level of 3.6 mmol/litre (plasma glucose 7.5 mmol/litre). Oligoclonal bands were present in both serum and CSF indicating both intrathecal and systemic IgG production; however the majority of the bands where in the CSF. Blood serology and CSF polymerase chain reaction (PCR) were negative for Herpes simplex virus, Cytomegalovirus, Epstein-Barr virus, Coxsackie, and Borrelia burgdofferi. Repeat MRI at three months revealed resolution of the T2 lesions and no new lesions. The patient improved following treatment with intravenous methylprednisolone 1 gram daily for 3 days. The discharge diagnosis was haemorrhagic acute disseminated encephalomyelitis (ADEM).Nine years later, she re-presented with ataxia and right arm incoordination. MRI revealed high T2 signal lesions in the basal ganglia, thalami and cerebellum with thinning of the corpus callosum. Repeat CSF analysis showed oligoclonal bands in the CSF only. Using the McDonald criteria, the second clinical event constituted a disease defining relapse for multiple sclerosis. Acute haemorrhagic leukencephalopathy (AHLE) and haemorrhagic ADEM are both considered acute monophasic demyelinating diseases of the central nervous system with a variable but often poor prognosis. To our knowledge, this is the first reported case of haemorrhagic ADEM progressing subsequently to multiple sclerosis. AHLE and haemorrhagic ADEM are both severe sub-forms of acute disseminated encephalitis (ADEM). The progression of ADEM to multiple sclerosis is well documented. The pathogenesis of AHLE, haemorrhagic ADEM and multiple sclerosis are similar and mediated by autoreactive T cells. Although, haemorrhagic ADEM is rare, prompt treatment with intravenous steroids may improve survival.With improved survival, more cases of progression to multiple sclerosis are likely to be reported. P578 Neuropsychiatric symptoms in multiple sclerosis patients S. Pires-Barata, I. Vieira, R. Lopes da Silva, J. C. Moniz Hospital do Espirito Santo (Évora, P) Background and purpose: Neuropsychiatric symptoms often occur in multiple sclerosis (MS) patients at all stages of the disease. Disorders of mood, affect and behaviour can be present among these patients. The purpose of our study was to characterize neuropsychiatric symptoms in our MS patients. Materials and Methods: Between 2001 and 2005, sixty eight MS patients (40 women) were observed at least 6 months after clinical diagnosis. Age ranged between 17 and 60 years. Median scholarship was 4 years. The MS protocol included an anamnesis questionnaire (that included age, age at diagnosis, MS type, EDSS, psychopharmacology and MS treatment) and SCL90 scale was used as a screening tool for neuropsychiatric symptoms (a cut point of 1.5 was considered for all items and above 1.5 symptoms were considered significant). All patients were diagnosed according to McDonald diagnostic criteria (McDonald, 2003) and classified according to EDSS scale (Kurtzke, 1983). Results: Most of our patients had their diagnosis between 30 and 40 years (30 %). Relapsing-remitting form was diagnosed in 72 % of our patients. Global severity index was present in 39 % of the patients. Significant somatization symptoms were observed in 57 % of the patients. Significant obsessive-compulsive symptoms were observed in 75 % of the patients, depressive in 61 % patients and anxiety in 43 %. Hostility symptoms were present in 31 % of the patients and psychotic symptoms in 16 %. In the additional SCL90 items, eating disorders were observed in 67 % of the patients and sleep disorders were present in 82 %. Thoughts of death were present in 33 % of the patients. No statistical association was observed between neuropsychiatric symptoms and any of the studied variables, including disease progression or years of evolution. Discussion: Severe neuropsychiatric symptoms were present in 39 % of the patients. The symptoms ranged from obsessive-compulsive, anxiety to psychotic symptoms. The neuropsychiatric symptoms observed were not associated with the disease variables.

General psychiatric is still mostly applied to neurological disorders such as MS, but not always be most effective considering such disorders. Future research is needed for neuropsychiatric sequelae associated with MS. P579 Psychiatric disorders in patients with multiple sclerosis P. Mihancea, N. Havasi, C. Brisc, M. Brisc Oradea University (Oradea, RO) Objectives: The presence of psychic disorders in multiple sclerosis (MS) is mentioned since the initial description of the disease by Charot. Still, in the last years, under the impulse of developing neurobiology and neuropsychiatry of the interest for psychic disorders associated to MS their importance has been managed to be better proved. Therefore, we propose to study psychic disorders at patients with MS at the Oradea Day Center of MS.We chose out of the psychic disorders depression, cognitive disorders, suicidal risk and anxiety. Method: Our study included 46 patients with MS from the Oradea Day Center of MS. The frequency of anxiety, depression, suicidal risk and cognitive disorders was studied.All patients were over 5 years diagnosed with MS. The subjects were asked to fill in a battery of tests, as honestly as possible, without timing interdiction (except for the memory testing). The batch of tests included: the anxiety scale, Beck’s depression scale, the scale of suicidal risk and the Rey’s memory test. Results: Following the results obtained by patient at the test for detecting anxiety, we notice that 34.8 % of them suffer from anxiety.While 65.2 % have no such disorders. 8.7 % have a moderate degree of anxiety, and 26.1 % a high one.A light and severe degree of anxiety was not detected at any patient. The depression scale detected that 62.5 % of our patients suffer from depression, of which 13 % is in a light degree, moderate 26.1 %, severe 26.1 % and none of them with a severe one.At 34.8 %there were no signs of depression forms. Regarding suicidal risk it was present at 60.9 % of patients in the following formula: 13 % light degree, 39.1 % moderate and 8.7 % severe. The patients without suicidal risk were represented 39.1 %. The memory deficit is present at 91.3 % of our patients, as following: light – 34.8 %, moderate 30.4 %, high 13 % and severe 13 %. Only 8.7 % of the patients have no cognitive disorders. Conclusions: Memory deficit is the most frequent psychic disorder at our patients, followed by depression, suicidal risk and anxiety. All psychic disorders at patients with MS at the MS Day Center of Oradea are at higher percentages than those in the medical literature. P580 Recognition difficulties when assessing depressive and fatigue symptoms in multiple sclerosis patients E. Papuc, A. Jamroz-Wisniewska, E. Belniak, K. Mitosek-Szewczyk, H. Bartosik-Psujek, Z. Stelmasiak Medical University of Lublin (Lublin, PL) Objectives: Fatigue and depression although often present in multiple sclerosis (MS) may encounter recognition difficulties as chronic fatigue and certain depressive symptoms such as lack of energy, mental and motor slowing, concentration problems may overlap symptoms of MS. The aim of this study was to assess the influence of disease related disability (in EDSS) and each functional systems separately on fatigue and depressive symptoms and to find correlation between these factors. Methods: 104 RR-MS patients according to McDonald criteria (M/F = 77/27; mean age = 36.9 ± 9.4, mean EDSS = 4.1 ± 1.7, mean disease duration = 9.1 ± 6.7 years) and 41 healthy controls matched in age and sex. All subjects were assessed with Mini Mental Status Examination (MMSE), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS) and underwent a standard clinical evaluation (including Expanded Disability Status ScaleEDSS). Results: Chronic fatigue was present in 53 % of patients, depressive symptoms in 47 % of MS patients. We found a positive correlation between depression and 2 functional systems: mental and pyramidal (p = 0.049, p = 0.058 respectively) Fatigue was highly positively correlated with general disability measured in EDSS (p = 0.001) and especially with pyramidal and sphincter dysfunction (p = 0.0006 and p = 0.004 respectively) We also found a positive correlation between the presence of depression and fatigue. (p < 0.001) Conclusions: Both chronic fatigue and depressive symptoms may accompany MS quite often. Among all functional systems assessed in EDSS, pyramidal dysfunction seems to contribute most to the presence of these symptoms. At the same time in MS patients with predominantly pyramidal dysfunction assessing depressive and fatigue symptoms may be more difficult.

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P581 Multiple Sclerosis Impact Scale in Polish subjects: relation to established measures of impairment and disability A. Jamroz-Wisniewska, E. Papuc, E. Belniak, H. Bartosik-Psujek, K. MitosekSzewczyk, Z. Stelmasiak Lublin Medical University (Lublin, PL)

P583 How to clinically differentiate between vestibular neuritis and “vestibular pseudoneuritis” C. D. Cnyrim, D. Newman-Toker, C. Karch, T. Brandt, M. Strupp Department of Neurology, University of Munich (Munich, D); John-Hopkins University (Baltimore, USA)

Objectives: To validate the Multiple Sclerosis Impact Scale (MSIS-29) that was first introduced by Jeremy Hobart et al. in 2001 (Brain 2001, 124: 962–73) and is not commonly applied, especially in Poland. We investigated the relation between the MSIS-29 and the Kurtzke Expanded Disability Status Scale (EDSS) and the Functional Assessment of Multiple Sclerosis (FAMS). Methods: One hundred four people with Multiple Sclerosis (MS) agreed to participate in the study: 77 men and 27 women; mean age was 36.9 ± 9.4 years. They had relapsing-remitting (RR) type of MS (according to McDonald criteria). Mean disease duration was 9.1 ± 6.7 years. The disability was assessed by the EDSS (including EDSS functional systems) and the FAMS. All patients were asked to complete the MSIS-29. Patients with speech disorders and major cognitive impairment were excluded from the study (aphasia or Mini Mental State Examination (MMSE) score < 27). Results: Mean EDSS score was 4.1 ± 1.7, mean FAMS score – 134.2 ± 35.6. Mean scores were 43.8 ± 23.9 for the physical and 43.8 ± 24.3 for the psychological impact score of the MSIS-29. There was a positive correlation between MSIS-29 physical score and EDSS (p < 0.001) and the individual functional systems: brainstem (p = 0.02), pyramidal (p < 0.001), cerebellar (p < 0.001) and sphincter functions (p < 0.001). A positive correlation was observed between the FAMS and the MSIS-29 physical (p < 0.001) and the MSIS-29 psychological score (p < 0.001). None correlation was observed between the MSIS-29 and disease duration. No statistically significant differences in the MSIS-29 score between sexes were present. Conclusion: Our findings support the use of the MSIS-29 as a measure of physical and psychological impact of MS on normal daily life and indicate that the MSIS-29 may be applied among Polish population to assess the disability of MS patients. The MSIS-29 could be useful as an outcome measure in clinical studies.

Background and objective: Vestibular neuritis (VN) is characterised by rotatory vertigo, horizontal rotatory spontaneous nystagmus, a tendency to fall, and a unilateral functional deficit of the horizontal canal. The most important differential diagnosis is “vestibular pseudoneuritis” (VPN), which is caused by central “fascicular” lesions of the vestibular nerve, vestibular nucleus, or vestibulo-cerebellum, most often due to ischemia or inflammation. It is especially difficult to diagnose in those patients who do not have additional non-vestibular brainstem signs. The aim of this study was to look for clinically useful signs that could help differentiate between VN and VPN. Method: In a retrospective study we analysed the clinical and neuro-orthoptic findings of patients with proven VPN and VN. Several parameters such as the determination of subjective visual vertical, ocular torsion, skew deviation as well as findings in electronystagmography and magnetic resonance imaging (MRI) or computer tomography (CT) were recorded. The diagnosis of VPN was based on a pathological MRI/CT; the diagnosis of VN, in patients with only signs and symptoms indicating an isolated peripheral vestibular lesion and a normal MRI/CT. Results: Forty-three patients with VPN (25 due to vascular lesions, 12 due to multiple sclerosis, and 6 due to other causes) and 40 with VN were included. A smooth pursuit deficit was detected in 86 % of the VPN patients, but in only 23 % of VN patients. Whereas 56 % of VPN patients had a gazeevoked nystagmus contralateral to the direction of the spontaneous nystagmus, only 20 % of VN patients did. A pathological head-thrust sign was found in 42 % of VPN and in 93 % of VN patients. Finally, skew deviation was measured in 17 VPN patients; all had a vertical divergence but none of the VN patients presented with a skew deviation. Conclusions: Smooth pursuit deficit, contralateral gaze-evoked nystagmus, and skew deviation were mostly found in VPN, i. e. if a patient has one of these signs, a central lesion should be suspected and an MRI should be performed. However, not all patients with VPN had these signs. Thus, a peripheral lesion cannot be assumed on the basis of their absence. The predictive value of these and other central oculomotor signs and symptoms should be re-evaluated in a larger sample.

Neuro-ophthalmology P582 The correlation between ocular tilt reaction and uni-/bilateral internuclear opthalmoplegia C. D. Cnyrim, M. Glaser, T. Brandt, M. Strupp Department of Neurology, University of Munich (Munich, D) Background and objective: The ocular tilt reaction (OTR) is characterised by a displacement of the subjective visual vertical (SVV), ocular torsion (OT), and skew deviation (SD). There is good evidence that OTR is caused by lesions of graviceptive otolithic pathways, which lead to vestibular tone imbalance. Their anatomical localisation within the brainstem, however, is not known. Since it is assumed that these fibres run along or within the medial longitudinal fascicle (MLF), we correlated OTR with unilateral and bilateral internuclear ophthalmoplegia (INO) and so tested the hypothesis that unilateral MLF lesions cause OTR, whereas bilateral lesions do not. Patients and methods: In a retrospective chart review we analysed the correlation between neuro-ophthalmological findings in 50 patients presenting with a unilateral and 28 patients with a bilateral INO. Correlation was evaluated by means of a chi-square test, differences by Wilcoxon’s ranksum test. Results: SVV displacement was recorded in 38 patients with a unilateral INO. The SVV deviated to the side contralateral to the INO in all patients (chi square = 38 p < 0.0001). Skew deviation was measured in 46 patients, 20 of whom showed a vertical divergence.A displacement of SVV was recorded in 28 patients with bilateral INO, but neither the side of SVV deviation nor further components of OTR correlated with the dominant side of the INO. The absolute values of SVV displacement and skew deviation were significantly lower than in patients with unilateral findings (p < 0.0001). Conclusions: The high correlation between the side of a unilateral INO and SVV deviation suggests that the graviceptive pathways on which the perception of verticality is based are in the vicinity or even a part of the MLF. In agreement with the hypothesis that bilateral lesions of the corresponding pathways mediating the perception of verticality can cancel each other, the absolute values of SVV displacement in bilaterally affected patients were significantly lower. To better understand these functional interrelations a correlation with MRI data will be performed.

P584 Central compensation of central vestibular lesions C. D. Cnyrim, N. Rettinger, T. Brandt, M. Strupp Department of Neurology, University of Munich (Munich, D) Background: Peripheral and central vestibular lesions cause a vestibular tone imbalance, that is centrally compensated. Whereas the central compensation of peripheral vestibular lesions has been studied in detail, little is known about central compensation of central lesions. The subjective visual vertical (SVV) – as a component of the ocular tilt reaction – is a useful psychophysical parameter to measure central compensation for two reasons: first, it deviates in most acute peripheral and central vestibular lesions and, second, it normalizes over time despite persisting vestibular deficits. Objective: To determine the time course and degree of central compensation of central vestibular lesions by measuring the deviation of the SVV and to compare these values with those of peripheral lesions in a retrospective study. Methods: 50 patients with Wallenberg’s syndrome (as a model for a central vestibular lesion) and 39 patients with vestibular neuritis (as a model for an isolated peripheral vestibular lesion) were examined. SVV was determined during at least two points of time within the first month after symptom onset. Results: The mean displacement of SVV was 10.6° in Wallenberg’s syndrome and 10.5° in vestibular neuritis within the first days after onset of symptoms. SVV deviation within the last days of the observation period was averaged at 4° in the former and 3.1° in the latter group.Wilcoxon’s rank sum test for matched pairs revealed a significant decrease of the deviation over time in both groups. Although the regression had an exponential character in both groups, the statistical power of individually fitted regression curves (ANOVA) was too low to perform a statistical comparison. Conclusions: We demonstrated that central compensation of a central vestibular lesion has a degree and time course similar to that of a peripheral vestibular lesion. These data provide the basis for a prospective study, which will determine the SVV and ocular torsion over a period of three months.

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P585 Deficits in paraflocculus function in patients with isolated downbeat nystagmus K. Hüfner, T. Stephan, R. Kalla, A. Deutschländer, M. Holtmannspötter, G. Schulte-Altedorneburg, M. Wiesmann, M. Strupp, T. Brandt, S. Glasauer Ludwig-Maximilians University (Munich, D) Introduction: Downbeat nystagmus (DBN) is a common sign of posterior fossa pathologies. In half of the patients with DBN an underlying structural pathology such as cerebellar atrophy can be demonstrated while in others no underlying cause can be found. The latter patients typically show now further cerebellar signs upon clinical examination, except for DBN associated ocular-motor deficiencies. A functional deficit of the floccular lobe (Kalla et al. 2006) has recently been demonstrated in DBN patients with cerebellar atrophy. In patients without cerebellar atrophy no morphological or functional CNS abnormalities have been reported to date. Methods: For 11 DBN Patients and 15 matched controls voxel based morphometry (Siemens 1.5 Tesla scanner, MPRAGE, 1 mm3 voxel size) was performed following the optimised protocol (Good et al. 2001; significance level p < 0.001, uncorrected). None of the patients showed cerebellar atrophy, as determined by two independent, experienced neuroradiologists. Ten of the 11 patients and 16 controls also took part in an functional magnetic resonance imaging (fMRI) experiment. Subjects either performed smooth pursuit downwards (SMDOWN) or fixated a central dot (FIXMID). A region of interest (ROI) analysis of cerebellar lobule X (flocculus), IX (paraflocculus) and lower brainstem was performed using SPM2 (significance level p < 0.05, FDR corrected). Results: Grey matter volumes of DBN patients without further signs of cerebellar pathology were compared to a control group. Atrophy was detected in the left cerebellar lobule VI, lobule VI of the cerebellar vermis, and in the inferior frontal gyrus bilaterally, while the flocculus and paraflocculus where not affected. The fMRI data revealed reduced activation in the paraflocculus and lower brainstem in the DBN group compared to controls when performing smooth pursuit downwards (contrast SMDOWNFIXMID). Conclusion: Patients with DBN of unknown origin showed localized grey matter reduction of the lateral cerebellum and oculomotor vermis, and functional deficits in the paraflocculus during downward pursuit. Our findings are in line with experiments in primates were ablation of the floccular and parafloccular lobes causes DBN (Zee et al. 1981) and support our recent hypothesis on the origin of DBN (Marti et al. 2005). References Kalla, et al. (2006) Neurology (in press) Good, et al. (2001) Neuroimage 14:21–36 Zee, et al. (1981) J Neurophysiol 46:878–899 Marti, et al. (2005) Ann N Y Acad Sci 1039:548–553

P586 Treatment of Menière’s disease with betahistine: an open trial V. C. Zingler, C. D. Cnyrim, C. Frenzel, D. Huppert, T. Brandt, M. Strupp University of Munich (Munich, D) Introduction: Menière’s disease is a frequent inner ear disease which is clinically characterized by recurrent attacks of vertigo, hearing loss, tinnitus, aural fullness and nausea. During the natural course of the disease persistent deficits can develop. Besides spontaneous recovery Menière’s disease manifests bilaterally in 15 % of patients after 2 years and in 30–60 % 10–20 years after disease onset. There is some evidence from previous studies that betahistine, an H1-agonist and H3-antagonist, in a dosage of 16 mg three times daily (tid), may be an effective treatment of Menière’s disease. However, no state-of-the-art studies have been conducted in this field. According to our experience, many patients profit only from a higher dosage of betahistine, namely 48 mg tid. Methods: We, therefore, first performed an open trial, including patients with Menière’s disease according to the diagnostic criteria of the American Academy of Ophthalmology and Otolaryngology, Head and Neck Surgery (1995). This trial is currently ongoing. The patients received betahistine in a dosage of 48 mg tid. The effects of this therapy regimen on the attacks of vertigo were evaluated after 1, 6 and 12 months. Here we present the results of an interim analysis. Results: So far, 22 patients with Menière’s disease have been included. Before inclusion in the study the average number of vertigo attacks was 11.3 attacks per month (standard deviation (SD) 4.24,median 10,minimum 4,maximum 19 attacks per month). So far, 12 patients have been treated with betahistine 48 mg tid for 12 months. In these patients the vertigo attacks decreased to an average number of one attack per month (SD 1.35, median 1,

minimum 0, maximum 7 attacks per month). The reduction of the frequency of attacks after one month was 57 %, after 6 months 78 % and after 12 months 93 %. Betahistine was in general well tolerated. Only 2 of all patients reported a little nausea. Conclusion: All in all, this interim analysis supports the view that betahistine 48 mg tid has a beneficial effect on the course of Menière’s disease. These data are the basis for a prospective, randomized, double-blind study comparing placebo with 16 mg tid and 48 mg tid betahistine which will be started in February 2006. P587 Symptoms improve in a patient with Cogan’s syndrome after escalation therapy with intravenous ultra high-dosage glucocorticoids C. Best, J. Koehler, K. Werhahn, M. Dieterich Johannes Gutenberg-University (Mainz, D) Objectives: Cogan’s syndrome was first described as a syndrome of nonsyphilitic interstitial keratitis with vertigo, tinnitus, and profound deafness. It is a rare autoimmunological disease with inflammation of inner ear and eye structures. The disease is progressive and can lead to a complete loss of hearing and bilateral vestibulopathy within a few days. In addition, inflammation of the blood vessels can induce systemic vasculitis. As the disease is often rapidly progressive and organ damage can be irreversible, early diagnosis and adequate treatment is important. Case: Here, we present the case of a 31-year-old woman with a 4-week history of progressive loss of hearing of the right ear and recurrent attacks of rotational vertigo. Initially, hearing loss started in the right but after 2 weeks it also occurred in the left ear. At that time attacks of rotational vertigo stopped and a motion-dependent non-rotational vertigo with oscillopsia during locomotion appeared, indicating a bilateral vestibular failure. Six months prior to this episode the woman had had recurrent keratitis. Clinical examination revealed a severe hearing loss, a bilateral vestibulopathy with bilateral pathological Halmagyi-Curthoys test, a head-shaking nystagmus to the left side, as well as severe unsteadiness of stance and gait. These findings were confirmed on audiometric and electro-oculographic testing. A high-dosage glucocorticoid therapy with 1000 mg/d decortin intravenously was initiated for 3 days. The daily progression of the symptoms stopped within 2 days. Then 100 mg/d decortin and in addition 100 mg/d azathioprin were administered orally. On the second day a further progression of the hearing loss occurred. Therefore an ultra high-dosage therapy with 2000 mg/d decortin intravenously was initiated for 3 days. Again progression stopped, and the decortin was lowered to 100 mg/d orally. No further progression occurred, and the function of the left ear improved clinically as well as on audiometric and electro-oculographic testing. Thus, further progression and a complete bilateral loss of hearing and vestibular function were prevented by escalation therapy with high-dosage glucocorticoid. Our findings based on this case report point to an additional efficacy of ultra high-dose glucocorticoids (2 g/d over 3 days) in Cogan’s syndrome if lower dosages failed. Non-genomic effects with induction of apoptosis could be a possible mechanism explaining the observed outcome of our patient. P588 Pupillary responses to single and sinusoidal light stimuli H. Zangemeister, R. Gronow Hamburg University (Hamburg, D) We examined effects of diabetes mellitus (DM) on the pupillary light reflex (PLR). Phasic pupillary response to a single light stimulus (200ms) [pPLR] and to continuous sinusoidal stimuli with four different frequencies (0.1, 0.3, 0.7, 1.3Hz) [cPLR] were examined in 52 DMpatients and 21 control subjects. We asked: Does recording and frequency analysis of cPLR together with short time fourier [STFT] analysis of pPLR differentiate better between DM patients and normal subjects than pPLR only? 1.Initial pupil diameter was signifcantly decreased in the DM group. 2.For pPLR, maximal contraction velocity(Vmax), Vmax of redilation1, reflex-amplitude, pPLR latency were significantly reduced in those patients that showed also signs of diabetic autonomic neuropathy (DNP). 3.Tests of dynamic pupillary light reflex [cPLR] revealed that all DM patients had a significantly reduced gain, at lower frequencies. Pupil phase lag was larger at 0.1&0.3Hz ‘and smaller at 0.7&1.3 Hz in the DNP group (p < 0.001). 4.Comparison of single pPLR recordings of five DNP-patients with five subjects using short time fast fourier (STFT) analysis revealed a characteristic change from low frequency content in healthy subjects to high frequency content in DNP-patients. Significant alterations of the PLR in DM can be found only when symp-

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toms of autonomic neuropathy have shown up. Both sympathetic and the parasympathetic nervous systems are affected by diabetic autonomic neuropathy. Only recording of cPLR, together with STFT of pPLR permits to discriminate significant pathological deficits of pupillary control in single cases. P589 Benign episodic unilateral mydriasis. Clinical characteristics in two male patients A. Camacho, A. Villarejo, R. Garcia-Ramos, T. Moreno, A. Martínez-Salio Hospital La Moraleja (Madrid, E); Hospital Doce de Octubre (Madrid, E) Introduction: The evaluation of patients with anisocoria can be difficult. In cases of acute mydriasis, physicians must rule out life-threatening causes as a third cranial nerve compression, but fortunately that is not always the case. Case reports: Case 1. A 36-year-old smoker man, with a 20-year history of migraine with and without aura, presented for evaluation of anisocoria and blurry vision when reading. He had no headache. An ophtalmological exam disclosed a left mydriasis. Both pupils were reactive to light, but the left showed no constriction on testing the near response. Neurologic examination was normal. A basic laboratory panel was normal. A CT, MRI and MRA brain scans were normal, as well as a lumbar puncture. In 24 hours pupil size returned to normal. Case 2. A 51-year-old man with episodic migraine, detected an asymmetric pupil size on awakening. Four hours later he developed a mild dull pain in his right temple. On examination the only abnormality was a right mydriasis with a poor response to light and no near response. Laboratory studies, visual evoked potentials, MRI and MRA brain scans were normal. Headache subsided in 8 hours, and mydriasis in 7 days. Conclusions: Benign episodic unilateral mydriasis is a rare entity usually described in women with migraine. A reversible vasospasm of the ciliary artery with transient ischemia of the ciliary ganglion has been postulated. We describe two male patients with this possibly underecognized condition. P590 Vascular pathology with neuro-ophthalmological implications E. Sisak, A. M. Scutaru, S. Sisak Neurofta Clinic (Brasov, RO); Universitary Emergency Hospital Bucharest (Brasov, RO) Objectives: Neuro-oftalmology imposed itself in practice covering a wide area of pathology at the border of neurology and ophtalmology. Some of this pathology is vascular-ischemic; it also can be caused by a systemic disease or rarely can be a localized one. The study’s aim is to present the diagnosis possibilities of neuro-ophtalmology pathology at “Neurofta” clinic in Brasov Romania, as well as the concordance between the initial diagnostic and the final one. Material and methods: We are presenting nine representative patients form a larger number that were investigated for different symptoms and initial diagnostics as follows: – vascular – ophthalmologic- fluorescein angiography – neurological – extra cranial echo-Doppler examination – functional – ophthalmologic – visual acuity – computerized visual field – evoked visual potentials Results: – 3 patients with the initial diagnosis of optic neuritis that after the tests were diagnosed with: – retinal epiteliopathy, suspected anterior ischemic optic neuropathy – bilateral optic atrophy caused by chronic ischemia – bilateral chorioretinal vasculitis – 1 patient with the initial diagnosis of optic atrophy of the right eye that had a final diagnosis of bilateral chorioretinal vasculitis – 1 patient with the initial diagnosis of bilateral optic atrophy that had a final diagnosis of anterior ischemic neuropathy – 1 patient with the initial diagnosis of papillary edema due to intracranial hypertension that was diagnosed after tests were made with anterior ischemic neuropathy – 1 patient with the initial diagnosis of central serous retinopathy whose final diagnosis was the same – 1 patient with the initial diagnosis of systemic autoimmune vasculitis with the same final diagnosis – 1 patient with the initial diagnosis of bilateral retinal dystrophy whose final diagnosis was the same Conclusions: In our study, from the group of patients we selected, in six cases

there was a lack of concordance between the initial diagnosis and the final one. Fortunately at the moment there is the possibility of diagnosis in the cases of vascular neuro-ophtalmologic pathology that enables an accurate treatment. P591 Unilateral vestibular failure modulates visual cortex activation during optokinetic stimulation: a central adaptive mechanism to reduce oscillopsia? A. Deutschländer, T. Stephan, K. Hüfner, R. Kalla, M. Strupp, M. Wiesmann, T. Brandt Klinikum Grosshadern (Munich, D) Objective: To elucidate central adaptive strategies that help reduce oscillopsia in patients with unilateral impairment of the vestibulo-ocular reflex (VOR). Background: During head movements, the VOR stabilizes gaze.VOR impairment causes oscillopsia, i. e., illusory movement of the environment due to excessive slip of images on the retina. Due to compensatory mechanisms that develop over time, oscillopsia decreases in patients with vestibular failure. A reduction of the sensitivity to slow visual motion may be one of these compensatory mechanisms. Visual motion detection thresholds were found to be raised in patients with bilateral vestibular loss (Grunbauer et al. 1998, Neuroreport; Shallo-Hoffmann and Bronstein, 2003, Vision Research). Methods: Fourteen patients with unilateral vestibular failure due to unilateral vestibular neurectomy (right-sided neurectomy: n = 7; left-sided neurectomy: n = 7) and seven healthy volunteers performed optokinetic eye movements during an fMRI experiment.A stationary visual stimulus served as rest condition. Results: Patients with unilateral neurectomy showed less activation of the motion-sensitive visual cortex area MT/V5 bilaterally compared to healthy volunteers (p < 0.001). Conclusion: Diminished activation of MT/V5 may be a central compensational strategy to reduce oscillopsia in patients with VOR deficiencies. It may be an underlying mechanism for raised visual motion detection thresholds in these patients.

Neurorehabilitation P592 Self-efficacy in neurorehabilitation – initial validation of a new scale G. Dixon, R. J. Mills, C. A. Young Walton Centre for Neurology and Neurosurgery (Liverpool, UK) An important concept that has been shown to influence people’s motivation and participation in neurorehabilitation is their self efficacy. Self efficacy is the belief in one’s capabilities to perform an activity that has influence over events affecting one’s life. The objective was to develop a new scale which would both measure self efficacy in patients undergoing neurorehabilitation, and generate data that would fit the Rasch measurement model; the Rasch model is the only way to convert ordinal scale scores into interval level data, suitable for standard, parametric analysis. A pool of scale items was generated from themes and phrases resulting from 24 semi structured interviews with patients who had had experience of neurorehabilitation with additional input from an expert panel of therapists and neurologists. A four point Likert response option was used, annotated with visual aids for patients with mild cognitive or communication difficulties. The scale was put to a pilot sample of twelve rehabilitation patients who were asked to provide a running commentary during completion; this allowed identification and remedy of any gross problems with wording etc. The scale was then administered to patients undergoing neurorehabilitation in two UK centres; initial analysis was made on 127 respondents.‘Non functioning’ items were deleted until the data from the scale had acceptable fit to the Rasch model. Items were examined for differential item functioning (DIF) for a wide variety of factors. External validation was made by comparison to the general self efficacy scale, the dispositional resiliency index, the hospital anxiety and depression scale and the multidimensional health locus of control. The resultant scale was shown to fit the Rasch model; the scale can therefore be assumed to both measure a unidimensional construct and generate data that can be transformed to an interval scale. Qualities of the scale are discussed, as well as plans for further validation.

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P593 Repetitive training with an arm-trainer post-stroke: quantitative evaluation of the effect on spasticity and motor control K. Diserens, F. Herrmann, N. Perret, D. Ruegg, P. Vuadens, J. Bogousslavsky, F. Vingerhoets CHUV (Lausanne, CH); University Hospital (Geneva, CH); Plein Soleil (Lausanne, CH); Department of Medicine (Fribourg, CH); Clinique Romande de Réadaptation (Sion, CH) Objectives: The quantification of motor control and spasticity after training is controversial and the effect of repetitive movement on spasticity using an arm-trainer is poorly studied [1, 2]. We designed a special arm-trainer (cyclo-ergometer) for the measurements and trained patients on a commercial motorised arm trainer. The purpose of this study is to evaluate quantitatively the spasticity and motor control of patients with hemisyndrome after stroke following daily training. Methods: 9 patients with a stabilised hemisyndrome underwent, in an ABA protocol, arm-training 15 minutes daily during 5 days over 3 weeks. In addition to 6 clinical tests, four quantitative measurements were performed on the cyclo-ergometer. The recorded data was analysed to obtain the average position, speed and force during a cycle. Results: After 3 weeks of training the motor control evaluated by the correlation of the Rivermead Motorik Assessement, Motricity index and cycling force showed significant improvement (p > 001). Spasticity evaluated by the correlation of the modified Asworth Scale, Range of Motion and Pedal Force (resistance) showed improvement but without statistical significance. Conclusion: Repetitive training using an arm-trainer can improve motor power, functional gain and diminish spasticity. In addition to conventional physiotherapy, such training can be achieved by the patient himself and can be conducted daily at home. [1] Bütefisch C, Hummelsheim H, Denzler P, Mauritz K-H (1995) Repetitive training of isolated movements improves the outcome of motor rehabilitation of the centrally paretic hand. J Neurol Sci 130: 59–68. [2] Hesse S, Schulte-Tigges G, Konrad M, Bardeleben A, Werner C (2003) Robot-assisted arm trainer for the passive and active practice of bilateral forearm and wrist movements in hemiparetic subjects. Arch Phys Med Rehabil 84 [6]: 915–920. This research was partly supported by a grant of Allergan (Switzerland), Reck- Technik (Germany). The technical assistance of S.Krattinger (Fondation Plein Soleil, Switzerland) is gratefully acknowledged. P594 Brain-computer interface: communication by cognition for neurological patients with severe cerebellar and brainstem lesions K. Diserens, U. Hoffmann, E. Giradet, R. Leroy, A. Massy, N. Gremaud, T. Ebrahimi, P. A. Despland, J. Bogousslavsky CHUV (Lausanne, CH); EPFL (Lausanne, CH); FST (Neuchatel, CH); Plein Soleil (Lausanne, CH) Objectives: A brain-computer interface (BCI) is a communication system that implements the principle of “think and make it happen without using peripheral nerves and muscles”. Our aim was to apply BCI to patients with neurological lesions which impair communication (dysarthria, cerebellar ataxia) and to evaluate the practicability of this communication form for patients with cognitive impairments. Methods: Two approaches to non-invasive BCI were distinguished. One approach relying on external stimuli and is referred to evoked potentials [1, 2]. The second approach requiring no external stimuli, allowing commands to be sent voluntarily, modifying the brain signals. The target population consisted of individuals presenting severe ataxia and severe brainstem lesions with disturbed but still functioning cognitive and concentration capacities. Given the restricted cognitive and concentration abilities in the target population, a BCI based on task-evoked potentials was proposed, notably P300. Task-evoked potential based BCI only requires a relatively small amount of concentration and training and, thus, is particularly suitable for patients with concentration impairments. Three kinds of stimuli were evaluated: sound tones variations, flashing letters and flashing pictures. Results: Five patients with different cognitive capacities (1 with neonatal brain ischemia, 3 with multiple sclerosis, 1 with cerebral hypoxia) were selected.After 2–3 training sessions, 3 of the patients were able to count letters offered in an oddball-paradigm evoking the P300 and to interact by BCI with their environment (to light a lamp) with the help of an environment control system. Conclusion: Communication is possible by BCI for patients with neurological lesions disabling the motor system and mild cognitive impairments. Further studies are planned to make the EEG system more functional and

user-friendly. Nevertheless, many obstacles still need to be overcome to increase communication speed and to improve ease of use for patients. References 1. Farwell LA, Donchin E (1988) “Talking off the top of your head:toward a mental prosthesis utilizing event-related brain potentials.” Electroencephalography and Clinical Neurophysiology 70:510–523 2. Birbaumer N, Ghanayim N, Hinterberger T, Iversen I, Kotchoubey B, Kübler A, Perelmouter J, Taub E, Flor H (1999) “ A spelling device for the paralysed.” Nature 398:297–298 P595 Routine assessment of nutritional status at admission to neurorehabilitation and evaluation of indication for nutritional strategies using the Innsbruck Nutrition Scale C. Haider, H. Zauner, N. Geringer-Manakanatas, V. Kraschl, K. Kadar, S. Wotzka, P. Bachleitner, A. Gassner Rehabilitation Center Grossgmain (Grossgmain, A) Objectives: Neurogenic dysphagia is observed in 30–45 % of stroke survivors, 50 % of these patients experience malnutrition, one third pneumonia. Malnutrition often provokes poorer rehabilitation potential and impaired functional outcome. Methods: 45 stroke patients were assessed using INS (Innsbruck Nutrition Scale), parameters see below. With a scoring system clear, moderate and absent indication for clinical nutrition strategies is established (enteral, parenteral nutrition). Setting: inpatient neurorehabilitation, therapy mainly according to the principles of Bobath, Affolter, speach and swallowing therapy(f. e. compensatory strategies), neuropsychological/psychological support. Statistics: Values expressed as median/mean/percentage-as appropriate, for non parametric difference testing: U-test 2-tailed. Levels of significance: *(p < 0.05), **(p < 0.01). Results: Outcome in rehabilitation was measured calculating the difference of Barthel Index (BI), of Basic and Extended Activities of Daily Living (BADL, EADL) and of Rivermead Motor Assessment (RMA) at admission and discharge: Delta values: median BI 50 ‘ median BADL 4, median EADL 2, median RMA 4. Nutritional status: Median BMI 25 [18–39]kg/m2 ‘ quotient BUN/Creatinine 17 [9–37], loss of weight in the early recovery phase: 21 patients(51 %) less than 2kg, 17%: 2–3 kg, 22%: 3–6.5 kg, 10%: > 6.5 kg. Estimated days of oral alimentary abstinence at start of rehabilitation: 29 patients(71 %) less than 2 days, 1 patient 2–5 days, 11 patients(27 %) > 5 days. According to INS in 28 patients(68 %) clinical nutrition was not indicated, in 2 patients(5 %) moderately and in 11 patients(27 %) strongly indicated, these patients received intensive swallowing therapy. The group with severe neurogenic dysphagia and actual malnutrition showed a highly significant better outcome as measured by BI (p < 0.001) and BADL (p = 0.001) compared with not swallowing disturbed patients even when BI was corrected for swallowing specific items. 7/25 patients with a BMI > 25kg/m2 had indication for clinical nutrition. Conclusion: Assessment of nutritional status at start of rehabilitaton is very feasable and shows a typical pattern for the incidence of dysphagia after stroke. Establishing the indication for clinical nutrition with INS is easy and reflects best clinical practice. In a rehabilitation scenario offering specific swallowing therapy we also could show a significant better outcome for patients with severe neurogenic dysphagia/malnutrition at admission. P596 Hearing loss following severe head injury S. Galbiati, D. Brambilla, S. Bernasconi, S. Bovo, S. Strazzer IRCCS E. Medea (Bosisio Parini, I) Objectives: Head injures are a considerable medical problem worldwide. Hearing difficulty is a well-known consequence of head trauma among both adult victims and head-injured children, but few data are reported in the literature. A direct or indirect mechanism can cause substantial damage to the

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inner ear or central auditory pathways. This study examined the hearing defect as a consequence of severe head injury and its correlations with the patient’s clinical and functional data. Methods: Amongst the patients hospitalized in our Rehabilitation Center between 2001 and 2005, we selected patients who suffered severe brain injury (Glasgow Coma Scale < 8) and collected their clinical data, i. e. the patients’ age at insult and sex, length of nonresponsive state and neurological deficits upon awakening. Each patient received clinical and functional evaluations, specifically: the Glasgow Outcome Scale (GOS), the Disability Rating Scale (DRS), and the Functional Independence Measure for children (Wee-FIM). The scales were assessed at admission and upon discharge. Audiometric testing was performed for all patients and repeated at follow-up. Results: We selected 120 patients (84 males, 36 females) with severe head injury (GCS < 8), the patients’ mean age at the time of the trauma was 14.9 (SD: 11.7), range 0–56 years: 43.3 % of the patients were aged 0–10 years, 33.3 % 11–20 years and 23.3 % 21–56 years. 29 patients (24.2 %) had a hearing deficit, with a prevalence of the deficit in the female group (30.6 %) vs. the male group (21.4 %). In 13 patients (10.8 %) the hearing impairment is a sensorineural defect, in 13 patients (10.8 %) it is a conductive defect and is mixed in 3 patients (2.5 %). The deficit risk is significantly directly associated to age at insult: the mean of age at trauma is 20.2 for patients with hearing defect and 13.1 for the others. In this mainly child population, the deficit is not correlated to the skull fracture. No significant correlation was found between the hearing deficit and the functional scales. Conclusions: The risk of hearing impairment is a frequent sequela of head injury and may pose problems during rehabilitation and social re-entry, although the hearing deficit does not significantly affect the outcome, as shown by functional scale scores. This study has shown a direct correlation between the hearing deficit and age at insult. The risk of the deficit seems to be more frequent among female patients. P597 Impact of therapeutic efficiency on the outcome of stroke rehabilitation. Results from a comparative long-term follow-up study of four European inpatient stroke rehabilitation centres J. Walter RehaClinic (Zurzach, CH) Objectives: The CERISE (Collaborative Evaluation of Rehabilitation in Stroke across Europe) study aimed to examine differences in the amount and content of therapy, in organisational characteristics and staff input. From this study we present data on therapeutic activities given to the patients and on other time allocations of the therapeutic staff, especially of physiotherapists (PTs) and occupational therapists (OTs). Frequent and well focused therapeutic activities are considered to have an important impact on patient’s outcome. Methods: In each of the four centres, 60 randomly selected stroke patients were observed at 10-minute intervals in their activities using a categorical mapping. Additionally in each centre, fifteen individual PT and OT treatment sessions with patients were videotaped and the content categorized as well. Thirdly all PTs and OTs documented categorically their activities in 15-minute slots in a diary during two randomly selected weeks. The functional outcome was monitored 2, 4 and 6 months after stroke. Results: The total time in therapy varied from 60 minutes in the UK centre, 1h59 minutes in the Belgian centre, 2h20 minutes in the German centre and 2 h and 46 minutes in the Swiss center. This difference could not be explained by differences in patient-staff ratios. In every centre, PTs did most therapeutic activities (TAs). OTs were the second except in the UK, where nursing was second. PTs mainly trained transfers, balance in sitting and standing and ambulation, whereas the OTs mainly cared for ADL, domestic and leisure activities as well as sensory and perceptual training. The time PTs were involved in TAs differed from 66.1 % to 45.9 % of their whole work time, for OTs the range was from 63.3 % to 32.9 %. These differences could mainly be explained by differences in organisational characteristics. Recent evaluation of further CERISE data revealed an important impact on patient’s long-term outcome. Conclusion: Therapeutic efficiency in stroke rehabilitation depends largely on the time of TAs performed by PTs and OTs. Differences in staff organisation determined the amount of TAs, whereas the content was very similar in all four centres. Financial support: European Commission (Quality of life, key action 6, 2001–2005, contract number QLK6-CT-2001–00170) and Sekretariat für Bildung und Forschung SBF (CH). It does not necessarily reflect its views and in no way anticipates the Commission’s

P598 Functional electrical therapy: retraining reaching and grasping functions in severe hemiplegic patients M. R. Popovic, A. T. Thrasher, V. Zivanovic University of Toronto (Toronto, CAN); Toronto Rehabilitation Institute (Toronto, CAN) Objective: The purpose of this study was to evaluate efficacy of functional electrical therapy (FET) for hemiplegic patients with severe arm and hand paralysis. Subjects and methods: The study was conducted only with stroke patients who had severe unilateral upper extremity paralysis (Chedoke McMaster Stages of Motor Recovery scores 1 or 2) measured at least three weeks after onset of stroke. Acute patients were recruited to the study at the rehabilitation unit at the Toronto Rehabilitation Institute at least three weeks after the onset of stroke. Long-term patients were recruited to the study through an outpatient follow-up clinic, also at the Toronto Rehabilitation Institute, at least 12 months after the onset of stroke. After they were admitted to the program the participants were randomly assigned to: Group A – the control group which was administered only conventional physiotherapy and occupational therapy; and Group B – the treatment group which was administered FET in addition to conventional physiotherapy and occupational therapy (further in the text referred to as FET). The following tests were administered to both Group A and Group B before and after the intervention: Functional Independence Measure, Barthel Index, Chedoke McMaster Stages of Motor Recovery, Fugl-Meyer Assessment and Rehabilitation Engineering Laboratory Hand Function Test The Compex Motion electric stimulator was used as a hardware platform for the neuroprosthesis. Hypotheses were: 1) On admission, Group A and Group B had all functional scores equal; 2) On discharge, Group A and Group B had the same differences in all functional scores equal on discharge; and 3) Group A had all functional scores equal, on admission and discharge. The hypotheses were tested using a Wilcoxon rank-sum test. Results: The study was conducted with 24 stroke patients of which 15 participated in FET and 9 were controls (8 female, 16 male; average age 56). Significant differences were found between Groups A and B in terms of change of the FMA and the torque, force and eccentric load components of the Rehabilitation Engineering Laboratory Hand Function Test. In summary, the statistical analysis suggests that the FET gives rise to greater improvement in arm and hand functions, compared to traditional physiotherapy and occupational therapy alone. P599 Extracorporeal shock waves in the rehabilitation of children with cerebral palsy H. Lohse-Busch, M. Kraemer, U. Reime Rheintalklinik (Bad Krozingen, D) Objectives: Children with cerebral palsy (CP) regularly are suffering from soft contractures due to muscular stiffness. This makes movements laborious and motor learning difficult. The goal of this investigation is to assess the effects of special ESW on these contractures. Methods: After the informed consent of children and parents the treatments were performed 5 times during 2 weeks with a modified Minilith SL lithotriptor (Storz Medical) producing diverging ESW of 0.012mJ/mm2 –0.024 mJ/mm2 energy flux density. This is about 10 % of what is considered in physical medicine as “low energy extracorporeal shock waves (ESW)”. We performed 2 different investigations. In group A we treated the muscles responsible for soft contractures of the upper limbs and in group B of the lower limbs. Before and after the treatments with ESW we assessed goniometrically the active range of motion (ROM) of the joints.All children received 4x600 ESW per treatment session while following daily the same basic physiotherapeutical program during the 2 weeks. Group A were 63 children with tetraplegia, group B 38 children with diplegia or tetraplegia. The children of both groups were 8.1 years old on average. In group A 20 randomly chosen children served at the beginning as a blinded control group. They received a sham treatment by interposition of a neoprene slide between the coupling cushion of the lithothriptor and the patient’s body. These children also were treated after the 2 weeks with real ESW. In group B we compared the results of 20 patients, which had served as a control group in a former investigation with the same design. Results: In group A the 126 limbs showed an improvement of the elbow extension of 21° and of the hand supination of 40°. Obviously as a result of the physiotherapy the control group augmented the extension with 6.7° and the supination with 4.2°.

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In group B the 76 limbs improved the extension of the hips by 19°, of the knees by 12° and the ankle joints by 9°. The historical control group has augmented the extension of these joints with 5.2°, 4.8° and 2.1° respectively. The treatments were painless. No undesired effects were observed.All results were statistically significant and lasted for at least 6 weeks. Then a lingering deterioration took place, if ever the children did not move the joints actively. Conclusion: Very low energy ESW enhance the ROM of joints affected by soft contractures in children with CP. P600 Gait analysis of myotonic dystrophy M. Bigoni, G. Misco, E. Milano, C. Trotti, A. Mauro, F. Rondena, M. Romei Istituto Auxologico Italiano (Verbania, I) Objective: To characterise the gait pattern in Myotonic Dystrophy (MD) adults patients by Gait Analysis. MD is an autosomal dominant muscle disease, characterised by a progressive muscle weakness and myotonia; most patients show axonal polyneuropathy (PNP). Little information has been published about the gait pattern in MD. Methods: Ten patients with clinically and genetically confirmed MD, with heterogeneous clinical pattern (6 males, 4 females; mean age: 43 + 1 years; mean disease duration: 18.4 years; 6/10 with PNP) were compared with control subjects (CS). MD patients performed gait analysis by an optoelectronic system, two force platforms and dynamic EMG (tibialis anterior (TA), gastrocnemius (GM)). Spatio-temporal and kinematic parameters were calculated. Medical Research Council Scale (MRC) for the quadriceps femoris, TA and GM was calculated. Results: We found significantly lower values for walking speed (0.8ms1 + 0.15ms-1, CS: 1.17ms-1 + 0.2ms-1) and stride length (0.48m + 0.07m, CS: 1.2m + 0.1 m) and higher duration of the stance phase (64.2 % + 2.8 %, CS: 61 % + 2.4 %). Eight patients showed absence of knee flexion of gait cycle 0–20 %, delayed ankle pattern, increased peak of plantarflexion in midstance and dorsiflexion at Toe Off. All the subjects presented increased absolute peak of ankle dorsiflexion (22.7° + 3.9°, cs: 10 + 3°), with higer timing (56.35 %2.9 %, CS:37 %3 %) and reduced range of motion of ankle in swing (11° + 5°, CS 17° + 5°). Theese parameters correlate with TA and GM muscle weakness; the weakness was observed in distal more than in proximal muscles (MRC TA = 3.1 + 1, MRC GM = 3.15 + 1.2), but only MRC- QF (mean value 3.6 + 0.83) correlate with reduced walking speed, step length and cadence. No correlation was found between kinematic data and presence of PNP. Conclusion: In our MD patients a typical knee (hyperextended knee) and ankle pattern was found; the gait disturbance correlates with proximal weakness, according to the severity of the disease. We conclude that Gait Analysis may be used as an objective tool to quantify the impairment of gait parameters in MD patients to follow up therapeutic interventions. P601 Effect of shock-wave therapy on spastic equinus foot in patients affected by cerebral palasy E. Amelio, P. Manganotti University Hospital (Verona, I) Different non-invasive treatments are used to reduce muscle hypertonia.Shock wave(ESW) are defined as a sequence of single sonic pulses largely used for bone,tendon diseases and muscular contractures.In our previous study we have documented the significant decrease of spastic hypertonia in the affected hand of patients with stroke after treatment by ESWT(Stroke vol. 36,n°9,September 20051967–1971). The aim of this study is to examine the effect of shock wave treatment in spastic equinus foot in a group of children with cerebral palsy. We evaluated 12 children with cerebral palsy. Placebo stimulation was performed one week before active stimulation in each patient. Clinical examination included a single passive range of motion (electronic goniometer) evaluation of the ankle of the affected side, and grade of spasticity (Ashworth Scale) of the plantar flexor muscles. Podobarometric evaluation was consisted of a force plate (FAS system). In each subject, the clinical measures were performed before and immediately after placebo. One week later, identical clinical measures were performed before, immediately after, after one, four and twelve weeks from the active shock wave treatment. No significant changes were noted after placebo.After active ESW,the average baseline evaluation Ashworth results for the plantar flexor were 3.0 (Sd 0.5).Immediately after the active treatment, the Ashworth for the plantar

flexor dropped to 2.0 (Sd 0.4) (P < 0.001). Post hoc comparisons showed a significant difference of muscle tone of plantar flexors between baseline and after the first week (P < 0.001), between baseline and after four weeks (P < 0.02). There were no statistically group differences between baseline and after twelve weeks (P = NS). As regards the podobarometric measures, the time effect was statistically significant (F [4, 9] = 78.127, P < 0.001). In the post hoc comparisons the significative increase of the whole plantar surface area (cm2) on the treated limb between baseline and immediately after (40.3 vs 80.2; P < 0.01), between baseline and the first week (40.3 vs 70.1; P < 0.05), between baseline and the four weeks (40.3 vs 68; P < 0.05). No statistically group differences between baseline and the twelve weeks (P = NS). Our findings suggest that shock wave therapy may be useful in decreasing flexor tone in the lower limbs spasticity in children and open a new field of research in the noninvasive treatment of this desease.Further studies with a larger group of patients with cerebral palsy are necessary. P602 Robotic in hand rehabilitation – an innovation in hand therapy P. Grieshofer, R. Scherer, A. Kollreider, M. Scarpatetti Klinik Judendorf Strassengel (Judendorf Strassengel, A); Technical University Graz (Graz, A) Background: The “Klinik Judendorf Strassengel” developed in cooperation with the technical university of Graz this technical device Methods: The development of the hand robotic System after 4 years of research and 3 years of engineering has produced a crucial improvement in hand rehabilitation Therapy. Our robotic hand and finger movement orthosis is being used successfully in our clinic as a prototype of the institute of neurorehabilitation and research. This hand robotic system is the first driven orthosis that assists finger movements of -upper limb impaired patients. The theoretical background is the experience of the locomotion therapy. This automated process relieves therapists of the manual labour; therefore, the training sessions can be longer and more repeatable. The therapy is more efficient and the patients achieve their goals faster. Even in the early phases of the rehabilitation, one therapist can accomplish the training.We are using this hand robotic system as a prototype about half a year and our clinic practice shows after viewing patients that rehabilitation of the hand could be accelerated. Results: Our first experience shows, that the rehabilitation of the hand could be accelerated and the spasticity is going down. Conclusion: We know we need more experience and data but we want to present this technology as an new opportunity for hand rehabilitation. P603 The Lokomat as a possibility in the rehabilitation of patients with neurological disorders. Results after three years of clinical practice P. Grieshofer, A. Kollreider, R. Scherer Klinik Judendorf Strassengel (Judendorf Strassengel, A); Technical University Graz (Graz, A) Background: New knowledge about brain plasticity and task-specific treatment like the treadmill training or the forced use therapy of E have been developed. Taub are reasons for new developments Methods: The Lokomat is a driven orthosis that assists walking movements of gait-impaired patients on the treadmill. Hip and knee joint angles are controlled in real time by software to achieve a physiologically meaningful gait pattern. Each of the four axes is individually controlled to correspond precisely to the desired joint angle trajectories. The Biofeedback displays the patient’s effort during therapy in real-time on an additional screen. Results: For 3 years we treated patients with 2 Lokomat units in addition to classical therapeutic methods. Every patient received this therapy 3–4 times per week. The mean therapeutic time was 40 minutes. Among 365 patients treated, there were 225 patients with cerebrovascular disease, 65 with Multiple Sclerosis, 25 with incomplete paraplegic patients, 20 with Infantile cerebral paresis and 30 with neuromuscular diseases. Conclusion: The locomat therapy reduces spasticity and improves physiological gait pattern (data from the gait laboratory). Clinically, this therapy may be able to accelerate the process of learning to walk. Patients participated were highly motivated to participate and no side effects were observed. The lokomat therapy was ceased for patients with severe arthritis of the hip or knee. These data are only preliminary data; therefore we are preparing a multicenter study to obtain further data.

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P604 Rehabilitation of sustained attention in young patients with brain injury S. Strazzer, S. Galbiati, M. Recla, V. Pastore, M. Liscio, S. Galbiati, E. Castelli IRCCS Eugenio Medea (Bosisio Parini, I); Ospedale Pediatrico Bambin Gesù (Rome, I) Objectives: To investigate the sustained attention deficit in post-traumatic children and adolescents, the efficacy of a specific neuropsychiatric treatment and persistence of treatment benefits at 1-year follow-up by comparing the post-traumatic group with a control group of untreated patients. Lastly, to explore the possible influence of some clinical variables on treatment success. Methods: The study involved 65 severe post-traumatic patients (age range: 6–18 years) presenting with marked attentional deficit: 40 patients received a 6-month specific training for sustained attention, while the remaining 25 patients were enrolled in the control group. Patients were re-assessed at the end of the rehabilitation period and at 1 year from insult. The cognitive assessment included an Intelligence Quotient test (IQ) and an attention test (Continuous Performance Test – CPT). All the data were statistically analyzed. Results: At baseline evaluation, the clinical group presented with a mild cognitive deficit (IQ = 69.50, SD = 3.03) but failed on Performance tasks (PIQ = 69.40, SD = 3.15). They showed a marked attentional deficit, with pathological scores on the CPT test. No significant differences were found between the baseline performances of the two groups. The end-of-treatment evaluation showed a significant improvement in the overall cognitive level (p < 0.01) and in performance (p < 0.01). On the CPT, the performances of the clinical group significantly improved, with shorter reaction times. No significant difference in IQ was found with the control group, but there were considerable differences in the CPT performances of treated patients. Persistence of treatment benefits in all investigated domains was found at 1year follow-up. The younger the age at insult, the lower the recovery of sustained attention and reaction times. Treated patients with frontal or posterior lesions completely recovered the attentional function, with a performance within the norm at the 1-year follow-up. Furthermore, the longer the time between trauma and treatment, the lower the efficacy of training. Conclusions: Good results were achieved across all treatment areas. As rehabilitation is crucial for the treatment of attentional deficits in post-traumatic patients, it is important to start treatment early and tailor it to the patient’s needs. P605 Modified pen-hold in the treatment of writer’s cramp B. Baur, W. Fürholzer, J. Hermsdörfer Krankenhaus München-Bogenhausen (Munich, D) Writer’s cramp (WC) is a focal, action-related dystonia which induces hypertonic co-contractions and severely impairs handwriting. One behavioural treatment approach is the handwriting training developed by Mai and coworkers, which includes among various motor exercises the use of a modified pen hold (stabilized between index and middle finger). This pen hold has proven particularly successful in clinical practice. We aimed at elucidating the immediate effects of the modified pen hold in WC patients and healthy controls. Further, we studied the effects of motor training sessions with the modified pen hold. All subjects wrote a sentence with their usual and also with the modified pen hold. WC patients did this before and after motor training. Movement and pressure were recorded with a digitizing tablet. Pressure, movement time for the whole sentence, script size and writing fluency were analysed. Additionally we examined subjective ratings of writing performance and handicap in daily life before and after training. When writing with their usual pen hold, pressure in the WC patients was elevated, and writing speed was decreased compared to healthy controls. The modified pen hold reduced immediately the pressure significantly in WC patients and controls, but left other aspects of their writing unaffected. Subsequent handwriting training lead to a further reduction of writing pressure in WC patients. This improvement of pressure was also present when returning to the usual pen hold. Patients’ ratings of the own handwriting performance also improved sig-nificantly after training. Results indicate that the use of the modified pen hold combined with subsequent handwriting training is an effective way to normalize hypertonia and pen pressure in WC patients.

P606 Successful neurorehabilitation in a patient with severe predominantly axonal form of chronic inflammatory demyelinating polyradiculoneuropathy under intravenous cyclophosphamide K. Schweikert, C. Kätterer, P. Fuhr, M. Tolnay, A. Steck, M. Mäder University Hospital Basel (Basel, CH); REHAB Basel (Basel, CH) Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated clinically heterogenous disease with acute, subacute, or chronic onset. If untreated, 25 % of patients become wheelchair bound or bedridden, 10 % die of complications. Fifty-three percent of patients with chronic course of CIDP do to respond to corticosteroids, intravenous immunoglobuline (IVIg), and plasmapheresis (PE). A recent Cochrane review provided no evidence for a benefit of cytotoxic drugs in CIDP, but several authors found pulse intravenous cyclophosphamide (IVCY) to be helpful in refractory CIDP, even in totally dependent patients. Goals: to describe course and rehabilitation outcome of a patient with severe, predominantly axonal form of CIDP under IVCY. Case report: a 62-year-old woman developed progressive ascending numbness and weakness in lower and upper limbs 1 week after respiratory infection. Repeated nerve conduction studies (NCS) and analysis of cerebrospinal fluid (CSF) were normal. Three months after onset of symptoms, NCS and needle myography showed signs of acute severe axonal damage, biopsy of the superficial peroneal nerve and peroneal muscle mild axonal neuropathy, no demyelination nor vasculitis. Extensive laboratory screening for secondary CIDP was negative. Diagnosis of idiopathic CIDP was postulated. Despite treatment with IVIg (0.4 g/kg/day over 4 days 1, 2, and 3 months after the onset) and PE (13 times within month 3 and 5), the neuropathy progressed. Five months after onset of symptoms, the patient was tetraplegic with severe motor cranial nerves and autonomic involvement and needed ventilation. Functional Independence Measure (FIM) score was 27 points (FIM: 18 to 126 points; 18 = total disability, 126 = no disability). Albuminocytological dissociation was found in CSF (protein > 1 g) and IVCY started (750 mg/m2 for 1 day in a total of 6 applications in monthly intervals). After the 3rd dose, under daily logopedics, physical and occupational therapy, muscle strength slowly recovered in proximal then distal upper and lower limbs. Tracheal canule and gastrostomy were removed 11 and 12 months after symptom onset. The patient walked without assistance 13 months after the onset. She returned home 2 months later with a FIM score of 119 points. Conclusions: In severe chronic CIDP with predominantly axonal signs refractory to conventional immunotherapy, IVCY together with intensive neurorehabilitation can cause substantial improvement. P607 Brain stimulation in rehabilitation after stroke Y. Bykov, S. Nickolaichjuk, M. Avetisjan, E. Faizulin, M. Chernikh, T. Surzsha Irkutsk State Medical University (Irkutsk, RUS); Southen-Sakhalin Hospital (Southen-Sakhalin, RUS) Objective: Greatest functional recovery after stroke is one of the main goals in neurology. Brain stimulation may be useful method in rehabilitation after ischemic stroke. Stimulation by light and sound impulses may be used in rehabilitation program. Methods: clinical (Lindmark Scale, Barthel Index), computerized analysis of sensory-motor processes. Stimulation was used for daily physiotherapy and exercise training. Results: Patients with cerebral infarction in the middle cerebral artery area in 1–2 months after stroke were treated within stimulation (I) or without one (II). Stimulation was used in process of daily physiotherapy for 2 or 3 weeks. In a group I (n = 29) the index of Lindmark Scale before stimulation was 326.3 ± 1.8, after stimulation – 371.2 ± 1.1 (p < 0.001). Barthel Index changed from 66.6 ± 0.8 to 78.2 ± 1.8 (p < 0.001). In a group II (n = 31) the index of Lindmark Scale before treatment was 323.3 ± 1.7, after treatment – 341.5 ± 2.9 (p < 0.01). Barthel Index was 68.4 ± 0.9 and 73.3 ± 1.7 accordingly (p < 0.01). Conclusion: Positive results were obtained in both groups. However, degrees of the efficacy were different. The better results in the first group may be explained by the finding of the individual pattern of movement. This conception implies that any person has individual characteristics of movement. Human activity is integral as usually. There are disintegrations of nerves system in pathology. Defining of individual frequency of movement pattern will become a basis for new matrix of movements. New pattern might be constructed with the help of brain stimulation.

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P608 Subthreshold rTMS in post-stroke depression V. Kistsen, V. Evstigneev Belarusian Medical Academy of Postgradua (Minsk, BLR) The object of this study was to reveal antidepression effects of subthreshold rTMS in hemispheric infarct patients in early and late rehabilitation period. Methods: We performed a study of 112 patients (67 man and 45 women aged from 29 to 77 years old, mean, 52.2 ± 9.17 years) with brain hemispheric infarct. rTMS was implemented using the original methodic: intensity of magnetic field was 1.7 T, frequency – 10 Hz, stimulus duration – 250 msec. The stimulated coil was applied on projection of stroke localization. The time of magnetic influence of the mentioned parameters was 10 min. The course treatment included from 8 to 10 daily procedures of rTMS. The patients of control group had traditional rehabilitation. The dynamic of psychoemotional disorders were detected by neuropsychological tests (Hamilton and Beck depression tests, Spilberger-Hanin anxiety scale). Results: The 68.3 % patients in early and 76 % in late rehabilitation period had poststroke depression by Hamilton and Beck depression tests. Positive dynamic was found in group after rTMS course only without dependence from infarct side localization. Statistically certain were data in young nonsmoking patients with high posturography efficacy, normal amplitude P300 and without internal hydrocephaly (g < 0.05). The personal and situational anxiety improved in rTMS group while in control group – personal anxiety only. Predictors of anxiety recovery were subcortical infarct localization, light hemiparesis, maximum quantity of rTMS procedures [1 12]. Conclusion: Subthreshold rTMS is effective in poststroke depression patients in early and late rehabilitation period.

Pain and headache P609 The burning mouth syndrome: clinical presentation and affective disorders M. Mijajlovic, J. Zidverc Trajkovic, L. Jankovic, D. Stanimirovic, N. Sternic Institute of Neurology (Belgrade, CS); School of Dentistry (Belgrade, CS) According to IHS classification, burning mouth syndrome (BMS) is intra oral burning sensation without obvious medical and dental cause. Nternational headache society (IHS) diagnostic criteria of the disorder include the presence of burning oral sensation during the most period of day without obvious changes of oral mucosa. Local and systemic causes have to be excluded by appropriate diagnostic procudures. Subjective feeling of dry mouth, paraesthesias and taste changes could be associated symptoms. The BMS is of unknown path physiology. The aim of the study was to analyze the clinical and affective parameters in BMS. We examined 85 patients fulfilled the diagnostic criteria for primary BMS. The average age was 65.5 ± 11.2 years, with female/male ratio 2/1. The disorder lasted more than twelve months in 62.7 % of patients. The burning sensations were distributed on the whole oral cavity in 39.2 %, on tongue or lips in 29.4 %, while in the other patients the sensation involved the part of oral cavity. In all patients the affective status was evaluated. High scores were obtained on Hamilton Depression Rating Scale (16.5 ± 4.5), Beck Depression Inventory (17.4 ± 8.2) and Hamilton Anxiety Rating Scale (20.6 ± 5.6). As the other chronic pain conditions, BMS is strongly associated with anxiety and depression. P610 Common and dissociable neural responses evoked by contact heat and nontactile laser pain stimulation C. Helmchen, M. Roehl, U. Bingel, C. Mohr, J. Lorenz, C. Büchel University of Lubeck (Lubeck, D); University of Hamburg (Hamburg, D) Our current knowledge of pain-related neural activation patterns is largely based on either contact heat or non-tactile laser painful stimulation which considerably differ in their physical and perceptual properties. We used functional magnetic resonance (fMRI) to intraindividually compare painrelated activation between laser and contact heat stimulation. Four different intensities of laser (350, 450, 550, 650 mJ) and contact heat (40°, 43°, 46°, 48.5°C) stimuli were applied to the left hand of healthy subjects in randomized order. To identify common and dissociable neural responses in the con-

text of different physical stimulus properties, we focused our analysis on the characterisation of regional stimulus response functions (SRF) relating changes of individually perceived pain intensities to fMRI signal changes. Regression slopes of stimulus intensity vs. graded pain perceptional levels did not reveal significant differences. The increase of BOLD signal changes with increasing pain intensities were used to describe pain-related SRF. Contact heat stimulation yielded activation with a significantly steeper increase of the pain-related SRF than laser stimuli in the lateral aspects of the secondary somatosensory cortex, posterior insula, frontal cortex, and the amygdala. In contrast, only the lateral prefrontal cortex revealed a stronger increase of activation for painful laser stimuli. Common pain-related increases in the BOLD signal across the two stimulus types were detected in the medial thalamus, medial parts of the secondary somatosensory cortex, anterior cingulate cortex, the anterior insula, and the cerebellum. Importantly, these differences have to be taken into consideration when comparing pain related neuroimaging studies conducted with either stimulus type. P611 Idiopathic intracranial hypertension with adrenal hyperplasia responsive to topiramate treatment: a case report M. Arnaoutoglou, V. Kosta, S. A. Kapsali, G. P. Spanos, G. Andriopoulou, K. Kozetzidou, M. Hatzidou, A. Arnaoutoglou, S. J. Baloyannis AHEPA Hospital (Thessaloniki, GR) Objective: Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure without clinical, laboratory or radiological evidence. Nevertheless it is commonly associated with other pathological conditions (endocrine disorders, obesity, hypercoagubility, SLE e. t.c) and the aim of this study is to evaluate that association Methods: A case report of a 17 y female is presented with a history of daily headache of moderate to severe intensity, which localized frontally and retro-orbitally. These symptoms persisted for six months after which visuals disorders (paracentral scotomas) developed. On admission bilateral papilloedema was observed (10 and 8 dt) and visual field examination revealed bilateral blind spot enlargement. The patient fulfilled the diagnostic criteria for IIH according to the classification of the International Headache Society (normal neuroimaging and laboratory testing).Additionally her endocrinological evaluation revealed hypomenorrhea, areomenorrhea, hirshutism, obesity (BMI = 42) and increased levels of: a-4- androstendione, aldosterone, DHEAS, testosterone, cortisol, DHS leading to the diagnosis of adrenal hyperplasia. Abdominal CT and ECHO were normal. The patient was treated with acetazolamide (125 mg X 3), furosemide (20 mg X 1) and topiramate (100 mg X 2). Weekly monitoring of visual acquity, visual fields and fundoscopy were performed. Hormonal quantification was done in time-dispersed intervals (in the 1st, 2nd, and 4th week). Results: In the 4th week significant amelioration of the patient’s neurological status was observed (cessation of headache and scotomas, limitation of papilloedema- from 8 and 10 dt to 2 dt). In addition a significant improvement of the patient’s endocrinological profile was observed (weight loss, initiation of normal menstruation, normalization of a-4-androstendione, aldosterone, DSH, cortisol levels) and an improvement on the levels of testosterone. Conclusion: IIH is successfully treated with carbonic anhydrase inhibitors (as acetazolamide and furosemide) through limitation of CSF production. Topiramate, on the other hand is a multipotent medication targeting several metabolic and neuromodulating pathways. Thus the endocrine stabilization of our patient could be attributed to topiramate, giving root for further investigation of its future role on endocrine disorders. To our knowledge a similar case of endocrine responsiveness to topiramate has not been reported. P612 Exercise-induced intracranial hypertension due to insufficient jugular vein drainage J. Morier, J. Bogousslavsky, P. Michel Centre Hospitalier Universitaire Vaudois (Lausanne, CH) Background: Intracranial hypertension without an intracranial structural lesion may be due to several systemic causes or may be idiopathic (“Pseudotumor Cerebri”). In the latter, insufficient drainage of cerebrospinal fluid (CSF) due to increased venous pressure is one presumed mechanism. We report a patient who developed intermittent intracranial hypertension manifesting as status migrainosus after a traumatic unilateral jugular vein occlusion. Patient and Methods: A 18-year-old man had a high velocity trauma resulting in a left brachial plexus avulsion and a left jugular vein occlusion. 8 years later, at age 26, he started developing intermittent headaches. Venous

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CT-angiography (VCTA), venous MR angiography (VMRA), lumbar puncture (LP) and fundoscopy were performed during and in between the headache episodes. Arterial and venous cerebral angiography with measurements of venous sinus pressure was performed between two episodes. Results: Headaches lasted between 4 to 10 days and resembled status migrainosus, preceded mostly by a visual aura. They were usually triggered by strenuous sporting activities. Usual analgesics and triptans were ineffective. LP showed an opening pressure of 42 to > 50 cm H20 during, and of 9 cm H2O in between the headache episodes. VCTA and VMRA during the episodes showed decreased diameter of the cerebral venous system without clear-cut focal stenosis, and in between, a normal diameter and a chronic occlusion of the left jugular vein.Cerebral angiography performed during a period without headache showed no abnormality of the intracranial sinus venous system or of the right jugular vein, and no pressure gradient was found on manometry. Drainage of 40 ml of CSF volume taps each time stopped the headache episodes within a few hours. Conclusion: We postulate that the physiologically increased elevation of central venous pressure during exercise induced a vicious circle of insufficient CSF drainage and intracranial hypertension, which in turn decreased the size and absorption capacity of cerebral venous sinuses. P613 Effects of magnesium, furosemide and metoprolol on spreading depression M. Alemdar, M. Selekler, Ö. Akman, N. Ates, S. Komsuoglu Kocaeli University, Faculty of Medicine (Kocaeli, TR) Objectives: CSD constitutes the biological basis for the neurological aura. It is likely that the aura is the generator of headache, since CSD triggers the activation of the trigeminovascular system. We studied the effects of intravenous Magnesium, Furosemide and Metoprolol infusion on CSD production by the use of a continuous CSD induction model in rats. Methods: Fifteen adult Wistar rats were anesthetized with 50 mg/kg thiopental infusion intraperitoneally. Right femoral vein was canulated for drug administration, and then were placed in a stereotactic frame. Continuous CSD induction was generated with application of 1 M KCL introduced through a burr hole into the left frontal dura-mater and recorded by an Ag/AgCl electrode placed on left parietal dura-mater. After a basal record of CSD production during the first 40 minutes, 90 mg/kg MgSO4 (n = 5) or 2 mg/kg furosemide (n = 5) or 5 mg/kg metoprolol (n = 5) was infused within four minutes. Then recordings were maintained for futher 80 minutes. Results: Total number and duration of CSDs in MgSO4 group are 6.3 ± 0.6 and 107 ± 4 sec in basal 40 minutes, 5.6 ± 0.5 and 120 ± 5 sec on first 40 minutes after infusion and 6 ± 0.6 and 107 ± 4 sec on second 40 minutes after infusion. In Metoprolol group: 7.8 ± 0.4 and 123 ± 5 sec in basal 40 minutes, 8.6 ± 1.0 and 122 ± 6 sec on first 40 minutes after infusion and 9.2 ± 1.0 and 120 ± 5 sec on second 40 minutes after infusion. In Furosemide group: 6.4 ± 0.5and 127 ± 5 sec in basal 40 minutes, 6.6 ± 1.8 and 130 ± 7 sec on first 40 minutes after infusion and 7.0 ± 0.8 and 131 ± 6 sec on second 40 minutes after infusion. A significant differences in total number and duration of CSDs within and inbetween these group was not detected. Conclusion: Magnesium which is thought to act as a NMDA receptor antagonist was shown to reduce the number of CSDs during continuous CSD induction in rats. Furosemide, an inhibitor of sodium-potassium-chloride (Na-K-Cl) cotransport, has also been shown to be effective in treatment of a case with prolonged migrainous aura and in inhibition of CSD production in cats. Metoprolol, a selective blocker of the beta 1-adrenoreceptors, was also proven to be effective in prophylaxis in clinical trials, but mechanism of its action in migraine has not been clarified yet. Findings in our study suggest that the effects of these drugs are not mediated by inhibition of CSD. Therefore, further studies are needed for determining their effects on trigeminal activation or its downstream consequences. Kocaeli University Research Foundation support this research. P614 Sporadic hemiplegic migraine with reversible DWI evidence of cerebral ischaemia – a migraine stroke? D. Weller, H. Hentschel, G. Gahn University Hospital Dresden (Dresden, D) Introduction: Migraine is a common and chronic disorder. It is usually considered benign but a number of studies have suggested it as an independent risk factor for ischemic stroke. The pathogenetic mechanisms underlying this condition are at present not known. Case: We present the case of a 37-year-old male with first onset of a sporadic hemiplegic migraine with reversible diffusion weighted magnetic resonance imaging (DWI) evidence of cerebral ischemia. The patient had been admitted to our stroke unit with right side hemiplegia and aphasia. The neu-

rological symptoms disappeared completely over the course of a few hours. A severe headache with bifrontal localisation lasted for 24 hours. On inquiry, the patient was known for a migraine without aura (MwoA) and he reported frequent holocephalic and bifrontal headaches associated with nausea and vomiting. Surprisingly he had never suffered from any aura symptoms before. The DWI showed a small cortical left hemispheric ischemia and the magnetic resonance angiography revealed a stenosis of the left middle cerebral artery, thrombotic material was considered as possible cause. Duplex sonography of the brain feeding arteries showed a reduced flow signal of the middle cerebral artery. Echocardiography, EEG and 24h-ECG gave findings within the normal range for the patient’s age group. 24-hour-blood-pressure measurement revealed a mild systemic hypertension. Clinical chemistry showed increased values for cholesterol and triglycerides which normalised on administration of fluvastatin. We started secondary prevention with clopidogrel. Furthermore metoprolol as antihypertensive and prophylactic treatment was given to the patient. Under prophylactic treatment with metoprolol the patient reported no further episodes of migraine without aura (MwoA) or migraine with aura (MwA) up to now. Imaging of the neocranium was repeated 3 month later and the DWI evidence of cerebral ischemia in the left hemisperic cortex had disappeared. Duplex sonography showed normal flow signals of the cerebral arteries. Discussion: It is still under debate whether the shown punctual ischemia could have been a sign of reduced cerebral blood flow (CBF) caused by temporal vasospasm of the middle cerebral artery. Therefore it could not be seen as a cerebral infarct – in the meaning of a migraine stroke. The neurological hemispheric symptoms cannot be explained by this small lesion but more by a typical cortical spreading depression as it is known. P615 Botulinum toxin type A compared with divalproex sodium for the prophylactic treatment of migraine: a 9-month randomised, evaluator-masked trial A. Blumenfeld, J. Schim The Neurology Center (Encinitas, USA) Objective: To evaluate the efficacy and safety of botulinum toxin type A (BoNTA; BOTOX®: Allergan, Inc., Irvine, CA, USA) compared to divalproex sodium (DVPX; DEPAKOTE®: Abbott Laboratories, Chicago, IL, USA) for the prophylactic treatment of migraine. Methods: A randomized, double-blind, single-center, prospective study was conducted over 9 months comparing the efficacy and safety of BoNTA and DVPX in patients with ≥ 3 migrainous headaches per month or migrainous headaches on ≥ 15 days per month warranting prophylactic treatment.At day 0 after a 1-month baseline screening period, eligible patients received either BoNTA 100 U (and placebo DVPX) or DVPX 250 mg bid (for the first week and titrated to 500 mg/bid) (and placebo BoNTA). A second BoNTA treatment was administered at month 3. Patients were evaluated at months 1, 3, 6, and 9. The impact of treatment on headache disability was evaluated by the use of MIDAS and HIT-6. Adverse events were reported. Results: 59 patients were enrolled (BoNTA n = 30, DVPX n = 29; mean age 42.4 years; 84.8 % female; 84.8 % Caucasian). 66.7 % of BoNTA and 44.8 % of DVPX patients completed the study (P = 0.09). During baseline the mean MIDAS total scores were 38.17 and 29.10 for BoNTA and DVPX patients, respectively (P = 0.101). BoNTA treatment resulted in significant mean changes from baseline in MIDAS scores at months 3 (–21.56, P = 0.0003), 6 (–22.74, P < 0.0001), and 9 (–21.44, P < 0.001). DVPX treatment also resulted in significant mean changes from baseline in MIDAS scores at months 3 (–10.0, P = 0.02), 6 (–14.82, P = 0.0008), and 9 (–12.73, P = 0.01). The differences between the groups were not statistically significant. Significant reductions in HIT-6 total scores occurred in the BoNTA group (baseline score 15.77) at months 1 (–2.17, P = 0.005), 3 (–3.07, P = 0.0005), 6 (–4.24, P = 0.0008), and 9 (–2.48, P = 0.01) and in the DVPX group (baseline 14.97) at months 6 (–2.19, P = 0.01) and 9 (–2.54, P = 0.03). A significantly greater percentage of DVPX patients reported adverse events possibly related to treatment than BoNTA patients (76 % vs 50 %, P = 0.04) and 27.6 % of DVPX patients discontinued the trial due to adverse events compared with 6.7 % of BoNTA patients (P = 0.04).Adverse events possibly related to treatment were predominantly mild to moderate in both groups. Conclusions: Both BoNTA and DVPX were similarly effective in reducing the disability associated with migraine. BoNTA demonstrated a superior tolerability profile than DVPX.

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P616 Continuous and simultaneous monitoring of extracranial common carotid and vertebral blood flow in migraineurs K. H. Park, H. J. Kim, S. Y. Baek, T. W. Yoo, K. P. Park Pusan National University (Pusan, KOR); Institute of Koryo Hand Therapy (Seoul, KOR) Object: We developed new frame hold for monitoring blood velocities of several arteries simultaneously and continuously using trancranial Doppler (TCD).The aim of this study was done to prove the change of velocity of extracranial arteries, such as common carotid and vertebral arteries in migraineurs before and after Korean Hand Acupuncture. Background: Migraine may be related with the change blood flow of posterior circulation, such as vertebro-basilar arteries. Some researchers show that acupuncture works for pain control, esp. migraine headache and that acupuncture produces specific and reproducible effects on cerebral blood flow. By Koryo Hand Therapy (KHT), health can be defined as well harmonized state of cerebral blood. The health state can be diagnosed by comparison of anterior and posterior circulation that means carotid and vertebral system Methods: The 30 migraineurs without aura were included. They had no neurological diseases and no other dysfunctions. TCD signals were recorded in carotid and vertebral arteries with EME TCD with new developed frame. Doppler systems allow online calculation of mean blood flow velocity (Vm) derived from averaging the mean velocities of the Doppler waveform envelope.We got all the basic data, and then we re-examined 20 minutes after applying KHT acupuncture needle on the examinees’ hands at point I-2, E-8, H-2 and I-38 of middle,4th and 5th fingers. Results: The 30 migraineurs noted headache relieved after management. The change of carotid and vertebral arteries were closely related. The gradual increased velocity of the vertebral artery (from 32.3 + 6.1 cm/sec. to 39.4 + 5.63 cm/sec.) accompanied the decreased velocity of the carotid arteries (from 29.7 + 5.4 cm/sec to 23.5 + 5.1 cm/sec.) on the affected side after inserting KHT needle at I-2 and E-8, H-2 and I-38. The flow change of two arteries was clsosely related after management. Conclusion: The effect of acupuncture in migraineurs might be proved through the change of cerebral blood flow.

P617 Circannual periodicity of migraine K. B. Alstadhaug, R. Salvesen, S. Bekkelund Nordlandssykehuset HF (Bodø, N); Universitetssykehuset i Tromsø (Tromsø, N) Objective: Several biological rhythms are generated in the suprachiasmatic nucleus (SCN) of the hypothalamus. Photoperiodism is a crucial phenomenon in animals, but more controversial in man. Seasonal rhythm of migraine attacks may support a role of SCN in the pathophysiology of migraine. We set out to study seasonal variation of migraine. Methods: Eighty-nine female migraineurs from an arctic area were instructed to record every migraine attack in detail for 12 consecutive months. By using Edwards’ model for recognition and estimation of cyclic trends, time-series analysis was made. Results: Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were experienced and recorded. Except for their migraine all patients were healthy. The mean age ± SD was 36.9 ± 6.0 (range 16 to 45). No seasonal trend of MO was found. However, patients with a lifetime story of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95 % CI: 1.08–1.55). Conclusion: We confirm that there is a seasonal trend with more migraine attacks in the light season compared to the dark season in arctic females with MA but not in females with MO.

P618 Migraine-like headache and pituitary adenoma O. Albertí, S. Santos, I. Beltran, L. García, T. Corbalán, L. Martínez, G. Piñol, L. F. Pascual, C. Iñiguez University of Zaragoza (Zaragoza, E) Introduction: Migraine and migrainelike are prevalent conditions in the general population. The majority of cases which respond well to oral treatment are benign. But, in some cases, there are several characteristics like: latter onset, campimetric failure, associated neurological conditions, etc; that

may lead us to ask for a neuroimaging probe in order to find a secundary origin of the headache, in spite of a good response with ergotics or triptans. Case history: We report a case of complete resolution of migraine, without aura, after succesful neurosurgery treatment, of pituitary adenoma. The patient started with migraine two years before at the age of 42 without any history of migraine in his family, and was well treated with ergotics from the beginning. He associated in the last two months vision difficulties and he presented to our emergency department. Magnetic resonance imaging (MRI) revealed a mass of pituitary gland with normal endocrinogical examinations. The improvement in headache following surgery implies a casual link between the tumor and presence of headache. Conclusion: Pituitary adenoma must be included on differential diagnosis of migraine and migrainelike conditions, althought they had a good response to ergotics or triptans.

Sleep disorders P619 Narcolepsy studied by magnetic resonance spectroscopy R. Poryazova, B. Schenpf, E. Werth, D. Meier, U. Dydak, P. Boesiger, C. L. Bassetti University Hospital (Zurich, CH); ETH (Zurich, CH) Objective: Two previous magnetic resonance spectroscopy (MRS) studies in narcolepsy have been presented in the literature. In the studies different regions of interest were examined. In the first one no metabolic changes were observed in the ventral pontine area. In the second one a reduction in Nacetylaspartate (NAA)/creatine-phosphocreatine (Cr) in the hypothalamus of narcolepsy patients with cataplexy was found. The aim of our study is to test for metabolic changes in specific brain areas, “regions of interest”, thought to be involved in sleep regulation and pathophysiology of narcolepsy: hypothalamus, pontomesencephalic junction and both amygdalas. Methods: In 8 narcolepsy patients with clear-cut cataplexy, CSF hypocretin deficiency (3/3) and HLA-DQB1*0602 positivity (8/8) and 5 age, gender and body mass index matched controls MRS was performed. Patients were treatment naive or off therapy for at least 14 days before scanning. MRS was performed on a Philips Intera 3.0 T scanner. Single-voxel proton MR spectra were acquired from the regions of interest and processed to determine metabolite concentration ratios. The concentration ratios of NAA/Cr, (total NAA)/Cr, (total Choline)/Cr and myo-Inositol (mI)/Cr were determined. The patient group was compared with the control group on the basis of these results. Results: A trend towards lower (total NAA)/Cr ratios in the right amygdala was observed in patients (1.1 ± 0.3) in comparison to controls (mean 1.5 ± 0.4). A trend towards higher NAA/Cr ratios in the pontomesencephalic junction was found in patients (mean 1.4 ± 0.4) compared to control subjects (1.05 ± 0.3). No metabolic differences were observed concerning the other voxels of interest. Conclusion: Our preliminary results suggest the presence of metabolic changes in the right amygdala and the pontomesencephalic junction in narcolepsy patients. SNF grant to CB, EFNS grant to RP P620 Absence of aversive startle potentiation in human narcolepsy-cataplexy R. Khatami, S. Birkmann, C. L. Bassetti University Hospital (Zurich, CH) Objectives: The blink reflex of acoustic startle reflex (ASR) is modulated by emotions. The absence of ASR potentiation during unpleasant stimuli has been reported in humans following amygdala lesions. Methods: ASR and the emotional modulation of the blink reflex of ASR were assessed during the presentation of standardized emotional pictures in drug free narcolepsy-cataplexy (NC) (n = 12, mean age 34 years SD 12) and in nine age- and gender-matched controls. Subjective ratings of emotional valence, emotional arousal and heart rate were also measured. Results: Emotional modulation of ASR could be assessed in seven NCpatients and in seven controls. ASR responses (latencies and recruitment pattern of involved muscles) were similar in both groups, although the magnitude was higher and was more variable in NC. While both groups had a mild enhancement of startle magnitude during pleasant pictures (relative to neutral pictures, p = 0.56), NC failed to evoke a potentiation of ASR during

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unpleasant pictures (p = 0.02). Considering result individually aversive startle potentiation was found in each individual control subject, but was absent in 3 of 7 NC-patients irrespective to the individual level of ASR magnitude. Subjective rating on the valence (p = 0.10) and emotional arousal (p = 0.12) were comparable in both groups (suggesting normal emotional perception and arousal following unpleasant pictures). Similarly differences were found in autonomic arousal as assessed by heart rate activation (p = 0.35). Conclusions: The absence of aversive startle potentiation further supports the hypothesis – suggested by animal data – of an amygdala dysfunction in NC. Supported by Swiss National Science Foundation grant 3200B0–104100/1 (to RK).

P621 Humour processing in narcoleptic patients assessed by functional magnetic resonance imaging A. Ponz, S. Schwartz, R. Poryazova, E. Werth, R. Khatami, P. Boesiger, C. L. Bassetti University of Geneva (Geneva, CH); University Hospital (Zurich, CH); University of Zurich – ETH (Zurich, CH) Background/objectives: Narcolepsy with cataplexy (NC) is a chronic sleepwake disorder characterized by excessive daytime sleepiness and cataplexy episodes. NC is accompanied by a loss of hypocretin/orexin transmission, and neuronal loss in the hypothalamus. Cataplexy consists of a sudden loss of postural muscle tone triggered by intense emotion, predominantly positive emotions such as mirth and laughing. The emotional triggers of cataplexy suggests that the neural networks underlying emotional processing may be implicated. Using fMRI, we tested whether NC patients might present altered neural response to humorous stimuli in mesolimbic and motor regions. Methods: Patients with narcolepsy with cataplexy and matched healthy controls were scanned while they performed a humour judgment task. Stimuli were “mini-action scenes” composed of a succession of two almost identical pictures, separated by a 300 ms blank. The first picture (3000 ms) always depicted a neutral scene whereas the second picture (3000 ms) could reveal either a funny or a non-funny new element. On each trial, the subjects had to indicate on a keypad whether they judged that the second picture was funny or not by. MRI data were acquired with a 3-T Philips INTERA system, using SENSE parallel imaging. To avoid that the subjects fall asleep during scanning, functional EPI images were obtained across 3 successive short sessions including 130 volumes each (TR = 2200 msec; 36 axial slices/volume). Data were preprocessed and analyzed using the general linear model for event-related designs using SPM2 (www.fil.ion.ucl. ac.uk/spm). For the analyses, humorous and neutral stimuli were categorized based on each subjects’ own ratings. Results: Behaviorally, NC patients had slower reaction times than controls; there was no group difference in humour rating. Our fMRI data (8 patients, 6 matched controls) showed that several regions were selectively activated during humorous trials (humour > neutral) in both patients and controls, including the amygdala, anterior cingulate, premotor cortex, posterior parietal, mesencephalon, and associative visual regions. By contrast, a direct statistical whole-brain voxel-wise group comparison revealed increased activity in the SMA and hypothalamus on humorous trials in the control group, with no such modulation in the NC group. Conclusion: Our fMRI findings provide direct evidence for altered hypothalamic response to humour in NC patients.

P622 The effect of phototherapy on the sleep-wake cycle of totally blind individuals R. Geraldes, H. Bértolo, T. Paiva Santa Maria Hospital (Lisbon, P) Objectives: Sleep-wake circadian rhythm disorders are common among totally blind humans. The role of phototherapy in the correction of these disturbances is controversial. This study aimed to: 1) to classify sleep-awake disturbances of total blind through actigraphy and sleep logs, while correlating this information with the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (EPW); 2) to study the effect of ocular and extraocular light stimulation on the correction of the disturbed rhythm. Methods: Seven total blind individuals (26.3 ± 5.94 years-old; 3 women) were monitored with actigraphy and sleep logs. To classify the sleep-awake rhythm disorder, data were analysed during 12 days without any intervention. The subjects had then morning ocular bright light stimulation for seven days and for another seven days, with the same schedule, extraocular

(behind the knee) bright light stimulation. A crossover, nonblinded study was adapted to the constraints related to blindness. A strict selection was made to exclude psychological, psychiatric or other sleep problems. Results: Six of the cases had high PSQI and EPW scores though only two complained about sleep disturbances. Inactivity during the day was the only variable that correlated with the PSQI score. No correlations were found for the EPW. Five of the cases was classified as having a sleep-awake rhythm disorder, four with a probable free-running rhythm. Conclusion: Ocular light stimulation had a positive effect on the reduction of sleep latency and nocturnal activity in less severe cases, and extraocular seemed to have a positive effect on diurnal activity, in free-runners. It was not possible, due to the reduced sample, to make safe conclusions about the effects of ocular and extraocular light stimulation on the correction of the sleep-awake disturbances in blinds. This preliminary study suggests that light response may depend on the studied rhythm disturbance but further investigation is needed to confirm this hypothesis

P623 Sleep-wake-disturbances after traumatic brain injury C. Baumann, E. Werth, R. Stocker, C. L. Bassetti University Hospital (Zurich, CH) Objectives: Posttraumatic sleep-wake disorders are common in clinical practice. Only few, mostly retrospective studies, however, have been published on this topic. The aim of this study was to assess prevalence and characteristics of posttraumatic sleep-wake disorders in a consecutive prospective trial, and to identify predictors for the development of posttraumatic sleep-wake disorders. Methods: 75 consecutive patients (59 males, 16 females, mean age 37 years) were recruited within four days after traumatic brain injury (TBI). Severity of TBI was classified (Glasgow Coma Scale = GCS). Assessment included brain CT, HLA typing, and cerebrospinal fluid hypocretin-1 measurements. Six months later, clinical outcome (according to Glasgow Outcome Scale = GOS) and presence of sleep-wake disorders were determined by means of standard questionnaires, polysomnography (PSG), and multiple sleep latency test (MSLT). Results: Nine patients died, and 13 patients were not able or refused to participate in all study procedures. Therefore, 53 patients participated in all study procedures. TBI was mild (GCS 13–15) in 21, moderate (GCS 9–12) in 12, and severe (GCS in 3–8) in 20 patients.At six months, good recovery (GOS 5) was observed in 26, mild disability (GOS 4) in 26, and severe disability (GOS 3) in one patient. Sleep-wake disorders were reported by 62 % of the patients. The most common complaints were excessive daytime sleepiness (EDS, defined by an Epworth Sleepiness scale > 10, 28 %), increased night sleep time (> = 2 hours more than pre-TBI) (19 %), and fatigue (11 %). Insomnia was reported by 2 %. Abnormal short mean sleep latencies (< 10 minutes) on MSLT were found in 57 %. Severe sleep apnea was identified on PSG in 11 %. There were no associations between posttraumatic sleep-wake disorders and severity or localization of TBI, gender, age, GOS, HLA typing, or hypocretin-1 levels. Conclusions: Sleep-wake disorders, particularly EDS/hypersomnia (but not insomnia) are frequent after TBI. In this analysis, however, we could not identify any predictors for the development of sleep-wake disorders after TBI.

P624 The influence of sleep disturbances on the health-related quality of life in Polish patients with moderate stage of Parkinson’s disease M. Boczarska-Jedynak, B. Jasinska-Myga, G. Opala, G. Klodowska-Duda, M. Smilowski Silesian Medical Academy (Katowice, PL) Objective: To evaluate the impact of sleep disturbances on the Health-Related Quality of Life in Polish patients with moderate stage of Parkinson’s Disease. Methods: 51 patients with PD of Movement Disorders Outpatient Clinics in Katowice with moderate stage of PD, according to both Hoehn&Yahr stageing [2–3] and motor section of UPDRS (15–65 points), without major depression as well as cognitive impairment, were included into the study. The occurrence of sleep disturbances was estimated by the positive answer to the question: “ Do you have sleep problems?”. Sleep disturbances were assessed by the Epworth Sleepiness Scale (ESS) and Parkinson’s Disease Sleep Scale (PDSS) too. Depression was evaluated with the Beck Depression Inventory (BDI). HRQoL was assessed by the Nottingham Health Profile and the Parkinson’s Disease Questionnaire (PDQ-39). Cognitive status was assessed using the Mini Mental State Examination (MMSE). The quality of life

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in patients with sleep disturbances was compared with those without sleep problems. Percentage differences between two groups were tested by the tStudent test. Results are presented with p values. P values of < 0.05 were considered significant. Results: The mean age of patients was 65.3 years. 25 patients (49 %) confirmed that they have problems with sleep (group I), 26 patients (51 %) answered negatively (group II). The mean age of patients with sleep disturbances was 63.2 years, and those without sleep problems 67.4 years. The mean ESS score was 7.47 (7.17 and 7.77 among group I and II respectively). Excessive daytime sleepiness was recognized among 21 (41.1 %) patients –13 men (44.8 %) i 8 women (38.1 %). The mean PDSS score was 95.1 (76.25 and 113.2 among group I and II respectively; p < 0.05). The mean results in NHP and PDQ-39 among group I and II were as following: NHP: physical mobility – 51.6 vs 35.5 (p < 0.05), energy –70.8 vs 56.9, pain – 45.3 vs 24.5 (p < 0.05), sleep problems – 65.8 vs 21.7 (p < 0.05), emotional reactions – 45.8 vs 25.5, social isolation – 30.0 vs 16.7 (p < 0.05). PDQ-39: mobility 47.5 vs 34.7, activities of daily living – 52.4 vs 43.7, emotional well being – 48.4 vs 28.0, stigma – 44.8 vs 30.5, social support – 26.0 vs 15.7, cognitions – 31.0 vs 21.6, communication – 29.7 vs 19.4, bodily discomfort – 50.7 vs 32.3 (p < 0.05). Conclusions: Patients with with sleep disturbances achieved much more scores in all NHP and PDQ-39 domains and they have worse quality of life than patients without sleep problems.

P625 Excessive daytime sleepiness is associated to longer night-time sleep X. Urra, H. Kumru, J. Santamaria Hospital Clínic Universitari (Barcelona, E) Objectives: In healthy subjects, insufficient night-time sleep produces daytime sleepiness.We analyzed if higher levels of sleepiness are associated with shorter sleep time. Methods: One hundred thirty-six patients with excessive daytime sleepiness were studied with a nocturnal polysomnogram followed by multiple sleep latency test (MSLT) and they completed the Epworth sleepiness scale (ESS). Diagnostic subgroups included idiopathic hypersomnia (n = 67), narcolepsy (n = 50) and obstructive sleep apnea syndorme (n = 19). The relationship between polysomnographic variables and the sleepiness measures as well as the correlation between objective and subjective measures of sleepiness were analyzed. Results: There was an inverse correlation between total sleep time and MSLT mean latency in patients with idiopathic hypersomnia (rho = –0.59; p < 0.001) and obstructive sleep apnea syndrome (rho = –0.46; p = 0.049). There was no correlation between polysomnographic parameters,MSLT and ESS in narcoleptic patients. Only in the obstructive sleep apnea patients ESS score was correlated to total sleep time and MSLT mean latency. When comparing patients with short (less than 5 minutes), intermediate (5 to 8 minutes) or long (more than 8 minutes) MSLT mean latency, total sleep time was significantly longer in the short MSLT mean latency group compared to the long MSLT mean latency group. Conclusions: In excessive daytime sleepiness, excluding narcoleptics, longer nocturnal sleep is associated to greater daytime objective sleepiness. This suggests that propensity to excessive sleepiness is not restricted to daytime but is a 24 hour phenomenom.

P626 CPAP treatment lowers sympathetic nerve activity and blood pressure in hypertensive obstructive sleep apnoea patients V. Donadio, P. Montagna, R. Vetrugno, M. Contin, F. Falzone, A. Baruzzi, M. Elam, G. Wallin, R. Liguori University of Bologna (Bologna, I); University of Goteborg (Goteborg, S) Objectives: The role of muscle sympathetic nerve activity (MSNA) in generating the systemic hypertension associated with Obstructive Sleep Apnea (OSA) is unclear. The aim of this study was to evaluate changes in blood pressure (BP) and MSNA after CPAP treatment in OSA patients with daytime systemic hypertension. Methods: We studied 10 male OSA patients with systemic hypertension (50 ± 3 years; mean age ± SE) before and after compliance-monitored CPAP treatment. To verify the stability of the parameters analysed, 8 male untreated OSA patients (50 ± 1 years) were studied twice within 1–2 months and used as controls. All patients underwent a polysomnographic study; daytime standardized cuff measurements of blood pressure and daytime microneurographic evaluation of MSNA recorded from the peroneal nerve. Results: OSA controls showed stable BP and MSNA levels in both recordings (mean difference – 4 and –3 mmHg for systolic and diastolic BP; –1 burst/100 Heart Beats for MSNA). For the treatment group, average BP was

144 ± 3/98 ± 1 mmHg and MSNA 84 ± 1 bursts/100HB (59 ± 3 bursts/min) before treatment. After 1 month of CPAP, BP was reduced to 124 ± 4/ 85 ± 2 mmHg and MSNA to 63 ± 2 bursts/100HB (40 ± 2 bursts/min). There was a direct linear correlation between MSNA (bursts/100HB) decrease and hours of CPAP use per night (r = 0.9; p < 0.01). After 3 and 6 months of CPAP treatment, BP remained at the level achieved after 1 month treatment whereas MSNA showed a slight further decrease. No significant changes in BMI, smoking or alcohol consumption occurred during the study. Conclusion: CPAP treatment is associated with a marked reduction in both BP and sympathetic vasoconstrictor nerve activity, evident after 1 month and sustained over a 6 month treatment period. CPAP compliance was linearly correlated to MSNA reduction and should be monitored.

P627 Fatal familial insomnia: clinical, neurophysiological, neuropathological, and genetic description of a new Spanish family M. A. Ortega-Casarrubios, J. Arpa, A. Ugalde, L. Yebenes, T. Ferrer, E. Izal, C. Morales, J. Nos, F. Palomo, F. Vivancos, J. Yagüe, R. Sánchez-Valle, A. Rodríguez-Albariño University Hospital La Paz. UAM (Madrid, E); Hospital Clinic (Barcelona, E) Objectives: The clinical presentation,evolution,neurofisiological,neuropathological findings, and genotyping of the proband and two members of a family affected with fatal familial insomnia (FFI) are reported. Methods: The proband, a 51-year-old man,belonging to a family with FFI (mother and a sister affected dead).On admission proband underwent the following studies:standard blood,polysomnographic (PSG),autonomic functions, neuroimaging and genetics.Finally, post-mortem examination was performed. Results: Five months before admission the proband developed: insomnia, with inability to initiate and maintain sleep, nervousness, fluctuating diplopia, profuse sweating, urinary retention and he suffered two episodes of confusion. Clinical examination: first, resting tremor and hypertension; later, tachycardia, hyperpyrexia, cough, and respiratory difficulty syndrome without evidence of pneumonia.Patient developed impairment of sleep with oneiric stupor, progressive confusional state, gait disturbances, disequilibrium, increasing dysarthria and dysphagia. Autonomic functions: Sympathetic hyperactivity. PSG findings: wakefulness with progressive diffuse slowing, absence of sleep spindles and K complexes with reduced total sleep time.Genetic analysis Patients harboured the PrP 178 Asn mutation (with deletion R3-R4 in the same allele) and were also homozygous for Met in the 129 codon. The proband’s mother, who suffered a similarly rapid dementing illness, without any reported insomnia, also had FFI proven by molecular testing on postmortem material. However, clinical features of the proband’s sister were similar to him. Both mother and sister developed myoclonus.Proband’ s death occurred 6 months after onset; his mother and sister were dead 5 and 6 months after onset respectively.Autopsy findings:severe neuronal loss and gliosis in the thalami and in the inferior olives. Proband’s mother and sister showed: moderately loss of Purkinje cells in the cerebellum and minor spongiform changes in the cerebral cortex. Immunohistochemistry was positive for deposits of PrP in all patients. Conclusion: The clinicopathological phenotype here reported is the classic clinical FFI presentation with short-term evolution insomnia, and severe thalamic pathology in relationship to the state of Met homocigosity in the codon 129. The proband and relatives had deletion R3-R4 in the same allele as the mutation D178N, which does not seem to be associated with special clinical characteristics.

P628 Sleep apnoea syndrome in neurological patients A. Büttner, H. Bennefeld, K.-H. Rühle, K.-H. Beine Heinrich-Mann-Klinik (Bad Liebenstein, D); Klinik Ambrock – Universität Witten/Herdecke (Hagen, D); St. Marien-Hospital (Hamm, D) Objectives: Sleep apnea syndrome (SAS) is a common disorder, which is characterized by repetitive transient reversible upper airway obstructions during sleep. Due to disrupted sleep architecture and intermittent hypoxemia, SAS [1] leads to impaired daytime functioning in various (neuro)psychological and affective domains and [2] can caused other physical diseases (e. g. neurological diseases, cardiovascular diseases etc.). The aim of our study was to investigate the prevalence of SAS in neurological patients. Methods: The study was carried out involving neurologic patients. During admission to the clinic, this patients were examined neurologically and neuropsychologically and with a special SBAS Questionnaire. So far, data have been gathered for 67 neurologic patients (38 male; 29 female; mean age:

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58.7315.74; Barthel index: 88.4120.18). Patients with negative questionnaire result were screened with MicroMesam (MAP). Results: 53/67 of patients with neurological diseases (79.10 %) got a negative questionnaire result. From this 53 patients 1 patient was nCPAP treated (1.9 %), 33 patients got a SAS diagnosis (62.3 %), 12 were high risk patients (22.6 %), 3 patients could be excluded (5.7 %) and 4 patients couldn’t be evaluated (7.5 %). Conclusion: Our first results revealed that neurologic patients show a high prevalence of SAS and cardiovascular diseases.

Abstracts which arrived after deadline 27 New treatments in Parkinson’s disease E. Melamed Rabin Medical Center (Petach Tikva, IL) Treatment of Parkinson’s disease is complex and artful. Strategies include symptomatic, neuroprotective and neuroregenarative- neuroregstorativ therapies. Treatment approaches should consider motor vs. non-motor phenomena, stage of illness, age of patients and levodopa complications. There have been many recent pharmacological as well as surgical therapeutic advances that are either already available or in development. Stem cells and therapy gene are also potential exciting options.

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Author index Abbruzzese, G. . . . . . . . . . . . . . . . O57 Abdelrahman, N. . . . . . . O104, P220, P221, P321, P323 Abdul Ghani, Z. Z. . . . . . . . . . . . . . P254 Abdul Rashid, F. . . . . . . . . . . . . . . P255 Abdul Wahab, N. . . . . . . . . . . . . . . P255 Abdullah, J. M. . . . . . . . . . . . P254, P255 Abele, M. . . . . . . . . . . . . . . . . . . O131 Abramsky, O. . . . . . . . . . . . . . . . P203 Acar, G. . . . . . . . . . . . . . . . . . . . P518 Accolla, E. . . . . . . . . . . . . . . . . . P560 Achiron, A. . . . . . . . . . . . . . . . . O116 Adams, D. . . . . . O46, O48, P332, P333, P427 Adib Saberi, F. . . . . . . . . . . . . . . . P562 Adobbati, L. . . . . . . . . . . . . . . . . O151 Afrantou, T. . . . P237, P250, P453, P472, P474 Aggelakis, K. . . . . . . . . . O145, P182, P207 Aggelou, A. . . . . . . . . . . . . . . . . . P360 Aggouridaki, C. . . . . . . . . . . . . . . P442 Agnesone, M. . . . . . . . . . . . . . . . P297 Agosta, F. . . . . . . . . . . . O32, O119, O101 Ahangari, R. . . . . . . . . . . . . . . . . O49 Ahmad Alias, N. A. . . . . . . . . . . . . P254 Aiello, I. . . . . . . . . . . . . . . . . . . P386 Akazawa, C. . . . . . . . . . . . . . . . . O148 Akhan, G. . . . . . . . . . . . . . . . . . P525 Akhvlediani, T. . . . . . . . . . . . . . . O137 Akman, Ö. . . . . . . . . . . . . . . . . . P613 Alberti, O. . . . . . . . . . . . . . . P522, P618 Albrecht, K. W. . . . . . . . . . . . . . . . O75 Alcázar, C. . . . . . . . . . . . . . . P563, P564 Alemdar, M. . . . . . . . . . . . . . P256, P613 Alexiou, E. . . . . . . . . . . . . . . . . . P257 Alfaro, A. . . . . . . . . . . . . . . . . . . P335 Algra, A. . . . . . . . . . . . . . . . . . . O133 Alikhani, K. . . . . . . . . . . . . . . . . P320 Alldersea, J. . . . . . . . . . . . . . . . . P198 Almaguer-Mederos, L. . . . . . . . . . . O131 Almendinger, C. . . . . . . . . . . . . . . P443 Alonso, M. . . . . . . . . . . . . . . . . . P248 Alonso de Leciñana, M. . . . . . . . O92, P243 Alpsan, M. H. . . . . . . . . . . . . . . . P450 Alstadhaug, K. B. . . . . . . . . . . . . . P617 Altmann, D. R. . . . . . . . . . . . O100, O102 Alvarez, S. . . . . . . . . . . . . . . . . . . O51 Alvarez-Cermeño, J. C. . . . . . . . . . . P393 Alves, L. . . . . . . . . . . . . . . . O85, P170 Amaral, V. . . . . . . . . . . . . . . . . . P369 Amelio, E. . . . . . . . . . . . . . . . . . P601 Ameri, A. . . . . . . . . . . . . . . . . . . P192 Anagnostopoulos, A. . . . . . . . . . . . P338 Anaya, B. . . . . . . . . . . . . . . . . . . P364 Anderesi, M. . . . . . . . . . . . . . . . . P397 Andersen, P. . . . . . . . . . . . . . . . . O116 Anderson, V. M. . . . . . . . . . . . O35, P492 Andrade, K. . . . . . . . . . . . . . . . . P365 Andresen, I. . . . . . . . . . . . . . . . . . O53 Andriopoulou, G. . . . . . . . . . . P442, P611 Angele, B. . . . . . . . . . . . . . . . . . P376 Angelini, C. . . . . . . . . . . . . . . O45, P310 Angelou, A. . . . P237, P250, P453, P472, P474 Angelucci, F. . . . . . . . . . P566, P575, P576 Aniello, M. S. . . . . . . . . . . . . . . . . O57 Annoni, J.-M. . . . . . . . . . . . . . . . P574 Annovazzi, P. . . . . . . . . . O66, P273, P275 Annunziata, P. . . . . . . . . . . . O103, O106 Anogiannakis, G. . . . . . . . . . . . . . P178 Antel, J. . . . . . . . . . . . . . . . . . . O109 Antonelli, F. . . . . . . . . . . . . . . . . P365 Anzellotti, F. . . . . . . . . . . . . . . . . P558 Apel, A. . . . . . . . . . . . . . . . P225, P500 Apostolakis, E. . . . . . . . . . . . P412, P418 Appel, S. H. . . . . . . . . . . . . . . . . O117 Apridonidze, S. . . . . . . . . . . . . . . O142

Aradhye, S. . . . . . . . . . . . . . . . . . P569 Arandi, N. . . . . . . . . . . . . . . . . . P224 Arber, C. . . . . . . . . . . . . . . . . . . P340 Arbizu, T. . . . . . . . . . . . . . . . . . P398 Arbusow, V. . . . . . . . . . . . . . . . . . O91 Ardolino, G. . . . . . . . . . . . . . O52, P344 Aretouli, E. . . . . . . . . . . . . . . . . . P360 Argentiero, V. . . . . . . . . . . . . . . . . O78 Argov, Z. . . . . . . . . . . . . . . . . . . P203 Argyriou, A. . . . . . . . . . . . . . . . . P535 Ariatti, A. . . . . . . . . . . . P390, P429, P432 Armani, M. . . . . . . . . . . . O45, O78, P310 Armellino, K. . . . . . . . . . . . . . . . P558 Armentero, M. T. . . . . . . . . . . . . . P507 Armstrong, D. . . . . . . . . . . . . . . . P555 Arnaoutoglou, A. . . . . . . . . . . P442, P611 Arnaoutoglou, M. . . . . . . . . . . P442, P611 Arnason, B. G. W. . . . . . . . . . . . . . P403 Arnold, M. . . . . . . . O79, O138, P312, P542 Arnold, P. . . . . . . . . . . . . . . . . . . O65 Arpa, J. . . . . . . . . . . . . . . . P194, P627 Arpaci, E. . . . . . . . . . . . . . . . . . P339 Arranz, E. . . . . . . . . . . . . . . . . . P565 Arslan, E. . . . . . . . . . . . . . . . . . . P162 Artemis, D. . . . . . . . . . . . . . . . . . P546 Artemis, N. . . . . . . . . . . P301, P472, P545 Artmonov, I. . . . . . . . . . . . . . . . . P388 Asgari Moghadam, E. . . . . . . . . . . . P549 Ashrafian, H. . . . . . . . . . . . . . . . . P512 Ashtari, F. . . . . . . . . . . . . . . P300, P572 Asshoff, D. . . . . . . . . . . . . . . . . . O70 Aste, R. . . . . . . . . . . . . . . . . . . . P495 Ates, N. . . . . . . . . . . . . . . . . . . . P613 Auburger, G. . . . . . . . . . . . . . . . . O131 Auckenthaler, A. . . . . . . . . . . . . . . O83 Auer, D. . . . . . . . . . . . . . . . P282, P355 Augustin, M. . . . . . . . . . . . . . . . . P447 Auriel, E. . . . . . . . . . . . . . . . . . . P290 Ausili Cèfaro, G. . . . . . . . . . . . . . . P470 Avanzino, L. . . . . . . . . . . . . . . . . . O57 Avetisjan, M. . . . . . . . . . . . . . . . . P607 Avila, M. . . . . . . . . . . . . . . . O143, P171 Awang, S. . . . . . . . . . . . . . . . . . . P255 Azevedo, A. . . . . . . . . . . . . . . . . P274 Babalini, C. . . . . . . . . . . . . . . . . . P201 Bachleitner, P. . . . . . . . . . . . . . . . P595 Bachofen, B. . . . . . . . . . . . . . . . . O153 Bae, J. S. . . . . . . . . . . . . . . . . . . P438 Baek, S. Y. . . . . . . . . . . . . . . . . . P616 Baek, W. K. . . . . . . . . . . . . . . . . . P483 Bahar, S. . . . . . . . . . . . . . . . . . . P450 Bairaktaris, C. . . . . . . . . . . . . . . . P449 Bajaj, N. . . . . . . . . . . . . P239, P282, P355 Bajko, Z. . . . . . . . . . . . . . . . . . . P349 Balachandran, S. . . . O107, P222, P226, P227 Balla, C. . . . . . . . . . . . . . . . . . . P301 Balnyte, R. . . . . . . . . . . . . . . P380, P520 Baloyannis, S. J. . . . . . . . . P342, P442, P611 Bär, I. . . . . . . . . . . . . . . . . . . . . P173 Bar-Or, A. . . . . . . . . . . . . . . . . . O109 Baranczyk-Kuzma, A. . . . . . . . . . . . P479 Barash, V. . . . . . . . . . . . . . . . . . . P203 Barbero, P. . . . . . . . . . . P326, P327, P489 Barbieri, F. . . . . . . . . . . . . . . . . . P245 Barbieri, S. . . . . . . . . . . . . . . . . . P560 Barbot, C. . . . . . . . . . . . . . . . . . P552 Barbov, I. . . . . . . . . . . . . . . P422, P454 Barcikova, A. . . . . . . . . . . . . P396, P559 Barinagarrementeria, F. . . . . . . . . . . O71 Barkhof, F. . . . . . . . . O38, O42, O110, P406 Barletta, L. . . . . . . . . . . . . . . . . . O96 Barletta, V. . . . . . . . . . . . . . . . . . P496 Baron, P. . . . . . . . . . . . . . . . P202, P352

Baron, R. . . . . . . . . . . . . . . . . . . P187 Barros, J. . . . . . . . . . . . . . . . . . . P236 Bartenstein, P. . . . . . . . . . . . . . . . O130 Barthel, H. . . . . . . . . . . . . . . . . . P189 Bartkova, A. . . . . . . . . . . . . . O77, P550 Bartosik-Psujek, H. . . . . . P230, P580, P581 Bartova, P. . . . . . . . . . . . . . . . . . . O56 Bärtschi, E. . . . . . . . . . . . . . P234, P235 Baruzzi, A. . . . . . . . . . . . . . . P533, P626 Barzegar, B. . . . . . . . . . . . . . . . . P392 Bascelli, A. . . . . . . . . . . . . . . . . . P470 Basile, A. M. . . . . . . . . . . . . . . . . . O78 Basiri, K. . . . . . . . . . . . . . . . . . . P159 Bassetti, C. L. . . . 18, O134, P528, P529, P530, P619, P620, P621, P623 Basta, A. . . . . . . . . . . . . . . . . . . P257 Batinic, D. . . . . . . . . . . . . . . . . . P476 Batocchi, A. P. . . . . . . . . . P566, P575, P576 Battaglia, C. . . . . . . . . . . . . . . . . P200 Battaloglu, E. . . . . . . . . . . . . . . . . O44 Bauer, G. . . . . . . . . . . . . . . . . . . O83 Bauer, J. . . . . . . . . . . . . . . . . . . . O40 Bauer, L. . . . . . . . . . . . . . . . O110, P406 Baum, K. . . . . . . . . . . . . . . . . . . P500 Baumann, A. . . . . . . . . . . . . . . . . O53 Baumann, C. . . . . . . . . . . . . P530, P623 Baur, B. . . . . . . . . . . . . . . . . . . . P605 Beard, S. . . . . . . . . . . . . . . . . . . P334 Bebek, N. . . . . . . . . . . . . . . . . . . P450 Becker, A. . . . . . . . . . . . . . . . . . P385 Bedin, R. . . . . . . . . . . . . . . . . . . P498 Bednarik, J. . . . . . . . . . . . . . . . . P430 Beine, K.-H. . . . . . . . . . . . . . . . . P628 Bekkelund, S. . . . . . . . . . . . . . . . P617 Beliakov, K. . . . . . . . . . . . . . . . . P341 Belis, K. . . . . . . . . . . . . . . . . . . P462 Bellini, A. . . . . . . . . . . . . . . . . . P319 Bellou, A. . . . . . . . . . . . . . . . . . . P568 Belniak, E. . . . . . . . . . . . . . . P580, P581 Belohlavek, D. . . . . . . . . . . . . . . . O70 Belova, A. . . . . . . . . . . . . . . . . . P341 Beltran, I. . . . . . . . . . . . . . . P522, P618 Bembich, S. . . . . . . . . . . . . . . . . P328 Ben Yaou, R. . . . . . . . . . . . . . . . . P408 Bendszus, M. . . . . . . . . . . . . . . . . O73 Benedetti, B. . . . . O32, O37, O38, O41, O119, O122, P485, P553 Benedict, R. H. B. . . . O111, P221, P322, P323 Benetin, J. . . . . . . . . . . . . . . . . . P559 Bennefeld, H. . . . . . . . . . . . . . . . P628 Bense, S. . . . . . . . . . . . . . . O115, O130 Benton, C. . . . . . . . . . . . . . . . . . . O98 Benuzzi, F. . . . . . . . . . . . . . . . . . P356 Berardelli, A. . . . . . . . . . . . . . . . . O57 Berciano, J. . . . . . . . . . . O146, O156, P428 Berenguer, J. . . . . . . . . . . . . . . . . P398 Berezin, V. . . . . . . . . . . . . . . . . . P353 Bergamaschi, R. . . . . . . . . . . . P228, P487 Bergsland, N. . . . . . O107, O111, P220, P222, P226, P227 Bergui, M. . . . . . . . . . . . . . . . . . P394 Bergui, P. . . . . . . . . . . . . . . . . . . P394 Beridze, I. . . . . . . . . . . . . . . . . . O142 Bernardi, G. . . . . . . . . . . . . . P201, P554 Bernasconi, L. . . . . . . . . . . . . . . . O66 Bernasconi, S. . . . . . . . . . . . . . . . P596 Bernati, T. . . . . . . . . . . . . . . P284, P285 Berthele, A. . . . . . . . . . . . . . . . . P419 Bértolo, H. . . . . . . . . . . . . . . . . . P622 Best, C. . . . . . . . . . . . . O115, O130, P587 Beyroud, P. . . . . . . . . . . . . . . . . . P192 Bezrodna, L. . . . . . . . . . . . . . . . . P351 Bialas, K. . . . . . . . . . . . . . . . . . . P166 Bieniek, M. . . . . . . . . . . . . . . . . O100

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Bienkowski, P. . . . . . . . . . . . . . . . P362 Bignamini, V. . . . . . . . . . . . . P307, P536 Bigoni, M. . . . . . . . . . . . . . . . . . P600 Bingel, U. . . . . . . . . . . . . . . . . . . P610 Bir, L. S. . . . . . . . . . . . . . . . . . . . P518 Birklein, F. . . . . . . . . O63, O64, P433, P508 Birkmann, S. . . . . . . . . . . . . . . . . P620 Bisin, Z. . . . . . . . . . . . . . . . . . . P513 Blanco, M. . . . . . . . . . . . . . . . . . P194 Blanco, Y. . . . . . . . . . . . . . . P532, P398 Blandini, F. . . . . . . . . . . . . . . . . . P507 Blanquet, P. . . . . . . . . . . . . . . . . P538 Blat, I. . . . . . . . . . . . . . . . . . . . P290 Bliesath, H. . . . . . . . . . . . . . . . . . P371 Blond, S. . . . . . . . . . . . . . . . . . . P445 Blumen, S. C. . . . . . . . . . . . . . . . O116 Blumenfeld, A. . . . . . . . . . . . . O61, P615 Boban, M. . . . . . . . . . . . . . . . . . P436 Bochynska, A. . . . . . . . . . . . . . . . P362 Bock, E. . . . . . . . . . . . . . . . . . . P353 Boczarska-Jedynak, M. . . . . . . . . . . P624 Bodammer, N. . . . . . . . . . . . . . . . P490 Bode, U. . . . . . . . . . . . . . . . . . . . O95 Bodet, D. . . . . . . . . . . . . . . . P465, P494 Bodner, C. . . . . . . . . . . . . . . . . . O109 Boelmans, K. . . . . . . . . . . . . . . . . P304 Boesiger, P. . . . . . . . . . . O137, P619, P621 Bogdahn, U. . . . . . . . . . . . . . . . . . O58 Böger, B. . . . . . . . . . . . . . . . . . . P289 Boggild, M. . . . . . . . . . . . . . . . . . P198 Bogousslavsky, J. . . 4, O94, P211, P313, P537, P543, P574, P593, P594, P612 Bogumil, T. . . . . . . . . . . . . . . . . . P403 Boguslawska, R. . . . . . . . . . . . . . . P362 Bojar, M. . . . . . . . . . . . . . . . . . . P240 Bonaiti-Pellié, C. . . . . . . . . . . . . . O147 Bonanni, L. . . . . . . . . . . . . . . . . . P558 Bonato, S. . . . . . . . . . . . . . . . . . P199 Boni, P. . . . . . . . . . . . . . . . . . . . P281 Bonikos, D. . . . . . . . . . . . . . P412, P418 Bonino, F. . . . . . . . . . . . . . . . . . P361 Bonnan, M. . . . . . . . . . . . . . . . . P491 Bonne, G. . . . . . . . . . . . . . . . . . . P408 Bonnet, D. . . . . . . . . . . . . . . . . . P365 Bordet, R. . . . . . . . . . . . . . . . . . . O68 Bordoni, A. . . . . . . . . . . . . . O151, P200 Borhani Haghighi, A. . . . . . . . . . . . P224 Boroojerdi, B. . . . . . . . . . . . . . . . . O60 Borratynska, A. . . . . . . . . . . . . . . P164 Borreca, A. . . . . . . . . . . . . . . . . . P201 Borruat, F. X. . . . . . . . . . . . . . O94, P409 Borton, J. . . . . . . . . . . . . . . . . . . P425 Boscá, M. . . . . . . . . . . . . . . . . . . P374 Bosch, B. . . . . . . . . . . . . . . . . . . O86 Bosco, A. . . . . . . . . . . . . . . . . . . P328 Bossi, B. . . . . . . . . . . . . . . . . . . . O52 Bossolasco, P. . . . . . . . . . . . . . . . P507 Bostantjopoulou, S. . . . . . . . . . . . . P370 Botez, S. A. . . . . . . . . . . . . . P409, P537 Bottlaender, M. . . . . . . . . . . . . . . P296 Bourg, V. . . . . . . . . . . . . . . . . . . P458 Bousser, M-G. . . . . . . . . . . . . O71, O138 Boutsi, A. . . . . . . . . . . . . . . . . . . P250 Bovo, S. . . . . . . . . . . . . . . . . . . . P596 Bowler, C. . . . . . . . . . . . . . . . . . P355 Boylu, E. . . . . . . . . . . . . . . . . . . P277 Braathen, G. J. . . . . . . . . P205, P206, P435 Brambilla, D. . . . . . . . . . . . . . . . . P596 Brandt, T. . . . . O91, O112, O130, P582, P583, P584, P585, P586, P591 Bratina, A. . . . . . . . . . . . . . . . . . P328 Brcic, I. . . . . . . . . . . . . . . . . . . . P447 Brekenfeld, C. . . . . . . . . . . . . O79, P542 Bresolin, N. . . O151, O155, P199, P200, P202, P233, P352, P361, P410, P411 Breuer, P. . . . . . . . . . . . . . . . . . . O115 Brex, P. . . . . . . . . . . . . . . . . . . . O33 Brighina, E. . . . . . . . . . . . . . . . . P233 Brinar, V. V. . . . . . . . . . . P436, P461, P476

Brisc, C. . . . . . . . . . . . . . . . P241, P579 Brisc, M. . . . . . . . . . . . . . . . P241, P579 Brodtkorb, E. . . . . . . . . . . . . . . . P296 Broglio, L. . . . . . . . . . . . . . . . . . . O50 Brok, H. P. M. . . . . . . . . . . . . . . . . O40 Brooks, D. J. . . . . . . . . . . . . . . . . . . 19 Brown, P. . . . . . . . . . . . . . . . . . . O124 Brück, W. . . . . . . . . . . . . . . P210, P490 Bruehlmeier, M. . . . . . . . . . . . . . . P235 Bruel, D. . . . . . . . . . . . . . . . . . . P296 Bruggimann, L. . . . . . . . . . . . . . . P574 Buccafusca, M. . . . . . . . . . . . . . . . O57 Büchel, C. . . . . . . . . . . . . . . . . . P610 Buchholz, H.-G. . . . . . . . . O36, O130, P288 Buchwald, B. . . . . . . . . . . . . . . . . O49 Bucil, J. . . . . . . . . . . . . . . . . . . . O77 Budak, F. . . . . . . . . . . . . . . . . . . P256 Büttner, U. . . . . . . . . . . . . . . . . . P448 Bugalho, P. . . . . . . . . . . . . . . . . . O85 Buhl, A. R. . . . . . . . . . . . . . . . . . P561 Buisset, N. . . . . . . . . . . . . . . . . . P445 Buitrago Tellez, C. . . . . . . . . . . . . . P346 Bukholm, G. . . . . . . . . . . . . . P205, P206 Buonsanti, C. . . . . . . . . . . . . . . . P202 Burduladze, I. . . . . . . . . . . . . . . . O142 Burguera, J. . . . . . . . . . . . . . . . . P374 Burton, K. R. . . . . . . . . . . . . . . . . P547 Burval, S. . . . . . . . . . . . . . . . . . . O77 Büscher, C. . . . . . . . . . . . . . . O36, P288 Bussfeld, P. . . . . . . . . . . . . . P196, P456 Busson, L. . . . . . . . . . . . . . . . . . . O78 Buttmann, M. . . . . . . . . . . . . . . . P232 Büttner, A. . . . . . . . . . . . . . . . . . P628 Bykov, Y. . . . . . . . . . . . . . . . . . . P607 Cabre, P. . . . . . . . . . . . . . . . . . . P491 Çabuk, T. . . . . . . . . . . . . . . . . . . P518 Caggiula, M. . . . . . . . . . P566, P575, P576 Calabrese, D. . . . . . . . . . . . . . . . . P437 Calabresi, P. . . . . . . . . . . . . . . . . P569 Calandra Bonaura, G. . . . . . . . . . . . P439 Calef, U. . . . . . . . . . . . . . . . . . . P286 Calvo, M. . . . . . . . . . . . . . . . . . . P366 Calzarossa, C. . . . . . . . . . . . . . . . P507 Camacho, A. . . . . . . . . . P252, P511, P589 Caminero, A. B. . . . . . . . . . . . . . . P565 Campagnolo, D. . . . . . . . . . . . . . . O109 Campdelacreu, J. . . . . . . . . . . P185, P188 Canales-Ochoa, N. . . . . . . . . . . . . O131 Canella, S. . . . . . . . . . . . . . . . . . P499 Canhão, P. . . . . . . . . . . . . . . . . . . O71 Cantalupo, L. . . . . . . . . . . . . . . . O106 Cantillon, M. . . . . . . . . . . . . . . . . P400 Capra, R. . . . . . . . . . . . . . . . O31, P228 Caputo, D. . . . . . . . . . . . . . . O119, P485 Caputo, E. . . . . . . . . . . . . . . . . . P560 Carapella, C. . . . . . . . . . . . . . . . . O96 Carasso, R. . . . . . . . . . . . . . . . . . O116 Cardani, R. . . . . . . . . . . . . . . . . O150 Carducci, C. . . . . . . . . . . . . . . . . P369 Carlesi, C. . . . . . . . . . . . . . . . . . O120 Carneiro, E. . . . . . . . . . . . . . . . . P249 Carone, D. A. . . . . . . . . . . . . . . . . P221 Carota, A. . . . . . . . . . . . . . . . . . P543 Carpo, M. . . . . . . . . . . . . . . . . . . O52 Carralero, R. . . . . . . . . . . . . . . . . O131 Carrera, E. . . . . . . . . . . . . . . . . . P537 Carreras, E. . . . . . . . . . . . . . . . . P398 Carrilho, I. . . . . . . . . . . . . . . . . . P552 Carsten, A. L. M. . . . . . . . . . . . . . . P413 Casanova, J. . . . . . . . . . . . . . P270, P305 Casellato, C. . . . . . . . . . . . . . O52, P344 Castelli, E. . . . . . . . . . . . . . . . . . P604 Castelnot, E. . . . . . . . . . . . . . . . . O76 Castillo, J. . . . . . . . . . . . . . . . . . O132 Castro, S. . . . . . . . . . . . . . . . . . . P258 Castro-Macias, J. I. . . . . . . . . . . . . P278 Catalan, M. . . . . . . . . . . . . . P328, P513 Ce, P. . . . . . . . . . . . . . . . . . . . . P339

Ceccarelli, A. . . . . . . . . . . . . . O32, O34 Celebi, A. . . . . . . . . . . . . . . . . . . P162 Cercignani, M. . . . . . . . . . . . . . . . P295 Cerny, R. . . . . . . . . . . . . . . . . . . P268 Cerri, F. . . . . . . . . . O66, O128, O129, P275 Cevher, D. . . . . . . . . . . . . . . . . . P339 Chamorro, A. . . . . . . . . . . . . . . . P270 Chanalet, S. . . . . . . . . . . . . . . . . P458 Chancellor, J. . . . . . . . . . . . . . . . . P426 Chandler, C. . . . . . . . . . . . . . . . . O55 Chandrasekhar, R. . . . . . . . . . . . . . P220 Chang, P. . . . . . . . . . . . . . . . . . . P391 Chang, T. . . . . . . . . . . . . . . O124, P239 Chard, D. T. . . . . . . . . . . . . . . . . O102 Chatel, M. . . . . . . . . . . . . . . . . . P458 Chaudhri, Q. . . . . . . . . . . . . . . . . P239 Chaudhuri, K. R. . . . . . . . . . . . . . . O55 Chaussenot, A. . . . . . . . . . . . . . . . P458 Chen, R. . . . . . . . . . . . . . . . . . . P440 Chen, X. Y. . . . . . . . . . . . . . . . . . O74 Chernikh, M. . . . . . . . . . . . . . . . P607 Chieffo, R. . . . . . . . . . . . . . O128, O129 Chippendale, T. . . . . . . . . . . . . . . . O61 Chirtes, A. V. . . . . . . . . . . . . . . . . P377 Chistik, V. . . . . . . . . . . . . . . . . . P290 Cho, J. Y. . . . . . . . . . . . . . . . . . . P480 Cho, S. J. . . . . . . . . . . . . . . . . . . P368 Cho, Y-W . . . . . . . . . . . . . . . . . . P539 Chofflon, M. . . . . . . . . . . . . . P466, P467 Choudhary, P. . . . . . . . . . . . . . . . P282 Christodoulou, K. . . . . . . . . . . . . . P424 Christoforakis, V. . . . . . . . . . . P517, P568 Chroni, E. . . . . . . . . . . . . . . . . . P535 Chung, P. W. . . . . . . . . . P262, P452, P540 Chwojnicki, K. . . . . . . . . . . . . . . . P548 Ciano, C. . . . . . . . . . . . . . . . . . . O43 Ciboddo, G. . . . . . . . . . . . . . . . . O122 Ciccocioppo, F. . . . . . . . . . . . . . . . P470 Cifelli, A. . . . . . . . . . . . . . . . . . . P282 Cifola, I. . . . . . . . . . . . . . . . . . . P200 Ciftci, F. D. . . . . . . . . . . . . . . O44, P450 Cioni, C. . . . . . . . . . . . . . . O103, O106 Cipolotti, L. . . . . . . . . . . . . . . . . . O35 Civati, F. . . . . . . . . . . . . . . . . . . P411 Clementi, E. . . . . . . . . . . . . . . . . P199 Clerici, F. . . . . . . . . . . . . . . . . . . O155 Clerico, M. . . . . P326, P327, P394, P489, P502 Clover, L. . . . . . . . . . . . . . . . . . . P469 Cnyrim, C. D. . . O112, P582, P583, P584, P586 Coban, O. . . . . . . . . . . . . . . . . . . P450 Cocco, E. . . . . . . . . . . . . . . . P495, P496 Cock, H. R. . . . . . . . . . . . . . . . . . O81 Cogiamanian, F. . . . . . . . . . . . . . . P560 Cohen, J. . . . . . . . . . . . . . . . . . . P570 Colak, I. . . . . . . . . . . . . . . . . . . P339 Coletti Moja, M. . . . . . . . . . . . . . . P297 Colombo, B. . . . . . . . . . . . O31, O32, O66 Colosimo, C. . . . . . . . . . . . . . . . . O57 Combarros, O. . . . . . . . . O146, O156, P428 Comi, C. . . . . . . . . . . . . . . . . . . P233 Comi, Giancarlo . . . . 28, O31, O32, O34, O37, O41, O66, O101, O122, O128, O129, P273, P275, P319, P391, P403, P455, P536, P570 Comi, G. P. . . . . . . . O151, P199, P200, P410 Comola, M. . . . . . . . . . . . . . . . . O129 Coniglio, G. . . . . . . . . . . . . . . . . . O31 Connors, R. . . . . . . . . . . . . . . . . P440 Conrad, B. . . . . . . . . . . . . . . . . . P419 Consalez, G. . . . . . . . . . . . . . . . . P199 Constantin, D. . . . . . . . . . . . . . . . P377 Contessa, G. . . . . . . P326, P327, P394, P489 Contin, M. . . . . . . . . . . . . . . . . . P626 Contu, P. . . . . . . . . . . . . . . . . . . P496 Cook, S. . . . . . . . . . . . . . . . P391, P403 Cookfair, D. L. . . . . . . . . . . . . . . . P322 Corbalán, T. . . . . . . . . . . . . . P521, P618 Cordioli, C. . . . . . . . . . . . . . . . . . P228 Corea, F. . . . . . . . . . . . . P307, P455, P536

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Corfini, A. . . . . . . . . . . . . . . . . . . O78 Corman, A. . . . . . . . . . . . . . . . . . P286 Corrà, B. . . . . . . . . . . . O155, P352, P361 Corral, I. . . . . . . . . . . . . . . . O92, P243 Correia Guedes, L. . . . . . . . . . . . . . P441 Cortez, J. . . . . . . . . . . . . . . . . . . P446 Cortini, A. . . . . . . . . . . . . . . . . . P328 Cossette, P. . . . . . . . . . . . . . . . . . O80 Costa, I. . . . . . . . . . . . . . . . . . . P274 Costa, J. . . . . . . . . . . . . . . . O126, P271 Costa, L. . . . . . . . . . . . . . . . . . . . O78 Costa, V. . . . . . . . . . . . . . . . . . . P342 Coutinho, P. . . . . . . . . . . . . . . . . P246 Cova, L. . . . . . . . . . . . . . . . . . . . P507 Coveñas, R. . . . . . . . . . . . . . . . . P494 Croci, L. . . . . . . . . . . . . . . . . . . P199 Cronin, S. . . . . . . . . . . . . . . O118, P384 Croquelois, A. . . . . . . . . . . . . . . . O82 Cruz, A. . . . . . . . . . . . . . . . . . . . O92 Cruz, M. . . . . . . . . . . . . . . . . . . . O47 Cuadrado, E. . . . . . . . . . . . . P215, P541 Cucci, A. . . . . . . . . . . . . . . . P394, P489 Cucurella, G. . . . . . . . . . . . . P215, P541 Cumurciuc, R. . . . . . . . . . . . . . . . O138 Cupidi, C. . . . . . . . . . . . . . . . . . P287 Czaplinski, A. . . . . . O117, P340, P346, P385 Czesnik, D. . . . . . . . . . . . . . . . . . P210 Czlonkowska, A. . . . . . . . . . . . O69, P548 D’Andreagiovanni, A. . . . . . . . . . . . P558 D’Angelo, F. . . . . . . . . . . . . . . . . P554 D’Angelo, M. G. . . . . . . . . . . . P410, P411 D’Onofrio, H. . . . . . . . . . . . . . . . P514 Dabadie, M. P. . . . . . . . . . . . . P465, P494 Daglioglu, E. . . . . . . . . . . . . P308, P451 Dahlqvist, M. . . . . . . . . . . . . . . . P312 Dahms, S. . . . . . . . . . . . . . . O110, P406 Dalmau, J. . . . . . . . . . . . . . . . . . P243 Dalton, C. M. . . . . . . . . . . . . . . . . P488 Dandamrongrak, W. . . . . . . . . . . . . P510 Dardioti, M. . . . . . . . . . O145, P182, P207 Dardiotis, E. . . . . . . . . . O145, P182, P207 Darius, H. . . . . . . . . . . . . . . . . . O135 Daumer, M. . . . . . . . . . . . . . . . . P229 Dávalos, A. . . . . . . . . . . . . . . . . . O132 Dave, J. . . . . . . . . . . . . . . . . P440, P503 Daveluy, W. . . . . . . . . . . . . . . O76, P445 Davies, G. R. . . . . . . . . . . O35, O100, P492 Davies, M. B. . . . . . . . . . . . . . . . . P577 Davis, S. . . . . . . . . . . . . . . . . . . P553 de Freitas, M. R. G. . . . . . . . . . . O54, P331 De Keyser, J. H. A. . . . . . . . . . . . . . P314 De la Maza, M. . . . . . . . . . . . O143, P171 De Lazzari, F. . . . . . . . . . . . . . . . P310 de León, J. C. . . . . . . . . . . . . . . . . P175 de Leòn, M. . . . . . . . . . . . . . . . . P494 de Mello Rieder, C. . . . . . . . . . . . . P179 De Riz, M. . . . . . . . . . . . . . . . . . P233 de Sá, J. . . . . . . . . . . . . . . . . . . . P375 De Santi, L. . . . . . . . . . . . . . O103, O106 de Souza, L. . . . . . . . . . . . . . . . . P365 De Stefano, N. . . . . . . . . . O38, O42, O103 Deckert, M. . . . . . . . . . . . . . . . . . O95 Defazio, G. . . . . . . . . . . . . . . . . . O57 Deftereos, S. . . . . . . . . . . . . . . . . P181 DeGreiff, A. . . . . . . . . . . . . . . . . P561 Deguchi, K. . . . . . . . . . . . . . . . . P555 Del Bo, R. . . . . . . . . . . . . . . . . . P410 Del Carro, U. . . . . . . . . . . . . . . . . P273 Del Corona, A. . . . . . . . . . . . . . . . O120 Delavelle, J. . . . . . . . . . . . . . . . . . O94 Denier, C. . . . . . . . . . . . . . . P332, P427 Deplanque, D. . . . . . . . . . . . . . . . . O68 Deretzi, G. . . . . . . . . . . . . . . . . . P318 Derfuss, T. . . . . . . . . . . . . . . . . . O91 Deriaz, O. . . . . . . . . . . . . . . . . . . O65 Deriu, M. . . . . . . . . . . . . . . . . . . P496 Despland, P. A. . . . . . . . . . . . . . . . P594 Deuschl, G. . . . . . . . . . . . . . . . . . P187

Deutschländer, A. . . . . . . . . . . P585, P591 Deymeer, F. . . . . . . . . . . . . . . . . . O44 Di Donato, S. . . . . . . . . . . . . . . . O149 Di Giandomenico, S. . . . . . . . . . . . O149 di Girolamo, I. . . . . . . . . . . . . . . . P554 Di Perri, C. . . . . . . . . . . . . . . . . . O103 Díaz Padilla, I. . . . . . . . . . . . . . . . P252 Diaz-Sanchez, M. . . . . . . . . . . . . . P393 Diederich, N.J . . . . . . . . . . . . . . . . P253 Dieguez, S. . . . . . . . . . . . . . . . . . P313 Diehl, V. . . . . . . . . . . . . . . . . . . . O95 Diener, H. C. . . . . . . . . . . . . O135, P561 Dieterich, M. . . . . . O64, O115, O127, O130, P174, P587 Dietis, A. . . . . . . . . . . . . . . . . . . P292 Dietrich, W. . . . . . . . . . . . . . P173, P195 Díez-Tejedor, E. . . . . . . . . . . . O132, P158 Dijk, J. M. . . . . . . . . . . . . . . . . . O133 Dimakopoulou, A. . . . . . . . . . . . . . P318 Dimitrakopoulos, A. . . . . . . . . . . . P338 Dimitrijeski, B. . . . . . . . . . . . . . . O136 Dimopoulos, M. A. . . . . . . . . . . . . P338 Dinanian, S. . . . . . . . . . . . . . . . . P333 Dionisi, L. . . . . . . . . . . . . . . . . . P201 Diosdado, N. . . . . . . . . . . . . . . . . P335 Diserens, K. . . . . . . . . . . . . . P593, P594 Dive, D. . . . . . . . . . . . . . . . . . . . P497 Dixon, G. . . . . . . . . . . . . . . . . . . P592 Djibuti, M. . . . . . . . . . . . . . . . . . O142 Djukic, M. . . . . . . . . . . . . . . . . . P210 Dobesberger, J. . . . . . . . . . . . . . . . O83 Dobrea, A. . . . . . . . . . . . . . . P352, P361 Doerck, S. . . . . . . . . . . . . . . . . . . O39 Doherty, C. . . . . . . . . . . . . . . . . . O87 Dolezal, O. . . . . . . . O107, P222, P226, P227 Domínguez, F. . . . . . . . . . . . . . . . P194 Donadio, V. . . . . . . . . . . . . . P533, P626 Donadoni, G. . . . . . . . . . . . . . . . O122 Doran, M. . . . . . . . . . . . . . . O144, P359 Dougenis, D. . . . . . . . . . . . . P412, P418 Doward, L. . . . . . . . . . . . . . . . . . P493 Doyle, M. . . . . . . . . . . . . . . . . . . P484 Dressen, T. . . . . . . . . . . . . . . . . . P279 Dressler, D. . . . . . . . . . . . . . . . . . P562 Drory, V. E. . . . . . . . . . . . . . P247, P388 Drugea, A. . . . . . . . . . . . . . . . . . P377 Du Pasquier, R. A. . . . . . . . . . . O94, P211 Dubois, B. . . . . . . . . . . . . . . . . . P365 Dukes, E. . . . . . . . . . . . P190, P191, P431 Duleu, S. . . . . . . . . . . . . . . . . . . P465 Dullinger, J. . . . . . . . . . . . . . . . . P383 Dunand, M. . . . . . . . . . . . . . P408, P409 Durelli, L. . . . . . . . . . . P297, P326, P327, P394, P489, P502 Durka-Kesy, M. A. . . . . . . . . . . . . . P531 Dusek, L. . . . . . . . . . . . . . . . . . . P430 Dutsu, K. . . . . . . . . . . . . . . . . . . P442 Duzgun, B. . . . . . . . . . . . . . . . . . P339 Dwyer, M. G. . . . . . . . . O104, O107, O111, P220, P221, P222, P226, P227, P321, P323 Dydak, U. . . . . . . . . . . . . . . O137, P619 Dziedzic, T. . . . . . . . . . . . . . P164, P381 Ebers, G. . . . . . . . . . . . . . . . . . . P401 Ebert, D. . . . . . . . . . . . . . . . . . . P456 Ebrahimi, T. . . . . . . . . . . . . . . . . P594 Eckert, B. . . . . . . . . . . . . . . . . . . P493 Eckhardt-Henn, A. . . . . . . . . . . . . O115 Edan, G. . . . . . . . . . . . . . . . O110, P406 Edomi, P. . . . . . . . . . . . . . . . . . . P328 Efendi, H. . . . . . . . . . . . . . . . . . P256 Egerer, G. . . . . . . . . . . . . . . . . . . O95 Egidi, M. . . . . . . . . . . . . . . . . . . P560 Egido, J. . . . . . . . . . . . . . . . . . . O132 Eguchi, K. . . . . . . . . . . . . . . . . . P378 Ehlers, J. . . . . . . . . . . . . . . . . . . P179 Eicke, M. . . . . . . . . . . . . . . . . . . P174 Eisen, A. . . . . . . . . . . . . . . . . . . O116

Elam, M. . . . . . . . . . . . . O63, P533, P626 Embacher, N. . . . . . . . . . . . . . . . . O83 Endo, M. . . . . . . . . . . . . . . . . . . O125 Endziniene, M. . . . . . . . . . . . . . . P294 Engelter, S. . . . . . . . . . . . . . . . . . P347 Engert, A. . . . . . . . . . . . . . . . . . . O95 Enzinger, C. . . . . . . . . . . . . . . . . . O42 Eraksoy, M. . . . . . . . . . . O44, O108, P573 Erban, P. . . . . . . . . . . . . . . . . . . P217 Erbguth, F. J. . . . . . . . . . . O70, P173, P195 Ergüngör, M. F. . . . . . . . . . . . P308, P451 Erkinjuntti, T. . . . . . . . . . . . . . . . . O90 Erne, B. . . . . . . . . . . . . . . . . . . . O50 Escada, T. M. . . . . . . . . . . . . . . . . O54 Escribano, L. . . . . . . . . . . . . . . . . P366 Esperança Pina, J. A. . . . . . . . . . . . P446 Espiño, M. . . . . . . . . . . . . . . . . . P393 Esposito, F. . . . . . . . . . . . . . . O31, P319 Estévez, S. . . . . . . . . . . . . . . . . . P243 Etemadifar, M. . . . . . . . . . . . . . . . P572 Euler, B. . . . . . . . . . . . . . . . . . . P317 Evangelopoulos, M. . . . . . . . . . . . . P556 Evstigneev, V. . . . . . . . . . . . . . . . P608 Exley, C. . . . . . . . . . . . . . . . . . . P315 Ezquerra, M. . . . . . . . . . O157, P185, P188 Fabbrini, G. . . . . . . . . . . . . . . . . . O57 Fabbro, F. . . . . . . . . . . . . . . . . . . P411 Fabrizi, G. M. . . . . . . . . . . . . . . . P437 Facchini, S. . . . . . . . . . . . . . . . . . P432 Fadrna, T. . . . . . . . . . . . . . . . . . . O56 Faggi, A. . . . . . . . . . . . . . . . . . . P455 Faggiano, F. . . . . . . . . . . . . . . . . P502 Faiss, J. H. . . . . . . . . . . . . . . . . . P500 Faizulin, E. . . . . . . . . . . . . . . . . . P607 Falcão, F. . . . . . . . . . . . . . . . . . . O71 Falcone, S. . . . . . . . . . . . . . . . . . P199 Faldum, A. . . . . . . . . . . . . . . . . . O127 Falini, A. . . . . . . . . . . . . . . . . O34, O37 Falup-Pecurariu, C. . . . . . . . . . . . . P169 Falzone, F. . . . . . . . . . . . . . . P533, P626 Fancellu, R. . . . . . . . . . . . . . . . . O149 Farrell, M. . . . . . . . . . . . . . . . . . P475 Farrell, R. A. . . . . . . . . . . . . . . . . P399 Fasbender, P. . . . . . . . . . . . . . . . . P567 Fattorello Salimbeni, C. . . . . . . . . . . P281 Favrole, P. . . . . . . . . . . . . . . . . . O138 Fazekas, F. . . . . . . . . . 21, O42, O90, P397 Fazio, R. . . . . . . . . . . . . . . . . . . P275 Federbusch, M. . . . . . . . . . . . . . . P443 Federico, A. . . . . . . . . . . . . . . . . O103 Fehm, N. P. . . . . . . . . . . . . . . . . . P217 Felber, S. . . . . . . . . . . . . . . . . . . O83 Feldmann, M. . . . . . . . . . . . . . . . O113 Fellay, B. . . . . . . . . . . . . . . . . . . P466 Fenger, K. . . . . . . . . . . . . . . . . . . O62 Fenoglio, C. . . . . . . . . . O155, P202, P233 Fereshtehnejad, S. M. . . . . . . . . . . . P330 Fernández, M. . . . . . . . . . . . . . . . O157 Fernández García, C. . . . . . . . . . . . P252 Fernández Martín, R. . . . . . . . . . . . P248 Fernández-Fernández, S. . . . . . . P270, P305 Fernando, K. T. M. . . . . . . . . . O102, P488 Ferreira, Aníbal . . . . . . . . . . . . . . . P446 Ferreira, André . . . . . . . . . . . . O48, O147 Ferrer, I. . . . . . . . . . . . . . . . . . . O157 Ferrer, T. . . . . . . . . . . . . . . . . . . P627 Ferrero, B. . . . . . . . . . . . . . . P327, P489 Ferro, J. M. . . . . . O71, O88, O90, P441, P446 Festa, B. . . . . . . . . . . . . . . . . . . P394 Festa, E. . . . . . . . . . . . . . . . . . . P489 Fetter, M. . . . . . . . . . . . . . . . . . O131 Ficarra, G. . . . . . . . . . . . . . . P245, P439 Figueira, F. F. A. . . . . . . . . . . . . . . P444 Filipov, V. . . . . . . . . . . . . . . . . . . P403 Filippi, M. . . . . . . . . . . 22, O32, O34, O37, O38, O41, O42, O101, O119, O122, P485, P570 Fimmers, R. . . . . . . . . . . . . . . . . . O95

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Fischer, M. . . . . . . . . . . . . . . . . . P279 Fischer, U. . . . . . . . . . . . . . . . . . P542 Fisher, M. . . . . . . . . . . . . . . . . . . . . 3 Fisk, J. . . . . . . . . . . . . . . . . . . . P493 Fisniku, L. . . . . . . . . . . . O33, O35, P492 Fliessbach, K. . . . . . . . . . . . . . . . . O95 Flowers, J. M. . . . . . . . . . . . . . . . . P186 Fluegel, D. . . . . . . . . . . . . . . . . . P295 Fluri, F. . . . . . . . . . . . . . . . P346, P347 Fondel, R. . . . . . . . . . . . . . . . . . . O64 Fonseca, J. . . . . . . . . . . . . . . . . . P258 Fontalba, A. . . . . . . . . . . . . . . . . O146 Foong, J. . . . . . . . . . . . . . . . . . . P295 Foreid, J. P. . . . . . . . . . . . . . . . . . P274 Forloni, G. . . . . . . . . . . . . . . . . . P202 Fornari, J. . . . . . . . . . . . . . . . . . P458 Forsting, M. . . . . . . . . . . . . . . . . . . 20 Fournier, B. . . . . . . . . . . . . . . . . P538 Fox, E. . . . . . . . . . . . . . . . . . . . P231 Fox, N. C. . . . . . . . . . . . . . . O154, P492 Franchimont, N. . . . . . . . . . . . . . . P497 Franciotta, D. . . . . . . . . . . . . P486, P487 Franzini, M. . . . . . . . . . . . . . . . . O120 Frau, J. . . . . . . . . . . . . . . . . P495, P496 Freedman, M. S. . . . . . . . O110, P397, P406 Frenzel, C. . . . . . . . . . . . . . . O112, P586 Friedrich, I. . . . . . . . . . . . . . . . . P195 Frigerio, S. . . . . . . . . . . . . . . . . . P312 Frisullo, G. . . . . . . . . . . P566, P575, P576 Fritz, D. . . . . . . . . . . . . . . . . . . O104 Fryer, A. A. . . . . . . . . . . . . . . . . . P198 Fuellgraf, H. . . . . . . . . . . . . . P505, P506 Fuentes, B. . . . . . . . . . . . . . O132, P158 Fuhr, P. . . . . . . . . . . . . . O50, P343, P606 Fujimura, H. . . . . . . . . . . . . P337, P477 Fumagalli, F. . . . . . . . . . . . . . . . . P455 Funauchi, M. . . . . . . . . . . . . . . . . P337 Fürholzer, W. . . . . . . . . . . . . . . . . P605 Furlan, P. M. . . . . . . . . . . . . . . . . P297 Gago, M. . . . . . . . . . . . . . . . P249, P258 Gahn, G. . . . . . . . . . . . . . . . . . . P614 Gaig, C. . . . . . . . . . . . . . . . . . . . P188 Gailani, D. . . . . . . . . . . . . . . . . . . O73 Gajewska, B. . . . . . . . . . . . . . . . . P479 Gal, A. . . . . . . . . . . . . . . . . O121, P203 Galassi, G. . . . . . . . . . . P209, P245, P390, P429, P432, P439 Galbiati, Sara . . . . . . . . . P200, P596, P604 Galbiati, Susanna . . . . . . . . . . . . . . P604 Galimberti, D. . . . . . . . . O155, P202, P233, P352, P361 Gallardo, E. . . . . . . . . . . . . . . . . P428 Gallati, S. . . . . . . . . . . . . . . . . . O152 Gallia, F. . . . . . . . . . . . . . . . . . . . O52 Gallo, A. . . . . . . . . . . . . . . . . . . P329 Gálvez, A. . . . . . . . . . . . P215, P350, P541 Gambardella, A. . . . . . . . . . . . . . . P296 Gambi, D. . . . . . . . . . . . . . . P470, P471 Garcés, M. . . . . . . . . . . . . . . . . . P197 García, A. . . . . . . . . . . . . . . . . . . P428 García, L. . . . . . . . . . . . . . . P521, P618 Garcia de la Fuente, A. . . . . . . . . . . P172 Garcia-Barragan, N. . . . . . . . . . . . . P393 Garcia-Cebrian, A. . . . . . . . . . P425, P426 García-Cossío, M. . . . . . . . . . . . . . P243 García-Ramos, R. . . . . . . . . . . P511, P589 García-Villanueva, M. . . . . . . . . . . . P243 Garren, H. . . . . . . . . . . . . . . . . . O109 Garrote, J. A. . . . . . . . . . . . . . . . . P565 Gaspari, A. R. . . . . . . . . . . . . . . . P470 Gasparro, D. . . . . . . . . . . . . . . . . P389 Gass, A. . . . . . . . . . . . . . . . . . . O105 Gassner, A. . . . . . . . . . . . . . . . . . P595 Gasverde, S. . . . . . . . . . . . . . . . . P297 Gaul, C. . . . . . . . . . . . . . . . . . . . P195 Geber, C. . . . . . . . . . . . . . . . . . . O64 Gedikoglu, G. . . . . . . . . . . . . . . . P283 Gedizlioglu, M. . . . . . . . . . . . . . . P339

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Greeve, I. . . . . . . . . . . . . . . . . . . P316 Greim, B. . . . . . . . . . . . . . . . . . . P225 Gremaud, N. . . . . . . . . . . . . . . . . P594 Gremion, G. . . . . . . . . . . . . . . . . P408 Gressner, A. M. . . . . . . . . . . . . . . . P501 Grieshofer, P. . . . . . . . . . . . . P602, P603 Griffin, J. W. . . . . . . . . . . . . . . . . . O49 Grigoriadis, N. . . . . . . . . . . . P237, P318 Grimaldi, L. M. E. . . . . . . . . . . . . . P329 Grimaldi, R. . . . . . . . . . . . . . . . . P329 Gronemeyer, S. . . . . . . . . . . . . . . P212 Gronow, R. . . . . . . . . . . . . . . . . . P588 Grotemeyer, K. H. . . . . . . . . . . . . . P161 Gruber, D. . . . . . . . . . . . . . . . . . P184 Guadalupi, R. . . . . . . . . . . . . . . . P554 Guaraldi, P. . . . . . . . . . . . . . . . . . P439 Guerrero, A. L. . . . . . . . . P563, P564, P565 Gugala, M. . . . . . . . . . . . . . . . . . P362 Guglieri, M. . . . . . . . . . . . . . P410, P411 Guidi, I. . . . . . . . . . . . . O155, P352, P361 Gulkevych, O. . . . . . . . . . . . . . . . P351 Guneri, A. . . . . . . . . . . . . . . . . . P162 Günther, P. . . . . . . . . . . . . . . P189, P306 Gurevich, T. . . . . . . . . . . . . . . . . P247 Gurruchaga, A. . . . . . . . . . . . . . . P564 Gursoy, E. . . . . . . . . . . . . . . . . . P162 Gutiérrez, F. . . . . . . . . . . . . . P563, P564 Gutierrez, J. . . . . . . . . . . . . . . . . P382 Gutowski, N. . . . . . . . . . . . . . . . . P379 Haas, J. . . . . . . . . . . . . . . . . . . . P218 Habek, M. . . . . . . . . . . . . . . P436, P461 Hadjigeorgiou, G. M. . . . . . . . O145, O151, P182, P207 Hadjisavvas, A. . . . . . . . . . . . . . . P481 Haefeli, T. . . . . . . . . . . . . . . . O79, P542 Hagenah, J. . . . . . . . . . . . . . . . . O114 Haghighi, S. . . . . . . . . . . . . . P160, P168 Hahn-Barma, V. . . . . . . . . . . . . . . P365 Hahntow, I. . . . . . . . . . . . . . . . . . P419 Haider, C. . . . . . . . . . . . . . . . . . P595 Halefoglu, A. . . . . . . . . . . . . . . . . O44 Halkes, P. . . . . . . . . . . . . . . . . . O140 Hamann, L. . . . . . . . . . . . . . . . . P407 Han, J. H. . . . . . . . . . . . . . . . . . . P516 Han, S. R. . . . . . . . . . . . . . . . . . . P216 Handschu, R. . . . . . . . . . . . . . . . . O70 Haque, S. . . . . . . . . . . . . . . . . . . P402 Hardiman, O. . . . . . . . . O118, P382, P384, P387, P389, P484 Hardmeier, M. . . . . . . . . . . . . . . . P385 ’t Hart, B. A. . . . . . . . . . . . . . . . . . O40 Hartmann, A. . . . . . . . . . . . . . . . O136 Hartung, H. P. . . . . . O110, P397, P403, P406 Harushukuri, J. . . . . . . . . . . . . . . P519 Hasbak, P. . . . . . . . . . . . . . . . . . P508 Hasegawa, O. . . . . . . . . . . . . . . . . P180 Hashim, R. . . . . . . . . . . . . . . . . . P214 Hatipoglu, H. G. . . . . . . . . . . . P308, P451 Hatt, H. . . . . . . . . . . . . . . . . . . . O49 Hatunic, M. . . . . . . . . . . . . . . . . P389 Hatzidou, M. . . . . . . . . . . . . . . . . P611 Hatzidounas, T. . . . . . . . . . . . . . . P546 Hauf, M. . . . . . . . . . . . . . . . . . . O152 Hauff, P. . . . . . . . . . . . . . . . . . . . O39 Havasi, N. . . . . . . . . . . . . . . P241, P579 Havrdova, E. . . . . . . . . . O108, P222, P226, P227, P325, P573 Hawkins, C. P. . . . . . . . . P198, P315, P577 Hayes, R. . . . . . . . . . . . . . . . . . . P440 Heckmann, J. . . . . . . . . . . . . . . . . O70 Hedrich, K. . . . . . . . . . . . . . . . . . P187 Heemann, U. . . . . . . . . . . . . . . . . P419 Heesakkers, J. . . . . . . . . . . . . . . . P324 Hefter, H. . . . . . . . . . . . . . . P196, P456 Hefti, M. . . . . . . . . . . . . . . . P234, P235 Heinze, H. J. . . . . . . . . . . . . . P304, P490 Heliopoulos, I. . . . . . . . . . . . . . . . P546 Hellman, U. . . . . . . . . . . . . . . . . O147

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Hellweg, R. . . . . . . . . . . . . . . . . . P508 Helmchen, C. . . . . . . . . . O114, P187, P610 Hemmer, B. . . . . . . . . . . . . . . . . P218 Henning, A. . . . . . . . . . . . . . . . . O137 Hénon, H. . . . . . . . . . . . . . . . . . . O72 Hentschel, H. . . . . . . . . . . . . . . . P614 Heppner, F. . . . . . . . . . . . . . . . . O121 Herberger, S. . . . . . . . . . . . . . . . . O91 Hermann, W. . . . . . . . . . P189, P306, P434 Hermsdörfer, J. . . . . . . . . . . . . . . P605 Herrmann, F. . . . . . . . . . . . . . . . P593 Hersberger, M. . . . . . . . . . . . . . . . P530 Herzig, R. . . . . . . . . O56, O77, P208, P303, P367, P473, P550 Hess, C. . . . . . . . . . . . . . . . . . . . O53 Hirsch, J. G. . . . . . . . . . . . . . . . . O105 Hofer, S. . . . . . . . . . . . . . . . P234, P235 Hoffmann, F. . . . . . . . . . . . . . . . . P500 Hoffmann, K. T. . . . . . . . . . . . . . . P184 Hoffmann, U. . . . . . . . . . . . . . . . P594 Hohlfeld, R. . . . . . . . . . . . . . P486, P569 Hojda, A. . . . . . . . . P263, P264, P265, P534 Hollenhorst, M. . . . . . . . . . . . . . . P501 Holtmannspötter, M. . . . . . . . . . . . P585 Hong, S. C. . . . . . . . . . . P262, P452, P540 Honoré, J. . . . . . . . . . . . . . . P284, P285 Horak, D. . . . . . . . . . . . . . . . . . . O77 Horakova, D. . . . . . . . . . P222, P226, P227 Horner, S. . . . . . . . . . . . . . . . . . P447 Horowski, R. . . . . . . . . . . . . . . . . P371 Hosback, S. . . . . . . . . . . . . . . . . . P484 Hotermans, C. . . . . . . . . . . . . . . . P497 Howell, P. . . . . . . . . . . . . . . . . . . P553 Hrusak, O. . . . . . . . . . . . . . . . . . P240 Hübner, J. . . . . . . . . . . . . . . . . . O114 Hufnagel, A. . . . . . . . . . . . . . . . . P296 Hüfner, K. . . . . . . . . . . . O91, P585, P591 Hughes, R. A. C. . . . . . . . . . . . . . . . 30 Humm, A. M. . . . . . . . . . . . . P193, P272 Huppert, D. . . . . . . . . . . . . . . . . P586 Hussein, S. . . . . . . . O104, P220, P321, P323 Husson, H. . . . . . . . . . . . . . P333, P427 Huster, D. . . . . . . . . . . . . . . . . . P189 Hutchinson, M. . . . . . . . . . . . . . . P404 Hutyra, M. . . . . . . . . . . . . . . . . . P550 Iarlori, C. . . . . . . . . . . . . . . . . . . P471 Iavorenciuc, G. . . . . . . . . . . . . . . . P293 Idris, M. . . . . . . . . . . . . . . . . . . P214 Idris, Z. . . . . . . . . . . . . . . . . . . . P255 Iglesias, A. . . . . . . . . . . . . . . . . . P248 Imberti, L. . . . . . . . . . . . . . . . . . P228 Imke, S. . . . . . . . . . . . . . . . . . . . O58 Infante, J. . . . . . . . . . . . . . . O146, O156 Iñiguez, C. . . . . . . . P515, P521, P522, P618 Inoue, K. . . . . . . . . . . . O148, P477, P555 Inuggi, A. . . . . . . . . . . . . . . O128, O129 Inzelberg, R. . . . . . . . . . . . . . . . . O116 Inzitari, D. . . . . . . . . . . . . . . . . . O90 Ioannidis, P. . . . . . . . . . . . . . . . . P360 Iorio, R. . . . . . . . . . . . . . . . . . . P575 Iranzo, A. . . . . . . . . . . . . . . . . . . P532 Iravani, M. . . . . . . . . . . . . . . . . . P251 Irie, T. . . . . . . . . . . . . . . . . . . . P482 Iseri, P. . . . . . . . . . . . . . . . . . . . P256 Iwahashi, Y. . . . . . . . . . . . . . . . . O125 Izal, E. . . . . . . . . . . . . . . . . . . . P627 Jäger, R. . . . . . . . . . . . . . . . . . . . O98 Jaiser, S. . . . . . . . . . . . . . . . . . . P239 Jakeman, P. . . . . . . . . . . . . . . . . . P484 Jakob, S. . . . . . . . . . . . . . . . . . . P312 Jalaluddin, S. . . . . . . . . . . . . . . . . P254 Jalili, F. . . . . . . . . . . . . . . . . . . . O109 Jamroz-Wisniewska, A. . . . . . . . P580, P581 Jang, M. U. . . . . . . . . . . . . . . . . . P438 Jang, S. S. . . . . . . . . . . . . . . . . . . P483 Jankovic, L. . . . . . . . . . . . . . . . . P609 Jann, S. . . . . . . . . . . . . . . . . . . . O43

Janousˇková, L. . . . . . . . . . . . . . . . P544 Janusauskaite, J. . . . . . . . . . . . . . . P509 Jarius, S. . . . . . . . . . . . P238, P468, P469, P486, P487 Jasinska-Myga, B. . . . . . . . . . . . . . P624 Jeannet, P. Y. . . . . . . . . . . . . . . . . P408 Jeanrenaud, X. . . . . . . . . . . . . . . . P408 Jeffery, D. R. . . . . . . . . . . . . . . . . P403 Jerabek, J. . . . . . . . . . . . . . . . . . P268 Jilek, S. . . . . . . . . . . . . . . . . . . . P211 Jongen, P. . . . . . . . . . . . . . . . . . . P324 Jordão, C. . . . . . . . . . . . . . . . . . P446 Jörg, J. R. . . . . . . . . . . . . . . . P279, P289 Jovell, A. . . . . . . . . . . . . . . . . . . P493 Judica, E. . . . . . . . . . O37, O38, O41, O122 Juergens, A. . . . . . . . . . . . . . . . . . O95 Juillard, C. . . . . . . . . . . . . . . P466, P467 Jung, H. H. . . . . . . . . . . . . . O121, O137 Jung, S. . . . . . . . . . . . . . . . . . . . O121 Jungehülsing, G. J. . . . . . . . . . . . . . P184 Jürgens, T. . . . . . . . . . . . . . . . . . P176 Jurkeviciene, G. . . . . . . . . . . . . . . P294 Kachuck, N. . . . . . . . . . . . . . . . . O109 Kadar, K. . . . . . . . . . . . . . . . . . . P595 Kafetsouli, D. . . . . . . . . . . . . . . . O151 Kahlen, U. . . . . . . . . . . . . . . . . . P196 Kahn, E. . . . . . . . . . . . . . . . . . . P425 Kajdasz, D. . . . . . . . . . . . . . . . . . P426 Kalamafkianaki, E. . . . . . . . . . P517, P568 Kalina, M. . . . . . . . . . . . . . . P523, P544 Kalla, R. . . . . . . . . . . . . . . . P585, P591 Kallikourdi, M. . . . . . . . . . . . . . . P449 Kamaci, S. . . . . . . . . . . . . . . . . . P256 Kannari, K. . . . . . . . . . . . . . . . . . P373 Kanovsky, P. . . . . . . . O56, O77, P177, P208, P303, P367, P473, P550 Kanta, O. . . . . . . . . . . . P472, P474, P519 Kantengwa, S. . . . . . . . . . . . . P466, P467 Kapina, V. . . . . . . . . . . . . . . . . . P178 Kaposzta, Z. . . . . . . . . . . . . . . . . P421 Kappeler, L. . . . . . . . . . . O79, O152, P542 Kappelle, L. J. . . . . . . . . . . . . . . . O133 Kappos, L. . . . . . . . . . O105, O108, O110, P403, P406, P569, P573 Kapsalakis, I. . . . . . . . . . . . . P181, P357 Kapsali, S. A. . . . . . . . . . . . . P442, P611 Karachalios, G. . . . . . . . . . . . P259, P302 Karageorgiou, C. E. . . . . . . . . . P181, P357 Karakoc, E. . . . . . . . . . . P283, P308, P451 Karakostas, D. . . . . . . . . . . . . P519, P545 Karandreas, N. . . . . . . . . . . . . . . . P478 Karantanas, A. . . . . . . . . . . . . . . . P207 Karantoni, E. . . . . . . . . . . . . . . . . P338 Kararizou, E. . . . . . . . . . . . . . . . . P478 Karch, C. . . . . . . . . . . . . . . . . . . P583 Karkhiaran, F. . . . . . . . . . . . . . . . P160 Karlsson, T. . . . . . . . . . . . . . . . . . O63 Karpathiou, N. . . . . . . . . . . . . . . . P357 Kartsaklis, L. A. . . . . . . . . . . . . . . P357 Karussis, D. . . . . . . . . . . . . . . . . P318 Kasper, L. . . . . . . . . . . . . . . . . . P402 Katsarou, Z. . . . . . . . . . . . . . . . . P370 Katsoulas, G. . . . . . . . . . . . . . . . . P535 Kätterer, C. . . . . . . . . . . . . . . . . . P606 Kaufmann, J. . . . . . . . . . . . . . . . . P490 Kawarai, T. . . . . . . . . . . . . . . . . . P201 Kawasaki, S. . . . . . . . . . . . . . . . . P180 Kay, A. . . . . . . . . . . . . . . . . . . . P165 Kay, C. S. K. . . . . . . . . . . . . . P414, P415 Kaya, S. . . . . . . . . . . . . . . . . . . . P162 Kayim, Ö. . . . . . . . . . . . . . . . . . P525 Kazibutowska, Z. . . . . . . . . . . . . . P261 Kazis, A. . . . . . . . . . . . . . . . . . . P178 Kazmierczak, B. . . . . . . . . . . . . . . P479 Keir, G. . . . . . . . . . . . . . . . O154, P165 Kell, C. A. . . . . . . . . . . . . . . . . . . O89 Kempkes, U. . . . . . . . . . . . . . . . . P289 Keogan, M. . . . . . . . . . . . . . . . . . P475

Kerr, M. . . . . . . . . . . . . . . . . . . P165 Kerting, N. . . . . . . . . . . . . . . . . . P267 Khajavi, M. . . . . . . . . . . . . . . . . O148 Khan, S. A. . . . . . . . . . . . . . . . . . P239 Kharaishvili, Z. . . . . . . . . . . . . . . O142 Khatami, R. . . . . . . . . . . P528, P620, P621 Khosravi, S. . . . . . . . . . . . . . . . . P300 Khoury, S. . . . . . . . . . . . . . . . . . P203 Kiefer, C. . . . . . . . . . . . . . . . P312, P423 Kilic, A. . . . . . . . . . . . . . . . . . . . P323 Kilidireas, K. . . . . . . . . . . . . . . . . P338 Kim, D. E. . . . . . . . . . . . . . . . . . P516 Kim, Hyun-Jung . . . . . . . . . . . . . . P480 Kim, Hak Jin . . . . . . . . . . . . . . . . P616 Kim, H. S. . . . . . . . . . . . . . . . . . O141 Kim, I.-H. . . . . . . . . . . . . . . . . . O135 Kim, K. K. . . . . . . . . . . . . . . . . . O141 Kim, M. . . . . . . . . . . . . . . . . . . . P438 Kim, M. K. . . . . . . . . . . . . . . . . . P348 Kim, N. K. . . . . . . . . . . . . . . . . . O141 Kim, O. J. . . . . . . . . . . . . . . . . . . O141 Kim, R. . . . . . . . . . . . . . . . . . . . P391 Kim, W. C. . . . . . . . . . . . . . . . . . O141 Kim, Y. B. . . . . . . . . . . . . . . . . . . P262 Kimiskidis, V. K. . . . . . . . . . . . . . . P178 Kimmig, H. . . . . . . . . . . . . . . . . O114 Kimura, K. . . . . . . . . . . . . . . . . . O125 Kinkingnehum, S. . . . . . . . . . . . . . P365 Kistsen, V. . . . . . . . . . . . . . . . . . P608 Kivi, A. . . . . . . . . . . . . . . . . . . . P184 Kkolou, E. . . . . . . . . . . . . . . . . . P291 Kladi, A. . . . . . . . . . . . . . . . . . . P424 Klapczynski, F. . . . . . . . . . . . . . . P192 Klausa, K. . . . . . . . . . . . . . . . . . P289 Kleer, B. . . . . . . . . . . . . . . . . . . P238 Klein, A. . . . . . . . . . . . . . . . . . . P219 Klein, C. . . . . . . . . . . . . . . . O114 P187, Klein, G. E. . . . . . . . . . . . . . . . . . P447 Klein, M. . . . . . . . . . . . . . . . O93, P376 Kleine, T. O. . . . . . . . . . . P212, P213, P501 Kleinschnitz, C. . . . . . . . . . . . . . . . O73 Klementiev, B. . . . . . . . . . . . . . . . P353 Kleopa, K. . . . . . . . . . . . . . . . . . P291 Klepac, N. . . . . . . . . . . . . . . . . . P557 Klimkowicz-Mrowiec, A. . . . . . . . . . P164 Klingelhoefer, J. . . . . . . . . . . . . . . P443 Klockgether, T. . . . . . . . . . . . O95, O131 Klodowska-Duda, G. . . . . . . . . . . . P624 Knudsen, S. . . . . . . . . . . . . . . . . P204 Ko, S. H. . . . . . . . . . . . . . . . . . . P216 Kocher, M. . . . . . . . . . . . . . . . . . O77 Koedel, U. . . . . . . . . . . . . . . O93, P376 Koehler, J. . . . . . . . . O36, O127, P288, P587 Koenig, N. . . . . . . . . . . . . . . . . . P225 Koennecke, H. C. . . . . . . . . . . . . . O136 Koepp, M. . . . . . . . . . . . . . . . . . P295 Köhler, W. . . . . . . . . . . . . . . . . . P500 Kokotis, P. . . . . . . . . . . . . . . . . . P478 Kolbe, M. . . . . . . . . . . . . . . . . . . P505 Koleva, N. . . . . . . . . . . . . . . . . . P298 Kollarova, K. . . . . . . . . . . . . . . . . P208 Kollreider, A. . . . . . . . . . . . . P602, P603 Kölmel, H. W. . . . . . . . . . . . . . . . P567 Komnos, A. . . . . . . . . . . . . . . . . P207 Komoly, S. . . . . . . . . . . . . . . . . . P421 Kömpf, D. . . . . . . . . . . . . . . . . . O114 Komsuoglu, S. . . . . . . . . . . . . P256, P613 Konczak, J. . . . . . . . . . . . . . . . . . O59 Konieczny, A. . . . . . . . . . . . . . . . P401 König, F. . . . . . . . . . . . . . . . . . . P490 Konstantinopoulou, A. . . . . . . . . . . P260 Kontogianni, V. . . . . . . . . . . . . . . P357 Kool, H. . . . . . . . . . . . . . . . . . . . O75 Koppelstaetter, F. . . . . . . . . . . . . . . O83 Koralnik, I. J. . . . . . . . . . . . . . . . . O94 Korchazhkina, O. . . . . . . . . . . . . . P315 Korczyn, A. D. . . . . . . . . . . . . . . . P247 Korman, S. . . . . . . . . . . . . . . . . . P203 Korteweg, T. . . . . . . . . . . . . . . . . O38

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Kosmidis, M-H. . . . . . . . . . . . . . . P360 Kosta, V. . . . . . . . . . . . . . . . P442, P611 Kotowicz, J. . . . . . . . . . . . . . P166, P167 Koukoulis, A. . . . . . . . . . . . . . . . P248 Kouroumalos, N. . . . . . . . . . . P517, P568 Koutoula, O. . . . . . . . . . . . . . . . . P545 Koutsonikolas, D. . . . . . . . . . . . . . P178 Koutsou, L. . . . . . . . . . . . . . . . . . P424 Koutsouraki, E. . . . . . . . . . . . . . . P342 Kouvatsou, Z. . . . . . . . . . . . . . . . P178 Kovarova, I. . . . . . . . . . . . . . . . . P325 Kozetzidou, K. . . . . . . . . . . . P442, P611 Kozlowski, O. . . . . . . . . . . . . . O76, P445 Kraemer, M. . . . . . . . . . . . . . . . . P599 Krämer, H. H. . . . . . . . . . . . . . O63, O64 Krarup, C. . . . . . . . . . . . . . . . . . . O51 Kraschl, V. . . . . . . . . . . . . . . . . . P595 Krasulova, E. . . . . . . . . . . . . . . . . P325 Kraus, C. . . . . . . . . . . . . . . . . . . P403 Krawczewski, K. . . . . . . . . . . . . . . O59 Krawczyk, R. . . . . . . . . . . . . . . . . P362 Krommyda, M. . . . . . . . . . . . P472, P474 Kroner, A. . . . . . . . . . . . . . . . . . . O39 Kroschinsky, F. . . . . . . . . . . . . . . . O95 Kroumova, M. . . . . . . . . . . . . . . . O68 Krstevski, M. . . . . . . . . . . . . . . . . P454 Krupai, F. . . . . . . . . . . . . . . . . . . P421 Krupin, V. . . . . . . . . . . . . . . . . . P341 Krupka, B. . . . . . . . . . . . . . . . . . P550 Kruse, R. . . . . . . . . . . . . . . . . . . P213 Kruttgen, A. . . . . . . . . . . . . . . . . P556 Ku, B. . . . . . . . . . . . . . . . . . . . . P354 Ku, Y. H. . . . . . . . . . . . . . . . . . . O141 Kuchukhidze, G. . . . . . . . . . . . . . . O83 Kühn, H. . . . . . . . . . . . . . . . . . . P189 Kulan, C. . . . . . . . . . . . . . . . . . . P339 Kumru, H. . . . . . . . . . . . . . . P271, P625 Kunkel, A. . . . . . . . . . . . . . . . . . P500 Kuntzer, T. . . . . . . . . . . . O65, P408, P409 Kunz, D. . . . . . . . . . . . . . . . . . . P213 Kupsch, A. . . . . . . . . . . . . . . . . . P184 Kuran, W. . . . . . . . . . . . . . . . . . P362 Kurca, E. . . . . . . . . . . . . . . . . . . O77 Kuroiwa, Y. . . . . . . . . . . . . . . . . . O125 Kurz, M. . . . . . . . . . . . . . . . . . . P196 Kurzepa, J. . . . . . . . . . . . . . . . . . P230 Kuzma, M. . . . . . . . . . . . . . . . . . P479 Kwon, K. H. . . . . . . . . . . . . . . . . P368 Kyriacou, K. . . . . . . . . . . . . . . . . P481 Kyriakides, T. . . . . . . . . . . . . P424, P481 Lacerda, L. . . . . . . . . . . . . . . . . . P552 Lachenmayer, M. L. . . . . . . . . . . . . P561 Lacroix, C. . . . . . . . . O46, O48, P332, P336 Ladewig, G. . . . . . . . . . . . . . . . . . O39 Laguzzi, E. . . . . . . . . . . . . . . . O96, O99 Laherran, E. . . . . . . . . . . . . . P563, P564 Lalive, P. . . . . . . . . . . . . . . . P466, P467 Laloux, P. . . . . . . . . . . . . . . . . . . P460 Lalu, T. . . . . . . . . . . . . . . . . . . . O48 Lam, W. M. W. . . . . . . . . . . . . . . . . O74 Lambertenghi Deliliers, G. . . . . . . . . P507 Landau, K. . . . . . . . . . . . . . . . . . O121 Landis, T. . . . . . . . . . . . . . . . O94, O139 Langdon, D. . . . . . . . . . . . . . . . . P401 Lanuti, P. . . . . . . . . . . . . . . . . . . P470 Lapierre, Y. . . . . . . . . . . . . . . . . O109 Lara, G. . . . . . . . . . . . . . . . . . . . P382 Larner, A. J. . . . . . . . . . . O144, P359, P363 Lassmann, H. . . . . . . . . . . . . . . . . O40 Laurà, M. . . . . . . . . . . . . . . . . . . O43 Laurent, C. . . . . . . . . . . . . . . . . . O68 Lauterburg, T. . . . . . . . . . . . . . . . P316 Lavie, P. . . . . . . . . . . . . . . . . . . . . 16 Lazarova, S. . . . . . . . . . . . . . . . . P422 Le, T. K. . . . . . . . . . . . . P334, P425, P426 Lebrun, C. . . . . . . . . . . . . . . . . . P458 Leclerc, X. . . . . . . . . . . . . . . . . . . O68 Lee, H. . . . . . . . . . . . . . . . . . . . P539

Lee, I. H. . Lee, J. J. . . Lee, K. S. . Lee, K. W. . Lee, L. . . Lehericy, S. Lehmitz, R. Leis, S. . . Lempert, T. Leocani, L.

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. . . . . . . . . . . . . . . . O141 . . . . . . . . . . . . . . . . P354 . . . . . . . . . . . . . . . . P216 . . . . . . . . . . . . . . . . P480 . . . . . . . . . . . . . . . . P223 . . . . . . . . . . . . . . . . P365 . . . . . . . . . . . . . . . . P213 . . . . . . . . . . . . . . . . P508 . . . . . . . . . . . . . . . . O113 . . . . . . . . . . O66, O128, O129, P273, P275 Leone, M. . . . . . . . . . . . . . . . . . . O31 Leppert, D. . . . . . . . . . . . . . . . . . O105 Leroy, M. . . . . . . . . . . . . . . . . . . P497 Leroy, R. . . . . . . . . . . . . . . . . . . P594 Leslie, D. . . . . . . . . . . . P190, P191, P431 Lesnicka, A. . . . . . . . . . . . . . . . . P526 Levandis, G. . . . . . . . . . . . . . . . . P507 Levi, N. . . . . . . . . . . . . . . . . . . . O62 Levtsuk, S. . . . . . . . . . . . . . . . . . P244 Leys, D. . . . . . . . . . . . . . . . . O68, O72 Lezius, F. . . . . . . . . . . . . . . . . . . O113 Li, D. . . . . . . . . . . . . . . . . . . . . P397 Liao, Z. . . . . . . . . . . . . . . . . P440, P503 Liebert, A. . . . . . . . . . . . . . . . . . P443 Liebsch, M. . . . . . . . . . . . . . . . . . P267 Lienau, F. . . . . . . . . . . . . . . . . . . P187 Liguori, R. . . . . . . . . . . . . . . P533, P626 Lim, B. . . . . . . . . . . . . . . . . . . . P483 Lim, J. G. . . . . . . . . . . . . . . . P483, P539 Limmroth, V. . . . . . . . . . . . . O108, P573 Lin, Jui-Jueng . . . . . . . . . . . . . . . . P372 Lin, Jeuei-Jueng . . . . . . . . . . . . . . . P372 Linde, M. . . . . . . . . . . . . . . . . . . O63 Lindquist, S. . . . . . . . . . . . . . . . . P490 Linington, C. . . . . . . . . . . . . . . . . O40 Linke, P. . . . . . . . . . . . . . . . P218, P383 Lipatov, K. . . . . . . . . . . . . . . . . . P341 Liscio, M. . . . . . . . . . . . . . . . . . . P604 Liu, C. . . . . . . . . . . . . . . . . . . . P372 Llado, A. . . . . . . . . . . . . . . . O86, O157 Lobsien, E. . . . . . . . . . . . . . . . . . P184 Locatelli, L. . . . . . . . . . . . . . . . . . P328 Lohse-Busch, H. . . . . . . . . . . . . . . P599 Lojkowska, W. . . . . . . . . . . . . . . . P362 Lomidze, G. . . . . . . . . . . . . . . . . O142 Lopes da Silva, R. . . . . . . . . . . . . . P578 Lopez, E. . . . . . . . . . . . . . . . . . . P515 López del Val, J. . . . . . . . . . . . . . . P515 López-Alburquerque, J. T. . . . . . . . . . P565 Lopez-Bresnahan, M. . . . . . . . . . . . P391 López-Pajares, R. . . . . . . . . . . . . . P194 Lopez-Sendon, J. L. . . . . . . . . . O92, P243 Lopez-Velez, R. . . . . . . . . . . . . . . . O92 Lorefice, L. . . . . . . . . . . . . . P495, P496 Lorenz, A. . . . . . . . . . . . . . . . . . P232 Lorenz, J. . . . . . . . . . . . . . . . . . . P610 Lorenzoni, P. J. . . . . . P369, P413, P414, P415 Lorusso, M. L. . . . . . . . . . . . . . . . P411 Lossos, A. . . . . . . . . . . . . . . . . . P203 Lotfi, J. . . . . . . . . . . . . . . . . . . . P320 Lothgren, M. . . . . . . . . . . . . . . . . P426 Loulidi, J. . . . . . . . . . . . . . . . . . O139 Lovati, C. . . . . . . . . . . . O155, P202, P233 Lovett, J. K. . . . . . . . . . . . . . . . . . P379 Löwer, C. . . . . . . . . . . . . . . . . . . P213 Lozeron, P. . . . . . . . . . . P332, P336, P427 Lu, M. . . . . . . . . . . . . . . . . P440, P503 Lublin, F. . . . . . . . . . . . . . . . . . . P397 Luciano, A. . . . . . . . . . . . . . . . . . P558 Ludolph, A. C. . . . . . . . . . . . . P218, P479 Ludwig, J. . . . . . . . . . . . . . . . . . P187 Luef, G. . . . . . . . . . . . . . . . . . . . O83 Lundblad, L. . . . . . . . . . . . . . . . . O63 Lupescu, T. . . . . . . . . . . . . . . . . . P377 Lupski, J. R. . . . . . . . . . . . . . . . . O148 Lurati-Ruiz, F. . . . . . . . . . . . . . . . O94 Lutz, J. . . . . . . . . . . . . . . . . . . . P419 Lynch, C. . . . . . . . . . . . . . . . . . . P484

Lyrer, P. . . . . . . . . . . . . . . . . . . . P347 Maag, R. . . . . . . . . . . . . . . . . . . P187 Maas-Enriquez, M. . . . . . . . . . . . . P397 MacManus, D. G. . . . . . . . . . . . . . O108 Mäder, M. . . . . . . . . . . . . . . . . . P606 Madero, R. . . . . . . . . . . . . . . . . . P158 Madureira, S. . . . . . . . . . . . . . O88, O90 Maeda, T. . . . . . . . . . . . . . . . . . . P373 Maeder, P. . . . . . . . . . . . . . . . . 4, P537 Maegli, J. . . . . . . . . . . . . . . . . . . P514 Maggiore, C. . . . . . . . . . . . . . P328, P513 Magherini, A. . . . . . . . . . . . . P209, P245 Magnoni, R. . . . . . . . . . . . . . . . . P199 Magri, F. . . . . . . . . . . . . . . . . . . P410 Majorana, G. . . . . . . . . . . . . . . . . O57 Makomela, N. . . . . . . . . . . . . . . . P351 Makrypidi, G. . . . . . . . . . . . . . . . P554 Makulec, A. . . . . . . . . . . . . . . . . P362 Malaise, M. . . . . . . . . . . . . . . . . . P497 Malas, S. . . . . . . . . . . . . . . . . . . P481 Malciene, L. . . . . . . . . . . P273, P380, P520 Mamaloukas, E. . . . . . . . . . . . . . . P545 Mamusa, E. . . . . . . . . . . . . . P495, P496 Mamutse, G. . . . . . . . . . . . . . P198, P315 Mancinelli, E. . . . . . . . . O150, P420, P499 Mancuso, M. . . . . . . . . . . . . . . . . O120 Mandrioli, J. . . . . . . . . . . . . . . . . P498 Manganotti, P. . . . . . . . . . . . . . . . P601 Mangas, A. . . . . . . . . . . . . . . . . . P494 Manios, E. . . . . . . . . . . . . . . P163, P260 Manta, P. . . . . . . . . . . . . . . . . . . P417 Marceglia, S. . . . . . . . . . . . . . . . . P560 Marchioni, E. . . . . . . . . . . . . . . . P486 Marchisio, M. . . . . . . . . . . . . . . . P470 Mareckova, H. . . . . . . . . . . . . . . . P325 Mares, J. . . . . . . . . . . . . . . . . . . P303 Margolin, N. . . . . . . . . . . . . . . . . P290 María Viguer García-Moreno, J. . . . . . P252 Mariani, C. . . . . . . . . . . . . . O155, P202, P233 Mariani, J. . . . . . . . . . . . . . . . . . P538 Marini, A. . . . . . . . . . . . . . . . . . P411 Marion, M. H. . . . . . . . . . . . . . . . P186 Mariotti, C. . . . . . . . . . . . . . . . . O149 Markakis, I. . . . . . . . . . . . . . . . . P257 Marques, A. C. . . . . . . . . . . . . . . . P444 Marques, F. . . . . . . . . . . . . . . . . . P236 Marquez, B. . . . . . . . . . . . . . . . . P481 Marquez, G. . . . . . . . . . . . . . . . . . O93 Marrosu, M. G. . . . . . . . . . . . P495, P496 Martí, M. J. . . . . . . . . . . . . . P185, P188 Martín-Polo, J. . . . . . . . . . . . P563, P564 Martinelli, V. . . . . . . . O31, O37, O41, O101, P273, P319, P455, P536 Martinelli Boneschi, F. . . . . O31, P273, P319 Martinez, L. . . . . . . . . . P521, P522, P618 Martínez Cabruja, R. . . . . . . . . . . . P252 Martinez Ponce De Leon, A. . . . . O143, P171 Martínez-Góngora, E. . . . . . . . . . . O131 Martínez-Salio, A. . . . . . . . . . P511, P589 Martínez-Torres, I. . . . . . . . . . P197, P374 Martino, D. . . . . . . . . . . . . . . . . . O57 Martino, S. . . . . . . . . . . . . . . . . . P554 Martins, A. . . . . . . . . . . . . . . . . . P236 Martins, J. . . . . . . . . . . . . . . . . . P170 Marzari, R. . . . . . . . . . . . . . . . . . P328 Maschke, M. . . . . . . . . . . . . . O59, P561 Masdrakis, V. . . . . . . . . . . . . . . . P302 Masjuan, J. . . . . . . . . . . . O92, P243, P393 Mason, L. M. . . . . . . . . . . . . . . . . P272 Masse, I. . . . . . . . . . . . . . . . . . . . O68 Massy, A. . . . . . . . . . . . . . . . . . . P594 Mateiescu, E. C. . . . . . . . . . . . . . . P293 Mateo, I. . . . . . . . . . . . . . . O146, O156 Mathias, C. J. . . . . . . . . . . . . P193, P272 Matijosaitis, V. . . . . . . . . . . . . . . . P380 Matsumoto, S. . . . . . . . . . . . . . . . P180 Mattle, H. P. . . . . . . . O79, P312, P316, P542

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Mäurer, M. . . . . . . . . . . . . . . O39, P487 Mauro, A. . . . . . . . . . . . . . . . . . . P600 Mavromatis, I. . . . . . . . . . . . . . . . P237 Mayer, L. . . . . . . . . . . . . . . . . . . P231 McCrink, L. . . . . . . . . . . . . . . . . P334 McKenna, S. . . . . . . . . . . . . . . . . P493 McLean, M. A. . . . . . . . . . . . . . . . O102 Meads, D. . . . . . . . . . . . . . . . . . . P493 Medeiros, E. . . . . . . . . . . . . . . . . P170 Meier, D. . . . . . . . . . . . . . . . . . . P619 Meier, U. . . . . . . . . . . . . . . . . . . P501 Meisel, C. . . . . . . . . . . . . . . . . . . P407 Mejstrikova, E. . . . . . . . . . . . . . . . P240 Meluzinova, E. . . . . . . . . O108, P240, P573 Mendes, A. . . . . . . . . . . . . . P249, P258 Mendonça, M. T. . . . . . . . . . . . . . . P552 Mendoza, A. . . . . . . . . . . . . . . . . P565 Meola, G. . . . . . . . . . . . O150, P420, P499 Merelli, E. . . . . . . . . . . . . . . . . . P498 Merli, R. . . . . . . . . . . . . . . . . . . . O96 Mestre, T. . . . . . . . . . . . . . . . . . . P375 Metting, Z. . . . . . . . . . . . . . . . . . P314 Metz, R.J . . . . . . . . . . . . . . . . . . . P253 Meuli. . . . . . . . . . . . . . . . . . . . . . . 4 Meyer, R. . . . . . . . . . . . . . . . . . . P218 Meyer, T. . . . . . . . . . . . . . . . P218, P383 Michel, P. . . . . . . . . . . . . . 4, P211, P612 Michmizos, D. . . . . . . . . . . . . . . . P342 Mihancea, P. . . . . . . . . . . . . . P241, P579 Mijajlovic, M. . . . . . . . . . . . . . . . P609 Milà, M. . . . . . . . . . . . . . . . . . . P305 Milani, M. . . . . . . . . . . . . . . . . . . O43 Milano, E. . . . . . . . . . . . . . . . . . P600 Milat, D. . . . . . . . . . . . . . . . . . . P476 Mildner, A. . . . . . . . . . . . . . . . . . P210 Miller, D. H. . . . . . . . O33, O38, O42, O100, O102, O108, O110, P406, P488, P492, P573 Mills, R. J. . . . . . . . . . . . . . . P504, P592 Milonas, I. . . . . . . . P237, P242, P250, P301, P318, P360, P453, P472, P474, P519, P545 Milone, M. . . . . . . . . . . . . . . . . . P416 Miltenburger, C. . . . . . . . . . . . . . . P401 Minn, Y. K. . . . . . . . . . . . . . . . . . P368 Minnet, T. . . . . . . . . . . . . . . . . . . O90 Mirabella, M. . . . . . . . . . P566, P575, P576 Miranda, B. . . . . . . . . . . . . . . . . . O88 Miscia, S. . . . . . . . . . . . . . . . . . . P470 Misco, G. . . . . . . . . . . . . . . . . . . P600 Misrahi, M. . . . . . . . . . . O47, O147, P333 Miszkiel, K. A. . . . . . . . . . . . O102, P488 Mitosek-Szewczyk, K. . . . . . . . P580, P581 Modaressi, S. . . . . . . . . . . . . . . . . P251 Moggio, M. . . . . . . . . . . O43, O151, P410 Mohamad Ghazali, M. . . . . . . . . . . P255 Mohr, C. . . . . . . . . . . . . . . . . . . P610 Moiola, L. . . . . . . . . . . . . . . . . . P319 Mojarrad, M. . . . . . . . . . . . . P160, P464 Moldovan, M. . . . . . . . . . . . . . . . . O51 Molinuevo, J. L. . . . . . . . . . . . O86, O157 Moll, M. . . . . . . . . . . . . . . . . . . P196 Monaco, F. . . . . . . . . . . . . . . . . . P233 Moneger, G. . . . . . . . . . . . . . . . . P192 Moniz, J. C. . . . . . . . . . . . . . . . . . P578 Montagna, P. . . . . . . . . . . . . P533, P626 Montalban, X. . . . . . . O38, O42, O110, P406 Montanari, E. . . . . . . . . . . . . . . . P327 Monz, B. . . . . . . . . . . . . . . . P425, P426 Monza, D. . . . . . . . . . . . . . . . . . P228 Moon, H. S. . . . . . . . . . . . . . . . . . P262 Moonen, G. . . . . . . . . . . . . . . . . P497 Moosavi, A. R. . . . . . . . . . . . . . . . P224 Morales, C. . . . . . . . . . . . . . . . . . P627 Morán, J. C. . . . . . . . . . . . . . . . . P565 Moravcova, E. . . . . . . . . . . . . . . . P430 Morbin, M. . . . . . . . . . . . . . . . . . O43 Moreno, M. . . . . . . . . . . . . . . . . P194 Moreno, T. . . . . . . . . . . . . . . . . . P589

Moreno-Ramos, T. . . . . . . . . . . . . . P511 Morgan, P. . . . . . . . . . . . . . . . . . P355 Morier, J. . . . . . . . . . . . . . . P543, P612 Moro, A. . . . . . . . . . . . . . . . . . . P175 Moroney, J. . . . . . . . . . . . . . . O87, P475 Moschella, V. . . . . . . . . . . . . . . . . P201 Moser, A. . . . . . . . . . . . P183, P505, P506 Mostacero, E. . . . . . . . . . . . . P521, P522 Motamed, M. R. . . . . . . . . . . . . . . P330 Motamedi, M. . . . . . . . . . . . . . . . P251 Mrakic-Sposta, S. . . . . . . . . . . . . . P560 Mubrin, Z. . . . . . . . . . . . . . . . . . P461 Muelas, N. . . . . . . . . . . P197, P335, P374 Muench, C. . . . . . . . . . . . . . . . . . P479 Muhl, C. . . . . . . . . . . . . . . . . . . P289 Mukhtar, M. . . . . . . . . . . . . . . . . P214 Munch, C. . . . . . . . . . . . . . . P218, P383 Munerati, E. . . . . . . . . . . . . . . . . P275 Muñoz, E. . . . . . . . . . . . P185, P188, P305 Munschauer, F. E. . . . . . . . . . . . . . P321 Munteis, E. . . . . . . . . . . . . . . . . . P215 Murphy, S. . . . . . . . . . . . . . . O87, P475 Murri, L. . . . . . . . . . . . . . . . . . . O120 Murru, R. . . . . . . . . . . . . . . . . . P495 Murshid, N. . . . . . . . . . . . . . . . . P255 Muselimi, L. . . . . . . . . . . . . . . . . P338 Mustelier, R. . . . . . . . . . . . . . . . . P382 Myrianthopoulou, P. . . . . . . . . . . . P292 Nabavi, D. . . . . . . . . . . . . . . . . . O135 Nabavi, M. . . . . . . . . . . . . . . . . . P392 Naegele, T. . . . . . . . . . . . . . . . . . P309 Naegelin, Y. . . . . . . . . . . . . . . . . O105 Nagata, K. . . . . . . . . . . . . . . . . . P373 Naing, N. N. . . . . . . . . . . . . . . . . P254 Najimi, N. . . . . . . . . . . . . . . . . . P330 Nakamura, Y. . . . . . . . . . . . . . . . . P482 Napoli, L. . . . . . . . . . . . . . . . . . . P410 Nascimbeni, A. . . . . . . . . . . . . . . . O45 Nascimento, O. J. M. . . . . . . . . . O54, P331 Nasis, G. . . . . . . . . . . . . . . . . . . P449 Nassogne, M. . . . . . . . . . . . . . . . P460 Nau, R. . . . . . . . . . . . . . . . . . . . P210 Navacerrada, F. . . . . . . . . . . . . . . P366 Navarra, V. . . . . . . . . . . . . . . . . . P287 Nazari, M. . . . . . . . . . . . . . . . . . P251 Nebe, T. C. . . . . . . . . . . . . . . . . . P213 Nedelka, T. . . . . . . . . . . . . . . . . . P268 Nedeltchev, K. . . . . . . . . . . . . O79, P542 Nestrasˇil, I. . . . . . . . . . . . . . P177, P367 Neufeld, M. . . . . . . . . . . . . . . . . P290 Neuhaus, A. . . . . . . . . . . . . . . . . P229 Neuhauser, H. . . . . . . . . . . . . O67, O113 Neumann, K. . . . . . . . . . . . . . . . . O89 Neves, C. . . . . . . . . . . . . . . . . . . P249 Nevrly, M. . . . . . . . . . . . P208, P303, P367 Newman, J. . . . . . . . . . . . . . . . . . P203 Newman-Toker, D. . . . . . . . . . . . . P583 Ng, H. K. . . . . . . . . . . . . . . . . . . O74 Nguyen, D. K. . . . . . . . . . . . . . . . . O80 Nichelli, P. . . . . . . . . . . . . . . P356, P498 Nickolaichjuk, S. . . . . . . . . . . . . . . P607 Nicolao, P. . . . . . . . . . . . . . . . . . . O45 Nider, G. . . . . . . . . . . . . . . . . . . P513 Niederkorn, K. . . . . . . . . . . . . . . . P447 Niehaus, L. . . . . . . . . . . . . . . . . . P304 Nieswandt, B. . . . . . . . . . . . . . . . . O73 Niino, M. . . . . . . . . . . . . . . . . . . O109 Nikolakaki, E. . . . . . . . . . . . . P517, P568 Nikseresht, A. R. . . . . . . . . . . . . . . P224 Nilavari, K. . . . . . . . . . . . . . . . . . P512 Nirkko, A. C. . . . . . . . . . O153, P269, P423 Nisipeanu, P. . . . . . . . . . . . . . . . . O116 Nitka-Sieminska, A. . . . . . . . . P526, P527 Nitulescu, R. . . . . . . . . . . . . . . . . P377 Nobile-Orazio, E. . . . . . . . . . . O52, P344 Nociti, V. . . . . . . . . . . . P566, P575, P576 Nolan, C. . . . . . . . . . . . . . . . . . . P484 Nolan, J. . . . . . . . . . . . . . . . . . . P389

Nomiya, T. . . . . . . . . . . . . . . . . . O125 Nordmann, M. . . . . . . . . . . . . . . . P448 Nos, J. . . . . . . . . . . . . . . . . . . . P627 Nosal, V. . . . . . . . . . . . . . . . . . . . O77 Noulas, G. . . . . . . . . . . . . . . O145, P182 Novikova, T. . . . . . . . . . . . . . . . . P353 Nückel, M. . . . . . . . . . . . . . . . . . O70 Nurmikko, T. J. . . . . . . . . . . . . . . . P395 Nuzzaco, G. . . . . . . . . . . . . . P455, P536 Nyka, W. . . . . . . . . . . . . . . . P526, P527 Nyka, W. M. . . . . . . . . . . . . . . . . P548 O’Brien, J. . . . . . . . . . . . . . . . . . . O90 O’Connor, P. . . . . . . . . . P229, P403, P569 O’Neill, G. N. . . . . . . . . . . . . O108, P573 O’Rourke, K. . . . . . . . . . . . . . . . . P404 O’Toole, O. . . . . . . . . . . P387, P389, P484 Obach, V. . . . . . . . . . . . . . . . . . . P270 Obermaier, B. . . . . . . . . . . . . . . . P376 Obermann, M. . . . . . . . . . . . . . . . P561 Ochudlo, S. . . . . . . . . . . . . . P280, P358 Odier, C. . . . . . . . . . . . . . . . . . . . O80 Oger, J. . . . . . . . . . . . . . . . O109, P400 Ohlraun, S. . . . . . . . . . . . . . . . . . P383 Ohyama, T. . . . . . . . . . . . . . . . . O148 Ois, A. . . . . . . . . . . . . . . . . P350, P541 Ojango, C. . . . . . . . . . . . . . . . . . P355 Olanow, W. . . . . . . . . . . . . . . . . . P371 Olausson, H. . . . . . . . . . . . . . . . . O63 Olindo, S. . . . . . . . . . . . . . . . . . . P491 Oliveira, J. . . . . . . . . . . . . . . . . . P249 Olsson, T. . . . . . . . . . . . . . . . . . . O40 Omer, S. . . . . . . . . . . . . . . . . . . P459 Omesti, M. . . . . . . . . . . . . . . . . . O96 Ono, S. . . . . . . . . . . . . . . . . . . . P482 Onofrj, M. . . . . . . . . . . . . . . P471, P558 Opala, G. . . . . . . . . . . . P280, P358, P624 Opavsky, R. . . . . . . . . . . . . . P473, P550 Orbán-Kis, K. . . . . . . . . P263, P264, P265, P349, P534 Orgogozo, J-M. . . . . . . . . . . . . . . . . 29 Orhan, G. . . . . . . . . . . . . . . . . . . P308 Orlacchio, Aldo. . . . . . . . . . . . P201, P554 Orlacchio, Antonio. . . . . . . . . . P201, P554 Orr, H. . . . . . . . . . . . . . . . . . . . P199 Ortega-Casarrubios, M. A. . . . . . P158, P627 Ortler, M. . . . . . . . . . . . . . . . . . . O83 Ortu, E. . . . . . . . . . . . . . . . . . . . P386 Oschmann, P. . . . . . . . . . . . . . . . P219 Ossemann, M. . . . . . . . . . . . . . . . P460 Ostacoli, L. . . . . . . . . . . . . . . . . . P297 Oudkerk, M. . . . . . . . . . . . . . . . . P314 Özdemir Esmeli, F. . . . . . . . . . . . . P518 Ozdoba, C. . . . . . . . . . . . . . . . . . P312 Pabst, W. . . . . . . . . . . . . . . . . . . P219 Pace, A. . . . . . . . . . . . . . . . . . . . O96 Padua, L. . . . . . . . . . . . . . . . P437, P566 Pagani, E. . . . . . . . . . . . . . . O101, P485 Paiva, T. . . . . . . . . . . . . . . . . . . P622 Pal, S. . . . . . . . . . . . . . . . . . . . . O55 Palace, J. . . . . . . . . . . . . . . . O42, P502 Palao, S. . . . . . . . . . . . . . . . . . . P366 Palla, D. . . . . . . . . . . . . . . . . . . P371 Palmeri, B. . . . . . . . . . . . . . . . . . P329 Palomo, F. . . . . . . . . . . . . . . . . . P627 Paludi, M. . . . . . . . . . . . . . . . . . P470 Panagopoulos, G. . . . . . . . . . . . . . P181 Panagopoulou, M. . . . . . . . . . . . . . P449 Panczel, G. . . . . . . . . . . . . . . . . . P421 Pandolfo, M. . . . . . . . . . . . . . . . . P199 Panico, A. . . . . . . . . . . . . . . . . . P281 Panina, P. . . . . . . . . . . . . . . . . . . P202 Pantaleo, G. . . . . . . . . . . . . . . . . P211 Pantoni, L. . . . . . . . . . . . . . . . . . O90 Paolicchi, A. . . . . . . . . . . . . . . . . O120 Papachronopoulou, V. . . . . . . . . . . . P449 Papacostas, S. . . . . . . . . P276, P291, P292 Papadimas, G. . . . . . . . . . . . . . . . P417

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Papadimitriou, A. . . . . . . O145, O151, P182 Papadimitriou, G. . . . . . . . . . . . . . P302 Papadopoulos, K. . . . . . . . . . . . . . P242 Papadopoulou, M. . . . . . . . . . . . . . P163 Papagiannopoulos, S. . . . . . . . . . . . P178 Papaioakim, M. . . . . . . . . . . . . . . P546 Papakonstantinou, I. . . . . . . . . . . . O145 Papanastasiou, I. . . . . . . . . . . . . . P449 Papanicolaou, E. . . . . . . . . . . . . . . P424 Papapetropoulos, T. . . . . . . . . P412, P418 Papapostolou, A. . . . . . . . . . . . . . P163 Papastavrou, E. . . . . . . . . . . . . . . P276 Papatriantafyllou, J. . . . . . . . . . . . . P357 Papuc, E. . . . . . . . . . . . . . . . P580, P581 Pareyson, D. . . . . . . . . . . . . . O43, P437 Parisis, D. . . . . . . . . . . . . . . . . . P301 Park, J. K. . . . . . . . . . . . . . . . . . . P480 Park, K. H. . . . . . . . . . . . . . . . . . P616 Park, K. P. . . . . . . . . . . . . . . . . . P616 Park, S. K. . . . . . . . . . . . . . . . . . P216 Park, S. S. . . . . . . . . . . . . . . . . . . P438 Parman, Y. . . . . . . . . . . . . . . . . . O44 Parsi, H. . . . . . . . . . . . . . . . . . . P320 Partyka, D. . . . . . . . . . . . . . . . . . P381 Paschalidou, M. . . . . P237, P453, P472, P474 Pascu, I. . . . . . . . . . . . . . . . . . . P169 Pascual, L. F. . . . . . . . . . P515, P521, P618 Pashapour, A. . . . . . . . . . . . . . . . P524 Paspaltsis, I. . . . . . . . . . . . . . . . . P318 Pasquier, F. . . . . . . . . . . . . . . . . . O72 Pasquini, M. . . . . . . . . . . . . . . O68, O72 Pastore, V. . . . . . . . . . . . . . . . . . P604 Patanella, A. K. . . . . . . . . P566, P575, P576 Paterakis, K. . . . . . . . . . . . . . . . . P207 Patrono, C. . . . . . . . . . . . . . . . . . P201 Pauer, U. . . . . . . . . . . . . . . . . . . . O73 Paul, R. . . . . . . . . . . . . . . . . . . . P376 Paulauskaite, L. . . . . . . . . . . . . . . P509 Paunier-Doret, A. . . . . . . . . . . . . . P466 Pauza, V. . . . . . . . . . . . . . . . . . . P380 Pech, C. . . . . . . . . . . . . . . . . . . O126 Pels, H. . . . . . . . . . . . . . . . . . . . O95 Pengo, V. . . . . . . . . . . . . . . . . . . O78 Penkowa, M. . . . . . . . . . . . . . . . . P353 Pera, J. . . . . . . . . . . . . . . . . P164, P381 Peralta, J. . . . . . . . . . . . . . . P563, P564 Perego, L. . . . . . . . . . . . . . . P352, P361 Pereira, P. . . . . . . . . . . . . . . . . . P249 Pérez, C. . . . . . . . . . . . . . . . . . . P515 Pérez, D. . . . . . . . . . . . . . . . . . . P565 Pérez-Conde, C. . . . . . . . . . . . . . . P194 Pérez-Lorensu, P. J. . . . . . . . . . . . . P175 Perez-Martinez, D. A. . . . . . . . . . . . P364 Pérez-Miralles, F. . . . . . . . . . . . . . P335 Perini, M. . . . . . . . . . . . . . . O119, P485 Perli, A. . . . . . . . . . . . . . . . . . . . P244 Perren, F. . . . . . . . . . . . . . . . . . . O139 Perret, N. . . . . . . . . . . . . . . . . . . P593 Petelin, Z. . . . . . . . . . . . . . . . . . P476 Petereit, H. F. . . . . . . . . . . . . . . . . P487 Petrikonis, K. . . . . . . . . . . . . P509, P520 Petzold, A. . . . . . . . . . . O154, P165, P230 Pfister, H. W. . . . . . . . . . . . . . O93, P376 Phanthumchinda, K. . . . . . . . . . . . P510 Phukan, J. . . . . . . . . . . . . . . . . . P389 Piazza, S. . . . . . . . . . . . . . . . . . . O120 Picard, F. . . . . . . . . . . . . . . . O94, P296 Piccio, L. . . . . . . . . . . . . . . . . . . P202 Piccoli, F. . . . . . . . . . . . . . . . . . . P287 Piccoli, T. . . . . . . . . . . . . . . . . . . P287 Pichler, G. . . . . . . . . . . . . . . . . . P447 Pielen, A. . . . . . . . . . . . . . . . . . . P311 Pieri, V. . . . . . . . . . . . . . . . . . . . P253 Pilato, V. . . . . . . . . . . . . . . . . . . . O31 Pilo, B. . . . . . . . . . . . . . . . . . . . . O92 Pimentel, J. . . . . . . . . . . . . . . . . . P375 Pimentel, T. . . . . . . . . . . . . . . . . P274 Piñol, G. . . . . . . . . P515, P521, P522, P618 Piperidou, C. . . . . . . . . . . . . . . . . P546

Piperos, P. . . . . . . . . . . . . . . . . . P478 Pipieri, A. . . . . . . . . . . . P326, P394, P489 Pires-Barata, S. . . . . . . . . . . . . . . P578 Pittermann, P. . . . . . . . . . . . . . . . P457 Pizzolato, G. . . . . . . . . . . . . . P328, P513 Plant, G. T. . . . . . . . . . . . . . O102, P488 Planté-Bordeneuve, V. . . . . . O46, O47, O48, O147, P333, P427 Pniewski, J. . . . . . . . . . . . . . . . . . O69 Poggi, A. . . . . . . . . . . . . . . . . . . O129 Poglia, D. . . . . . . . . . . . . . . . . . O139 Pohl, C. . . . . . . . . . . . . . . . O110, P406 Politi, A. . . . . . . . . . . . . . . . . . . P338 Polli, E. . . . . . . . . . . . . . . . . . . . P507 Pollo, C. . . . . . . . . . . . . . . . . . . P211 Polman, C. H. . . . . . . . . . O38, O42, O108, O110, P406, P569, P573 Polo, J. M. . . . . . . . . . . . . . . . . . O156 Polwart, A. . . . . . . . . . . . . . . . . . P315 Polychronopoulos, P. . . . . . . . . . . . P535 Pompella, A. . . . . . . . . . . . . . . . . O120 Poniatowska, R. . . . . . . . . . . . . . . P362 Pont-Sunyer, C. . . . . . . . . P215, P350, P541 Ponz, A. . . . . . . . . . . . . . . . . . . P621 Popovic, M. R. . . . . . . . . . . . . . . . P598 Popoviciu, D. . . . . . . . . . . . . . . . . P293 Popp, B. . . . . . . . . . . . . . . . . . . P376 Porta-Etessam, J. . . . . . . . . . . . . . P364 Poryazova, R. . . . . . . . . . P528, P619, P621 Postelnicu, A. . . . . . . . . . . . . . . . P169 Poulletier de Gannes, F. . . . . . . . . . . P465 Poyraz, M. . . . . . . . . . . . . . . . . . O44 Prang, P. . . . . . . . . . . . . . . . . . . P217 Prehn, J. . . . . . . . . . . . . . . . . . . P384 Prella, M. . . . . . . . . . . . . . . . . . . P211 Prelle, A. . . . . . . . . . . . . . . O119, P410 Price, M. . . . . . . . . . . . . . . . . . . O109 Priller, J. . . . . . . . . . . . . . . . . . . P210 Prinsen, T. J. . . . . . . . . . . . . . . . . O133 Prinz, M. . . . . . . . . . . . . . . . . . . P210 Priori, A. . . . . . . . . . . . . . . . . . . P560 Prochazkova, L. . . . . . . . . . . . . . . P396 Prod’homme, T. . . . . . . . . . . . P223, P405 Pruissen, D. M. O. . . . . . . . . . . . . . O133 Psaras, R. M. . . . . . . . . . . . . . . . . P449 Puchner, C. . . . . . . . . . . . . . . . . . P176 Puente-Muñoz, A. I. . . . . . . . . . . . . P364 Pugnaghi, M. . . . . . . . . . . . . . . . . P429 Pulizzi, A. . . . . . . . . . . . . . . . O37, O41 Puz, P. . . . . . . . . . . . . . . . . . . . P261 Pye, E. . . . . . . . . . . . . . . . . . . . P315 Quadros, C. . . . . . . . . . . . . . . . . O104 Quattrone, A. . . . . . . . . . . . . . . . P437 Quilici, S. . . . . . . . . . . . . . . . . . . P426 Rackova, Z. . . . . . . . . . . . . . . . . . P559 Radaelli, M. . . . . . . . . . . . . . . . . P319 Rados, M. . . . . . . . . . . . . . . . . . P436 Radtke, A. . . . . . . . . . . . . . . O67, O113 Radue, E.-W. . . . . . . . . . . . . . . . . O105 Ragé, M. . . . . . . . . . . . . . . . . . . P460 Ragonese, P. . . . . . . . . . . . . . . . . P329 Rahmat, M. . . . . . . . . . . . . . . . . P512 Raman, A. . . . . . . . . . . . . . . . . . P239 Rambold, H. . . . . . . . . . . . . . . . . O114 Rami, L. . . . . . . . . . . . . . . . . . . . O86 Rangel-Guerra, A. . . . . . . . . . . . . . P172 Rascheva, M. . . . . . . . . . . . . . . . . P298 Rashid, W. . . . . . . . . . . . O35, O100, P492 Rasiah, C. . . . . . . . . . . . O97, P238, P468 Rauer, S. . . . . . O97, P238, P317, P468, P487 Ray, P. S. . . . . . . . . . . . . . . . . . . O144 Reale, M. . . . . . . . . . . . . . . . . . . P471 Recla, M. . . . . . . . . . . . . . . . . . . P604 Reder, A. . . . . . . . . . . . . . . . . . . P401 Rees, J. . . . . . . . . . . . . . . . . . . . . O98 Reichel, G. . . . . . . . . . . . . . . P189, P434 Reichhart, M. D. . . . . . . . . . . . . . 4, P211

Reichmann, H. . . . . . . . . . . . . . . . O95 Reime, U. . . . . . . . . . . . . . . . . . . P599 Reinhardt, M. . . . . . . . . . . . . . . . . O39 Reis, C. . . . . . . . . . . . . . . . . . . . P258 Rejdak, K. . . . . . . . . . . . . . . . . . P230 Rektor, I. . . . . . . . . . . . . . . O108, P573 Relja, G. . . . . . . . . . . . . . . . . . . P513 Relja, M. . . . . . . . . . . . . . . . . . . P557 Remonda, L. . . . . . . . . . . . . . P312, P542 Renaud, S. . . . . . . . . . . . . . . O50, P343 Renne, T. . . . . . . . . . . . . . . . . . . O73 Ressner, P. . . . . . . . . . . . . . . P208, P367 Rettinger, N. . . . . . . . . . . . . . . . . P584 Retzlaff, K. . . . . . . . . . . . . . . . . . P219 Reuß, R. . . . . . . . . . . . . . . . . . . P219 Rey, M. J. . . . . . . . . . . . . . . . . . . O157 Rhodes, S. . . . . . . . . . . . . . . . . . O109 Ribeiro, O. . . . . . . . . . . . . . . . . . P446 Ricci, Alessandra . . . . . . . . . . . . . . P327 Ricci, Antonio . . . . . . . . . . . . . . . . P394 Rice, G. . . . . . . . . . . . . . . . . . . . P502 Richard, C. . . . . . . . . . . . . . . . . . P284 Richter, B. . . . . . . . . . . . . . . . . . P286 Richter, R. . . . . . . . . . . . . . . . . . P286 Rieckmann, P. . . . . . . . . P232, P391, P397 Riether, F. . . . . . . . . . . . . . . P267, P463 Ringelstein, B. . . . . . . . . . . . . . . . O135 Rinkel, G. J. E. . . . . . . . . . . . . . . . . O75 Rinkin, C. . . . . . . . . . . . . . . . . . P497 Ripolone, M. . . . . . . . . . . . . . . . . O43 Riva, M. . . . . . . . . . . . . . . . . . . P273 Riva, N. . . . . . . . . . . . . . . . . . . . P275 Rizki, G. . . . . . . . . . . . . . . . . . . P481 Rizzuto, N. . . . . . . . . . . . . . . . . . P437 Röbke, M. . . . . . . . . . . . . . . . . . P173 Robotti, M. . . . . . . . . . . . . . . . . . P499 Rocca, M. . . . . . . . . . . . . O32, O34, P319 Rodegher, M. E. . . . . . . . . . . . O31, P319 Rodiger, L. . . . . . . . . . . . . . . . . . P314 Rodríguez-Albariño, A. . . . . . . . . . . P627 Rodriguez-Campello, A. . . . P215, P350, P541 Rodríguez-de-Rivera, F. . . . . . . . . . . P194 Rodriguez-Espinosa, N. . . . . . . . . . . P175 Rodríguez-Gallego, M. . . . . . . . P563, P564 Rodriguez-Rodriguez, E. . . . . . O146, O156 Roehl, M. . . . . . . . . . . . . . . . . . . P610 Roelcke, U. . . . . . . . . . . . . . P234, P235 Roether, J. . . . . . . . . . . . . . . . . . O135 Rog, D. J. . . . . . . . . . . . . . . . . . . P395 Roig, S. . . . . . . . . . . . . . . . . . . . P197 Rolfs, A. . . . . . . . . . . . . . . . . . . O114 Rolke, R. . . . . . . . . . . . . . . . O64, P457 Romano, S. . . . . . . . . . . . . . . . . O149 Romei, M. . . . . . . . . . . . . . . . . . P600 Ron, M. A. . . . . . . . . . . . . . . . . . . O35 Ronchi, D. . . . . . . . . . . . . . . . . . O151 Rondena, F. . . . . . . . . . . . . . . . . P600 Roquer, J. . . . . . . . . . . . P215, P350, P541 Rosas, M. J. . . . . . . . . . . . . . P249, P258 Rosche, B. . . . . . . . . . . . . . . . . . P407 Rosenmann, H. . . . . . . . . . . . . . . P203 Roser, F. . . . . . . . . . . . . P267, P309, P463 Rösler, K. M. . . . . . . O53, O152, O153, P316 Rossor, M. . . . . . . . . . . . . . . . . . O154 Rostami, P. . . . . . . . . . . . . . . . . . P563 Rothen, H. U. . . . . . . . . . . . . . . . . P312 Rotondo, G. . . . . . . . . . . . . . . . . O150 Roumenov, D. . . . . . . . . . . . . . . . P296 Rousseaux, M. . . . . . . . . . O72, O76, P284, P285, P445 Roux-Lombard, P. . . . . . . . . . . . . . P409 Rovaris, M. . . . . . . . . . . . O37, O38, O41, O101, P273, P570 Rovera, A. . . . . . . . . . . . P297, P394, P489 Rovira, A. . . . . . . . . . . . . . . . O38, O42 Rowbotham, D. . . . . . . . . P190, P191, P431 Rozsa, C. . . . . . . . . . . . . . . . . . . P421 Rudà, R. . . . . . . . . . . . . . . . . O96, O99 Ruegg, D. . . . . . . . . . . . . . . . . . . P593

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Schaeren-Wiemers, N. . . . . . . . . . . . O50 Schäfer, G. . . . . . . . . . . . . . . . . . O127 Schaller, A. . . . . . . . . . . . . . . . . . O152 Schaller, C. . . . . . . . . . . . . . . . . . O95 Scheltens, P. . . . . . . . . . . . . . . . . . O90 Schenone, A. . . . . . . . . . . . . . . . . P437 Schenpf, B. . . . . . . . . . . . . . . . . . P619 Scherer, R. . . . . . . . . . . . . . . P602, P603 Schestatsky, P. . . . . . . . . . . . . . . . P179 Schim, J. . . . . . . . . . . . . . . . . . . P615 Schiopu, M. . . . . . . . . . . . . . . . . P293 Schlegel, U. . . . . . . . . . . . . . . . . . O95 Schlereth, T. . . . . . . . . . . . . . . . . P433 Schlindwein, P. . . . . . . . O115, O130, P174 Schluep, M. . . . . . . . . . . . . . . . . P574 Schmidt, C. . . . . . . . . . . . . . . . . . O93 Schmidt, H. . . . . . . . . . . . . . . . . P210 Schmidt-Wolf, I. G. H. . . . . . . . . . . . O95 Schmierer, K. . . . . . . . . . . . . . . . O108 Schneider, G. H. . . . . . . . . . . . . . . P184 Schneider, J. . . . . . . . . . . . . . . . . P189 Schneider, R. . . . . . . . . . . . . . . . . P317 Schott, B. . . . . . . . . . . . . . . . . . . P304 Schranz, S. . . . . . . . . . . . . . . . . . P457 Schreckenberger, M. . . . . . . . . . O36, P288 Schreiber, V. . . . . . . . . . . . . . . . . P219 Schröder, M. . . . . . . . . . . . . . . . . P217 Schroth, G. . . . . . . . . . . . O79, P312, P542 Schulte-Altedorneburg, G. . . . . . . . . P585 Schulte-Mattler, W. . . . . . . . . . O58, P176 Schulz, D. . . . . . . . . . . . . . . . . . . P500 Schulz, H. . . . . . . . . . . . . . . . . . . O95 Schumann, R. R. . . . . . . . . . . . . . . P407 Schwab, S. . . . . . . . . . . . . . . . . . . O70 Schwartz, S. . . . . . . . . . . . . . . . . P621 Schwarze, J. J. . . . . . . . . . . . . . . . P443 Schwegler, G. . . . . . . . . . . . . . . . . O53 Schweikert, K. . . . . . . . . . . . . . . . P606 Scibor, M. . . . . . . . . . . . . . . . . . . O70 Sciupokas, A. . . . . . . . . . . . . . . . P520 Scola, R. H. . . . . . . . P369, P413, P414, P415 Scotti, G. . . . . . . . . . . . . . . . . . . O34 Scutaru, A. M. . . . . . . . . . . . . . . . P590 äebesta, P. . . . . . . . . . . . . . . . . . P523 Seewald, B. . . . . . . . . . . . . . . . . . P433 Seewann, A. . . . . . . . . . . . . . . . . . O42 Segev, Y. . . . . . . . . . . . . . . . . . . P247 Segura, N. . . . . . . . . . . . P215, P350, P541 Seidel, E. . . . . . . . . . . . . . . . . . . P289 Seidl, Z. . . . . . . . . . . . . . . . O107, P227 Seifried, C. . . . . . . . . . . . . . . . . . O131 Selekler, K. . . . . . . . . . . . . . . . . . P283 Selekler, M. . . . . . . . . . . . . . . . . P613 Seltenreichová, K. . . . . . . . . . . . . . P544 Senol, M. . . . . . . . . . . . . . . . . . . P277 Sepien, A. . . . . . . . . . . . . . . . . . P531 Serdaroglu, P. . . . . . . . . . . . . . . . . O44 Servent, D. . . . . . . . . . . . . . . . . . P296 Sessa, M. . . . . . . . . . . . . . . . P455, P536 Shakarishvili, R. . . . . . . . . . . . . . . O142 Shanahan, P. . . . . . . . . . . . . . . . . P459 Shariatpanahi, V. . . . . . . . . . . . . . P392 Shaygannejad, V. . . . . . . . . . . P300, P572 Sheehan, C. . . . . . . . . . . . . . . . . P387 Sheikh, K. A. . . . . . . . . . . . . . . . . O49 Shi, F. . . . . . . . . . . . . . . . . . . . . O109 Shigidi, M. . . . . . . . . . . . . . . . . . P214 Shimamura, M. . . . . . . . . . . . . . . O125 Shirabe, S. . . . . . . . . . . . . . . . . . P378 Shirzadi, M. . . . . . . . . . . . . . . . . P159 Shon, E. J. . . . . . . . . . . . . . . . . . P348 Siccoli, M. M. . . . . . . . . . . . . O134, P529 Siciliano, G. . . . . . . . . . . . . . . . . O120 Sidiropoulou, E. . . . . . . . . . . . P472, P474 Sieminski, M. . . . . . . . . . . . . P526, P527 Sienkiewicz-Jarosz, H. . . . . . . . O69, P362 Signate, A. . . . . . . . . . . . . . . . . . P491 Silani, V. . . . . . . . . . . . . . . . . . . P507 Silva, F. C. . . . . . . . . . . . . . . . . . P444

Silvani, A. . . . . . . . . . . . . . . . . . . O96 Simioni, S. . . . . . . . . . . . . . . . . . P574 Simon, D. . . . . . . . . . . . . . . . . . . P426 Simpson, E. P. . . . . . . . . . . . . . . . O117 Sinanovic, O. . . . . . . . . . . . . . . . . P266 Singhal, S. . . . . . . . . . . . . . . . . . P355 Singleton, A. . . . . . . . . . . . . O145, P182 Sinicina, I. . . . . . . . . . . . . . . . . . O91 Sirbu, C. A. . . . . . . . . . . . . . . . . . P377 Sirbu, O. . . . . . . . . . . . . . . . . . . P377 Sirca, A. . . . . . . . . . . . . . . . . . . P496 Sirch, J. . . . . . . . . . . . . . . . . . . . P195 Sisak, E. . . . . . . . . . . . . . . . . . . P590 Sisak, S. . . . . . . . . . . . . . . . . . . P590 Siuda, J. . . . . . . . . . . . . . . . P280, P358 Sivakumar, R. M. . . . . . . . . . . . . . P551 Sixt, C. . . . . . . . . . . . . . . . . P267, P463 Sklaviadis, T. . . . . . . . . . . . . . . . . P318 Skoloudik, D. . . . . . . . . . . . . . . . . O56 Slama, M. . . . . . . . . . . . . . . . . . P333 Slotboom, J. . . . . . . . . . O153, P312, P423 Slowik, A. . . . . . . . . . . . . . . P164, P381 Smadja, D. . . . . . . . . . . . . . . . . . P491 Smajlovic, D. . . . . . . . . . . . . . . . . P266 Smilowski, M. . . . . . . . . . . . . P280, P624 Smith, T. . . . . . . . . . . . . . . . . . . P504 Soelberg-Sørensen, P. . . . . . . . P391, P397 Soffietti, R. . . . . . . . . . . . . . . O96, O99 Sohn, S-I. . . . . . . . . . . . . . . . . . . P539 Sokrab, T-E. . . . . . . . . . . . . . . . . P214 Sola, P. . . . . . . . . . . . . . . . . . . . P498 Solari, A. . . . . . . . . . . . . . . . . . . P437 Soligo, D. . . . . . . . . . . . . . . . . . . P507 Solla, M. . . . . . . . . . . . . . . . . . . P495 Solla, P. . . . . . . . . . . . . . . . . . . . P496 Sommer, C. . . . . . . . . . . . . . . O64, P430 Sommerauer, B. . . . . . . . . . . . . . . P397 Song, D. K. . . . . . . . . . . . . . . . . . P483 Sˇonka, K. . . . . . . . . . . . . . . . . . . P523 Sˇonkova, Z. . . . . . . . . . . . . . P523, P544 Sormani, M. P. . . . . . . . . . . . . O37, O101 Sottini, A. . . . . . . . . . . . . . . . . . P228 Soulaeva, E. . . . . . . . . . . . . . . . . P420 Sousa, L. . . . . . . . . . . . . . . . . . . P246 Sovova, E. . . . . . . . . . . . . . . . . . P550 Spanos, G. P. . . . . . . . . . . . . . P442, P611 Spengos, K. . . . . . . . . . P163, P259, P260, P302, P417 Spengos, M. . . . . . . . . . . . . . . . . P302 Spinazzi, M. . . . . . . . . . . . . . O45, P310 Spinelli, M. . . . . . . . . . . . . . P455, P536 Sprenger, A. . . . . . . . . . . . . . . . . O114 Sprenger, T. . . . . . . . . . . . . . . . . P419 Srekopytov, S. . . . . . . . . . . . . . . . P315 Srinivasaraghavan, B. . . . . . . . O111, P221 Stam, J. . . . . . . . . . . . . . . . . . . . O71 Stanimirovic, D. . . . . . . . . . . . . . . P609 Stapf, C. . . . . . . . . . . . . . . . . . . O138 Staszewski, J. . . . . . . . . . P166, P167, P531 Steck, A. J. . . . . . . . . . . . O50, P340, P343, P346, P347, P385, P606 Steinborn, B. . . . . . . . . . . . . . . . . P296 Steinkamp, M. . . . . . . . . . . . . P505, P506 Steinke, R. . . . . . . . . . . . . . . . . . P304 Steinman, L. . . . . . . . . . . . . O109, P405 Stelmasiak, Z. . . . . . . . . P230, P580, P581 Stenner, A. . . . . . . . . . . . . . . . . . P434 Stephan, T. . . . . . . . . . . . . . P585, P591 Stepien, A. . . . . . . . . . . . . . . P166, P167 Sterlicchio, M. . . . . . . . . . . . . . . . P420 Stern, E. . . . . . . . . . . . . . . . . . . . O81 Sternic, N. . . . . . . . . . . . . . . . . . P609 Stewart, H. . . . . . . . . . . . . . . . . . O116 Stich, O. . . . . . . . . . . . . . . . P238, P468 Stocchi, F. . . . . . . . . . . . . . . . . . P371 Stocker, R. . . . . . . . . . . . . . . . . . P623 Stoeter, P. . . . . . . . . . . . . . . . . . . P174 Stoll, G. . . . . . . . . . . . . . . . . . . . O73 Stone, M. J. . . . . . . . . . . . . . . . . . P577

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Storch, M. K. . . . . . . . . . . . . . . . . O40 Straffi, L. . . . . . . . . . . . . . . . . . . O128 Strange, R. C. . . . . . . . . . . . . . . . P198 Strazzer, S. . . . . . . . . . . . . . . P596, P604 Stromillo, M. L. . . . . . . . . . . . . . . O103 Strupp, M. . . . . . . . O91, O112, P582, P583, P584, P585, P586, P591 Stueve, O. . . . . . . . . . . . . . . . . . P223 Sturzenegger, M. . . . . . . . . . . . . . . O53 Suhr, O. . . . . . . . . . . . . . . . . . . O147 Summers, M. . . . . . . . . . . . . . . . . O35 Sunami, K. . . . . . . . . . . . . . . . . . O91 Suozzi, R. . . . . . . . . . . . . . . . . . . P432 Surzsha, T. . . . . . . . . . . . . . . . . . P607 Sutter, R. . . . . . . . . . . . . . . . P340, P346 Suzuki, M. . . . . . . . . . . . . . . P336, P482 Suzuki, Y. . . . . . . . . . . . . . . . . . O125 Svátova, K. . . . . . . . . . . . . . . . . . P523 Svyshchenko, E. . . . . . . . . . . . . . . P351 Swanton, J. K. . . . . . . . . . . . . O102, P488 Swiat, M. . . . . . . . . . . . . . . . . . . P280 Swistak, J. . . . . . . . . . . . . . . . . . P166 Symms, M. . . . . . . . . . . . . . . . . . P295 Szász, J. A. . . . . . . . . . . P263, P264, P265, P349, P534 Szatmári, S. . . . . . . . . . P263, P264, P265, P349, P534 Szczudlik, A. . . . . . . . . . . . . P164, P381 Szekeres, C. C. . . . . . . . . . . . . P263, P265 Szocs, I. . . . . . . . . . . . P263, P264, P265, P349, P534 Sztajzel, R. . . . . . . . . . . . . . . . . . O139 Tai, K. . . . . . . . . . . . . . P190, P191, P431 Takahashi, T. . . . . . . . . . . . . . . . O125 Takala, J. . . . . . . . . . . . . . . . . . . P312 Takashima, S. . . . . . . . . . . . . . . . P555 Tambasco, N. . . . . . . . . . . . . . . . P307 Tamma, F. . . . . . . . . . . . . . . . . . P560 Tan, E. . . . . . . . . . . . . . . . . . . . P283 Tanridag, O. . . . . . . . . . . . . . . . . P277 Taroni, F. . . . . . . . . . . . . . . . O43, O149 Tasiou, A. . . . . . . . . . . . . . . . . . . P207 Taskos, N. . . . . . . . . . . . . . . P250, P519 Tassone, G. . . . . . . . . . . . . . P390, P429 Tatagiba, M. . . . . . . . . . P267, P309, P463 Taurah, L. . . . . . . . . . . . . . . . . . . O55 Tavella, A. . . . . . . . . . . . . . . . . . P489 Tavolato, B. . . . . . . . . . . . O45, O78, P310 Teive, H. A. G. . . . . . . . . . . . . . . . P369 Tekeli, H. . . . . . . . . . . . . . . . . . . P277 Tekwe, C. I. . . . . . . O107, P222, P226, P227 Terenghi, F. . . . . . . . . . . . . . . O52, P344 Terrazas, J. . . . . . . . . . . . . . . . . . O146 Terzoudi, A. . . . . . . . . . . . . . . . . P546 Thaler, D. . . . . . . . . . . . . . . . . . . P447 Tharakan, J. . . . . . . . . . . . . . P254, P255 Theil, D. . . . . . . . . . . . . . . . . . . . O91 Thoeni, A. . . . . . . . . . . . . . . . . . O105 Thomas, A. . . . . . . . . . . . . . P471, P558 Thompson, A. J. . . . . . . . . O33, O38, O42, O100, O102, P488 Thompson, E. . . . . . . . . . . . . . . . P165 Thrasher, A. T. . . . . . . . . . . . . . . . P598 Thümen, A. . . . . . . . . . . . . . . . . P183 Tichelli, A. . . . . . . . . . . . . . . . . . P340 Tinazzi, M. . . . . . . . . . . . . . . . . . O57 Tintoré Subirana, M. . . . . . . . . O42, P502 Tiribuzi, R. . . . . . . . . . . . . . . . . . P554 Tiriticco, M. . . . . . . . . . . . . . P352, P361 Todeschini, A. . . . . . . . . . . . . . . . P209 Tofts, P. . . . . . . . . . . . . . . . . . . . O98 Togha, M. . . . . . . . . . . . . . . . . . P512 Togrol, R. . . . . . . . . . . . . . . . . . . P277 Toledano, R. . . . . . . . . . . . . . O92, P366 Tolnay, M. . . . . . . . . . . . O50, P343, P606 Tolosa, E. . . . . . . . . . . . O157, P185, P188 Tomik, B. . . . . . . . . . . . . . . . . . . P381 Tomlinson, G. . . . . . . . . . . . . . . . P547

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Werhahn, K. . . Wermer, M. J. H. Werneck, L. C. . Werth, E. . . . .

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