J Neurol (1998) 245 : 335–504 © Springer-Verlag 1998

ABSTRACTS

8th Meeting and 10th Anniversary of the European Neurological Society, June 6–10, 1998, Nice, France Abstracts of Symposia, Free Communications and Posters

The abstracts have been reviewed by: T. Brandt, J. Berciano, S. DiDonato, D. A. S. Compston, C. Kennard, A. Steck, H.-P. Hartung, E. Tolosa, J. Van Gijn, D. Leys, J. Bogousslavsky, C. Krarup, H. Kwiecinski, F. G. A. Van der Meché, G. Said

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Contents Abstracts of the Symposia

Clinical Neurophysiology 367 Muscle Disorders (1) 368 Multiple Sclerosis (2) 369 Multiple Sclerosis (3) 370

Presidental Symposium: Vertigo and Vestibular Disorders Neurology of the Vestibulo-Ocular Reflex 337 Vestibular Cortex: Its Locations, Functions and Disorders 337 Cortical Control of Eye Movements 337 Three-Dimensional Analysis of Ocular Motor and Vestibular Dysfunction 337

Wednesday Cerebrovascular Disorders (5) 372 Functional Neuroimaging 373 Infection of the Nervous System 374 Pain and Migraine 376 Extrapyramidal Disorders (4) 377 Epilepsy 378 Neuro-Oncology (1) 379 Neuro-Oncology (2) 380 Muscle Disorders (2) 381 Muscle Disorders (3) 382 Multiple Sclerosis (4) 383 Multiple Sclerosis (5) 385

Symposium 2: Mitochondriopathies Clinical and Biological Aspects of Mitochondrial Encephalomyopathies 338 Anita Harding Lecture. Mitochondrodriopathies: Nuclear Gene Defects 338 Management of Patients with Mitochondrial Disease 339 Mitochondrial Diseases of Man and Mouse 339 Symposium 3: Paraneoplastic Neuromuscular Disorders Paraneoplastic Neurological Disorders (PND): Clinical-Immunological Correlations 339 Paraneoplastic Peripheral Neuropathies 340 Paraneoplastic Channelopathies: Models for Cancer-Provoked Autoimmunity? 340 Management of Paraneoplastic Neuromuscular Syndromes 340 Symposium 4: The Clinical Problems of Brain Repair Growth Factors and Development of the Central Nervous System Gene Therapy Based Delivery of Neurotrophic Factors for the Treatment of Neurodegenerative Diseases 341 Neuron-Glia Interactions in the Injured PNS and CNS 342 The Neurobiology of Peripheral Nerve Regeneration 342 Symposium 5: Memory Disturbances The Functional Anatomy of Human Memory Memory and Event-Related Potentials 343 Memory and Pharmacology 343 Memory and Psychopharmacology 343

Abstracts for Poster Sessions

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Monday Abstracts for Oral Sessions Cerebrospinal Disorders (1) 343 Cerebrovascular Disorders (2) 345 Amyotrophic Lateral Sclerosis – Motor Neuron Disease (1) Amyotrophic Lateral Sclerosis – Motor Neuron Disease (2) Genetics of Ataxias 348 Extrapyramidal Disorders (1) 349 Child Neurology 350 Peripheral Neuropathy (1) 351 Higher Functions Disorders (1) 353 Higher Functions Disorders (2) 354 Immunology 355 Multiple Sclerosis (1) 356 Cerebrovascular Disorders (3) 357 Cerebrovascular Disorders (4) 358

Tuesday General Neurology (1) 360 General Neurology (2) 361 Extrapyramidal Disorders (2) 362 Extrapyramidal Disorders (3) 363 Peripheral Neuropathy (2) 364 Peripheral Neuropathy (3) 366

A4

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Poster Session 1 Epilepsy 386 Child Neurology 391 Higher Functions Disorders 394 Motor Neuron Disease 401 Sleep Disorders 404 Extrapyramidal Disorders 405 Poster Session 2 Genetics 408 Immunology 412 Multiple Sclerosis 418 Muscle Disorders 422 Neurobiology 426 Cerebrovascular Disorders

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Poster Session 3 Cerebrovascular Disorders 431 Infection of the Nervous System 434 Motor Neuron Disease 437 Multiple Sclerosis 439 Peripheral Neuropathy 447 Cerebrovascular Disorders 450 Poster Session 4 Cerebrovascular Disorders (1) 452 Extrapyramidal Disorders 454 History of Neurology 456 Multiple Sclerosis 457 Neuro-Oncology 460 Neuro-Ophthalmology 462 Pain and Headache 463 Peripheral Neuropathy 465 Clinical Neurophysiology 468 Cerebrovascular Disorders (2) 470 Poster Session 5 Cerebrovascular Disorders 472 Extrapyramidal Disorders 475 General Neurology 479 Higher Functions Disorders 486 Neuro-Oncology 487 Peripheral Neuropathy 489 Clinical Neurophysiology 490

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Presidental Symposium: Vertigo and Vestibular Disorders Chair: Thomas Brandt, Munich Neurology of the Vestibulo-Ocular Reflex J. Leigh, Case Western Reserve University, Cleveland, Ohio, USA Neurologist concepts of the vestibulo-ocular reflex (VOR) have largely been fashioned by the two commonest settings in which they are called upon to test reflex; in the investigation of the complaint of dizziness, and as part of the examination of the unconscious patient. Often, the purpose of the VOR during natural activities is overlooked. The VOR generates eye rotations to compensate for head movements, so that the line of sight can be held on an object of interest. Knowledge of certain fundamental properties of the VOR will help to guide the examination: when the head is stationary, there is spontaneous neuronal activity (“vestibular tone”); simulation of any semicircular canal (SCC) will induce eye rotations in the plane of that canal; the VOR acts at short latency; during natural activities, such as locomotion, inputs from the SCC, otoliths and vision are used to guarantee clear vision and study posture; under some circumstances, the VOR must be negated in order for vision of an object to remain clear. Thus, disease affecting one labyrinth causes an imbalance of vestibular tone that the brain misinterprets as self-rotation or tilt. The direction of nystagmus will be related to vector sum of SCC involved. An ocular tilt reaction consisting of skew deviation, head tilt, ocular cyclotorsion, and deviation of the subjective visual vertical reflects an imbalance of otolithic inputs. Patients who have bilateral loss of their vestibular sense complain of impaired vision while they are in motion. This is because each football produces high-frequency head perturbations and the VOR, which acts as short latency (< 15 msec) can generate eye movements to compensate for these head movements but visually generated eye movements, which act a latency of > 70 msec, cannot. This difference in latencies can be used to test the VOR at the bedside. During locomotion, eye movements must be generated to compensate for translational head movements if we view an object located nearby, on side of our direction of movement. Thus, during natural activities, the brain must use inputs from the SCC, otoliths and visual stimuli (including the optic flow) to generate eye movements that will ensure clear vision of the environment; such an integrative process may be affected by a variety of central disorders. Finally, when we view a “headfixed” visual display while we are in motion (e.g., reading while walking), then vestibular eye movements must be negates so that vision remains clear; patients who have lost their vestibular sense perform better than normal subjects in this task. Thus, application of tests bases on how the VOR performs during natural activities provides insights into how a variety of neurological disorders disrupt vision and equilibrium in everyday life.

Vestibular Cortex: Its Locations, Functions and Disorders Thomas Brandt, Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany Animal studies have identified several distinct and separate areas of the parietal and temporal cortices which receive vestibular afferents, such as area 2 v at the tip of the intraparietal sulcus, area 3 aV in the central sulcus, the parietoinsular vestibular cortex at the posterior end of the insula, and area 7 in the inferior parietal lobule. Not only do these areas receive bilateral vestibular input from the vestibular nuclei, but they in turn directly project down to the vestibular nuclei. Thus, corticofugal feedback may modulate vestibular brainstem function. The two major cortical functions of the vestibular system are spatial orientation and selfmotion perception. These functions, however, are not specifically vestibular, they also rely on visual and somatosensory input. All three systems – vestibular, visual, and somatosensory provide us with redundant information about the position and motion of our body relative to the external space. Although the vestibular cortex function is distributed among several multisensory areas in the parietal and temporal cortices, it is also integrated in a larger network for spatial attention and sensorimotor control of eye and body motion in space. The analysis of vestibular cortex function must concentrate on how the system successfully integrates multisensory input into a unique perception and how it uses this information for accurate motor performance in space. Neurological syndromes with cortical vertigo include paroxysmal excitation (vestibular epilepsy, room-tilt illusion) or lesional dysfunction (tilt of perceived vertical with lateropulsion, spatial hemineglect). Our knowledge about vestibular cortex function in human is derived mainly from stimulation experiments reported anecdotally in the older lit-

erature and from recent brain activation studies with PET and WRI. The human homologue of the parieto-insular vestibular cortex can be activated by optokinetic stimulation and galvanic vestibular stimulation of the otolithic and semicircular canal input. In PET activation studies a deactivation of the human visual cortex was found during caloric stimulation of the vestibular cortex. With visual motion stimulation that elicits apparent self-motion (vection) the parietoinsular vestibular cortex was inhibited. This finding supports a new functional interpretation: Reciprocal inhibitory visualvestibular interaction as a sensorimotor mechanism that protects visual perception of selfmotion from potential vestibular mismatches caused by involuntary head accelerations during locomotion. This mechanism allows the dominant sensorial weight during selfmotion perception to shift from one sensory modality to the other.

Cortical Control of Eye Movements Charles Pierrot-Deseilligny, Hôpital de la Salpêtrière, Paris Eye movements include ocular saccades, ocular smooth pursuit, the vestibular ocular reflex (VOR) and convergence. Saccades allow a new image to be caught on the fovea and may be intentional (internally triggered) or reflexive (externally triggered towards a suddenly appearing target). Smooth pursuit allows the moving image of a small target to be maintained on the fovea (foveal pursuit) or of the whole visual field to be immobilised on the retina (eliciting optokinetic nystagmus). The VOR compensates body movements and convergence is required for near vision. All these eye movements are controlled by a number of cortical areas, which are connected via subcortical regions to brainstem structures, where the movements are actually generated. In humans, this cortical control may be studied using three main methods providing complementary information: functional imagery determines the precise location of the ocular motor areas, lesion studies the degree of involvement of these areas during a given paradigm, and transcranial magnetic stimulation (TMS) the temporal organization of the control of each area. Studies using PET-scan and functional MRI have determined the location of the five areas involved in saccades: the frontal eye field (FEF) around the precentral sulcus, the dorsolateral prefrontal cortex (PFC) anterior to the FEF, the supplementary eye field (SEF) in the medial part of first frontal gyrus, the cingulate eye field (CEF) just below the SEF, and the parietal eye field (PEF) in the intraparietal sulcus. The areas involved in smooth pursuit are, besides the FEF, the middle temporal area (MT) and the medial superior temporal area (MST), located close to each other at the temporoparietooccipital junction. The vestibular cortex is dealt with in another talk and little is known about the cortical control of convergence. Lesion studies have shown that the PEF is involved in the triggering of reflexive saccades, the FEF in that of intentional saccades made with visual stimulation and the SEF in that of saccades made with vestibular stimulation. The P17C is involved in the inhibition of unwanted reflexive saccades and the preparation of predictive saccades (a type of intentional saccades made in anticipation towards a visual target). The CEF could prepare, through a motivation process, all the areas involved in intentional saccades, and the posterior parietal cortex (PPC), around the PEF, could facilitate, through attentional processes, the triggering of reflexive saccades. Smooth pursuit is apparently controlled equally by the FEF and area MST and, upstream, by area MT. TMS is the best method to determine the precise time an area exerts its control in a specific task. Thus, for memoryguided saccades (another type of intentional saccades, made towards the remembered position of a visual target), the PPC is involved during visuomotor integration, and the PFC during shortterm spatial memorization (less than to 20 seconds). Longer periods of memorisation appear to be controlled by the parahippocampal region, in the temporal lobe. Lastly, the SEF controls the learning and launching of a sequence of memory-guided saccades, as does the supplementary motor area for similar motor programmes involving limb movements. The study of eye movements therefore appears to be particularly helpful for analyzing general physiological mechanisms, which are shared by eye and body movements in their preparation at the cortical level.

Three-Dimensional Analysis of Ocular Motor and Vestibular Dysfunction M. Fetter, Department of Neurology, Eberhard-Karls-University, Tübingen, Germany In the last 15 years interest has been resurrected in three-dimensional approaches to the control of eye movements. This was boosted by the fact that three-dimensional eye movement analysis has become practical with

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the development of the magnetic-field search-coil technique. New analytical approaches have made the mathematics of eye rotations and co-ordinate transformations more tractable and intuitive. Unfortunately, the evaluation of eye movements grows increasingly complex when we move from 1-D to 3-D descriptions, since each dimension adds new qualities. In 1-D the amount of the eye velocity is sufficient to determine the movement, in 2-D the direction of the response becomes important, and in 3-D additional kinematic principles like noncommutativity of 3-D rotations and Listing’s law come into play. All this has to be taken into account when studying 3-D eye movements in normals and in patients. From studying 3-D eye movements in pathology we hope not only to be able to identify specific patterns for vestibular lesions but also to find out which neural structures are involved in the generation of the specific kinematic principles that govern 3-D eye movements such as Listing’s law. Strabismus, labyrinthine dysfunction and brain disorders leading to nystagmus and other eye movement disorders are ubiquitous clinical problems and demand a three-dimensional approach for their understanding. This is especially true when dealing with vestibular problems. The vestibular system is intrinsically 3-D trying to stabilize the retinal image in all 3 rotational degrees of freedom. Under pathological conditions, we often do find spontaneous or elicited eye movements with torsional components. The key for understanding vestibular induced eye movements has been found in the early sixties. Since then we know that electrical stimulation of single semicircular canal (SCC) nerves induces eye movements roughly in the plane of the canal. If more than one canal are stimulated the different canals combine at least roughly linearly to drive the eyes. Thus, if multiple canals are stimulated, the slow phases should be in a direction that is a weighted vector sum of the axes of the involved canals. To test the function of all SCCs we developed a 3-D computer-controlled human rotating chair which allows for rotations about any axis in space. With this apparatus we have investigated spontaneous as well as visually and vestibularly induced eye movements in a large number of normals as well as patients with vestibular or central lesions. The results show that with these new techniques we are able to test the vestibular system on the level of single SCC function. Furthermore, it can be shown that cerebellar failure results in non-physiological kinematic behavior of the eyes. This suggests that the cerebellum is involved in the computing of appropriate 3-D eye movement trajectories, e.g. by processing feedback signals of eye position. These findings are very reassuring that 3-D eye movement analysis may help to obtain new insights in how the ocular motor and vestibuloocular systems are organized and how pathological conditions can disturb the responses in a predictable way and by that tremendously increasing our diagnostic capabilities.

Symposium 2 Mitochondriopathies Chair: M. Zeviani, Milan; C. Desnuelle, Nice Clinical and Biological Aspects of Mitochondrial Encephalomyopathies Claude Desnuelle, Laboratoire Neurobiologie Cellulaire, UMR CNRS 6549, Faculté de Médecine de Nice, France The mitochondrial encephalomyopathies are a heterogeneous group of disorders that share inherited or acquired mitochondrial dysfunction as pathogenic process. More than ten years ago, Di Mauro and colleagues subclassified the group according to the primary site of the biochemical defect in term of transport, substrate utilization, Krebs cycle, oxidative phophorylation coupling and respiratory chain. Because the respiratory chain is under the influence of mitochondrial and nuclear genomes, a classification scheme based upon the site of the molecular genetic lesions seems now more convenient and the concept is often restricted to the respiratory chain defects. Whatever the molecular defect the clinical manifestations are with a wide variability in age of onset and features. Organ systems dependant upon aerobic metabolism are mainly affected focusing the attention on the brain, skeletal muscle and heart. While the diagnosis is made on the basis of abnormal mitochondrial function in muscle or other tissues the key problem in clinical practice is the recognition of a disease which develops in most cases with multisystem involvement. Some distinctive phenotypes are now well known as the Kearns-Sayre syndrome, MERRF, MELAS or NARP but the diagnosis of mitochondrial encephalomyopathy is to be suspected in several occurrence. Presentation in infancy causes a delayed psychomotor development or short stature. Incoordination, ataxia, hypotonia, con-

vulsion are common as sensorineural hearing loss, optic atrophy, retinal pigmentation degeneration, migraine, ocular muscle involvement, limb muscle weakness or atrophy. Many patients may develop a cardiomyopathy, a liver or a tubular kidney dysfunction. Isolated or combined endocrinopathies, especially diabetes mellitus, are increasingly recognized. Laboratory abnormalities in blood lactate or ketone bodies and in urine citric acid cycle intermediates may represent help. When present they are a good indication for the metabolic pathway involved. Sometimes provocative tests such as glucose loading in children or analysis of exercise pattern in adults through the anaerobic threshold evaluation or by 31P magnetic resonance spectroscopy are the only biological marks. Several non-specific brain CT or MRI abnormalities have been discussed. Clinical and biological features are only predictive for the diagnosis, recognition have to be confirmed by histopathological, biochemical or genetic clues and supported by diagnostic criteria. On the other hand it is clear that only patients with a carefully monitored diagnosis may benefit from genetic counselling or appropriate treatment if any. Moreover there are evidence for a presently under evaluation of the incidence of this group of disease and a good clinical characterization of each case is essential for a valuable evaluation and classification of the mitochondrial encephalomyopathies in respect with phenotype-genotype correlation.

Anita Harding Lecture. Mitochondriopathies: Nuclear Gene Defects Massimo Zeviani, MD, PhD, Istituto Neurologico C. Besta, Milano Defects of the respiratory chain (RC), the set of mitochondrial enzymatic complexes carrying out oxidative phosphorylation (OXPHOS), are the biochemical hallmarks of human mitochondrial disorders. Faulty OXPHOS can be due to mutations in either nuclear or mitochondrial genes, that are involved in the synthesis of individual RC subunits or in their post-translational control. A third category comprises mendelian traits associated with molecular lesions of mtDNA, possibly due to mutations of nuclear genes involved in mitochondrial biogenesis. While the number of mutations of mtDNA has reached the hundred or so, very few mutations of the nuclear genetic complement have been reported. Leigh’s syndrome (LS) is the most common RC disorder in infancy. A generalized defect of complex IV (Cytochrome c Oxidase, COX) is found in the majority of patients, but several reports failed to identify mutations in either mtDNA-encoded or nucleus-encoded COX subunits. In order to make progress toward the identification of the gene(s) responsible for LS(COX–) we followed two strategies: the creation of informative cellular models, and the identification of candidate genes. Cellular models We have worked out cell culture systems by which the nuclear origin of an OXPHOS defect can be persuasively demonstrated. These systems are based on the creation of cybrids from patient-derived rho° transformants, or on the generation of hybrids by fusing tumor-derived rho° cells with patient-derived transformants. Using these models, we selected a large series of LS(COX–) cases due to a primary nuclear-gene defect. Then, hybrids obtained by fusing different patient-derived cell lines with each other were used to determine whether and to what extent LS(COX–) is a homogeneous or a heterogeneous disease. Results indicated that our LS(COX–) cases all belong to a single complementation group, suggesting genetic homogeneity of the trait. As a further step toward the identification of the gene(s) reponsible for LS(COX–) we have tried to complement the COX defect in our cell lines by transfer of specific human chromosomes. The reappearance of a COX+ phenotype is supposed to indicate the presence of a complementing gene in the specific heterologous human chromosome introduced in the hybrid. Preliminary results have already excluded a number of human chromosomes as complementers of the defect. Candidate genes Most of the genes involved in the formation and function of RC are not known in humans. An effective and rapid method to obtain cDNAs of important mitochondrial genes has recently been worked out in our lab, relying upon a computer-based screening of EST databases probed with yeast mitochondrial protein sequences. Five full-length cDNAs have recently been found in our lab, namely BCS1, COX11, COX15, SCO1, PET112. These cDNAs are the human orthologs of genes involved in the formation/ function of RC in yeast. BCS1 is necessary for the expression of functional complex III. SCO1 is supposed to be involved in either mitochondrial copper transport or insertion of copper into the active site of COX. Yeast COX11 protein may be involved in formylation of the heme A por-

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phyrin ring. COX15 is involved in COX assembly. PET112 controls the turnover of COX subunit II. We are testing the ability of each of these human cDNAs to complement the corresponding defect in yeast and, by a similar approach, will verify as whether any of these genes, expressed in an index LS(COX–) cell line, can correct the OXPHOS deficiency.

Management of Patients with Mitochondrial Disease D. M. Turnbull, Department of Neurology, The Medical School, University of Newcastle upon Tyne The management of patients with mitochondrial disease involves several different aspects including: Supportive care – includes provision of appropriate aids, ophthalmic surgery, pacemaker for cardiac defects, hearing aids Preventative care – includes establishing if there is diabetes or swallowing difficulties Genetic advice – maternal transmission of point mutations but uncertain risk in the presence of heteroplasmy Prognostic advice – risk of developing specific problem in patient or relative Drug treatment – ubiquinone and antioxidants are widely used and are generally non-toxic but of limited value. Dichloracetate has been reported to have been effective but has multiple adverse effects. New developments – 1. Whilst supportive care for the patients is helpful, no specific treatment has been developed. Several novel approaches are being devised and some promising in vitro results have emerged. In the majority of patients with mtDNA defects there is heteroplasmy – the presence of both mutated and wild-type DNA in the same cell. Studies in tissues from patients and in cell culture have shown that the ratio between mutated and wild-type mtDNA is crucial since the mutated mtDNA is usually recessive and a biochemical defect only occurs with high levels of mutated mtDNA. Correcting the genetic defect could be achieved by either increasing the amount of wild-type mtDNA or decreasing the amount of mutated mtDNA. We have taken the later approach and have synthesised sequence specific peptide nucleic acids which specifically inhibit the replication of mutated mtDNA in vitro. We have shown that these peptide nucleic acids are taken up into cultured human muscle. Finally, we have attached a mitochondrial targeting sequence to the peptide nucleic acid and this seems to target the peptide nucleic acid to the mitochondria. 2. A surprising finding in a number of patients with mtDNA defects is a low amount of mutated mtDNA in cultured muscle cells, whilst there is a very high level in the mature muscle. This suggests that the muscle satellite cells have a low amount of mutated mtDNA. The satellite cells are the muscle precursor cells, which in the presence of muscle necrosis, will form new muscle. In a patient with a mitochondrial myopathy who had very high levels of mutated mtDNA in muscle but no detectable mutated mtDNA in muscle culture, we induced muscle necrosis by injecting the muscle with bupivicaine (0.75%). Prior to the injection the majority (75%) of muscle fibres had low cytochrome c oxidase activity associated with a high level of mutated mtDNA. Following injection all the regenerating muscle fibres had normal cytochrome c oxidase activity and either absent or very low levels of mutated mtDNA. In some patients induced muscle necrosis may be of value in the treatment of the mitochondrial myopathy. Conclusion. There has been a dramatic increase in interest in mitochondrial disease and an improved ability to diagnose these patients. However, at present there is no effective treatment but several novel approaches are being considered.

Mitochondrial Diseases of Man and Mouse Douglas C. Wallace, Center for Molecular Medicine, Emory University School of Medicine, Atlanta, USA A variety of degenerative diseases have been associated with defects in oxidative phosphorylation (OXPHOS). OXPHOS is assembled from subunits distributed throughout both the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), and is the major cellular source of ATP and of endogenous oxygen radicals (reactive oxygen species or ROSs). Maternallyinherited mtDNA mutations have been associated with a variety of diseases. Missence mutations in several mtDNA Complex I genes have been linked to Leber’s Hereditary Optic Neuropathy (LHON). The most severe LHON mutation, at np 14459 in the ND6 gene, causes LHON and dystonia and results in a cytoplasmically-inherited complex I deficiency due to a defect in CoQ binding. Mutations in the mitochondrial tRNALys gene at

np 8344 cause myoclonic epilepsy and ragged red muscle fiber (MERRF) disease, and the phenotype of np 8344 patients relates to both their percentage of mutant mtDNAs and their age. MtDNA rearrangement mutations can be associated with diabetes and deafness or chronic progressive external ophthalmoplegia (CPEO). Somatic mtDNA mutations have been found to accumulate with age in post-mitotic tissues in both man and mouse and have been hypothesized to be involved in aging and senescence. The pathophysiology of mitochondrial diseases is being explored using knockout mice in which the nuclear-encoded genes for the mitochondrial heart-muscle isoform of the adenine nucleotide translocator (ANT1) and the Mn superoxide dismutase (MnSOD) have been genetically inactivated. There are two ANT isoforms, both of which exchange mitochondrial ATP for cytosoloic ADP. Inactivation of ANT1 starves the heart and skeletal muscle for ATP, and results in lactic acidosis, fatigability, hypertrophic cardiomyopathy, and mitochondrial myopathy with (RRFs) and hyperproliferation of mitochondria. To better understand the mitochondria proliferation associated with mitochondrial myopathy, the genes involved in mitochondrial proliferation are being cloned by differential display of mRNAs from skeletal muscle of ANT1-deficient versus normal animals. This has resulted in the isolation of cDNAs for both known structural OXPHOS genes as well as other novel genes. MnSOD converts mitochondrially-generated superoxide anion (O2.–) to H2O2. Mice lacking this enzyme die at about 8 days of age of a dialated cardiomyopathy, associated with fatty liver and the inactivation of mitochondrial iron-sulfur center enzymes including aconitase and succinate dehydrogenase. Treatment of MnSOD-deficient animals with a chemical SOD mimic, MnTBAP, rescues the animals from the cardiomyopathy and fatty liver. However, this drug does not cross the blood-brain barrier. Consequently, these animals go on to develop movement disorders associated with spongiform encephalopathy. These mouse models demonstrate that both ATP depletion and increased mitochondrial ROS production are important factors in the pathophysiology of mitochondrial disease.

Symposium 3 Paraneoplastic Neuromuscular Disorders Chair: F. Graus, Barcelona; J. Newsom-Davis, Oxford Paraneoplastic Neurological Disorders (PND): Clinical-Immunological Correlations Josep Dalmau, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, USA Concept and Pathogenesis: There is increasing evidence that many PND are immune mediated. These immune responses are usually defined by the serum and CSF. Two broad groups of pathogenic mechanisms can be considered. In one group (i.e., lymphoma, Waldenström’s macroglobulinemia), the neoplastic cells synthesize antibodies that damage peripheral nerves (i.e., antibodies against GM1 and myelin associated glycoprotein). In the other group (on which this review is focused), the expression of neuronal proteins by a tumor contributes to breaking the immune tolerance for these proteins. Classification and clinical-immunological associations: Immunerelated PND may be classified according to the molecular characteristics and location of the target antigens, or according to the area of the nervous system involved. The only immune-related PNDs for which animal models exist, or which improve significantly with treatment, are those in which the antigens are located on the surface of cells of the peripheral nervous system or neuromuscular junction. The best known of these disorders include, the Lambert-Eaton myasthenic syndrome and voltage-gated calcium channel antibodies, myasthenia gravis and acetylcholine receptor antibodies, and neuromyotonia and voltage-gated potassium channel antibodies. In contrast, the target antigens of antibody-associated PND of the central nervous system are usually cytoplasmic (i.e., CDR34, CDR 62; Tr) or nuclear (Hu, Nova) neuronal proteins. These syndromes respond poorly to treatment. The corresponding antibodies, rather than perceived as pathogenic, should be considered markers of syndromes associated with specific neoplasms. The detection of each antibody (anti-Yo, Tr, Hu, and Ri) also has prognostic and therapeutic implications and, sometimes, neuropathological correlations (i.e anti-Hu and paraneoplastic encephalomyelitis and sensory neuronopathy (PEM/SN)). Other paraneoplastic antigens include: 1) The synaptic protein amphiphysin recognized by sera of patients with

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stiff-person syndrome (or less frequently PEM) and breast cancer, smallcell lung cancer (SCLC), or other neoplasms, and 2) The 66 kDa glial protein (C-22) identified by CV2 antibodies present in the sera of some patients with PEM/SN or paraneoplastic cerebellar degeneration (PCD) and thymoma or SCLC. Recent studies indicate that in SCLC patients with PEM/ SN, the Hu proteins are identified much more frequently than amphiphysin or C-22. We have recently cloned two novel genes that encode two proteins, called “MM1” and “Ta”. These antigens are specifically recognized by sera of two groups of paraneoplastic patients: “MM1” is expressed brain and testis, and identified by serum of patients with PCD/brainstem encephalitis and several types of cancer. “Ta” expressed only in brain, and recognized by serum of patients with limbic/brainstem encephalitis and testicular cancer. Confounding issues about antineuronal antibodies: The mere serological detection of antineuronal antibodies does not prove that a disorder is paraneoplastic. Only well characterized antineuronal antibodies (i.e., those mentioned above) have diagnostic significance; other antineuronal antibodies may be detected in non-cancer related disorders. Other confounding factors include, poor antibody characterization (antibodies having similar immunostaining different antigen specificities), and the coexistence of several antibodies (i.e., anti-Hu, anti-amphiphysin, anti-CV2) in the same serum. A lack of awareness of these possibilities may lead to diagnostic errors.

Paraneoplastic Peripheral Neuropathies J. C. Antoine (MD), Saint-Etienne, France Paraneoplastic peripheral neuropathies are rare malignancy-associated disorders of the nervous system which do not depend on tumoral infiltration, treatment toxicity or metabolic perturbations. Different neuropathies have been reported as paraneoplastic with both carcinomas and lymphomas. Some occur as an isolated manifestation while others are part of complex syndromes affecting simultaneously the peripheral and central nervous system (CNS), and sometimes muscles. The recent demonstration that antibodies reacting with the nervous system can be detected in the serum of patients with paraneoplastic neurological syndromes has improved the diagnosis of these disorders. At present, neuropathies associated with high titer of one of these antibodies can securely be ascribed to a paraneoplastic process. The most frequent is the well-known paraneoplastic sensory neuronopathy (PSN) which usually occurs in association with small cell lung cancer (SCLC), anti-Hu antibodies, and paraneoplastic encephalomyelitis. PSN is usually subacute and severely disabling, but indolent and chronic forms occur that can be difficult to diagnose. A dysautonomic neuropathy including orthostatic hypotension or intestinal pseudo-obstruction is frequently associated with PSN and can be predominant. PSN likely depends on a shared immunopathological process involving humoral and cellular immunity directed against the Hu antigens expressed by both sensory neurons and SCLC. However, reports of peripheral nerve vasculitis or demyelinating lesions in patients with PSN and anti-Hu antibodies suggest that the pathophysiology of the disorder can be more complex. Rarely, patients with anti-Hu antibodies present with a lower motor neuron syndrome. Peripheral nervous system involvement has been reported with the other paraneoplastic auto-antibodies (anti-Yo, anti-Ri, anti-CV2, and antiamphiphysin antibodies) in association with CNS disorders but in most cases there is no clear description of the neuropathy. Peripheral neuropathies associated with lymphopathies and monoclonal IgM gammopathies of known antibody activity can be regarded as true paraneoplastic syndromes. The case is more difficult with patients who did not have detectable antibodies. Their absence does not exclude a paraneoplastic syndrome but the possibility of a coincidental association must be considered. Some neuropathies similar to those associated with auto-antibodies are likely paraneoplastic. In others, the close relationship between the neuropathy and the tumor, the similarities of the reported cases, and sometimes an improvement of the neuropathy after treatment of the cancer suggest a paraneoplastic syndrome. In this setting, the neuropathy can have an acute, subacute, relapsing, or chronic evolution, and a motor, sensory, sensorymotor, or dysautonomic presentation. Contrarily to patients with known antibodies, the cancers associated with these neuropathies are various. If these neuropathies are paraneoplastic, their pathophysiology is probably heterogeneous. Some of them may depend on inflammatory process. Thus, mononeuropathy multiplex with lymphocytic microvasculitis is a possible paraneoplastic disorder and can be steroid responsive. Guillain-Barré syndrome associated with Hodgkin’s disease may be favoured by the particular immunological status associated with this disease. Chronic inflammatory demyelinating neuropathies have also been reported with carcinomas. Their significance is controversial but interestingly, those associated with malignant melanoma may involve antigens shared between Schwann cells and melanocytes.

Paraneoplastic Channelopathies: Models for Cancer-Provoked Autoimmunity ? John Newsom-Davis, Neurosciences Group, Institute of Molecular Medicine, University of Oxford, UK The tumour types that underlie the great majority of paraneoplastic neurological disorders are rather few (small cell lung cancer, gynaecological cancers, thymoma, neuroblastoma), while the disorders associating with a particular tumour type can be several. Small cell lung cancer (SCLC), for example, can associate with encephalomyelitis, cerebellar degeneration, sensory neuropathy, Lambert-Eaton myasthenic syndrome, autonomic dysfunction, and retinal cell degeneration. Thymoma can be present in patients with autoimmune neuromyotonia or myositis as well as in myasthenia gravis. Gynaecological cancers predominantly associate with cerebellar degeneration, but may also do so with opsoclonus-myoclonus. Circumstantial evidence that the immune system is implicated in many paraneoplastic neurological disorders is strong. Serum anti-Hu antibodies are present in the great majority of SCLC patients associated with paraneoplastic encephalomyelitis, cerebellar degeneration and sensory neuropathy. Anti-Yo antibodies are regularly detected in patients with paraneoplastic cerebellar degeneration and ovarian cancer. Antibodies to a variety of muscle antigens (titin, ryanodine receptor, acetylcholine receptor) and also to neuronal determinants (voltage-gated potassium channels, neurofilaments) can be detected in some patients with thymoma. Antibodies to P/Qtype voltage-gated calcium channels are present in virtually all SCLCassociated LEMS patients. However, the presence of a particular tumour is not an absolute requirement for the development of the neurological disorder. For instance, opsoclonus-myoclonus may occur in the absence of a detectable tumour. Patients with the Lambert-Eaton syndrome have been followed for many years without the development of SCLC or lymphoma (with which it occasionally associates). The value of these autoantibodies as diagnostic markers is undoubted. Two further questions arise. What is the evidence that these antibodies are the effector mechanisms underlying the neurological disorders and how are they generated? Studies of the paraneoplastic disorders in which ion channels are specifically targeted by autoantibodies may be informative here. The disorders that will be considered in this context are the LambertEaton myasthenic syndrome and neuromyotonia, in which the targets are voltage-gated calcium channels and voltage-gated potassium channels respectively, and myasthenia gravis in which the target is a ligand-gated cation channel, the acetylcholine receptor. Ion channels are particularly amenable for study because their function is known, so that the pathophysiological effects of specific autoantibodies can be readily evaluated. In addition, they can be radiolabelled with neurotoxins and thus enumerated, or used in radioimmunoassays for precise quantification of the specific antibody titres. Ion channels are transmembrane proteins, often having substantial extracellular domains that can be ‘seen’ by the immune system, making them potentially vulnerable to autoantibody attack. This is especially the case at the neuromuscular junction which lacks the protection of the blood-brain barrier. In these important characteristics they differ from the intracellular Hu and Yo antigens, for example. Experimental evidence that these antiion channel antibodies directly cause the associated neurological disorder is now compelling while, by contrast, the pathophysiological role of the anti-Hu and anti-Yo antibodies remains uncertain. How thymoma might provoke myasthenia gravis and neuromyotonia is presently unresolved, but there is strong experimental and clinical evidence that expression of voltage-gated calcium channels by SCLC triggers and sustains the autoantibody response in the Lambert-Eaton syndrome.

Management of Paraneoplastic Neuromuscular Syndromes Francesc Graus, Service of Neurology, Hospital Clinic i Provincial, Barcelona, Spain The management of patients with paraneoplastic neuromuscular disorders requires to take important diagnostic and treatment decisions. This presentation will try to address some of them and present which level of evidence exists to justify its indication. When to look for a tumor: In patients with Lambert-Eaton myasthenic syndrome (LEMS), sensory neuropathy (SN), mixed, motor or autonomic neuropathies with anti-Hu antibodies (Hu-Ab), or stiff-man syndrome with anti-amphyphisin antibodies, invasive and repeated tumor searches up to four years is justified. In patients with SN, the absence of HuAb does not rule out completely a paraneoplastic origin. In a study of 126 patients with SN who where referred for the presence of Hu-Ab, 49 turned out paraneo-

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plastic but Hu-Ab were detected in 40 whereas 9 (18%) were Hu-Ab negative in spite a tumor (a small-cell lung carcinoma (SCLC) in 4) was discovered in the follow-up. In other neuromuscular syndromes the chances of being paraneoplastic are low and a complete physical examination with pelvic and rectal examinations, routine analysis and a chest film should suffice. Why to look for a tumor? An obvious reason is to find the tumor in a limited stage and potentially curable. In addition, tumor remission seems to offer the best chance to arrest the progression of the paraneoplastic disorder. In 48 patients with Hu-Ab associated syndromes and SCLC, stabilization of the paraneoplastic neurologic syndrome was statistically associated with complete response of the SCLC. Progression occurred in 57% of patients whose tumor did not achieve a complete response in contrast to 12% of those who went into complete response. What is the role immunosuppressive treatment? Treatment with steroids are indicated in LEMS, paraneoplastic neuropathy due to nerve microvasculitis, and dermatomyositis. Plasma exchange seems to improve paraneoplastic neuromyotonia. Intravenous high-dose immunoglobulins have been effective in patients with LEMS and dermatomyositis. The course of paraneoplastic SN is usually unchanged by any immunosuppressive therapy although a few SN patients improved with combinations of the above mentioned drugs. Do immunosuppressors adversely affect the course of cancer? Immunosuppressor drugs could in theory favor the growth of cancer cells by decreasing the immune surveillance. There is no clear evidence that this fact usually occurs in clinical practice. Survival of SCLC patients with Hu-Ab associated paraneoplastic syndromes did not differ between those treated with antineoplastic therapy alone and those who also received immunosuppressors. Is the evolution of cancer better in patients with paraneoplastic syndromes? In a series of 65 Hu-Ab associated paraneoplastic neurologic syndromes whose tumor was diagnosed in life, the tumor had a spontaneous remission in one patient or an unusual slow evolution without treatment in two. Patients with SCLC, low titers of Hu-Ab (16% of all cases), and no neurologic paraneoplastic syndromes have a longer survival because the presence of Hu-Ab is an independent predictor of complete response of the tumor. We conclude early diagnosis of the tumor in patients with suspected paraneoplastic neuromuscular syndromes offers the best chance to stabilize the clinical progression of the neurologic disorder. Concomitant inununosuppressor therapy does not seems to negatively affect the outcome of the tumor that probably have a more benign evolution at least in patients with Hu-Ab.

Symposium 4 The Clinical Problems of Brain Repair Chair: D. A. S. Compston, Cambridge, UK Growth Factors and Development of the Central Nervous System Michael Sendtner, Klinische Forschergruppe Neuroregeneration, Dept. of Neurology, University of Würzburg, D-97080 Würzburg The development of the nervous system is guided by a variety of regulatory processes involving either cell-autonomous genetic programs or signals from contacting tissue. Many types of neurons, in particular in the peripheral nervous system, undergo cell death at significant extent once they have made contact with their target tissue. This process called “physiological cell death” is regulated by neurotrophic factors. Recent research has shown that neuronal activity can modulate production as well as action and function of neurotrophic factors (Meyer-Franke et al., 1995). The cell bodies of spinal and bulbar motoneurons reside within the central nervous system and receive synaptic input from a variety of other neurons including proprioceptive sensory neurons, excitatory and inhibitory interneurons. The cell bodies are contacted by astrocytes, and the axons ensheathed by Schwann cells within the peripheral nervous system. When the axons of these neurons are lesioned, regeneration is supported by factors provided from Schwann cells and the extracellular matrix. We have investigated the role of neurotrophic factors such as ciliary neurotrophic factor (CNTF) and Leukemia inhibitory factor (LIF) and others for lesioned motoneurons (Sendtner et al., 1996), as well as the effect of the excitatory neurotransmitter glutamate on survival, dendrite and axonal outgrowth of motoneurons.

Peripheral nerve lesion in newborn rodents leads to massive cell death of corresponding motoneurons within a few days. The application of neurotrophic factors such as CNTF, LIF, Brain-derived neurotrophic factor (BDNF) or Glial-derived neurotrophic factor (GDNF) can significantly inhibit cell death both in newborn as well as in adult rodents after proximal lesion close to the cell body (Gravel et al., 1997). In order to investigate whether CNTF, released after nerve injury from the cytosol of myelinating Schwann cells, supports motoneuron survival, we transected the facial nerve in 4 week old pmn mutant mice (Sendtner et al., 1997). In this mouse mutant, a rapidly progressing degenerative disease of motoneurons starts by the 3rd postnatal week in hind limb muscles and progresses to the anterior part of the body, leading to death of the animals by the 7th to 8th postnatal week. In 6 week old unlesioned pmn mice, about 40% of the facial motoneurons have degenerated. Transection of the facial nerve at 4 weeks dramatically increased the number of surviving motoneurons in pmn mice. This protective effect was absent in pmn mice lacking endogenous CNTF. Quantitative analysis of LIF mRNA expression revealed that the dramatic upregulation seen in wildtype mice after peripheral nerve lesion did not occur in pmn mice. Therefore, endogenous LIF cannot compensate for the lack of CNTF in pmn crossbred with CNTF knockout mice. Thus endogenous CNTF released from lesioned Schwann cells acts as a lesion factor which supports survival of axotomized motoneurons. It has been hypothesized that excessive excitatory input can lead to motoneuron cell death under a variety of pathological conditions (Greensmith et al., 1994), such as spinal cord lesion, peripheral nerve lesion, or in neurodegenerative disorders. NMDA and AMPA receptors are expressed in bulbar and spinal motoneurons, in particular during early development. To investigate whether glutamate can induce cell death and/or influence specific parameters of embryonic motoneurons, we have isolated spinal motoneurons from 15 day old rat embryos and tested the effects of glutamate at different concentrations up to 100 µM (Metzger et al., 1998). During a culture period of 7 days, glutamate did not affect motoneuron survival. In contrast, a concentration-dependent and reversible reduction of dendrite growth was observed. This effect could be blocked by inhibitors of AMPA and kainate receptors, but not by NMDA or metabotropic receptor antagonists. Moreover, the effect was abolished under depolarizing conditions and by treatment with the blocker of Ca2+-conduction AMPA receptors, joro spider toxin. In contrast, the Na+ channel blocker tetrodoxin did not alter process outgrowth in the presence of glutamate. Removal of glutamate after 5 days of culture led to increased dendrite growth during the following culture period, and delayed glutamate addition resulted in a reduction in length of already existing dendrites. Axonal outgrowth was not affected by glutamate under any condition. Our observation that the effect is reversible reflects a potential physiological function of excitatory neurotransmission on dendrite growth and morphology during a developmental period when synaptic contacts from afferent neurons to motoneurons are made in the spinal cord. Moreover, our data indicate that enhanced excitatory neurotransmission under a pathological situation could lead to significant changes in dendrite morphology, which could be responsible for changes in motoneuron function after spinal cord injury or in degenerative motoneuron diseases. References: Meyer Franke A, Kaplan MR, Pfrieger FW, Barres BA: Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 1995, 15 : 805–819. Sendtner M, Götz R, Holtmann B, Escary J-L, Masu Y, Carroll P, et al: Cryptic physiological trophic support of motoneurons by LIF disclosed by double gene targeting of CNTF and LIF. Current Biol 1996, 6 : 686–694. Sendtner M, Götz R, Holtmann B, Thoenen H: Endogenous ciliary neurotrophic factor is a lesion factor for axotomized motoneurons in adult mice. J Neurosci 1997, 17 : 6999–7006. Greensmith L, Mentis GZ, Vrbova G: Blockade of N-methyl-D-aspartate receptors by MK-801 (dizocilpine maleate) rescues motoneurones in developing rats. Brain Res Dev Brain Res 1994, 81 : 162–170. Gravel C, Götz R, Lorrain A, Sendtner M: Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to longterm survival of axotomized motoneurons. Nature Medicine 1997, 3 : 765–770. Metzger F, Wiese S, Sendtner M: Effect of glutamate on dendrite growth in embryonic rat motoneurons. J Neurosci 1998, 18 in press.

Gene Therapy Based Delivery of Neurotrophic Factors for the Treatment of Neurodegenerative Diseases P. Aebischer, Division Of Surgical Research And Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, Lausanne University Medical School, Switzerland Neurotrophic factors hold promise for the treatment of neurodegenerative diseases. Neuroprotective effects of trophic factors in the central nervous

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system (CNS) and in various animal models of neurodegeneration has led to the development of strategies for the treatment of neurodegenerative disorders. The presence of the blood brain barrier remains, however, a major concern for the delivery of neurotrophic factors in the CNS. A technique involving the intrathecal implantation of polymer encapsulated celllines genetically engineered to release neurotrophic factors provides a means to continuously deliver neurotrophic factors directly within the CNS, avoiding the numerous side effects observed following their systemic administration. Transplantation of cells isolated within a permselective polymer capsule restricts cell growth to the capsule space and protects them from immune destruction while allowing exchange of molecules between the entrapped cells and host tissue. In the event of capsule breakage, cells from a xenogeneic origin are rejected by the host immune system. To increase the safety level, the engineered cells also express a suicide gene (thymidine kinase) rendering the cells sensitive to ganciclovir mediated destruction. Encapsulated cells engineered to release either GDNF or neurturin are being evaluated in rodent and primate models of PD, whereas cells engineered to release GNTF are being evaluated in rodent and primate models of HD. Significant morphological and behavioral improvement were observed in several of these models. The technique of transplanting polymer encapsulated cells genetically engineered to release a neurotrophic factor has been recently implemented in-patients suffering from amyotrophic lateral sclerosis. This first clinical trial based on the intrathecal delivery of ciliary neurotrophic factor (CNTF) has demonstrated the safety of the technique, the viability of the transplanted xenogeneic cells as well as the longterm expression of the transgene.

Neuron-Glia Interactions in the Injured PNS and CNS A. J. Aguayo, A. Di Polo, L. Aigner, H. Friedman, S. Singel and G. M. Bray, Centre for Research in Neuroscience, McGill University, Montreal General Hospital Research Institute, 1650 Cedar Avenue, Montréal, Québec H3G 1A4, Canada In the injured central nervous system of mature mammals, the substitution of CNS glia by Schwann cells is associated with a lengthy regrowth of the interrupted axons from some but not all CNS neurons and the formation of new synapses with distant targets. Such effects of Schwann cells on CNS regeneration may be influenced by neurotrophins that are not expressed by glia in the adult CNS. To enhance the role of non-neuronal cells as sources of critical molecules for survival and growth in the CNS, we infected Müller cells in the rat retina with an Ad.BDNF.c-myc vector injected intravitreally. Müller cells expressed BDNF for approximately one month and their BDNF expression transiently rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis. However, the long-term survival of these neurons was apparently curtailed by lesion-related changes in the receptiveness of RGCs to the available BDNF. A better understanding of the changes induced by axotomy on neurotrophin receptors and intracellular signaling pathways appears essential to the long-term range use of these factors for traumatic CNS lesions. Other strategies for gene-delivery promise to influence neurons directly via retrograde axonal transport from their target tissues. Thus, new tools are being developed that may be used to modulate cellular interactions by gene-targeting to neurons and glia.

The Neurobiology of Peripheral Nerve Regeneration Christian Krarup, Department of Clinical Neurophysiology, The Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark Restoration of function after Wallerian degeneration is dependent on regrowth of axons from the proximal nerve stump, reinnervation of target organs, and recovery of physiological and morphological features of regrown axons. Already observations by Ramon y Cajal showed that extension and guidance of neurite processes involve neuronal as well as glial factors. Subsequent work in a number of species and involving different methodological approaches have reinforced that nerve regeneration is contingent upon tightly controlled cellular processes and humoral and structural factors. Directional cues appear to attract neurites to Schwann cell tubes (bands of Büngner) of the distal denervated nerve stump. These neurotropic factors may be released by Schwann cells undergoing dedifferentiation and proliferation as a consequence of loss of axonal-glial contact during Wallerian degeneration. In connection with disintegration of the axon due to activation of Ca++-dependent proteases, macrophage attractant factor is re-

leased by the Schwann cell, and macrophages are recruited from the circulation. The resulting removal of axon and myelin debris, upregulation of neurotrophic factors, and induction of Schwann cell proliferation appear to have central importance for permitting growth of axons through the distal nerve stump. In the Ola mutant mouse (Wld s) Wallerian degeneration is markedly delayed and regeneration from the proximal stump is impaired. Similarly, if cells in the distal nerve stump are destroyed by freezing and recruitment of cells from the environment is prevented, regeneration of axons is restricted. During elongation axons have extremely small diameter. Axolemmal components and ion-channel proteins are transported from the cell body and inserted into the regenerating neurite. These premyelinated axons propagate action potentials at low conduction velocities of 2–3 m/s. In parallel with the axon-glial contact Schwann cells are stimulated to form myelin. Maturation, including caliber growth and myelination, is controlled by the axon as indicated by the ability of previously non-myelinating Schwann cells to form myelin around axons which regenerate from myelinated parent fibers. This maturation proceeds in parallel with elongation before formation of axon-target organ contacts. Though elongation of axons is crucial in nerve regeneration, little useful function is attained if reinnervation of target-organs by appropriate axons does not occur. This has raised the important question whether reinnervation is a guided process. This might occur if regenerating axons were attracted to appropriate Schwann cell tubes; good functional recovery is achieved after crush lesions without interruption of the basal lamina. Experimental studies indicate that motor and sensory nerve fibers preferentially regenerate into motor and sensory nerves respectively. The mechanism for preferential reinnervation is uncertain but evidence suggests that branching at the proximal lesion site followed by pruning of aberrant sprouts may be significant. The broadening understanding of factors which influence nerve regeneration will have implications for treatment and clinical restoration after peripheral nerve lesions and disorders associated with axonal degeneration. Application of neurotrophic and neurotropic factors to repair axonal degeneration is under investigation but is complicated by their biological properties and side effects. A promising area may be transfer of genes coding for growth factors into proliferating Schwann cells during Wallerian degeneration.

Symposium 5 Memory Disturbances Chair: D. Y. von Cramon, Leipzig The Functional Anatomy of Human Memory R. J. Dolan, Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK Cognitive psychology and neuropsychology provides compelling evidence that memory can be dissociated into discrete processes The most fundamental, and widely recognised distinction within memory is a dichotomy, based upon temporal duration, into short and longterm cornponents. Long term memory is itself subdivided according to the accessibility (declarative or explicit memory) or inaccessibility (procedural or implicit memory of the retrieved elements to consciousness. Within declarative memory, a. further division into semantic and episodic memory systems has been prposed. Semantic memory represents facts or knowledge about the world and is manifest in the process of knowing. Episodic memory, on the other hand, deals with events that have a spatio-temporal context which provides the autobiographical component that we associate with the process of remembering. Non-declarative forms of memory include forms of memory that manifest in skilss, habits or altered performance on indirect memory tests. The dissociation of non-declarative from other forms of memory is exemplified by observations in amnesic patients who show intact procedural learning and priming. While lesion data have historically neuroimaging techniques, positron emission magnetic resonance imaging (fMRI), are now radically altering our views concerning the brain systems and mechanisms of memory. Data using both these modalities will be presented that will address longterm memory function. What brain and retrieval of episodic memory? Do discrete brain regions implicated in memory subserve distinct psychological functions? What psychological functions are mediated by the human hippocampus? How do different brain regions interact when subjects learn? Are brain systems involved in non declarative memory the same as those involved in declarative memory? What neural changes occur in association with learning?

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The data presented will implicate much more widespread systems in memory than those suggested by lesion data. In addition to involvement of hippocampus these data implicate prefrontal, medial parietal and anterior cingulate cortices in human memory function. On the basis of task manipulations it will be shown that there is a high degree of functional specialisation associated with regional patterns of activation. Finally, a rapidly acquired neural plasticity will be shown to underlie the acquisition of !c!’ forms of nondeclarative memory.

Memory and Event-Related Potentials Axel Mecklinger; Max-Planck-Institute of Cognitive Neuroscience, Leipzig, Germany In the last decade there has been a large number of event-related potential (ERP) studies addressing issues relevant to contemporary work on memory. ERPs not only allow one to investigate the functional architecture of memory systems and processes, but also enable the examination of the neuronal structures mediating these processes. In other words, ERP measures can serve as markers of memory processes, and as markers of the brain. Unlike measures of the brain’s metabolic activity such as PET or fMRI, ERPs provide an excellent temporal resolution (in the range of 10 to 100 ms) to study the processes underlying memory performance. There is now considerable evidence that memory performance relies on multiple systems and processes. An analytical and empirical distinction that has become especially important in memory research in the last couple of years is that of encoding, rehearsal/storage and retrieval processes. ERP measures allow one to examine the functional characteristics and the neuronal correlates of these processes in detail. Encoding: ERPs evoked at the time of learning can be predictive for the memorability of an item. That is, items that are remembered later, evoke more positive ERP waveforms during learning than items that are subsequently not remembered. These effects are found for a large variety of learning materials and are assumed to be a measure of encoding effectiveness. Based on their scalp distribution, some portions of these effects most likely arose from synchronous neuronal activity in the frontal cortex. Retention/Rehearsal: Negative slow wave components in the ERP have been found to be sensitive to rehearsal processes in working memory and long-term memory tasks. These components’ amplitudes are positively correlated with the amount of information has to be held in memory. In showing task-related scalp distributions, negative slow waves also allow one to directly monitor rehearsal-related cortical activation patterns in memory tasks. Retrieval: Another approach to examine memory processes with ERPs is to compare ERPs evoked by the first and by subsequent occasions within an experiment. ERPs to the first presentation of items (new items) are more negative going than ERPs evoked by subsequent presentations of these items (old items). Early portions of these so-called old/new effects (between 300 and 600 ms after stimulus onset) are assumed to index recollection, i.e. the retrieval of information from a prior study episode. Conversely, late old/new effects (between 1200 and 1800) are associated with post-retrieval memory processes such as recollection of episodic or source information. Recent ERP studies employing intracranial recordings suggest that the early portions of the old/new effects are generated in the anterior medio-basal temporal lobes, whereas the late effects most likely arise from generators in the right frontal cortex. Given their above mentioned functional characteristics, memory-related ERPs provide a valuable tool to examine the focus of memory dysfunctions in neurological patients. For instance, studies with temporal lobectomy patients revealed attenuations of ERP old/new effects and degraded recognition memory performance, whereas implicit memory functions were preserved in these patients. Evidence for a similar dissociation (preserved implicit memories and degraded explicit memory functions) has recently been reported in an ERP study with patients suffering from cerebral hypoxia. This talk will give an overview about memory-related ERP studies and discuss their implications for the diagnoses of memory dysfunctions in neurological patients.

Memory and Pharmacology H. V. Curran, London, UK

Memory and Psychopharmacology H. Valerie Curran, Clinical Health Psychology, University College London, Gower Street, London WC1E 6BT, UK Pharmacological studies can provide potentially important insights into the neurobiological bases of memory and its disorders. They can also al-

low pharmacological dissociations to be made between different aspects of memory. Many centrally-acting drugs can produce impairments in some aspects of memory whilst sparing other aspects. Studies of these effects are relevant clinically in specifying how prescribed psychotropic drugs affect patients’ memory functions and in developing new treatments aimed at ameliorating organic cognitive dysfunctions. They are also relevant to diagnosis of brain damage in patients with brain injury who are taking licit or illicit psychotropic drugs. To date, psychopharmacological studies have predominantly focussed on the mnemonic effects of two classes of drug: cholinergic drugs (e.g. the antagonist, scopolamine, the agonist, nicotine and the acetylcholinesterase inhibitor, tacrine) and benzodiazepine (BDZ) receptor ligands (including a range of agonists (e.g. alprazolam, lorazepam), the BDZ antagonist, flumazenil and the new inverse agonists (e.g. beta-carbolines). BDZs as a class produce marked and robust impairments of episodic memory whilst leaving semantic, procedural and working memory relatively intact. Episodic memory impairments are valued by anaesthetists who use BDZs as premedicants partly because they want patients to be amnesic for surgical events. However, when prescribed for anxiety disorders and insomnia, BDZ-induced memory impairment is an unwanted effect. Indeed, in older adults, BDZs can sometimes cause an apparent pseudo-dementia. Although all BDZs are thought to operate in the same way, and all produce episodic impairments, studies in several laboratories have found that one BDZ (lorazepam) differs from others in impairing perceptual priming. The cholinergic blocker, scopolamine, produces a profile of memory effects which is broadly similar to most BDZs. Psychopharmacological studies have some methodological advantages when compared with brain lesion studies. Amnesia following a single dose is graded, reversible and participants can act as their own controls in predrug or placebo conditions. At the same time, conceptual and methodological issues in drug studies concern (1) drug state itself being a retrieval cue and (2) delineating specific memory effects as distinct from non-memory effects of drugs. State-dependent effects of drugs like BDZs cannot explain their amnestic effects. State-dependent effects are often asymmetrical and are generally small compared with the large effects on acquisition of information. Further, the retrieval facilitation effects sometimes observed following BDZs are the opposite to that predicted by state-dependency. Given the effects of centrally acting compounds on mood, it is conceivable that drug state-dependent effects are themselves a reflection of mood congruency. Recent studies are reviewed which, taken together, imply that scopolamine and BDZs have specific effects on memory which are not secondary to their effects on arousal. BDZs and BDZ-like molecules occur naturally in the brain and may play a role in normal and disordered brain functioning. Specific BDZ receptors are found in greatest concentrations in the limbic system, cerebellum and throughout the cerebral cortex. In terms of pharmacological therapy for clinical disorders of memory, research has so far been disappointing. However, two cholinergic compounds are now licensed for treatment of Alzheimer’s disease and there is evidence that they can slow down the rate of progression of dementia.

Monday Oral Sessions Cerebrovascular Disorders (1) 1 IMPROVEMENT OF ARTERIAL THROMBOLYSIS WITH TRANSCRANIAL LOW-FREQUENCY ULTRASOUND IN VITRO. Michael Daffertshofer, Stephan Behrens, Dagmar Spiegel and Michael Hennerici. Department of Neurology University Heidelberg, Klinikum Mannheim, Germany The effectiveness of thrombolysis in acute stroke patients does not only depend on the time between symptom onset and begin of therapy, but also on the variable time frame between initiation of thrombolysis and recanalization. Shortening of the recanalization time 1.) may enable thrombolysis to patients with strokes beyond the 3 h or 6 h interval and 2.) may improve the neurological outcome even in patient within the hyperacute phase. Since direct insonation of thrombi with low-frequency ultrasound (US) have already shown a thrombolytic effect this study investigated the potential of transcranial low frequency US to accelerate rt-PA mediated

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thrombolysis. The attenuation through the skull of low-frequency (33–75 kHz) continuous-wave US (DWL, Sipplingen) and the reduction of the recanalization interval, were analysed in a tube model using various transcranial pathways. The effect of rt-PA (100 µg/ml) with simultaneous US insonation on the reduction of thrombus weight (Fibrin rich thrombi from whole blood samples) was measured after 1h and 3h. Highest penetration was seen employing 33 kHz emission frequency via a transtemporal insonation route (80% ± 6%) and lowest penetration was seen using a transorbital pathway (42 ± 8%). The average attenuation was 5.2 dB for transtemporal, 7.5 dB for transoccipital, and 8.9 dB for transorbital application. Thrombolysis was significantly increased (22.3% increase) after 1h (p < 0.025) and after 3 h (p < 0.01) US treatment in combination with rt-PA vs. exclusive rt-PA treatment. Low-frequency US has a low attenuation through the skull and increases the rt-PA mediated thrombolysis significantly. If further studies can demonstrate the safety of that method, it may be a tool to accelerate both local and systemic thrombolysis in acute ischemic stroke.

2 APOLIPOPROTEIN E AND COMMON CAROTID ARTERY ATHEROSCLEROSIS: THE ROTTERDAM STUDY. A. J. C. Slooter, M. L. Bots, D. E. Grobbee1, 2, A. Hofman1, C. Van Broeckhoven3, J. C. M. Witteman1, C. M. van Duijn1. 1Department of Epidemiology & Biostatistics, Erasmus University Medical School, Rotterdam, 2Julius Centre for Patient Oriented Research, Utrecht University, the Netherlands and 3 Neurogenetics Laboratory, University of Antwerp, Belgium Ultrasonographically assessed atherosclerosis of the carotid arteries is a predictor of future stroke. Apolipoprotein E (gene: APOE; protein apoE) plays a crucial role in lipid metabolism, but it is controversial whether the APOE*4 allele increases the risk of atherosclerosis. To study the association between APOE and atherosclerosis of the carotid arteries, data were used from a population-based cross-sectional study on 934 subjects aged ≥ 55 years. Atherosclerosis was ultrasonographically assessed by the presence of plaques in the common carotid arteries (CCAs), and by the CCA intima-media thickness. The odds ratio (OR) for any CCA plaques was studied in a logistic regression model. The CCA intima-media was studied in a linear regression model. Statistical analyses were adjusted for age and sex, using APOE3E3 as a reference. APOE*2 carriers had a lower risk of CCA plaques (OR = 0.5; 95% confidence interval (CI) 0.5; 0.9), and a thinner CCA intima-media (mean difference –0.04 mm; 95% CI –0.06; –0.01 mm). APOE*4 was not related to CCA plaques (OR 0.7; 95% CI 0.4; 1.1), or to CCA intima-media thickness (–0.02 mm; 95% CI –0.03; 0.00). Our study suggests that the APOE*4 allele is not a risk factor for CCA atherosclerosis, and that APOE*2 has a protective effect.

3 BALINT’S SYNDROME ASSOCIATED WITH BILATERAL PULVINAR INFARCTION. D. Crowther Wefferson, A. Nisbet. Department of Neurology, Queen’s Medical Centre, Nottingham, UK A 34-year-old female suffered a cardiac arrest of unknown aetiology from which she was rapidly resuscitated and DC cardioverted. She remained in a coma for three days with no focal neurology except bilateral Babinski signs. On recovery she was found to be profoundly visuo-spatially disorientated. She was unable to voluntarily direct her gaze or her hands to a visual target, frequently looking in the opposite direction even to objects she had previously identified. She displayed dramatic tactile searching to locate targets, for example groping her way along the examiner’s arm to get to his finger even though she could ‘see’ the finger. Eye movement to either side was also restricted and she used compensatory head thrusts. There was marked visual inattention to both peripheral fields. Complete recovery of the Balint’s syndrome ensued over the following 12 months. The MRI scan revealed a selective bilateral thalamic lesion predominantly involving the pulvinar. Implications for the role of the pulvinar in visuomotor processing are discussed.

4 THE NATURAL HISTORY OF CADASIL: CLINICAL FINDINGS IN 102 CASES. Dichgans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J3, Rungger G4, Ebke M5, Klockgether T6, Gasser, T1. 1Department of Neurology, 2 Department of Radiology, Klinikum Grosshadern, LudwigMaximilians-Universität, 3 Department of Pathology, Ludwig-MaximiliansUniversität, Munich, Germany; 4 Department of Neurology, Universität

Insbruck, Austria; 5 Department of Neurology, Krankenhaus Bremen Ost, Germany; 6 Department of Neurology, Eberhard-Karls-Universität, Tübingen, Germany We present clinical findings in 102 affected individuals from 29 families with biopsy proven CADASIL. Recurrent ischemic episodes (TIA or stroke) where the most frequent presentation (71%) with a mean age at onset of 46.2 years (30–66; SD 9.0) followed by cognitive deficits (48%) and migraine (38%). Mean age at onset for migraine was 26.0 years (SD 8.2) with 87% of the cases being classified as migraine with aura. Psychiatric disturbances were found in 30% and epileptic seizures in 10% of the cases. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. within each group aged above 45 there was the full spectrum of disability. Fifty-five percent of the patients aged above 60 were unable to walk without foreign assistance. However, 14% of the patients within this age group displayed no disability at all. Kaplan-Meier analysis revealed median survival times of 67 (males) and 69 years (females). As demonstrated by an investigation of the 18 multiplex families, there are marked intrafamilial variations both in clinical presentation and severity of the phenotype.

5 STRONG CLUSTERING AND STEREOTYPED NATURE OF Notch3 MUTATIONS PROVIDE AN EASY AND RELIABLE DIAGNOSTIC TEST FOR CADASIL. A. Joutel1, K. Vahedi2, C. Corpechotl, A. Troesch3, H. Chabriat2, C. Vayssière1, C. Cruaud4, J. Maciazek1, M. G. Bousser2 and E. Tournier-Lasserve1. 1INSERM U25, Paris, France; 2 Service de Neurologie, Hôpital Lariboisière, Paris; 3 bioMérieux, Lyon; 4 Généthon, Evry We recently established that Notch3 is the defective gene in CADASIL, an autosomal dominant arteriopathy causing ischaemic infarcts, migraine, mood disorders and vascular dementia. Notch3 encodes a large transmembrane receptor, including an extracellular domain containing 34 tandemly repeated Epidermal Growth Factor like (EGF) repeats and three cysteine rich repeats, a single transmembrane domain and an intracellular domain containing six ankyrin repeats. Objectives To set up a direct diagnostic test and delineate Notch3 critical domains. Methods Screening for mutations along the 33 coding exons, using single-strand conformation polymorphism, heteroduplex and sequence analysis of 50 unrelated patients and 100 healthy controls. Results We identified pathogenetic mutations in 47 patients, 45 mis-sense mutations and 2 splice-site mutations. All these mutations lead to loss or gain of a cysteine residue within the EGF repeats and therefore to an unpaired number of cysteine residues within a given EG17 domain. Thirty four patients carried a mutation within the 2 exons encoding the 5 first EG17 domains. Conclusion: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations in CADASIL patients, an easy and reliable diagnostic test for CADASIL is feasible. This test will be used to determine the prevalence of CADASIL among the group of small cerebral arteries disorders.

6 CADASIL: PROPOSED DIAGNOSTIC CRITERIA. Patrick Davous. Argenteuil, France CADASIL is commonly overlooked or misdiagnosed and their is a need for identification of putative cases upon well established diagnostic criteria. These criteria are proposed from our experience of the disease and the review of the literature. 1) Definite CADASIL: Criteria of probable CADASIL associated with genetic linkage to chromosome 19 and/or with pathological findings demonstrating small vessel arteriopathy with granular osmiophilic material. 2) Probable CADASIL: 1. Young age at onset (< 50). 2. At least two of the following clinical findings: – Stroke-like episodes with permanent neurological signs – Migraine – Major mood disturbances – Subcortical dementia. 3. No vascular risk factor etiologically related to the deficit. 4. Evidence of an inherited autosomal dominant transmission. 5. Abnormal MRI imaging of the white matter without cortical infarcts. 3) Possible CADASIL: 1. Late age at onset (> 50) – 2. Stroke-like episodes without permanent neurological signs – Minor mood disturbances – Global dementia. 3. Minor vascular risk factors such as mild hypertension, mild hyperlipidemia, smoking, use of oral contraceptive. 4. Unknown or incomplete family pedigree. 5. Atypical MRI imaging of the white matter. 4) Exclusion criteria: 1. Age at onset > 70 – 2. Severe hypertension or complicated heart or systemic vascular disease. 3. Absence of any other case in a documented pedigree. 4. Normal MRI imaging, age > 35. Conclusion. If widely accepted and validated, these criteria may have strong implications for epidemiology, genetic testing and counselling.

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Cerebrovascular Disorders (2) 7 PATTERNS OF PREHOSPITAL AND EARLY COURSES OF ISCHEMIC STROKES AS A PREDICTIVE FACTOR FOR OUTCOME. D. Sablot, T. Moulin, L. Tatu, F. Vuillier, E. Berger, L. Rumbach. Department of Neurology University Hospital Besancon, France There is little data on the prehospital and early courses of ischemic stroke in spite of the importance of this information in the therapeutical decision. The aim of our study was to analyze stroke profiles in the early stage of stroke during both prehospital and hospital courses within the first 24 hours. Method: We prospectively studied 100 consecutive patients (pts) admitted to our department for TIA or infarction. All pts were analyzed using the methodology of the Besançon Stroke Registry. Pts with intracerebral hematoma or cerebral venous thrombosis were excluded. Stroke profiles were analyzed from their onsets to the 24th hour. Prehospital neurological status was based on retrospective interviews of the pt and/or their family using a neurological dysfunction grading (NDG) and controlled by a telephone interview of the general practitioner (GP) using the NIHSS. Neurological status was evaluated by NIHSS and NDG at admission, the 48th hour and discharge. Outcomes were analyzed using Rankin scale. Results: There were 57 men (mean age 68.3 years). Ischemic stroke involved anterior circulation in 67, and was a TIA in 25. The timing for admission was: 43 pts within 3 hours, 64 within 6 hours and 80 before the 12th hour. Patterns of the first stage were: progressive in 6 pts (4/6 had a progressive onset), stable in 26, regressive in 49 and fluctuating in 3. Prehospital NDG (10.3) and NIHSS-GP (mean 8.1) figures were correlated, as well as were admission-NIHSS figure. The mean NIHSS-GP was correlated with the type of stroke: TIA (3.0), infarction (9.4) and subsequent Rankin scale. At discharge, a poor outcome was correlated with a progressive onset and a more severe prehospital score (mean NIHSS-GP 16.5 vs 4.9; mean NDG 18.4 vs 7.8) while a regressive pattern of the first stage was associated with a good outcome (96.4%). Types of strokes were also correlated with the duration of the first stage: TIA with no lesion (mean 55.6 mim), TIA with lesion (197.1 min), and infarction (644.6 min), as well as outcome (R 1–3: 340.9 min, R 4.5: 927.4 min, and death: 1440 min). Conclusion: Our preliminary results suggest that it is possible to predict the subsequent stroke outcome at an early stage and to determine thresholds in the duration of signs which will predict the subsequent stroke severity. 8 THE FREQUENCY OF PUNCTATE AREAS OF SIGNAL LOSS (MICROBLEEDS) ON GRADIENT-ECHO T2*-WEIGHTED MAGNETIC RESONANCE IMAGING OF THE BRAIN IN HEALTHY ELDERLY NORMALS: THE AUSTRIAN STROKE PREVENTION STUDY. F. Fazekas, A. Lechner, R. Schmidt, P. Kapeller, G. Roob, E. Flooh, H. P. Hartung, Graz, Austria The risk for primary intracerebral hemorrhage (PICH) has been associated with microangiopathy related damage of the brain such as leukoaraiosis or white matter hyperintensities on magnetic resonance imaging (MRI). More recently it has become apparent that MRI also shows a high rate of punctate areas of signal loss compatible with old microbleeds (MB) in PICH patients. The frequency of this finding in the healthy elderly population is still unknown, however. We therefore performed gradient echo T2*weighted MRI of the brain in a consecutive series of 281 volunteers. This was done in the context of the Austrian Stroke Prevention Study which examines randomly selected, neurologically asymptomatic individuals. 131 women and 150 men with a mean age of 60 years (range 44–79) were examined. WMH were seen in a total of 179 (63.7%) volunteers and they were patchy to confluent in 39 (13.8%). MB were noted in 18 (6.4%) individuals only. The preferential location was cortical/subcortical in 9, in the basal ganglia in 6, and infratentorial in 3 individuals, respectively. MB were significantly associated with higher age, hypertension, more extensive WMH and lacunes. The observed associations confirm MB as another consequence of microangiopathy. Their low frequency in elderly normals suggests that MB are a better predictor concerning the risk for PICH, than the presence of WMH. 9 BEHAVIOR AND SUBJECTIVE EXPERIENCE IN THE ACUTE PHASE OF STROKE. Ghika-Schmid, G. van Melle, P. Guex, J. Bogousslavsky. Lausanne, Switzerland We tried to assess subjective experience in acute stroke and correlate it with stroke features and emotional behavior. We prospectively studied,

during the first 4 days, all patients with first-ever stroke. We rated behavioral reactions using a specifically designed scale, subjective experience (happiness, sadness, irascibility, fear) and mood (Hamilton). 53 patients (30 men, 23 women, 60 ± 19 years) completed the 3rd month follow-up. Results: strokes were in the anterior (32 /53) or posterior circulation (21/53) (17 right, 33 left, 3 bilateral). 11 (20%) patients had impaired consciousness. 17 (32%) did not seek medical care. 9 (30%) had reactions of sadness, 4 (13%) of aggressiveness, 8 (26%) of denial. Recall of the acute event was partial in 15 (28%), impossible in 3 (6%). 8 (15%) were anosognosic, 12 (53%) anosodiaphoric. 24 (45%) expressed happiness, 20 (37%) sadness, 7 (13%) anger and 11 (20%) fear. 4/12 patients with aphasia required delayed questioning. Statistical analysis showed that observed denial reactions and anosognosia were independent (p < 0.416). Nosognosia related with care seeking ( p < 0.001). Acute denial reactions were independent of lesion side, more frequent in deep involvement ( p < 0.010), inversely related to subjective fear ( p < 0.078) and associated with delayed depression ( p < 0.02). Conclusions: Acute behavioral denial was related to less frequent subjective experience of fear, to delayed depression and independent of anosognosia. Other emotional reactions were dissociated from the patients’ subjective experience.

10 ISCHEMIC STROKE IN PATIENTS WITH KNOWN HEART DISEASE. François Nicoli, Isabel L. Henriques, Guy van Melle, Julien Bogousslavsky. University of Lausanne, Lausanne, Switzerland Patients with stroke and known heart disease do not always have a cardioembolic (CE) cause for their stroke. We adressed the hypothesis that concomitant factors could predict a cardiac vs. a non cardiac etiology. Methods: From more than 3500 patients with first ischemic stroke prospectively included over 20 years in the Lausanne Stroke Registry, we looked at those with known heart disease (myocardial infarct (MI), angina, arrhythmia (ARR), left ventricular hypertrophy (LVH), or valvulopathy). Stroke causes included CE, large artery disease (LAD), lacunar infarct (LI) and other causes (OC). We studied associated factors using logistic regression with stepwise selection of the variables. Results: In a preliminary study concerning 2097 patients, 734 had known heart disease while only 367 had a CE cause for their stroke. Non ARR patients with previous MI had a non cardiac etiology in 32% of the cases (37/115). In patients with no history of MI or ARR only 20% of strokes (77/370) were due to CE, independently of previous history of angina, LVH or valvulopathy. The patients without hypertension (HBP) were equally represented in the CE, LAD, and OC groups. Conclusions: Half of the patients with heart disease had a non cardiac etiology for stroke. In patients with previous ARR or MI, CE was the most likely cause of stroke. In other patients, a history of HBP, smoking and TIA indicated a potential non cardiac etiology.

11 CEREBRAL WHITE MATTER CHANGES AND ATHEROSCLEROSIS – THE ROTTERDAM SCAN STUDY. F.-E. de Leeuw1, J. C. de Groot1, E. Achten2, R. Heijboer 2, M. Oudkerk 2, J. van Gijn3, A. Hofman1, M. M. B. Breteler1. 1Department of Epidemiology & Biostatistics, Rotterdam, The Netherlands; 2 Department of Radiology, Dr. Daniel den Hoed Clinic, Rotterdam; 3 Department of Neurology, University Hospital Utrecht Goal: To assess the relation between atherosclerosis and cerebral white matter changes. Background: White matter changes (WMC) seem associated with cognitive impairment. Small vessel disease plays a role in their pathogenesis. It is unknown whether subcortical and periventricular WMC have the same etiology. Methods: Non-demented subjects, aged 60–90 years, were randomly selected from two ongoing population based studies, the Zoetermeer Study (baseline 1975–1978) and the Rotterdam Study (baseline 1990–1993). Axial T1, T2 and PD weighted MRI images were obtained in 1995–1996. WMC were scored according to location, size and number. Number of plaques and intima media wall thickness (IMT) of the carotid arteries were measured as indicators of intracranial atherosclerosis. The relation between atherosclerosis and WMC was assessed by age and sex adjusted logistic regression. Results: 1084 subjects participated (response 65%). Prevalence of any WMC was 95%, of subcortical WMC 92%, and of periventricular WMC 79% respectively. IMT was associated with periventricular WMC (OR 1.2; 95%CI 1.0–1.4 per 10 µm IMT increase), but not with subcortical WMC. Increasing number of carotid plaques was associated with both periventricular and subcortical WMC (test for trend, p = 0.005 and p = 0.03, respectively). Conclusion: Intracranial atherosclerosis is associated with both periventricular and subcortical white matter changes.

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12 INFLAMMATION IN HIGH-GRADE CAROTID STENOSIS: ROLE OF MACROPHAGES AND T CELLS IN PLAQUE DESTABILIZATION. G. Stoll, S. Jander, M. Sitzer, R. Schumann, M. Schroeter, M. Siebler and H. Steinmetz. Dept. Neurology, Heinrich-Heine-Univ., Düsseldorf, Germany Inflammatory mechanisms have been implicated in the initiation and progression of atherosclerotic vascular lesions (Ross (1993) Nature 362 : 801– 809). In this study, endarterectomy specimens from 37 consecutive patient undergoing surgery for high grade ICA stenosis were stained immunocytochemically for T cells (CD3) and macrophages (CD68). Staining was quantitated by counting individual cells (CD3) or planimetry of immunostained areas (CD68). Plaque instability was determined by preoperative assessment of recent ischemic symptoms attributable to the stenosis as well as the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery (Siebler et al. (1993) 116 : 1005–1015). The percentage of macrophage-rich areas and the number of T cells per mm2 was significantly larger in recently symptomatic than asymptomatic patients (macrophages: 18 ± 10 vs. 11 ± 4, p = 0.005; T cells: 71.2 ± 34.4 vs. 40.5 ± 31.4, p = 0.005) and correlated to the individual microemboli count (macrophages: p = 0.05; T cells: p = 0.013). Our data suggest a role of plaque-infiltrating macrophages and T cells in the destabilization of high-grade ICA stenosis. (Supported by the Hermann- and Lilly-Schilling-Stiftung to G.S. and H.S.).

Amyotrophic Lateral Sclerosis – Motor Neuron Disease (1) 13 A SPORADIC CASE OF AMYOTROPHIC LATERAL SCLEROSISPARKINSONISM. Silani V, Brioschi A, Rango M, Bozzali M, Moggio M, Prelle A, Comi G, Gellera C°, Cappellari A, Bernasconi S, Braga M, Checcarelli N*, Pellegrini G*, Scarlato G. Institute of Neurology, Milano; *Department of Neurology, Ospedale Valduce, Como; °Istituto Neurologico Besta, Milano, Italy Several lines of evidence have indicated a possible involvement of the presynaptic dopaminergic system in amyotrophic lateral sclerosis (ALS) inducing several authors to consider parkinsonism (PD) associated with sporadic ALS simply variants of the disease. A 63-year-old man has admitted to the hospital because of a L-Dopa responsive-right emiparkinsonian syndrome. Main clinical findings were bradikynesia and rigidity. Family history was insignificant. After one year the patient developed definite ALS with upper left limb onset and bulbar impairment. No cognitive changes were demonstrated. Electromyographic studies confirmed the diagnosis. The cortical-spinal pathways were affected. Anti-ganglioside and paraneoplastic antibodies were negative. Th proton magnetic resonance spectroscopy (1H-MRS) detected a lactate peak in the basal ganglia. This finding suggested further screening for mitochondral abnormalities. Muscle biopsy showed neurogenic changes and a slight COX deficiency. Mitochondrial genetic screening resulted in multiple DNA deletions by PCR. By SSCP, no alteration in the migration pattern for SOD1 has been detected, but the full sequence analysis of the gene is still in progress. This case further indicates the need for a complete mitochondrial and SOD1 DNA analysis to gain insight into the mechanism of disease in the ALS-PD variants. 14 AN ADULT CASE OF SPINAL MUSCULAR ATROPHY (SMA) WITH ISOLATED DELETION OF EXON 8 OF SURVIVAL MOTOR NEURON (SMN) GENE. Toscano A, Annesi F*, Fazio MC, Mazzel R*, Romano M**, Pasqua A*, Vita G. Clinica Neurologica 2, University of Messina, *Laboratorio di Genetica Molecolare, C.N.R., Cosenza, **Servizio di Neurofisiopatologia, Villa Sofia, Palermo, Italy Deletions involving the SNIN gene and the neuronal apoptosis inhibitory protein (NAIP) gene are often found in patients with SMA. We have recently reviewed a number of patients with SMA from the molecular point of view. Among them, we report on a 38 year old patient that, at 32 years of age, started to complain of progressive limb muscle wasting and weakness and increasing difficulties in prolonged walking. He presented with a mild waddling gait and a difficult rising from squatting posture, marked muscle wasting and weakness of proximal muscles of lower limbs, hypertrophic calves and bilateral pes cavus. Serum CK was mildly elevated (380/420 µ/l). Concentric needle electromyography showed on both vastus lateralis muscles the presence of fibrillation potentials and positive sharp waves at rest; motor unit potentials were abnormally increased in

duration and amplitude and maximum effort pattern was markedly reduced. Similar changes were also present on deltoid, brachial biceps, hand dorsal interosseus, tibialis anterior and gastrocnemius muscles. Right vastus lateralis muscle biopsy revealed a marked loss of myofibers with a sclero-adipose replacement with fiber size variation due to atrophic and hypertrophic fibers. The great majority of remaining fibers belonged to type 2. These findings were indicative of recent denervation and previous denervation, followed by reinnervation. Polymerase chain reaction (PCR) analysis of telomeric and centromeric exons 7 and 8 on chromosome 5q13, showed a homozygous deletion of the telomeric exon 8, but no deletion of telomeric exon 7. In addition, exon 5 of the neuronal apoptosis inhibitory protein (NAIP) gene was not deleted. To our knowledge, this is the first description of an adult case of SMA with isolated deletion of the exon 8 of the SMN gene. 15 FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS. A STUDY OF ITS GENETIC TRANSMISSION. Khoris J1, Boukhaftane Y2, Rouleau G2, Camu W1 and the French Research Group on ALS. 1Laboratoire de Physiopathologie Neuromusculaire, INSERM CJF 97-02, Montpellier, France. 2 Centre de Recherche en Neurosciences, McGill University, Montréal, Canada About 10% of the amyotrophic lateral sclerosis cases are of familial inheritance (FALS). To date, the transmission of the disease is considered as autosomal dominant. In 10 to 20% of the FALS cases a mutation of the Cu/Zn superoxyde dismutase (SOD1) has been described. Especially in Europe, a homozygous mutation (D90A) responsible for the disease has been found, corresponding to a recessive mutation. Among the 11 families with SOD1 mutations in France, 4 (36%) are carrying either the D90A mutation or another recessive abnormality: L84F. We analysed the transmission of ALS in our families. 109 French ALS families were studied. The transmission is compatible with a recessive trait in 21% of the cases. The pedigree is restricted to a nuclear family with two affected patients (a father and his son, or an uncle and his nephew) in 47% of the families. The pedigree is multigenerational with at least 3 affected subjects on at least three generations in 32% of the cases. In the nuclear families there is an overrepresentation of the maternal transmission as in 66% of the cases the trait is transmitted by the mother. These results are strong to suggest that recessive forms of FALS are largely underestimated. Moreover, the gender-related desequilibrium of transmission may explain variations of penetrance in some families. Supported by ALSA, AFM and ARS. 16 A PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDY OF NEURONAL DYSFUNCTION IN MOTOR NEURON DISEASE. C. M. Ellis, A. Simmons, C. Andrew, A. Glover, J. Dawson, S. C. R. Williams, P. N. Leigh. London, UK Proton magnetic resonance spectroscopy (1H-MRS) has been used to assess neuronal loss and/or dysfunction in vivo by the measure of N-acetyl aspartate (NAA), a chemical localised to neurons and their processes. We have previously demonstrated a reduction in the NAA/(creatine and phosphocreatine) (Cr + PCr) ratio in the motor region in bulbar onset MND patients, attributed to neuronal loss/dysfunction leading to a reduction in NAA. We have expanded this analysis to evaluate absolute concentration of NAA, (Cr + PCr) and choline (Cho) in the motor region in 8 subjects with bulbar onset ALS, 8 with limb onset ALS and 8 healthy, age-matched controls. Single voxel 1H-MRS was performed (GE Signa 1.5T system) using a PRESS localisation sequence, TR 2000ms, TE1 136ms, TE2 272 ms. Metabolite concentrations were determined using the water signal as the internal standard and a correction was made for CSF contamination. We found no differences in the concentrations of NAA, (Cr + PCr) or Cho in the motor region on comparing the total ALS group and controls (p > 0.3). No difference was found in NAA in the bulbar onset group compared with the limb onset group ( p = 0.70), but (Cr + PCr) was significantly higher in the bulbar onset group ( p = 0.04). Our results suggest that the (Cr + PCr) may be affected by the pathological process in ALS, and this should be considered in the interpretation of metabolite peak area ratios. 17 CLINICAL AND MOLECULAR CHARACTERIZATION OF 14 FAMILIES WITH KENNEDY’S DISEASE. Mariotti C1, Gellera C1, Castellotti B1, Testa D1, Eoli M1, Pareyson D1, Confalonieri P1, Marconi R2, Siciliano G3, Grosso E4, Tezzon F5, Brunati L6, Marchini C7, Pomes A8, Taroni F1 and Di Donato S1. 1Istituto Neurologico Nazionale “C. Besta”, Milan; and Neurology Departements of 2 Grosseto, 3 Pisa, 4 Torino, 5 Verona, 6 Istituto “Don Gnocchi” Milan, 7 Udine, 8 Pordenone, Italy

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Kennedy’s disease is a rare X-linked recessive neurodegenerative disorder characterized by adult-onset of slowly progressive spinal and bulbar muscular atrophy (SBMA) often associated with signs of androgen insensitivity and mild sensory involvement. It has been demonstrated that the genetic mutation consists of an increased number of CAG repeats in the first exon of the androgen receptor gene (AR). As reported for other disorders caused by expansion of unstable CAG trinuclotide repeats, the age of onset and the severity of the disease significantly correlate with the size of the expanded region. We evaluated 35 patients, from 32 families, with clinical evidence of bulbar and spinal motor neuron dysfunction, variably associated with gynecomastia. The molecular analysis allowed the identification of 17 patients, from 14 families (44%), carrying a pathological CAG expansion in the AR gene. We also identified 10 women, from 4 pedigrees, heterozygous for expanded alleles. In one case chromosome X trisomy was present. In our series of patients the mean age of onset was 45.6 years (range 26–63); the two patients with onset of symptoms before age 30 had the largest expanded alleles. Gynecomastia was present in the 45% of the cases. Molecular diagnosis allowed the identification of a significant number of italian families with this rare syndrome, as well as a broad range of clinical and genetic variability. Further molecular and clinical investigations to characterize genotype-phenotype correlations are under way. 18 PERCUTANEOUS ENDOSCOPIC GASTROSTOMY (PEG) IN AMYOTROPHIC LATERAL SCLEROSIS (ALS): WHEN IS IT BEST TO PERFORM IT? Chiò A, Cucatto A, Terreni AA, Calvo A, DaPont C, Rivetti M, Onorati P, Schiffer D, Meineri P1, Finocchiaro E. Torino, 1Cuneo, Italy Bulbar involvement in ALS is related to a worse prognosis, due to the higher risk of pulmonary aspiration and undernutrition. PEG is used as symptomatic treatment for dysphagia, but its effects on survival and nutritional status and the best timing for performing it remain unclear. Since 1993, 46 patients with definite ALS (23 men and 23 women, mean age 62.0 years) underwent PEG. Patient evaluations included forced vital capacity (FVC), MRC and Norris scale, body mass index [BMI], health body weight [HBW], current weight [CW], albumin, and transferrin. Daily energy and protein intake followed recommended dietary allowances. These patients have been compared to 92 ALS cases diagnosed between 1989 and 1992, matched by age, gender, and severity of disease. At the time of PEG, mean weight loss (WL = HBW/CW) was 15.5% (SD 14.0), and mean BMI was 21.9 (SD 6.1). There was no procedure-related mortality, nor major complications. The median survival from ALS onset (1305 days) was slightly higher than that of the control group (1203 days) (p = n.s). A worse survival after PEG was significantly related to FVC ≤ 70% ( p = 0.03), and LW ≤ 10% ( p = 0.01). In our experience PEG is safe and ameliorates nutritional parameters and quality of life of ALS patients, but has little effect on survival. It should be performed relatively early in the course of ALS, when WL does not exceed 10%.

Amyotrophic Lateral Sclerosis – Motor Neuron Disease (2) 19 AMYOTROPHIC LATERAL SCLEROSIS: A CASE-CONTROL STUDY ON LIFELONG OCCUPATIONAL HISTORY. Cucatto A, Terreni AA, Calvo A, Juenemann C, Mocellini C1, Chiò A. Torino, Savigliano1, Italy Amyotrophic lateral sclerosis (ALS) has been associated with various occupational exposures, the most consistent of which is agriculture. However, all but one studies assessed only the last occupation of the patients. In the present case-control study we evaluated the risk of developing ALS considering lifelong occupational exposures and the influence of cultural background, as indicated by place of birth. The cases were 155 patients with definite ALS, consecutively seen between 1993 and 1997; the controls were 310 patients affected by other neurologic diseases, matched by sex, age (± 4 years), and place of birth (1 control) or residence (1 control). All jobs made and the years in which each job began and ended were asked. Occupations were classified according to ILO Standard Classification of Occupations (ISCO-88). The demographic characteristics of cases and controls were similar. No significant associations between occupations and ALS was found. The only occupations with on odds ratio (OR) more than 2.0 were painters and varnishers (2.05, 95% confidence interval [c.i.] 0.65–6.5), textile workers (2.1, 0.88–4.97), motor vehicle drivers (2.1, 0.92–4.83), and rubber product workers (2.03, 0.96–2.76). Odds ratio for farmers was 1.19 (0.70–2.02) and that for livestock breeders 3.43 (0.81–14.48). Our findings indicate (1) the absence of a definite occupational risk in ALS, and (2) the relevance of considering cultural back-

ground and lifelong occupational history when comparing cases and controls in ALS. 20 ALTERED TRANSFER FUNCTION OF ARTERIAL BLOOD PRESSURE AND HEART RATE IN AMYOTROPHIC LATERAL SCLEROSIS. D. Linden, R. R. Diehl, P. Berlit. Autonomic Laboratory, Dept. of Neurology, Krupp Hospital, Essen, Germany Subclinical involvement of autonomic function may be present in the early course of ALS while clinically relevant autonomic disturbances have been reported for respirator-dependent patients. We studied 18 patients with early-stage ALS and 18 age-matched controls by means of standard autonomic tests (heart rate response to deep breathing and tilt-table testing) and spectral analysis of heart rate (HR) and arterial blood pressure (ABP) using the associated transfer function as a measure of baroreflex sensitivity for the mid frequency band (MF band, 0.05–0.15 Hz) and as a measure of cardiorespiratory transfer for the high frequency band (HF band, 0.15–0.33 Hz). For both supine and tilted position mean HR and ABP were increased in ALS while results of standard autonomic tests were similar for ALS and controls. Transfer function analysis revealed reduced baroreflex sensitivity and diminished cardiorespiratory transfer during normal breathing. Our results suggest that cardiovascular autonomic functions are intact in patients with ALS. However, there is evidence of sympathetic enhancement and vagal withdrawal accompanied by reduced baroreflex sensitivity. These findings are similar to those reported for essential hypertension and may suggest that both disorders have some pathophysiological features in common. 21 CYCLIN DEPENDENT KINASE (cdk-5) INDUCES APOPTOSIS IN CULTURED MAMMALIAN CELLS AND ACCUMULATES IN LIPOFUSCIN IN AMYOTROPHIC LATERAL SCLEROSIS (ALS). N. P. S. Bajaj, P. N. Leigh, C. C. J. Miller. Department of Neurosciences and Clinical Neuroscience, Institute of Psychiatry and King’s College Medical and Dental School, De Crespigny Park, Camberwell, London, UK Cdk-5 is a neurofilament kinase that will phosphorylate neurofilaments such that they resemble the hyperphosphorylated neurofilament aggregates seen in some neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To study the distribution of cdk-5 in ALS tissues, we took spinal cord sections from sporadic and familial cases of ALS, caused by mutations in the SOD1 gene, together with aged controls. Staining these sections for cdk-5 revealed high levels of this kinase in lipofuscin in motor neurones in ALS. Over-expression of cdk-5 and its activator p35 in fibroblasts was shown to induce cell death. Further studies have demonstrated that this mode of cell death is via apoptotic mechanisms. Together, these studies suggest that cdk-5 may be involved in the neurodegenerative process in ALS. 22 ANTIOXIDANT DRUGS DO NOT PROLONG SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS. P. Janik, H. Kwieciñski, Z. Jamrozik, A. Opuchlik. Warsaw, Poland Much evidence already supports the potential usefulness of antioxidant agents in the treatment of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Recent data even suggest that selegiline can ameliorate the progression of Parkinson disease and Alzheimer disease. Vitamin E (a-tocopherol) has been shown to slow the progression of Alzheimer disease and its therapeutic benefit was also observed in a transgenic model of familial ALS. We conducted a randomized treatment trial with oral vitamin E (600 IU daily) and selegiline (10 mg daily) for 18 months in 67 patients with sporadic ALS. The primary end points were survival and functional status. Thirty five patients were randomly assigned to receive antioxidative therapy (vitamin E and selegiline) and the remaining 32 patients were considered the ALS controls who received symptomatic treatment. Baseline clinical characteristics including disease duration and pulmonary function did not differ between the two groups. Results: After 18 months 13 (37.1%) treated patients and 14 (43.8%) controls reached the primary end point. In the treatment group 11 patients died and 2 underwent tracheostomy whereas in the control group 13 patients died and 1 patient was tracheostomized. No significant differences were found in Kaplan-Meier survival curves among the two groups. We observed no treatment effect on functional status as measured by Norris score. Conclusion: The results of our study failed to show a beneficial effect of antioxidative therapy for 18 months on the disease course in ALS.

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23 THE IRISH MOTOR NEURON DISEASE REGISTER. B. J. Traynor, M. Codd, B. Corr, C. Forde, E. Frost, O. Hardiman Motor neuron disease (MND) is a degenerative disorder affecting motor neurons characterised by a combination of upper and lower motor neuron signs with progression. Retrospective studies report an incidence of MND ranging from 0.4 to 1.8/100,000 per year. This study prospectively documents the incidence and prevalence of MND in Ireland from January 1995 to January 1998. As an island Ireland is ideal for such a study because the community is well defined. Using multiple sources of information, 209 Irish individuals fulfilled the El Escorial criteria. The age-adjusted incidence rate was 2.75/100,000 for the population over 15 (95% CI, 2.16– 2.44). The male and female age-adjusted rates was 3.30 and 2.22 respectively. Mean annual incidence was higher for men in all age groups, with the exception of the 70–74 age group. In both sexes incidence rates generally increased with advancing age reaching a peak of 80–84 and 70–74 for men and women respectively and declining rapidly thereafter. Median age at diagnosis was 64.4 years of age (range, 20.2–87). Prospective studies are inherently more precise than mortality statistics in measuring incidence rates, because of possible underreporting on death certification. A prospective study of MND during the year 1989 performed in Scotland reported a crude incidence of 2.24/100,000 per year. According to our figures, which span 3 years, crude incidence of MND in Ireland is higher than reported for most other countries with the exception of Varmland, Sweden and middle Finland. Our study provides the most accurate epidemiological data on MND reported to date. 24 MEASUREMENT OF INSPIRATORY MUSCLE STRENGTH (IMS) IN PATIENTS WITH MOTOR NEURONE DISEASE (MND). Ra. Lyall, J. Moxham and P. N. Leigh. Departments of Clinical Neuroscience’s and Respiratory Medicine, Kings College Hospital, London, UK Objective measurements of IMS are of use in the management of a variety of neuromuscular disorders, but methods of measurement vary with respect to accuracy and ease of application. Vital capacity (VC) and maximal inspiratory mouth pressures (MIP) were measured in 16 MND patients. Additionally, the trans-diaphragmatic pressure (Pdi) elicited during cervical magnetic stimulation of the phrenic nerves (CMSPdi) was performed after placement of oesophageal and gastric balloon catheters. During maximal sniff manoeuvres, the Sniff Pdi was acquired and concurrently the sniff nasal pressure (SNP) obtained using a plug placed in one nostril. In five patients, the SNP was recorded concurrently by our conventional means (computer running Labview software) and by a portable pressure meter. CMSPdi correlated well with Sniff Pdi (correlation coefficient {r} = 0.83, p < 0.001) and SNP (r = 0.78, p <0.001), but less with the percentage predicted VC (r = 0.65, p = 0.006) and MIP (r = 0.37, p = 0.157). The SNP as recorded by portable pressure meter and computer was not significantly different (p = 0.791). Whilst we acknowledge that CMSPdi is primarily a measure of diaphragm strength and other tests reflect global IMS, we suggest the maximal SNP as a more sensitive noninvasive screening tool for inspiratory muscle weakness than VC and MIP. Additionally the SNP has the advantages of utilising a simple manoeuvre, without a mouth piece and is easily portable. Support from Amgen PLC.

Genetics of Ataxias 25 NO MUTATIONS IN THE GENE RESPONSIBLE FOR ATAXIA TELANGIECTASIA IN PATIENTS WITH CEREBELLAR ATAXIA. Sharon Hassin-Baer, Anat Bar-Shira, Shlomit Gilad, Yaron Galanty, Rami Khosravi, Alexander Lossos, Nir Giladi, Yochanan Goldhammer and Yosef Shiloh. Department of Neurology and Department of Human Genetics, Sackler school of Medicine, Tel-Aviv University, Tel-Aviv, Israel Objective: To identify mutations in the gene for Ataxia Telangiectasia (AT), designated ATM (Ataxia Telangiectasia- mutated) in patients with progressive cerebellar ataxia. Background: A-T is a devastating multisystem autosomal; recessive disease, manifesting in early childhood with progressive neurological degeneration composed mainly of ataxia. Other features are oculocutaneous telangiectasia, immune deficiency and cancer predisposition. Truncation mutations in ATM, which codes for a protein involved in cell cycle control and response to genotoxic damage, were identified in nearly all the patients. The clinical phenotype of missense mutations in ATM is unknown but might consist of a partial A-T phenotype, perhaps a

progressive cerebellar syndrome. The molecular basis of many cases of familial ataxia transmitted in an autosomal recessive manner is unknown, therefor we speculated that mild mutations in ATM might cause late onset or slowly progressive ataxia without other features of A-T. Methods: We searched for patients with either familial (recessive) or sporadic idiopathic cerebellar ataxia. The patients were interviewed and examined and blood samples were collected for immunoglobulin and, alpha-fetoprotein levels and molecular studies. The ATM coding region was amplified and mutations were searched for by Restriction Endonuclease Fingerprinting. Results: 34 patients with idiopathic cerebellar ataxia were screened and characterized clinically. Their age ranged between 3 to 77 years (mean: 34). Consanguinity was documented in 2 cases and there were 12 familial cases (from 7 other families). All patients had normal levels of immunoglobulins, and alpha-fetoprotein. We found no mutations in the ATM coding region in any of the patients. Conclusions: ATM mutations are probably not a common cause of progressive ataxia other than classical A-T. 26 AUTOSOMAL DOMINANT CEREBELLAR ATAXIA TYPE II: GENETIC AND CLINICAL STUDY. Giunti P*, David G, Stevanin G, Worth P*, Brice A, Wood N*. *Institute of Neurology, London UK; Inserm U289 Hôpital de la Salpetrière, Paris, France Autosomal dominant cerebellar ataxia (ADCA) type II is clinically distinguished from all the others ADCAs by the presence of pigmentary macular dystrophy. We have identified and clinically evaluated 14 families with ADCA II originating from Brazil, Italy, West Indies, Philippines, UK. Recently the mutation that causes the disease has been identified as a highly unstable CAG expansion in the coding region of the SCA7 gene. Expanded and normal alleles ranged from 39 to 120 and from 7 to 34 repeats, respectively. A statistically significant negative correlation has been found between number of CAG and age at onset. We observed striking anticipation that is greater in paternal transmissions with earlier age at onset and with a more rapid clinical course in successive generations.This accounts for some cases of incomplete penetrance with analysis of pedigrees revealing the presence of obligate carriers with an age at death and/or examination ≤ 72 years. Parent-child pair analysis confirms that the underlying molecular mechanism of anticipation is the meiotic instability of the CAG expansion.Thirteen out of fourteen ADCA II families carried the SCA7 expansion showing that ADCA II, appears to be genetically heterogeneous. 27 CHARACTERIZATION OF CACNA1A MUTATIONS IN FAMILIAL AND SPORADIC FORMS OF EPISODIC ATAXIA TYPE 2 (EA-2). Denier Ch1, Ducros A1, Joutel A1, Vahedi K2, Bousser M-G2, TournierLasserve El. 1INSERM U 25, Faculté Necker, 2 Hopital Lariboisière, Paris, France EA-2 is an autosomal dominant disorder characterized by acetalozamide responsive recurrent attacks of cerebellar ataxia, sometimes associated with interictal nystagmus and mild progressive cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage dependant calcium channel. Two mutations disrupting the reading frame have been identified in 2 EA-2 unrelated families. Interestingly, missense mutations of CACNA1A have been identified in familial hemiplegic migraine, and small expanded CAG repeats in spinocerebellar ataxia 6 (SCA 6). Moreover, recently, a CAG expansion was identified in three families with EA-2 features associated to a progressive ataxia. Design/Methods: 9 EA-2 families and 11 sporadic cases were selected for this study. All 47 exons of CACNA1A are screened for point mutations using a combination of SSCP and sequencing analysis. In addition, the length of the CAG repeat is determined in all patients. Results/Conclusion: 10 exons have already been screened, leading for the detection of 2 potential new mutations in exons 29 and 23. Our study will help to determine if all EA-2 mutations are nonsense mutations, if they are clusterized in specific domain, and to evaluate the role of an expansion of the CAG repeat in the occurrence of this phenotype. 28 THE FRIEDREICH’S ATAXIA MUTATION CONFERS CELLULAR SENSITIVITY TO OXIDANT STRESS WHICH IS RESCUED BY IRON CHELATORS AND INHIBITORS OF APOPTOSIS. Wong A, Taroni F, Gellera C, Cortopassi GA. Davis, Usa; Milan, Italy Friedreich’s ataxia (FA) is the most frequent hereditary ataxia (1 : 50,000). The most common mutation in FA is an intronic GAA triplet-repeat ex-

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pansion that reduces expression of frataxin, a novel mitochondrial protein whose function is unknown. Disruption of the yeast frataxin homolog leads to mitochondrial iron overload. As iron is redox-active and a critical reagent in Fenton chemistry, an increase in reactive oxygen species may result. Fibroblasts from 5 FA patients homozygous for the GAA expansion and 2 controls were exposed to 50–700 µM H2O2 for six hours. Cell viability was then determined by the trypan blue exclusion assay. FA cells were significantly more sensitive to H2O2 than controls, and this sensitivity significantly correlated with GAA repeat size. This oxidant sensitivity appears to require Ca2+, as depletion of Ca2+ from the intracellular compartment following treatment with BAPTA-AM, an intracellular Ca2+ chelator, provided significant protection for all cell lines against H2O2-induced toxicity. Notably, FA cells were also significantly more sensitive to exogenous iron, and the iron chelator deferoxamine rescued FA but not control cells from oxidant-induced death. Finally, treatment with apoptosis inhibitors rescued FA but not control cells, consistent with the possibility that a mitochondrial apoptosis pathway is induced in FA cells downstream of oxidant stress. These results indicate that FA is a neurodegenerative disease of mitochondrial Fenton chemistry and provide the rationale for potential therapeutic strategies. (Supported by a NIH grant to GAC and a Telethon-Italia grant to FT).

29 A NEW MUTATION IN THE HUMAN VOLTAGE GATED POTASSIUM CHANNEL (Kv1.1) ASSOCIATES WITH EPISODIC ATAXIA TYPE I AND EPILEPSY. Hanna MG1, Zuberi SM2, Eunson L1, De Silva R3, Tolmie J4, McWilliam RC2, Stephenson JPB2 and Wood NW1. 1Neurogenetics section Institute of Neurology, Queen Square, London, UK. 2 Department of Neurology and Child Development, Royal Hospital for Sick Children, Glasgow, Scotland. 3 Department of Neurology, Institute of Neurological Sciences, Glasgow, Scotland. 4 Institute of Medical Genetics, Royal Hospital for Sick Children, Glasgow, Scotland We have identified a British Kindred in which five members over three generations have episodic ataxia type I. In addition two affected family members have partial epilepsy. We will present the detailed clinical (with video of attacks) and EEG findings in this kindred. Direct genomic DNA sequence analysis of the shaker related voltage gated potassium channel on chromosome 12p (Kv1.1) identified a novel heterozygous transition point mutation at position C677G. The mutation segregated with the disease and was not detected in 200 control chromosomes using a mismatch PCR technique. This mutation caused a radical amino acid substitution in an evolutionarily conserved position and would be predicted to impair the function of the second transmembrane domain of the channel. We suggest that in addition to causing EA1 in all affected members this mutation may be relevant to the genesis of the partial epilepsy observed in two members. Five lines of evidence support this suggestion. First, on theoretical grounds decreased function of Kv1.1 is predicted to impair neuronal repolarisation and increase excitability. Second, drugs which block Kv1.1 are potent proconvulsants in man. Third, analysis of affected members in other reported EAI kindreds shows a significantly higher incidence of epilepsy than in unaffected relatives. Fourth, a Kv1.1 knockout mouse with a severe epilepsy phenotype has been described. Finally, a benign form of neonatal epilepsy has recently been shown to associate with a potassium channel on chromosome 20. Taken together these observations suggest that dysfunction of potassium channels may be relevant to the genesis of epilepsy in humans.

Extrapyramidal Disorders (1) 30 IS CEREBELLUM THE SITE OF GENESIS OF ORTHOSTATIC TREMOR? F. Setta1, J. Jacquy2, J. Hildebrand3, M. Manto3. 1Neurologia, La Sapienza, Roma (I); 2Neurologie, CHU-Charleroi, Charleroi (B); 3Neurologie, Hôpital Erasme-ULB, Bruxelles (B) Orthostatic tremor (OT) is characterized by a high-frequency burst firing (13 to 18 Hz) in weight-bearing muscles. Its pathophysiology is poorly understood. Although cerebellum is considered as a primary site for tremorgenesis, OT has not been described so far in association with an isolated cerebellar disease. We report OT in 3 patients presenting ataxia due to sporadic cerebellar cortical atrophy (CCA). The 3 patients (1 man, 2 women; age: 48, 61 and 63) complained of unsteadiness while standing, and exhibited a typical cerebellar syndrome with cerebellar dysarthria, intention tremor and limbs dysmetria. None exhibited pyramidal or extra-pyramidal

signs. Cerebellar atrophy was demonstrated by brain MRI in 2 patients and by brain CT-scan in 1 patient. Recordings of surface EMG activity showed a typical OT in weight-bearing muscles while standing, with a frequency of 14 Hz, 15 Hz and 14 Hz respectively. Dysmetria of fast wrist movements in upper limbs was demonstrated in all, with a delayed onset latency of antagonist activity. Only 1 patient sligthly improved with oral clonazepam. This is the first report showing that OT may be associated with CCA, indicating that cerebellum might be the site of genesis of OT. OT might have been underestimated in patients with degenerative disease of cerebellum. We conclude that patients with CCA should be investigated for OT. 31 THE MOVEMENT DISORDERS OF THE PARKINSONISM-DEMENTIA COMPLEX OF GUAM. H. R. Morris, N. W. Wood, A. J. Lees, J. C. Steele. London, UK The Parkinsonism dementia complex of Guam has been studied intensively over the last forty years in the search for an environmental and now a genetic factor in its aetiology. The pathology of the disease involves tau neurofibrillary tangle formation and cell loss in the mesial temporal cortex, basal ganglia and brainstem reticular formation. The clinical features of the disease have been comparatively under-reported. We report a detailed assessement of a series of clinical syndromes: 1. Mesial temporal dementia with widespread fasciculation 2. Tremulous parkinsonism with amyotrophy and fasciculation 3. Writing tremor 4. Axial rigidity and supranuclear gaze palsy 5 L-DOPA responsive Parkinsonism with LDOPA induced dyskinsesia 6 Gait asterexis 7 Oculogyric crisis We discuss the pathological confirmation of diagnosis for some of these cases. The diversity of these cases illustrates the range of clinical signs seen in the Parkinsonism dementia complex of Guam and the co-ocurrence of anterior horn cell signs in some patients. We suggest that this clinical spectrum is likely to be due to differential cell loss or functional differences between individuals with the same underlying disease process. Study of the clinical spectrum of these diseases with fine pathological and functional imaging correlation may provide new insight into the functional anatomy of the basal ganglia.

32 THALAMIC STIMULATION IN TREMOR DISORDERS. J. Vesper, Th. Funk, B.-C. Kern, U. Jahnke, M. Straschill, M. Brock. Berlin, Germany Thermolesional thalamotomy was until now standard procedure in drug resistant tremor disorders. High-frequency stimulation, however is a nondestructive method offering an alternative approach. We report on our experience with this new technique. Material and Method: Stereotactical placement is performed under intraoperative functional mapping by recording techniques as well as stimulation testing. Between March 1996 and December 1997 stimulations were performed in 21 patients in the ventral intermediate nucleus (VIM) of the thalamus. Seven (7) patients with tremordominant Parkinson’s disease (PD), 9 suffering from essential tremor (ET) and 5 with tremor related to brain stem disorders were treated. Evaluation was performed using the tremor scale according to Fahn. The ADL-score of the UPDRS was applied additionally. Results: Tremor reduction was achieved in all patients. The best results (98%reduction) were obtained in cases of ET. In PD results were almost as favorable (mean reduction: 93%). Minor speech disturbances were observed in all 3 patients submitted to bilateral stimulation depending on the stimulation amplitude. In cases of brain stem lesions gross tremor was reduced to a level of impairement enabling the patients to perform normal daily life activities (mean reduction: 85%). Conclusion: Deep brain stimulation in the ventrolateral thalamic region is an effective treatment for various tremor disorders. The option to vary the stimulation parameters postoperatively allows an optimization of the effect. Therefore possible side effects are mostly reversible. 33 MIDBRAIN DYSKINESIA. P. Rondot1, N. Bathien2, G. Said1, D. Fredy2. 1Hôpital de Bicêtre; 2 Hôpital Sainte Anne, Paris, France Lesion of midbrain can provoke abnormal movements of several types as illustrated by the following eight cases: midbrain tremor similar to parkinsonian tremor, rhythmic palatal myoclonus, cerebellar tremor, hyperkinetic tremor (hyperkinesie volitionnelle). Midbrain tremor, like parkinsonian tremor, is a resting tremor, but it also manifests itself as a postural

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and an action tremor. Three cases are here reported: one due to a midbrain metastasis of a breast carcinoma, another provoked by a cavernoma and the third due to a bullet which terminated its path in the midbrain. In the first and third cases, fixation of labelled levodopa indicated a striatal dopamine deficiency on the side of the lesion. Administration of dopamine stopped the tremor which most likely was due to dopamine deficiency. Palatal myoclonus occurs after a lesion of the central tegmental bundle, lesion followed by hypertrophy of the bulbar olivary. The neuropathological data of the present case showed a medial midbrain cavernoma, provoking a Wernekink syndrome. In this case, improvement of myoclonus by propranolol suggests a state of adrenergic hypersensibility. The classical intentional cerebellar tremor is observed when the lesions are localised to the dentato-thalamic pathway. Such a tremor is one of the elements of the above mentioned Wemekink syndrome. It can be allievated partially by gabaergic drugs, but its only partial improvement suggests that several neuromediators are also involved. The hyperkinetic tremor manifests itself as rhythmical movements of increasing amplitude, interfering with the voluntary movements. It is an intentional tremor, yet it is amplified by associated lesions of deep sensations. Such a tremor is relatively common in multiple sclerosis, as mentioned in two cases of this study.

34 HIGH PREVALENCE OF PROGRESSIVE SUPRANUCLEAR PALSY (PSP) IN CARIBBEAN ISLANDS MAY BE RELATED TO THE NEUROTOXICITY OF BENZYL-TETRA-HYDRO-ISOQUINOLINES ISSUED FROM HERBAL TEA. D. Caparros-Lefebvre, V. Bolivar, P. Pollak, C. Sengler, G. Mevel, A. Lannuzel, H. Joseph. CHU Antilles-Guyane, CHU Grenoble, France We tried to assess the prevalence of PSP and its relation with dietary habits of tropical herbal tea and fruits in patients native from the French West Indies (FWI). PSP represents less than 4% of all parkinsonian syndromes in Europe and North America. In comparison, neurological practice in the FWI suggests a high percentage of levodopa-resistant parkinsonism, resembling to PSP. In this region, dietary habits include fruits and herbal tea of annona muricata, annona squamosa and annona reticulata, which contain benzyl-tetra-hydro-isoquinolines (BTHQ). These alcaloids are neurotoxic and induce parkinsonism in animals. Design/Methods: We carried out a standardised clinical, neurophysiological, cognitive and radiological evaluation of 68 consecutive parkinsonian outpatients referred to our neurological department from September 1996 to November 1997. We assessed parkinsonian symptoms according to the unified Parkinson’s disease rating scale, and PSP criteria which have been recently validated. Patients underwent standard biological study, EMG, and brain CT or MRI. They were asked about their use of both tropical fruits and herbal tea. Amongst these patients, 3 were Caucasian, 7 had Indian origins, and 58 were Afro-Caribbean. Results: Out of the 68 patients, 31 had all criteria for a probable PSP, and 20 had a possible PSP, due to the lack of 1 criterion, which was a family history in 4, the paucity of ophthalmologic signs in 13, and levodopa responsiveness in 3. One patient had a multiple system atrophy. In addition, 44 of the possible or probable PSP had evidence of spinal motor involvement. Only 16 (23.5%) patients met the criteria of idiopathic Parkinson’s disease. All patients with possible or probable PSP (75%) used daily or weekly herbal tea of annona muricata or fruits of annona squamosa, containing BTHQ, unlike patients with Parkinson’s disease (χ2 = 32; P < 0.001). Conclusion: Our study suggests a relationship between the ingestion of BTHQ and the high prevalence of PSP in FWI. This hypothesis is supported by the dopaminergic toxicity of methyl or benzyl-quinolines in animals. In 4 patients, the familial history of PSP could indicate a genetic susceptibility to BTHQ toxicity.

35 CLINICAL FEATURES OF 1134 CASES OF DYSTONIA. THE EPIDEMIOLOGICAL STUDY OF DYSTONIA IN EUROPE (ESDE) COLLABORATIVE GROUP. Coordinator: T. T. Warner. London, U.K. ESDE is a multicentre study of the prevalence and clinical features of all cases of diagnosed dystonia registered at 12 movement disorder centres in 8 countries during 1997. Clinical data of 1134 cases are presented in this paper. 958 (84%) of patients had primary (idiopathic) dystonia of which 728 (76%) were focal and 200 (21%) segmental. Cervical dystonia was the commonest form of focal dystonia. A family history was recorded most frequently for primary generalised dystonia (27%) and only in 6% of individuals with focal dystonia.161 cases of secondary dystonia were seen, the commonest cause being neuroleptic exposure. There was a significant excess of female patients for primary segmental and focal dystonia. The fe-

male:male ratios for cervical dystonia, blepharospasm and laryngeal dystonia were 1.4 : 1, 2.3 : 1 and 2.6 : 1 respectively. However, this ratio was reversed for writer’s cramp and focal limb dystonia (1 : 1.3 and 1 : 1.8 respectively). A novel finding was the effect of sex on age of onset. A significantly earlier age of onset in males compared to females was seen for primary segmental (mean ages 44.6 versus 53.3) and focal dystonia (43.8 versus 47.8). This trend was also apparent for cervical dystonia, blepharospasm, and laryngeal dystonia. For writer’s cramp and focal limb dystonia, however, this trend again was reversed with a significantly earlier age of onset in females. Possible reasons for these sex differences will be discussed.

Child Neurology 36 IDENTIFICATION AND EXPRESSION OF RARE MUTATIONS IN ACID β-GLUCOCEREBROSIDASE CAUSING NEURONOPATHIC TYPE II AND III GAUCHER DISEASE IN NON-JEWISH PATIENTS. Bettina Albrecht1, Peter Bauer1, Annette Pautzke1, Franziska Schöpa1, Eilhard Mix1, Klaus Harzer2, Stefan Maeser3, Mia Horowitz4, Arndt Rolfs1. 1Klinik für Neurologie, Universität Rostock; 2Institut für Hirnforschung, Tübingen; 3Genzyme Corp., Alzenau, Germany; 4Dept. of Cell Research and Immunology Tel Aviv University, Israel Mutations of the acid β-glucocerebrosidase gene on chromosome 1q21 lead to deficiency of its enzyme product, a lysosomal hydrolase and the accumulation of glucosylceramide in monocytes and glial cells. The resultant storage disorder, Gaucher disease (GD), is characterized by pancytopenia, hepatosplenomegaly in presence (types II and III) or absence (type I) of neurological involvement. Analyses of genotype/phenotype correlations are relevant in formulating decisions regarding e.g. therapeutic strategies, particularly for affected families of non-Jewish GD ancestry whose mutations are mostly private. Within the scope of a prospective sequencing study in patients with type II and III GD we analyzed the complete coding glucocerebrosidase gene. In 11 patients with neuronopathic GD we found exclusively the 304 Tyr→Cys and 237 Ser→Phe mutations and with a significant higher frequence, but not exculsively, the 444 Leu→Pro (but not 444 Leu→Arg) and 409 Asp→His mutations. To understand the correlation between the phenotypic expression exerted by these mutations and the biochemical defect associated with them, the mutations were expressed in human neuronal and non-neuronal cells using the T7/EMC/vaccinia virus expression system published by Pasmanik-Chor et al. (1997). This assay allows to investigate in a cell-specific environment RNA stability, protein stability and in situ activity of the enzyme and will clarify the cell-specific interaction of the genetic defect with the specific metabolism of brain-derived cells.

37 PROTEOLIPID PROTEIN GENE INVOLVMENT IN LEUKODYSTROPHIES SUGGESTING A DYSMYELINATING PROCESS. Cailloux F*, Giraud G, Isabelle V*, Courtois V*, Mimault C*, J Pharn Dinh W, Boespflug-Tanguy O* and the European Network on Brain Dysmyelinating Disease. (ENBDD) clinical group. *Clermont-Ferrand, France and Paris, France Among the numerous leukodystrophies without biological markers, we individualised those suggesting a developmental defect of myelination by: (1) a very early onset abnormal motor milestones without rapid degradation, (2) severe abnormal CNS nerve conduction velocities (3) a CNS hypomyelination on MRI analysis. Among the 198 undetermined leukodystrophies we collected, 154 suggested a dysmyelinating process. In 131, we performed an extensive molecular analysis of the proteolipoprotein gene (PLP), a gene localized in the Xq22 region which codes in the oligodendrocytes for the main protein of the CNS myelin, PLP and DM20. In the 89 patients with neurological signs typical of Pelizaeus Merzbacher Disease (PMD), large duplication of the PLP gene was observed in the majority of cases (50%), whereas point mutation was found in 25% of cases and no abnormalities in 25%. In the 42 cases without a typical PM1) aspect, no PLP abnormalities have been found. These results suggest a PLP gene involvement only in clinically select patients and a genetic heterogeneity essentially in the group of patients with a more severe forms. ENBDD: Germany: M. Baethmann, T. Wit (Essen), A. Kohischutter (Hamburg), D. Rating (Heidelberg); Italy: E. Bertini (Roma), G. Uziel (Milano); England: R. Surtees (London); France: J. M. Cuisset, L. Vallee (Lille) P. Landrieu (Bicetre), M. Mayer, D. Rodriguez (Paris), S. Peudenier (Rennes).

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38 MUTATIONS IN THE DOUBLECORTIN GENE CAUSES SUBCORTICAL LAMINAR HETEROTOPIA (SCLH) IN FEMALE AND LISSENCEPHALY IN MALE. J.-M. Pinard #, V. Desportes*, F. Francis*, J. Motte£, I. Snoeck°, C. Beldjord*, J. Chelly*. # Garches, *Paris, £ Reims (France). °Amsterdam (The Netherlands). [email protected]. France Subcortical laminar heterotopia is a defect of the cortical development with homogeneous anatomical and clinical characteristics: bilateral subcortical band of grey matter heterotopia, epilepsy and mental retardation. SCLH affects mainly females. Lissencephalies are an other group of cortical dysgenesis with heterogeneous characteristics: diffuse agyria or diffuse pachygyria, severe mental retardation and intractable epilepsy. Mutations in the doublecortin gene, linked to Xq22.3, cause SCLH in heterozygous females and lissencephaly in hemizygous males. Here we report the clinical and genetic mutations study carried out in 4 multiplex families with females affected with SCLH and males affected with lissencephaly, and in 13 sporadic patients with SCLH (11 females and 2 males). Patients have various origins (European, Asian, Indian, West Indies). Most female patients with SCLH (14/15) and male patients with lissencephaly show a mutation in the doublecortin gene, mostly in exon 3. Nonsense mutations in females seem to be associated with more severe clinical features. However, in females, this correlation could be modulated by the random pattern of X chromosome inactivation. We are studying sporadic patients and families with SCLH or lissencephaly and we can provide prenatal diagnosis. Pathological and genetic studies of the doublecortin gene and protein will contribute to a better understanding of the human cortical development. 39 LONG-TERM SELECTIVE IGG IMMUNOADSORPTION IMPROVES RASMUSSEN’S ENCEPHALITIS (RE). C. Antozzi, T. Granata*, N. Aurisano, G. Zardini**, P. Confalonieri, G. Airaghi**, R. Spreafico*** and R. Mantegazza. Dept. of Neuromuscular Research; *Dept. of Child Neurology; ***Dept. of Experimental Neurophysiology and Epileptology; **Language Disorder Unit, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy RE is childhood epilepsy characterized by partial and secondarily generalized seizures and recurrent status epilepticus associated with progressive dysfunction of one cerebral hemisphere and cognitive decline; it is drugresistant and the only effective treatment is functional hemispherectomy. Autoantibodies to glutamate receptor 3 (GluR3) and a transient efficacy of plasma exchange suggest an immune pathogenesis. We used protein A immunoadsorption (PAI) as an alternative to hemispherectomy in a RE patient every 4–6 weeks for 15 months. GluR3 antibodies were assayed by an ELISA test using 2 peptides corresponding to regions of GluR3. The patient was monitored by neurological and neuropsychological examinations, and EEG recordings. Seizure frequency, neuropsychological deficits and anti-GluR3 antibodies were markedly reduced during follow-up. The efficacy of protein A, which removes selectively IgG, supports the autoimmune hypothesis and strongly implicates GluR3 antibodies as the pathogenetic agent of RE; moreover, an effective immunosuppressive treatment should be considered as RE is diagnosed, and PAI is suggested as an alternative to functional hemispherectomy. 40 DEVELOPMENTAL DEFECT OF MYELINATION DUE TO PROTEOLIPIDPROTEIN (PLP) MUTATIONS IN HEREDITARY SPASTIC PARAPLEGIA (SPG) OF CHILDHOOD ONSET. Mimault C*, Pitiot G*, Courtois V*, Giraud W, Bertini E**, Baethmann W, Fontan D°, Uziel G+, Voit T, Bernard I°, Cailloux R*, Boespflug-Tanguy O*. *ClermontFerrand, France; **Roma, Italy; °Essen, Germany; +Bordeaux, France; + Milano, Italy and ++ Rodez, France We collected 13 families with at least 2 boys affected by a slow progressive form of early onset SPG suggesting a CNS myelin defect on MRI or central evoked potentials analysis, and tested the involvment of the proteolipid protein (PLP) locus. In 4 families, the PLP gene was excluded by linkage analysis whereas a PLP gene mutation was found in 4. Clinical analysis of the 13 PLP mutated patients revealed that 6 patients had a pure SPG whereas the others had associated features (nystagmus in 5, ataxia in 5 and mental retardation in 4). In all cases, SPG has a very slow progression with patients wheelchair bound between 15 and 21, 6 patients developed a severe bladder dysfunction. Among the 10 heterozygeous PLP mutated female analysed, the 8 older than 30, expressed a mild SPG with

bladder dysfunction in 4 and dementia developed after 60 in 2. In conclusion, in a male patient, early onset SPG associated with nystagmus or ataxia and late onset paraplegia in mother, are arguments to look after a developmental defect of myelination on MRI, evoked potentials and perform a PLP gene analysis. 41 DIRECT SEQUENCING OF NIEMANN-PICK C1 (NPC1) DISEASE GENE CDNA IN FIVE GERMAN FAMILIES AFFECTED WITH NIEMANN-PICK TYPE C (NP-C) DISEASE. Peter Bauer, Bettina Albrecht, Arndt Rolfs. Dept. of Neurology, University of Rostock, Germany NP-C disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. It occurs at low frequency (affecting one in 106 individuals) and is inherited in an autosomal recessive manner. By positional cloning NPC1 cDNA sequence has been characterized. Its expression corrected NP-C fibroblast’s excessive lysosomal storage of LDL cholesterol. In a pan-ethnic selection of 9 NP-C patients numerous mutations in NPC1 sequence have been identified by Carstea et al. 1997. Therefore, familyspecific mutations should be prevalent. In order to clarify the segregation and genotype-phenotype correlations in NP-C disease, it was our first goal to establishing direct sequencing on NPC1 gene. As NPC1 DNA structure is not yet published, direct sequencing of NPC1 cDNA was done in human leucozyte RNA preparations obtained from five German families affected with NP-C disease. These samples were reverse transcribed (SuperScript™, Gibco) and PCR amplified with NPC1 specific primers before M13 and revM13 sequencing and electrophoresis (ALF™ DNA Sequencer, Pharmacia) was performed in small NPC1 amplicons (200 base pairs). Sequencing data obtained in these families provide the basis to work out genotype-phenotype correlations and in-vitro expression of mutant NPC1 proteins to assure the severity of observed mutations. Genotyping will be the basis for simple diagnostic procedures and will allow a heterozygous screening in suspected families.

Peripheral Neuropathy (1) 42 REDUCED EXPRESSION OF PERIPHERAL MYELIN PROTEIN 22 (PMP22) IN PATIENTS WITH HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES (HNPP) HARBOURING PMP22 POINT MUTATIONS. Gabriel J-M, Botti S, Erne B, Sghirlanzoni A, Nemni R, Gabriel C, Steck AJ, Pareyson D, Taroni F. Milan, Italy; Geneva and Basel, Switzerland; London, UK HNPP is usually associated with a 1.5-Mb deletion involving the same region that is duplicated in Charcot-Marie-Tooth disease type 1A (CMT1A) and includes the PMP22 gene. We (Gabriel, 1997) and others (Vallat, 1996) have previously reported that PMP22 protein expression was reduced in deleted HNPP and increased in duplicated CMT1A as a result of an abnormal gene dosage in these diseases. Occasionally, CMT1A can be traced to dominant PMP22 missense mutations. Only exceptionally, PMP22 nonsense and frameshift mutations have been found in HNPP (Nicholson, 1994; Young, 1997). We have identified two dominant PMP22 mutations in two families with the typical HNPP phenotype. Both mutations are expected to result in the premature truncation of the fourth transmembrane domain of the protein. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from these patients by quantitative immunohistochemistry. We found that PMP22 protein expression relative to that of myelin protein zero was reduced by half in both HNPP patients as compared to patients with normal PMP22 gene. The reduction was consistently observed with two distinct antibodies directed against both PMP22 extracellular loops, which would suggest that the mutant protein is not incorporated into myelin. These data conclusively demonstrate that HNPP invariably results from a reduction of PMP22 protein expression, regardless of the genetic mechanism involved. (Supported by TelethonItalia grants to FT and AS). 43 UNCOUPLING OF MYELIN ASSEMBLY AND SCHWANN CELL DIFFERENTIATION IN A TRANSGENIC RAT MODEL OF CONGENITAL AMYELINATION. S. Niemann, M. Sereda, I. Griffiths, U. Suter, K.-A. Nave. Center of Molecular Biology Heidelberg (ZMBH), Germany

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A transgenic rat overexpressing Peripheral Myelin Protein 22 kD (PMP22) has been generated as a model for peripheral neuropathies. Heterozygous transgenic rats, carrying 3 additional copies of the PMP22 gene, display features of Charcot-Marie-Tooth type 1A (CMT 1A) patients. Homozygous rats, which have an additional 6 transgenic copies of the PMP22 gene, completely lack peripheral myelin. Hence, they may serve as a model of congenital amyelination. These mutants have a consequently severe behavioral phenotype, an early onset of disease and marked atrophies. By electron microscopic analysis of homozygous transgenic rats, Schwann cells have segregated with axons in a 1 : 1 ratio, but fail to elaborate myelin. Morphologically, they closely resemble promyelinating Schwann cells, an intermediate stage in the development of myelinating Schwann cells. Surprisingly, although these cells appear arrested at the promyelin stage, their differentiation proceeds at the molecular level. They abundantly express myelin genes encoding P0, MBP, PMP22 at both the mRNA and protein level, as shown by semiquantitative RT-PCR analysis and immunofluorescence studies of mutant sciatic nerves. Moreover, upregulation of “early” Schwann cell markers, such as the low-affinity nerve growth factor receptor (LNGFR) and the transcription factor SCIP, is detected. By double-immunolabeling studies some mutant Schwann cells coexpress both LNGFR and P0, which has never been observed in wildtype Schwann cells, indicating impaired differentiation. To investigate the intracellular trafficking of PMP22 in homozygotes, the glycosylation profile of PMP22 was determined in total sciatic nerve extracts. Deglycosylation analysis and Western blot studies showed normal processing of PMP22 in the endoplasmic reticulum and early Golgi complex. Our data suggest, that strong PMP22 overexpression inhibits the assembly of compact myelin which is uncoupled from the underlying myelin gene expression in Schwann cells. 45 A NEW CONNEXIN 32 MUTATION IN X-LINKED CHARCOTMARIE-TOOTH DISEASE ASSOCIATED WITH DEAFNESS. T. Stojkovic1, A. Vandenberghe2, P. Latour2, J. F. Hurtevent1, P. Vermersch1. 1Department of Neurology and Neurophysiology, CHRU of Lille, France. 2Department of Neurogenetics and Molecular Biology, Hôpital de l’Antiquaille, Lyon, France X-linked Charcot-Marie-Tooth disease 1 (CMTX1) is a form of demyelinating hereditary neuropathy associated with mutation in the connexine 32 gene (Bergoffen et al., 1993), a member of the family of proteins forming intercellular channels. The purpose of the study was the identification of a new mutation of connexine 32 gene in a X-linked CMT associated with deafness. Eight patients of a CMTX family, five males and three females, were clinically studied The clinical purpose is consistent with CMT peripheral neuropathy with onset of disease between 7 and 15 years. Male patients were severely affected whereas female patients presented only with distal hypoesthesia. Male patients had slowed motor nerve conduction velocity (MNCV) of median nerve (range 32–43 m/s), whereas female patients showed normal value for MNCV. Deafness was present in 3 males and one female. In male patients, deafness required auditory fittings. Genetic analysis disclosed a new point mutation consistent with substitution of Arginine by Glutamine at position 142. Conclusion: This is the first report of deafness in X-linked CMT associated with a new point mutation of connexine 32. The physiopathology of deafness will be discussed. 46 A NOVEL PERIPHERAL MYELIN ZERO (MPZ) MUTATION IS ASSOCIATED WITH A CLINICALLY DISTINCT CHARCOT-MARIETOOTH TYPE 2 PHENOTYPE. De Jonghe1, 2, V. Timmerman1, C. Ceuterick3, E. Nelis1, E. De Vriendt1, A. Löfgren1, A. Vercruyssen2, L. Van Maldergem4, J.-J. Martin2, C. Van Broeckhoven1. 1Laboratory of Neurogenetics, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Antwerpen, Belgium. 2Division of Neurology, University Hospital Antwerpen (UZA), Antwerpen, Belgium. 3Laboratory of Neuropathology, Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Medicine, Antwerpen, Belgium. 4 Institut de Pathologie et de Génétique, Loverval, Belgium Mutations in the myelin protein zero (MPZ) gene lead to clinically and electrophysiologically distinct peripheral neuropathies such as CharcotMarie-Tooth disease type 1 (CMT1), Dejerine-Sottas syndrome and congenital hypomyelination. These demyelinating peripheral neuropathies are characterised by severely reduced nerve conduction velocities (NCV) of less than 38 m/s for the motor median nerve. Recently 2 distinct MPZ mutations were observed in patients with NCVs higher than 38 m/s. We re-

port a novel Thr124Met MPZ mutation in 9 apparently unrelated Belgian families. All patients with this mutation have some clinical features in common. The disease starts in the 4th decade with lancinating pains in the legs. Rapidly progressive weakness develops in the legs and some patients eventually become wheel-chair dependent. Additional features such as hearing loss and pupillary abnormalities (Argyll-Robertson pupil) were often present. NCVs of the median and ulnar nerves ranged respectively from 24 to 59 m/s and 26 to 58 m/s. A young asymptomatic mutation carrier at the age of 18 years had a normal clinical examination except for an Argyll-Robertson pupil and his NCVs were completely normal. A nerve biopsy showed de- and remyelination with small onion bulbs and clusters of remyelinating axons indicating axonal involvement with axonal regeneration. We conclude that the Thr124Met mutation is associated with a particular phenotype. Families with NCVs higher than 38 m/s, that usually are diagnosed as CMT type 2, should also be screened for mutations in the MPZ gene. 47 DEJERINE-SOTTAS DISEASE: RECESSIVE TRANMISSION OF A NEW POINT-MUTATION OF THE PMP22 GENE IN 3 SIBS. Y. Parman*, V. Planté-Bordeneuve°, A. Mantel #, M. Eraksoy*, G. Said°. *Department of Neurology, Medical Faculty, Istanbul-Turkey; °Department of Neurology, # Department of Molecular Biology, Hôpital de Bicêtre. Le Kremlin Bicêtre, Univ. Paris-Sud, France Déjerine-Sottas disease (DSD) is a severe demyelinating neuropathy of childhood with delayed milestones, pes cavus, generalised weakness, areflexia, sensory loss and nerve hypertrophy. The disease, originally described in 2 sibs born to non-consanguinous unaffected parents, was presumably inherited as an autosomal recessive trait. Molecular genetic studies have subsequently demonstrated mutations of the P0 or of the PMP22 genes in some patients with the DSD phenotype, but in all documented cases mutations occurred in the heterozygous state, corresponding to a dominant allele. In this study, we report on 3 siblings of 10, 5 and 2 years of age, with DSD. The parents who were first cousins, were clinically unaffected and their nerve conduction velocity was normal. All 3 children had delayed motor milestones, pes cavus, scoliosis, distal muscle wasting and weakness in all four limbs, areflexia, decreased vibratory sensation in the lower extremities. The signs and symptoms were less pronounced in the youngest. Motor conduction velocities were at 6–7 m/s in the upper limbs. Sural nerve biopsy of the eldest patient showed reduction of the density of myelinated fibres, all demyelinated or surrounded by a thin myelin sheath and often by onion bulb formations. Molecular screening of the P0 and PMP22 genes revealed a new homozygous missense point mutation (Arg157Trp) of the PMP22 gene in all 3 sibs. The parents were heterozygous for the same mutation. These findings confirm recessive transmission originally described in DejerineSottas disease. 48 CLINICAL, ELECTROPHYSIOLOGICAL, MORPHOLOGICAL AND GENETICALLY EVALUATION OF A FAMILY WITH X-LINKED DOMINANT CHARCOT-MARIE-TOOTH DISEASE. S. Quasthoff, J. Senderek*, C. Bergmann*; J. M. Schröder*, B. Conrad. Dept. of Neurology, TU, Munich, Germany; *Dept. of Neuropathology, RWTH Aachen, Germany Because of overlapping clinical, electrophysiological and morphological data, X-linked Charcot-Marie-Tooth neuropathy (CMTX) patients are often misdiagnosed, since they meet the criteria of autosomal-dominant CMT2. We report the clinical, electrophysiological, morphological and genetic evaluation of a family, that was initially misdiagnosed as CMT2. According to the X-linked pattern of inheritance, females tend to be less severely affected than males. Our initial index patient (a 46 year old female) showed only moderate gait disturbance and atrophy of the thenar muscles. Electrophysiological examination revealed a primary axonal neuropathy with reduced NCV in motor nerves (in average 44 m/s) and more severely in sensory nerves (in average 35 m/s). Both of her two sons are suffering from neuronal muscle atrophy with electrophysiological examination indicating a primary axonal neuropathy with NCV in motor nerves (34 m/s) and (31 m/s) in sensory nerves. Furthermore, one sister of our index patient has been diagnosed as CMT2 polyneuropathy. However, her affected son was classified as a benign form of the Duchenne muscular dystrophy. Another sister of our index patient who is also suffering from gait disturbance was classified as Friedreich’s ataxia. The final diagnosis of this unusual family came from the DNA analysis of the paraffin-embedded sural nerve biopsy of our 46 year old index female. A mutation was found corresponding to amino acid substitution of arginine for tryptophan in

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codon 15 of the connexin 32 gene on Xq13 which was confirmed by DNA analysis of her two sons. This study is additional proof that connexin 32 mutations represent their genetically defect as of predominantly neuronal CMT phenotype. S.Q is supported by the W. Sander Stiftung.

Higher Functions Disorders (1) 49 DO MEMORY COMPLAINTS PREDICT INCIDENT DEMENTIA? THE ROTTERDAM STUDY. A. Ruitenberg, A. Ott, J. C. van Swieten, A. Hofman, M. M. B. Breteler. Rotterdam, The Netherlands It is unclear whether subjective memory complaints are predictive of incident dementia. We performed the present study, as part of the Rotterdam Study, to further investigate the predictive value of memory complaints to incident dementia. The Rotterdam Study is a community-based follow-up study among 7983 persons, aged 55 years and over. At baseline-examinations during 1990–1993, subjects were asked about memory complaints. Cognitive performance was measured by the Mini-Mental State Examination. Dementia diagnoses were made according to internationally accepted guidelines. For on average 2.2 years we followed-up 6723 subjects who were not demented at baseline and had complete data on memory complaints. During that period 130 developed dementia. 1255 subjects had memory complaints and 737 were cognitively impaired. Relative risks (RR) and 95% confidence intervals (95% CI) were obtained with Cox regression, adjusting for age, age square, gender and education. Results: Subjects who complained about their memory were at increased risk of incident dementia (RR 2.30, 95% CI 1.62–3.26). The risk remained after stratification by objective memory performance in 4 groups: MMSE-score 28– 30 (RR 1.52, 95% CI 0.67–3.46), MMSE-score 26–27 (RR 2.03, 95% CI 1.21–4.73), MMSE-score < 26 (RR 2.54, 95% CI 1.43–4.54). We conclude that memory complaints at baseline is a strong predictor for incident dementia. 50 COMPARISON OF FRONTAL METABOLIC IMPAIRMENT IN NORMAL AGING, SUBCORTICO-FRONTAL DEMENTIA, AND CORTICAL FRONTAL DEMENTIA. G. Garraux, E. Salmon, G. Franck. Department of Neurology and Cyclotron Research Centre; University of Liège, B30 Sart Tilman, 4000 Liège, Belgium Normal aging, progressive supranuclear palsy (PSP) and dementia of frontal lobe type (DFT) are known to share decline in frontal lobe functions. We used statistical parametric mapping (SPM96) to analyse frontal metabolic impairment obtained at rest with 18FDG-PET in 21 elderly healthy subjects, 20 PSP patients, and 7 DFT patients compared to 15 young healthy subjects. The SPMs were thresholded at p < 0.001 corrected for multiple comparisons. In our healthy elderly population, a widespread metabolic decrease was observed in left lateral and medial Brodmann’s area 8 (BA8), Broca’s area (left BA44/45), left prefrontal area (BA9/46), bilateral premotor areas (BA6), bilateral cingulate areas (BA32), and right BA22. In both PSP and DFT, the cortical hypometabolism was more diffuse in premotor, prefrontal, cingulate, and orbitofrontal areas. Reduction of metabolism extended bilaterally to the temporal lobes and supramarginal gyri in DFT. Subcortical metabolic decrease occurred bilaterally in striatum, thalamus, and mesencephalon in PSP while it predominated in the striatum in DFT. The data suggest that metabolic impairment in normal aging is more widespread than usually thought and may account for many cognitive changes reported with aging. On the other hand, PSP and DFT share most subcortical and cortical metabolic impairments. Frontal hypometabolism was more prominent in DFT while there is characteristic mesencephalic involvement in PSP. 51 SURVIVAL IN EARLY-ONSET ALZHEIMER’S DISEASE. G. Roks1, M. Cruts2, H. Backhovens2, J. Theuns2, G. Van Gassen2, A. Hofman1, C. Van Broeckhoven2, C. M. van Duijn1. 1Department of Epidemiology & Biostatistics, Erasmus University Medical School, Rotterdam The Netherlands. 2 Neurogenetics Laboratory, Flanders Interuniversity Institute for Biotechnology, Borne-Bunge Foundation, University of Antwerp, Antwerp, Belgium We have studied predictors of survival in 198 patients from a populationbased study of Early-Onset Alzheimer’s Disease (EOAD) with onset before age 65 years. Patients were ascertained from four regions in the

Netherlands in the period of 1980–1987. Mortality data are available up to July 1994. Predictors of survival including sex, age at onset, apolipoprotein E genotype (APOE), and a polymorphism in intron-8 of the presinilin-1 gene (PS-1) were studied with Kaplan-Meier analysis. Survival was lower in men (73 months) compared to women (108 months) (P < 0.001). Early age of onset (before age 55 years) was associated with a longer survival (102 months) compared to onset after 55 years (92 months) (P = 0.05). The E2 allele of APOE was associated with a decrease in survival (76 months) compared to E4 carriers (113 months) (P < 0.001) and those homozygote for the E3 allele (96 months) (P = 0.01). The PS-1 intron 8 polymorphism showed no significant association with survival. Our study shows that sex, age at onset, and APOE genotype are important predictors of survival. 52 CEREBRAL WHITE MATTER CHANGES AND COGNITIVE DECLINE – THE ROTTERDAM SCAN STUDY. J. C. de Groot, F. E. de Leeuw, E. Achten, R. Heijboer, M. Oudkerk, J. van Gijn, A. Hofman, J. Jolles, M. M. B. Breteler. Rotterdam, Utrecht, Maastricht; The Netherlands Goal: To assess the association between cognitive decline and distribution and severity of white matter changes (WMC). Background: White matter changes (WMC) may play a role in cognitive decline. Periventricular changes (PVWMC) and deep subcortical changes (DWMC) presumably have a different aetiology and may relate differently to cognitive decline. Methods: 555 non-demented subjects (aged 60–90) were randomly sampled from the prospective population-based Rotterdam Study (response 68%). Cognitive function was assessed twice (baseline 1990–1993, follow-up 1995–1996) using the Mini Mental State Examination (MMSE). Cognitive decline was defined as > 0.4 points MMSE/year (upper quartile). Axial MRI images (1.5T) were obtained at follow-up. WMC were scored according to location, size and number. PVWMC severity and number of small, medium, or large DWMC were categorised in quintiles. The association between cognitive decline and PVWMC or DWMC was assessed using age and gender adjusted logistic regression. Analyses for PVWMC were adjusted for DWMC and vice versa. Results: Cognitive decline was associated with PVWMC (upper quintile versus rest OR 2.3; 95%CI 1.1–4.7; trend over quintiles; p < 0.01). There was some indication for an association with large and medium-sized DWMC, but these associations were not statistically significant (e.g. trend over quintiles for medium sized DWMC p = 0.23). Conclusion: Previous cognitive decline is associated with severity of PVWMC rather than DWMC. 53 CHRONIC TRAUMATIC BRAIN INJURY IN PROFESSIONAL SOCCER PLAYERS. J. T. Matser, Msc, A. G. H. Kessels, MD, B. D. Jordan, MD, M. D. Lezak, PhD, J. Troost, MD The objective of this study was to determine the presence of chronic traumatic brain injury (CTBI) in professional soccer players. Fifty-three active professional soccer players from several professional Dutch soccer clubs were compared to a control group of 27 elite noncontact sport athletes. All participants underwent neuropsychological examination. The main outcome measures were neuropsychological tests proven to be sensitive to cognitive changes incurred in contact and collision sports. The professional soccer players exhibited impaired performances in memory, planning, and visuo-perceptual processing when compared to controls. Among professional soccer players, performance on memory, planning and visuoperceptual tasks were inversely related to the number of concussions incurred in soccer and the frequency of heading the ball. Performance on neuropsychological testing also varied according to field position, with forward and defensive players exhibiting more impairment. Preventive strategies are recommended. 54 INFLAMMATORY CYTOKINES AND ALZHEIMER’S DISEASE: A STUDY OF IL-1β AND IL-1ra GENETIC POLYMORPHISMS. V. Casadei, C. Ferri, A. Gavazzi, L. Caputo, J. Tagliabue, E. Calabrese, L. Bava, I. Biunno, G. Annoni, C. Mariani, M. Franceschi, L. M. E. Grimaldi. Milano, Italy Genetic factors play a relevant role in the development of Alzheimer’s disease (AD). Inflammatory mechanisms might foster deposition and neurotoxicity of β-amyloid in AD brains, likely through the expression of inflammatory cytokines, among which the interleukin-1 family members are

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of particular interest. We investigated whether two polymorphisms, a restriction fragment lenght polymorphism within the promoter of interleukin (IL)-1β and a variable number of tandem repeat intronic polymorphism of its natural antagonist, IL-1 receptor antagonist (IL-1ra), are associated with occurrence or relevant clinical features of AD. Genomic DNA was obtained from 212 clinically diagnosed italian AD patients (mean age 70.2 ± 9.9) and 279 healthy controls (HC) (mean age 59.1 ± 24.11). The allele frequency (AF) of the two alleles of IL-1β did not differ significantly between HC (A1: 0.37, A2: 0.62) and AD patients (A1: 0.34, A2: 0.65), irrespective to their age at disease onset (early vs late onset). On the contrary, when we analyzed the AF of the two major alleles of IL-1ra, a significant increase in A1 and decrease in A2 was found in AD patients (A1: 0.72, A2: 0.24) compared to HC (A1: 0.66, A2: 0.31; p < 0.025). In the early onset AD patients (43 subjects) a further, although not significant, increase in A1 AF (A1: 0.75) was shown. Out of 161 patients genotyped for ApolipoproteinE (ApoE), 87 subjects (54%) carried at least one ε4 allele. In these ε4+ patients, the A2 IL-1ra AF was even more reduced than in the whole AD group, compared to HC (A2 ε4: 0.19, A2 HC: 0.31, p < 0.025). We conclude that a polymorphism of the anti-inflammatory cytokine IL-1ra gene contributes to the susceptibility to AD, probably acting in concert with other genetic factors, such as Apoε4.

Higher Functions Disorders (2) 55 A CASE OF D178N PrP GENOTYPE AND PATHOLOGICAL FEATURES OF FAMILIAL FATAL INSOMNIA IN THE ABSENCE OF PATHOLOGICAL INSOMNIA. B. Traynor1, F. Brett1, L. Cervenakova2, J. Collinge3, M. A. Farrell1, C. J. Gibbs2, H. Staunton1. Beaumont Hospital, Dublin, Ireland1, NIH, Bethseda, Maryland, USA2, Imperial College, London3 A 33-year-old man presented with a three month history of intermittent right arm numbness associated with progressive gait ataxia of more recent onset. On examination cerebellar signs were evident, together with features of autonomic dysfunction such as a persistent pyrexia, hyperhydrosis and tachycardia. The patient subsequently deteriorated cognitively and developed myoclonus. Sleep pattern was only mildly abnormal in the later stages of his illness. Death ensued 16 months after first clinical presentation. Of note there was no family history of dementia or ataxia. MRI revealed minor cerebellar vermian atrophy. Investigations revealed the 14-3-3 protein present in two out of three CSF samples obtained at different stages of the illness. Analysis of the PrP gene showed an aspartic acid to aspartate gene mutation at codon 178 in conjunction with the met-val polymorphism at codon 129. Post-mortem examination demonstrated a normal gross cortex with normal ventricles. There was pan-cerebellar atrophy. Histology failed to reveal any abnormality in the cortex or sub-cortical white matter. However significant nerve cell loss and gliosis was present in the thalamus, especially the dorsal medial nucleus and in the inferior olivary nucleus. Spongiform changes were not seen in any area of the brain and 3F4 immunocytochemistry for PRP was negative in all areas. The pathological changes in the thalamus will be illustrated on a neuroanatomy atlas as an explanation of the lack of classical sleep disturbance.

57 DEFICITS OF PROCEDURAL LEARNING IN FOCAL PREFRONTOSTRIATAL LESIONS AND HUNTINGTON’S DISEASE. K. Schmidtke, H. Manner, H. Vollmer. Freiburg, Germany Deficits of procedural learning (PL) have been demonstrated in Parkinson’s (PD) and Huntington’s disease (HD). It has been suggested that the implementation of new routines depends critically on the integrity of cortico-striatal loop systems. However, PD and HD cause more widespread neuronal damage, and few data exist on focal prefronto-striatal lesions. We studied 30 patients with HD, focal caudate or focal fronto-lateral lesions, and 40 normal controls. A perceptual (mirror reading), a motor (pursuit rotor) and four cognitive tasks described earlier (Brain & Cognition 32 : 441 ff.) were trained over three days. Progress was analysed with regard to group differences and to the effect of cognitive measures (word fluency, visuo-spatial ability). All patient groups showed normal perceptual PL. Prefrontal, but not caudate and HD patients showed normal motor PL. All groups showed marked impairment of PL of the cognitive tasks. When a measure of cognitive frontal lobe function (word fluency) was entered as a covariate, group differences in favour of controls became non-significant in two cognitive tasks that place demand on planning and central executive function. However, differences remained significant in two tasks requiring visuo-spatial and semantic processing. These results indicate that the integrity of “complex” prefronto-striatal loop systems is not a prerequisite for perceptual and motor PL. It appears essential for cognitive PL only as far as the generation of new procedures requires cognitive faculties attributed to the prefrontal cortex.

58 MEMORY PROCESSING IN FRONTAL-LOBE AND DIENCEPHALIC BRAIN-DAMAGED PATIENTS. P. Calabrese1, H. F. Durwen1, M. Haupts1, W. Gehlen1, and A. G. Harders2. Dept. of Neurology (Knappschaftskrankenhaus), University of Bochum, Germany; Dept. of Neurosurgery (Knappschaftskrankenhaus),University of Bochum, Germany While memory deficits due to bilateral thalamic lesions or after bilateral medial temporal lobe damage are well documented there are conflicting results concerning the mnestic abilities of patients with brain injuries restricted to the frontal lobes. Animal experiments as well as human studies point to memory problems on the basis of a deficient orchestration of mnemonic processes in frontal lobe damaged subjects. In our study we compared the cognitive-mnestic performance of altogether 30 patients with either bilateral frontal (n = 15) or bilateral thalamic (n = 15) brain damage by administering a variety of neuropsychological tests. While the diencephalic patient-group exhibited a profound and homogeneous deficit covering all memory domains the deficits of the frontal-lobe-group were highlighted in tasks with increasing impact on autonomous structurization and organization of the probe material. In this group the poorest results were found in tasks with high impact on flexibility and internal organization while the performance in other memory tests was at least in the lower normal limits. We conclude from these findings that memory deficits in frontal lobe damaged patients are based on a relative inefficiency of internal, frontal-lobe mediated, structuring and organization processes.

56 NEURAL SUBSTRATE OF FREE AND CUED VERBAL RECALL IN ALZHEIMER’S DISEASE. E. Salmon1, 2, C. Chicherio1, 3, M. Van der Linden3, C. Degueldre1, G. Franck2. Cyclotron Research Center1, Neurology2, Neuropsychology3. University of Liege, 4000 Liege, Belgium

59 MANIPULATING INFORMATION: A FUNCTION OF THE CENTRAL EXECUTIVE OF WORKING MEMORY. Collette1, C. Chicherio2, M. Van der Linden1, G. Delfiore1, E. Salmon2. 1Department of Neuropsychology, 2 Cyclotron Research Centre; University of Liège, Belgium

Deficit in episodic long-term memory (LTM) is a characteristic feature of Alzheimer’s disease (AD). The Grober and Buschke test is a classic examination of verbal LTM. A deep semantic encoding of the material is performed by presenting each verbal item will its category. The task then comprises free recall followed by cued recall of forgotten items, for which the category is proposed. The aim of the study was to explore the neural substrate of those verbal recall tasks in AD. Methods: 38 subjects will probable AD performed the Grober & Buschke task, and underwent resting 18FDG-PET. A correlational (parametric) analysis was performed between mapping (SPM 96). Results: The performance at free recall was significantly related to the level of metabolism in prefrontal regions. The performance at cued recall was correlated with metabolic level in right hippocampal formation. Conclusions: The study fist confirms the importance of prefrontal cortex in free recall of verbal items. The date demonstrates also the relationship between the residual level in hippocampal formation of AD patients and their capacity to benefit from cues to recall verbal material.

Previous PET studies investigating the central executive (CE) found activation in the prefrontal cortex. However, the tasks used did not permit to separate precisely the functions of the CE from those of storage of information. The aim of the present study was to look for brain areas that subserve a task tapping a precise function of the CE, the manipulation of information, when the influence of storage function was removed. A PET activation study was performed with right-handed male volunteers (N = 7) using four cognitive tasks, crossing the conditions of memory and manipulation: a reading task (to read words in serial order); a manipulation task (to read words in alphabetical order); a recall task (to recall words in serial order) and an alphabetical recall task (to recall words in alphabetical order). The manipulation conditions induced an activation in the right (BA 10/46) and left (BA 9/6) middle frontal gyrus and in the left parietal area (BA7). The interaction between the memory and manipulation conditions revealed no significant changes in activation. Conclusion. These results are in accordance with the hypothesis of a CE distributed between anterior

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and posterior brain areas. Moreover, the absence of interaction between the memory and manipulation conditions indicates that the functioning of the CE is not related to the memory load.

60 MORPHOMETRIC DIFFERENCES IN CEREBRAL MAGNETIC RESONANCE IMAGING BETWEEN DEMENTIA WITH LEWY BODIES AND DEMENTIA OF THE ALZHEIMER TYPE. Stadler K, Ransmayr G, Luginger E, Kremser C #, Schmidt R*, Poewe W, Aichner F #. Depts. of Neurology and # Magnetic Resonance, University Hospital, Innsbruck, and *Dept. of Neurology, University Hospital, Graz The differential diagnosis between dementia with Lewy bodies (DLB) and dementia of the Alzheimer type (DAT) may be difficult. The aim of this magnetic resonance (MR) study was to find out whether MR reveals different patterns of cerebral atrophy in DLB and DAT. We compared T2weighted spin-echo images (Siemens Magnetom Vision 1.5 tesla) of 12 patients with DLB (age 66.1 ± 6.2 years, mean±S.D.), 13 DAT patients (age 66.7 ± 8.6) and 12 normal controls (age 62.6 ± 8.1) with respect to bicaudate, bifrontal and bioccipital ratios, interuncal distance, hippocampal height, silvian fissure width, third ventricular width, fourth ventricular index, width of the brachium pontis and ventricle-brain ratio. Kruskal-Wallis ANOVA revealed significant differences between the three groups in respect of hippocampal height ( p = 0.03) and ventricle-brain ratio (p = 0.0001). Hippocampal height was similar in the DLB group (1.6 ± 0.2 cm) and the controls (1.59 ± 0.2 cm) and reduced in DAT patients (1.36 ± 0.2 cm; p = 0.02 and 0.04, respectively). The ventricle-brain ratio was 0.21 ± 0.07 in controls, 0.15 ± 0.5 in the DLB group and 0.09 ± 0.02 in the DAT group (Co/DLB, p = 0.0005; Co/DAT, p = 0.0001; DLB/DAT, p = 0.014). In concluding, MR demonstrates normal hippocampal height in DLB, reduced hippocampal height in DAT and more severe subcortical atrophy in DAT than in DLB.

Immunology 61 SOLUBLE INTERLEUKIN-1 RECEPTOR ANTAGONIST INTRON 2 POLYMORPHISM IS ASSOCIATED WITH OCCURENCE AND CLINICAL DISABILITY IN PATIENTS WITH MULTIPLE SCLEROSIS. F. L. Sciacca*, C. Ferri*, C. Gobbi?, D. Franciotta§, M. Zaffaroni¶, M. Marrosu¥, G. Comi$, L. M. E. Grimaldi*$. * ? $ Milano, § Pavia, ¶ Varese, ¥ Cagliari; Italy Multiple sclerosis (MS) is an autoimmune disorder thought to be under polygenic control. At present, the only established genetic association is with the human leukocyte antigens class II region. Inflammation is one of the main exacerbating factor of the relapses of the disease. The soluble interleukin-1 (IL-1) receptor antagonist (IL-1ra) is a natural anti-inflammatory protein which antagonizes IL-1 by. IL-1ra gene is polymorphic; the intron 2 polymorphism is represented by five alleles, named from A1 to A5. We had previously evaluated the functional role of this polymorphism and found that an A1 increase/A2 decrease in allele frequencies (AF) fosters a decreased production of the IL-1ra mRNA and soluble protein production. To fully evaluate its effect on the natural hystory of MS, we analyzed the IL-1ra AF in 458 patients affected by MS and in 314 healthy controls (HC) from two italian cohorts with different genetic background (caucasian and sardinian). We found that AF significantly differed between healthy Caucasians and Sardinians ( p = 0.007 for A1; p = 0.004 for A2). Among Caucasians, a significant A1 increase/A2 decrease in AF was associated with MS ( p = 0.003 for A1 and 0.002 for A2) and with a more aggressive clinical course, being progressively more evident when going from HC to patients with “benign MS” [i.e. stabilized expanded disability status scale (EDSS) score = 3, after at least 10 years of disease] and to patients with “non benign MS” (i.e. stabilized EDSS > 3 within the first 10 years of disease) (Trend test for A1 and for A2, p = 0.001). We then observed that the percentage of patients with EDSS = 3 was always higher, and progressively more relevant with time, within the A1–/A2+ group compared to A1+ groups ( p = 0.047 at 20 years). A cross-sectional study in MS patients showed that mean serum levels of sIL-1ra were higher in A1–/A2+ compared to A1+ MS patients. We conclude that an A1 increase/A2 decrease in AF of the polymorphic IL-1ra gene predisposes caucasian/italian, but not sardinian, MS patients to a decreased production of the antiinflammatory cytokine sIL-1ra and is associated with a more aggressive clinical course and a greater accumulation of disability over time.

62 CENTRAL NERVOUS SYSTEM DELIVERY OF CYTOKINES USING NON-REPLICATIVE HERPETIC VECTORS. R. Furlan, P. L. Poliani, A. Bergami, F. Galbiati, G. Martino. Milano, Italy Cytokines are promising therapeutic tools for immune-mediated as well as degenerative neurological diseases. However, cytokine act in an autocrine/ paracrine fashion and therefore should be administered directly in the site of therapeutic action. Central nervous system (CNS) is a protect environment scarcely permissive to cytokine when injected systemically. We have developed a system to deliver cytokines directly within the CNS using vectors obtained from herpes simplex type (HSV)-1 virus. Naive BALB/c mice were injected intracisternally (i.c.) with a non-replicative HSV-1derived vector (named d120) containing the interferon (IFN)g gene and a reporter gene (bgal) which were both inserted in an expression cassette placed in the viral genome instead of the thymidine kinase viral gene under the control of two different promoters (respectively ICP4 and CMV promoters). After i.c. injection, we found that the vector diffused in all ventricular spaces where it consistently infected the ependymal cells surrounding the ventricles. No toxic effect were observed on CNS-resident cells up to one months post-injection (p.i.) indicating the relatively low vector virulence. IFNg was produced (up to 4.5 ng/ml) and released into the cerebrospinal fluid (CSF) by ependymal cells up to day 28 p.i. When secreted, IFNg reached the CNS parenchyma where it showed to be active since we observed upregulation of MHC class I expression on CNS-resident cells. Our results indicate that the use of viral vectors to deliver cytokines within the CNS is a feasible and non-toxic technique. The direct injection in the CSF compartment of cytokine-bearing viral vector may represent an alternative therapeutic way to deliver cytokines within the CNS. 63 MATRIX METALLOPROTEINASE PRODUCTION BY CNS VASCULAR ENDOTHELIUM-A POTENTIAL ROLE IN AUTOIMMUNE CNS DISEASE. K. A. Harkness* # M. N. Woodroofe*, J. D. Sussman #, G. A. B. Davies-Jones #. # Dept. of Neurology, Royal Hallamshire Hospital, Sheffield University, *Dept. of Biomedical Science, Sheffield Hallam University, U.K. Matrix metalloproteinases (MMPs) are a family of zinc containing enzymes that play an important role in inflammation and tissue degradation. Local production of MMPs by CNS vascular endothelium may play a role in the inflammation, and the breakdown of the blood-retinal and bloodbrain barriers, seen in the putative autoimmune conditions posterior uveitis and CNS vasculitis. The aim of the study was to assess MMP production in resting and cytokine activated CNS vascular endothelium in the Lewis rat. Studies were carried out on primary endothelial cell cultures and the Lewis rat retinal and brain vascular endothelial cell lines JG2 and GP8 respectively. (kindly provided by Dr. J. Greenwood). The expression of MMP2 and MMP9 in cell supernatants was assessed using gelatin substrate zymography. MMP3 expression was assessed using casein substrate zymography. MMP expression at the mRNA level was assessed using RTPCR. Specific primer pairs for MMPs 2, 3 and 9 were kindly provided by British Biotechnology. Resting primary rat brain endothelial cells and the cell lines JG2 and GP8 secrete MMP2, detectable with gelatin zymography. Primary endothelial cells and the cell lines JG2 and GP8 secrete MMP2 and MMP9 when activated with PMA, LPS and TNF-a for 24 hours. MMP3 mRNA is upregulated in primary brain endothelium following 24-hour activation. MMP3 is not however seen with casein zymography and may therefore not be expressed to sufficient levels to be detectable by this method. Matrix metalloproteinases 2, 3 and 9 are expressed by activated CNS endothelium in-vitro and may play a role in the pathogenesis of CNS vasculitis and posterior uveitis in-vivo. 64 THE NOVEL ANTIBODY (ANTI-MA) FROM PATIENTS WITH PARANEOPLASTIC BRAINSTEM AND CEREBELLAR DYSFUNCTION RECOGNIZES MM1, A PROTEIN EXPRESSED IN BRAIN AND TESTIS. Josep Dalmau, Humayun Gultekin, Raymond Voltz, Jerome B. Posner, Myrna R. Rosenfeld. New York, USA Objectives: To identify novel antineuronal antibodies in sera of patients with paraneoplastic neurologic disorders (PND) and characterize the corresponding antigens. Methods: Sera were examined using immunohistochemistry on rat and human tissues, and immunoblots of cortical neurons. Antigen cloning was done by probing a cDNA expression library with paraneoplastic serum. Expression of the cloned antigen in normal human tissues was examined by Northern and Western blots. For competition assays, purified IgG from sera was labeled with biotin. Results: The sera of

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4 patients with cancer (lung, breast, colon, parotid) and PND (3 brainstem andlor cerebellar dysfunction; 1 motor weakness) showed similar granular reactivity with 37 and 40 kDa neuronal nuclear proteins. These sera (anti-Ma) competed with each other for the same epitopes. Probing of a cDNA expression library resulted in the cloning of a novel 37 kDa protein (called M111) recognized by all anti-Ma sera, but not by control sera. The expression of MM1 mRNA and protein was restricted to neurons and germ cells of testis. One of two paraneoplastic tumors was labeled by anti-Ma serum. Conclusions: We report a novel antineuronal antibody (anti-Ma) in the serum of patients with brainstem/cerebellar dysfunction. A cloned protein (MMI) exclusively expressed in immunoprivileged tissues (brain and testis), is the target antigen of anti-Ma sera. 65 IDENTICAL EXPANDED CD8+ T CELL CLONES IN BOTH MUSCLE AND PERIPHERAL BLOOD OF POLYMYOSITIS PATIENTS DETECTED BY CDR3 SPECTRATYPING. N. Goebels* +, S. Wiesener +, W. Müller-Felber #, D. Pongratz #, H. Wekerle+, R. Hohlfeld* +. *Dept. of Neurology, Klinikum Großhadern; # Friedrich-Baur-Institute, Munich. + Dept. of Neuroimmunology, MPI of Neurobiology, Martinsried, Germany Polymyositis (PM) is an autoimmune disease caused by CD8+ T lymphocytes that destroy HLA class I-expressing skeletal muscle fibers. Recently we demonstrated that the autoaggressive T lymphocytes in PM muscle are clonally expanded (1). Design/Methods: We employed a new PCR-based method to identify and characterize clonally expanded T cell populations. The method (“CDR3 spectratyping”) relies on the natural length variation of the third hypervariable region (CDR3) of the rearranged T cell receptor gene: whereas a polyclonal T cell population shows a random, Gauss-distributed length variation of the CDR3, a clonally expanded population has a uniform CDR3 length, which can be identified as a single band on a sequencing gel. Results: We analysed matched pairs of cDNA from muscle biopsies and peripheral blood lymphocytes of PM patients and confirmed previously identified expanded T cell clones in muscle biopsy specimen (1). Moreover, we repeatedly detected identical clonally expanded T cell populations both in the inflamed muscle tissue and in the peripheral blood of untreated PM patients. Conclusions: 1) CDR3 spectratyping may be more sensitive than previous methods in detecting clonally expanded T cell populations. 2) Expanded T cell clones are present in both muscle and blood of PM patients. 3) CDR3 spectratyping may be useful for the systematic identification of autopathogenic T cell clones and their monitoring during the course of disease and treatment. Lit.: (1) Bender et. al, J. Exp. Med. 1995. 66 THE Vd6 GENE USAGE OF THE gdTCR IN EAE. Szymanska B, Tronczynska E, Berkowicz T, Mycko M, Brosnan CF*, Raine CS* and K. Selmaj. Lodz, Poland, *New York, USA In inflammatory infiltrates in the CNS of experimental autoimmune encephalomyelitis (EAE) animals are T cells that express the gd T cell receptor (TCR), and a significant role for these cells in disease expression has been suggested by the observation that their depletion reduces both clinical and pathological signs of disease. How these cells contribute to disease pathogenesis is not known, but it has been suggested that they are activated by stress-induced proteins in the inflamed CNS. In the mouse the major subset of gd T cells reactive to hsp-60 has been shown to reside within the Vd6 subset, particularly the Vd6.4 subset. To determine whether these cells are present in EAE lesions we have cloned with pCR-Script Amp SK(+) vector and sequenced automatically by dideoxy chain termination method Vd6+ TCR in the CNS and spleen of mice sensitized to develop EAE. In both the spleen and the CNS, the Vd6 sequences could be divided into 2 major subfamilies Vd6 and Vd6.4. Most of these clones used elements of both Dd1 and Dd2 with frequent use of the entire coding region for Dd2. In spleen extensive diversity was evident within the CD3 region. In contrast, in the CNS homological sequences were frequently found within each sample, with some identical sequences present in different animals. Furthermore, the majority of clones within the CNS samples used the Vd6.4 gene. These data support the conclusion that there are specific accumulation of gd T cells in the CNS in EAE, and further suggest that some of these cells may be responding to hsp60.

Multiple Sclerosis (1) 67 ASSOCIATION OF APOLIPOPROTEIN E E4 ALLELE WITH DISEASE ACTIVITY IN MULTIPLE SCLEROSIS. Nikos Evangelou, Jackie Palace, Mandy Jackson, David Beeson. Oxford, U.K.

There is increasing evidence that apolipoprotein E (ApoE) is a pivotal component in reinnervation and dendritic remodelling following neuronal injury. Allelic variants of the ApoE gene are known to influence the risk and the age of onset of Alzheimer’s disease and may influence the presentation of other neurological diseases. Previous smaller study did not show significant differences of the ApoE allele frequencies in Multiple Sclerosis (MS) compared with controls but did not examine for correlation with disease severity. 85 patients with definite MS were studied. Age of onset, type and activity of the disease were studied. ApoE genotyping was performed according to standard protocols. Allele frequencies of the group as a whole, the relapsing remitting/secondary progressive group or the primary progressive group were not significantly different from those reported from similar populations in Britain. Although the number of patients was small we did not find any difference in different types of MS. No genotype showed any significant association with the age of onset of the disease, but the ε4 allele was more common in patients with more aggressive type of MS (p = 0.06). These results suggests that although ApoE does not seem to be implicated in the early pathogenesis of the disease, patients possessing the ε4 allele might have a reduced capacity for neuronal remodelling following relapses. 68 IL-1β AND IL-1-RN RECEPTOR ANTAGONIST GENE COMBINATION ANALYSIS IN 109 FRENCH MULTIPLE SCLEROSIS FAMILIES. E. Quelvennec1, M. Alizadeh1, J. Yaouanq1, B. Fontaine2, M. Clanet3, G. Edan1, G. Semana1. 1Rennes, 2 Paris, 3 Toulouse (France) Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system genetically controlled. Among the candidate genes the IL-1 and IL-1RN (receptor antagonist) gene cluster has been recently proposed in M.S. Moreover, preliminary reports have suggested that an imbalance between IL-1 and IL-1 RN secretion level controls the inflammatory process in certain autoimmune diseases and that some particular alleles are associated with the degree of secretion. In a previous study (Lancet 1997, 349, p 476), we showed that the IL-1 RN gene polymorphism analysed isolately is not involved in the genetic susceptibility to MS. The aim of the present study is to further analyse IL-1 and IL-1 RN gene polymorphism relationship by studying a population of 109 MS simplex families yielding to determine 400 haplotypes. Three polymorphisms have been studied: IL-1 Taq I, IL-1 AVA I and IL-1 RN VNTR generating 2, 2 and 5 alleles respectively. First, we compared the frequencies of haplotypes transmitted (diseased haplotypes) and not transmitted (control haplotypes) to the probands. No difference was observed whatever the combination of the 3 polymorphisms examined. Second in order to consider cis or trans IL-1 and IL-1-RN associations, we compared the phenotypic combinations observed in MS subjects with those expected from a random parental transmission. Such an analysis was conducted to take into account the potential functional relevance of the IL-1/IL-1 RN ratio in the demyelinating process since IL-1 Taq I allele 2 and IL-1 RN allele 2 have been described to be associated with a high level of cytokine secretion. In our study, the distribution observed in MS patients was exactly similar to that expected by chance. Taken together our data do not support the notion that the IL-1/IL-1 RN gene interaction is of importance in MS susceptibility. 69 DIFFERENT HLA-DR ASSOCIATIONS IN PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS (PPMS)? G. V. McDonnell, D. Middleton, C. A. Graham, A. G. Droogan, C. W. Kirk, S. A. Hawkins. Belfast, Northern Ireland, U.K. Objective: To investigate the HLA-DR associations in relapsing-remitting/secondary progressive MS (RR/SPMS) and PPMS. Background: The HLA-DR2 allele is felt to be a risk factor for MS, rather than a genetic marker for the population of origin. Some studies have indicated a different HLA-DR antigen profile in PPMS patients compared with those having an initially relapsing-remitting course, only those with relapsing disease showing an increase in HLA-DR2. Association of PPMS with DR4 has also been suggested. Methods: Genomic DNA was prepared from peripheral blood of 202 RR/SPMS patients identified in a population-based prevalence study, 102 PPMS patients identified throughout Northern Ireland and 383 normal controls (Nor) matched for postcode areas of those identified in the prevalence study. Samples were typed for the HLA-DR antigens using polymerase chain reaction (PCR) technology and sequence specific oligonucleotide probes (SSOP). Results: A high incidence (number of patients either hetero- or homozygous) of HLA-DR2 was found in each MS group- PPMS (64%), RR/SPMS (67%) – compared with normals (32%), (PPMS vs Nor, p < 0.0001, df = 1: RR/SPMS vs Nor, p < 0.0001,

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df = 1). HLA-DR4 occurred at a lower incidence in both MS groups compared with controls – RR/SPMS (22%), PPMS (30%), Nor (36%). Overall, highly significant differences existed across the full HLA-DR allele distribution (RR/SPMS vs Nor, p < 0.0001, df = 13: PPMS vs Nor, p < 0.0001, df = 13). Conclusion: These data suggest that in this population, HLA-DR2 is associated with PPMS and that PPMS has a HLA-DR profile distinct from the normal population. 70 HLA CONDITIONING IN A MULTIPLE SCLEROSIS GENOME SCREEN. Francesca Coraddu, Stephen Sawcer, Robert Feakes, Jeremy Chataway, Simon Broadley, Hywel B. Jones, David Clayton, Craig Taylor, Peter N. Goodfellow and Alastair Compston. Cambridge, United Kingdom In our previously published genome screen we demonstrated significant excess transmission of the 121 base pair allele of the TNFa marker from the major histocompatibility region (MHC). Given the linkage disequilibrium which is known to exist in this region we HLA-DR and DQ typed the same families in order to investigate whether the effect seen occurred as a result of alleles which form part of an extended haplotype also involving DRB1*1501 and DQB1*0602, or was independent of these class II alleles. We used the GENEHUNTER program to calculate the most likely haplotypes for each individual and studied the transmission of the extended haplotype (121-1501-0602). Excess transmission of this haplotype was seen in all affecteds and in the index cases alone using a transmission disequilibrium test (TDT). Interestingly outside the haplotype none of the alleles showed excess transmission. The phenotype frequencies in the index cases were compared with those from organ donor controls and the expected associations of multiple sclerosis with DR15 (p = 8.7E-18), DQ6 (p = 2.0E09) and DRB5 ( p = 2.8E-16) were confirmed. Conditioning the genome screen data on the basis of identity by state (IBS) sharing of the DR15 phenotype, revealed an interesting segregation of the regions of potential linkage that had been identified in the original screen. Tentative evidence for transmission distortion was seen at several of these segregating regions, providing further evidence for complexity in the genetics of multiple sclerosis. 71 CENTRAL NERVOUS SYSTEM DEMYELINATION AND HEPATITIS B VACCINATION: THE FRENCH EXPERIENCE ABOUT GenHevac B®. Jean-Jacques Ventre, Elisabeth Loupi, Henry Debois, Benoit Soubey, Sandra Vukusic and Christian Confavreux. Service de Neurologie, Hôpital Saint Joseph-Saint Luc, Pasteur Mérieux Connaught, and Service de Neurologie, Hôpital de I’Antiquaille, Lyon, France Fifty-one cases of demyelinating disorders have been reported to Central Pharmacovigilance Department of Pasteur Mérieux Connaught since the vaccine became available in 1989, while more than 30 million doses of GenHevac B ® have been distributed, which represents about 10 million vaccinees until December 96. The incidence rate of demyelinating disorders in our data is 1 case for 196 000 vaccinees (0.51 for 100 000). The incidence rate of MS in France is about 5 for 100 000 every year, which is far from what was reported even if we extend the diagnosis of MS to all demyelinating disorders, including monophasic episodes. Furthermore, the exposed population is mostly young female (74%). Hepatitis B disease is a widespread infection which incidence in France is estimated to 50 000 new cases every year, with a lethal rate of 2%. 72 NF-kB INHIBITION ENHANCES EAE IN SJL/J MICE. Mycko M, Berkowicz T, Kaminska B #, Mosieniak G #, Kwinkowski M, Glabinski A, Raine CS* and K Selmaj. Lodz and # Warsaw, Poland and *New York, USA The transcription factor NF-kB is a critical intracellular regulator of TNF induced expression of specific cell function including cell apoptosis. NFkB is a heterodimer consisting of p50, p52, RelA, RelB and RelC proteins. It has been shown that inhibition of NF-kB nuclear translocation enhanced apoptotic killing by TNF. TNF involvement in EAE mechanisms has convincingly been demonstrated. Therefore, we investigated whether NF-kB is protective against development of EAE. NF-kB inhibitor, gliotoxin, was applied to mice sensitized with PLP peptide 139–151 for EAE development. We observed that animals injected with NF-kB inhibitor had more severe form of EAE. Clinical scoring of the gliotoxin treated mice was significantly higher than control EAE mice (3.8 v. 2.0). Also, at the patho-

logic level animals receiving NF-kB inhibitor showed more enhanced pathology of EAE including features typical for TNF activity like widening of periaxonal space. Gliotoxin did not change electrophoretic mobility of NF-kB proteins isolated from spleen and CNS confirming that it inhibits IkB-a proteolysis but not NF-kB DNA binding. Interestingly, mice with EAE showed different pattern of electrophoretic mobility of NF-kB from naive mice suggesting that during EAE development NF-kB activation involved changes in heterodimer composition. The findings suggest that NF-kB inhibition in EAE animals enhanced TNF induced pathology. Thus, NF-kB might represent an attractive target for therapeutic intervention in EAE.

73 INTERFERON BETA-1b (IFN BETA-1b) DELAYS PROGRESSION OF DISABILITY IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS: RESULTS OF THE EUROPEAN MULTICENTRE STUDY. Ludwig Kappos, Chris Polman, Carlo Pozzilli, Alan Thompson, Frank Dahlke and the European Study Group on IFN beta-1b in secondary progressive MS, Basel (CH), Amsterdam (NL), Rome (I), London (GB), Berlin (D) Treatment with IFN beta-1b has proven efficacy in relapsing-remitting MS. No data are available on its effect in patients with secondary progressive (SP) MS, characterised by steady progression of neurological deficits and disability after a period of relapses and remissions. Therefore, a double-blind controlled study was conducted in 32 centres in 12 European countries to compare 8 MIU IFN beta-1b given s.c. every other day with placebo (PL) for up to 3 years. An interim analysis was planned after all patients had completed at least two years on study. Key inclusion criteria were: EDSS 3.0–6.5, SP-MS with sustained progressive deterioration for > 6 months, age 18–55, and no other immunomodulatory treatment. The primary efficacy variable was time to confirmed progression by 1.0 in the EDSS up to a score of 6.0 (0.5 steps from 6.0–7.0). Increase in EDSS was confirmed at two consecutive visits by a blinded evaluating physician not otherwise involved in the trial. Of 718 enrolled patients, 360 patients were randomised to active treatment, 358 to placebo. Treatment groups were well balanced for all disease variables. Mean (standard error) disease duration since diagnosis for PL vs. IFN beta-1b was 8.16 (0.33) vs. 8.05 (0.30) years, time since diagnosis of SP-MS 2.05 (0.12) vs. 2.22 (0.13) years. 169 and 153 patients respectively had an EDSS > 5.5 at entry. A highly significant difference in time to disease progression favouring IFN beta-1b was found (p = 0.0008) in the intention to treat analysis of all data available at interim. The effect was confirmed in the patients both with (n = 418) and without any relapse during the study (n = 300). A significant effect was also found for the proportion of patients with confirmed progression, time to becoming wheelchair bound, annual relapse rate, and other clinical variables. As recommended by an independent advisory board, the study was stopped in February 98 and active treatment offered to all study patients. This study provides convincing evidence that treatment with IFN beta-1b delays sustained neurological deterioration in SPMS. Study supported by Schering AG.

Cerebrovascular Disorders (3) 74 HELICAL CT FOR THE FOLLOW-UP OF CERVICAL INTERNAL CAROTID ARTERY DISSECTIONS. C. Lucas*; X. Leclerc**; O. Godefroy*; H. Tessa**; P. Martinat**; D. Leys*; J. P. Pruvo**. Departments of Neurology* and Radiology*. University Hospital of Lille, France The typical appearance of internal carotid artery (ICA) dissection on computed tomographic (CT) scan has already been reported at the acute stage. However, the long-term course of arterial lesions remains poorly documented. The aim of this study was to assess the course of ICA dissections by the use of helical CT. Patients and methods: We followed-up 27 patients with 30 angiographically-proven ICA dissections; helical CT was performed in the late course (median: 24 months, range: 7 to 62). CT images were analyzed by two independent radiologists in a blinded fashion. We evaluated the presence of mural thickening, aneurysm and occlusion. In cases without persisting occlusion and aneurysm, the external diameter of the ICA at its upper segment was performed. Results: The interobserver agreement was good. A mild mural thickening was observed in 4 cases of 30 previously dissected ICA. Stenotic and near occlusive dissections tended to normalize. Half aneurysms spontaneously resolved. Of 10 occluded ICA at the acute stage, 9 were recanalized, but their external diameter was

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significantly lower than that of normal carotid arteries and a hypoplasic appearance throughout the cervical segment of the ICA was found in 3 cases. Conclusion: Helical CT seems to be a reliable tool to assess the long-term course of ICA dissection. Most arterial lesions tend to improve or disappear spontaneously but persisting ICA narrowing may be observed in the late course of occlusive-type dissections.

75 IS LEFT ATRIAL ENLARGEMENT A MARKER FOR ISCHEMIC STROKE? Henriques IL, Correia J*, Leitão AL. Neurology and Internal Medicine* Departments; Hospital Espírito Santo, Évora, Portugal High blood pressure is associated with an increased risk for ischemic stroke. Left ventricular hypertrophy (LVH) and left atrial enlargement (LAE) are related with hypertension. LAE is the first echocardiographic hypertension sign. We studied the hypothesis that LAE could be a marker for ischemic stroke. Material and methods: We prospectively included all patients that were consecutively submitted to transthoracic echocardiography in our department (1/6/1995–31/12/1997). All stroke patients were studied according to a protocol including at least one CT-scan or MRI. Hypertension was defined according to the JNC V criteria. LAE and LVH were defined as the American Heart Association criteria (Henry WL, et al.). We analysed the association of ischemic stroke with hypertension, LAE and LVH, using a statistical package, including logistic regression analysis. We studied 623 patients (280 male) with a median age of 66 years. Results: Recent ischemic stroke (less than 8 days) was present in 133 patients (21.3%). Hypertension was observed in 292 patients(47%), LVH in 89 and LAE in 174. Concerning ischemic patients, although not reaching statistical significance, LAE tends to be more related with ischemic stroke (p = 0.0917; Odds Ratio: 1.62; 95% Confidence Interval: 0.92–2.87) than LVH (p = 0.656; O.R: 0.86, 95% CI: 0.44–1.72) or hypertension ( p = 0.992; 95% CI: 0.55–1.82). Conclusion: LAE is the first echocardiographic sign of hypertension. In this study, LAE is more related with ischemic stroke than hypertension. LAE might be an independent marker for ischemic stroke, with the advantage from hypertension of being more reliable. Further research is needed studying the relationship between LAE and ischemic stroke.

76 PRESERVED THERMAL AND NOXIOUS REACTIVITY WITHOUT AWARENESS IN A PATIENT WITH LATERAL CERVICO-MEDULLARY INFARCT. M. Rousseaux, F. Cassim, B. Bayle, V. Lahousse, J. F. Hurtevent, J. D. Guieu. Services de Rééducation Neurologique et de Neurophysiologie Clinique. CHU Lille, France The aim of this study is to describe that preservation of thermal and noxious withdrawal reactivity can be observed in the case of complete thermoalgic anesthesia resulting from lateral upper cervical and medullary infarct. Case report. This 57 year-old patient presented with complete lateral medullary syndrome: rotatory vertigo, standing and gait ataxia with right deviation, right kinetic ataxia, complete left thermo-algic anesthesia with relative facial preservation, oblique diplopia and skew-deviation, right nystagmus, and right Horner’s syndrome. Somatosensory epicritic cutaneous perception was perfectly preserved. MRI showed right sided hyperintensity in the lateral medulla and the cervico-medullary junction. On angiography, thrombosis of the right vertebral artery was demonstrated, blood flow of the right posterior inferior cerebellar artery being supplied by the left vertebral artery. Neurological and functional recovery was fair (Barthel index: 100/100). However, a complete left thermoalgic anaesthesia persisted. The patient described that in many occasions, in contact with arm objects, his left arm and forearm abruptly presented with a withdrawal reaction. This occurred without any heat consciousness. The motor reaction explained why cutaneous lesion never occurred. Thermal reactivity was investigated using hot water (37 to 47°). On the left side, the patient had no awareness of temperature. Moderate withdrawal reaction was elicited at 44°, the patient reporting vague sensation of ‘distal trouble’. At 47°, the motor reaction was more rapid an systematic. Algic reaction were assessed electrophysiologically using left and right ulnar and median nerve stimulation with surface electrodes: the reflex threshold was lower on the left side than on the right side, without awareness of pain. The threshold was normal on the right side (4 mA). Discussion. This study shows that unilateral severe and selective lesion of spino-thalamic tract can be associated with preservation of withdrawal reaction to noxious stimuli. This accounts for absence of cutaneous lesion, which differs from what observed in other conditions like syringomyelia. This clinical reaction can be associated with a reduction of the reflex threshold.

77 PARAOXONASE POLYMORPHISM Met-Leu54 IS ASSOCIATED WITH CAROTID ATHEROSCLEROSIS. Reinhold Schmidt, Helena Schmidt, Kurt Niederkorn, Martin Schumacher, Gert M Kostner, KarlFranzens University, Graz, Austria Recently paraoxonase polymorphism Met-Leu54 has been shown to be associated with serum paraoxonase concentration and enzyme function, and has been considered to be a genetic risk factor for cardiovascular disease. We studied the association between paraoxonase polymorphism MetLeu54 and carotid atherosclerosis in a cohort of 329 randomly selected neurologically asymptomatic individuals aged 44–79 years. The methionin (M allele)-leucin (L allele) polymorphism was determined by using restriction enzyme digestion of PCR products. All study participants underwent a complete laboratory work-up, ECG and echocardiography. Carotid atherosclerosis was assessed by color-coded Duplex-scanning and was graded on a five point scale ranging from 0 (= normal) to 5 (= complete luminal obstruction). The LL, LM and MM genotypes were noted in 143 (43.5%), 137 (41.6%) and 49 (14.9%) individuals, respectively. The three genotype subsets did nor differ in terms of age, distribution of gender and major vascular risk factors. Plasma lipid and lipoprotein concentrations were also similar. Carotid atherosclerosis (score 1–5) was present in 50.3% of the LL, in 37.0% of the LM and in 12.7% of the MM subset ( p = 0.0109). The Mantel-Haenszel test showed a significant, linear relationship between paraoxonase genotype and the severity of carotid atherosclerosis ( p = 0.0107). Logistic regression analysis created a model of independent predictors of carotid atherosclerosis including the paraoxonase LL genotype (OR 2.26, p = 0.029), apolipoprotein A-I (OR 0.090/10 mg/dl, p = 0.0125), apolipoprotein B (OR 1.16/10 mg/dl, p = 0.0002), fibrinogen (OR 1.05/10 mg/dl, p = 0.0125) and age (OR 2.68/10 years, p < 0.0001). These data suggest that the paraoxonase Leu54 polymorphism may represent a genetic risk factor for carotid atherosclerosis in the elderly population.

78 EARLY CT SIGNS OF ISCHEMIA IN ACUTE MCA INFARCTION: A RELIABLE PREDICTIVE FACTOR FOR SUBSEQUENT INFARCT VOLUME. T. Moulin, L. Tatu, F. Vuillier, F. Cattin, E. Berger, D. Blum, J. F. Bonneville, L. Rumbach. Departments of Neurology, Neuroradiology, University Hospital 25030 Besançon, France There is much controversy over the early CT signs of ischemia found in patients with MCA ischemia, hence little data on its predictive value for subsequent infarct volume and outcome. Methods: Patients with an acute ischemia clinically involving the MCA territory were consecutively evaluated within 12 hours after symptom onset. Early CT signs (contrast reduction involving the lentiform nucleus, the insular ribbon and the cortex, and spontaneous hyperdense MCA) were analyzed on the first CT and volume and location of infarcts estimated on the second CT. The outcome, was determined at 1 month using Rankin scale. The potential predictors of outcome were analyzed. Multivariate analyses were performed to define early predictive factors and volume thresholds for outcome. Results: 100 patients were studied. Early CT signs were correlated with subsequent location, extension and volume of MCA infarcts. The presence of 2 or 3 early CT signs was associated with a poor outcome ( p < 0.001), a large MCA infarct ( p < 0.0001) and a greater volume (mean 108.3 ml). Two volume thresholds were found to define good outcome (Rankin 1 to 3) and direct death. Three variables, the Orgogozo scale, early CT sign of ischemia and the clinical course established a predictive model for death. Conclusions: Our findings suggest that early CT signs allow the prediction of the location and volume of subsequent infarct. If determined early, infarct volume may be the most reliable of all predictive factors.

79 ENDOVASCULAR THERAPY OR CLIPPING? C. Kremer, N. KrausePape, C. Groden*, H. C. Hansen, K. Kunze. Departement of Neurology, *Department of Neuroradiology, University of Hamburg, University Hospital Eppendorf Aneurysm occlusion with electrically detachable coils (GDC-coils) offers a therapeutic alternative for patients with subarachnoid hemorrhage. Risks and benefits of this new procedure are evaluated in a retrospective study of 101 Patients (39 men, 62 women,mean age 49 years) and compared with conventionally treated patients (pat.). In 36 of 101 pat. the aneurysm was occluded with endovascular therapy (ET) (23 aneurysms in the posterior, 13 in the anterior circulation) and in 32/101 pat. with clipping (6 aneu-

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rysms in the posterior, 26 in the anterior circulation). Complications during ET (vs. clipping) were vasospasm in 10 (vs. 5), thrombosis of a parent vessel in 4 (vs. 3),rebleeding in 4 (vs. 7) and acute brain edema in one (vs. 7) pat..Complications after ET (vs. clipping) were brain edema in 12 (vs. 15),cerebral infarction in 14 (vs. 14) and 18 (vs. 20) pat. developed a neurological deficit, progressive in 2 (vs. 8) cases. The Outcome after 30 days of pat. treated with ET (vs. clipping) was vegetative or dead in 8 (vs. 1) – severe neurological deficit in 1 (vs. 2) – moderate neurological deficit or good recovery in 26 (vs. 27) pat. Pat. treated with ET, who had multiple or giant aneurysms had a high risk to develop severe complications. Conclusion: Mortality and bad outcome rate was higher in patients treated with endovascular therapy including “high risk aneurysms”. The frequency of complications in both groups didn’t differ substantially.

Cerebrovascular Disorders (4) 81 EARLY GENERATION OF OXYGEN FREE RADICALS FOLLOWING PERMANENT AND REVERSIBLE MIDDLE CEREBRAL ARTERY OCCLUSION (MCAO) IN THE RAT. Tobias Back, Oliver Peters1, Dirk Megow1, Ulrich Dirnagl. Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-University Munich, and 1Department of Neurology, Charité, Humboldt-University Berlin, Germany In stroke, reactive oxygen species (ROS) may participate in the pathophysiological cascade leading to ischemic damage. We directly measured the generation of ROS in the infarct border and compared the effects of permanent and reversible MCAO. Methods: In barbiturate anaesthetised rats we induced three hours of permanent MCAO by an intraluminal thread (n = 6), or one hour MCAO followed by two hours of reperfusion (n = 6). Through a cranial window over the parietal cortex, ROS were measured online using the novel technique of lucigenin-enhanced chemiluminescence (CL). Simultaneously, the direct current (DC) potential was recorded to detect peri-infarct depolarizations (PID). The borderzone localization of the measurements was confirmed by additional experiments (n = 10) which characterized the blood flow profile as present under the cranial window. Results: CL measurements after permanent MCAO revealed a brief period (10–30 min post-occlusion) of decreased ROS production followed by a significant steady increase to nearly twofold levels from 1.5 h onward. Reperfusion after 1-h MCAO lead to a burst-like pattern of increased ROS levels (maximum: 490 ± 330%; baseline = 100%; p < 0.05). At the end of the 3-h observation period, CL was still increased after permanent and reversible MCAO (to 190 ± 67% and 211 ± 64%, respectively). DC potential recordings revealed a frequency of PID ranging between 2.8 and 6.4 DC-shifts/h (means) following permanent MCAO. In reperfusion experiments, PID were abolished from 15-min recirculation onward. There was no temporal relationship between the production of ROS and the occurrence of PID. Conclusions: We observed that permanent MCAO was accompanied by a sustained increase of ROS levels during the initial 3-h of infarct development, while reperfusion produced a ROS burst to nearly fivefold levels. We speculate that oxygen free radicals may play an important pathogenetic role for the acute phase of infarct development. 82 ECHOCONTRAST-ENHANCED TRANSCRANIAL COLOR-CODED DUPLEX SONOGRAPHY OF INTRACRANIAL VEINS DURING STEPWISE EMBOLISATION OF DURAL ARTERIOVENOUS FISTULAE. O. Popescu, Ch. Klötzsch, P. Berlit. Essen, Germany Objective: To study noninvasively the hemodynamic changes during stepwise embolisation of dural arteriovenous fistuae (DAVFs), we used echocontrast-enhanced transcranial color-coded duplexsonography (cTCCD). Design/Methods: We used an Acuson 128 XP ulstasound system with a 2.5 Mhz transducer to examine 33 patients (mean age 61.4 years; range 37 to 77 years) with DAVFs before the first and after each embolization. Color coded signals from the dural sinuses were displayed transtemporally before and after injections of an pulmonary stable ultrasound contrast agent. Sonographic findings were correlated with the digital subtraction angiography. Results: Using echocontrast-enhanced TCCD before the first embolization in 25 patients the venous drainage into the transverse sinus, the sigmoid sinus, the inferior or superior sinus, straight sinus or the cavernous sinus was identified through the temporal bone window. In 11 cases the draining dural sinus was identified on plain TCCD. 3 patients had a poor temporal bone window and in 5 cases no draining dural sinus was identified. After the final embolisation we found a mean reduction of peak flow velocity of 38.8 ± 17.4% compared to the values which were ac-

quired before the first embolization. On the contralateral side only the transverse sinus was identified in 23 cases with a max. peak flow of 18.7 ± 5.6 cm/sec. without hemodynamic changes during endovascular treatment. Conclusions: Compered to non-enhanced TCCD cTCCD enables the identification of draining dural sinus in patients with DAVFs and the monitoring of hemodynamic changes during stepwise embolization. 83 CLINICAL AND GENETIC STUDY OF 57 FRENCH FAMILIES WITH CAVERNOMAS. P. Labauge*, S. Laberge*, L. Brunereau**, C. Uvy**, E. Maréchal*, E. Tournier-Lasserve* et la société Française de Neurochirurgie. *INSERM U25, Paris. **CHU Saint-Antoine, Paris. France Objective: To study phenotypes and genetic characteristics of familial forms of cavernomas. Background: Cavernomas are vascular malformations, which familial forms seem to be particularly frequent in hispano-american patients. The first cavernomas gene (CCMI) has been assigned to the long arm of chromosome 7. Design/Methods: All of the 28 french neurosurgery centers participated in this study. Inclusion criteria: families of probands with at least one other affected relative (group 1) or families of probands suffering from multiple cavernomas (group 2). Clinical history, MR Imaging and blood samples were collected from all consenting relatives aged above 18 year-old. Informative meioses were analyzed with highly polymorphic microsatellites markers closely linked to the CCM1 locus. Results: Of the 57 analyzed families, 35 fitted inclusion criteria of group 1. In the 22 families fitting group 2 criteria, MRI screening of relatives demonstrated hereditary background in 73% (n = 16). Clinical data: symptoms leading to diagnosis in the 100 symptomatic patients: seizures (45%) and hemorrhage (41%). Multiple cavernomas detected in 84% of individuals. Of 164 asymptomatic relatives, MRI diagnosed cavernornas in 44 percent. Increase of lesion count with age (p < .01). Genetic data: Autosomal dominant inheritance pattern. Incomplete clinical penetrance and complet radiological (MRI) penetrance. Conclusions: Isolated multiple cavernomas revealed a familial form in 73 percent of cases. Nearly half of the relatives had asymptomatic cavernomas. Linkage analysis will be shown at the meeting. 84 TRANSCATHETER OCCLUSION OF PATENT FORAMEN OVALE IN PATIENTS WITH STROKE AND PRESUMED PARADOXICAL EMOLISM – COMPARISON OF THREE DIFFERENT TECHNIQUES. Rainer Schräder, Patrick Keppeler, Sascha Rux, Horst Sievert. Cardioangiologisches Centrum Bethanien, Frankfurt a. M., Germany Non-surgical closure of patent foramen ovale (PFO) has been proposed to prevent recurrence of presumed paradoxical embolism in patients with unexplained stroke. Over the past years, several devices for transcatheter PFO-occlusion have been developed. Patients: Between 2/94 and 1/98 transcatheter PFO-occlusion was attempted in 55 patients (28 females, 27 males). The patients were 17–77 years old (mean, 43 years) and had suffered 1–4 neurologic events. Indication for closure was based on the results of both neurologic (angiography, cranial CT- and MRI-scan, transcranial Doppler) and cardiovascular (phlebography, blood coagulation, transesophageal contrast-Doppler-echocardiography) examination. The stretched diameter of the PFOs ranged from 4–24 mm. Results: PFO-closure was successfully performed in 23/26 patients with Buttoned-Devices (25–45 mm), in 20/20 patients with Angelwings-Devices (18–30 mm), and in 9/9 patients with Cardioseal-Occluders (17–28 mm). The follow-up period was 1–47 months. One Buttoned-Device was surgically removed because of partial unbuttoning, and two patients suffered reccurent embolic events. In two patients with an Angelwings-Device thrombotic material on the right and left atrial disk was observed but no embolic events occurred. After implantation of the Cardioseal-occluder there were no complications or embolic events. Conclusion: All three systems can be used for transcatheter PFO-Occlusion. In comparison to the Buttoned-Device the Angelwings-Device and the Cardioseal-Occluder seem to be more stable and reliable in preventing recurrent embolism. 85 THE CLINICAL APPROACH TO THE NUTRITIONAL PROBLEMS OF PATIENTS ADMITTED TO STROKE-UNIT. Alfredo Seneghini, Dario Santoloci, Tommaso Regesta and Giovanni Regesta. Dept. of Neurology and Stroke Unit, San Martino Hospital, Genoa – Italy Stroke patients have often nutritional problems, due both to impaired state of consciousness and dysphagia. The latter is a very common event, ranging approximately from 13% for patients with unilateral brain damage to

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71% of patients with bilateral brainstem lesions (Kuhlemeier et al., 1989). Hence it ensues that dehydration and caloric-nitrogen deficit can contribute to the poor neurological outcome or be a cause of death in these patients. In order to evaluate the real impact of the bad nutritional state after a stroke as well as the feasibility and efficacy of the medical nutritional intervention, we evaluated 302 patients, consecutively admitted to our Stroke-Unit for a first-ever ischaemic stroke. In our population, 97 out of 302 (32%) had some kind of swallowing impairment at entry to StrokeUnit and 62 (21%) needed enteral nutrition (EN). EN was given by nasogastric tube, providing water and polymeric solutions sufficient for a complete nutritional support. The length of the treatment with E N was different in each case, until the patient became able to swallow again or until he/she died, ranging from 3 to 57 days. Statistical analysis was carried out in order to prove the role of the nutritional state in the final outcome. Multiple linear regression was given (Independent variable SSS at 6 weeks). For patients who died before the 42nd day (18 out of 62, 29%) an arbitrary score of 2 was considered. Dependent variables taken into account were: serum sodium value, BUN (for evaluation of dehydration, according to DePippo et al., 1994), serum albumin (for evaluation of caloric-nitrogen deficit), ketonuria without glycosuria (DePippo, 1994), Glasgow Coma Scale and Canadian Scale as indicators of the consciousness and neurological state. Surprisingly no effect of the bad nutritional state was found. In fact the difference between metabolic parameters in patients who died and who survived, at the last possible blood sample, did not result significant. On the contrary both initial Glasgow and Canadian Scales score showed a significant role for the worst outcome. These results seem to demonstrate a good nutritional management of the patients. The final poor outcome, in fact, was correlated in our population to the worst neurological condition. We conclude that a good management of the stroke patients with nutritional problems is possible and the effect of the dysphagia can be faced. No patient should be lost for this reason. Unfortunately other aspects of the stroke problem, like the effect of the initial neurological condition, remain unfavourable factors.

Tuesday

Generalized myasthenia gravis is often refractory despite various symptomatic and immunosuppressive treatments. We report 9 cases of patients with refractory myasthenia gravis treated with a combination of azathioprine and prednisolone. The “induction phase” starts with a thymectomy, immediately followed by an dose of up to 1 mg/kg daily and azathioprine 2.5 mg/kg daily. The objective is to reach complete clinical remission without any symptomatic therapy. When this objective is not achieved within 2 or 3 months, the prednisolone dose is increased up to a new threshold of 1.5 and then 2.5 mg/kg daily. When reaching clinical remission and maintaining it for about 3 months, corticosteroids may be decreased gradually by monthly steps of 10 mg. With this kind of protocol, all the patients are asymptomatic without anticholinesterase inhibitors. However, because of the potentially severe side this should be considered as a “rescue-therapy” only for severe myasthenia gravis. 88 DRIVING ADVICE GIVEN IN A BRITISH GENERAL NEUROLOGY CLINIC. Christopher Tiley. Queen’s Medical Center, Nottingham, UK The number of road accidents attributable to neurological illness is small, but some disorders carry a higher relative risk than the general population and are over-represented in analyses of medical driving deaths (especially epilepsy). The Driver Vehicle Licensing Authority (DVLA), a branch of the Department of Transport, takes close interest in such conditions and epileptic patients are obliged to inform the DVLA of their diagnosis. The aim of this study was to see whether case notes recorded appropriate advice on driving and notifying the DVLA. Clinical notes and letters were reviewed from 117 patients, mainly on a sequential basis but supplemented by notes of patients awaiting results. Of 23 cases of confirmed epilepsy, only 12 had documented evidence that driving was discussed at any point in clinic. This could be construed as negligence in nearly 50%. In addition it was only discussed in one of three patients with dementia and one of six patients with stroke. It was not discussed with any patients with Parkinson’s disease, multiple sclerosis or a range of other disorders. The study suggests that driving advice is inadequate. There is a four way relationship between the patient, their General Practitioner, their neurologist and the DVLA, but the neurologist cannot assume that the issue has been discussed appropriately and has a responsibility to do so and record it.

General Neurology (1) 86 NEUROPSYCHOLOGICAL TESTING OF THE HIGHLY PREVALENT PROGRESSIVE SUPRANUCLEAR PALSY IN FRENCH WEST INDIES DISPLAYED THE SEVERITY OF INSTRUMENTAL FRONTAL DISORDERS. D. Caparros-Lefebvre, V. Bolivar. CHU AntillesGuyane, France Objective: To assess cognitive & frontal-lobe functions of progressive supranuclear palsy (PSP) in FWI. Background: PSP represents less than 4% of parkinsonian syndromes in Europe while neurological practice in FWI suggests high percentage of levodopa-resistant parkinsonism, resembling to PSP, with association of early postural disability, ophthalmoplegia, parkinsonism and frontal lobe syndrome. In FWI, dietary habits include annonaceous containing benzyltetrahydroisoquinolines which produce parkinsonism in animals. Patients & Methods: 68 consecutive parkinsonian patients were assessed for parkinsonian, PSP criteria according to well-defined scales. Patients with vascular lesions were excluded. 51 had possible or probable PSP, only 16 met the criteria of idiopathic Parkinson’s disease (IPD). Neuropsychological testing included mini-mentalstate, verbal fluency, Mattis scale, Rey figure, digit span, praxis skills. Results: in PSP group, mean age was 67 years (SD = 7), mean disease duration was 3 year. MMS was 25 (SD = 3), fluency were low (animals: 13, “P” = 7). Mattis score was 104 (SD = 17). Praxis skills were low (verbal = 33/47; reflexive = 10/15). Span was 5.2. In IPD group, mean age was 66 years (SD = 6), disease duration was 8 (SD = 5). MMS was 26 (SD = 2), fluency were 16 for animals, 12 for words “P”. Praxis skills were 42/47 for verbal orders, 12/15 for reflexive skills. Span was 5.7. Conclusion: Despite longer disease duration, IPD had less frontal lobe dysfunction. PSP had severe frontal disorders, which are usual in most European PSP. Praxis skills were impaired in both groups, but this could be related to educational and cultural specificities of FWI. 87 SEVERE REFRACTORY MYASTHENIA GRAVIS: COMPLETE CLINICAL REMISSION WITH INTENSIVE IMMUNOSUPPRESSION. Sandra Vukusic, Thibault Moreau, and Christian Confavreux. Department of Neurology, Hôpital de l’Antiquaille, Lyon, France

89 SPINAL XANTHOMATOSIS: A VARIANT OF CEREBROTENDINOUS XANTHOMATOSIS. Verrips A1, Lycklama à Nijeholt G2, Barkhof F2, van Engelen BGM1, Wesseling P1, 3, Wevers R 4, Stam J5, Wokke JHJ6, v d Heuvel LPWJ4, Keyser A1, Gabreëls FJM1. Departments of Neurology1, Pathology3, Laboratory of Pediatrics and Neurology4, University Hospital Nijmegen. Department of Diagnostic Radiology2, Free University Hospital, Department of Neurology5, Academic Medical Center, Amsterdam. Department of Neurology6, University Hospital Utrecht, The Netherlands We describe seven patients from six families with cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease, who neurologically presented with a predominant spinal cord syndrome. Classically, disease onset is in childhood with bilateral cataract and diarrhoea, followed by progressive cerebellar and pyramidal signs, mental retardation, seizures, and tendon xanthomas. Most patients have cerebellar signs and mental retardation from the age of 20 onwards. Characteristic in our seven patients is the slow clinical course, and the absence of cerebellar symptomatology in the early disease stages. Spinal cord MR imaging identifies diffuse white matter abnormalities in the lateral and dorsal columns. Pathological examination in one patient revealed extensive myelin loss in the lateral columns and in the fasciculus gracilis. In these patients we found different genotypes for the sterol 27-hydroxylase gene. In one patient a novel mutation was found. We conclude that “spinal xanthomatosis” is a clinical variant of CTX that should be included in the differential diagnosis of “chronic myelopathy”. 90 NEUROPSYCHOLOGICAL DEFICITS IN MINOR HEAD TRAUMA – A PROSPECTIVE CONTROLLED STUDY. M. Keidel, J. Hansmeyer, E. Sigges, T. Leniger, H. Wilhelm, H. C. Diener. Dept. of Neurology, University of Essen, FRG In most patients with minor head injury neuroimaging techniques do not detect any morphological damage. However, a variety of patients complain of having neuropsychological difficulties in daily life. Current knowledge of the time course of recovery of posttraumatic neuropsychological

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deficits is mainly based on retrospective studies with a selection bias. They are not validated by a healthy control group. Thus a 6-month prospective study was carried out, in which 23 patients with acute minor head injury (Glasgow Coma Scale 14/15) and a matched cohort of 30 normal subjects were investigated with an extensive neuropsychological test battery in the acute phase (< 14 days) and again 6, 12 and 24 weeks after the trauma. In all 4 sessions in both groups concentration, attention, visual and verbal memory and higher cognitive functions were measured using standardized tests, including self-assessment and depression-scales. Changes over the prospective observation period were analyzed. In the acute posttraumatic phase the neuropsychological functions were below the individual’s normal level. A significant recovery of concentration, attention and of mnestic and higher cognitive functions occurred within 24 weeks. We conclude that subjective neuropsychological deficits in minor head trauma can be quantified by neuropsychological testing. The time course of recovery can be monitored by repeated measurements in a prospective manner. The neuropsychological deficits are transient and recover within six months after the trauma. Therefore, the diagnosis of a posttraumatic pseudo-neurasthenic or neurotic syndrome in acute minor head trauma should be made with caution. Long term courses with chronic neuropsychological difficulties in daily life and related problems in litigation are rare events. (Supported by IFORES, University of Essen). 91 GENOTYPE-PHENOTYPE CORRELATIONS IN FAMILIAL HEMIPLEGIC MIGRAINE (FHM). Anne Ducros1, Anne Joutel1, Katayoun Vahedi2, Marie-Germaine Bousser2, Elisabeth Tournier-Lasserve1. *INSERM U25, Faculté Necker, hôpital Lariboisière, Paris, France We have previously established the genetic heterogeneity of FHM, mutations of the CACNA I A gene located on chromosome (ch.) 19 being involved in 50% of affected families, 20% of the families being linked to ch. 1 and 30% being unlinked to both loci. Design/Methods: In order to identify genotype-phenotype correlations in FHM, we compared genetic/clinical data between three family-groups: ten ch.19-linked families (94 patients), three ch. 1-linked families (24 patients) and four families unlinked to both loci (24 patients). Results: Migraine attacks: a high individual, intrafamilial and interfamilial variability was observed with no major difference between the 3 groups. 40% of the patients had one severe attack with impaired consciousness, during which 5 patients had seizures. 16% had migraine with aura and 34% migraine without aura, alternating with HM attacks. Associated symptoms: one major genotype-phenotype correlation was observed: permanent cerebellar symptoms were found in 50% of ch. 19-linked families and in this group only. In one of the 5 families with associated ataxia, 5 patients had essential tremor. FHM penetrance was incomplete in all families but lower in ch. 1 than in ch. 19linked families. Conclusion: No major correlation was observed except for the presence of cerebellar symptoms only in ch. 19-linked families. Characterization of CACNA 1 A mutations in FHM with or without cerebellar symptoms, as well as ch.1 gene identification will help to understand the molecular basis of these phenotypes.

General Neurology (2) 92 METACHROMATIC LEUKODYSTROPHY IN AN ADULT PATIENT, WITH JUVENILE ONSET: STABILIZATION AFTER BONE MARROW TRANSPLANTATION. Turpin JC, Sutton L*, Binet JL*, Leblond V*, Lefèvre M, Baumann N. INSERM Unit 495, and *Hematology Department, Salpêtrière Hospital, 75651 Paris cedex 13, France We report a case of metachromatic leukodystrophy, starting in a boy at age 14. There was a mental deficit which made him go out of school, a cerebellar ataxia and pyramidal signs.The diagnosis was established on arylsulfatase A deficiency, nerve biopsy showing metachromatic deposits, and molecular study (Institute of Neurology, Vienna, Austria) showing P426L homozygosity. As the mental and motor deficits, remained compatible with the evolution of the so-called adult form, a bone marrow transplantation was decided 4 years ago, at age 16. The donor was not related to the family. After irradiation of his bone marrow, the transplantation succeeded, although for some time, there was a coexistence of both some of his own original cells and the transplanted ones. The level of arylsulfatase A, although increasing, remained at the heterozygote level. The patient improved; his ataxia decreased, but the spastic paraplegia remained. There was still dysphonia. His mental status also improved. Bone marrow transplantation could be of therapeutic use in adult forms of low evolutivity.

93 CLINICAL IMPRESSION AND FINAL DIAGNOSIS IN 100 CONSECUTIVE SUBJECTS WITH CHRONIC INSOMNIA. Alvarez D, Ondzé B, Espa E, Carlander B, Besset A, Billiard M. Department of Neurology B, Gui-de-Chauliac Hospital, Montpellier, France Effective treatment of chronic insomnia is based on understanding its cause(s). How determining the cause(s) of chronic insomnia may not always be done at once. We were interest comparing the clinical impression after the first visit and the final diagnosis after a complete work up. 100 subjects, 61 female and 39 male, aged 48 ± 14 years were studied in our sleep laboratory. Mean age of onset was 34.4 ± 15.1 years and duration of evolution 13 ± 11 years. Subjects underwent a standardised interview, a physical examination, a psychological evaluati Pittsburgh sleep quality index (PSQ1), and according to the clinical impression, a personality test (M) a sleep-log and a morning-evening circadian questionnaire (Horne & Ostberg) and one to two nights polysomnography. Clinical impression was revised in 32 cases, because of overdiagniosis or underdiagnosis. Insomnia with mental disorder (IAMD) was the most frequently underdiagnosed condition while sleep ind respiratory disorders (SIRD) and the cireadian rhythm sleep disorder (CRSD) were the most frequt overdiagnosed. Final diagnosis consisted of 46 cases of IAMD, 21 cases of psychophysiological insomnia, 8 cases of SIRD, 7 cases of restless legs and/or periodic limb movements syndrome, 3 cas CRSD and 4 cases of sleep misperception. No diagnosis was obtained in 3 cases. The distribution of causes of insomnia was similar to the one already published (Buysse et al. 1994). The underevaluation of insomnias associated with mental disorders may have several causes: we systematically searched for organic insomnias more easily treated than insomnias associated mental disorders. Besides, as neurologists, we may well have underdiagnosed these conditions at first. The overevaluation of respiratory disorders and circadian rhythm disorders may stem for growing interest for these disorders and the possibility to propose an efficient treatment. Reference: Buysse et al., Sleep 1994; 17 (7) : 630–637. 94 RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER – COMPARISON OF POLYSOMNOGRAPHIC FEATURES. I. Eisensehr1, S. Noachtar1, and B. L. Ehrenberg2. Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-University, Munich1, Department of Neurology, New England Medical Center, Tufts University, Boston2 Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be two clinical manifestations of the same central nervous system dysfunction. We compared the polysomnograms of patients with pure PLMD and patients with RLS. Methods: We compared the polysomnograms of 19 RLS-patients (7 men, 12 women, age: 50.1 a ± 11.4 a, periodic limb movement index (PLMI): 25 ± 28.1, total arousal index (TAI): 18 ± 13.3) and 33 PLMD-patients (20 men, 13 women, age: 43.1 a ± 13.0 a, PLMI: 28.6 ± 19.6, TAI: 15.2 ± 9). The groups showed no significant differences as regarding age and sex. None of the patients took sleep influencing medications. Results: Total sleep time (TST) was significantly longer (7.6 ± 3.7 hr, p = 0.02) and percentage of REM-sleep significantly higher (19.4 ± 9.1% of TST, p = 0.004) in RLS-patients (PLMD-patients: TST = 5.8 ± 1.5 hr, REM = 12.6 ± 6.8% of TST). In PLMD-patients, the PLMI correlated significantly and negatively with the percentage of periodic limb movements associated with an arousal (Spearman correlation coefficient = –0.5, p = 0.005), whereas the PLMI of RLSpatients correlated significantly and positively with the PLM-arousal-index (Spearman correlationcoefficient = 0.9, p < 0.0001). Further, RLSpatients had more arousals not associated with periodic limb movements or other sleep related events (8.4 ± 8.8/hr, p = 0.001), than the PLMDpatients (2.8 ± 3.2/hr). Conclusions: The sleep disorder in RLS-patients is not only caused by PLM-associated arousals as in PLMD-patients. In addition arousals, which are not preceeded by respiratory or movement events play a significant role in the sleep disorder of RLS. Therefore, arousals with no such associations should be included in the analysis of sleep quality in RLS. This could be important for drug studies. 95 THE SPINAL DURAL ARTERIOVENOUS FISTULA: DIAGNOSIS, TREATMENT AND PROGNOSIS. L. R. Canta, W. J. J. van Rooij, M. Sluzewski, D. Wijnalda, R. L. L. A. Schellens, C. C. Tijssen. St. Elisabeth Hospital Tilburg, The Netherlands We present the results of a retrospective study of 45 patients from 7 Dutch hospitals with spinal dural arteriovenous fistula (SDAVF). The SDAVF is

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a connection between a radicular artery and the perimedullar venous plexus, eventually resulting in myelopathy. The aim of this study was to identify specific clinical features of SDAVF, and their relation to the prognosis after treatment. Most patients were males (mean age: 55) presenting with sensory loss in the lower body, paraparesis, gait disturbance, bladder dysfunction or impotence, that had developed gradually over a period of several months. Diagnosis was made by MRI and spinal angiography. Treatment consisted of embolisation, or ligation of the draining vein. The delay between the onset of symptoms and treatment (treatment delay) was rather long (mean: 23 months), probably because many neurologists are unfamiliar with SDAVF. Most fistulas were located at mid-thoracal level, the associated myelopathy predominantly in the lower half of the spinal cord. Our data show that paraparesis and sensory loss benefit most from treatment. There was no clear relationship between the size of the myelopathy and the prognosis. However, the prognosis of the gait disturbance gets worse as the treatment delay increases. We conclude that especially in middle-aged males who present with lower body sensory loss and/or paraparesis, SDAVF should be suspected. Prompt recognition and treatment, are vital for the prognosis. 96 CRANIAL MRI FINDINGS IN BEHÇET’S DISEASE: A STUDY OF 134 MRI OF 98 CASES. Akman-Demir G, Bahar S, Çoban O, Tasçi B, Parman Y, and Serdaroglu P. University of Istanbul, Istanbul Faculty of Medicine-Department of Neurology Istanbul, Turkey

moderately or severely disabled by this time (EDSS ≥ 6). As to the prognostic variables for disability; onset with cerebellar symptoms and a progressive course were predictors of a worse outcome (p < 0.05), while onset with headache was a significantly good prognostic sign (p < 0.05). Considering survival times only cerebellar onset and a progressive course were predictors of a shorter survival. None of the other factors were significantly associated with outcome. Conclusion: Neurological involvement in BD may cause significant disability in long term and a progressive CNS involvement with prominent cerebellar symptoms at onset predicts an unfavorable prognosis.

Extrapyramidal Disorders (2) 98 TIME COURSE OF AUTONOMIC DYSFUNCTION IN PARKINSONIAN SYNDROMES: A CLINICOPATHOLOGICAL STUDY. Wenning GK*, Bösch S, Verny M, Ray Chaudhuri K, Granata R, Jellinger K, Poewe W, Litvan I. *Department of Neurology, University Hospital, Innsbruck, Austria

Patients with Behçet’s disease seen between 1990–1996 who had undergone cranial MRI investigation were included. There were 98 patients (M/F: 72/26) with a total of 134 MRI’s read by two masked observers. Clinically, 59 cases had parenchymal central nervous system (CNS) involvement, 14 had intracranial hypertension, while 25 cases had nonspecific neurological complaints without any evidence of CNS involvement. 33 MRI’s were performed during an acute parenchymal CNS attack. The most common finding was a large lesion located either at brainstem or the basal ganglia, extending to diencephalic structures. 57 MRI’s were performed as a control after an acute attack (16), during secondary progression (15) or in cases with neurological findings without any attacks (26). In the former two groups the most common lesion was again located in the above mentioned area, however they were small or scattered; in the latter group the most common lesion type was periventricular white matter lesions, however half of these were normal. In cases with intracranial hypertension, brain parenchyma was normal in all but one. And 25 MRI’s of the cases without CNS involvement were usually normal; in only 3 there were scattered white matter lesions. In conclusion, MRI findings in Behçet’s disease show a correlation with the clinical status. At an acute attack a large and extensive lesion at brainstem or the basal ganglia region is common; which usually resolves in the chronic stage.

Although autonomic features have been reported in a number of parkinsonian syndromes, such as Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), differences in the evolution of autonomic dysfunction have not been studied systematically in pathologically confirmed cases. Methods: 77 cases with pathologically confirmed parkinsonian syndromes (PD: n = 11, MSA: n = 15, DLB: n = 14, CBD: n = 13, PSP: n = 24), collected up to 1994, formed the basis for a multicentre clinicopathological study organized by the NINDS in order to improve differential diagnosis of parkinsonian disorders. In the present study, we determined the potential improvement of diagnostic accuracy by analyzing latencies to onset of autonomic dysfunction such as syncope or urinary incontinence. Results: Autonomic dysfunction was frequent in all parkinsonian syndromes without significant group differences (PD, MSA, DLB, CBD, PSP. Significant group differences for latency, but not duration of autonomic dysfunction were observed (p < 0.01). Post-hoc testing revealed significant latency differences between MSA (18.2 ± 25.1) and PD (148.3 ± 83.1) ( p < 0.005) as well as PSP (50.4 ± 49.3) and PD ( p < 0.02). Latencies in the other groups were intermediate between MSA and PD (DLB (62.5 ± 92.8), CBD (59.2 ± 15.1). Conclusion: Early autonomic dysfunction was present in MSA in contrast to PD whereas intermediate latencies were observed in the remaining parkinsonian syndromes. There was no significant difference in the duration of autonomic dysfunction. Our data demonstrate that the latency to onset of autonomic dysfunction is different among parkinsonian syndromes and may be helpful for differential diagnosis.

97 NEURO-BEHÇET SYNDROME (NBS): PROGNOSTIC FACTORS AND SURVIVAL. A. Siva, O. Kantarcy, S. Saip, V. Hamuryudan, A. Altyntaș, H. Yazycy. Departments of Neurology and Rheumatology, Istanbul University, Cerrahpașa School of Medicine, Istanbul, Turkey

99 5HZ TRANSCRANIAL MAGNETIC STIMULATION APPLIED TO THE MOTOR CORTEX HAS A BENEFICIAL EFFECT ON SKILLED DRAWING MOVEMENTS IN PARKINSON’S DISEASE. H. R. Siebner, C. Auer, D. Weindl, C. Mentschel, B. Conrad. Department of Neurology, Technical University, Munich, Germany

10–15% of the Behçet’s disease (BD) patients have neurological involvement through the course of disease, i.e. Neuro-Behçet syndrome (NBS). This study aims to define prognostic factors related to disability and survival in NBS patients. Patients & Method: Out of 164 patients with any neurological involvement, that have been seen and referred within the multidiciplinary BD clinic, 144 patients with definite NBS (clinically definite or imaging and/or CSF supported) are included. These patients were analyzed for the prognostic effect of demographic aspects, mode and symptoms of onset, course, findings in initial imaging studies and the final diagnosis’ (venous sinus thrombosis – VST, vs. CNS parenchymal involvement – CNS-p). Outcome was measured as time to either survival or a disability of 6 or more attained in the modified Extended disability status scale for NBS, using Cox proportional hazards model. Results: Male to female ratio was 3.92, mean age at onset of NBS was 32.0 ± 8.7 years. The mean duration of BD before the onset of NBS and the mean follow-up period thereafter were 5.3 ± 4.5 and 2.97 ± 3.2 years, respectively. The most common onset symptom was headache (61.6%) followed by motor (53.7%), cerebellar and brainstem symptoms (30%). Considering longer than three year follow-up, 32.8% had only a single attack while 29.3% had relapses and 37.9% had a progressive course. Including clinical features, imaging and CSF studies together: 12.2% were diagnosed as VST and 75.6% as CNS-p. 10th year survival rate was 96% while 55% of the patients were

Pascual-Leone et al. (Neurology 1995; 45 : A315) reported a lasting improvement of motor performance in patients with Parkinson’s disease (PD) after 5Hz repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (MC). Methods: We evaluated the lasting effects of 5Hz rTMS applied to the left MC on skilled hand movements in ten right-handed PD patients (Hoehn & Yahr Stage 1–2) and eight age-matched controls. In PD patients, medication was discontinued 12 hours prior to rTMS. Before and 30 minutes after 5Hz rTMS, all subjects were instructed to draw continously superimposed circles for a 10 s period. Pencil movements were recorded using a digitizing tablet. The mean vertical drawing velocity (Vmean) and the mean number of changes in direction of velocity (NCV) per half circle were calculated. 15 trains of 5Hz rTMS were applied to the left primary motor hand area using a focal eight-shaped coil. Each train lasted 30 seconds, and stimulus intensity was set at 90% of motor threshold. Results: PD patients showed an increase in velocity and a decrease in NCV indicating an improved feed-forward control of drawing movements after rTMS ( p < 0.05, Paired t-test). In the control group, kinematics of handwriting remained unchanged after 5Hz rTMS. Conclusion: In patients with PD, 5Hz rTMS applied to the primary motor hand area can improve openloop circle drawing beyond the time of stimulation. Our preliminary data support the notion that sub-threshold 5Hz rTMS may have a therapeutic application in PD. Supported by the Wilhelm-Sander-Stiftung, Munich.

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100 PROTON MR-SPECTROSCOPY IN VIVO REVEALED BIOCHEMICAL ASYMMETRY IN BASAL GANGLIA OF PATIENTS WITH IDIOPATHIC PARKINSON’S,DISEASE. Diklic V, Delibasic N, Stefanovic D, Zikic M. Institute of Neurology, Psychiatry and Mental Health, and MRI Center, University of Novi Sad, Yugoslavia Proton MR-spectroscopy in vivo (1H-MRS) in patients with idiopathic Parkinson,s disease (IPD) often gave contradictory results. One of possible explanation could be the duration of illness and levodopa treatment, and the other, site of voxel location. In this study we performed 1H-MRS (Siemens Magnetom 63SP4000, 1.5T) in 18 patients with IPD and ageand sex-matched controls. Voxels were placed in the caudo-putaminal regions of both hemispheres. Dimensions of voxels were 1.25 cm3 and 1.5 cm3, for sequences SE 135 and STEAM 20, respectively. The measured metabolites: N-acetylaspartate (NAA), neuronal marker, choline (Cho), marker of biomembranes, myoinositol (mI), glia marker, glutamine and glutamate (Glx), were expressed as the ratios to total creatine (tCr), marker of free energy pool. We found significant differences in 56% of IPD patients when we compared the NAA/tCr ratios between right and left basal ganglia. The greatest differences vs. control values were in striata contralateral to the worse symptom side. These differences were also more pronounced in younger patients (age: 43–50 yr.) than in older (age: 56–65 yr.), being 0.826 + 0.571, and 0.318 + 0.125, respectively ( p < 0.05). Glx, marker of excitatory metabolites, was often elevated in IPD, and because tCr was often diminished, the Glx/tCr ratios were always elevated. In few patients mI was slightly elevated, but without statistical significance. Lipids were almost invariably elevated in patients with advanced IPD, and lactate was never found. Our results revealed that bilateral MRS measurements show significant asymmetric reduction of NAA/tCr in IPD, which was more pronounced in younger patients. 101 FUNCTIONAL STEREOTACTIC NEUROSURGERY IN PARKINSON’S DISEASE – IN VITRO ACCURACY OF MRI- AND CT-GUIDED TARGET LOCALISATION. C. Gaebel, J. Gliemroth2, I. Grande-Nagel, U. Kehler2, H. Arnold2, H.-D. Weiss. Institute of Neuroradiology, 2Neurosurgical Clinic, Medical University, Lübeck, Germany For target localisation in functional stereotactic interventions most centers use either computed tomography (CT) or ventriculography. Magnetic resonance imaging (MRI) offers several advantages like increased tissue contrast, direct nonreformatted multiplanar imaging and reduced imaging artefacts. The major potential disadvantage of MRI is anatomical inaccuracy due to inhomogenity of the magnetic field. We present an in vitro model to evaluate and compare the accuracy of MRI- and CT-guided target localisations. Methods: Formalin fixed brains were modelled in a plaster-cast shell simulating the skull bone and fixed in a Leksell stereotactic frame. After defining the x-, y- and z-coordinates of two different targets in both nuclei lentiformes of each brain using CT- or MRI-images in ten brains respectively we performed burrhole craniotomy, tubeplacement and electrocoagulation. The topographic relations of lesion-coordinates concerning the targets were evaluated gross- and histopathologically. Results: The model allows a safe and practice-orientated carrying out using clinical standard equipment. All CT-guided and 40% of MRI-guided lesions ranged within a 1 mm-diameter related to the target and 60% of the MRI-guided lesions ranged within a 2 mm-diameter. There were no significant differences of lesion-deviation concerning the x-, y- and z-coordinates. Conclusions: CT- and MR-images offer satisfactory accuracy for target localisation using the Leksell stereotactic frame and can be used as complementary methods for functional pallidotomy in Parkinson’s disease. 102 IS PARKINSON’S DISEASE A PRIMARY OLFACTORY DISORDER? C. H. Hawkes1, B. C. Shephard2, R. K. B. Pearce3 and S. E. Daniel3. 1Essex Neurosciences Centre, Oldchurch Hospital, Romford, Essex; 2Department of Neurology, Ipswich Hospital, Ipswich; 3Institute of Neurology, London, UK The olfactory defect in cognitively unimpaired patients with Parkinson’s disease (PD) is severe and develops early in the course of disease. Our data suggest a pivotal role for olfaction in PD: University of Pennsylvania Smell Identification Tests were highly abnormal: 126/155 patients with PD (81%) scored outside the 95% limits of our 156 age matched controls Evoked responses to hydrogen sulphide were absent in 36/73 patients with PD. In the remaining 37, 12 (32%) were delayed (66% abnormal overall). Pathological examination of Brain Bank olfactory bulbs were all diag-

nosed PD on the basis of characteristic Lewy Body pathology. Quantitative study of the anterior olfactory nucleus (AON) showed marked reduction in AON neurons in all but one of 7 patients. Disease duration correlated strongly with neuronal loss. It has been shown that mutation of asynuclein causes some forms of familial PD. Rat expression of synuclein, assessed by in situ hybridisation, is highest in olfactory areas, exceeding that of extrapyramidal zones. Conclusion. All clinical, pathological and molecular data point to severe and selective damage in the olfactory system. This suggests a primary role of the rhinencephalon in PD. It is proposed that PD and allied conditions with olfactory impairment are reclassified as olfactomotor disorder. 103 DEEP BRAIN STIMULATION (DBS) OF THE SUBTHALAMIC NUCLEUS (STN) AND GLOBUS PALLIDUS INTERNUM (GPi) IN PARKINSON’S DISEASE. M. C. Rodriguez, A. Gorospe, J. Guridi, A. Mozo, E. Ramos, G. Linazasoro, J. A. Obeso. Neurologia, Clinica Quiron, San Sebastian, Spain Objectives: To study the safety, efficacy and fiability of DBS of the STN and GPi in the treatment of PD. Background: In MPTP monkeys DBS improves all the parkinsonian signs. It is necessary to confirm this data in parkinsonian patients. Methods: Bilateral electrodes were implanted in 15 parkinsonian patients (9 in the STN and 6 in the GPi). The target was defined by stereotactic surgery and microrecording. Patients were evaluated following the CAPIT protocol preoperatively in the basal “off” and in “on” treatment and postoperatively at 1, 3, 6 and 12 months in every drug condition with the DBS “on” and “off”. Results: In patients with STN stimulation there was a significant decrease of 60% in the UPDRS motor score in the drug “off” condition and of 52% in dyskinesias with suppression of dystonia and a reduction in the daily levodopa intake of 37%. In patients with GPi stimulation there was a significant decrease of 51% in the UPDRS motor score in the “off” treatment condition, 57% in dyskinesias, 20% in dystonia and 11% reduction in levodopa intake. There were no significant changes in the “on” drugs condition. In 5 patients there were important complications. Conclusion: DBS of the STN and GPi are effective in the treatment for PD. Complications may be important.

Extrapyramidal Disorders (3) 104 MOTOR CORTICAL EXCITABILITY CHANGES IN PARKINSON’S DISEASE: A MOVEMENT-RELATED POTENTIAL CORRELATE? P. Praamstra, F. Plat, M. Horstink, D. Stegeman; Dept. of Neurology, University of Nijmegen, The Netherlands We investigated motor cortex function in Parkinson’s disease by means of movement-related potentials derived from the scalp-recorded EEG. The lateralized readiness potential (LRP) was recorded in 10 Parkinson patients and 10 age-matched controls using a noise-compatibility task. In this two-choice task, visual stimuli containing incompatible target and distractor elements, which simultaneously instructed for responses from both hands, initially caused activation of the motor cortex controlling the wrong response hand. The incorrect response activation, as expressed in the LRP, was of higher amplitude in patients than in control subjects, replicating Praamstra et al. (1998). This group difference was only observed, however, when the LRP was averaged with reference to the reaction stimulus and not when it was time-locked to the response. Given that the LRP is generated in the primary motor cortex, this feature suggests that the higher amplitude incorrect response activation in the patient group is caused by differences in susceptibility to sensory input in the motor cortex. The results indicate that, besides abnormalities due to deficient supplementary motor area function, there are movement-related potential abnormalities attributable to primary motor cortex dysfunction in Parkinson’s disease. The movement-related potential evidence for primary motor cortex dysfunction in Parkinson’s disease is compatible with recent evidence from transcranial magnetic stimulation (TMS) for reduced corticocortical inhibition in the motor cortex of Parkinson patients. 105 A STUDY OF 5 CANDIDATE GENES IN PARKINSON’S DISEASE AND RELATED NEURODEGENERATIVE DISORDERS. Nicholl DJ, Bennett P, Bonifati V, Colosimo C, Fabbrini G, Hiller L, Lamberti P, Marconi R, Meco G, Salvetti S, Stocchi F, Vanacore N, Vieregge P and Williams AC on behalf of the ESGAP investigators

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Parkinson’s disease (PD) is thought to be due to a combination of genetic and environmental factors. We have studied several loci which have been said to be associated with PD in previous smaller studies: CYP2D6 (debrisoquine hydroxylase), CYP1A1, GSTM1 (glutathione S-transferase M1), NAT2 (N-acetyltransferase 2) and DAT1 (dopamine transporter). We have performed a large-scale investigation of several loci within these genes in subjects with PD (178 – sporadic; 46 – familial), multiple system atrophy (MSA; 35), progressive supranuclear palsy (PSP; 30), motor neurone disease (MND; 54), and Alzheimer’s disease (23) along with a large number of controls (548). The PD, MND and Alzheimer subjects were all recruited from the West Midlands region, UK. The MSA and PSP cases were recruited from the UK and Italian ESGAP (European Study Group on Atypical Parkinsonism) centres along with at least 1 matched control. Cases were matched with controls according to age (± 3 years), sex, ethnicity and locality. No association was found between disease status and any of the loci studied either by univariate or multivariate analysis. In summary, this is one of the most comprehensive candidate gene studies performed in PD to date. The results suggest that these loci are highly unlikely to be involved in the aetiology of PD. Future studies should be directed towards other loci and use appropriately matched controls.

106 A LARGE BRITISH KINDRED WITH AUTOSOMAL DOMINANT PARKINSON’S DISEASE: A CLINICAL, PATHOLOGICAL, PET AND GENETIC STUDY. J. R. Vaughan1, D. J. Nicholl2, D. E. W. Aldous2, P. Piccini3, S. E. Daniel4, D. J. Brooks1, 3, A. C. Williams2 and N. W. Wood1. 1Institute of Neurology, Queen Square, London; 2Department of Neurology, Queen Elizabeth Hospital, Birmingham; 3MRC Cyclotron Unit, Hammersmith Hospital, London; 4Parkinson’s Disease Society Brain Research Centre, Wakefield Street, London, UK We have identified 2 branches of an extensive Parkinsonian kindred. Detailed genealogy established their common ancester born in 1578 in Fressingfield, England. Eight affected members in 2 generations have been identified (4 male:4 female). The 6 cases personally examined are indistinguishable clinically and pathologically from the sporadic form of Parkinson’s disease (PD) with a mean age of onset of 64 years old (SD ± 11.2; range 42–75). 18 Fluorodopa-dopa uptake in the proband was reduced in a pattern specific to sporadic PD. The segregation ratio was 36% (4/11) for those who lived to 75 years fitting with a model of autosomal dominant inheritance with reduced penetrance. Two more local families (B,C– 4.5 affecteds) have been identified: a firm genealogical link has not yet been established. No linkage to the PD-1 locus (4q21–23) was found in the kindred using the two polymorphic markers most closely linked (D4S1647 and D4S2380). Screening of the kindred for Ala53Thr mutation described in the α-synuclein gene was negative and direct sequencing of all 7 exons of the α-synuclein gene failed to reveal any further mutations. Genetic linkage studies underway may identify another PD locus and further our understanding of the pathogenesis of PD.

107 18F-DOPA PET IN TWINS DISCORDANT FOR PARKINSON’S DISEASE: A FOLLOW-UP. P. Piccini, D. J. Burn, R. Ceravolo, D. J. Brooks. MRC Cyclotron Unit, Hammersmith Hospital, London, UK Twin studies are a classical tool for assessing the influence of hereditary factors in diseases. The application of this approach to late-onset illnesses like Parkinson’s disease (PD) poses, however, some problems due to the identification of subclinical cases. The critical pathology underlying PD is nigral degeneration, leading to impairment of nigro-striatal dopaminergic function. PD patients invariably display reduction of striatal 18F-dopa uptake measured by positron emission tomography (PET); a lesser alteration can also be found in some asymptomatic relatives of P13 patients. This suggests that striatal 18F-dopa reduction is a reliable marker of the biochemical phenotype associated with PD and 18F-dopa PET a useful method to study twins clinically discordant for PD. We investigated 17 monozygotic (MZ) and 15 dizygotic (DZ) co-twins of PD patients with 18F-dopa PET; nine of the NIZ and eight of the DZ co-twins were scanned twice over a period of 7 years. A greater number of MZ (53%) than DZ (13%) co-twins had 18F-dopa uptake abnormally reduced at the time of first scan (Fisher exact test, p = 0.02). NIZ co-twins also showed a more rapid decrease over time in 18F-dopa putamen uptake compare with the DZ (t-test, p = 0.0079), and two developed clinical PD. The data strongly support the role for inheritance in the development of the nigro-striatal dopaminergic impairment characteristic of the PD.

108 Ala30Pro MUTATION IN THE A-SYNUCLEIN GENE CAUSING AUTOSOMAL-DOMINANT PARKINSON’S DISEASE. R. Krüger1, 2, W. Kuhn1, Th. Müller1, D. Woitalla1, H. Przuntek1, J. T. Epplen2, L. Schöls1, O. Riess2. 1Department of Neurology & 2Department of Molecular Human Genetics, Ruhr-University, Bochum, Germany The neuropathological diagnostic hallmark of PD are Lewy bodies, which are located in many brain regions. An Ala53Thr missense mutation in the a-synuclein (SNCA) gene causing autosomal dominant PD (ADPD) has been shown as main component of Lewy bodies in sporadic PD. For further elucidation of a-synuclein in PD we performed a detailed mutation analysis in 192 patients with sporadic PD and 7 unrelated patients with a family history for PD. None of our patients carried the Ala53Thr mutation. We therefore searched for other DNA changes in the coding exons of SNCA. In one patient we identified a G88C substitution causing an Ala30Pro exchange, which could be detected by MvaI digestion. This mutation was not observed in 1140 chromosomes of control individuals. The index patient (age 63) presented with typical signs of PD. Clinical investigation of family members of the index patient revealed other affected individuals suggesting that the disease is inherited as an autosomal dominant trait. The analysis of the Ala30Pro substitution demonstrates that the mutation cosegregates with PD in the family. We conclude that the Ala30Pro mutation is causative for ADPD. Our results underline that SNCA participates in the pathogenesis of some rare forms of ADPD.

109 ZYDIS SELEGILINE: PREFERENCE FOR A FAST-DISSOLVING DOSAGE FORM IN PATIENTS WITH PARKINSON’S DISEASE. A. Clarke1, F. Hartig1, R. Bhardwaj1, F. Brewer1, E. S. Johnson1, N. J. Mallard1 and D. G. MacMahon2. 1Scherer DDS, Swindon, UK & 2Camborne/Redruth Hospital, UK To avoid first-pass metabolism of selegiline, a fast-dissolving form (Zydis selegiline) has been developed, from which the drug is absorbed pre-gastrically [1]. This permits a reduction in the administered dose. We surveyed the preferences for selegiline given as either the Zydis dosage form or as conventional tablets, to patients with Parkinson’s disease. Study 1: 145 patients received one 5mg selegiline unit and one Zydis placebo in a randomised sequence. Patients liked both formulations (placebo 97%: active 61%) and 97% of patients found them easy to swallow. Both formulations were preferred to conventional tablets (placebo 90%: 65% active), despite lower palatability for active units (96% liked the taste of placebo: 46% for active). Study 2: 120 patients switched from tablet selegiline to 1.25 mg Zydis selegiline (ZELAPAR‰) or 10mg Zydis selegiline for up to 3 months. Both Zydis units were liked (91% and 86% respectively) and patients preferred both Zydis units to selegiline tablets (80% and 73% respectively). Palatability of the 1.25 mg dose was high (81% liked the taste). The Zydis dosage form provides a convenient means of administering medication to patients with Parkinson’s disease, particularly those with swallowing difficulties [Clarke A, Brewer F, Johnson ES, et al (1997) Ann Neurol Abstract M69 (In press)].

Peripheral Neuropathy (2) 110 ELECTROPHYSIOLOGIC CORRELATES OF EXTENSOR DIGITORUM BREVIS MUSCLE ATROPHY IN CHILDREN WITH CHARCOTMARIE-TOOTH DISEASE TYPE 1A. J. Berciano, A. García, J. Calleja and O. Combarros, Santander, Spain Objective: To describe the electrophysiologic abnormalities accounting for the appearance and progression of extensor digitorum brevis (EDB) muscle atrophy in children with Charcot-Marie-Tooth disease type 1A (CMT1A). Background: Evolution of EDB muscle atrophy in CMT-1A has not been documented. Design/Methods: Twelve children with CMT-1A duplication were serially evaluated. Initial ages ranged from 1 month to 5 years (mean, 1.5 years) and final ages from 6 to 19 years (mean, 10). All subjects had three or more electrophysiological studies of the peroneal nerve. Results: EDB muscle atrophy was observed in 2 (19%) patients by age 5, in 7 (58%) by age 10, and in 5 out of the 7 (71%) patients who had reached the second decade at the end. Nerve conduction maturation was systematically abnormal, but by age 5 the mean values of nerve conduction parameters of peroneal nerve did not significantly differ from those

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observed in adult patients. Compound motor action potential (CMAP) amplitudes of EDB muscle were reduced in 50% and 100% of cases by age 5 and 10, respectively. Furthermore, an almost constant finding throughout the study was progressive attenuation of CMAPs, these becoming unobtainable in two cases. Conclusion: EDB muscle atrophy in children with CMT-1A is an age-depending finding which is accounted for by gradual reduction of the distal peroneal nerve CMAP amplitudes. Supported by “Fundación Marcelino Botín”, Santander, Spain.

111 MULTIFOCAL NEUROPATHY IN DIABETIC PATIENTS. G. Said, M. Arzel, C. Lacroix, V. Planté, D. Adams. Service de Neurologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France Inflammatory lesions of peripheral nerves occur in proximal diabetic neuropathy (PDN). In order to see whether the same pattern of lesions occurred in multifocal diabetic neuropathy (MDN), we reviewed the clinicopathological data of 16 diabetic patients (12 males, 6 females; mean age: 66 ± 11, range 41–83 yrs; 7 with insulin dependent diabetes mellitus) with MDN investigated in our center between 1988 and 1997. The course of the neuropathy was subacute and the peroneal nerve affected in all patients; bilaterally in 10. Proximal deficit of the lower limbs was also present in 4 patients and the upper limbs affected in 6. EMG showed an axonal pattern in the affected territory in all patients. The superficial peroneal nerve (SPN) was biopsied in 15 patients, the superficial radial nerve in one and both the intermediate cutaneous nerve of the thigh and the SPN in one. Nerve biopsy showed marked axon loss in all of them, with a myelinated fiber density 1796 ± 1718 per mm2. In the patients with the most severe axon loss, the unmyelinated fibers were also affected on EM examination. Fibers undergoing axonal degeneration markedly predominated on teased fiber preparations in association with 10 to 45% demyelinated or remyelinated fibers in 7 specimens. Epineurial lymphocytic vasculitis was present in 4 patients, along with endoneurial vasculitis and inflammation in 1. Most inflammatory cells were CD4 T cells. Conclusion: The lesions found in MDN are similar to those of PDN with a variable proportion of ischemic and inflammatory nerve lesions. 112 NEUROLOGICAL MANIFESTATIONS IN CHRONIC MOUNTAIN SICKNESS. P. K. Thomas, R. H. M. King, J. R. Muddle, J. Gambon, R. Tapia, M. Vargas, A. Appenzeller. London, UK; Lima, Peru; Albuquerque, NM, USA Chronic mountain sickness (CMS) or Monge’s disease, a maladaptation syndrome in individuals living at high altitude, occurs in the Peruvian Andes. Neurological symptoms of CMS include headaches, tinnitus and ‘dizziness’. We studied 15 subjects living in Cerro de Pasco, Peru (4338 m altitude): 5 had classical symptoms of CMS with a mean haematocrit of 69% (range 60–78%); 5 control subjects had a mean haematocrit of 55% (range 49–60%) (P < 0.005). Recurrent headaches were reported by 11 subjects and 5 CMS patients had episodic ‘dizziness’. Burning and tingling paraesthesiae in their feet were experienced by 14 of the 15 subjects and also by 9 CMS patients in their hands. Reflex depression or loss, or distal cutaneous sensory impairment was found in 3. In 13 all symptoms rapidly disappeared on moving to low altitude. Sural nerve biopsies performed in 3 subjects with ‘burning feet’ revealed minor abnormalities only. In conclusion, typical symptoms and signs of CMS were present in the subjects with high haematocrits. Burning feet and hands were found to be common and independent of CMS and represented additional evidence of maladaptation to altitude in Andean natives. The rapid reversibility of this symptom on sojourn at low altitude suggests altered axolemmal excitability rather than the effect of a structural neuropathy. 113 PREDICTIVE VALUE OF ANTI-SULFATIDE ANTIBODIES IN PERIPHERAL NEUROPATHY. M. Carpo, M. Gamba, S. Allaria, A. Toscano, G. Cavaletti, S. Monaco, G. Scarlato, E. Nobile-Orazio. Milan, Messina, Monza, Verona, Italy High titers of anti-sulfatide IgM antibodies have been variably associated with predominantly sensory or sensorimotor, demyelinating or axonal neuropathy with or without IgM monoclonal gammopathy. Not only the clinical correlate of this reactivity is debated but also their diagnostic role in clinical practice. In order to clarify the potential clinical usefulness of antisulfatide IgM antibodies we reviewed the results of anti-sulfatide IgM

antibodies by ELISA and the clinical diagnosis of 547 patients referred to our Laboratory from 1991 to 1997. 139 patients had polyneuropathy (PN) associated with IgM monoclonal gammopathy, 60 had IgM M-protein without PN, 38 had chronic inflammatory demyelinating polyneuropathy (CIDP), 79 other dysimmune PN, 185 PN of other or undetermined causes, and 46 other diseases. High titers of anti-sulfatide antibodies (> 1/16,000) were only found in 12 patients including 9 with PN associated with IgM M-protein and 3 with CIDP: the review of electrophysiological studies in 6 of these patients always showed a demyelinating neuropathy. Lower anti-sulfatide titers (1/4,000–1/8,000) were found in 68 patients and were homogeneously distributed in all patient’s groups and had no predictive value for any neuropathy. In conclusion in this retrospective series of referred patients, high titers of anti-sulfatide IgM antibodies (> 1/16,000) were highly predictive for chronic demyelinating dysimmune neuropathy often associated with IgM monoclonal gammopathy and may therefore have potential diagnostic relevance. 114 THE CLINICAL FEATURES OF PATIENTS WITH POLYNEUROPATHY ASSOCIATED WITH IGM MONOCLONAL GAMMOPATHY WITH ANTI-MAG, ANTI-SGPG AND/OR ANTI-SULFATIDE ANTIBODY ACTIVITY. Van den Berg LH, Bosboom W, Notermans NC, Eurelings M, Wokke JHJ. Utrecht. The Netherlands In patients with polyneuropathy associated with IgM monoclonal gammopathy, serum antibody activity to myelin antigens may be detected. To determine the frequency and clinical relevance of these antibo-dies we measured the antibody activity to the myelin associated glycoprotein (MAG), glyulfated glucuronyl paragloboside (SGPG) and sulfatide in a large group of 75 patients with polyneuropathy associated with IgM monoclonal gammopathy. Antibody titers to MAG were determined by Western blotting, to SGPG by thin layer chromatography and to sulfatide by ELISA. Thirtyfour patients had anti-MAG antibodies which crossreacted with SGPG in all patients and with sulfatide in 13 patients: all patients had a slowly progressive sensorimotor demyelinating polyneuropathy. Of the 41 patients without anti-MAG antibodies 9 had anti-SGPG antibodies which crossreacted with sulfatide in 7 patients: 5 patients had a slowly progressive sensorimotor demyelinating polyneuropathy similar to those with anti-MAG antibodies, 2 patients had a prodominantly motor demyelinating polyneuropathy and 2 patients had a sensorimotor axonal polyneuropathy. Five patients only had anti-sulfatide antibodies: 3 patients had a mild sensory axonal polyneuropathy and 2 patients had a subacute sensorimotor demyelinating polyneuropathy. We conclude that patients with polyneuropathy associated with anti-MAG antibodies constitute a similar clinical presentation. Patients with anti-SGPG and anti-sulfatide antibodies have a more heterogeneous clinical presentation, although patients with anti-SGPG antibodies tend to have more motor deficit, while patients with anti-sulfatide antibodies tend to have more sensory abnormalities. 115 DETRIMENTAL EFFECT OF STEROIDS AND PLASMA EXCHANGE IN DYSIMMUNE NEUROPATHIES. Meucci N, Cappellari A, Carpo M, Di Troia A, Manfredini E, Scarlato G, Nobile-Orazio E. Milan, Italy Some patients with multifocal motor neuropathy (MMN) were recently reported to deteriorate after steroid therapy. It is unclear whether this effect is restricted to MMN and steroids or involves other dysimmune neuropathies or treatment. Since 1990 we observed 7 patients (3 men and 4 women, aged 26–63 years, mean 49.7) with dysimmune neuropathies who worsened after steroids or plasma-exchange. Four patients had an asymmetric, step-wise, pure motor neuropathy lasting 2–25 years; nerve conduction studies (NCS) in two confirmed the diagnosis of MMN while no conduction block was detected in two; one patient had mildly increased CSF proteins. The other three patients had an asymmetric, step-wise or chronic progressive, predominantly motor (2) or sensory-motor neuropathy (1) lasting 0.5–10 years; in all these patients NCS were consistent with a demyelinating neuropathy and CSF proteins were increased, supporting the diagnosis of CIDP. Of the four patients with pure motor neuropathy, two, including one with MMN, rapidly worsened after plasma-exchange, one developed neuropathy and subsequently worsened concomitantly with topical endonasal steroids for severe asthma, while the other, similarly to patients with predominantly motor or sensory-motor neuropathy worsened 4–5 days after starting prednisone 50–125 mg/die. All patients subsequently improved with high-dose intravenous immunoglobulin (IVIg). This report not only draws attention on the possible untoward effect of steroids and plasma-exchange in dysimmune neuropathies but also highligths the different response to these therapies and IVIg in some patients.

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Peripheral Neuropathy (3) 116 SUSCEPTIBILITY TO GUILLAIN-BARRÉ SYNDROME AND IgG RECEPTOR POLYMORPHISMS. W.-L. van der Pol1, R. H. M. Scheepers1, J. H. J. Wokke2, P. J. A. Capel1, J. G. J. van de Winkel1, L. H. van den Berg2. 1Department of Immunology, and 2Department of Neurology, University Hospital Utrecht, The Netherlands Guillain-Barré syndrome (GBS) is a subacute inflammatory, demyelinating neuropathy, mediated by both humoral (IgG) and cellular immune components. Interaction of IgG with receptors for the constant part of IgG (FcγR) on leukocytes, may trigger potent cellular effector functions such as phagocytosis and cytotoxicity. Three subclasses of FcγR (IIa, IIIa, IIIb) display bi-allelic functional polymorphisms, which significantly influence receptor affinity for IgG2 and IgG3 (FcγRIIa), or IgG1 and IgG3 (FcγRIIIa and FcγRIIIb) isotypes, and – consequently – efficacy of IgG mediated effector-functions. To assess the relevance of these polymorphisms for susceptibility to Guillain-Barré syndrome, we studied genotype- and allelic frequencies of these three FcγR polymorphisms in 163 healthy Caucasian controls and 28 Guillain-Barré patients using allele-specific PCRs. We observed skewed distributions of both the FcgRIIa (CD32) and FcγRIIIa (CD16) genotypes with enrichment of the FcγRIIa-H131 homozygous individuals (48% in GBS vs. 27.6% in controls), and FcγRIIIa-158F homozygous (57.1% in GBS vs. 43% in controls) and increased frequencies of both alleles. These results are compatible with a role for FcγR alleles as risk factors for GBS. 117 THE EXPRESSION OF GELATINASES A AND B AND THEIR NATURAL INHIBITORS TIMP-1 AND -2 IN THE INFLAMED PERIPHERAL NERVOUS SYSTEM. B. C. Kieseier1, A. J. H. Gearing2, K. V. Toyka3, H.-P. Hartung1. 1Department of Neurology, University of Graz, Austria; 2British Biotech Pharmaceuticals Limited, Oxford, UK; 3Department of Neurology, University of Würzburg, Germany The matrix metalloproteinases (MMPs) belong to a large group of proteolytic enzymes that can degrade all protein components of the extracellular matrix, thus playing a key role in many physiologic as well as pathologic conditions. Therefore, a finely tuned regulation of MMP activity is of critical importance, since any imbalance in favour of increased enzymatic activity will result in tissue destruction or cell invasion. An emerging body of evidence suggests MMPs to be of paramount importance in the pathogenesis of inflammatory diseases of the peripheral nervous system. We investigated the expression pattern of MMP-2 (Gelatinase A) and MMP-9 (Gelatinase B) and their physiologic inhibitors (tissue inhibitors of the MMP family, TIMP-1 and TIMP-2) in sural nerve biopsies from patients with Guillain-Barré syndrome (GBS) in comparison with non-inflammatory neuropathies. Using a polymerase chain reaction assay an increase of MMP-9 mRNA expression was noted in the GBS cases, whereas MMP-2, TIMP-1, and TIMP-2 mRNAs were found to be consitutively expressed at lower levels, both in GBS and non-inflammatory controls. Increased mRNA expression of MMP-9 was associated with enhanced proteolytic activity, as shown by gelatine zymography, and with positive immunohistochemistry predominantly around blood vessels. Our findings suggest that Gelatinase B is upregulated in GBS whereas the expression of its natural inhibitors remains unchanged, implying that an increased enzymatic activity of MMP-9 may contribute to the pathogenesis of inflammatory demyelinating disorders of the peripheral nervous system. 118 CIRCULATING MATRIX METALLOPROTEINASE-9 (GELATINASE B) CORRELATES WITH DISEASE SEVERITY IN GUILLAIN-BARRÉ SYNDROME (GBS). Créange A, Clair B, Planchenault T, Poron F, Raphaël J-C, Gherardi RK. Créteil and Garches, France We investigated the implication of metalloproteinases in GBS. Matrix metalloproteinases (MMP) forms a family of extracellular proteinases suspected to be implicated in cell transmigration and extracellular matrix (ECM) degradation in inflammatory diseases. Circulating levels (ELISA) and zymographic activities of proMMP-2 (gelatinase A), proMMP-9 (gelatinase B), and circulating levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), were evaluated in 11 patients with GBS at day 1, 7 and 15 of hospitalization, and in 10 controls with non-inflammatory neurological diseases. Patients were in the progression phase at day 1, and 9/11 were recovering at day 15. MMP-9 circulating levels were increased at day 1 (46% of patients) and levels and activity decreased from day 1 to day 15

( p = 0.06). ProMMP-9 and TIMP-1 plasma levels correlated positively with disability, the highest values being observed in the most disabled patients. The ratio MMP-9/TIMP1 was higher in the most disabled patients than in the less disabled ones and controls suggesting an unbalance between the enzyme and the inhibitor. ProMMP2 levels and activity were not regulated. Conclusion: Early phase of GBS is characterized by an increase of gelatinase B, that may favor TNF-a processing, breakdown of the blood nerve barrier, traffic of immune cells into nerve, and myelin degradation. 119 THE INTENSITY OF LYMPHOCYTIC INFILTRATION IN NERVE BIOPSIES IN INFAMMATORY NEUROPATHY. S. Hughes1, A. BenSmith2, J. Cooper, P. C. Barber1, C. Savage2 and J. B. Winer 3. Birmingham, England, UK Guillain-Barré Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are immune mediated demyelinating disorders of the peripheral nervous system in which both T cells and humoral mechanisms are involved. Sural nerve biopsies of patients with GBS and CIDP reveal T lymphocyte infiltrates which we have previously shown can be cultured into T cell lines1. In this study we examined sensory nerve biopsies from 40 patients (39 sural, 1 radial) to determine factors that might influence the ability to culture T cell lines from biopsy material. Biopsies were processed for tissue culture and immunocytochemistry using anti CD3 antibody (Dako) as a marker for T lymphocytes. The number of lymphocytes per mm2 (SD) ranged from 416 (38) to undetectable levels. There was a significant association between the ability of lymphocytes to be established in culture and their density in histological sections with 10 successful cultures out of 18 biopsies with a density greater than 4 cells per mm2 compared with 4 out of 22 densities less than 4 (Chi2 = 4.5; p < 0.05). In a few cases lymphocytes had the ability to grow in culture even where their density in histological sections was undetectable by our methods. T cell lines were established in six out of eighteen biopsies in patients without GBS or CIDP. Three of these patients had vasculitis and one had paraneoplastic neuropathy. These results suggest that absolute numbers of lymphocytes present in culture is not the only factor influencing the success of establishing T cell lines from nerve biopsy material and factors such as the presence and nature of tissue adhesion molecules may be important. 1. Ben Smith A, Gaston JSH, Barber PC, Winer JB. Neurol. Neurosurg & Psych 61 : 362–368, 1996. 120 THE SPECTRUM OF ANTECEDENT INFECTIONS IN THE GUILLAIN-BARRÉ SYNDROME: A CASE-CONTROL STUDY. B. C. Jacobs, Ph. H. Rothbarth, F. G. A. van der Meché, P. Herbrink, P. I. M. Schmitz, M. A. de Klerk, P. A. van Doorn. Erasmus University Rotterdam, The Netherlands The Guillain-Barré syndrome (GBS) is an acute polyneuropathy which is usually preceded by an infection. Many infectious agents have been reported in case-reports and series of GBS patients, but their relation to GBS remains unclear. To investigate which infections are specifically associated with GBS, we conducted a serological study for 16 infectious agents in 154 GBS patients and 154 sex- and age-matched controls with other neurological diseases. The seasonal distribution of serum sampling in the GBS and control group was the same. In GBS patients Campylobacter jejuni (32%), cytomegalovirus (13%), Epstein-Barr virus (10%), and Mycoplasma pneumoniae (5%) were the most common causes of recent infections. These infections were all significantly more frequent in GBS patients than in the controls. Infections with Haemophilus influenzae (1%), parainfluenza 1 virus (1%), influenza A virus (1%), influenza B virus (1%), adenovirus (1%), herpes simplex virus (1%) and varicella zoster virus (1%) were also demonstrated in GBS patients, but not more frequently than in controls. C. jejuni and CMV infections were respectively associated with antibodies to the gangliosides GM1 and GM2, and with pure motor and severe motor-sensory variants of GBS. Infections with EBV and M. pneumoniae were not associated with specific anti-ganglioside antibodies and neurological patterns. This study identifies four infectious agents which are specifically related to GBS. The variety of infections may contribute to the clinical and immunological heterogeneity of GBS. 121 TREATMENT RESULTS IN IDIOPATHIC CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP). Osvaldo J. M. Nascimento, Marcos R. G. de Freitas, Edmar S. Araújo, Tania Escada. Rio de Janeiro, Brazil

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Corticosteroids (CS), plasma exchange (PE), and immunoglobulin (IVIg) are effective for CIDP, but there is little information on the frequency of response and the most effective modality of treatment. The proportion of patients who respond to a second type of treatment after failure of the initial therapy is also unknown. Ninety three consecutive patients with idiopathic CIDP treated with CS (prednisone-PD; or pulse intravenous methylprednisolone-IVMP), and IVIg, during the last eight years were retrospectively reviewed. The course of the neuropathy was progressive in 52 patients and relapsing in 41. The mean age, duration of symptoms, strength (MRC scale), and motor conduction studies were similar in both groups: 73 were initially treated with CS (66 with PD; 7 with IVMP), and 20 with IVIg. The proportion of responders to the initial treatment was similar (CS = 80.8%, IVIg = 75%). The interval before the response was also similar (CS = 4 weeks, IVIg = 3.6 weeks). Patients not responding to IVIg as the initial (5) or subsequent (6) treatment improved with CS isolated or in association. IVMP was efficient in 6 patients initially not responsive to PD. Side-effects were lesser with IVMP than those of long term oral PD or IVIg. Our results suggests that CS, especially IVMP, is a cost-effective treatment for CIDP, contrasting with the subtantial cost of IVIg. 122 RANDOMISED TRIAL: CEREBROSPINAL FLUID FILTRATION VERSUS PLASMA EXCHANGE IN GUILLAIN-BARRÉ SYNDROMEINTERIM ANALYSIS. Wollinsky KH*, Hülser P-J+, Schreiber H+, Bößenecker W&, Huber-H KH&, Brinkmeier H#, Mehrkens H-H*. Depts. Anaesthesiology/Intensive Care*, and Neurology Rehabilitation Hospital Ulm+, Dept. Neurology Heidenheim&, Dept. General Physiology University#, Ulm, Germany Cerebrospinal fluid filtration (CSFF) has been shown to remove pathogenetically relevant inflammatory and antiexcitatory factors from the CSF in acute Guillain-Barré syndrome (GBS). CSFF is compared in a multicenter trial with plasma exchange (PE). 32 GBS patients, at least unable to walk (score 4, GBS Study Group) have been recruited and randomly assigned to CSFF (15 patients, treatment period 2 weeks, daily filtration volume 200–300 ml), or PE (17 patients, 6 × 50 ml/kg exchange within 2 weeks). The mean age was 51 (± 14) years in the CSFF- and 53 (± 18) in the PE-group. When randomised, the mean score was 4.2 (± 0.5) in the CSFF-compared to 4 (± 0.3) in the PE-group. Both groups had an improvement after 4 weeks of 0.8 score points. The median time for an one score point improvement lasted 23.5 (CSFF-) and 23 days (PE-group). The median time to reach score 2 (walking unaided) was 43 days (CSFF-) and 51.5 days (PE-treatment). Our data are in the upper range of PE- and IVIG-studies (4 weeks improvement 0.7–1.1 score points, one score improvement after 19–41, score 2 after 53–69 days). CSFF and PE were equivalent effective. CSFF (without potential transfusion risks) was well tolerated.

Clinical Neurophysiology 123 DYNAMIC ELECTROPHYSIOLOGICAL FINDINGS IN PATIENTS WITH EFFORT RELATED SYMPTOMS. J. Koehler, P. P. Urban, A. Mika-Grüttner, H. C. Hopf, B. Tettenborn. Department of Neurology, Mainz University, Langenbeckstr., Mainz, Germany In this prospective study we evaluated pre and post exercise somatosensory evoked potentials (SSEP), F-wave latencies and motor evoked potentials (MEP) in patients with effort related symptoms of the lower limbs. The results were correlated with neuroradiological findings. In 16 of 23 patients (age 24–71, 12 male, 11 female) with effort related pain, dysesthesia or fatigue of the lower limbs spinal stenosis was found according to neuroradiological criteria. Within this group 7 of 14 patients showed abnormal (i.e. delay or absence of potentials) SSEP, 6 of 7 abnormal Fwaves and 0 of 7 abnormal MEP before effort. After walking SSEP and Fwave recordings deteriorated in 5 of 7 and 1 of 6 patients, respectively. The patients without radiological spinal stenosis showed normal latencies before and after effort (7/7 SSEP, 1/1 F-wave and 2/2 MEP). After walking in 6 of 7 SSEP the P40-latency decreased. Our findings suggest, that in spinal stenosis with neurogenic claudication SSEP and F-waves are often abnormal in rest. Following effort these parameters increased which is more pronounced for SSEP than F-wave recordings. The findings are interpreted in terms of functional disturbances of the somatosensory pathway under effort. Patients without spinal stenosis show normal electrophysiological findings. These patients however developed a decrease of the P40-latency under effort. This could be caused by facilitation of the so-

matosensory pathway. MEP recordings were not useful for distinguishing patients with and without neurogenic claudication. 124 MAGNETONEUROGRAPHIC 3D-LOCALIZATION OF CONDUCTION BLOCKS IN PATIENTS WITH UNILATERAL S1 ROOT COMPRESSION. Bruno-Marcel Mackert1, Gabriel Curio1, Martin Burghoff 2, Lutz Trahms2, Peter Marx1. 1Neurophysics Group, Dept. of Neurology, Freie Universität Berlin; 2 Physikalisch-Technische Bundesanstalt, Berlin; Germany Tibial nerve Somatosensory Evoked magnetic Fields (tSEFs) over the lower back reflect the propagation of compound action currents along fibers of plexus, nerve roots and cauda equina. One clinical perspective for this “magnetoneurography” is the non-invasive 3D-localization of focal slowing or blocks of conduction. Here Tsef mappings in three consecutive patients with acute unilateral S1 nerve root compression are reported: inside a magnetically shielded room right and left tibial nerves were electrostimulated in alternation; Tsef responses were recorded using a 49 channel SQUID detector and averaged off-line. Additionally, for comparison spinal and cortical SEPs, F-wave and H-reflex tests were performed. In all patients an intraindividual side-to-side comparison of spinal Tsef mappings was obtained: using a dipolar source model compound action currents could be visualized propagating along plexus, nerve roots and cauda equina on the non-affected side whereas on the affected side normally propagating dipolar field patterns could be recorded only distal to the spinal transforaminal root entrance; this reflects focal slowing or block of conduction in nerve root fibers as indicated by the SEP, F-wave and H-reflex study results. Conclusion: with a registration time of 15 min a 3D-localization of proximal slowing or block of conduction was successfully performed in patients suffering from acute nerve root lesions. Hence, electrophysiological examinations may be usefully complemented by SEF-mappings. 125 SENSORY POTENTIALS EVOKED BY TACTILE STIMULATION OF DIFFERENT INDENTATION VELOCITIES AT THE FINGER AND THE PALM IN NORMAL SUBJECTS. M. Baba*, S. Simonetti, C. Krarup. Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark (*presently, Department of Neurology, Hirosaki University Hospital, Hirosaki, Japan) To investigate whether different skin mechanoreceptors are activated by different indentation velocities of a tactile probe, indentations of 300 µm at velocities of 100 and 400 µm/ms were applied to the tip and the proximal phalanx of digit III, and the thenar eminence. Compound sensory action potentials (CSAPs) were recorded from the median nerves at the wrist and the elbow. CSAPs were also recorded after electrical shocks to the finger tip. The maximal conduction velocities (SNCVs) were similar at electrical and 400 µm/ms tactile stimulation, but around 15% lower at 100 µm/ms stimulation. With either indentation velocities, SNCVs were similar regardless of different stimulation sites. Amplitudes of tactile CSAPs with finger-tip stimulation were < 1–2 µV at 400 µm/ms indentation, and 0.3–0.4 µV at 100 µm/ms indentation. Thenar evoked CSAPs with 100 µm/ms indentation showed more than 50% decrease in amplitude and area in compare with those with finger-tip stimulation, whereas with 400 µm/ ms indentation thenar-evoked CSAP amplitudes were 20–30% lower than finger-tip evoked ones. The results support previous results that indentation at 400 µm/ms activated mainly deeply placed (Pacini corpuscles) and to some extent superficial mechano-receptors whereas the 100 µm/ms indentation activated primarily superficially situated receptors (Meissner corpuscles). 126 SENSORY MODULATION OF THE BLINK REFLEX IN PATIENTS WITH BLEPHAROSPASM. J. Valls-Solé, E. Gomez-Wong, M. J. Marti, E. Tolosa. Servei de Neurologia. Hospital Clinic. Barcelona, Spain Some patients with dystonic blepharospasm experience a transient relief of their symptoms by using a sensory trick or ‘geste antagonistique’. We have hypothesized that such a clinical effect may be partly due to a gating action of the sensory inputs on the trigemino-facial blink reflex. We studied 17 patients with dystonic blepharospasm and 11 age-matched control subjects. Eight patients used a sensory trick to alleviate the spasms, while the remaining 9 did not. Blink reflexes to supraorbital nerve stimulation were preceded in test trials by a prepulse electrical stimulus to the 3rd finger at various leading intervals. We measured amplitude of R1 and area of

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R2 responses, and determined the percentage facilitation or inhibition induced by the prepulse. Facilitation occurred in the R1 between 60 and 100 ms, and was normal in all patients. Inhibition occurred in the R2 between 50 and 200 ms, and was abnormally reduced in 11 patients (64.7%). These were all 9 patients who did not use a sensory trick, and only 2 of the 8 patients who used a sensory trick (chi square = 23.8; p < 0.0001). Patients with blepharospasm might have an abnormal prepulse inhibition of the trigemino-facial reflex, which is more frequent in those not using a sensory trick. This sensory derangement may contribute to the maintenance of the dystonic spasms by reducing the amount of physiological gating from peripheral nerve inputs on trigemino-facial reflexes. 127 NEUROPHYSIOLOGY OF THE “GO/NO-GO” DECISION PROCESS. Sasa R. Filipovic, Marjan Jahanshahi, John C. Rothwell. The Institute of Neurology, MRC Human Movement And Balance Unit, Queen Square, London, UK There is a certain confusion in the literature about psycho-physiological properties of the GO/NOGO decision. Although almost every study employed two-stimuli paradigm (S1 and S2 separated by an interval), there are variations in paradigm design that might substantially influence the type of decision that should be made. Generally, there are two types of GO/NOGO studies: studies where S1 is a warning stimulus only while information is delivered with S2, and studies where S1 gives the clue while S2 is only the trigger when to release the pre-programmed action. Although, terminologically the same, two tasks reveal different psycho-physiological mechanisms. Therefore, the data and conclusions derived from them regarding the psycho-physiology of GO/NOGO decision process, do not necessarily correspond among different studies, and there might be different phenomena lumped together under the same name. In this study we tried to compare and to establish the relationship between these two approaches by the mean of the composite CNV paradigm with two-level GO/NOGO decision task. In this task both S1 and S2 deliver information and demand from subject to make a GO/NOGO decision, although after S1 this decision does not include immediate motor activity while in after S2 the motor activity is imminent part of the task performance. Two different phenomena were noted. A) A slow rising negativity after the S1 GO that corresponds to the classical Contingent Negative Variation (CNV) and lack of it after S1 NOGO – the difference that represents the presence/absence of movement preparation (magnitude of the difference shows clear contralateral dominance unobservable in the standard [GO] CNVs). B) Two groups of Evoked Potentials (EPs), elicited by S1 and S2 respectively. The S1 GO/NOGO EPs did not differ substantially, but in comparison with control EP a prominent negativity around 300 ms was apparent in both, GO and NOGO EPs, at central frontal site – probably reflecting the early frontal activation in decision making process. In S2 EPs the surplus of activity was noted in NOGO EPs manifesting as augmented negativity around 230 ms (N2) and pronounced and delayed positivity (P3) around 365 ms after the presentation of the stimulus. By NOGO–GO subtraction it became evident that the surplus of negativity in NOGO EPs started with latency around 200 ms and coincided roughly with the EMG onset latency in GO trials – suggesting that this NOGO N2 most probably reflects motor suppression mechanisms but that decision must be made earlier. 128 TIME CONSTRAINTS IMPROVE REACHING MOVEMENTS IN AN ATAXIC PATIENT. T. Schenk, J. Philipp, A. Häussler, N. Mai. Munich, Germany The ataxic reaching disorder is a common complaint in patients with severe head trauma (SHT). The study of task variables that serve to ameliorate the disorder offers a promising approach for developing new treatments. Motion of the target object seems to be such a variable. A number of patients who developed a reaching disorder subsequently to SHT show almost perfect movements when reaching toward a moving object, although they are unable to reach for static objects. We built a machine that permits controlled movement of the target object. This machine is coupled with a movement registration system and a pair of glasses with liquidcrystal lenses that function as a tachystoscope. A number of experiments were conducted with an ataxic patient and a group (n = 8) of healthy subjects. The reaching movements (assessed by kinematic variables and by the number of successful grasps) improved with increasing speed of the target object. Reaching movements were also improved if another object moved rapidly toward a static target object or if the patient’s view of the target object was restricted to short intervals (100 ms). Both conditions caused shortened reaction and movement times in healthy subjects. Thus,

co-ordinated reaching movements in this patient are not restricted to moving target objects but can occur with static objects if objective or subjective time constraints are imposed. These results promise new strategies for the physical rehabilitation of ataxic patients.

Muscle Disorders (1) 129 THE OCULOPHARYNGEAL MUSCULAR DYSTROPHY IN CATALONIA: A CLINICAL STUDY OF 9 FAMILIES AND ASSESSMENT OF THE MORPHOLOGICAL DATA FOR THE DIAGNOSIS. PouSerradell1, J. Roquer1, J. Pascual1, A. Ugarte, J. Lloreta3, J. Mª. Corominas 3. Servei de Neurologia1, Unitat de Neuropatologia3, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona. Hospital General de Manresa, Manresa3 Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic disorder with late-onset progressive muscle disease of late onset associated with progressive ptosis of the eyelids and dysphagia, autosomal dominant inheritance, and unique tubulofilamentous inclusions within the muscle fiber nuclei. It is more common in certain ethnic communities. We report the study of 9 families living in Catalonia, 4 being Catalan autochthonous and 5 being immigrants from other Spanish communities. These observations were taken in the past eight years (1989–1997). Weakness and atrophy occur, besides the ptosis and dysphagia, in the shoulder or pelvic-girdle muscles on the half of the index cases and in one of these the distal muscles in the legs were also involved. Oesophageal manometry was performed in 5 patients, and the most common finding was the incomplete lower oesophageal relaxation (in 4 of these cases). The surgical correction of the ptosis, when be done, offers good results. Muscle biospy has been performed in one member of each family, and the ultrastructural study (US) of muscle in 6 of them. In 7 patients, the microscopic study showed the presence of “rimmed vacuoles” and among the 6 cases being submitted to US, 4 presented the typical subsarcolemmal nucleus filled with filamentous inclusions and one presented only mitochondrial abnormalities (but rimmed vacuoles in light microscopy). In conclusion, we demonstrate that OPMD is also common in communities not considered as classical ethnic community for OPMD, that dynamic studies of pharyngo/esophageal motility are determinant for understanding the dysphagia in OPMD. We confirm the nuclear filamentous inclusions (different from the inclusions found in IBM) as the marker of the OPMD and we discuss the signification of mitochondrial abnormalities in OPMD. Molecular genetic studies are under way. 130 SEQUENCE ANALYSIS OF T-CELL RECEPTOR (TCR) EXPRESSION OF INFILTRATING LYMPHOCYTES IN INCLUSION BODY MYOSITIS (IBM) REVEALS THAT Tcr EXPRESSION BECOMES MORE RESTRICTED OVER TIME. K. Amemiya, M. C. Dalakas. NINDS, NIH, Bethesda, MD, USA We examined the repertoire of TCR expression of infiltrating lymphocytes in multiple biopsies from the same IBM patient. Three muscle biopsies taken over a two year period were first processed by immunohistochemistry with family-specific TCR monoclonal antibodies to determine the autoinvasive T-cells. We found that TCRs belonging to the VB3, VB5.1, VB6.7, and VB13 subfamilies were the predominantly autoinvasive Tcells that remained consistent in all the muscle biopsies. RNA was then prepared from the three biopsy specimens, and complementary DNA (cDNA) was produced by reverse transcription-polymerase chain reaction for cloning and sequence analysis. Sequence analysis of the TCR cDNA clones belonging to the VB5.1 and VB6 subfamilies revealed that in the earliest biopsy there was a moderate diversity of specific TCR joining regions expressed by the infiltrating T-cells. In the two subsequent biopsies, however, a further decrease in the number of specific TCR subfamilies was found with persistent amino acid sequence conservation of the CD3 joining region. The results indicate that in patients with IBM there is specific clonal expansion of the TCR by the endomysial autoinvasive T-cells that becomes even more restricted over time. 131 A POSSIBLE ROLE OF THE HUMAN MITOCHONDRIAL TRANSCRIPTION FACTOR (h-mtTFA) IN MITOCHONDRIAL MYOPATHIES (MM). Siciliano G, Tessa A, Manca ML, Renna M, Mancuso M, Pollina LE, Murri L

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Mitochondrial diseases with respiratory chain defect are a heterogeneous group of disorders due to mutations of mitochondrial DNA (mtDNA) in enzymatic subunit coding genes, or in tRNA genes. An additional species of mutations which may lead to a disease state are those affecting nuclear genes of regulatory proteins which control mitochondrial biogenesis, suggesting the importance of the inter-relationship between nuclear and mitochondrial DNA. The h-mtTFA is a 25 kDa protein encoded by the nuclear genome which is an important regulator of both transcription and replication of mtDNA. Goals The aim of the work was to evaluate the role of h-mtTFA in a group of 8 patients affected by mitochondrial myopathies (MM), characterised by different types of mtDNA mutations. Methods: Levels of h-mtTFA in skeletal muscle were evaluated by western blotting and immunohistochemical techniques, by using a polyclonal antibody to h-mtTFA. Results Protein levels were markedly reduced in patients harbouring a point tRNA gene mutation, while they were increased in chronic progressive external ophtalmoplegia (CPEO) patients. It was remarkable that in one CPEO case the coexistence of the factor with normal and reduced molecular weight was present. Conclusion Different feedback mechanisms can explain the heterogeneity of our results in MM. Related to mitochondria plasticity, a possible role of h-mtTFA in cellular mechanisms of adaptation to the respiratory chain defect is suggested. The financial support of Telethon-Italy (project n° 955c) is gratefully acknowledged. 132 AN ATYPICAL CASE OF DESMINOPATHY WITH ABNORMAL EXPRESSION OF CYCLIN-DEPENDENT KINASES. M. Sciacco, A. Prelle, G. P. Comi, S. Messina, P. Ciscato, M. Carpo, E. Nobile Orazio, F. Fortunato, G. Mora, V. Bignotti, G. Fagiolari, G. Scarlato, M. Moggio. Milan, Italy In the last years there have been increasing reports of desmin abnormalities in a number of muscle disorders with extremely variable clinical presentation. Recently abnormal expression of multiple cyclin-dependent kinases has been proposed as possible cause of desminopathy. Kinase overexpression would determine hyperphosphorylation and consequent pathological accumulation. We describe a 49 year old man with severe respiratory distress due to diaphragm and chest muscle paresis. Symptoms got progressively worse to the point of requiring respiratory assistance. Clinical examination showed prominent shoulder girdle hypostenia and hypotrophy with mild pelvic girdle involvement. Neurophysiological pattern was both neurogenic and myogenic. We performed muscle biopsy and examined the sample using histological, histochemical and ultrastructural methods. Immunological analysis was performed using antibodies against desmin, vimentin, dystrophin, CDC2 kinase, CDK2 kinase, lamin B and nuclear protein (NuMa). Muscle examination shows several fibers with subsarcolemmal and intrarcytoplasmic areas, hyperchromic with GT and eosinophilic at HE. They intensively stain with anti desmin antibodies and contain electrondense filamentous material at ultrastructural level. Desmin WB analysis shows a 30% increase of protein signal compared to controls. An intense immunostain for CDC2 and CDK2 kinase and a faint reaction for NuMa were found in fibers with desmin accumulation. 133 A NEW DIAGNOSTIC TEST TO DIFFERENTIATE POLYMYOSITIS FROM INCLUSION BODY MYOSITIS? M. F. G. van der Meulen1, J. E. Hoogendijk1, K. G. M. Moons2, U. A. Badrising3, J. H. J. Wokke1. University Hospital Utrecht, Dept. Neurology1 and Clinical Epidemiology2; University Hospital Leiden, Dept. Neurology3, The Netherlands Because sporadic inclusion body myositis (s-IBM) does not respond to corticosteroid treatment it is important to differentiate it from polymyositis (PM). However, the classical histopathological abnormalities of s-IBM may be scarce or absent. Recently, immunohistochemistry with an antineurofilament antibody (SMI-31) has been proposed as a diagnostic test for s-IBM. Here, we evaluate the additional diagnostic value of this method. On the basis of criteria for age, mode of onset, distribution of weakness, CK elevation and response to treatment, in the presence of endomysial infiltrates, 18 patients complied with the diagnosis of s-IBM, and 17 with PM. Consecutive cryostate sections were stained with hematoxylin-eosin (HE) and SMI-31. A blinded observer counted the percentage of abnormal fibres in the SMI-31 and HE separately, and after combination of both sections (HE + SMI). The area under the receiver operating characteristic (ROC)-curves, calculated for the three tests, was highest (0.95) for the HE + SMI test, indicating that it is the best test. The most optimal cut-off in this test, based on the lowest number of false-positive observations, yielded a positive predictive value of 100%, and a negative predictive value of 85%. Since in the HE test the optimal cut-off yielded a

positive predictive value of 80% and a negative predictive value of 87%, we conclude that the SMI-31 test is of additional diagnostic value, especially to reduce the number of false positive observations. 134 FIRST EUROPEAN TIBIAL MUSCULAR DYSTROPHY FAMILY OUTSIDE FINLAND. J. de Seze, B. Udd, H. Haravuori, B. Sablonnière, C. A. Maurage, N. Boutry, J. F. Hurtevent, H. Petit, S. Schraen, P. Vermersch. Lille (France), Vasa (Finland) Background: Tibial muscular dystrophy (TMD) is a rare autosomal dominant inherited distal myopathy with late adult onset. Recently a linkage was found on chromosome 2q31 (Haravuori et al., Neuromusc. dis. 1997; 7 : 459). Aim of the study: To report the first European TMD family outside Finland and to determine if a linkage is found on the same location. Patients and methods: Seven patients of a French TMD family were clinically studied. Tibial atrophy progressively occurs at the age of 40–50 years. Upper limbs and proximal muscles were normal. Muscular CT-scan and muscular biopsy argued for the diagnosis. Microsatellites method (especially with D2S364 and D2S2310) are now used to confirm if the linkage is located in the same region in our family. Results will be presented in the VIIIth ENS meeting. Conclusion: TMD is probably frequently misdiagnosed because of a late onset and a poor disability. The recent linkage finding on chromosome 2 now allows to confirm if other similar clinical features provides to the same genetic disorder.

Multiple Sclerosis (2) 135 HERPETIC VECTOR BEARING INTERLEUKIN 4 DELAYS THE ONSET AND AMELIORATES THE SYMPTOMS OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN BIOZZI MICE. R. Furlan, F. Galbiati, P. L. Poliani, A. Bergami, L. Grimaldi, G. Comi, L. Adorini, G. Martino, Milano, Italy Gene therapy of organ-specific autoimmune diseases using viral vectors can be approached by introducing heterologous protective genes in the autoreactive T cells or in the target organ. We assessed the therapeutic potential of non-replicative herpetic vectors bearing cytokine genes injected intracisternally (i.c.) in mice with experimental allergic encephalomyelitis (EAE), a CD4+ (Th1)-mediated demyelinating disease of the central nervous system (CNS). We tested the therapeutic potential of a vector containing interleukin (IL)4 on Biozzi mice in which EAE was induced with 200 mg of myelin oligodendrocyte glycoprotein (MOG) in complete Freund adjuvant. IL4 was used in order to counteract the activity of antiMOG CD4+ Th1-cells that are pathogenic in this model. Nine mice were injected twice (day 1 and 8 p.i.) with 107 PFU of the d120-IL4 vector. Control animals included 7 MOG-immunized mice treated with the empty vector and 3 immunized but non-treated mice. All control animals developed EAE. Eight of the 9 d120-IL4 vector-treated mice developed EAE but the disease onset was delayed by 8 days (28.6 vs. 20.3) and the mean cumulative disease score was lower compared to controls (36.6 vs. 64.1). To exclude that the protective effect of the d120-IL4 vector was not due to the IL4 effects on peripheral autoreactive T cells, we analyzed the proliferation and the cytokine pattern of the anti-MOG CD4+ cells obtained at day 10 p.i. from lymph nodes of treated and control mice. Proliferation and % of IFNγ/IL4-secreting anti-MOG CD4+-cells was similar between the two groups. Our results indicate that i.c. injection of a non-replicative herpetic vector bearing IL4 might represent an alternative approach to treat inflammatory CNS diseases. The vector therapeutic activity is possibly exerted via the modification of the cytokine milieu in the target organ and not via the perturbation of the peripheral balance of autoreactive Th1/Th2 cells. 136 HLA DRB1-DQA1-DQB1 LOCI AND MULTIPLE SCLEROSIS PREDISPOSITION IN SARDINIANS. M. G. Marrosu§, M. R. Murru^, G. Costa^, R. Murru§, F. Muntoni*, F. Cucca**. §Chair of Neurophysiopathology, ^Clinic of Neuropsichiatria Infantile, Department of Neuroscience, University of Cagliari (Italy). *Department of Paediatrics, Hammersmith Hospital, London (UK); **Department of Pediatrics, Ospedale Brotzu of Cagliari (Italy) We have recently found in Sardinians that MS is associated with the HLADRB1*0301 and -DRB1*04 alleles. The fact that MS is associated with

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different HLA-DR alleles in Sardinians and in other Caucasians gives rise to the question whether HLA-class II alleles themselves are primarily responsible for disease predisposition or whether they are in linkage disequilibrium with the true etiologic determinants. To further explore this issue we have extended the number of Sardinian MS families analysed and performed a transmission disequilibrium test (TDT) for the whole DRB1DQA1-DQB1 haplotype. The present study has been carried out on 264 MS Sardinians families. All patients had clinically defined MS. Amplification of the polymorphic second exon of the DRB1, DQA1 and DQB1 genes and dot blot analysis of amplified DNAs with sequence specific oligonucleotide probes were carried out. Evidence of association with MS were found with both the Sardinian specific DRB1*0405-DQA1*0501DQB1*0301 and the DRB1*0301-DQA1*0501-DQB1*0201 haplotypes, which were preferentially transmitted to affected patients (67.9% and 58%; p = .005 and p = .01 respectively.Two hypotheses, mutually exclusive, can be suggested by these data: i) in analogy with type I diabetes mellitus, the predisposing region of HLA is constituted by the whole DRB1-DQA1-DQB1 haplotype and requires a combination of alleles at these loci or ii) none of the DRB1, DQA1 or DQB1 genes are directly responsible for predisposition to MS. In favour of the second hypothesis is cross-ethnic analysis showing associations with different DRB1-DQA1DQB1 haplotypes in Sardinian and Caucasian MS patients, with the failure to find a shared epitope between them. This work has been supported by Istituto Superiore di Sanità (grant 22) and by Dompè Biotec grant. 137 THE EUROPEAN MULTICENTRE PROSPECTIVE “PRIMS” STUDY ON PREGNANCY AND MULTIPLE SCLEROSIS: 12 MONTHS POST-DELIVERY RESULTS. Michael Hutchinson (Dublin, Ireland), Martine Hours, Patricia Cortinovis-Tourniaire, Thibault Moreau and Christian Confavreux for the PRIMS Group. EDMUS Coordinating Center and Service de Neurologie, Hôpital de I’Antiquaille, Lyon, France Although multiple sclerosis particularly (MS) affects young women in their child bearing years, a definitive, large scale prospective study of pregnancy in MS has never been performed. In a collaborative study involving 12 European countries, women with MS who became pregnant were recruited as early as possible during pregnancy and followed up prospectively to twelve months after delivery. The natural history of attack frequency and residual disability and the pregnancy outcome were determined. A total of 254 patients were recruited and 269 pregnancies followed. By comparison to the year prior to pregnancy, the mean annual relapse rate which was 0.73 relapse/year (95% confidence interval Cl, 0.61 to 0.85) significantly decreased during the first two trimesters of pregnancy (0.54; 95% Cl, 0.40 to 0.68; p < 0.05) and more dramatically in the last trimester of pregnancy (0.22; 95% Cl, 0. 14 to 0.26; p < 0.00 1). It rose to 1.23 (95% Cl, 0.96 to 1.49; p < 0.05) during the first three months post partum before returning to 0.88 (95% Cl, 0.53 to 1. 13; NS) in the fourth to sixth month post-partum. For the 12 month period of the pregnancy year, the relapse rate was similar to that of the pre-pregnancy year. Residual EDSS disability score worsened by 0.51 from the 12th month prior to pregnancy to the sixth month post partum with no apparent marked worsening in the delivery and post partum periods. The attack frequency and disability score were not affected by breastfeeding or epidural analgesia. No adverse effect of MS on pregnancy outcome was observed. Pregnancy has a significant beneficial effectand the post partum three month period a significant deleterious effect oil ralc in ‘,IS. However, the overall effect of the pregnancy year is neutral. Breastfeeding and epidural analgesia can be used quite safely. The beneficial effect of pregnancy per se in MS deserves further study. Supported by grants from the Conunission of the European Communities DG XII (Contracts N’ BMHI-CT931529, N- CIPD-CT94-0227 and N’ BMH4-CT96-0064), and by funds from the Ligue Française contre la Sclerose En Plaques (L.F.S.E.P.), the Association pour la Recherche sur la Sclerose en Plaques (A.R.S.E.P.), the Hospices Civils de Lyon and the Multiple Sclerosis Society of Ireland. 138 CLINICAL AND DEMOGRAPHIC FEATURES IN AFFECTED PAIRS OF ITALIAN MULTIPLE SCLEROSIS MULTIPLEX FAMILIES. Trojano M, Liguori M, De Robertis F and Livrea P. Institute of Neurology, University of Bari, Bari, Italy A comparative analysis of clinical and demographic findings between 45 Multiple Sclerosis (MS) pairs belonging to 40 MS Multiplex families was conducted. Data were recorded in different Italian areas (Bari, Florence, Catanzaro, Rome, Chieti) by the standardized use of European data base for Multiple Sclerosis (EDMUS) and analyzed by the Intra-class corre-

lation, “k” statistic and the t-paired samples test. Results: In sib pairs (no. 36) a concordance for age at onset (r = 0.34, p = 0.044) but not for year of onset (r = 0.06) was found suggesting that genetic factors and random exposure to an environmental trigger may influence the onset of the disease. Sibling pairs were not concordant for sex (k = –0.37), but concordant for Progression Index (r = 0.34, p = 0.047) and sensory symptoms at onset (k = 0.37). In the small group of parent/child pairs (no. 9) parents developed MS at an age of 18.74 yrs greater than their children (t = 3.86, p = 0.005). The mean interval from first symptom to diagnosis was not different (F = 0.46, p = 0.51) in parents and in children. A recall bias of parents in the retrospective definition of age at onset and/or an “anticipation” phenomenon must be considered. Conclusions: The present study provides the first objective information on concordance of demographic features and clinical manifestations between pairs concordant for the disease in a cohort of MS Italian Multiplex families. 139 EXTRACELLULAR MATRIX TENASCINS IN MULTIPLE SCLEROSIS LESIONS. N. J. Gutowski, J. Newcombe and M. L. Cuzner. Multiple Sclerosis Laboratory, Institute of Neurology, UCL, London, UK A major factor impeding regeneration in the adult central nervous system (CNS) is considered to be glial scar tissue. The extracellular matrix molecules, tenascin-C (TN-C or cytotactin), tenascin-R (TN-R, janusin or restrictin) and chondroitin sulphate have been shown to reduce neurite outgrowth in vitro and to be present at sites of glial scarring in vivo. Snapfrozen post-mortem tissue from cases of multiple sclerosis and normal controls were examined by using immunocytochemical techniques with antibodies to extracellular matrix molecules at different stages of plaque evolution. Normal expression of the tenascins within the CNS was location dependent. There was a striking loss of matrix TN-R in the acute plaque up to the edge and a similar loss of TN-C within the acute plaque but also extending into adjacent white matter. Some reactive astrocytes were TN-C and TN-R immunopositive. In chronic plaques TN-R and TN-C were expressed diffusely at levels similar to that seen in white matter remote from lesions. In acute plaques the loss of TN-R and TN-C is consistent with inflammatory-mediated breakdown of the matrix. The return of TN-C and TN-R in chronic plaques is in agreement with previous reports that glial scar formation leads to the production of tenascins which may impede CNS regeneration. 140 CORRELATION OF MYELIN CONTENT, AXONAL DENSITY AND NMR FINDINGS IN THE SPINAL CORD POST MORTEM IN MULTIPLE SCLEROSIS. L. P. Mottershead, M. Clemence, L. S. Thornton, F. Scaravilli, J. Newcombe, M. L. Cuzner, R. J. Ordidge, D. H. Miller, W. I. McDonald. NMR Research Unit, Institute of Neurology, Queen Square, London, England WC IN 3BG A better understanding of the relationships between Nuclear Magnetic Resonance (NMR) appearances and pathology in multiple sclerosis (MS) will improve estimates of prognosis and may provide insights into the pathophysiology of MS. Sections of spinal cord from four MS patients were imaged in a 7 Tesla Bruker Spectrometer using a 13 mm diameter coil. After fixation, the specimens were stained with Bielschowsky’s silver (axons) and luxol fast blue (myelin). Axonal density and tissue myelin content were quantitated and were correlated with NMR parameters within the corresponding area of the section. Strong correlations were found between TI relaxation time, magnetisation transfer ratio, diffusion anisotropy, proton density and both axonal density and myelin content (Spearman Rank Correlation Coefficients (SRCC) 0.53–0.78, p < 0.001). T2 relaxation time correlated less strongly with tissue parameters (SRCC –0.36, p = 0.014). Myelin content and axonal density were themselves strongly correlated (SRCC 0.67, p < 0.001). Several NMR measurements are sensitive to tissue myelin and axonal content. In the (chronic) lesions studied here, there is a close relationship between myelin and axonal density, which might suggest that demyelination renders axons vulnerable to damage, or that a common pathological process affects myelin and axons in turn.

Multiple Sclerosis (3) 141 PREVALENCE OF PSYCHOSOMATIC COMPLAINTS AND SYMPTOMS IN OFFSPRINGS OF MULTIPLE SCLEROSIS (MS) PARENTS. Steck B, Kappos L, Bürgin D. Basel, Switzerland

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Do children, adolescents and young adults of a parent with MS present psychosomatic complaints or symptoms resembling the symptomatology of their ill parent? Background: The psychosocial impact of MS on the family and on children can be very important. Children tend to identify with their parents; does this imply identification with MS related symptoms? or does fear of the illness lead to avoidance of identification with a sick parent? Design and Methods: 52 Families with a MS parent and 80 offspring’s 3–26 years old were recruited. Semistructured interviews with both parents and each child were videotaped. Projective testing and drawings were used with the offspring’s. Results: None of the 80 children presented at the time of the interviews psychosomatic complaints or symptoms resembling the symptoms of their affected parent, yet all children had been or still were preoccupied with the disease of their parent, expressing consciously or in the projective material fantasies and fears of getting the disease themselves through contamination or heredity. Few however had in the past similar symptoms such as fatigue, trouble of vision, dizziness, difficulties in walking, pain. Conclusions: Offspring’s of MS parent are without exception burdened by preoccupation, anxieties, fears about the consequences of the illness. Younger children fear to loose their parent, older children to get the disease, some expressing hypochondrial complaints. A minority of the offspring’s temporarily presented similar symptoms as the MS parent. 142 A LONGITUDINAL BRAIN MRI STUDY COMPARING THE SENSITIVITIES OF THE CONVENTIONAL AND A NEWER APPROACH FOR DETECTING ACTIVE LESIONS IN MULTIPLE SCLEROSIS. G. Mastronardo, M. A. Rocca, M. Rovaris, C. Gasperini, S. Bastianello, M. Filippi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan In this longitudinal study, we evaluated and compared the sensitivities of the conventional approach (i.e., dual echo conventional spin-echo [CSE] and standard dose [SD] post-contrast T1-weighted scans) and of a newer approach (i.e., fast-fluid attenuated inversion recovery [fast-FLAIR] and triple dose [TD] post-contrast T1-weighted scans) in detecting active lesions on serial magnetic resonance imaging (MRI) scans from patients with relapsing remitting multiple sclerosis (MS). Monthly MRI scans were obtained in 13 patients on four occasions in two separate sessions (interval between 12 and 24 h). In one session, dual-echo CSE and SD T1-weighted scans were obtained; in the other, fast-FLAIR and TD T1-weighted scans. Three observers counted by consensus the numbers of active lesions detected by each of the two approaches. Fifty-three active lesions were seen on dual-echo CSE scans, 100 on post-SD T1-weighted scans, 74 lesions on fast-FLAIR and 174 on post-TD T1-weighted scans. Fast-FLAIR detected 23 lesions not seen on dual-echo CSE scans and dual-echo CSE scans detected four lesions not seen on fast-FLAIR scans. All the lesions seen on SD scans were seen on TD scans. The combination of the dual-echo CSE and post-SD scans enabled a total of 104 active lesions to be detected, whilst the combination of fast-FLAIR and post-TD scans enabled a total of 199 active lesions to be detected (average increase per patient = 75%, range = 0–325%). This study indicates that the combined use of monthly fast-FLAIR and TD enhanced T1-weighted scans increases significantly the sensitivity of MRI in detecting disease activity in MS. 143 FACIAL MYOKYMIA IN MULTIPLE SCLEROSIS. Mefkure Eraksoy, Emre Öge, Gülsen Akman-Demir, Yüksel Kaplan. Department of Neurology, Istanbul Faculty of Medicine, Turkey Facial myokimia (FM) is a relatively underdiagnosed symptom of multiple sclerosis (MS). The origin of FM,the pathophysiology underlying FM and its exact incidence in MS are unknown. This study was designed in an attempt to identify clinical, electrophysiological and neuroradiological characteristics and to determine its incidence and in a large MS series prospectively. Between January 1, 1987 and December 31, 1997, 22 (16 female, 6 male) of 934 patients with MS, developed FM and one female developed facial synkinesia (FS) without facial weakness. The incidence of FM as an isolated initial symptom was 5 per 1000. The age at onset of FM ranged from 17 to 45. The patients had clinically definite MS with Kurtzke’s scores of 0.5 to 5.5, and all but one had relapsing remitting clinical course. All patients had cranial MRI before the FM and FS episode which were compatible with MS. Repeat cranial MRI was performed in 15 of 23 patients during FM and FS episode. Four of 15 patients had a pontine tegmental lesion. Electromyographic studies carried out in 16 of 23 patients were compatible with FM in 15 patients, and FS in one. In 19 of 23 patients, FM was seen as an isolated symptom and improved spontaneously

or with carbamazepine within a month without sequela. When FM and FS occured during an attack (3 patients and 1 patient, respectively) the patients received corticosteroid therapy. This study confirmed that FM is a rather less frequent and relatively benign isolated manifestation of MS originated from brain stem but further prospective studies may require to reveal the exact anatomic-radiologic and electrophysiologic basis of FM. On the other hand, to our knowledge FS without facial weakness in MS has not been reported before. 144 DOSAGE EFFECT OF INTERFERON β-1a (Rebif ®) IN PREVENTING RELAPSES AND PROGRESSION OF DISABILITY IN RELAPSINGREMITTING MULTIPLE SCLEROSIS WITH BASELINE EDSS > 3.5. Blumhardt LD, Nottingham UK, Paty DW, Vancouver, Canada; Hughes RAC, London, UK; Weinshenker B, Rochester, USA, on behalf of the PRISMS Study Group Natural history studies have shown that patients with relapsing remitting (RR) multiple sclerosis (MS) and EDSS > 3.5 are at greater risk for an unfavourable clinical outcome than are patients at lower EDSS levels. We report on a cohort of 94 patients in the PRISMS study of IFN β-1a (Rebif ® Ares-Serono) in RRMS with a baseline EDSS > 3.5 who were randomised to a placebo (n = 28), IFN β-1a 22 mcg (n = 35) or IFN β-1a 44 mcg (n = 31) three times a week subcutaneously. Disease exacerbations, progression of disability and MRI activity and burden of disease (BOD) were monitored for two years. In this cohort of patients, the baseline attack rate and BOD on MRI were significantly greater than those with lower EDSS ( p < 0.0001) and the disease more aggressive as evidenced by a higher exacerbation rate and disability progression in the placebo group. Compared to placebo, both treatment regimens significantly reduced exacerbation counts per patient ( p < 0.02), but only the high dose significantly delayed disability progression (p < 0.05). Both treatment regimens reduced the MRI BOD ( p < 0.05) and the high dose significantly reduced active lesions on MRI ( p < 0.05). The treatment benefit was consistently greater in patients on 44 mcg compared with those on 22 mcg three times weekly. These results suggest that patients with a baseline EDSS > 3.5 have a more aggressive disease course and may require a higher therapeutic dose of IFN β-1a. 145 THE RELATIONSHIP BETWEEN T1 LESION LOAD AND CEREBRAL ATROPHY IN MULTIPLE SCLEROSIS. M. Sailer, N. Losseff, L. Wang, M. L. Gawne-Cain, W. I. McDonald, A. J. Thompson, D. H. Miller. NMR Research Unit, Institute of Neurology, London, UK Introduction: Earlier studies suggested a relationship between hypointense lesions detected on T1 weighted MRI brain scans and disability1, 2. The underlying changes are regarded mainly as areas of tissue loss. Recent studies also demonstrated the significance of cerebral atrophy in the development of disability3. We therefore investigated the relationship between T1 lesion load and cerebral atrophy in a longitudinal 18 month follow-up study. Patients and Method: MRI brain scans from 29 patients from the London arm of the anti-CD4 trial were restudied. Results: We found a correlation between the change in T1 lesion load and the change in atrophy over the follow-up period (SRCC 0.49, p < 0.006). Moreover, the change in T1 lesion load correlated strongly with the change in EDSS (SRCC 0.52, p < 0.004). The group of MS patients with a sustained increase in EDSS (n = 10) had a significantly greater accumulation of T1 lesion volume ( p < 0.01, Mann-Whitney) and a significant increase in atrophy (p < 0.03, Mann-Whitney) compared to the clinically stable group. Conclusion: T1 lesion load and atrophy show a strong relationship and both findings correlate well with disability over time. Ref: van Walderveeren et al.1; Truyen et al.2, Neurology 19951; 19962; Losseff et al.3, Brain 1996. 146 COPAXONE® IS EFFECTIVE IN RELAPSING FORMS OF MULTIPLE SCLEROSIS (MS): MULTICENTRE OPEN STUDY OF ALTERNATE DAY ADMINISTRATION. Amos D. Korczyn, MD, MSc, Edna Kott, MD, Puiu Nisipeanu, MD, Bettina Steiner-Birmanns, MD, Shlomo Flechter, MD. Assaf-Harofeh Medical Center, Zerifin, Israel Copaxone® has been shown in a two year double blind placebo controlled study to decrease the relapse rate by about 30% when given subcutaneously (S.C.) 20 mg daily. In a previous open label study, conducted in our centers, Copaxone® administered daily decreased the relapse rate by 73.4%. In the present open label study, relapsing MS patients were treated

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with Copaxone® 20mg S.C. every other day. 68 patients were recruited: 51 and 40 patients completed one and two years respectively. Results: Relapse rate during the two years of treatment decreased by 80.8%, and was significantly lower than in the two years prior to treatment (mean 0.56 ± 1.02 vs 2.91 ± 1.10, P < 0.0001). The EDSS did not differ from baseline following the first year of treatment; However at the end of the second year EDSS scores increased somewhat (baseline = 2.72 ± 1.55, one year 2.71 ± 1.59, two years 2.97 ± 1.80, P < 0.008). Conclusions: Copaxone® even when given on alternate days reduces the relapse rate. Disability has not increased initially, although minor deterioration was observed during the second year of treatment. This preliminary open label study suggests that alternate day therapy has beneficial effects and is well tolerated in relapsing MS, comparing favourably with the effects of daily injection of Copaxone®. 146 B THE BETAFERON SAFETY TRIAL: AUTOIMMUNITY DURING INTERFERON BETA-1B (IFNB) THERAPY FOR MULTIPLE SCLEROSIS (MS). L. Durelli, B. Ferrero, Torino, U. Ecari, Rome, and Betaferon Safety Trial group, Italy Prospective 1-year follow-up of 108 MS patients treated with IFNB. Liver and thyroid function, anti-thyroid (AT) (detected by IRMA), and antitissutal (anti-nuclear, -smooth-muscle, -parietal-cell, -microsomal, -mithocondrial) Abs (detected by indirect immunofluorescence) were monitored. RESULTS. During treatment, hepatic enzymes transiently increased in 8 patients (7.4%). Hyperthyroidism, observed in 3 patients (2.8%) at baseline, occurred in a further 3 (2.8%), persistent in 2. Hypothyroidism, observed in one patient (1%) at baseline, occurred in a further 2 (1.9%) during treatment. Baseline thyroid dysfunctions did not worsen during IFNB. Baseline AT-Abs (11 patients, 10.2%) increased during IFNB in 5. De novo AT-Abs occurred in 9 patients(8.4%). AT-Ab disappeared or returned to baseline level in all patients, with the exception of 2 developing thyroid dysfunction. Baseline anti-tissutal autoAb (8 patients, 7.4%) did not change during IFNB. Transient de novo anti-tissutal autoAb occurred in 4 patients (3.7%). Transient liver dysfunction with anti-tissutal autoAb occurred in 4 patients (3.7%). Conclusions: Liver dysfunction, with or without autoAb, was always transient, and never so severe to require IFNB withdrawal. De novo autoimmune thyroid dysfunction was rarer and usually stable. It was treated and IFNB continued with a satisfactory decrease of MS relapse rate. In one patient (1%) with autoimmune hyperthyroidism, however, IFNB was stopped with thyroid function recover in 4 months. AutoAb and autoimmune disease frequency was highest at 3 months of therapy, decreasing thereafter. Baseline autoimmune alterations did not persistently worsen during IFNB.

Wednesday Cerebrovascular Disorders (5) 147 3-D RECONSTRUCTION IN TRANSCRANIAL COLOUR-CODED SONOGRAPHY (TCCS). Christof Klötzsch1, Alessandro Bozzato1, Gero Lammers1, Michael Mull2, Armin Thron2, Johannes Noth1. Depts. of 1Neurology and 2Neuroradiology, RWTH Aachen, Germany The clinical value of a new work-station based three-dimensional reconstruction system for transcranial colour-coded sonography (TCCS) was evaluated in patients with intracranial vessel disease. Group I. consisted of 24 patients with intracranial stenoses and while in group II. 15 patients with intracranial aneurysms were investigated (25 men, 14 women; mean age 52 ± 15 years (± SD). The TCCS examinations were performed with an Acuson XP128 machine using (2/2.5 MHz-probe) using the powermode. In 20 patients D-galactose (Levovist, Schering, Germany) was used as echo contrast agent to improve the signal to noise ratio. All patients underwent digital subtraction angiography (DSA) to demonstrate intracranial vessel disease. In 20 of 24 (83%) patients with intracranial stenoses 3-D TCCS was able to visualise the intracranial stenosis. In the remaining 4 (17%) patients a bad bone window was responsible for the insufficient demonstration of the stenosis. In 12 of 15 (80%) patients with intracranial aneurysms of group II. 3-D TCCS revealed an excellent correlation of the intracranial aneurysmal size and location compared to DSA. The use of the contrast agent improved the visualization in 18 of 20 (90%) patients.

Conclusion: 3-D TCCS is a new non-invasive method to investigate intracranial vessel disease. Compared to conventional 2-D TCCS the differentiation between artefacts and true changes of the vessel anatomy is much more easier and reveals an excellent correlation with the gold standard DSA. The echo contrast agent enables the 3-D reconstruction of small vascular alterations. 148 PROGNOSIS IN ACUTE ISCHEMIC STROKE – SIGNIFICANCE OF STANDARD BIOCHEMICAL, HAEMATOLOGICAL AND CLINICAL PARAMETERS. A. Szczudlik, A. Slowik, T. Róg, J. Pankiewicz, M. Rudziñska, R. Motyl, K. Kasprzyk, G. Zwoliñska, U. Wyrwicz-Petkow. Department of Neurology, Jagiellonian University, Krakow, Poland The aim of this study was to identify early clinical, biochemical and haematological predictors of 30 day mortality in acute ischemic stroke patients and their relation to stress response. 262 consecutive patients, mean age: 71 ± 12 years, admitted within 24 hours after a first ever supratentorial ischemic stroke confirmed by CT and/or autopsy were entered into the study. Prognostic significance of sex, age, history of diabetes mellitus, history of ischemic heart disease, obesity, blood pressure, body temperature, severity of stroke deficit (Scandinavian Stroke Scale), level of consciousness, and EKG evidence for atrial fibrillation as well as hematocrit, fibrinogen level, platelets count, leukocytes count, sedimentation rate, gamma globulin level, serum glucose, serum cholesterol and creatinine kinase (CK) activity were assessed in univariate and multivariate models. 24 hour catecholamines urine collection on the 1-st and 3-rd day of hospitalisation and serum cortisol levels collected every 6 hours on the 1-st day were assessed in 53 consecutive patients without history of diabetes mellitus, cardiac insufficiency and infection on admission. Multivariate analysis showed that only severe neurological deficit (SSS < 10 points) both on admission and on day 2 (OR = 5.32, 95% CI 1.98–14.28), decreased level of consciousness within the first 24 hours of hospitalisation (OR = 4.84, 95% CI = 1.79–13.10), atrial fibrillation (OR = 2.77, 95% CI 1.13–6.81) and female sex (OR = 0.32, 95% CI = 0.13–0.83), were independent predictors of death within 30 days. Increased daily excretion of norepinephrine (but not epinephrine) and higher serum cortisol levels were correlated with worse clinical status and higher early mortality ( p < 0.05). Linear regression analysis showed that fibrinogen, platelets count, leukocytes count and body temperature were significantly related to mean serum cortisol level ( p < 0.05). Glucose level, CK activity and blood pressure on admission were significantly related to daily urine norepinephrine excretion (p < 0.05). Urinary excretion of norepinephrine and mean serum cortisol level are related to the independent predictors of early death and different biochemical, haematological and clinical parameters in acute stroke patients. 149 WHITE MATTER CHANGES CORRELATE WITH SEMIQUANTITATIVE MEASUREMENT OF REGIONAL CEREBRAL BLOOD FLOW IN ELDERLY NORMALS. F. Payer, R. Schmidt, F. Fazekas, H. Offenbacher, P. Kapeller, M.D., K. Brodtrager, H. P. Hartung, M.D. Graz, Austria White matter hyperintensities (WMH) are an incidental finding in normal individuals. Dilated perivascular spaces and minor ischemic damage are the most likely underlying histopathology. The functional significance of these abnormalities still needs further elucidation, however. The purpose of this study was to determine a possible effect of the number and size of WMH on regional cerebral blood flow (rCBF). The study population consisted of 331 randomly selected healthy volunteers between 50 and 70 (60 ± 6) years of age. All subjects unterwent an extensive medical examination and were studied with magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) using Tc-99m HMPAO as tracer. On morphologic images number and size of WMH were determined and several planimetric measures for atrophy were obtained. For rCBF measurements a predefined set of regions of interest (ROI) was overlaid on cortical and subcortical regions. ROI to cerebellum ratios were calculated and compared to MRI abnormalities. WMH were present in 275 (83%) of individuals with a mean area of 1.1 ± 4.1 cm2. The increase in both number ( p < 0.001) and size (p < 0.01) with age. After adjustment for age and atrophy higher number and larger size of WMH correlated significantly with lower rCBF in the parietal white matter and some cortical regions, with predominance of the parietal inferior and temporal superior regions. Our data indicate that even in normal individuals increasing number and size of WMH may affect rCBF. This finding may be related to the vascular nature of WMH and/or reflect significant interruption of cerebral pathways by these lesions.

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150 COMPLICATIONS IN THE ACUTE AND POSTACUTE STAGE OF DECOMPRESSIVE SURGERY IN MALIGNANT BRAIN INFARCTION. F. Reinhardt, A. Druschky, F. Erbguth, B. Neundörfer. Department of Neurology, University of Erlangen, Germany In about 10 to 15% of all ischemic strokes, extending to major parts of a hemisphere a space occupying brain edema develops, mainly in the first 2 to 5 days. This edema seems to be the main factor of early mortality in supratentorial brain infarction. In the case of “malignant”, that means space occupying brain edema, conservative measures, e.g. hyperventilation, application of hyperosmotic agents or corticosteroids, are not effective enough in most patients to prevent from fatal consequences of mass effect. Surgical decompressive therapy in unilateral brain edema is currently discussed critically. Alltogether the clinical studies and case reports to date presented 125 patients, who underwent decompressive surgery in space occupying supratentorial infarction. We present 4 cases with complications of surgical decompression, that lead to prolonged hospital stay and in 3 cases to the necessity of surgical revision. Patient 1 with required early anticoagulation suffered from an epidural hematoma in the region of the durapatch, patient 2 presented with a myoarthropathia in the temporomandibular joint following the detachment of the temporal muscle, patient 3 developed an abscess and patient 4 a CSF-pouch in the region of the durapatch. Except in the case of myoarthropathia the patients suffered from typical complications of neurosurgerical measures. Such experiences with complications of surgical decompression are rare in this experimental therapeutic strategy, but nevertheless very important for the estimation of its risks and benefits. 151 THE YIELD OF TRANSESOPHAGEAL (TEE) OVER TRANSTHORACIC (TTE) ECHOCARDIOGRAPHY IN DIAGNOSING MAJOR SOURCES OF CARDIAC EMBOLISM IN PATIENTS WITH TIA OR STROKE. Schumacher HC, Paul M, Marx P, Mast H, Hartmann A, Dissmann R, Völler H, Schultheiß H-P. Dept. of Neurology and Cardiology, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Berlin, FRG Objective: To investigate the yield of TEE over TTE in the identification of major sources of embolism (mCSE) in patients with recent TIA or stroke. Material and Methods: 931 consecutive patients with TIA or stroke were included in the Berlin Cerebral Ischemia Databank during a 4.5 year period. From the whole population 537 patients with both TTE and TEE were analysed. mCSE was defined as left atrial or ventricular thrombus, myxoma, and/or left-sided valvular vegetations. Results: 205 (38%) of the patients suffered from heart diseases (HD) such as atrial fibrillation, angina pectoris, previous infarction, and/or congestive heart failure as defined by case history, clinical and electrocardiographic examination. TTE findings were: atrial (n = 2) or ventricular thrombi (n = 3), segmental (n = 92) or global (n = 14) ventricular hypokinesia, and left atrial enlargement (n=85). Combining the clinical, electrocardiographic and the TTE findings 272 (50.7%) patients had either a cardiac disease or a TTE abnormality. TEE revealed a mCSE in 27 (5.0%) of the patients (19 left atrial and 5 left ventricular thrombi, and 3 left atrial myxomata). mCSE were more likely in patients with known cardiac disease or TTE abnormality. (8.6% versus 1.9%; odds ratio 5.0, 95%CI 1.9–3.3.) Conclusions: TEE adds relevant pathological findings in about 9% of stroke patients with cardiac abnormalities diagnosed from case history, clinical findings, ECG, or TTE. 152 ANALYSIS OF RISK FACTORS FOR RECURRENT CEREBRAL INFARCTION. Ying-dong Zhang, Jing-ping Shi, Zuo-han Li. Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, P.R. China Objective: To investigate the pathogenesis and risk factors for recurrent cerebral infarction. Methods: In this paper, we studied the incidence of the accompanied disorders and a panel of biochemical parameters, including plasma triglyceride, total-cholesterol, LDL, HDL, Lp(a), apoA–, apoB, tissue-plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), anticardiolipin IgG, IgA and IgM, and fibrinogen, of 145 patients with recurrent cerebral infarction and 414 patients with first cerebral infarction after longer than 3 years following-up. Results: Incidence of having hypertension in the patients with recurrent cerebral infarction (71.11%) was more common than that in the patients with first cerebral infarction (51.75%) (P = 0.05), while there were no the phenomena to that of doing diabetes or ischemic heart diseases. The plasma PAI-1 activity (1165.71 ±

505.27 AU/ L) and fibrinogen level (3.75 ± 1.13 g/L) in the patients with recurrent stroke were significantly higher than those (590.13 ± 405.93 AU/ L and 3.14 ± 1.13 g / L, respectively) of the patients with first stroke (P = 0.001 and 0.002, respectively). Conclusions: It is suggested that hypertension, increased plasma PAI-1 activity and fibrinogen level are the risk factors for the recurrent cerebral infarction, and indicated that antihypertension, decreasing plasma fibrinogen level and modifying the plasma fibrinolysis are the important ways to the secondary prevention of the ischemic stroke.

Functional Neuroimaging 153 COMPARING SELF-GENERATED BRAIN ACTIVATION AND ELECTROMAGNETIC BRAIN ACTIVATION USING F18-FDG PET. H. R. Siebner, F. Willoch*, H. Boecker, M. Peller, C. Auer, P. Bartenstein*, B. Conrad. Departments of Neurology and Nuclear Medcine*, Technical University, Munich, Germany Six healthy right-handed volunteers underwent three F18-FDG PET scans performed on different days with separate acquisitions at rest, during 2Hz repetitive transcranial magnetic stimulation (rTMS) of the left sensorimotor cortex (SM1), and during imitation of rTMS-induced arm movements. In the 2Hz rTMS condition, 1800 suprathreshold magnetic stimuli were applied during the uptake period of F-18 FDG. The activated brain areas were defined by a pixelwise statistical subtraction analysis on group levels with results expressed in Z-scores defined in the stereotactic space of Talairach and Tournoux. Compared to the resting condition, both activation conditions caused a significant increase in regional cerebral metabolic rate of glucose consumption (rCMRglc) of the left SM1 motor hand area (Zscores > 4; p < 0.001). The relative rCMRglc increase within SM1 was significantly greater in magnitude and larger in area during voluntary imitation of rTMS-induced arm movements (Z-score = 3.13; p < 0.001). In addition, the rostral part of the supplementary motor area was significantly more activated by voluntary movements than during rTMS (Z-score = 3.01; p < 0.005). In conclusion, combining rTMS and F18-FDG PET has the potential to visualise rTMS-related net brain activation, and may open up new possibilities for functional network analysis by comparing selfgenerated brain activation to electromagnetic brain activation. 154 AN ANALYSIS OF THE PROGNOSTIC VALUE OF CLINICAL, MRI AND RCBF ASSESSMENT AFTER RUPTURE OF ANTERIOR COMMUNICATING ARTERY ANEURYSM. M. Rousseaux, M. Steinling, V. Lahousse, B. Bayle, J. P. Pruvo, J. P. Lejeune, O. Godefroy. Services De Réducation Neurologique, De Médecine Nucléaire, De Neuroradiologie et De Neurochirurgie. CHU Lille, France The prognosis of patients suffering from rupture of anterior communicating artery aneurysm (ACAA) has been assessed using early clinical evaluations as explicative variables. However, it has also been suggested that secondary phase evaluations has better prognostic value than the first ones, this being explained by the occurrence of arterial spasm in the first two weeks after hemorrhage. In this study, we were interested in assessing (and comparing) the prognostic value of clinical and functionnal deficits, MRI lesions and rCBF disorders of the secondary phase post stroke on the 2 years status. Patients and methods. Each patient admitted in the rehabilitation unit between 1990 and 1995 was assessed clinically: Glasgow Coma Scale at day 1 (D1), D15, D30; gait (FAC), vigilance and motor disorders (Orgogozo scale), orientation and MMS, Rankin scale, FIM at D30. Lesions were evaluated (0 to 2) using MRI (0.5 T; T2 sequences), in 4 frontal areas of each hemisphere and in the corpus callosum. The rCBF analysis used SPECT technique (Tomomatic 564) with Xenon inhalation, and was possible in 35 cases, that were selected for this study; flow was quantified in 5 areas of each hemisphere and in the cerebellum. At 2 years (Y2), we sucessively evaluated deficits (FAC, Orgogozo scale, MMS), disability (Rankin, FIM), and handicap (Holbrook scale). We used multiple correlations analysis between the the Y2 and the D1 to D30 variables, then stepwise variable selections (p = 0.05). Results. The Rankin scale (Y2) was best explained (R2 = 0.803) by the education level, motor disorders (Orgogozo scale, D30), hospitalization duration (HD), and right premotor and subcortical lesions (MRI); the FIM (R2 = 0.709) by the sex (better prognostic in males), HD and right premotor lesions; the Holbrook scale (R2 = 0.790) by the prelesional performance on the same scale, disorientation and MMSE (D30), HD, and left prefrontal lesions. Furthermore, the MMS was explained (R2 = 0.599) by the education level, HD

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and right prefrontal lesions. Discussion. This study shows that a correct prognostic can be built using in first intention clinical variables, and more especially the sex, education level, Orgogozo scale, MMS and HD. The assessment of premotor lesions using MRI can also be of prognostic value. However, the interest of the rCBF study seems to be low.

157 UNILATERAL HAND MOVEMENTS AND BILATERAL ACTIVATION PHENOMENA – AN EMG AND FMRI STUDY IN NORMAL ADULT SUBJECTS. H. F. Durwen*, A. Falk+, P. Calabrese*, U. Becker*, E. Müller+, L. Heuser+, W. Gehlen*. *Dept. of Neurology, +Dept. of Radiology, Ruhr-University, Bochum, Germany

155 PREDICTION OF RECOVERY FROM THE POSTTRAUMATIC VEGETATIVE STATE USING CEREBRAL MAGNETIC RESONANCE IMAGING. A. Kampfl, G. Franz, E. Schmutzhard, B. Pfausler, H. P. Haring, S. Felber, S. Golaszewski and F. Aichner. Department of Neurology, Intensive Care Unit; Department of Magnetic Resonance and Spectroscopy; University Hospital Innsbruck, Austria

Using fMRI, in some individuals a bilateral cortical activation in the primary motor area can be observed despite strictly unilateral hand movements. With electromyographic recording mirror activity can be observed in some subjects using the same motor paradigm. In order to further elucidate these phenomena, a total of 19 right-handed normal adult volunteers was evaluated by fMRI and the results compared to those of subsequent bilateral electromyographic recordings of the relevant hand muscles. Under both conditions the subjects had to carry out hand movements (spreading) with the dominant as well as non-dominant side. The fMRI was carried out with a conventional MRI scanner (Siemens Vision) using Echo Planar Imaging Technique (EPI). The electromyographic recording was carried out with a Picker-Schwarzer polygraph using surface electrodes. In fMRI bilateral cortical activation was found in only 6 subjects using the dominant right hand, however seen in 12 moving the subdominant left hand. In the electromyographic recording mirror activity was found in 7 subjects using the right dominant and in 15 using the left non-dominant hand. In 11 left-handers these striking differences between movements of the dominant and subdominant side were not observed in a previous study. In right-handers bilateral cortical activation in fMRI and mirror activity in electromyographic recordings are rather frequent and particularly associated with unilateral hand movements of the subdominant left side. The findings in fMRI may be the cortical equivalent to mirror activity in electromyographic recordings.

Background: The early posttraumatic vegetative state is compatible with recovery. However, various clinical and laboratory tests have failed to allow prediction of recovery. We therefore examined the value of cerebral magnetic resonance imaging in predicting recovery from a posttraumatic vegetative state. Methods: Eighty adult patients in a posttraumatic vegetative state underwent cerebral magnetic resonance imaging (MRI) between six and eight weeks after injury. MR images were reviewed by three neuroradiologists for the number, sizes, and location of brain lesions. Three neurologists evaluated the neurologic outcome of the patients at the time of MR scanning, and at 2, 3, 6, 9 and 12 months after injury using the Glasgow Outcome Scale. Findings: All patients were in a vegetative state at the time of MRI. At 12 months, 38 patients had recovered while 42 patients remained in the vegetative state. The demographic characteristics, and causes and severity of injury were similar in persistent vegetative and non-vegetative survivors. An average of 6 different brain areas were injured in persistent vegetative compared to 4.6 areas in non-persistent patients. Patients in the persistent vegetative state revealed a significantly higher frequency of corpus callosum, corona radiata, and dorsolateral brainstem injuries than did patients who recovered. Logistic regression analysis determined that corpus callosum and dorsolateral brainstem injuries were predictive of non-recovery. The adjusted odds ratios for nonrecovery of patients with a corpus callosum lesion and dorsolateral brainstem injury was 12.1 (95% confidence interval, 3.6 to 40), and 3.2 (95% confidence interval, 1.3 to 7.6), respectively. In contrast, clinical characteristics, such as initial Glasgow Coma Scale score, age, and pupillary abnormalities failed to predict recovery. Interpretation: Cerebral MRI in the subacute stage after head injury determines the outcome of the posttraumatic vegetative state. Corpus callosum and dorsolateral brain stem lesions are highly significant in predicting non-recovery. 156 BRAIN REGIONS FUNCTIONALLY ACTIVATED BY PAIN STIMULATION: AN FMRI-STUDY. V. H. Scholz*, R. Brüning*, M. Strupp¥, J. Weber*, Th. Brandt¥, M. Reiser*. *Institute of Diagnostic Radiology, ¥ Department of Neurology, University of Munich, Germany Painful events are modulated by central nervous structures such as the thalamus, anterior cingulate, somatosensory gyrus, and associated areas depending on the pain quality, intensity, and emotional affectability of the subject. Using fMRI we studied areas that are constantly activated by noxious thermal stimulation. Methods: Fifteen volunteers were examined with a 1.5T MR. A thermode placed in the volunteers’ palm warmed up/cooled down from 22° C to 43° C or respectively, from 22° C to 8° C when noxious heat/cold stimulation was applied for 14 sec. A constant thermal and tactile stimulation of 22° C was used as baseline. Twenty-eight images were collected over a 45 sec period. Post-processing including motion correction was done using cross-correlation calculation at p < 0.001. Colorcoded activation maps were generated and overlayed onto high-resolution anatomical images. The volumes, mean of signal changes, and standard deviation of the areas activated (localization by Talaraich coordinates) were compared. Results: All noxious heat and cold stimulations caused functional activation in the postcentral gyrus. Averaged data revealed the following statistically significant constant activated volumes: 3971 ± 36.4 (mean pixels ± SD) in the somatosensory cortex contralateral to the stimulation; ipsilateral activation was much smaller: the anterior cingulate (425 ± 25.5) and the thalamus (96 ± 11.2) were activated bilaterally. In addition, there was functional activation in the anterior superior part of the insula, basal ganglia (lentiforme nuclei and caudates) contralaterally, and associated frontal and parietal regions bilaterally, but there was a large variance in the appearance. The percentage of signal changes was largest in the somatosensory cortex. Discussion: Thermal noxious hot or cold stimulation can be used to study pain response with fMRI. Areas that are integrated in the limbic pathway show functional activation bilaterally.

158 IPSILATERAL BRAIN ACTIVATION FOLLOWING FUNCTIONAL HEMISPHERECTOMY STUDIED WITH PET. Hufnagel A, Bingel U, Müller S+, Kurthen M*, Leonhardt G. Depts. of Neurology and Nuclear Medicine+, Univ. of Essen, Germany and Dept. of Epileptology, Univ. of Bonn*, Germany The objective was to investigate localisation and extent of brain activation during passive movements of the paretic arm in patients who underwent functional hemispherectomy for control of medically intractable epilepsy. Six patients (3 women, 3 men) aged 21–53 years underwent a PET activation study utilising 15[O]H2O in a standard slow bolus technique. RCBF was measured during 12 runs, 6 at rest and 6 at passive movement of the elbow of the paretic arm in a motor gauge. Active and rest conditions were compared by use of statistical parametric mapping (FIL, London, UK). Results: Significant activation of rCBF between the resting and active condition ( p < 0.05) was shown in the non affected hemisphere, ipsilateral to the paretic arm, in all patients during passive movements. In patient 1 activation was marked in Brodman’s area 45 and supplementary motor cortex (SMA) and weak in the sensorimotor cortex (SMC) and parietal cortex. In patient 2 little activation was found in BA 45 only. In patient 3 marked activation was found in SMC and the anterior cingulate gyrus. In patient 4 and 5 activation was confined to the SMC. In patient 6 marked activation was found in the SMC and the SMA. In conclusion, all patients demonstrated an individual pattern of brain activation in the remaining hemisphere ipsilateral to the paretic arm. A similar pattern of activation may be seen in normal subjects during the same task but in our patients activation extended into circumscribed fronto-lateral and prefrontal brain areas.

Infection of the Nervous System 159 CLINICAL PRESENTATION OF CHILDHOOD NEUROCYSTICERCOSIS AND EFFICACY OF ALBENDAZOLE IN SINGLE LESION NCC. P. Singhi, M. Ray, A. K. Baranwal, N. Khandelwal, S. Singhi. Departments of Pediatrics and Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India Clinical presentation of neurocysticercosis was studied prospectively in 500 consecutive cases diagnosed on the basis of neuroimaging and serology. There were 272 males and 228 females; age range 1.5–12.5 yrs. Seizures were present in 94.8% cases – focal in 83.7%; headache and vomiting in 33%. Single lesions were seen in 76%; 82% of these were ring enhancing. Perilesional oedema gr 11 or more was seen in 57.4%. The site

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of lesion was parietal 46%, frontal 19.8%, frontoparietal 9%, occipital 6%. Albendazole 15 mg/kg/day for 28 days was given to all children with two or more lesions. To evaluate the efficacy of albendazole in single lesions, 63 children with single lesions were entered in a randomized double blind trial to receive either albendazole (n-31) or placebo (n-32), and followed up. CT scans were repeated after one and three months, CT lesion disappeared more frequently in albendazole treated group as compared to placebo group – 41% versus 16.2% after 1 month ( p < 0.05) and 64.5% versus 37.5% after 3 months (p < 0.05). Seizure recurrence was similar within first 8 weeks of therapy in both groups, but after 8 weeks, the recurrence was significantly less in albendazole group as compared to placebo ( p < 0.05). No adverse effects of albendazole were reported. In conclusion, partial seizures are the commonest presentation of NCC in children. Albendazole is effective even in children with single lesion NCC. 160 HAEMOPHILUS INFLUENZA MENINGITIS IN ADULTS. Biran I, Steiner I, Rahav G, Haviv Y, Leker RR. Department of Neurology, Hadassah University Hospital, Jerusalem, Israel Objective: To delineate the clinical, microbiological, laboratory and outcome features of Haemophilus Influenza (HI) bacterial meningitis in adults. Background: HI meningitis is an uncommon form of HI infection in adults, accounting for up to 5% of bacterial meningitides with most reported cases being of the non-B phenotype. HI meningitis in adults is usually secondary to trauma, bony defects, otitis media or compromised immunity. DESIGN: We analysed the files of all consecutive patients over 14 years of age with culture confirmed HI meningitis, who were hospitalized in our institute between 1989 to 1997. Results: In 6/259 patients with bacterial meningitis (2.3%) the causative agent was HI. The mean age was 37. None had trauma, bony defects, acute sinusitis or any evidence for immune abnormality but one had purulent otitis media. Three did not have meningeal irritation signs. Four had maxillary mucosal thickening on brain CT without clinical features of acute bacterial sinusitis. In five the infection was due to HI type-B and in one it was due to Non-B serotype. All patients made a complete recovery without long term complications. Conclusion: HI meningitis is an infrequent cause of bacterial meningitis in adults. It may present without known risk factors or meningeal irritation signs. Therefore, a high index of suspicion is needed. Contrary to previous reports, HI type-B may be more common than non-B serotype as the cause of meningial infection. 161 ELEVATED LEVELS OF MATRIX-METALLOPROTEINASE-9 IN THE CEREBROSPINAL FLUID (CSF) OF PATIENTS WITH LYMENEUROBORRELIOSIS. A. Kirchner, V. Fingerle*, B. Wilske*, U. Koedel, R. Paul, H.-W. Pfister. Dept. of Neurology, *Max v. PetttenkoferInstitut, University of Munich, Germany The pathophysiological mechanisms of the blood-CSF/brain-barrier dysfunction frequently found in patients with Lyme-neuroborreliosis are unknown in detail. Matrix-Metalloproteinases (MMP’s) are possible mediators of blood-CSF/brain-barrier disruption and are upregulated by mediators of inflammation. There is evidence that the transcription factor NF-κB is essential for the up-regulation of several inflammatory mediators by Borrelia (B.) burgdorferi. We measured MMP-9 activities as well as its tissue inhibitor (TIMP) in (CSF) samples of 33 patients with acute neuroborreliosis and of 15 patients with non-inflammatory neurological disorders (controls) by zymography and by ELISA. The 92-kDa gelatinase corresponding to MMP-9 was detectable in 27 of the 33 CSF-samples of patients with neuroborreliosis, but not in control samples. There was no correlation of MMP-9 or TIMP-levels with CSF total protein content or with CSF white blood cell count. Using a mouse macrophage cell line (RAW 264.7) MMP-9 activity was induced by stimulation with two different ultrasonicated Borrelia-strains (B. afzelii and B. garinii). This MMP-9 activity was reduced by inhibition of NF-κB (NF-κB SN50) in a dose-dependent manner. Our data suggest that B. burgdorferi-induced MMP-9 release may contribute to the blood-CSF/brain barrier dysfunction in patients with neuroborreliosis. The in vitro experiments showed that activation of NFκB plays a crucial role in the upregulation of MMP-9 by B. burgdorferi. 162 TREATMENT OF NEUROBORRELIOSIS: CORTICOSTEROIDS – EFFECTIVE OR NOT? C. Schäfer, P. Oschmann, J. J. Halperin, W. Dorndorf. Dept. of Neurology, University of Giessen, Germany; Dept. of Neurology, North Shore University, Manhasset, USA

The purpose of our study was to evaluate the superiority of a combination therapy of antibiotics and corticosteroids versus antibiotics alone in neuroborreliosis, stage II. Methods: Patients were recruited consecutively at the Dept. of Neurology Giessen (N = 92), Wuerzburg (N = 61) and Long Island NY (N = 18). 130 patients were treated with intravenous antibiotics and 41 with a combination of antibiotics and corticosteroids. The duration of therapy was between 10 to 14 days. A follow-up has been done twice – after 3 months and 12 months of treatment. Clinical symptoms as sensory signs, paresis and cranial nerve palsy were classified with scoring-Systems to estimate the severity of the disease. As short term criteria we used the duration of radiculitic pain and CSF cell count at the 3 months intervall. Results: At the second follow-up examination patients with antibiotic therapy showed better results than patients with a combination of antibiotics and corticosteroids (Wilcoxon-test p = 0.03) regarding the criteria cranial nerv palsy (N = 43 versus N = 19) and spinal radiculitic paresis (N = 58 versus N = 21). However regarding sensory signs no difference was found between both treatment regimens. Also the short-term criteria duration of radiculitic pain and CSF cell count showed no superiority of an additional corticosteroid therapy. The cell count in CSF decreased about 90% over 3 months with both treatment regimen. Conclusion: According to our results a combination therapy of antibiotics and corticosteroids is not superior to antibodies alone in neuroborreliosis stage II. 163 HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 NEF PROTEIN INDUCES BLOOD-BRAIN BARRIER LEAKAGE IN A RAT MODEL: INVOLVEMENT OF MATRIX-METALLOPROTEINASE (MMP)-9. B. Sporer, U. Koedel, R. Paul, B. Kohleisen*, V. Erfle* and H.-W. Pfister. Dept. of Neurology, University of Munich and *Institute of Molecular Virology, GSF, Neuherberg, Germany Recently, we have shown that intracisternal (i.c.) administration of HIV-1 Nef protein induces the recruitment of both polymorphonuclear and mononuclear cells into the cerebrospinal fluid (CSF) in a well established rat model. In this study, we investigated (1) whether Nef induced CSFpleocytosis is accompanied by a blood-brain barrier (BBB) leakage and (2) whether MMPs are involved as mediators of these pathophysiological changes. The integrity of the BBB was evaluated by the Evans blue (EB) extravasation technique. MMP-9 activity in the CSF was analyzed by zymography. In rats injected i.c. either with phosphat-buffered saline (100 µl, n = 5) or heat-inactivated-Nef (100 ng, n = 5) no EB extravasation and no CSF-MMP-9 activity was detectable. Six hours, but not 24 hours after i.c. injection of Nef in a dosage of 100 ng (n = 5) or 1000 ng (but not 10 ng) a blood-brain barrier breaching was found. In addition, 6 hours, but not 24 hours after administration of 100 ng or 1000 ng Nef an increased CSF-MMP-9 activity was detected. The co-administration of the MMPinhibitor BB-94 (n = 7) significantly reduced EB extravasation, CSFMMP-9 activity and CSF pleocytosis (Nef/BB-94 vs Nef 100 ng: 1.1 ± 0.3 vs. 5.1 ± 1.6 µg/ml CSF-EB; 334 ± 241 vs. 1.471 ± 374 cells/µl). In conclusion, beside its chemotactic properties HIV-1 Nef protein causes a BBB damage possibly via the induction of MMP-9 after i.c. challenge in the rat. 164 HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 NEF PROTEIN IS A VIRAL FACTOR FOR THE RECRUITMENT OF LEUKOCYTES INTO THE CENTRAL NERVOUS SYSTEM. Koedel U, Kohleisen B$, Sporer B, Lahrtz F§, Fontana A§, Erfle V$, Pfister HW. Dept. of Neurology, University of Munich, $Institute of Molecular Virology, GSF Neuherberg, Germany;§Institute of Clinical Immunology, Zürich, Switzerland Intracisternal (i.c.) injection of recombinant Nef protein, but not Tat, gp120, and gp160, of HIV-1 provoked leukocyte recruitment (923 ± 194 cells/µl) into the central nervous system in a rat model. The strong reduction of bioactivity by heat-treatment of Nef (188 ± 65 cells/µl), and the blocking effect of a mixture of monoclonal antibodies (mAbs) to Nef (125 ± 27 cells/µl), but not of mAbs to CD4 (843 ± 114 cells/µl) provided evidence of the specifity of the observed effects of Nef. Experiments using two different mAbs to Nef and Nef peptides demonstrated that (1) Nefinduced CSF pleocytosis was blocked almost completely by mAb 2H12 which maps to the carboxy-terminal domain of Nef (177 ± 102 cells/µl), and (2) that the corresponding Nef peptide was ineffective (46 ± 12 cells/ µl). Since both polymorphonuclear (PMN) and mononuclear cells (PBMC) could be detected in CSF samples of rats injected i.c. with Nef – dependent on the time of investigation (6 hrs versus 24 hrs after i.c. injection) – we examined whether Nef exhibits chemotactic activity on both cell types using a modified Boyden chamber technique. Nef acts as a chemoattractant on both PMN and PBMC in vitro. These data propose a mechanism by

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which Nef may be essential for AIDS neuropathogenesis – as a mediator of the recruitment of leukocytes which may serve as vehicles of the virus and perpetrators for disease through their production of neurotoxins.

Pain and Migraine 165 SR Ca2+-ATPASE IN BRODY’S DISEASE: RELIEF OF MUSCLE PAIN WITH VERAPAMIL. G. Meola *, V. Sansone*, G. Rotondo*, S. Giannasi*, E. Damiani**, R. Sacchetto**, and A. Margreth**. *Dept. Neurology, Univ. Milan, San Donato Hospital, Italy; **Dept. Experimental Biomed. Sci., Univ. Padova, Italy Brody disease is characterised by a specific deficiency (2 to 50% of control values) of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA), accounting for pseudomyotonia, the main clinical feature. Differential diagnosis from Na- or Cl-channelopathies requires biochemical confirmation of reduced SR Ca2+ -ATPase in muscle tissue. Recent findings suggest a structural abnormality rather than a reduction in the amount of fast twitch SERCA1 protein isoform. We describe a 10-year-old boy with an autosomal dominant history of muscle pain since the age of 3, exacerbated by exercise and cold. CK levels, EMG studies and potassium challenge were normal. Immunofluorescence studies of muscle cryostat sections using monoclonal antibodies, and immunoblots of the SR enriched microsomal fraction indicated that SERCA1 and slow-twitch SERCA2 isoforms were normally expressed relative to control muscle. Biochemical assay of the Ca2+-dependent, Mg2+-ATPase activity showed a 50% reduction, relative to control values. These results contrast with our previous observations in myotonic dystrophy (Damiani et al., Neuromusc Disord 6 : 33, 1996). Our present results further argue for a molecular abnormality of SERCA1, specifically affecting its functional behaviour and muscle relaxation in Brody disease. A correct diagnosis has important therapeutic implications: our patient is currently favourably being treated with verapamil. Work supported by grant funds from Telethon to A.M. 166 AUTONOMIC FAILURE IN ACUTE TRAUMA PATIENTS – ANALOGY TO CRPS? N. Sieweke, F. Birklein, W. Künzel, B. Riedl, B. Neundoerfer. University of Erlangen, Germany Complex Regional Pain Syndrome (CRPS) – characterized by a triad of sensory, motor and autonomic dysfunctions – develops in up to 3% of the patients after trauma such as fractures etc. Autonomic dysfunctions include edema, skin color changes, vaso- and sudomotor disturbances. This study investigates whether acute trauma patients not only present with signs of inflammation but also with autonomic dysfunctions similar to CRPS. In this case one could speculate that CRPS is an exaggerated form of a general reaction to a traumatic lesion. 20 patients with external fixation after distal radius fracture and without signs of CRPS were included in the study. Median disease duration was 7 days. Skin temperature was measured by computer-aided infrared thermography. Hyperalgesia to heat was tested by a feedback-controlled thermode, and to mechanical stimuli by an impact stimulator. Thermoregulatory sweating (TST) was induced by drinking 0.51 hot tea, sweating via peripheral axon reflex (QSART) by transcutaneous carbachol iontophoresis. Skin temperature was significantly increased ( p < 0.001), hyperalgesia to heat and to mechanical stimuli were both significant ( p < 0.001). Compared to a control group there was a significant side difference of sweating in the TST (p < 0.003), n = 15 with a tendency to hypohidrosis, but 2 patients showed a pronounced hyperhidrosis. No side difference was found in the QSART. We conclude that traumatic lesions not only lead to signs of peripheral inflammation, but also alter the function of the autonomic nervous system similarly to CRPS. Supported by the DFG/SFB 353. 167 SPECTRUM OF CACNA1A MUTATIONS IN FAMILIAL HEMIPLEGIC MIGRAINE (FHM). Anne Ducros,* Christian Denier,* Anne Joutel,* Katayoun Vahedi, Marie-Germaine Bousser, Elisabeth Tournier-Lasserve*. *INSERM U25, Faculté Necker, Hôpital Lariboisière, Paris, France Different types of mutations of the calcium-channel gene CACNAIA, located on chromosome 19, have been identified in various autosomal dominant neurological disorders including FHM: – four different missense mutations in five FHM families, including 2 with associated mild progressive cerebellar-ataxia (PCA); – two mutations disrupting the reading frame in

two families with episodic ataxia type-2 (EA-2); – small CAG trinucleotide expansions in large series of patients with spinocerebellar ataxia 6 (SCA6), a late-onset PCA. In addition, a missense mutation was recently identified in a pedigree with severe PCA, and CAG expansions in three families with EA-2 features associated to PCA. Thus, genotype-phenotype correlations in CACNA 1 A associated conditions need to be further clarified in large panels of families. Design/Methods: In order to characterize CACNAIA mutations in FHM, we selected 30 unrelated patients fulfilling the International Headache Society criteria for FHM, including 16 belonging to pedigrees with associated PCA. All 47 exons of CACNA1A are screened by SSCP, abnormal conformers are then sequenced. The lenght of the CAG repeat is determined in all patients. Results/Conclusion: Testing of 10 exons already revealed one potential new mutation. Our study will help to determine if FHM causing mutations are all missense mutations, if mutations are different in FHM with and without associated PCA, and if the CAG lenght plays a role in producing the phenotype. 168 HYPERALGESIA IN EXPERIMENTAL NEUROPATHY IS DEPENDENT ON THE TNF RECEPTOR 1. C. Sommer, C. Schmidt, A. George. Würzburg, Germany Recent evidence points to a role of cytokines like tumor necrosis factor-α (TNF) in the generation of hyperalgesia not only in inflammatory, but also in neuropathic pain. The present study was carried out to investigate which of the two known TNF receptors is involved in the process that leads to hyperalgesia after nerve injury. Mice (n = 30) underwent unilateral chronic constrictive injury (CCI) of the sciatic nerve and contralateral sham surgery. Neutralizing antibodies to TNF, to TNF receptor 1 (TNFR1) and to TNF receptor 2 (TNFR2) were administered by epineurial injection once daily. Thermal and mechanical nociceptive thresholds were measured. Animals were sacrificed at day 7 post surgery. Immunohistochemistry for TNF was performed on sciatic nerve sections. Quantitation was carried out using computer-assisted densitometry. Sham treated mice developed thermal hyperalgesia which was present between day 3 and 7 (thermal difference score (d.s) between –2.47 ± 0.09 and –3.13 ± 0.27; mechanical 50% thresholds (thr.) 0.005 ± 0.006 to 0.019 ± 0.009 mN). Thermal hyperalgesia and mechanical allodynia were attenuated in mice treated with neutralizing antibodies to TNF (d.s. –1.26 ± 0.20 to –2.02 ± 0.08; thr. 0.036 ± 0.04 mN to 0.075 ± 0.03 mN) and to TNFR1 (d.s. –1.43 ± 0.20 to –2 ± 0.24; thr. 0.02 ± 0.01 and 0.09 ± 0.001 mN. Neutralizing antibodies to TNFR2 had no effect. TNF-immunoreactivity of the injured sciatic nerve was reduced after treatment with anti-TNF and anti-TNFR1, not after antiTNFR2. We conclude that TNFR1, but not TNFR2 is mediating thermal hyperalgesia and mechanical allodynia after nerve injury. 169 RESULTS OF SURGICAL TREATMENT OF TRIGEMINAL NEURALGIA IN 1500 CASES. Broggi G, Franzini A, Servello D, Fabbrica D, Feroli P, Dones I. Dept. Neurosurgery – Istituto Nazionale Neurologico “C.Besta”, Milano, Italy Trigeminal neuralgia is a severely painflal condition that, when refractory to drug therapy, needs surgical treatment. Radiofrequency percutaneous rizothomy of trigeminal root (TRZ), percutaneous microcompression of gasserian ganglion (PMC) and microvascular decompression of trigeminal root (MVD) are the three most used surgical procedures. From 1974 to June 1997 2154 patients affected by trigeminal neuralgia have been operated on at the Istituto Nazionale Neurologico “C. Besta” of Milan: between 1990 and 1997 320 were submitted to TRZ while 180 to PMC and in 250 WD was performed. Results: a) TRZ: pain paroxysms immediately disappeared after surgery in 95% of patients. At long term follow-up (6 months –18 years) pain recurred in 18.1% of patients, in 12.8% within three years from surgery. There was no mortality. b) PMC: pain paroxysms immediately disappeared after surgery in 74% of patients. At long term follow-up (6 months – 8 years) pain recurred in 39% of patients within two years from surgery. There was no mortality. c) MVD: in all patients a neurovascular conflict was found, even in 12 patients affected by multiple sclerosis. Pain paroxysms disappeared immediately after surgery in 85% of cases, faded away slowly within two weeks in 7.5% and remained unchanged post-operatively in 7.5%. Postoperative relief from trigeminal neuralgia at long term follow-up (6 months –7 years) was complete in 84% of cases. Recurrency appeared in 16% of patients. There was no mortality. Conclusions: WD is more satisfactory on long term than other procedures. It is the only method without long term unacceptable complications like painful anesthesia. Percutaneous techniques should be used only in patients in poor general conditions. PMC should be preferred to TRZ in those cases in whom the first trigeminal branch is mostly affected.

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170 ANALGESIC RESPONSE TO SYSTEMIC LIDOCAINE DIFFERS BASED ON SITE OF NERVOUS SYSTEM INJURY. M. LantériMinet #*, H. Alchaar #*, N. Memran#, M. Chatel #. #Département d’Evaluation et Traitement de la Douleur; *Service de Neurologie, CHU de Nice, France Intravenously administered lidocaine (IVL) has an analgesic effect in a variety of painful syndromes with nervous system damage. Despite many clinical studies, the neuropathic pain conditions most responsive to IVL have not been fully agreed on. We retrospectively reviewed IVL infusions performed from January 1996 through July 1997 on neuropathic pain patients. Methods: Eighty-five patients were evaluated and underwent an IVL infusion (5 mg/kg for 60 minutes). Seventy-five patients had a definite peripheral nervous system injury (PNS) including mononeuropathies or polyneuropathies (n = 26), lumbosacral arachnoiditis (n = 34) and trigeminal neuralgia (n = 15). Ten patients had a definite central nervous system injury (CNS). Assessment of pain relief was based on the change in pain severity on visual analogue scale (VAS) from preinfusion baseline to 1 hour postinfusion. Results: Eighty percent (60/75) of patients with pain generated from PNS experienced partial (a 30% to 70% decrease in VAS) or excellent (greater than a 70% decrease in VAS) relief. In contrast, only 7/10 (70%) of the patients with CNS pain experienced partial or excellent relief. Conclusion: Patients with PNS injury reported substantially more pain relief than those with CNS one suggesting the analgesic mechanism of systemic lidocaine is through suppression of ectopic impulse generators in damage peripheral nerve.

pexole plus levodopa (PPX-L). The mean change (± SE) from baseline UPDRS Part II score for PPX-A was –1.8 ± .25 (4.7 vs 6.5 baseline). For PPX-L it was –3.8 ± .88 (6.0 vs 9.7 baseline). The mean change UPDRS Part III scores for PPX-A was –5.2 ± .68 (11.9 vs 17.7 baseline). For PPXL it was –8.0 ± 1.41 (12.6 vs 20.6 baseline). Pramipexole is an effective treatment for early PD and efficacy is maintained for at least 1 year. 173 MOTOR, COGNITIVE AND MRI FEATURES FOR DIFFERENTIAL DIAGNOSIS OF CORTICOBASAL DEGENERATION (CBD) AND PROGRESSIVE SUPRANUCLEAR PALSY (PSP). Soliveri P, Monza D, Fetoni V, Testa D, Genitrini S, Grisoli M, Savoiardo M, Caraceni T and Girotti F. Istituto Nazionale Neurologico C. Besta, Milano, Italy CBD and PSP often share common clinical and pathological features and are difficult to distinguish on clinical grounds alone. In an attempt to identify the most important features for the clinical diagnosis of these diseases we compared motor, cognitive and MR characteristics in 16 patients with CBD and 28 with PSP examined over the last three years at our centre in Milan. Patients with CBD had asymmetric fronto-parietal atrophy on MRI associated with asymmetric akinetic-rigid syndrome; while PSP patients showed mesencephalic and superior collicular atrophy associated with a parkinsonian syndrome and oculomotor and early balance disturbances. Myoclonus was only present in CBD. Cognitive examination revealed that ideomotor apraxia was prevalent in CBD while PSP patients had greater impairment of executive functions. We discuss the most important features for the differential diagnosis of these two disorders in the light of these findings.

Extrapyramidal Disorders (4) 171 DYNAMIC FUNCTIONAL MRI IN PARKINSON’S DISEASE: CORTICAL MECHANISMS UNDERLYING RIGIDITY AND BRADYKINESIA. M. Humberstone, S. Clare, J. Hykin, P. G. Morris, G. V. Sawle. Departments of Neurology & Physics, University of Nottingham, UK The functional deficits in Parkinson’s Disease (PD) are not fixed but depend upon the nature and rate of task performed. We studied 6 subjects with PD and 6 age-matched controls performing both self and externally paced tasks over a range of rates from 0.5–4Hz. This enabled the dynamic properties of their dysfunctional cortical networks to be analysed. The brain was scanned in 10 coronal echo-planar images every 1.5 s. The most parkinsonian hand (or matched hand in controls) was used to press a button at each rate. Functional images were segmented into primary sensory, primary motor, lateral premotor, SMA-proper, Pre-SMA, anterior cingulate and prefrontal cortices. Mean task related signal change in each region was plotted against actual rate of task performance. Pre-SMA and rostral anterior cingulate were underactive in PD vs controls (p = 0.003). Activity increased with rate in controls but decreased in PD. Lateral premotor cortex was overactive in PD (p < 0.001) but activity fell when PD subjects failed to achieve target rate. These changes probably reflect bradykinesia. Primary motor cortex (both contra- and ipsilateral) and primary sensory cortex were overactive in PD at all rates (p = 0.005). This overactivity was not confined to focal areas of task related signal change. We believe that this reflects diffuse disinhibition of primary sensory and motor cortex and is the cortical mechanism underlying rigidity in PD. 172 LONG TERM SAFETY AND EFFICACY OF PRAMIPEXOLE IN PARKINSON’S DISEASE (PD). Paolo Barone1, C. Eugene Wright2, PanYu Lai2 and Pramipexole Early Parkinson European Group. 1Department of Neurological Sciences, University of Napoli-Federico II, 2Pharmacia & Upjohn, Kalamazoo, MI, USA Pramipexole is a non ergot-derived dopamine agonist selective for D2 /D3 receptors. The purpose of this study is to evaluate the long term safety and efficacy of pramipexole for PD. Patients with idiopathic PD not requiring levodopa (Hoehn and Yahr I-III) were enrolled after completing a 6 month double-blind, placebo-controlled study of pramipexole. Patients were titrated with open-label pramipexole from 0.375 mg/day to an optimal dose or a maximum of 4.5 mg/day. During the maintenance phase, the dose could be increased twice before adding levodopa. Selegiline and anticholinergics were allowed. Periodic efficacy evaluations included UPDRS Part II (Activities of Daily Living) and Part III (motor examination). At 1 year (7 weeks titration, 10 months maintenance) 150 patients were inlcuded in the analysis with 128 (85%) on pramipexole alone (PPX-A) and 22 on prami-

174 LEVODOPA-INDUCED DYSKINESIAS ARE IMPROVED BY ACUTE IV AMANTADINE ADMINISTRATION. N. Pavese, G. Gambaccini, G. Dell’Agnello, P. Del Dotto, U. Bonuccelli. Department of NeurosciencesClinical Neurology,University of Pisa, Pisa, Italy Although levodopa remains the mainstay treatment of Parkinson’s disease (PD), abnormal involuntary movements during its chronic use complicate the management of the majority of patients with advanced disease. Amantadine has been shown to be an effective antiparkinsonian agent in both the absence and presence of concurrent levodopa therapy. Recently it has been observed that Amantadine and related drugs are potent antagonists at the N-methyl-D-aspartate (NMDA) receptor. Experimental evidence suggests that NMDA receptor blockade may improve the dyskinetic complications of long-term levodopa therapy. We evaluated the effects of Amantadine in six patients with severely disabling levodopa-dyskinesia. The patients, after their first morning dose of levodopa, received iv Amantadine (200 mg) or placebo in a double-blind way, on two different days. Assessments of parkinsonian motor performances and dyskinesias (UPDRS, SPES, AIMS, Video-tape) were made every 15 minutes, during the two-hour infusion and three hours thereafter. Amantadine treatment, but not placebo, determined in all patients studied a significant improvement of both parkinsonian motor performances and levodopa-induced dyskinesias. These results show a clear anti-dyskinetic effect of Amantadine and warrant a trial of oral Amantadine in levodopa-induced dyskinesia. 175 REGIONAL CHANGES IN CEREBRAL METABOLISM DUE TO STEREOTAXIC PALLIDOTOMY, EVALUATED BY FDG-PET. B. M. de Jong, R. Haaxma, A. W. F. Rutgers, M. J. Staal, J. Pruim. Depts. of Neurology, Neurosurgery and PET Center, University Hospital Groningen, Dept. of Neurology, Martini Hospital, Groningen, The Netherlands Stereotaxic lesioning of the ventral globus pallidum has a therapeutic effect on extrapyramidal symptoms such as levo-dopa associated dyskinesia and rigidity. Apparently, such lesion reorganises cortical function in specific outflow regions of the basal ganglia. In this study we aimed to identify such cortical regions that were assumed to be affected by acute disconnection following the applied surgical procedure. To that end, changes in regional cortical metabolism were assessed by repeated 18-fluor labeled deoxyglucose (FDG) positron emission tomography (PET). In 7 patients cerebral uptake of FDG around 2 weeks after pallidotomy was compared with the uptake before operation. Unilateral pallidotomy was carried out on the left side in 5 patients, in 2 patients a right sided lesion was made. The latter were mirrored to the left, thus providing a similar position of the lesion. Analysis was done using Statistical Paramater Mapping (SPM ’95, London) which included stereotaxic and global metabolic normalization.

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Compared to pre-pallidotomy, a relative decrease in FDG uptake was observed ipsilateral to the site of the lesion, over (i) both the lateral and medial premotor cortex, (ii) dorsolateral prefrontal cortex, and (iii) medial prefrontal cortex (Z-scores 3.0 and above). Conclusion: In the acute stage after pallidotomy, specific ipsilateral frontal regions show a decrease in metabolism. This points at the connection of these regions with movement related outflow of the basal ganglia. The metabolic changes were less robust as seen after ventrolateral thalamotomy. Moreover, in contrast to thalamotomy, no decreases of parietal cortex was seen in the present study, which indicates that pallidotomy may be a more specific procedure than thalamotomy. 176 PRAMIPEXOLE IN ADVANCED PARKINSON’S DISEASE: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY. Oertel W1*, Provinciali L2*, Meier DH3*. 1Klinik für Neurologie der Philipps-Universität Marburg; 2Clinica Neuroriabilitazione, Università di Ancona; 3Boehringer Ingelheim Pharma KG; * on behalf of the Pramipexole Study Group Of 354 PD patients with motor fluctuations under optimised dose of levodopa, 174 received pramipexole (PPX) and 180 placebo (PL). The dose titration lasted maximally seven weeks (up to 4.5 mg/day of PPX, tolerated in 57%) and was maintained for at least 24 weeks. Under PPX treatment the Unified Parkinson’s Disease Rating Scale (UPDRS) part II (activities of daily living) and part III (motor examination) improved by 30%; “off”-times by 2.5 hours per day. Differences between PPX and PL were significant from the second week of titration (daily dose 0.75 mg) to the endpoint. Dose limiting toxicity occurred in 13 PPX patients and 8 PL patients, drug related serious adverse events in 4%, both under PPX and PL. With PL treatment 36% of patients withdrew due to adverse events (versus 18% under PPX). Adverse events, more frequent under PPX, included dyskinesia and visual hallucinations. Postural hypotension was not more frequent under PPX. The results of this European study are in line with a similar recently published US study (Lieberman et al, 1997) and confirm the usefulness of PPX treatment in patients with advanced PD. PPX’s adverse events related to the CNS are expected from dopamine agonists, gastrointestinal and cardiovascular events appear to be infrequent.

Epilepsy 177 AUTOCHTONOUS CSF ANTIBODIES IN MESIOTEMPORAL AUTOIMMUNE-ENCEPHALITIS. C. Bien1, A. Schulze-Bonhage1, P. A. Berg2, C. E. Elger1. 1Clinic of Epileptology, University of Bonn, 2 Institute of Immunopathology, University of Tübingen, Germany Mesiotemporal MR-hyperintense lesions are among the most common causes of temporal lobe epilepsy. Limbic encephalitis is a rare and not always easily diagnosed underlying process. We present three cases of nonparaneoplastic limbic encephalitis in which autochtonous CSF antibodies against gangliosides and CNS tissue were present. All three patients presented with subacute development of severe impairment of recent memory and of epilepsy with simple and complex partial seizures of mesiotemporal semiology. In addition, psychiatric abnormalities like labile mood, irritability, depression, and loss of inhibition were present. MRI showed unilateral mesiotemporal hyperintensities in the hippocampal formation and adjacent regions of the temporal lobe. EEG confirmed mesiotemporal seizure onset. CSF showed raised cell count and oligoclonal bands in one patient each, elevated protein and blood-brain-barrier disturbance in two cases. In all three patients intrathecal production of anti-CNS and anti-ganglioside antibodies could be demonstrated. Histologically, chronic subacute encephalitis was confirmed in the two patients investigated. The occurrence of isolated authochthonous CSF production of anti-ganglioside and anti-CNS antibodies may be an important marker of an autoimmunological process in patients with unclear mesiotemporal MR lesions. 178 A NEW AUTOSOMAL DOMINANT PARTIAL EPILEPSY PEDIGREE. Kinton L1, 2, Sander JWAS2, Wood NW1, Walker F2. 1Neurogenetics Section, Dept. of Clinical Neurology, Institute of Neurology & 2 Epilepsy Research Group, 33 Queen Square, London WC1N 3BG, UK A large family spanning five generations with partial epilepsy is described. It is phenotypically dissimilar to any of the previously described inherited epilepsy pedigrees. The mode of inheritance would best fit an autosomal dominant pattern; there is a male:female ratio of 13 : 16 and the

presence of male-male transmission. Seizure types include simple partial seizures, complex partial seizures that were often nocturnal, and secondarygeneralised seizures occurring in approximately half of the affected individuals (15/29).Onset was in the first or second decade. The seizure characteristics suggest a varying focal origin both within affected individuals and within the family. The severity of the seizure disorder was also variable: one member with central discharges on his EEG was entirely asymptomatic, others had continuing seizures into middle age and two members of the family died aged 8 days and 12 years with severe seizure disorders. In those that accepted treatment, the seizures were responsive to Phenobarbitone or Carbemazepine. Imaging was normal in all but three individuals who had two symmetrical calcified lesions deep in the white matter, most commonly in the parietal lobes. CSF analysis excluded neurocysticercosis as a cause for these lesions. Electroencephalograms were normal in some family members and others had focal epileptiform abnormalities. The clinico-physiological details will be discussed and progress on gene mapping will be presented. 179 ALCOHOL USE IS NOT A RISK FACTOR FOR A FIRST SYMPTOMATIC EPILEPTIC SEIZURE. The Ares (Alcohol Related Seizures) Study Group, Italy Objective: to evaluate with a case-control study whether alcohol consumption is a risk factor for a first symptomatic epileptic seizure. Background: two studies (Ng et al., N Engl J Med 1988; 319 : 666–673; Leone et al., Neurology 1997; 48 : 614–620) found alcohol to be a risk factor for a first seizure, the risk beeing higher for idiopathic than symptomatic seizures. Cases were compared to controls with acute surgical or medical conditions, without considering “the cause of the seizure”. However, since alcohol is a risk factor for some of these, such as stroke or head trauma, it could act as a confoundent. Methods: cases are adult patients with a first seizure, symptomatic (either acute or remote) of stroke, intracranial tumor or head trauma. Controls are patients with stroke, intracranial tumor or head trauma, free of seizures. Results: the recruitment is expected to end by April 1998 with 250 cases. Preliminary analysis shows an odds ratio (OR) of 1.1 for drinkers, and 0.9 for ex-drinkers. Alcoholics are equally distributed among cases and controls. The risk of having a seizure is not significantly higher than 1 for all the classes of daily alcohol intake: it is 1.1 for 1–25 grams, 1.3 for 26–50 g., 1.3 for 51–100 g., and 1.2 for more than 100 g. Patterns of drinking are not significantly different between cases and controls. Conclusion: alcohol consumption is not a risk factor for a first acute or remote symptomatic seizure if an appropriate study design is used to control confounding. 180 SUDDEN UNEXPECTED DEATH IN EPILEPSY(SUDEP): A SERIES OF WITNESSED CASES. Langan Y, Nashef L, Sander JWAS. London, England, UK Up to 400–500 sudden deaths in epilepsy(SUDEP) occur yearly in the UK. The literature would suggest that 3–43% of these deaths are witnessed. As part of case ascertainment for a case-control study a series of 12 witnessed SUDEPs has been collected so far. We were made aware of these deaths by coroners, doctors and interviews with bereaved families conducted with the help of the charity Epilepsy Bereaved? There were six males and six females ranging in age from 10 to 47 years. Resuscitation was attempted in 10 cases and was initially successful in two but these patients subsequently died in hospital. The majority of deaths were in association with a seizure. Possible mechanisms for SUDEP include ictal or post-ictal hypoventilation and cardiac bradyarrhythmias. In a proportion of the above cases a detailed description of the final event was available which suggested that respiratory depression was a prominent feature. This series supports the view that the majority of SUDEP cases are seizure related and has implications for the prevention of such deaths. 181 USING PROTON MAGNETIC RESONANCE SPECTROSCOPY (1HMRS) FOR METABOLIC CHARACTERIZATION OF NEURONAL MIGRATION DISORDERS (NMD) AREAS. Simone IL, Tortorella C, De Blasi R*, Bellomo R, Federico F, Carrara D, Lucivero V, Livrea P. Institute of Neurology, *Service of Neuroradiology, University of Bari, Bari, Italy Object. To assess the role of 1H-MRS in metabolic characterization of cerebral areas of NMD patients. Methods. 1H-MRS was performed on 17

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brain areas of 15 epileptic patients showing at MR imaging (MRI) NMD identified as polymicrogyria (no. 4), cortical dysplasia (no. 4) and gray matter heterotopias (no. 9). Spectra were acquired from volumes of interest localized on NMD and contralateral MRI normal-appearing areas (Spin Echo sequence, TE 135 msec). Choline (Cho), creatine (Cr), N-acetyl Aspartate (NAA), lactate were evaluated in each spectrum; NAA/Cr, NAA/ Cho and Cho/Cr ratios were calculated and compared to those obtained from localized white and gray matter areas of 18 neurological controls (NC). Results. NMD lesions showed significantly lower NAA/Cr and Cho/Cr ratios in comparison to white and gray matter of NC. A significant decrease of Cho/Cr ratio was found also in MRI normal-appearing contralateral side. Lactate signal was detected both in NMD and contralateral areas of 3 patients. Conclusions. NAA/Cr decrease in NMD side suggests neuronal damage, whereas the reduction of Cho/Cr may be related to a diffuse hypomyelination sometimes undetectable at MRI. Lactate presence is probably related to the short time intercurrent from the last seizure (12 hours). In conclusion, we think that 1H-MRS may offer significant biochemical information in vivo on physio-pathological processes underlying NMD.

182 LEVETIRACETAM IN PARTIAL EPILEPSY: RESULTS OF TWO PHASE III CLINICAL TRIALS. Genton P. Centre St. Paul, Marseille on behalf of all investigators Preclinical studies with Levetiracetam (UCB Pharma) have shown a potent and broad-spectrum activity in animal models for epilepsy with a high therapeutic index. Pharmacokinetics show complete absorption, dose linearity, absence of protein binding and a half-life time permitting twice daily dosages. Metabolites are essentially non-hepatic and the main elimination route is renal. There are no drug interactions. Steady state plasma levels are reached after two days of oral administration. Methods and results: Levetiracetam was evaluated in two double blind, placebo-controlled clinical trials, one in Europe and one in USA with respectively 324 and 294 patients and a follow-up period of 12 and 14 weeks. Treatment-refractory epileptic patients with predominantly partial-onset seizures were randomized to receive placebo, 1 g and 2 g in Europe and placebo, 1 g and 3 g in the USA. The least square means of log transformed partial onset seizures frequency showed in bot studies a significant overall treatment effect (Eu; p = 0.006, USA; p = 0.0001). The responder rate was for all dosages significantly higher compared to placebo (Eu; plac 11.2%, 1 g 22.8%, 2 g 30.6%/USA; plac 10.8%, 1 g 33%, 3 g 39.8%). There were more seizure free patients with levetiracetam (Eu; plac 0%, 1 g 5%, 2 g 2%/USA; plac 0%, 1 g 3%, 3 g 8%). At all doses of levetiracetam, the overall incidence of adverse events was not significantly different from placebo, neither was the dropout rate. Somnolence, dizziness, headache and asthenia, mostly moderate and transient were the most frequent reported adverse events. Conclusion: Two double blind, placebo controlled, randomized clinical trials showed that levetiracetam 1 g to 1.5 g twice daily as add-on treatment in treatment-refractory epileptic patients with partial onset seizures significantly reduced seizure frequency. Levetiracetam was well tolerated.

Neuro-Oncology (1) 183 CV2 ANTIGEN, A PARANEOPLASTIC NEUROLOGICAL SYNDROME ANTIGEN, IS A PROTEIN OF THE ULIP FAMILY. Honnorat J1, 4, Byk T 3, Kusters I4, Quach T4, Aguera M4, Antoine JC5, Kolattukudy P1, Trouillas P1, Michel D5, Sobel A3, Belin MF4. 1Lyon, France, 2Colombus, USA, 3INSERM U440, Paris, France, 4INSERM U433 Lyon, France, 5St Etienne, France Anti-CV2 autoantibodies are associated with paraneoplastic neurological syndroms. They recognize a brain protein of 66 kDa, that we have named POP66 (Paraneoplastic Oligodendrocyte Protein). This protein is developmentally regulated and specifically expressed in the adult brain by a subpopulation of oligodendrocytes. By ultracentrifugation, ammonium sulfate precipitation and 2D electrophoresis, we purified an homogeneous protein preparation that showed a single band in SDS-PAGE, specifically recognized by anti-CV2 autoantibodies. Seven tryptic peptides belong to a recently described protein family named Ulip or CRMP according to the authors (Byk et al, J Neurosci, 1996; 16 : 688–701; Wang et al, J Neurosci, 1996, 16 : 6197–6207). The four mammalian neuronal members of the Ulip protein family are closely related to the Caenorabditis elegans Unc-33

gene product, required for neurite outgrowth and axonal guidance. We determined that anti-CV2 autoantibodies recognized specifically several posttranslationally modified forms of Ulip4/CRMP3 and not the other members of the Ulip family. The human Ulip4 cDNA was sequenced and the location of its gene was determined on the q25–q26 region of the long arm of chromosome 10, a chromosomal region containing potential tumor suppressor genes.

184 DIAGNOSTIC VALUE OF ANTI-HU ANTIBODIES (Hu-Ab) FOR PARANEOPLASTIC SENSORY NEUROPATHY (PSN). Molinuevo JL, Refle R, Illa I, Guerrero A, Graus F. Hospital Clinic, Hospital de Sant Pan, CSU Beilvitge, Barcelona. Hospital Universitario San Carlos, Madrid, Spain Background: Hu-Ab are considered a diagnostic marker of PSN associated with small cell lung carcinoma (SCLC). The incidence of Hu-Ab in large series of PSN has never been evaluated. Objective: To analyze the sensitivity and specificity of Hu-Ab in the diagnosis of PSN. Methods: We reviewed the diagnosis of 126 patients who presented with pure sensory neuropathy mainly involving the Joint position and vibratory senses and whose sera was sent for determination of Hu-Ab. PSN was defined by the presence of a tumor within a diagnostic interval of 4 years. Idiopathic sensory neuropathy (ISN) required the absence of a tumor during a follow-up period of at least 4 years. Hu-Ab were detected with immunohistochemistry and confirmed by immunoblot. Results: We identified 77 patients with non-PSN (25 with ISN). All but one patient, with ISN, were Hu-Ab negative. Hu-Ab were found in 40/49 patients with PSN. HU-Ab had a specificity of 99% (95% C.I.: 92%–100%) and a sensitivity of 82% (95% C1: 68%–91%) for PSN. Similar figures were obtained if only the ISN were taken as control group. Hu-Ab positive patients had higher incidence of SCLC (82.5% vs 44.4%; p = 0.049). Conclusions: Hu-Ab have high sensitivity and specificity for the diagnosis ot’ PSN. However, its absence does not rule out the possibility of PSN.

185 SERA OF PATIENTS WITH TESTICULAR CANCER AND PARANEOPLASTIC LIMBIC/BRAINSTEM ENCEPHALITIS HARBOR AN ANTINEURONAL ANTIBODY (ANTI-Ta) THAT RECOGNIZES A NOVEL NEURONAL PROTEIN. Raymond Voltz, Humayun S. Gultekin, Jerome B. Posner, Myrna R. Rosenfeld, Josep Dalmau. New York, USA We report 9 patients with paraneoplastic focal encephalitis (limbic, brainstem, basal ganglia) associated with testicular germ cell tumors and a novel antineuronal antibody (anti-Ta). Sera (or CSF when available) were examined using immunohistochemistry on rat and human brain, and immunoblots of human cortical neurons. IgG isolated from sera and labelled with biotin was used for competition assays. Screening of a X-ZAP cerebellar expression library was used for cloning experiments. Anti-Ta sera immunostained subnuclear structures and cytoplasm of human and rat neurons, but not other cells in the nervous system or systemic tissues. Anti-Ta sera were able to block the index patient’s immunoreactivity. On immunoblots of human cortex, 5 sera reacted with a 40 kDa, and 2 with an additional 50 kDa band. Screening of the X-ZAP library resulted in the cloning of a partial gene sequence (Ta) that contains epitopes recognized by all anti-Ta sera, but not by 30 control sera. No homologous sequence was identified in a GenBank data base search. Northern analysis, using 16 different normal tissues (including testis), demonstrated expression restricted to brain. In conclusion, the sera of patients with testicular cancer and limbic/ brainstem encephalitis harbour anti-Ta antibodies that recognize a novel neuronal protein.

186 ANTI-AMPHIPHYSIN ANTIBODIES (Amph-Ab) IN PATIENTS WITH PARANEOPLASTIC NEUROLOGIC DISORDERS (PND) AND SMALL-CELL LUNG CANCER (SCLC). A. Saiz1, J. Dalmau2, M. Butler3, Q. Chen4, J. Y. Delattre4, P. De Camilli3, F. Graus1. Hospital Clínic, Barcelona, Spain1. Memorial Sloan-Kettering Cancer, New York2, and Howard Hughes Medical Institute, New Haven3, USA. Hôpital de la Pitié-Salpêtrière, Paris, France4 We tried to determine the frequency of Amph-Ab in patients with PND and analyze the location of the dominant autoepitopes. In patients with breast cancer, paraneoplastic stiff-man syndrome is associated with Amph-

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Ab that primarily recognize the C-terminus of the protein. A few patients with PND and SCLC harbor Amph-Ab; the significance of this association is unclear. Amph-Ab were evaluated by immunohistochemistry and immunoblots of rat brain in 134 patients with encephalomyelitis/sensory neuronopathy (PEM/SN) and anti-Hu antibodies (Hu-Ab) (83% had SCLC), 44 with SCLC and PND without Hu-Ab, 63 with PND and Yo, Tr, or Ri antibodies, 146 SCLC patients without PND, and 104 with non-PND. The specificity of positive sera was confirmed with immunoblots of recombinant amphiphysin. Immunoblots of peptide fragments covering the full length amphiphysin were used to identify the major epitopes. Nine sera had Amph-Ab, but only one was detected by immunohistochemistry. Positive sera included 7 patients with PND and 2 with SCLC without PND. The type of PND was PEM/SN (5 patients), cerebellar degeneration (1), and opsoclonus (1). Six of them had SCLC and 4 Hu-Ab. All positive sera recognized epitopes located in the C-terminus of amphiphysin. Conclusions: The frequency of Amph-Ab in SCLC patients with PND is low. Amph-Ab primarily recognize autoepitopes localized in the C-terminus of the protein.

187 PATTERNS OF EXPRESSION OF RB AND P16 IN GLIOMAS, AND CORRELATION WITH SURVIVAL. V. K. Puduvalli, Houston, USA; A. P. Kyritsis, Houston, USA; K. R. Hess, Houston, USA; M. L. Bondy, Houston, USA; G. Fuller, Houston, USA; V. A. Levin Houston, USA, and J. M. Bruner, Houston, USA The retinoblastoma-p16 pathway controls the passage of cells through the G1 checkpoint, and is a frequent target of genetic alteration in gliomas. This study examined the correlation between survival and expression of Rb and p16 in 174 cases of gliomas. Glioma tissue samples, obtained at initial surgery, were graded for p16 and Rb expression, based on percentage of immunopositive cells and visual intensity. Abnormalities in either Rb or p16 expression were sees in the majority (> 90%) of the gliomas studied. Expression of Rb was either present in < 5% of tumor cells, or absent, in 36/125 (28%) of the glioblastomas (GBM), 12/36 (33%) of anaplastic astrocytomas (AA), and 3/6 (50%) of juvenile pilocytic astrocytomas (JPA). The remainder of the tumors were immunopositive for Rb in varying degrees (5–100% of immunopositive cells). Negative immunoreactivity for p16 was seen in 70/125 (56%) of GBM, 28/36 (77.8%) of AA, 5/7 (71%) of low grade astrocytomas and 3/6 (50%) of JPA. Immunostaining for either p16 or Rb, was seen to be inhomogeneous and did not correlate with pathological grade. Kaplan-Meier survival plots (log rank test) and Cox proportional hazards regression analysis adjusted for age and histology, showed no correlation between Rb and p16 immunohistochemical status, and survival. These results suggest that despite their known significance in the process of glioma formation and progression, p16 and Rb are poor immunomarkers for predicting either grade of malignancy or prognosis for survival in patients with gliomas.

188 PROGNOSTIC FACTORS FOR TUMOR RECURRENCE AND OVERALL SURVIVAL IN PATIENTS WITH ANAPLASTIC OLIGODENDROGLIOMAS. V. K. Puduvalli, Houston, USA; M. Hashmi, Houston, USA; K. R. Hess, Houston, USA; L. D. McAllister, USA, M. Prados, San Francisco, USA; W. K. A. Yung, Houston, USA; K. A. Jaeckle, Houston, USA; V. A. Levin, Houston, USA, and A. P. Kyritsis Houston, USA The optimal management of anaplastic oligodendrogliomas is controversial because of the rarity of these tumors and the lack of sufficient data regarding their response to various therapies. In this multi-center, retrospective study, we analyzed the response to treatment, and the prognosis, of 105 patients with anaplastic oligodendrogliomas treated with multimodality therapy. Overall median time to first progression was 48 months. Age was the only factor that correlated significantly with rate of progression. Patients < 52 years of age had a median time to progression of 48 months compared to 17 months for those > 52 years of age (p = 0.0032). Median time to second progression (50 cases) was 22 months, with patients who received either chemotherapy, surgery, or both, after their first progression, having a median survival of 7.3 years with the 5-year survival rate being 62%. Both age and KPS correlated significantly with survival. Patients < 52 years of age ( p = < 0.0001) and those with a KPS of 100 (p = 0.04) had longer survival. In conclusion, overall survival in patients with anaplastic oligodendrogliomas correlates significantly with age and KPS at diagnosis but not to the therapies currently in use. Our results underscore the need for developing novel therapeutic regimens to improve treatment options for patients with anaplastic oligodendrogliomas.

Neuro-Oncology (2) 189 RESPONSE TO PCV CHEMOTHERAPY OF RECURRENT ANAPLASTIC AND LOW GRADE ASTROCYTOMAS. R. Rudà, M. Nobile, M. Borgognone, F. Benech, R. Soffietti. Torino, Italy There is an increasing tendency to employ the PCV regimen in anaplastic astrocytomas and in the “high-risk” (contrast-enhancing) low grade astrocytomas. We are investigating the value of the standard PCV in a phase II study on patients with anaplastic and low grade astrocytomas recurrent after surgery and radiotherapy. Thirty patients (pts) have been treated so far (13 anaplastic astrocytomas, 1 anaplastic pilocytic astrocytoma and 16 recurrent low-grade astrocytomas) and 25 of them are evaluable for response. Results: Among patients with anaplastic astrocytomas at original surgery, responses were as follows: complete response (CR) none; partial (PR) (> 50% reduction in tumor area on CT/MRI) in 7/11 (64%); stable disease (SD) in 3/11 (27%); PD in 1/11 (9%). Among pts with low grade astrocytomas at original surgery, responses were as follows: CR none; PR in 5/14 (36%) (in contrast enhancing tumors only); SD in 6/14 (43%); PD in 3/14 (21%). Median time to tumor progression is now 32 weeks for anaplastic astrocytomas and 45.5 weeks for low grade astrocytomas. One patient, bearing a pilocytic astrocytoma with anaplastic features located in the thalamus, displayed a partial response (about 80% reduction of contrastenhancing tumor) lasting 48+ weeks. Conclusions: Anaplastic astrocytomas are chemosensitive tumors. Among recurrent low-grade astrocytomas, only the contrast enhancing tumors seem to respond to chemotherapy. 190 USEFULNESS OF RADIOTHERAPY IN PATIENTS WITH LOW GRADE ASTROCYTOMA AND EPILEPSY. R. Soffietti, M. Borgognone, M. Nobile, R. Rudà, E. Vasario. Torino, Italy Some authors (Rogers et al, Neurology, 43, 1599, 1993) have suggested that radiotherapy (RT) may be useful to control epilepsy in patients (pts) with low grade astrocytoma. We have reviewed the medical records of 15 pts with histologically verified low grade astrocytoma (WHO grade II) and epilepsy (more than 1 seizure per week), who were treated in recent years by conventional external RT (40–60 Gy, median 54 Gy). Nine pts were treated after surgery and 6 at tumor progression. The frequency of seizures after RT was judged as reduced, unchanged or increased, being the antiepileptic medication and steroids unmodified. Response on CT or MRI was evaluated by measuring the tumor size. Results: A significant reduction in seizure frequency after RT was observed in 10/15 pts (67%), with generalized and complex partial seizures being more responsive. Four out of 15 pts (27%) displayed a partial response (PR) (> 50% reduction of tumor area) on CT or MRI. Among pts with a reduced frequency of epileptic seizures (10), 3 (30%) had a PR and 7 (70%) a SD (stable disease), whereas among those with an unchanged frequency (4), 1 (25%) had a PR and 3 (75%) a SD. Five out of 9 pts (56%) who underwent at original surgery a biopsy and 5/6 pts (83%) who underwent a resection (subtotal or total) had a reduction of seizure frequency. No correlation was seen between response of epilepsy to RT and enhancement on CT/MRI or tumor site. Conclusions: Irradiation can reduce seizure frequency in patients with low grade astrocytoma, and this may occur without any change of tumor size on neuroimaging. 191 POLYCHEMOTHERAPY WITHOUT RADIOTHERAPY AS FIRST LINE TREATMENT FOR PRIMARY CNS LYMPHOMAS. U. Schlegel, H. Pels, A. Glasmacher*, R. Kleinschmidt* and U. Bode**. Dept. Neurology, *Dept. Internal Medicine and **Dept. Pediatric Hematology/Oncology; University Hospital Bonn, Bonn, Germany Combination radiotherapy (RT) and chemotherapy is an efficient treatment in primary CNS lymphomas with a median survival of up to four years in immunocompetent patients. However, treatment related late neurotoxicity is frequent in older patients. Patients and methods: From Aug. ’95 onwards 12 patients (mean age 58 ys) with histologically proven primary CNS lymphomas have received a polychemotherapy regimen without RT as first line therapy in our institution. Chemotherapy consisted of six cycles including sytemic high dose MTX, high dose Ara-C, Dexamethasone, Ifosfamide, Cyclophosphamide and intraventricular MTX/Ara-C/ Dexamethasone therapy in n = 9 or of systemic high dose MTX and Ara-C alone in n = 3. Results: 11/12 patients showed complete or partial tumour response under therapy. One patient (71 ys) died of treatment related septicemia. One other patient (71 ys) showed clinical signs of progressive dis-

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ease under therapy; and treatment was discontinued after the third cycle of chemotherapy. Eight patients have completed chemotherapy so far and all of these showed complete tumour remissions. Recurrence free survival in patients having completed therapy is 15 months+. Only one patient suffered from a tumour recurrence 22 mo after first diagnosis; he experienced a complete remission again under the same chemotherapy regimen. This patient showed white matter changes detectable on MRI without deterioration of intellectual function; no other permanent treatment related neurotoxicity was encountered. Conclusion: Chemotherapy including high dose MTX is an efficient first line treatment of primary CNS lymphomas. Follow up in our series is to short to state as to whether this therapy is as efficient as combination radio-/chemotherapy; however, neurotoxic sequelae seem to be much less frequent and severe. 192 LIPOSOME BEARING DAUNORUBICINE IN RECURRENT GLIOBLASTOMA (GBM) PATIENTS. Silvani A, Pozzi A, Salmaggi A, Broggi G, Boiardi A. Istituto Nazionale Neurologico “C. Besta”, Milano, Italy Daunorubicin encapsulated in liposomes may reach malignant glioma cells by leaking through the altered capillary walls of the tumor neovasculature. The aim of the study was: to evaluate the safety and potential effectiveness of different doses in 16 recurrent GBM patients. (life expectancy not longer than 2 months) All patients underwent surgery, repeated chemotherapy (with nitrosureas, platinum compounds, etoposide and procarbazine) and radiotherapy; 9/16 had been reoperated on at recurrence. Four pts received daunorubicine at 80 mg/sqm; 5 pts 100 mg/sqm and 7 pts 120 mg/sqm respectively, every 3 wks. Each patient was treated at least for 2 cycles, and treatment was repeated at the same dose until evidence of disease progression. No haematological toxicity occurred until 100 mg/sqm dose, 2 pts treated with 120 mg/sqm showed grade 3° leucopenia and thrombocytopenia. Two patients were partial responders.(PR) (with 100 and 120 mg/sqm respectively). Stable disease (SD) lasting 2 months at least was seen in 25–20–28% respectively, of the 3 subgroups treated at different dosages. Therefore, PR + SD was obtained in 40% of patients treated with 100 mg and in 42% of those treated with 120 mg, respectively. It is to early to draw conclusion owing to the preliminary experience, but we feel confident it is worth continuing the treatment in a phase II study. 193 FISH (FLUORESCENCE IN SITU HYBRIDIZATION) ANALYSIS OF ANEUPLOIDY IN MALIGNANT GLIOMAS. Amalfitano G, Paquis P, Michiels JF, Chatel M. Groupe de Neuro-Oncologie de Nice, CHRU, Nice, France Grading of malignant gliomas is difficult to establish by conventional methods. Molecular genetics indicate that glioblastomas (GB) and anaplastic astrocytomas (AA) may differ and that the sequence of chromosomal abnormalities may be significant of their biological behaviour. The study was planned *1- to explore the occurrence of chromosome (Chr) 7trisomy, Chr10-monosomy and gonosome X,Y aneuploidy * 2- to check if it may lead to a differential diagnosis between GB and AA. Methods: Chr7-, 10- and X-aneuploidy was simultaneously analysed by FISH on smears of 15 GB and 19 AA. Results: 93% (14/15) and 80% (12/15) of GB were found to be Chr7-trisomic and Chr10-monosomic, respectively. 100% (19/19) and 95% (18/19) of AA were found to be Chr7-trisomic and Chr10-monosomic, respectively. In women, 33% (3/9) of GB and 71% (5/7) of AA were found to be ChrX-monosomic. In men, 67% (4/6) of GB and 58% (7/12) of AA were found to be ChrX-disomic. Comparison of percentages between both groups was not found to be statistically significant. Conclusion: FISH technique on smears is a rapid and reliable method for chromosome analysis of malignant gliomas. Even if the data on Chr7-, 10- and X-aneuploidy do not seem to be specific of histologic subtypes, we think that the method should be extended to complementary probes. 194 [METHYL-11C] THYMIDINE POSITRON EMISSION TOMOGRAPHY IN TUMORAL AND NON-TUMORAL CEREBRAL LESIONS. J. De Reuck, P. Santens, P. Goethals, K. Strijckmans, I. Lemahieu, P. Boon, E. Achten, M. Lemmerling, T. Vandekerckhove, J. Caemaert. PET Centre, UZ/RUG, Gent, Belgium No ideal radiopharmaceutical exists for positron emission tomography (PET) that fulfils all clinical requirements for the study of brain tumors.

The usefulness of a recently developed PET tracer, [metıhyl-11C] thymidine ([methyl-11C]TdR) is explored in brain tumors. Twenty patients with confirmed tumoral and non-tumoral brain lesions were investigated with [methyl-11C]TdR PET. The 11C activity was visually and quantitatively assessed. In two patients dynamic scans were performed. The PET findings were compared to those of magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and to the final diagnosis. Eight out of ten patients with confirmed tumoral lesions or tumor recurrence had increased 11C activity within the lesion. In ten non-tumoral lesions no increased 11C uptake was found. The dynamic PET studies showed that [methyl-11C]TdR first acts as a blood flow tracer but that later on the uptake of 11C activity is due to labelled metabolites, crossing the blood-brainbarrier. Increased tracer activity was only observed in tumoral and not in non-tumoral contast enhanced lesions on MRI or CT. [Methyl-11C]TdR is not a selective PET radiopharmaceutical for brain tumors but can be used as a tracer for tumoral blood-brain barrier disruption.

Muscle Disorders (2) 195 CONGENITAL MYASTHENIA ASSOCIATED WITH MUSCLE AChR SUBUNIT GENE PROMOTER MUTATIONS. P. Nichols, R. Croxen, A. Vincent, J. Newsom-Davis, D. Beeson. University of Oxford, Oxford, UK The skeletal muscle acetylcholine receptor (AChR) consists of five subunits (α2, β, γ/ε, δ). During development of the neuromuscular junction there is a switch in AChR expression from the fetal (α2βγδ) to the adult (α2βεδ) form. Studies in animals have established that AChR expression is dependent on nucleotide sequences within the promoter regions of the AChR subunit genes, called E- and N-boxes. The E-boxes control tissue-specific and the N-boxes synapse-specific expression. Mutation of the N-box in the mouse ε-subunit promoter causes disruption of normal synaptic expression. Single strand conformational polymorphism analysis has identified several abnormal conformers in the α- and ε-subunit promoters of patients with congenital myasthenia. DNA sequence analysis has shown these to be due to homozygous and heterozygous point mutations and insertions. The consequences of the mutations are yet to be fully determined but in one consanguineous family, in which two of seven siblings had clinical and electromyographic features of congenital myasthenia, the disorder cosegregates with recessive inheritance of a single point mutation, a transition (G ‡ A) in the N-box region of the ε-subunit promoter. This finding would predict a disruption of ε-subunit transcription, resulting in a reduction in adult AChR synthesis. It would be consistent with the clinical and muscle biopsy evidence for reduced numbers of functional AChRs, establishing the disorder as postsynaptic. These cases suggest that AChR subunit promoter mutations are likely to underlie some forms of congenital myasthenia. 196 ROLE OF THE D2/S4 SEGMENT IN HUMAN MUSCLE SODIUM CHANNELS. N. Mitrovicl2, A. L. George3 and R. Horn1. 1Dpt. of Physiology, Thomas Jefferson University, Philadelphia, USA, 2Dpts. of Applied Physiology and Neurology, University of Ulm, Germany, 3Dpt. of Pharmacology, Vanderbilt, Nashville, USA Recent studies on mutant sodium channels causing paramyotonia congenita have shown that S4 segments are part of the voltage sensor. Depolarization is associated with an outward movement of S4 segments, and this movement is coupled with opening of the channel. To study the role of the S4 segment in the second domain (D2/S4) the outermost arginine was substituted by a cysteine and chemically modified with methane-thiosulfonate-ethyl-trimethyl-ammonium (MTSET). The modification causes a left shift of both the current-voltage relationship and the kinetics of activation, whereas the time constant of inactivation is not changed. A steady-state inactivation protocol surprisingly produces an increase of the peak current at –20 mV when the 300 ms prepulse potential is depolarized from –190 to –110 mV. Further depolarization reduces the current as expected for steady-state inactivation. Recovery from inactivation in modified channels is non-monotonic at voltages more hyperpolarized. than –100 mV. At –180 mV, for example, the amplitude of the recovering current is briefly almost twice as large as it was before the channels inactivated. These data can be explained by a model in which the movement of modified D2/S4 is sluggish. This behavior allows the possibility of inactivation having faster kinetics than activation, as in HERG potassium channel. Our results show that D2/S4 is intimately involved with activation but plays little role in either inactivation or recovery from inactivation.

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197 POSSIBLE INTERACTION OF THE INACTIVATION GATE AND A RESIDUE IN iv/S4–S5 OF THE HUMAN SKELETAL MUSCLE SODIUM CHANNEL. H. Lerche, A. Skudelny, E. Derra, N. Mitrovic and F. Lehmann-Horn. Department of Applied Physiology and Neurology, University of Ulm, D-89069 Ulm, Germany Na+-channelopathies are caused by various point mutations in the gene encoding the a-subunit of the human muscle Na+ channel. The functional defect of all of these mutants is a failure of inactivation causing myotonia or paralysis. A current model for the molecular mechansim of fast Na channel inactivation proposes that a cluster of three amino acids (IFM) within the cytoplasmic III–IV linker occludes the channel pore in a hinged-lid fashion. A receptor for the inactivation particle may be located in an intracellular S4–S5 loop which is connected to the voltage sensor and might therefore couple inactivation to activation. To study a possible interaction of these two regions, we introduced cysteines at the inactivation gate (F1311C) and a site in IV/S4–S5 (L1482C). WT and mutant Na+ channels were expressed in Xenopus oocytes and studied by two microelectrode voltage clamp. The Na+ current decay was best fit to a second order exponential function yielding two time constants of inactivation and a constant term. The relative amplitude of the faster time constant was markedly decreased for mutant when compared to WT channels (91% for WT vs. 80% for L1482C, 78% for F1311C and 41% for the F1311C/ L1482C double mutant). The steady-state inactivation curve showed a depolarizing shift of 12, 16 and 21 mV, respectively, indicating a severe destabilization of the inactivated state by the mutations. Mutant cycle analysis suggested that both mutations do not act independently indicating that L1482 may be involved in forming a receptor site for the inactivation particle.

198 MYOTONIC DYSTROPHY WITH MITOCHONDRIAL DELETION. Sukumaran S, Brett F, Farrell MA, Gallagher P, Harmey M, Murphy J, O’Connor K, Perryman R, Ryan F, Hardiman O. Dept Neurology & Neuropathology Beaumont Hospital Dublin, Ireland; School of Biological Sciences University College Dublin, Ireland and Louth Hospital, Louth, Ireland Myotonic dystrophy (MD) is a multisystem disease associated with an 3´ untranslated expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. As knockout studies of the DMPK have not produce an MD phenotype in animals, it has been suggested the expansion may affect the expression of flanking genes. We have identified a 65-year-old man with clinical features of MD, and additional atypical features of adult-onset external ophthalmoplegia and pigmentary retinopathy. Analysis of trinucleotide repeats revealed an expansion in the DMPK gene. A muscle biopsy was performed for analysis of mitochondrial integrity. Histochemical analysis revealed ragged red fibres, and a combined cytochrome oxidase and succinic dehydrogenase stain demonstrated interfibre mosaicism. Analysis of mitochondrial DNA (mtDNA) revealed the “common deletion”. To determine whether the coexistence of MD with the common deletion was a chance occurrence or due to a previously unknown effect of the expanded region on the regulation of mtDNA replication, we analysed biopsies from other patients with MD, and have identified a second patient with combined MD and the common deletion in mtDNA. We postulate that the coexistence of the common deletion with MD is not a chance occurrence, and that the phenotype of classic MD may relate in part to an effect of the expanded region on the integrity of mtDNA replication, possibly due to faulty signalling between nuclear and mitochondrial DNA.

199 BASIC FIBROBLAST GROWTH FACTOR IN INFLAMMATORY AND DYSTROPHIC MUSCLE DISEASES. P. Confalonieri, P. Megna, N. Aurisano, P. Bernasconi, L. Morandi, F. Cornelio and R. Mantegazza. Department of Neuromuscular Research, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Basic fibroblast growth factor (bFGF) is a potent angiogenic, mitogenic and chemotactic factor for many types of cells involved in tissue repair and in diseases with an abnormal proliferation of extracellular matrix. We evaluated the expression of this cytokine by quantitative-PCR (Q-PCR) and immunocytochemistry in muscle biopsies of patients affected by inflammatory myopathies (IM) (n = 13) and Duchenne muscular dystrophy (DMD) (n = 8). We found levels of bFGF mRNA significantly increased in IM patients compared to control muscles (p < 0.02); the mean value

was still significantly high when the single subgroup of IM patients (i.e. polymyositis, dermatomyositis and inclusion body myositis) were considered. The protein was localized in some areas of IM perimysial connective tissue, in some of the degenerating muscle fibers and signal was found also on some capillaries in dermatomyositis patients. No significant increase of bFGF transcript was found in DMD muscles ( p > 0.05); a very low staining for the protein was observed in correspondence of muscle fibers and in areas of connective tissue. On the basis of these results bFGF does not seem to play a major fibrogenic role in IM and DMD muscles but appear to be involved in angiogenesis and muscle fiber degeneration.

200 LONGITUDINAL ANALYSIS OF SERUM CALCIUM CHANNEL AUTOANTIBODIES AND DISEASE SEVERITY IN THE LAMBERTEATON MYASTHENIC SYNDROME. Paul Maddisona, Bethan Langb, Kerry Millsa, John Newsom-Davisa, b. a University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK; b Neurosciences Group, Institute of Molecular Medicine, University of Oxford, Oxford, UK Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies to voltage-gated calcium channels (VGCCs) at motor nerve terminals reduce acetylcholine release. Immunoprecipitation assays using 125I-w-conotoxin MVIIC-labelled (P/Q-type) VGCCs in human cerebellar extract are positive in over 90% of patients with LEMS. We collected longitudinal data over a median duration of 7 years on 28 patients with clinically and electromyographically definite LEMS and compared anti-P/Q-type VGCC antibody titres with a combined muscle strength score and with the amplitude of the compound muscle action potential (CMAP) in abductor digiti minimi. There was no significant correlation between initial pre-treatment anti-P/Q-type VGCC antibody titres and CMAP amplitude or muscle score (Spearman’s correlation coefficient, P > 0.05) in 17 patients. In 12 patients, the antibody titre declined over the follow-up period; in 5 the titre remained stable (to within 20%) and in 11 patients, the titre increased by over 50%. The only significant correlation was between percentage change in antibody titre and percentage change in CMAP amplitude (Spearman’s correlation coefficient r = –0.493, P = 0.012). Antibody titres were reduced to control levels in 3 patients, each of whom had regained full muscle strength. The lack of correlation between the initial CMAP amplitude and anti-P/Q-type VGCC antibody titre but the significant positive correlation between the change in these measurements with time would be consistent with functionally heterogeneous anti-VGCC antibodies.

Muscle Disorders (3) 201 GENETIC ANALYSIS OF MUSCLE GLYCOGENOSES. Matthias Vorgerd1, MD, Jean-Pierre Malin1, MD, Manfred W. Kilimann2, MD, PhD. 1Department of Neurology, Kliniken Bergmannsheil, 2 Institute for Physiological Chemistry; Ruhr-University, Bochum, Germany Glycogen storage diseases are caused by deficiencies of various enzymes either directly involved in glycogen metabolism or indirectly linked to it such as glucose-6-phosphatase or enzymes of glycolysis. Glycogen storage disease type II (GSDII) is an autosomal recessive inherited deficiency of lysosomal a-glucosidase (GAA). Inherited deficiency of myophosphorylase leads to glycogen storage disease type V (GSDV). Genetic defects of the muscle-specific isozyme of phosphofructokinase (PFK) cause a metabolic myopathy known as glycogenosis type VII (GSDVII). We performed mutation analysis in seven German patients with GSDII, in nine patients with typical clinical presentation of GSDV and in two family members with GSDVII. In GSDII, we characterized four new mutations: IVS6 (–22T→G), delG inAsp91, Gly638Trp and insC in Leu811, beside previously described mutations: IVS1(–13T→G), Dexon 18, Pro545Leu. Two affected siblings and an unrelated patient with adult GSDII were apparently homozygous for Dexon 18. Both siblings were also heteroallelic for IVS1(–13T→G). In GSDV, four novel mutations were found: Met0Val, Gly204Ser, Gly685Arg, Arg575Stop, beside previously described mutations: Arg49Stop and delA in Lys753. In GSDVII, both patients were compound heterozygotes for delC in Pro667 and IVS5(+1G→A). In conclusion, we observe phenotypic homogeneity in GSDV and GSDVII, but clinical presentation of GSDII is strikingly heterogenous. Our findings demonstrate pronounced allelic heterogeneity in German patients with GSDII, V and VII.

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202 MUTATION ANALYSIS IN SARCOGLYCAN-DEFICIENT PATIENTS. Barresi R, Di Blasi C, Morandi L, Negri T, Nigro V*, Cornelio F, Mora M. Istituto Nazionale Neurologico “C. Besta”, Milano, Italy. *II Università degli Studi, Napoli, Italy By immunohistochemistry of α-, β-, γ- and δ-sarcoglycans we have identified altered sarcoglycan expression in 25 patients with limb girdle muscular dystrophy. All sarcoglycan components were absent in 7 patients; γsarcoglycan was absent and the others reduced in 5 patients; all sarcoglycans were variably reduced in 11 patients; δ-sarcoglycan was absent and the other proteins were reduced in 2 other patients. According to immunocytochemical results we are screening these patients genetically by SSCP analysis. By sequencing abnormal conformers we found 2 missense αsarcoglycan mutations in 3 patients, 1 missense and 1 nonsense β-sarcoglycan mutation in 2 patients and an exon duplication of γ-sarcoglycan in 3 patients. We also found polymorphisms, mainly in the γ-sarcoglycan gene. In the 2 patients with absence of δ-sarcoglycan no mutation was found when the entire gene was sequenced. Cardiomyopathy is not frequent in sarcoglycan-deficient patients. Since the discovery of a δ-sarcoglycan mutation in the cardiomyopathic hamster, a mutation in this sarcoglycan in humans is suspected to be the main cause of cardiomiopathy. Interestingly both our β-sarcoglycan mutated patients had cardiomyopathy that required intensive care in one patient and digitalis therapy in the other. These clinical data suggest that β-sarcoglycan may play a role in the pathogenesis of cardiomyopathy. 203 MUSCULAR DYSTROPHIES: SARCOLEMMAL MEMBRANE ATTACK COMPLEX (MAC) DEPOSITS ON NONNECROTIC MUSCLE FIBERS. Simone Spuler and Andrew G. Engel*. Department of Neurology, University of Munich, Munich, Germany and *Department of Neurology, Neuromuscular Laboratory, Mayo Clinic, Rochester, MN, U.S.A. In addition to T cell-mediated muscle fiber injury in polymyositis and complement-mediated vessel injury in dermatomyositis, antibody-dependent muscle fiber damage is a hypothetical immune effector mechanism in inflammatory muscle diseases. We therefore searched for C5b9 complement membrane attack complex (MAC), IgG and IgM deposits on nonnecrotic muscle fibers in muscle biopsy specimens from 81 patients with inflammatory myopathies, 4–5 with muscular dystrophies, and 19 with necrotizing myopathies. In inflammatory myopathies, only two very unusual types (scleromyxedema, infantile polymyositis) displayed sarcolemmal MAC deposits. In Becker or Duchenne dystrophy specimens (13), complement-positive nonnecrotic fibers were never detected. In contrast, 14/32 specimens from other dystrophies (7/17 with facioscapulohumeral dystrophy, 4/9 with limb girdle dystrophy, 316 with laminin (alpha-2 positive congenital dystrophy) displayed sarcolemmal complement-deposits on nonnecrotic muscle fibers. The MAC-positive fibers failed to immunostain for IgG or IgM. Our findings do not support a role for antibodydependent complement-mediated muscle fiber injury in the major inflammatory muscle diseases. In muscular dystrophies, the cause and significance of the MAC-positive fibers remains to be elucidated. 204 IL-12 IS REQUIRED FOR THE INDUCTION OF EXPERIMENTAL AUTOIMMUNE MYASTHENIA GRAVIS, AN ANTIBODY-MEDIATED DISEASE. L. Moiola, F. Galbiati, G. Martino, S. Amadio, E. Brambilla, G. Comi, A. Vincent, L. Grimaldi, L. Adorini. Milano, Italy and Oxford, UK IL-12 has been shown to be involved in the pathogenesis of Th1-mediated autoimmune diseases, but its role in antibody-mediated autoimmune pathologies has not been studied. We investigated the effects of exogenous and endogenous IL-12 in experimental autoimmune myasthenia gravis (EAMG); this is an animal model for MG, a T cell-dependent, autoantibody-mediated disorder of neuromuscular transmission caused by antibodies to the muscle nicotinic acetylcholine receptor (AChR). Administration of IL-12 with Torpedo AChR (ToAChR) to C57BL/6 (B6) mice resulted in increased ToAChR-specific IFN-γ production and increased antiToAChR IgG2a serum antibodies compared with B6 mice primed with ToAChR alone. These changes were associated with earlier and greater neurophysiological evidence of EAMG in the IL-12 treated mice, and reduced numbers of AChRs. By contrast, when IL-12-deficient mice were immunized with ToAChR, ToAChR-specific Th1 cells and anti-ToAChR IgG2a serum antibodies were reduced compared to ToAChR-primed normal B6 mice, and the IL-12 deficient mice showed almost no neurophysiological evidence of EAMG and less reduction in AChR. These results

demonstrate the critical role of IL-12 in an antibody-mediated autoimmune disease and possibly indicate that complement-fixing IgG2a antiToAChR antibodies play an important part in the pathogenesis of EAMG. 205 HIGH DOSE INTRAVENOUS IMMUNOGLOBULIN (IVIG) IN THE TREATMENT OF INCLUSION BODY MYOSITIS (IBM) – A DOUBLEBLIND, PLACEBO-CONTROLLED STUDY. Hirschmann M1, Lochmüller H1, Toepfer M1, Schlotter B1, Schröder M1, Müller-Felber W1, Naumann M2, Schneider C2, Toyka, KV2, Pongratz D1. Munich1 and Würzburg2, Germany IBM is an acquired inflammatory muscle disease of unknown etiology. In general, IBM presents with slowly progressing, asymmetric muscle weakness and atrophy. There is lack of responsiveness to standard immunosuppressive treatment such as corticosteroids and azathioprine. A 12 month, clinical study was conducted to determine side-effects and therapeutic efficacy of IVIG in IBM patients. Of 22 recruited patients between 30 and 80 years of age and a duration of disease between 1 and 14 years, 20 were treated for the full 12 month period. They were randomized by a doubleblind, placebo-controlled, crossover design using monthly infusions of 2 g/kg IVIG (Intraglobin F, Biotest, Germany) or placebo (2.5% glucose, 1% albumin) for 6 month each. After 6 and 12 months, response to treatment was evaluated. Throughout treatment no severe side-effects were seen. Throughout the 12 months study, there was no progression of the disease, but rather mild improvement (17% on average) in both groups as measured by Neuromuscular Symptoms Score (NSS). NSS were significantly better in patients on treatment if compared to patients off treatment ( p < 0.05). The validity of the study is potentially reduced by mismatching of the two groups with regards to age of onset. Therapy with IVIG may be mildly effective in the treatment of IBM patients. Long-term studies are needed to further evaluate the benefit from IVIG therapy in IBM. 206 FOCAL INFILTRATIVE MACROPHAGIC MYOFASCIITIS: A NEW INFLAMMATORY MYOPATHY OF RECENT EMERGENCE. Gherardi RK, Coquet M, Cherin P, Authier FJ, Eymard B, Figarella-Branger D, Mussini JM, Pelissier JF, Fardeau M. Créteil; Bordeaux; Marseille; Nantes; Paris, France A most unusual inflammatory myopathy was recorded with an increasing frequency from May 1993 to October 1997, in 5 french myopathologic centers. The 18 patients had been referred with the presumptive diagnosis of polymyositis (10), polymyalgia rheumatica (4), mitochondrial cytopathy (3), and congenital myopathy (1). Detailed clinical information was available for 13 patients. Symptoms included myalgias (12/13), arthralgias (9/13), marked asthenia (5/13), muscle weakness (4/13), and fever (4/13). Abnormal laboratory findings included elevated CK levels (6/12), markedly increased erythrocyte sedimentation rate (5/11), and myopathic EMG (4/11). Muscle biopsy showed a unique myopathological pattern consisting in: (i) centripetal infiltration of epimysium, perimysium and perifascicular endomysium by large cells with finely granular PAS-positive cytoplasms of the monocyte/macrophage lineage (CD68+, CD1a–, S100p–); at electron microscopy the inclusions appeared as small osmiophilic spiculated structures of unknown nature; necrosis, epithelioïd or giant cells, and mitotic figures were not observed; (ii) occasional CD8+ T, intermingled with macrophages or surrounding microvessels, (3) unconscpicuous myopathic changes. The picture is easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. Macrophagic myofasciitis shares some similarities with reactive histiocytoses of infectious origin, such as Whipple’s disease, Mycobacterium avium intracellulare infection and malakoplasia, that were unsuccessfully searched in our patients. Eleven of 13 patients improved under steroid therapy, associated or not with antibiotic therapy.

Multiple Sclerosis (4) 207 CORRELATIONS BETWEEN CLINICAL AND MRI INVOLVEMENT IN MULTIPLE SCLEROSIS: ASSESSMENT WITH T2, T1 AND MT HISTOGRAMS. M. Filippi, G. Iannucci, M. A. Rocca, L. Minicucci, G. Mastronardo, M. Rovaris, M. E. Rodegher, G. Comi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan The degree of disability and cerebellar and brainstem impairments in multiple sclerosis (MS) patients were correlated with several magnetic reso-

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nance (MRI) measures of tissue damage in the whole brain, cerebellum and brainstem to define the relative contributions of the factors underlying the development of disability in MS. Dual echo conventional spin echo, T1-weighted and magnetization trasfer (MT) scans were obtained from 72 patients with MS and 20 age- and sex-matched controls. The following MRI-derived quantities were considered for the brain as a whole, the cerebellum and the brainstem: a) the number and volume of lesions seen on T2-weighted images; b) the number and volume of lesions seen on T1weighted images; c) the size of these structures measured on T1-weighted scans; d) the average MT ratio (MTR), peak height and peak position for the MT histogram. With univariate analysis, many MRI measures were significantly different in patients with different levels of disability or cerebellar and brainstem functional system impairments. However, with multivariate analysis, only whole brain average MTR was significantly related to physical disability, while cerebellar and brainstem T1 lesion volume and average MTR were indipendent predictors of cerebellar and brainstem impairment. This study shows that an increased proportion of lesions with severely-damaged tissue in clinically eloquent sites is the major cause of disability in patients with MS. It also suggests that measures derived from MT histogram analysis and T1 hypointense lesion load should be considered when evaluating long-term MS evolution. 208 Gd-MRI ACTIVITY IN RELAPSING REMITTING MULTIPLE SCLEROSIS; A SHORT-TERM NATURAL HISTORY STUDY. F. Bagnato1, C. Gasperini1, C. Pozzilli1, S. Bastianello1 C. Bash2, N. Richert2, H. McFarland3, J. A. Frank2. 1Department of Neurological Science, University of Rome “La Sapienza”, 2Laboratory of Diagnostic Radiology Research 3Neuroimmunology Branch National Institute of Health We analyzed serial monthly Gadolinium-enhanced MRI activity over a 6 months period in 104 relapsing remitting multiple sclerosis (RRMS) patients. The purpose of the study was to determine whether the disease activity at the first scan would predict MRI activity on subsequent scans. The Mean (± SD) enhancing lesions frequency was 3.85 (± 6.08). On the first scan 34.6% of the patients showed no disease activity while 65.4% were active; the proportion of inactive/active scan patients was similar at each month of follow-up. In the baseline inactive group, 22.2% (7.7% of the total group) showed an inactive scan at each time of observation; 61.1% (21.1%) of patients were inactive for two consecutive scans, 47.2% (16.3%) showed no disease activity for three consecutive scans while 33.3% (11.5%) and 25% (8.6%) showed no disease activity for four and five consecutive MRI scans, respectively. Linear regression analysis showed that baseline mean enhancing lesion frequency influences (p value < .0001) but it does not predict future lesion activity (R 2 = 0.5). Therefore in individual patient, the first scan does not have sufficient predictive value to determine the natural history of the disease over the next months in RRMS patients. 209 ASYMMETRY OF N-ACETYL ASPARTATE (NAA) IN THE INTERNAL CAPSULE OF PATIENTS WITH MULTIPLE SCLEROSIS CORRELATES WITH LATERALISATION OF MOTOR IMPAIRMENT: A SPECTROSCOPIC, CLINICAL AND ELECTROPHYSIOLOGICAL STUDY. M. A. Lee, A. Blamire, K. Ho, S. Pendlebury, P. Styles, J. Palace and P. M. Matthews. Oxford, U.K. Magnetic resonance imaging (MRI) is used widely in Multiple Sclerosis (MS) to monitor both response to new therapeutic agents and to investigate the underlying disease dynamics. However, conventional MR does not correlate well with clinical disability. Reasons for this discrepancy may include poor pathological specificity and lesion location. To better define MR parameters associated with clinical disability we have attempted to correlate NAA levels (a marker of axonal loss and dysfunction) in the posterior limb of the internal capsule (PLIC) with specific tests of motor function in 12 MS patients with stable asymmetric motor deficit. Suppressed and non- water suppressed proton magnetic resonance spectroscopy (MRS) was performed bilaterally within the PLIC using a voxel of 2 × 2 × 1.5 cms3. Conventional T1 and T2 weighted MR imaging and bilateral central motor conduction times (CMCTs) were also acquired. Results: The ratio of NAA/Cr in MS patients was significantly lower than in controls ( p = 0.01). Within patients, a strong correlation was found between lateralisation of motor deficits (composite score) and asymmetry of NAA (r = 0.6, p = 0.04). This correlation was further strengthened by using specific tests of hand function (grip strength r = 0.64, p = 0.03, myometry r = 0.78, p = < 0.01). CMCTs correlated with EDSS, a global measure of disability, (r = 0.73, p < 0.05) but not with specific tests of motor func-

tion. These findings suggest that axonal loss contributes to functional deficit in MS and that assessment of NAA may be useful for monitoring effects of new therapies. 210 IMMUNMONITORING OF PATIENTS WITH RR-MS UNDER THERAPY WITH BETA-INTERFERON 1b. PRELIMINARY RESULTS. P. Oschmann*, J. Tofighi*, B. Engelhardt #, R. Bauer*, C. Schiel*, C. Hornig*, A. Kern°, H. Traupe°, W. Dorndorf*. *Justus-Liebig-University of Gießen, Department of Neurology and °Neuroradiology, Germany; # Max-Planck Institute, Bad Nauheim, Germany Objective: To investigate the suitability of certain cytokines and adhesion molecules in the blood of MS patients treated with beta-interferon 1b as parameters for disease activity. Methods: In this ongoing study 60 patients, who were selected upon the recommendations of the German MS Society, will be observed over a period of 2 years. 30 patients are treated with beta-interferon 1b, the other 30 patients are without any immunmodulatory treatment. Cytokine- and adhesion molecule levels of all patients are assessed every 3 months by applying a sandwich-ELISA. The therapy is stratified into patients with active disease (≥ 1 relapse) and patients without disease activity (no relapse) over the observation period. The statistical evaluation focuses on the change of mean values of the parameters investigated and the inter- and intragroup comparison of those changes. Furthermore changes of disease activity within the therapy group are compared. Results: Both the therapy (n = 20) and the control group (n = 12) showed a decrease in the mean value of TNF-β over 6 months (therapy group (0.6 months): 29.03 to 22.11 pg/ml; control group: 24.26 to 13.44 pg/ml). In the therapy group during an observation time of 9 months, the mean value of TNF-β of the group without disease activity (n = 9) decreased from 30.24 to 24.83 pg/ml while the active group (n = 11) showed no significant change (29.42 and 28.98 pg/ml). Over a 6 month observation period no significant increase of the median TNF-R1-value has been found in the therapy group (1.00 and 0.97 ng/ml) whereas the TNF-R1value of the control group rose about 18% (1.25 to 1.48 ng/ml). Over a 9 month observation period therapy group without disease activity showed an increase of the median TNF-R1-value about 39% (0.94 to 1.30 ng/ml). In contrast to a decrease of 17% in the treated patient group with active disease (1.05 to 0.87 ng/ml). The evaluation of the median TNF-R2-value revealed a general increase in all groups, which was most distinct in the therapy group without disease activity (1.90 to 2.94 ng/ml). Similary a general increase of the median VCAM-1-value could be observed, which was initially significant in the therapy group compared to the control group over the first three months. The evaluation of sICAM-1 showed a general increase in the therapy-group (576.6 to 635.3 ng/ml) with no differences between the active and inactive group. On the other hand a decrease of both sICAM-3 and IL10 could be observed in the active-therapygroup without disease activity whereas an increase could be shown in the therapy group with active disease. Conclusion: These preliminary results hint to TNF-β, TNF-R1, TNF-R2 and IL10 as the most promising markers for disease monitoring of MS. (Shortened by editor.) 211 DISCONTINUATION OF IFN β TREATMENT IN MULTIPLE SCLEROSIS: THE ROLE OF MRI MONITORING. C. Pozzilli, O. Ciccarelli, C. Mainero, E. Millefiorini, M. Gherardi, S. Cannoni, C. Gasperini, S. Bastianello. Department of Neurological Science, University “La Sapienza” Rome, Italy It has been suggested that patients with relapsing-remitting multiple sclerosis (RRMS) who do not show a reduction in their exacerbation rate and those with a decline in EDSS score over the course of a year should discontinue the treatment with interferon beta (IFN β). Aim: To determine whether MRI monitoring is useful in the characterization of patients who may discontinue IFN β treatment. Methods: Sixty-two patients with RRMS completed 2 years of treatment with IFN β (Rebif) s.c. three times per week. Disease progression was defined as the occurrence of relapses and/or an increase of at least 1 point in EDSS score during the study period. Gd-enhanced MRI performed at month 6 and 12 of treatment was considered for the analysis. Results: Thirty (48%) patients, showed a disease progression during the first year of IFN-β-1a treatment. Of these, twenty patients showed also progression during the second year while in the remaining 10 patients the disease was stable during the second year. Gd-enhancing scans at the end of the first year of treatment were found in 1 of 10 patients who remained stable and in 10 of 20 patients with disease progression ( p = 0.03 by χ 2 ). Conclusions: Gd-enhanced MRI scan performed after 12 months of treatment in patients who do not clinically re-

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spond to IFNβ may help neurologists in evaluating whether therapy should be discontinued. 212 A PILOT STUDY OF THE EFFECT OF WEEKLY INTRAMUSCULAR (IM) 6.0 MIU INTERFERON BETA-1a (IFNB-1a) ON MONTHLY GADOLINIUM-ENHANCED (Gd+) BRAIN MRI ACTIVITY IN PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS (MS). Waubant E, Sloan R, Vermathen M, Rooney W, Weiner M, Goodkin D Objective: Compare the number and volume of new T1W, T2W and Gd+ lesions on monthly MRI before and after initiating weekly IM 6.0 MIU IFNB-1a. Background: IFNB-1b subcutaneous every other day and IFNB1a subcutaneous 3 times/week reduce monthly Gd+ activity in patients with relapsing MS. The effect of weekly IFNB-1a 6.0 MIU IM on monthly Gd+, T1W and T2W MRI activity has not been rigorously evaluated. Design/Methods: 7 female and 2 male patients who participated in a natural history study of MRI activity and had ≥ 6 monthly scans with ≥ 0.5 new Gd+ lesions/month started weekly IFNB-1a 6.0 MIU IM. Monthly scans were continued for 6 additional months and mean MRI activity for each patient was compared during pre and on-treatment phases. 8 patients had relapsing remitting MS and 1 had secondary progressive MS with relapses. Results: The mean number of new pre-treatment lesions/patient was: 1) 6.0, 2) 1.3, 3) 3.2, 4) 2.7, 5) 4.7, 6) 0.6, 7) 0.7, 8) 1.0, 9) 1.2. Data on-treatment and rate of T1W lesions rising from new Gd+ or T2W lesions pre and on-treatment will be presented. Conclusion: This study will provide information regarding the effect of IFNB-1a IM 6.0 MIU on monthly new Gd+, T1W and T2W MRI lesions in patients with relapsing MS.

Multiple Sclerosis (5) 213 CLINICAL CORRELATES OF SPINAL CORD AND CEREBRAL ATROPHY IN MULTIPLE SCLEROSIS. C. Liu, S. Edwards, Q. Gong*, N. Roberts*, L. D. Blumhardt. Clinical Neurology, Nottingham University; *MRR Centre, Liverpool, UK There is much interest in the relationship between fixed functional deficit in multiple sclerosis (MS) and spinal cord and cerebral atrophy. We aimed to estimate the rates of volume changes and their disability correlates by comparing MS patients with controls. 3-Dimensional magnetisation-prepared rapid acquisition gradient echo MRI was performed on 40 MS patients [20 relapsing-remitting (RR), 20 secondary progressive (SP)] and 10 controls. Volumes of both infratentorial [upper cervical cord (UCC); cerebellum (CER); brainstem (BS)] and supratentorial compartments [cerebral hemispheres (CH); white matter (WM); grey matter; ventricles; corpus callosum] were determined using stereology and normalised to head size. Patient volumes were significantly reduced infratentorially (UCC: –40% & –51%; CER: –15% & –21%; BS: –18% & –22%; for RR and SP respectively; p = 0.0001–0.004), and in CH (–4% & –6%; p = 0.0011– 0.0043) and WM (–8% & –16%; p = 0.0001–0.0007). UCC and WM losses correlated with Kurtzke (r = –0.4; p = 0.018–0.023) and Scripps (r = +0.4 & +0.5; p = 0.002–0.007) scores. Atrophy rates were estimated by extrapolation from symptom durations: UCC and BS rates were significantly higher in RR than SP (p = 0.007–0.038), which also correlated inversely with Kurtzke (r = –0.4 & –0.3; p = 0.027–0.049) and Ambulation Index (r = –0.5 & –0.4; p = 0.004–0.012) scores. Our study shows (i) significant supratentorial white matter and infratentorial losses in both MS types, (ii) correlation of UCC and WM atrophy with disability, and (iii) faster infratentorial volume loss in RR. As RR and SP represent different stages of the same disease, either the rate of infratentorial atrophy declines with time, or some myelin and axonal loss must antecede clinical manifestations. 214 CEREBROSPINAL FLUID LEVELS OF SOLUBLE CD27 CORRELATE WITH DISEASE STATE IN HTLV-I ASSOCIATED DISEASES AND MULTIPLE SCLEROSIS. R. Q. Hintzen, MD, PhD (Amsterdam, Netherlands), D. Paty and J. Oger, Vancouver, Canada Activated T-lymphocytes are likely to play a crucial role in MS and HAM/TSP. However, there is still no reliable lymphocyte-specific marker for immunological disease activity in these disorders. Stimulation of Tlymphocytes via the T-cell receptor strongly enhances CD27 membrane expression and induces the release of a 32 kDa (s) form of CD27. CD27 is

a member of the TNF-receptor family, a group of molecules that play important roles in lymphocyte differentiation and survival. Elevated levels of sCD27, measured by ELISA, have been reported in a variety of immunopathological conditions. We compared the concentration of sCD27 in cerebrospinal fluid (CSF) in four groups: 1. MS patients, 2. HAM/TSP patients, 3. HTLV-I/II carriers and 4. patients with other, non-inflammatory neurological disease (OND). Quantification of CSF-sCD27 differentiates MS from OND ( p < 0.0001) and HAM/TSP patients from HTLV-I carriers ( p < 0.01). Moreover in MS, CSF-sCD27 levels correlated with clinical disease activity. Measurement of CSF-sCD27 may provide an additional tool to differentiate between inflammatory and non-inflammatory white matter disease and may also help determine immunological disease activity in future trials for MS patients. 215 INCREASED EXPRESSION OF TGFβ1- AND TGFβ-R-II-mRNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH MULTIPLE SCLEROSIS TREATED WITH INTERFERONBETA1b. L. M. Ossege, E. Sindern, T. Patzold, J.-P. Malin. Institute of Neurology, Ruhr-University, BG Kliniken Bergmannsheil, Bochum, FRG The positive effects of a treatment of patients with relapsing-remitting form of multiple sclerosis (MS) with interferon-beta1b (IFNβ1b) on the annual rate, severity and duration of relapses, the relapse-free interval and the brain-lesions in MRI are well demonstrated. Until now complete and detailed informations about changes of and influences on the immunosystem of patients undergoing an IFNβ1b-therapy are not known. Our investigations were focused on the mRNA-expression of the immunosuppressive cytokine transforming-growth-factor-beta1 (TGFβ1) and its receptor type II (TGFβ-R-II) by peripheral blood mononuclear cells (PBMC) of MS-patients treated with IFNβ1b. IFNβ1b was subcutaneously administered to ten patients every other day with an initial single dose of 4 million units followed by a constant dose of 8 million units. Blood samples were collected before starting the treatment (day 0), 1 day, 5 days, 15 days, 6 weeks, 3 months, 6 months and 9 months later. For control samples from MS patients in the remission phase of the disease were collected every three month, too. The mRNA-expression of TGFb1 and TGFβ-R-II by PBMC was investigated by non-radioactive in situ hybridization at cytospin preparations. A significant increase of TGFβ1-mRNA in PBMC was detectable in 50% of the patients after the first injection (p < 0.01). At all other time points the mRNA-expression of TGFb1 was increased compared to day 0 in all patients ( p < 0.02). The TGFβ1-mRNA-expression increased continuously up to a maximum at week 6 and month 3 followed by a decline ( p < 0.05). The expression of TGFβ-R-II-mRNA of all patients was increased at all time points compared to day 0 (p = 0.001). At the initial phase (day 1, 5, and 15) this expression was higher than that of TGFβ1 but had the maximum not before month 6 (p = 0.001). The control group demonstrated no significant alterations of the TGFβ1- and TGFβ-RII-mRNA expression. These data suggest that the mRNA-expression of TGFβ1 and TGFβ-R-II in PBMC is induced by IFNβ1b in vivo. There seem to be no antagonistic regulatory mechanisms between TGFβ1 and its receptor. On the base of the current knowledge about TGFβ1 this might be an other mechanism by which IFNβ1b mediate its positive effects in the treatment of MS-patients. 216 COMPARISON OF THE THERAPEUTIC EFFECT OF INTERFERON β-1a (REBIF ® ) ON BASELINE MRI ACTIVITY. David Li1, Guojun Zhao1, Robert Hyde2, Florilene Dupont2, Ayad Abdul-Ahad2, Yan Cheng1, Xiuyu Wang1, Donald Paty1. The UBC MS/MRI Research Group, The PRISMS Study Group. 1UBC, Vancouver, Canada; 2Ares Serono, Geneva, Switzerland The PRISMS trial of interferon β-1a in relapsing remitting (RR) multiple sclerosis (MS) used MRI to demonstrate a significant reduction in burden of disease accumulation and disease activity, thereby supporting the positive clinical results showing reduction in disease progression and exacerbation. Here, the relationship between baseline MRI activities and disease activities in the placebo and treatment arms of the study were compared. 198 of the 560 PRISMS trial patients (placebo, n = 66; 22 mcg (6 MIU), n = 64; 44 mcg (12 MIU), n = 68) underwent monthly scans (2 before and 9 after treatment initiation) to assess PD/T2, Gd-T1 and combined unique (CU) activities. At baseline, patients were stratified to 3 groups: No activity (0 active lesions); low activity (1–2 active lesions) and high activity (> 2 active lesions). Cumulative mean number of lesions in stratified placebo and treatment groups was monitored for 9 months. Placebo patients with high baseline activity demonstrated a persistently greater accu-

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mulation of activity than patients with low or no activity. Placebo patients with low baseline activity had only slightly greater activity on follow-up than those with no activity, the difference being more apparent with T2 than Gd-T1 or CU activities. A reduction in mean cumulative activity seen in both treatment groups compared with placebo, was more evident in high activity patients, and greater in 44 mcg than 22 mcg treatment regimens. 217 A DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER TRIAL OF PENTOXIFYLLINE IN PATIENTS WITH RELAPSING REMITTING MULTIPLE SCLEROSIS. P. Rieckmann*, A. Bitsch and The Multiple Sclerosis Study Group, Departments of Neurology, University of Göttingen, University of Wüzburg*, Germany Pentoxifylline (PTX) is a phosphodiesterase inhibitor and decreases the production of proinflammatory cytokines, like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in vitro as well as in vivo. We therefore performed an initial dose escalation trial to determine the amount of pentoxifylline necessary to inhibit TNF-α production in MS patients. The effective dose of 2 × 800 mg per day was then used in a phase-II crossover trial. Fifty patients with relapsing remitting MS were evaluated after a two years treatment period. Twenty-four patients received placebo during the first year followed by PTX, whereas 26 patients were started on PTX and crossed-over to placebo in the second year. Patients were examined every three months and a magnetic resonance image of the brain was performed at study entry as well as at months 12 and 24. Both groups were matched for age, sex and disease activity. Primary end point of the study was a reduction in the composite variable consisting of relapse rate, changes in EDSS, magnetic resonance images or global assessment of the patient. In addition, an immunological monitoring consisting of cytokine mRNA expression of blood mononuclear cells and serum levels for soluble adhesion molecules was performed. The medication was well tolerated. No obvious clinical effect of this treatment regimen was detected but transient changes in immunological markers occurred. 218 COMPARISON OF CYCLOPHOSPHAMIDE AND MITOXANTRONE IN PROGRESSIVE MULTIPLE SCLEROSIS. P. Vermersch, J. de Seze, T. Stojkovic, M. Ayachi, C. Daems, B. Delisse, J. P. Pruvo. Departments of Neurology and Neuroradiology, CHU of Lille, France Background and objective: mitoxantrone (MX) combined with methylprednisolone (MP) have been shown to be effective in selected patients with very active multiple sclerosis (MS).We compared MX and cyclophosphamide (CYP) in progressive MS. Methods: thirty patients with primary and secondary progressive MS were randomized to receive monthly MP (500mg) with either MX (15 mg/m2) or CYP (500 mg/m2) over 10 months. Criteria for inclusion were patients with EDSS score between 5 and 7 and either two relapses or sustained progression of at least 0.5 point within the previous 12 months. EDSS scores, 9 hole peg test (9-HPT) and MRI data were compared. Results: the number of relapses per month of treatment was not significantly different between the CYP and MX groups (0.083 and 0.096 respectively). The EDSS scores remained stable, improved or worsened in 8/15, 4/15 and 3/15 respectively in both groups and were not significantly modified between inclusion and exit. MRI data and 9-HPT scores were not significantly different. The drug was stopped in 1 case in the CYP group and in 8 cases in the MX group for the following main reasons: severe leucopenia (n = 5), sepsis (n = 4), pericarditis and hepatitis (n = 1) and treatment failure (sustained progression or at least 2 clinical relapses) (n = 3). Conclusion: this study did not provide clinical differences between the two drugs in these severely affected patients. At this dosage, tolerance of MX is poor. Sustained progression or clinical relapses are noted in the MX group even in absence of side-effects. 218 B A PRELIMINARY STUDY OF A HUMANISED MONOCLONAL ANTIBODY TO ALPHA4 BETA1 INTEGRIN ON BRAIN LESION ACTIVITY DETECTED BY MRI IN MULTIPLE SCLEROSIS. Tubridy N, Miller DH, Moseley IF, Donoghue S. UK AntegrenTM MS Trial Group. NMR Research Unit, Institute of Neurology, London, UK. Athena Neurosciences Inc. Multiple sclerosis (MS) is characterised by inflammation in the central nervous system (CNS). It is thought that T Iymphocytes become activated in the periphery, and cross the blood brain barrier (BBB) where they initiate a process of immune mediated inflammation and demyelination. Ad-

hesion molecules play an important role in cell migration into the CNS, and we are conducting an exploratory therapeutic trial of AntegrenTM, a humanised monoclonal anti-adhesion molecule (VLA-4 [alpha4 beta1 integrin]) antibody. The study is placebo-controlled and of 6 months duration, with MRI activity as the primary outcome. Seventy patients with either relapsing-remitting or secondary progressive MS have been enrolled. At weeks 0 and +4, study drug (AntegrenTM or placebo) was administered by intravenous infusion. The MRI’s are obtained at weeks –4, 0, 1, 2, 4, 6, 8, 12, 16, 20, and 24. MRI outcomes include the effect of treatment on new enhancing lesions and pre-existing enhancing lesions. The study thus examines the relationship between anti-adhesion molecule therapy and the (BBB). The drop-out rate has been very low with few significant adverse events. The study is in progress and currently still blinded but the results will be available for presentation by the time of the meeting.

Poster Session 1 Epilepsy P1 MICROSTRUCTURAL ABNORMALITIES IN THE BRAIN DETECTED WITH DIFFUSION TENSOR IMAGING. Udo C. Wieshmann, Chris A. Clark, Mark R. Symms, Florence Franconi, Gareth J. Barker, Kim D. Birnie, Simon D. Shorvon. Institute of Neurology, Queen Square, London, UK Diffusion tensor imaging (DTI) is a magnetic resonance method which provides quantitative measurements of diffusion and diffusion anisotropy. These measurements reflect characteristics of brain microstructure: diffusion is restricted by membranes; in normal asymmetrically organized white matter diffusion is anisotropic because diffusion is restricted perpendicular but less restricted parallel to tracts. We used DTI to investigate patients with epilepsy interictally. The trace of the tensor and the fractional anisotropy index, quantitative rotationally invariant measures of diffusivity and diffusion anisotropy, were measured. We established a normal range using 10 control subjects and compared the normal values with values measured in nineteen patients with epilepsy and different structural abnormalities (malformation of cortical development, foreign tissue lesion, cerebral palsy). Diffusivity was markedly increased in acquired lesions but normal or only mildly increased in malformations of cortical development. In contrast anisotropy was reduced in all structural abnormalities including malformations of cortical development. Our findings imply that reduced anisotropy reflecting a loss of the asymmetrical organisation of subcortical white matter can be associated with epilepsy. P2 WATER DIFFUSION IN THE HUMAN HIPPOCAMPUS IN EPILEPSY. Udo C. Wieshmann, Chris A. Clark, Mark R. Symms, Gareth J. Barker, Kim D. Birnie, Simon D. Shorvon. Institute of Neurology, Queen Square London, UK Quantification of water diffusion allows the characterization of intrinsic features of tissue microstructure. To quantify water diffusion in the hippocampus in epilepsy during the interictal stage we scanned 20 subjects (14 patients and 6 controls) with a 1.5T magnetic resonance (MR) system. We used a cardiac-gated, navigated spin echo diffusion-weighted sequence. Hippocampal ADC measurements were performed on maps of the ADC measured in three orthogonal directions x, y, z. The mean ADC (ADCav) and an anisotropy index (AI) were calculated. T2-relaxation time and hippocampal volume were correlated with ADCav and AI. ADCav correlated with T2-relaxation time (r = 0.76, p < 0.00) and hippocampal volume (r = – 0.61, p < 0.00). There was a weak correlation of AI and T2-relaxation time (r = – 0.39, p = 0.01) and volume (r = – 0.37, p = 0.02). Hippocampi which fulfilled the MR criteria for HS had a higher ADCav (p < 0.00) and a lower AI ( p = 0.04) than normal appearing hippocampi in patients and hippocampi in controls. These results imply a loss of structural organization in sclerotic hippocampi and an expansion of the extracellular space. Quantitative measurements of diffusion can be used as an independent parameter for the identification and characterization of abnormal hippocampi in epilepsy. P3 INTERICTAL EPILEPTIFORM DISCHARGES IN MESIAL AND NEOCORTICAL TEMPORAL LOBE EPILEPSIES. S. Noachtar1, M. Pfänder1, S. Arnold1, K. J. Werhahn1, A. Müller1, P. A. Winkler2. 1Dep. of Neurology and 2Neurosurgery, University of Munich, Munich/Germany

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The distinction between mesial (MTE) and neocortical temporal lobe epilepsies (NTE) has implications for epilepsy surgery. Interictally, mesial and neocortical temporal spikes occur in both syndromes. We investigated whether a predominance of non-invasive interictal epileptiform discharges helps distinguish mesial from neocortical seizure onset. We included 122 consecutive patients with MTE and NTE in the study. MTE patients (n = 86) had mesial temporal sclerosis (MTS) and NTE patients (n = 36) had neocortical lesions and no MTS. The patients underwent continuous EEGvideo monitoring, magneto-resonance-tomography and fluor-desoxy-glucose-positron-emission-tomography. Random interictal EEG samples in wakefullness and sleep were prospectively counted and analyzed. Ipsilateral spike predominance was defined as a greater than 2 : 1 relation between mesial and neocortical temporal regions. We found that ipsilateral mesial temporal spikes predominanted in 65% of the MTE patients and 33% of the NTE patients (p < 0.0001). None of the 86 MTE patients had a neocortical temporal spike predominance (p < 0.0001). We conclude from our results, that although most patients with MTE and NTE show spiking in the mesial and neocortical temporal regions, non-invasive spike predominance (2 : 1) is helpful in the distinction between MTE and NTE. P4 FLUMAZENIL- AND FDG-PET REFLECT DIFFERENT ASPECTS OF EPILEPTOGENICITY IN EXTRATEMPORAL EPILEPSIES. S. Arnold1, A. Drzezga5, A. Berthele6, K. J. Werhahn1, P. Bartenstein5, T. R. Tölle6, S. Weis4, T. A. Yousry2, P. A. Winkler3, S. Noachtar1. Dep. of 1Neurology, 2Neuroradiology, 3Neurosurgery, 4Neuropathology, University of Munich; Dep. of 5Nuclear Medicine and 6Neurology, Technical University Munich, Germany Interictal hypometabolism as measured with FDG-PET exceeds the epileptogenic zone in extratemporal epilepsies. We studied whether alterations of benzodiazepine-receptor binding (BDZ-RB) measured with FlumazenilPET (FMZ-PET) are more sensitive in detecting the seizure onset zone. Ictal EEG-Video-recordings, high-resolution MRI, interictal FDG-PET and Flumazenil-PET were performed in 18 patients. The epileptogenic zone was consistent with MRI results in 6, with FDG-PET in 11 and with FMZ-PET in 12 patients. FMZ-PET demonstrated areas of reduced BDZ-RB, which were more restricted than the regional hypometabolism on FDG-PET in 8 patients. FMZ-PET revealed reduced BDZ-RB in 4 of 6 patients with normal MRI, whereas FDG-PET showed hypometabolism in 2 of these patients. Invasive EEG studies were performed in three patients with focal cortical dysplasias (FCD). The regional reduction of BDZ-RB corresponded to the seizure onset, whereas hypometabolism extended beyond the FCD and included the region of interictal spiking. All three patients remained seizure free following resective surgery. Histopathological and autoradiographic analyses of the specimen showed that the reduced BDZ-receptor density involved only a part of the FCD, consistent with the findings on FMZPET. These results suggest that interictal hypometabolism and altered BDZ receptor density reflect different aspects of epileptogenicity in extratemporal focal epilepsy. FMZ-PET corresponds to the seizure onset zone and is more specific than FDG-PET. P5 ARE UNILATERAL TONIC SEIZURES HELPFUL IN DIFFERENTIATING BETWEEN DIFFERENT EPILEPTIC SYNDROMES? K. J. Werhahn1, S. Arnold1, A. Müller1, P. A. Winkler3, H. O. Lüders2, S. Noachtar1. Department of Neurology1 and Neurosurgery3, University of Munich, Germany, Cleveland Clinic Foundation2, Cleveland, Ohio The localizing value of tonic seizures (TSZ) in focal epilepsy is thought to be low. We wanted to know whether there are differences in the type of TSZ between different focal epilepsies. We studied 511 patients and identified 149 (29%) with TSZ. We only included patients with a focal epilepsy, who had 170 TSZ documented using video-EEG (n = 123). Overall, 129 (76%) TSZ were bilateral and 41 (24%) unilateral. Unilateral TSZ often (56%) involved one arm or one side of the body (20%) or occurred in one hand (10%). Unilateral TSZ occurred in 5 (12%) patients with frontal, in 3 (19%) with parieto-occipital, in 3 (21%) with supplementary sensorimotor and in 5 (56%, vs. 22% in the remaining patients, χ2 = 5.13, p < 0.025) with perirolandic epilepsy (PRE). In PRE all unilateral TSZ involved one arm. In contrast, only 60–66% of the unilateral TSZ in the other groups involved one arm. 177 (37%) of focal epilepsy patients (n = 481) had temporal lobe epilepsy (TLE). However, only 3 (1.7%) patients with TLE had TSZ, which all were unilateral and occurred in parts of the body contralateral to seizure onset. We conclude: Unilateral TSZ point to the opposite hemisphere and are more frequent in PRE. Although rare in TLE compared to other focal epileptic syndromes they were always uni-

lateral. The findings underline the need to include the side of occurrence of TSZ in seizure classification. P6 A CLINICALLY SILENT DEFECT IN MOTOR CONTROL OF VOLUNTARY MOVEMENTS IN PARTIAL EPILEPSY. 1F. Adlerfligel, 1G. Hildebrand, 2 J. Jacquy, 1M. Manto. 1Neurologie, Hôpital Erasme-ULB (B); 2Neurologie, CHU-Charleroi, Charleroi (B) It has been demonstrated by PET studies that patients with partial epilepsy of frontal origin may present with contralateral interictal cerebellar hypometabolism. We tested the hypothesis that 3-dimensional kinematic analysis of fast limb movements might show contralateral abnormalities in epileptic patients with a frontal interictal EEG focus and normal neurological examination. We analysed fast upper limb movements towards fixed targets in 5 healthy subjects (HS; mean age: 42; range: 25–50; 2 women) and in 3 patients with a left frontal interictal EEG focus (age: 20, 35 and 39; 1 woman; duration of epilepsy of 6 years, 2 months and 27 years, respectively) and no lesion on brain CT or MRI. All subjects were righthanded. We found no dysmetria in patients. We also computed the symmetry ratios (SR) consisting of acceleration duration/deceleration duration for dominant hand divided by acceleration duration/deceleration duration for non-dominant hand. This ratio has been showed previously to be in favor of dominant hand in normal subjects. The mean SR was 1.03 ± 0.03 in HS and 0.95 ± 0.01 in patients (range: 0.94 to 0.96; p = 0.03). We conclude that kinematics of fast movements are impaired in the limb contralateral to the epileptic focus in patients with no structural lesion demonstrated by brain imaging. We thus show a clinically silent deficit in motor control of fast limb movements ispilaterally to the epileptic focus. P7 AUTOSOMAL DOMINANT NOCTURNAL FRONTAL LOBE EPILEPSY: A FIVE GENERATION SPANISH FAMILY WITH 14 AFFECTED MEMBERS. P. Gómez-Garre2, F. Díaz-Otero1, M. Martín1, R. Peraita1, Y. Fernández-Bullido1, J. M. Serratosa2. 1. Hospital Gregorio Marañón. 2. Fundación Jiménez Díaz. Madrid, Spain Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic partial epilepsy characterized by clusters of nocturnal motor seizures. ADNFLE has been associated with mutations in the α4 subunit of the nicotinic cholinergic receptor in chromosome 20q13.2–13.3. The purpose of this study is to identify Spanish families and define their phenotypic, genetic, and molecular characteristics. We have identified a five generation family with 14 affected members. Interviews, EEGs, and VideoEEGs were used to study the phenotype. Microsatellite markers in chromosome 20q13.2–13.3 are being typed. Mean age of onset of seizures was 11.6 years (range 1–26 years). Seizures were only nocturnal (7), only daytime (2), or both (2). Twelve patients presented secondary generalized tonicclonic seizures. Interictal EEGs showed bursts of sharp waves of variable localization: bilateral (3), temporal (2), rolandic (1). Video-EEG demonstrated hypertonia of one limb, sitting up, extension of the head, and search movements during seizures. Mode of transmission was consistent with an autosomal dominant model with low penetrance. Conclusions: The clinical phenotype and hereditary pattern of this family is similar to that described by other authors. However, we have found a higher incidence of EEG abnormalities and secondary generalized tonic-clonic seizures. P8 CSF NEURON-SPECIFIC ENOLASE IN PATIENTS WITH RECENT TONIC-CLONIC SEIZURES. Jaana Suhonen*, Johanna Palmio*, Pauli Vuorinen†, Jukka Peltola* and Tapani Keränen* Tampere University Hospital, *Department of Neurology, †Department of Clinical Microbiology, Tampere, Finland Neuron-specific enolase (NSE) is accepted marker of acute brain injury after neurologic insults such as stroke and anoxia. Increased serum levels of NSE have been measured in status epilepticus but whether single tonicclonic seizures can damage the brain is controversial. The aim of this study was to investigate if recent single tonic-clonic epileptic seizures lead to arise in serum and cerebrospinal fluid (CSF) levels of NSE and to compare serum and CSF levels of NSE. Methods: A total of 20 serum and CSF samples were analyzed from adult patients with < 24 h from the last tonicclonic seizure and 20 serum and CSF samples from control patients. NSE assays were performed using a radioimmunoassay technique (Cobas Core NSE EIA, Hoffmann-La Roche, Switzerland). NSE serum levels above 30

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ng/ml are clearly pathological. Results: The mean concentration of NSE in the patient group was 8.4 ng/ml (range 6–15 ng/ml) in the serum and 7.1 ng/ml (range 0–19) in the CSF. Mean concentrations for the control group were 10.2 (range 7–28) in the serum and 11.9 ng/ml (range 8–24 ng/ml) in the CSF. Conclusion: Our study is the first one to report CSF-NSE levels after noncomplicated single seizures. Serum and CSF levels of NSE correlated well after epileptic seizures. However, there was no significant difference between mean values of NSE between the patients and controls. These results do not confirm the previous observation of raised serum NSE-levels after single epileptic seizures arguing against neuronal damage after single tonic-clonic seizures. P9 SEQUENCES OF POCKET MONSTER CARTOON INDUCING PAROXYSMAL DISCHARGES IN A PHOTOSENSITIVE PATIENT. P. Masnou, Le Kremlin-Bicêtre, France On December 16 th, 1997, several hundreds of children experienced an epileptic seizure while watching a cartoon called Pocket Monster on TV in Japan. In order to detect the triggering sequence of this cartoon, we performed an EEG-video recording of a 18-year-old photosensitive patient while he was watching the Pocket Monster cartoon. The basal EEG was normal. Photosentivity was found at flashes rates between 18 and 40 Hz. The subject watched the Pocket Monster cartoon at 2 meters distance on a 50 Hz TV screen (0.60 meter diameter) in a normal surrounding light condition. A generalised paroxysmal discharge occurred when stroboscopic lights appeared on the screen. We stopped the video-tape immediately. The same sequence was shown again to the patient a few moments later, inducing an identical EEG response. Further analysis of the video-tape showed that 7 sequences of multicolor stroboscopic lights, lasting 1 to 4 seconds each, occupying the majority of the screen, with an identical flicker frequency of 12 Hz, occur during the eight minutes program. We conclude that a repetitive and regular stroboscopic effect seems the triggering factor of cases of epileptic seizures reported in youngsters watching Pocket Monster. P10 ORNITHINE TRANSCARBAMYLASE (OTC) DEFICIENCY PRESENTING AS RECURRENT COMA IN A MIDDLE AGED WOMAN. M. Bogdanovic, D. Kidd, J. Land, J. S. Duncan. London, U.K. A 57-year-old lady presented at the age of 28 with recurrent episodes of loss of consciousness preceded by a aura of a whistling noise. She had sustained a traumatic brain injury at the age of 16 in a motor cycle accident. The diagnosis of complex partial seizures was made and she was rendered seizure free on clonazepam. At the age of 53 she presented with a progressive subacute coma thought to be due to a viral encephalitis. She recovered fully. In 1996–1997 she suffered two further episodes of progressive disorientation then stupor. EEG was diffusely slow. The diagnosis of non-convulsive status epilepticus was made and, following appropriate treatment, complete recovery occurred. When she presented in her third episode in October 1997 the diagnosis was reviewed; she was found to hyperammonaemic (NH3 = 380). The urinary orotate/creatinine ratio was 38 (< 15) confirming the diagnosis of Ornithine transcarbamylase (OTC) deficiency. She was successfully treated with protein restriction and Sodium Phenylbutyrate and the NH3 reduced. Presentation of this disorder in middle age is exceedingly rare, and emphasises the need to consider such disorders in the differential diagnosis of recurrent coma. P11 DETERMINATION OF LANGUAGE DOMINANCE WITH FUNCTIONAL MAGNETIC RESONANCE IMAGING, EDINBURGH HANDINESS INVENTORY AND DICHOTIC LISTENING. S. Golaszewski1, Ch. Kremser1, V. Smekal2, S. Felber1, T. Benke2, F. Aichner1, 2. 1Department of Magnetic Resonance,2 Department of Neurology, University, Innsbruck, Austria Functional Magnetic Resonance Imaging (fMRI) is a method for the visualisation of brain activation based to hyperoxygenation within the activated brain area. Signal intensity changes are about 3–5 percent. Using adequate paradigms it is possible to localise higher cognitive brain functions such as language and memory. FMRI is a very good method to determine language dominance in patients suspected for epilepsy surgery. The aim of this study was the development of an fMRI adapted testing battery consisting of paradigms, that are able to localise those neuronal networks relevant for language and memory functions. Results: We tested six right and

six left handed subjects who underwent fMRI examination with the Verbal Fluency Test (VFT) and the Rivermead Behavioural Memory Test (RBMT) and determined language dominance by calculating the lateralisation index LI /1/. FMRI results were compared with the Edinburgh Handiness Inventory (EIH) and Dichotic Listening (DL). Within each subject we found consistent results between fMRI and neuropsychological testing. Conclusion: In conclusion, fMRI holds promise to replace the invasive Wada test in patients scheduled for epilepsy surgery. (Binder, J. R. et al., Neurology, 46 : 978–984, 1996.) P12 UNVERRICHT-LUNDBORG DISEASE: CLINICAL, ELECTROPHYSIOLOGICAL AND GENETIC STUDY OF 22 MAGHREBIAN FAMILIES. A. Gargouri*, R. Gouider*, S. Ibrahim**, M. Fredj*, A. Gargouri*, H. Saidi*, R. Ouazzani***, A. Malafosse****, M.Yaliyaoui***, D. Grid**, A. Mrabet*. Service de Neurologie EPS Charles Nicolle, Tunis – Tunisia; Service de Neurologie, Hôpital Mustapha, Alger – Algeria Service de Neurologie – Hopital des Spécialités, Rabat – Morocco; Division de Neuropsychiatric, Hopitaux Universitaires de Genève, Switzerland We describe clinical, electrophysiological and genetic correlations in 50 patients with Unverricht-Lundborg disease in 22 families living in Maghrebian countries. The mean age of patients is 25,5 years with a mean age of onset at 11.3 years. The disease begin at a mean age of 11.3 years, more frequently with seizures (80%), myoclonus (80%) than ataxia (18%). Subsequently myoclonus and generalized seizures are present in all patients, cerebellar signs am absent in four cases. EEG findings include normal background activity (90%), spontaneous fast generalized spikes (93%) and photosensitivity (71 %). Antiepileptic polytherapy (clonazepam and/or phenobarbital and/or valproic acid) is used in 86% of cases, Antiepileptic drugs are more effective in controlling epileptic seizures (less than one seizure/month in 60%) than in myoclonus which persist daily in 64% of cases. Mean evolution is 13.7 years and one patient died in the course of status epilepticus. Consanguinity is noted in 18 families (first degree in 15 families). Linkage to chromosome 2 1 q22.3 is confirmed in 11 families. We have noted an inter and intrafamilial variability for the clinical signs and the disease evolution. P13 MUSICAL ABILITIES AFTER A RIGHT OR LEFT TEMPORAL CORTECTOMY. Catherine Liégeois-Chauvel1, Isabelle Peretz2, 3, Myriam Babaï 2, 3, Virginie Laguitton1 and Patrick Chauvel1. 1INSERM CJF 97-06Laboratoire de Neurophysiologie et Neuropsychologie-Marseille-France; 2Department of Psychology, University of Montréal, Montreal (Quebec), Canada; 3Centre de Recherche, Centre Hospitalier Côte-des-Neiges, Montreal (Quebec), Canada Music processing was studied in 69 right-handed patients with unilateral temporal cortectomy for the relief of intractable epilepsy and their matched 24 normal controls. Musical sequences varied either along the pitch or temporal dimension. The present results show that a right temporal cortectomy impaired use of both contour and interval informations in the discrimination of melodies and a left temporal cortectomy impaired only use of interval information. Moreover, they underscored that the superior temporal gyrus (STG) is critical for observing a deficit in melody processing. The excision of a part of auditory areas (posterior part of STG) would be most detrimental for pitch and temporal variations processing. On the temporal dimension, we observe a double dissociation between meter and rhythm and the critical involvement of the anterior part of STG in the metric processing. The comparison between the performances of epileptic patients tested before and after surgery shows a score improvement when the STG is not excised. This study highlight the relevance of decomposing musical abilities into their most significant cognitive components in order for their cerebral location to be pinpointed. P14 EPILEPSY IN PATIENTS WITH MULTIPLE SCLEROSIS: PREVALENCE AND CLINICAL FEATURES. M. Lemesle, D. Sochurkova, G. Madinier, M. Giroud, R. Dumas. Service of Neurology. University Hospital of Dijon – France An analysis of the last 402 clinically and radiologically defined multiple sclerosis patients including de novo cases in the neurology service of the University Hospital of Dijon, revealed epileptic seizures in 17 cases (47%). Age of onset of Multiple Sclerosis was 28 years and it was a progressive form in 6/17 cases. A severe paraplegia with a frontal syndrome were pre-

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sent in 8 cases out of 17. Epilepsy occurred 6 years on average after the first manifestations of MS. Partial seizures were present in 13 cases out of 17, with marked focal spikes on EEG. On MRI, several features were present: a severe frontal and callosal atrophy, and the localization of the plaques mainly in the frontal lobes and in the sub-cortical area. The seizures were well controlled with anti-epileptic therapy. The authors discuss the relationship between the motor deficit, the partial seizures, the frontal atrophy and the sub-cortical and frontal plaques on MRI. P15 ECONOMIC DECLINE AND COMPLIANCE WITH ANTICONVULSANT THERAPY IN THE NORTHERN PART OF YUGOSLAVIA. Milana Diklic and Ivana Savkovic. University of Novi Sad, Yugoslavia In this study we intended to document the influence of economic decline in the Northern part of Yugoslavia during the period of civil war upon the compliance with anticonvulsant therapy. The effective treatment of epilepsy requires the maintenance of stable drug concentrations at the active receptor sites. Noncompliance with antiepileptic drugs (AEDs) is the major factor in the recurrence of seizures in persons with epilepsy. In this study, we assumed that fluctuations in drug serum levels during times of constant prescribed dose, beyond those expected from assay error pharmacologic fluctuations, reflect noncompliance with the prescribed regimen. The degree of fluctuation for each drug we have calculated using the coefficient of variation as well as the percent deviation from the mean of three or more drug levels. All patients involved met the criterion that the dose did not change during at least three successive drug level measurements. Our results indicate that drug level fluctuations were low in the period from 1975 to 1990 yr.; in 87% of patients deviation of 19.8% or less from the mean of previous AEDs levels was evidence for adequate compliant behaviour. In the period from 1991 to 1993 yr., AEDs level fluctuations were high: 56.52% for phenobarbital, 35.29% for carbamazepine, and 34.78% for valproate.Marked noncompliance in this period, in the beginning of civil war, resulted as a direct consequence of the lack of AEDs on the pharmaceutical market (loss of business contacts with former Yugoslav republics where AEDs pharmaceutical industry was located), and later, as a consequence of economic embargo done by the U.N. resolution, significantly diminished the efficiency of treatment. P16 PSYCHOGENIC SEIZURES IN JUVENILE MYOCLONIC EPILEPSY: A VIDEO-EEG STUDY. A. Dunac*, P. Thomas*, E. Hirsch**, C. Marescaux**, M. Chatel**. *Service Neurologie et Consultation d’Epileptologie, Hôpital Pasteur, Nice; **Services d’Epileptologie et de Neurologie, Hôpital Civil, Strasbourg, France Psychogenic seizures (PS) in Juvenile Myoclonic Epilepsy (JME) are unusual and have rarely been documented. We describe 5 patients (18- to 33years-old, 4 female and 1 male) with JME and PS. In all cases, PS occurred during the course of a previously treated and well-controlled JME. Long-term video-EEG monitoring with or without placebo-induction was the only way to assess correct diagnosis. In 3 cases, PS mimicked tonicclonic convulsions. In 2 cases, video-EEG documentation of the symptoms were consistent with non-epileptic myoclonias of psychological origin. Symptoms occurred several years after the characteristic myoclonic jerks of cortical origin were controlled by valproate. In one of these cases, true epileptic myoclonus recurred because of non-compliance and followed the documentation of psychogenic myoclonus (PM). In the other case, a retrospective diagnosis of JME was made, because PM mimicked the spontaneous seizures that occurred several years ago. PS in JME must be suspected when a previously effective treatment becomes ineffective, if a non-compliance problem is ruled out. Video-EEG documentation is the key point of diagnosis. P17 DO LIFE-EVENTS PROVOKE EPILEPTIC SEIZURES? M. Engelsman1, W. A. M. Swinkels1, D. G. A. Kasteleijn-Nolst Trenité1, M. G. Baal2, G. J. de Haan1, J. Oosting1. 1Instituut voor Epilepsiebestrijding, Heemstede, 2Rivierenland ziekenhuis, Tiel, The Netherlands Although stress is very often noted by patients to be a precipitating factor for seizures, no conclusive data are available. This matched-controlled, retrospective study investigated the influence of the evacuation in the central region of the Netherlands in of 1995 due to a threatening flood. Seizure frequencies of epileptic patients living in- or outside the evacuation area were inside compared to outside. Of the 30 evacuees, eight showed an

increase and one a decrease in seizure frequency during or shortly after the evacuation period (compared to one and zero control patients respectively) (Bowker test p < 0.05). Fifty-three patients filled in a questionnaire about general provocative factors and how they emotionally experienced the situation. Thirty-seven evacuees (70%) reported having one or more provocative factors, of whom 34 mentioned stress, 6 sleep deprivation and fatigue, and 7 other minor provocative factors. Twenty-one evacuees (40%) described the evacuation as a stressful event. Twelve evacuees (23%) reported having an increase in seizure frequency, and one (2%) a decrease during or shortly after evacuation. Five out of the six evacuees who stated that they had more seizures as a result of the evacuation, actually did have more seizures, such as supported by the seizure diaries and seizure patterns. Our data support the hypothesis that there is a relation, albeit small, between a stressful life-event and seizure frequency. P18 AN AUDIT OF THE PERCEIVED EFFICACY AND TOLERABILITY OF GABAPENTIN IN A COHORT OF PATIENTS WITH CHRONIC EPILEPSY. Langan Y, Sander JWAS. London, England, UK The purpose of this study was to examine the perceived efficacy and tolerability of gabapentin therapy in an outpatient population with chronic epilepsy. A number of patients were identified who could be rechallenged with gabapentin to a higher dosage. Data was extracted from the case-notes of 263 patients, 119 males and 144 females ranging in age form 15 to 81 years. The mean duration of epilepsy was 23.3 years. The mean dose of gabapentin administered was 1600 mgs (300–4800 mgs). 29 (11%) of patients had a reduction in seizures of 50% or more and 7(3%) achieved seizure freedom while taking gabapentin. Side-effects were reported by 169 (60.5%) of patients and in 40 (15%) an increase in seizures of 50% or greater occurred and was the commonest reason for withdrawal. 11 patients were rechallenged with gabapentin and doses up to 4800 mgs were found to be well tolerated suggesting that a small proportion of patients may benefit from a rechallenge with gabapentin to dosages higher than those previously administered. P19 FUNCTIONAL IMAGING IN READING EPILEPSY: A CASE REPORT. Aytaç Yig˘ it, H. Özdenșener, Ayșe Bingöl, Özlem Küçük*, Erkan Ybiș*, Nermin Mutluer. Ankara University, Medical Faculty, Departments of Neurology and Nuclear Medicine*, Ankara, Turkey Reading epilepsy is an uncommon epileptic syndrome preferentially related to the temporo-parietal region of the language-dominant hemisphere, but also to other regions functionally involved in reading. We report a 28year-old woman who, since the age of 17, had focal tonic contractions of the left leg, sometimes evolving to a generalized convulsion. At the age of 24, after a 5 year remission of the seizures while on primidone, she began with jaw jerking and groaning when reading. The baseline electroencephalogram (EEG) was unremarkable, whereas bilateral paroxysms of short spike and wave complexes appeared in about 30 minutes when reading. Sodium valproate eliminated her symptoms. Magnetic resonance imaging and interictal single photon emission computed tomography (SPECT) were normal, but ictal SPECT demonstrated an increased perfusion on the right superior temporal region. The lateralization of the ictal SPECT to the right side seems discordant with the right-handedness of the patient, strongly suggested by neuropsychological assessment of hemispheric dominance. We propose that the seizure focus in reading epilepsy may not be lateralized to the presumed language-dominant hemisphere. P20 BIZARRE AUTOMATIC BEHAVIOR AND MUSICAL VOCAL PRODUCTION DURING COMPLEX PARTIAL SEIZURE (VIDEO-EEG PRESENTATION). Kuba, R.; Rektor, Dpt. of Neurology, St. Anna Hospital, Brno Case report: Reported patient is a 45-year-old female, who has had complex partial seizures (CPS) since age 20 years. Tonic-clonic seizures occurred occasionally. Seizures were poorly controlled despite trials of multiple AED drugs therapy. CT performed several years later was negative. The patient was admitted to our hospital for evaluation because of intractable epilepsy of temporal lobe origin. Scalp EEG study showed no epileptic discharges. We repeated CT investigation, which showed small hyperdensity with enhancement of contrast tissue in the right temporopolar region. This finding was in favor of a small cavernoma which was supported MRI findings. Long term video EEG monitoring with sphe-

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noidal electrodes was performed and two ictal were recorded. Seizure started always in the contacts recorded the activity from right sphenoidal electrode. We can observe a CPS with bizarre automatic behavior (clasping her hand together as if praying) and musical vocal production (st. like “chant”) together with motor manifestations. According to her anamnesis she was always humming the melody of “Ode for Joy” written by L. van Beethoven during the CPS. Surgical removal of the lesion with peroperative electrical corticography and subsequently the removal of amygdala and adjacent part of right parahippocampal gyrus was performed. Patient is seizure-free for 6 months.

P21 INTERICTAL AND ICTAL VIDEO-EEG MONITORING. Boon P, Michielsen G, Buyle M, Goossens L, Drieghe C, D’have M, Vandekerckhove T, De Reuck J. Epilepsy Monitoring Unit, Department Of Neurology, And Department Of Neurosurgery, University Hospital Gent, Belgium We report an extensive experience with video-EEG monitoring and confirm its diagnostic and therapeutic relevance in a population with a longterm follow-up. Patients and methods: Between October 1990 and May 1997, 400 patients were monitored at the Epilepsy Monitoring Unit (EMU). Patients were screened at the epilepsy clinic, and a tentative diagnosis was made. After monitoring, diagnosis and therapy were reviewed. Post-monitoring seizure control was assessed. Results: 257 patients were referred for refractory epilepsy (presurgical candidates: n = 143). 145 patients were evaluated for attacks of uncertain origin. Mean duration of a single monitoring session was 4 days (range: 2–7 days). Prolonged interictal EEG was recorded in all and ictal EEG in 258 patients; on average, 3.6 episodes were recorded (range: 1–20). In total 929 episodes were recorded (outside day-time hours: n = 569). Pre-monitoring tentative seizure diagnosis was available in 341 patients, 238 of whom had clinical attacks. Pre-monitoring diagnosis was confirmed in 100 and changed in 29 patients. In 107 patients, diagnosis was specified. 184 patients were lost in follow-up and 8 patients died of an underlying disease. After monitoring, antiepileptic drugs (AED’s) were started in 19 patients, stopped in 6 and left unchanged in 114. The type of AED was changed in 110, while in 17 patients only dose(s) was changed. 60 patients underwent epilepsy surgery; surgical decisions are presently pending in 18 patients. Implantation of a vagus nerve stimulator (VNS) was performed in 11 patients and planned in 3. Average follow-up was 28 months (range: 6–80 months). In the non-invasively treated group in which follow-up was available (n = 129), 68 patients became seizure-free or experienced significant reduction in seizure frequency. In the same group, 47 patients had no change in seizure frequency. In the group of patients who underwent surgery and could be followed to date (n = 48), 29 became seizure-free and 16 experienced a significant improvement, while deterioration in seizure frequency did not occur. Out of 11 VNS-treated patients, 2 became seizure-free and 7 markedly improved. Outcome was unrelated to the availability of ictal video-EEG recording. Conclusions: Video-EEG monitoring proves important in assessing patients with refractory epilepsy and attacks of unknown origin. While prolonged interictal EEG monitoring has immediate therapeutic relevance, ictal registration is indispensible in patients enrolled for presurgical evaluation or suspected of having pseudoseizures.

P22 A RETROSPECTIVE ANALYSIS OF THERAPEUTIC EFFICACY OF VARIOUS MODALITIES IN STATUS EPILEPTICUS. P. Czapiñski, Kraków, Poland The study compared the efficacy of controlling status epilepticus in 120 patients treated employing three different modalities: 1) administration of diazepam (10 mg IV) and phenytoin (infusion of 15–18 mg/kg within 1 hour), n = 40; 2) administration of diazepam (10 mg IV) and phenobarbital (infusion of 10–20 mg/kg within 1 hour), n = 40; 3) administration of valproic acid (bolus of 15 mg/kg) and subsequently infusion of valproic acid (1 mg/kg/hr), n = 40. Therapeutic efficacy was measured as the number of successfully treated patients and as half-time determined from the moment of drug administration to the time of full seizure control. Halftime below 20 minutes was considered good, and within 20–30 minutes – satisfactory. Half-time above 30 minutes called for the use of alternative methods of status epilepticus control. The therapeutic results were correlated with the duration of status epilepticus prior to drug administration, its type and etiology. Therapeutic effects achieved in particular groups were comparable: therapeutic efficacy was noted in 34 patients from Group 1 (85%), 33 patients from Group 2 (82.5%) and 33 patients from Group 3

(82.5%). Mean half-time values were as follows: 22 minutes in Group 1, 18 minutes in Group 2, and 18 minutes in Group 3. In all the groups better results were achieved in controlling generalized seizures and poorer in partial simple seizures. Failures in controlling status epilepticus in all the groups were in 80% of the cases related to its etiology (poorer results in acute status epilepticus than in static status epilepticus) and to its duration prior to treatment initiation (the poorest prognosis was noted in patients with status epilepticus of more than 6-hour duration). The results of the analysis suggest a comparable efficiency of the employed methods of status epilepticus controlling (benzodiazepine + phenytoin and/or phenobarbital, and valproic acid employed as the sole drug). Therapeutic failures are related to the etiology of status epilepticus, its type and its duration prior to treatment institution.

P23 PARTIAL SEIZURES AND NON KETOTIC HYPERGLYCAEMIA. D. Hervé, J. M. Trocello, A. Améri, B. Bigorie, F. Chédru. Neurology Department, Centre Hospitalier de Meaux, France Two cases of focal seizures occuring during non ketotic hyperglycaemia are reported. In the first case, the patient was presenting complex seizures with versive movements toward the right side. The other patient had leftsided simple partial seizures of the sensory-motor type with a jacksonian progression, one of which occurred during an electroencephalogram recording, with a good EEG-clinical correlation (epileptiform discharges in the right hemisphere). The two patients had several seizures a day, each one lasting 1 to 3 minutes. CT scan and MRI were normal. Blood glucose on admission were respectively 19.5 and 22.3 mmol/l without ketonuria or acidosis. The calculated serum osmolarity was moderated high (305 and 309 mosm/l; normal = 280 ± 10). Hyperglycaemia was treated with IV insulin and hydratation until satisfactory glycaemic control was achieved. No further episodes occurred when, after 3–4 days, antiepileptic drugs (started on admission) were discontinued. In the second case, epilepsy revealed the diabetes. Focal epileptic seizures during non ketotic hyperglycemia are not exceptional. They continue, despite antiepileptic treatment, as long as the hyperglycaemia is not controlled. The occurrence of focal seizures in the elderly should suggest a diabetes mellitus decompensation. An early diagnosis could avoid progression to hyperosmolar coma.

P24 BACLOFEN IN THE TREATMENT OF MYOCLONUS IN UNVERRICHT LUNDBORG DISEASE. R. Gouider, A. Gargouri, M. Fredj, H. Saidi, F. El Bahri -Ben Mrad, A. Mrabet. Neurological Department. Eps Charles Nicolle. Tunis. Tunisia Baclofen was used by Awadh et al. (1995) in one patient with progressive myoclonus epilepsy with dramatic improvement of the myoclonus. For seven patients with Unverricht Lundborg disease who have a polytherapy with clonazepam, valproate and/or phenobarbital, we added progressively baclofen to a daily dose of 50 to 70 mg. A decrease in the myoclonus intensity and an improvement of functional ability was observed in six cases. No improvement was observed in one case. However In three cases baclofen was stopped due to side effects in one case and bad compliance in two. Our study confirms the case report of Awadh et al. and demonstrates the efficacy of baclofen in treating myoclonus in ULD.

P25 FOCAL EPILEPTIC SEIZURES IN PATIENTS WITH MODERATE HYPERGLYCEMIA. G. A. Tagaris, S. Giannakodimos, M. Grillia, V. Papadopoulou, P. Gavrielidou, K. Karageorgiou, Department of Neurology, Athens General Hospital, Athens, Greece We present three patients with focal epileptic seizures associated to moderate hyperglycemia. Two patients had recurrent episodes of focal motor seizures and one had visual seizures with an epileptic focus in the left occipital lobe. Blood glucose level was between 300 and 450 mg/dl; blood pH was within normal limits. Seizures were documented with ictal electroencephalogram and regressed with correction of the hyperglycemia with insulin. Brain CT scan did not reveal any abnormalities. In one patient, poor control of the blood glucose level induced a recurrence of the seizures despite the continuation of antiepileptic treatment. Focal epileptic seizures in adults may indicate poorly controlled diabetes mellitus. Possible pathogenic mechanisms are discussed.

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Child Neurology P27 EXCESSIVE PRODUCTION OF TNFα BY PERIPHERAL BLOOD MONONUCLEAR CELLS IN X-LINKED ADRENOLEUKODYSTROPHY. A. Lannuzel, P. Aubourg, C. Wallon, M. Tardieu. CHU de Pointeà-Pitre; Laboratoire “Virus, Neurone, Immunité”; Le Kremlin Bicêtre; INSERM U342, Hôpital Saint Vincent de Paul, Paris; France Objective: Analyze the in vitro production by peripheral blood mononuclear cells (PBMC) and the levels of various cytokines in serum and cerebrospinal fluid (CSF) in X-linked adrenoleukodystrophy (ALD) patients. Background: The presence of an inflammatory process at the active edge of demyelinating lesions of childhood cerebral ALD and the absence of correlation between the accumulation of very long chain fatty acid (VLCFA), the ALD gene mutations and the clinical phenotype have suggested a role of cytokines in the cerebral demyelination and phenotypic variations of ALD. Patients and Methods: 35 patients with different clinical forms of the ALD, followed up from 1990–91 up to 1996 at Hopital St Vincent de Paul, were included. Cytokines were measured by ELISA. Results: PBMC from 15 symptomatic ALD and 2/6 asymptomatic ALD patients produced higher levels of TNFα than controls after in vitro stimulation by lipopolysaccharide. At initial evaluation, the serum titer of TNFα of 12 ALD patients with cerebral demyelination, was higher than that of controls and of 6 ALD patients without cerebral demyelination. In a serial study of 15 patients over 2 to 5 years, the level of serum TNFα paralleled the progression of demyelination. CSF levels of TNFα were in normal ranges and production, serum and CSF levels of IL1α, IL1β, IL6, IL4, IL10 and INFγ were normal. Discussion: These data suggest that monocytes of ALD patients have an intrinsic alteration in the regulatory pathway of TNFα production which may play a direct role in the initial induction of demyelination. P28 HIGH INCIDENCE OF MENTAL RETARDATION IN DUCHENNE MUSCULAR DYSTROPHY PATIENTS DELETED IN THE DISTAL DOMAIN OF THE GENE: EFFECT OF UNEXPRESSED DP 140 APODYSTROPHIN? Felisari G, Martinelli F, Turconi AC, Salandi A, Bardoni A, Lai M, Robotti M, Comi GP, Bresolin N. IRCCS E. Medea, Bosisio Parini, IRCCS Ospedale Maggiore Policlinico Milan; Italy Cognitive impairment in Duchenne Muscular Dystrophy (DMD) represents a common feature of the clinical picture and many hypotheses have been formulated about its origin since gene and dystrophin discovery. Apo-dystrophin Dp140 is a recently isolated brain-specific fetal isoform coded in the distal part of the gene, commonly deleted in DMD, and its lack is supposed to account for intellectual impairment early in development. In order to test this hypothesis we reviewed 70 DMD patients referred to our Institute. General intelligence testing (Wechsler scale) was administered to 63 patients. All the subjects underwent lymphocyte DNA analysis by means of standardized PCR protocols. The detected macrodeletions were clustered in three domains: D1 spanning from promoter to exon 9, D2 from exon 10 to exon 44 and D3 from exon 45 to exon 60, thence including the critical region for Dp140 synthesis. Macrodeletions were found in 44 subjects and subdivided in two groups, the former mutated in D1 & 2, the latter in D3. Statistical comparison between Full IQ (FIQ) levels in the two groups resulted significant (p < 0.01) indicating a strong correlation between macrodeletions in D3 and cognitive impairment. In the mentally retarded group (15 boys) 14 spanned for deletion in D3. These data suggest that cognitive dysfunction depends upon the site of deletion and could be related to the absence of Dp140 apodystrophin. P29 A COMPLETE FUNCTIONAL INSTRUMENTAL ASSESSMENT FOR BOTULINUM TOXIN INJECTION IN CEREBRAL PALSY (C.P.). Turconi AC; Piccinini L; Motta F; Stefanoni G; Felisari G; Salandi A; Maghini C; Bresolin N. IRCSS “E. Medea” Bosisio Parini (Lc), H. Bassini Cinisello Balsamo Botulinum toxin type A has been used in the treatment of children with C.P. for the past 7 years. We studied effectiveness of injection of botulinum toxin in spasticity and in dynamic deformities. 20 patients aged 3 to 10 years were treated (8 haemiplegics, 8 diplegics, 4 quadriplegics). The dose used by our group was in the range of 2–5 I.U./kg body weight per muscle. Muscle treated were gastrocnemius in haemiplegics, and in 5 out of diplegics, hamstrings in 3 diplegics and in quadriplegics. Functional and instrumental assessment included: 1) Goniometric evaluation of joint

range of motion; 2) Gross Motor Functional Measure (GMFM); 3) Ashworth scale; 4) Gait Analysis; 5) Posturometry. Evaluation at 1–3–6 months showed improvement of gait pattern in timing and step length measured by gait analysis; goniometric evaluation showed an increase of passive ankle dorsiflexion of about 15 %. Posturometry showed a decrease of sway of about 15% with improvement of stability. Ashworth scale demonstrated a reduction of spasticity in about 40% of patients. In 30% of patients we observed an increase of the score in the standing and gait sections of GMFM. P30 DIFFERENT OUTCOME OF SEVERE TRAUMATIC BRAIN INJURY (TBI) IN DEVELOPMENTAL AND ADULT AGES. Castelli E, Poggi G, Bardoni A, Beretta E Objective: To identify whether indices of severe traumatic brain injury (TBI) in children and adults are related with early and late outcome. Background: TBI is the most common cause of acquired disability. Evaluation in children is complicated from contemporary development of motor, sensorial, cognitive functions and personality organization. Design/Methods: The relationship between patients’ clinical features, type and localization of lesions, EEG and evoked potentials recording and outcome was studied in 63 children and 51 adults with severe nonpenetrating TBI. Multidisciplinary assessment of clinical, neuropsycological and psychological features, CT scan – NMR, EEG and evoked potentials, Glasgow Outcome Scale (GOS), were performed 3 months, 1, 3 and 5 years after trauma. Results: 77% of children under 4 years of age sustained injury to other body regions. 61% of babies and toddlers had raised intracranial pressure. Frontotemporal lobes lesions are present in more than 75 % of cases independently from their age, whereas brainsteam damage is rarer at lower age. Neuropsychological assessment showed a higher impairment of cognitive functions at lower ages. Interestingly a statistically significant correlation was found between lower ages and these parameters: duration of coma, intracranial hypertension, subdural hemorrhages, brain atrophy, cognitive damage, post-traumatic epilepsy and GOS Score. Conclusions: From our data it’s clear that children under 4 years of age have a worse prognosis; however, long term follow-up and rehabilitation treatments can improve the late outcome, also in these cases. P31 DEXAMETHASONE-INDUCED HEPATOMEGALY IN THREE CHILDREN. Verrips A1, Rotteveel JJ1, Lippens R2. Department of Paediatric Neurology1 and Paediatric Oncology2, University Hospital Nijmegen, The Netherlands Dexamethasone is prescribed frequently for patients with neurological diseases. Dexamethasone-induced hepatomegaly sometimes occurs if high doses are administered. We investigated three children who received high doses of dexamethasone for different conditions: a six year old girl with a cerebral abscess, a four year old girl with a brainstem tumor, and a one year old boy who was operated on because of a tethered spinal cord. During this therapy, the two girls developed hepatomegaly with disturbance of liver function. The one year old boy developed hepatosplenomegaly without disturbance of liver function. In these three children the prognosis was good. Both liver size and function returned to normal after withdrawal of dexamethasone and replacement by (hydro)cortisone. Our observations were compared to previously published data. We conclude that if this condition occurs, dexamethasone should be stopped or replaced by cortisone. Therefore, extensive investigations for other causes of hepatopathy, including a liver biopsy, are not indicated. P32 FATAL ACUTE DISSEMINATED ENCEPHALOMENINGITIS (ADEM) IN A NEONATE. Jira PE1, Verrips A2, Wesseling P2, 3, Galama J4, Rotteveel JJ2, Merx H5, Semmekrot BA1. Department of Pediatrics 1, Pediatric Neurology 2, Pathology 3, Virology 4 and Radiology 5, University Hospital Nijmegen, The Netherlands We describe a three-weeks-old boy with a progressive subacute encephalopathy, resulting in coma, respiratory failure and death within two weeks. Cranial CT-scan showed diffuse supratentorial white matter hypodensity with preservation of the basal ganglia. Initially, he was treated with aciclovir. No corticosteroids were administered. Extensive examination of serum and cerebrospinal fluid (CSF) for bacterial, viral, fungal and parasitic etiology was non-revealing. Metabolic disorders were excluded. In the CSF, besides a high protein level, a high myelin basic protein level was found, suggestive for extensive demyelination. Autopsy of the CNS revealed se-

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vere brain oedema with dispersed necrosis and petechial haemorrhages. Perivascular lymphocytic infiltrates were present in both brain and leptomeninges. No viral inclusions were found. All viral and bacterial cultures of tissues obtained by autopsy including heart, liver, lung and brain were negative. PCR on brain tissue against herpes simplex virus (type I and II), human herpesvirus-6, varicella zoster virus, mycoplasma pneumoniae, and enterovirus showed no positive reaction. The clinical, laboratory, and pathological findings are consistent with the diagnosis acute disseminated encephalomyelitis (ADEM). To our knowledge, a neonatal ADEM with pathologic examination has never been reported. P33 OPERATIVE TREATMENT OF PES EQUINO-PLANUS-VALGUS FORMATION IN CHILDREN WITH CEREBRAL PALSY. A. Shchurovsky, O. Fabri. Regional Specialized Children’s Hospital, Lviv, Ukraine Pes equino-planus-valgus formation is common in children with cerebral palsy and makes up to 20% of all pes deformations. The hardest stage is the most complex for orthopaedic treatment because even bone surgery is not always effective. Fifteen patients, 7 to 14 years of age, with hard stage of pes-equino-planus-valgus formation underwent an operation of osteomyoplasty of the foot, as suggested by AM Zhuravlev (1991) in 1992–1997. In 3 patients the operation was performed in both foots. The operation consists of 4 stages: 1) bringing down the heel; 2) reduction of talus dislocation; 3) bringing the bone autograft in talus-calcanean joint; 4) transference of tendon of m. peroneus longus and the part of tendon of m. tibialis anterior and bringing them in the neck of talus. Follow-up results were studied in all patients 4 months to 5 years after surgery. The interrelation of foot bones was improved, and talus position was normalized. In 14 patients the arthrodesis of talus-calcanean joint took place. Conclusion: The osteomyoplasty eliminates each element of deformation and causes conditions impeding its reappearance. The results based on follow-up period investigation show better form and functioning of the foot in all patients. P34 IMMATURE DIENCEPHALIC TERATOMA DISCOVERED IN A FEMALE FOETUS. M. Catala, P. Sonigo, M.-C. Auvray, M.-C. Aubry, M. Bucourt. Service d’Histologie, Embryologie et Cytogénétique. Groupe Hospitalier Pitié-Salpêtrière. Paris. France A 35-year-old woman was referred at 18.5 weeks of gestation (WG) for a routine fetal echography which disclosed a huge heterogeneous intracranial tumour. Magnetic resonance imaging (MRI) was performed at 21 WG and showed a heterogeneous intracranial mass with both cystic and solid components. These features were highly suggestive of a teratoma. The pregnancy was terminated. The foetus was female with no visceral malformations. Neuropathological examination of the brain evidenced a very huge tumour adherent to the diencephalon. The rest of the brain appeared compressed with no macroscopic malformation. Microscopical examination of the tumour showed a combination of various tissues deriving from the three primordial layers. The major component was neural with immature neuroepithelial tissue and choroid plexus-like differentiation. Bronchial tissues were also observed as well as cartilage, smooth and striated muscle fibers. In conclusion, this tumour was an immature teratoma the development of which was prenatal. This observation is the first case of a prenatal teratoma for which a foetal MRI was performed during pregnancy. P35 PSEUDODEFICIENCIES IN LYSOSOMAL STORAGE DISORDERS: THE CASE OF β-D-MANNOSIDOSIS. G. Rodier, E. Cohen, P. Bronner, C. Junges, C. Boulay, S. Courtois. Mulhouse, France Inherited deficiency of lysosomal hydrolase often displays clinical expression. However, a greatly reduced enzyme activity may be observed in clinically healthy individuals who, in spite of having greatly reduced enzyme activity, remain clinically healthy. Such persons are said to have a “pseudodeficiency” of the concerned enzyme. To date, at least nine lysosomal hydrolases are involved in pseudodeficiencies. We present the first case of pseudodeficiency of β-D-mannosidase. The two males and one femal probands were the children of related parents of moroccan ancestry. The clinical presentation of our three patients was homogenous : mental retardation, facial dysmorphism, speech impairment and severe epileptic encephalopathy. The activities of different lysosomal enzymes were measured out. A severe deficiency of the β-mannosidase activity was found in two of the three patients and in their mother. β-mannosidase activity levels were slightly reduced (consistent with an heterozygote status) in the third

patient and the father. If the clinical presentation was markedly similar to that of previously reported cases of β-mannosidosis, the enzyme activity of the mother and the third patient failed to confirm the diagnosis of βmannosidosis and were rather consistent with a pseudodeficiency of βmannosidase. The presence of pseudodeficiencies may arise different problems. In the case of carrier screening, pseudodeficiency alleles may be a result of the assignement of carrier status. Of even more serious concern, is the possibility of an incorrect prenatal diagnosis of disease, due to the unrecognized presence of a pseudodeficiency allele. P36 ABNORMALITIES IN LONG-LATENCY COMPONENT OF SOMATOSENSORY EVOKED POTENTIALS (SEPS) IN CEREBRAL PALSY. L. Piccinini^; V. Scaioli*; G. Felisari^; A. C. Turconi^; A. Salandi^, Bresolin§. ^IRCCS E. Medea. Bosisio Parini (LC). *Istituto Neurologico “Besta”. Milano. §IRCCS Ospedale Maggiore Policlinico di Milano. Italy Short-latency SEPs have been previously investigated in neonatal children at high risk for development of Cerebral Palsy (C.P.). No survey has been so far performed to analyse SEPs pattern in older children focusing attention to long-latency components. We studied 6 male patients with a mean age of 7.6 years (S.D. = 3.5) affected by C.P. (4 left haemiplegic, 2 right haemiplegic). All patients underwent MRI and recording of nerve velocity conduction and somatosensory evoked potentials using E.E.G. electrodes caps. Peak and amplitude were evaluated for the components N9, N13, N20, N25, N30 and N37. Statistical analysis was performed to correlate latency and amplitude alterations with age and tallness. In parietal recordings, N20 showed normal mean latency, whereas in frontal recordings N30 showed an increased mean latency and a decreased mean amplitude. Patients affected by cerebral palsy do not present statistically significative alterations in nerve conduction and latency of cortical response within the parietal component (N20). An important delay in latency of cortical response within the frontal component (N30) has been found, thence we suppose a more significative involvement of the sensorimotor part of signal. SEPs can be an useful instrument to compare neurophysiological, neuroimaging and clinical data and predict functional outcome. P37 MEGALENCEPHALY WITH DIFFUSE WHITE MATTER SWELLING IN ADULTS WITH INFANTILE ONSET AND SLOWLY PROGRESSIVE COURSE. R. Blattner, W. Köhler, G. Hertel, Moabit Hospital, Berlin, Germany We describe three affected siblings without detectable biochemical defect who presented with megalencephaly, diffuse white matter swelling and similar neurological disturbances. The first born child of the non-consanguineous parents was most severely affected and died at the age of 23 years. The younger sisters were seen by our department at the age of 29 and 30 years. All suffered from progressive severe tetraparesis and disproportionately slower mental retardation. Epilepsy was present in two and dystonia in one of the siblings. Family history was otherwise unremarkable. MRI showed predominantly supracortical leukoencephalopathy with diffuse swelling and cysts. Megalencephalopathy and leukencephalopathy occur in some defined neurodegenerative disorders. Alexander disease was first diagnosed in the described cases, but rapid progression with early death is usual in this condition. Canavan disease, that presents with spongiform swelling of the white matter was ruled out biochemically as were other organic acid disorders and lysosomal defects such as mucopolysaccharidoses. Clinically there was no evidence for congenital muscular dystrophy. Few similar cases with megalencephalopathy and diffuse white matter swelling of unknown origin are published recently suggesting a new disease entity (Harbord et al. 1990, Van der Knaap et al. 1995). Our patients are among the oldest to be described with this condition. P38 CONTRIBUTION OF NUCLEAR MAGNETIC SPECTROSCOPY IN THE DIAGNOSIS OF INTRACRANIAL NEOPLASMS IN CHILDHOOD – TWO CASES REPORT. Ana Kelemen1, Ksenija Gebauer1, Ksenija Bozic1, Robert Semnic2, Danka Filipovic1. Department for Child Neurology; Institute of Neurology, Psychiatry and Mental Health1, Novi Sad, Yugoslavia. Institute of Oncology and Magnetic Resonance2, Sremska Kamenica, Yugoslavia The development of magnetic resonance spectroscopy (MRS) has become an important diagnostic tool in the differentiation of cerebral neoplasms in doubtful cases. Characteristic spectroscopic finding in tumours are: lack or

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decrease of the neuronal marker-N-acetylaspartate (NAA) and the markers of mobile energy depot – phosphocreatine and creatinine. On the other hand, the amounts of the biomembrane marker choline (cho) and the energy metabolism indicator – phosphor mono ester (PME) may be increased. We report two children with partial epilepsy caused by focal cerebral lesions which were initially by MRI diagnosed as low grade glomas according to their morphology. In both cases, the absence of afford mentioned spectroscopic findings rejected the MRI diagnosis, so the lesions were not removed surgically. In both our cases MRI follow up did not show any growth of the lesions. Both children responded well to antiepileptic drugs. MR spectroscopy as a non invasive method will hopefully be more available to inform us about biochemical processes in the brain and could possibly substitute invasive diagnostic procedures. P39 THE NEUROPSYCHOLOGY OF BILATERAL PERISYLVIAN POLYMICROGYRIA IN CHILDREN. D. Riva, V. Saletti & F. Nichelli. Milan, Italy In this study we report the neuropsychological findings of a family (mother and 2 sons), 2 twins (one normal) and 2 children with bilateral perisylvian polymicrogyria. The cerebral malformation is pure in 2 cases and in the others is present in a more complex malformative pattern. The patients underwent a neuropsychological assessment in the following areas: intelligence, language production and comprehension, memory and attention, visuo perceptual and grapho-motor abilities and practice functions, depending on the age. The results show an important variability in the intellectual performances and in the neuropsychological functionality in relation to severity and extension of the malformation. The expressive language (verbal and gestual) is always impaired. The neuropsychological deficits are related with the lesion site, confirming that also congenital brain structural changes, if sufficiently localized, produce specific focal deficit. P40 NEUROPSYCHOLOGICAL PERFORMANCES IN CHILDREN WITH SYMPTOMATIC AND PRE-SYMPTOMATIC X-LINKED ADRENOLEUKODYSTROPHY. Riva D and Bova S. Istituto Nazionale Neurologico C.Besta, Milano, Italy We tried to identify the signs of neuropsycological malfunctioning in presymptomatic and symptomatic children with X-linked adrenoleukodystrophy. For this purpose, six symptomatic and six pre-symptomatic children were assessed. All children had neurological examination, MRI, biochemical tests, EEG and Brain Evoked Potentials. A battery of neuropsychological tests to assess verbal and non-verbal intelligence, visual and auditory memory, visuo-perceptual abilities and object denomination was used. We found a dramatic difference between the affected children and the presymptomatic ones. The affected subjects showed an important global deterioration with a high variability of severity of deficits in the different tasks. All of them did very poorly only on denomination tests. The presymptomatic subjects mantained good intellectual abilities but showed intersubjects variability, with poor performances only on some isolated tasks. The results show that a specific pattern of neuropsychological malfunctioning does not exist, both in affected or in pre-symptomatic children. Longitudinal evaluations of larger samples are necessary to confirm our results. P41 CHILDHOOD DIABETIC NEUROPATHY: CLINICAL AND ELECTROPHYSIOLOGICAL STUDY. F. El Bahri-Ben Mrad*, R. Gouider*, M. Fredj*, Mrad-Mazigh**, A. Gargouri*, S. Ben Becher**, A. Mrabet*. *Neurological department. EPS Charles Nicolle. Tunis. Tunisia. **Hopital d’enfants. Tunis. Tunisia Clinical diabetic neuropathy in childhood is rare, however electrophysiological involvement of peripheral nerve is more frequent. We assessed clinically and electrophysiologically the peripheral nervous system in 69 children and adolescent suffering from diabetes mellitus (DM). The mean age of the patients was 12.8 years and the mean age at onset was 6.8 years with a mean duration of the DM of 6.3 years. Seven patients had clinical neuropathy (10%). Abolition of ankle jerk reflexes was the most frequent sign. Twenty patients (29%) had a neurophysiological neuropathy and lower limbs were mostly affected. Peripheral neuropathy was correlated to the age of patients, later age at onset, duration of DM, height and poor glycaemic control. In a subgroup of 13 patients conduction nerve velocities controlled after one year showed a significant decrease in peroneal motor nerve conduction velocity (–2.5 m/s).

P42 MULTIPLE SCLEROSIS IN CHILDREN – OVERVIEW OF 12 CASES. Siskova D, Hadac J. Prague, Czech Republic The authors describe the clinical, neurophysiological and magnetic resonance imaging (MRI) findings in 12 children with multiple sclerosis (MS) and specific diagnostic prroblems. Twelve children, 8 girls and 4 boys with diagnosis of MS have been followed up since 1992. The diagnosis is clinically definite laboratory supported (according to Poser’s criteria) in 10 cases, in 2 is clinically definite. The mean age at onset was 13 (7–16) years and the average number of attacks was 2.7 (1–6). The early symptomatology is reviewed (often brainstem and cerebellar, only in 1 case optic neuritis). All patients underwent cerebrospinal fluid (CSF) analysis, MRI examination, evoked potentials (EP) and fundoscopy. The results as well as some peculiarities (pleocytosis, tumor like lesions etc.) are presented. For the purposes of differential diagnosis virology examination, Borrelia garinii antibodies, metabolic examination (very long chain fatty acids, lactic acid etc) were completed. The therapy of attack as well as long term treatment (corticosteroids, azathioprin) and adverse events are discussed. Seven additional children are followed for clinically probable MS. P43 INFANTILE PURE HEREDITARY SPASTIC PAPAPLEGIA WITH UPPER LIMB AND BULBAR MUSCLE INVOLVEMENT. M. Di Capua, M. Mastrosimone, *O. Boespflug-Tanguy, E. Bertini. Division of Child Neurology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. *INSERM U 384, Clermont-Ferrand, France Uncomplicated or pure hereditary spastic paraplegia (pHSP) is generally characterized by progressive spasticity of the lower limbs with variable gait disturbance without clear evidence of corticobulbar tract and upper limb involvement. We report four cases, two sporadic and two sibs, affected by pHSP, who presented a severe pyramidal syndrome progressing to tetraplegia and anathria. Two male sibs are 13 and 8 years old and sporadic patients are a 20-year-old female and a male aged 19 years. The patients were all wheel-chair bound by the age of 10 years and around the age of 7–8 years they started to present bulbar muscle involvement with dysphagia and dysarthria and weakness with spasticity of upper limbs. In the second decade the disease progressed to anarthria and tetraplegia. There were no urinary or sensitive symptoms and the cognitive functions were normal. MRI showed the presence of spinal atrophy in two oldest cases. Cerebral MRI, metabolic studies and somatosensory evoked potentials were normal while motor evoked potentials were abnormal in all cases. In one sporadic case the parents were consanguineous. Our impression is that these cases represent a severe and unreported form of pHSP with autosomal recessive inheritance. Genetic studies are in progress to verify linkage to the pericentromeric region of chromosome 8. P44 PHYSICAL DEVELOPMENTAL PROFILE IS A PREDICTOR OF OTHER DEVELOPMENTAL PROBLEMS AND EPILEPSY IN CHILDREN WITH HEMIPLEGIC CEREBRAL PALSY. P. Singhi, S. Aggarwal, S. Katariya, P. Malhi. Departments of Pediatrics and Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India We studied prospectively comprehensive clinical and neurodevelopmental profile of hemiplegic cerebral palsy (CP) in 50 consecutive patients (boys: 35, girls: 15) upto 14 years of age; 80% were: 5 6 years. Detailed history, clinical examination, developmental profile (Alpern’s) cognitive and social assessment (Vineland Social Maturity Scale) and CT scdns were obtained in all. Hemiplegia was right sided in 58%, proportional (i.e. arm and leg affection equal) in 70%, predominance of either arm or leg in 30%. Mild motor impairment was seen in 48%, moderate in 36% and severe in 16%. Developmental profile of patients showed maximal delay in the physical age domain (50%); self help, social, academic and communication domains were affected in 14–28%. Those with normal physical age domain were normal in other domains. Impairment of cognitive functions was found in 30% of patients. Severity of motor impairment was significantly associated with mental retardation (SO: 580) (in mild impairment 16%, moderate – 28%, severe – 75%; p < 0.01). Overall disability showed a strong tendency to cluster. CT was normal in 20%; 80% had one or more abnormal findings – porencephalic cyst (n = 20), infarct (n = 11), unilateral ventriculomegaly (n = 19), periventricular leucomalacia (n = 6), cerebral atrophy (n = 19). Side of hemiplegia had no correlation with seizures or mental retardation. We conclude that severity of motor impairment is a reliable predictor of underlying seizure disorder, mental retardation and overall handicap in children with hemiplegic CP.

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P45 ACUTE MYELOPATHY IN ADULTHOOD AS A DELAYED CONSEQUENCE OF RADIATION DURING EARLY INFANCY. C. de Andrés, J. Romero*, and S. Giménez-Roldán. Departments of Neurology and Radiology*, Hospital General Universitario Gregorio Marañón, Madrid. Spain Both neural structures and surrounding non-nervous tissues may be damaged by the effects of radiation. Direct injury to cells of large and small vessels appear to be the most important mechanisms. The ultimate effect is narrowing or occlusion of vessels lumen, the clinical effects of which may be delayed for months or even years. We report a 28-year-old man with renovascular hypertensive disease who presented with legs weakness, sensory impairment, and faecal and urinary incontinence of acute onset. At the age of two years he had received deep radiation around the lower abdominal wall for treatment of a testicular tumour. An angiogram of the lower aorta demonstrated segmental narrowing of both renal arteries. In addition, MRI studies showed focal abnormalities in conus medullaris consistent with ischaemic infarction. The patient was given anticoagulation therapy. The 26-year-interval between radiation and spinal cord injury, so far one of the longest ever reported, stresses the difficulties of establishing a prognosis following spinal cord radiation, even in patients with extremely long asyntomatic intervals.

Higher Functions Disorders P46 RECIPROCAL INHIBITORY VISUAL-VESTIBULAR INTERACTION: VISUAL MOTION STIMULATION DEACTIVATES THE PARIETOINSULAR VESTIBULAR CORTEX (PET STUDY). Th. Brandt1, P. Bartenstein2, A. Janek2, M. Dieterich1. Departments Of Neurology1, LudwigMaximilians-University Munich, And Nuclear Medicine2, Technical University Munich, Germany The vestibular system – a sensor of head accelerations – cannot detect motion at constant velocity and thus requires supplementary visual information. The perception of self-motion during constant velocity is completely dependent on visually induced vection (e.g., circularvection, CV). CV is induced by large-field visual motion stimulation during which the subject perceives the actually moving surroundings as being stable, while he is being moved. Hitherto, CV was explained neurophysiologically by visualvestibular con-vergence with activation of the vestibular nuclei, thalamic subnuclei, and the vestibular cortex. To determine the unknown cortical visual-vestibular interaction during CV, we conducted a PET activation study in 10 human volunteers. The PET images of activated cortical areas during motion stimulation without CV were compared to those with CV. If CV were mediated by the vestibular cortex, one would expect that an adequate visual motion stimulation would activate both the visual and the vestibular cortex. Contrary to this expectati-on, however, we show for the first time that visual motion stimulation with CV not only bilaterally activates a medial parieto-occipital visual area separate from MT/MST, but significantly deactivates the parieto-insular vestibular cortex. This finding supports a new functional interpretation: reciprocal inhibitory visualvestibular interaction as a sensorimotor mechanism that protects visual perception of self-motion from potential vestibular mismatches caused by involuntary head accelerations during locomotion. This mechanism allows the dominant sensorial weight during self-motion perception to shift from one sensory modality to the other. P47 PERCEPTUAL AND SEMANTIC PRIMING IN ALZHEIMER’S DISEASE (AD) AND PARKINSON’S DISEASE (PD). S. Pomati, E. Imbornone, E. Magni, E. Farina, G. Gattellaro, and C. Mariani. Neurorehabilitation Unit, Don Gnocchi Foundation, University of Milan, Italy Priming in AD and PD is still a matter of debate. So far, literature data indicate that AD patients show a more preserved effect in perceptive than in semantic tasks. In PD patients, both normal and defective perceptual identification priming, and hyperpriming in a lexical decision task have been reported. We studied the variables influencing perceptual and semantic priming in AD and PD using a word identification task. Methods: In 17 AD patients, 8 PD patients and 16 controls, matched for age and education, the time necessary to read 40 pseudo-words and 40 words presented on a computer screen for an increasing length of time was assessed. In a previous study section, the subjects had been allowed to read half of the items. The colour of the items was employed as a pure perceptual variable. Results: We found a significant priming effect in all the three groups for

words (paired samples t-test: .1723 ± .092 seconds employed to read words unstudied versus .1557 ± .109, studied, p < .05 in AD; .1450 ± .058 versus .1259 ± .042, p < .05 in PD; .1280 ± .074 versus .1081 ± .066, p < .001 in controls), while only in AD and controls the effect was present for pseudo-words (.3262 ± .140 versus 2935 ± .144, p < .05, in AD; .2313 ± .109 versus .2028 ± .110, p < .005, in controls). In AD we observed a significant effect of colour for words (.1621 ± .102, same, versus .2935 ± .144, changed colour, p < .05). Discussion: Our results confirm the existence of perceptual priming in AD, an effect probably due to sparing of primary sensory areas. The absence of a perceptual priming effect in PD patients could be attributed to dysfunction of neostriatum, which seems to play a role in the incremental learning characteristic of automatic learning. Preserved priming effect for words could indicate a role for the semantic repertoire in this kind of processing or alternatively a conscious recollection of the stimuli besides the automatic recognition. P48 NATURAL HISTORY OF A FRENCH GERSTMANN-STRÄUSSLERSCHEINKER FAMILY: IMMUNOHISTOCHEMICAL AND MOLECULAR GENETIC STUDIES. Destée A (1), El Hachimi KH (2), Laplanche JL (3), Durieu I (1), Delasnerie-Laupretre N (4), Launay JM (3), Foncin JF (2). (1) Service de Neurologie, CHRU Lille, (2) EPHE Neurohistologie and INSERM U106, Hôpital de la Salpétrière, (3) Service de Biochimie, Hôpital Lariboisière, Paris, (4) INSERM U360, Hôpital de la Salpétrière. France The individuality of Gertsmann-Sträussler-Scheinker disease (GSS) among spongiform encephalopathies is questionable. A number of mutations of PRNP gene are associated with GSS as well as with other heritable spongiform encephalopathies, notably Creutzfeldt-Jakob disease (CJD), and there is overlap between the clinical and neuropathological signs of both diseases. Particularly, the “new form” V-CJD recently described in Great-Britain (1) shows similarities to GSS as observed in a family originating in northern France (2). 10 persons are now known to be affected in 5 generations, 7 female and 3 male. The mean age of onset was 29 years, range 24–34. Ataxia was the first symptom in well-observed cases. Psychiatric-like symptoms caused the hospitalisation of 4 patients in psychiatric institutions under various diagnoses. Dementia occurred progressively and late in the evolution. Total course was 7 years in the proband. Histological and immunohistochemical studies were done on autopsy material from the proband (2). Briefly, classical neuropathology was characterized by lesions of the cerebellar cortex: the molecular layer was moderately atrophied and gliotic. It showed Kuru plaques and a few multicentric plaques, without neuritic component. Ultrastructural study showed uni or multicentric plaques made of radiating amyloid fibrillary bundles. At the immunohistochemistry level, plaques were selectively immunostained with antiPrP and were located throughout the molecular layer of the cerebellar cortex. Numerous anti-PrP immunostained plaques, mostly multicentric, were also observed in the frontal and temporal cortex. GFAP immunoreactivity was intense. Spongiosis was not prominent and was practically limited to the periphery of plaques. Molecular biology studies were performed on DNA obtained from living collaterals of the proband. They showed an 192 bp insert (eight repeats of 24 bp) in the octapeptide coding region associated with the met polymorphism at codon 129. (1) Will et al. Lancet, 347 : 921–925. 1996. (2) Foncin et al. Rev. Neurol, 138 : 123–135. 1982. P49 ASSESSMENT OF NEUROBEHAVIORAL IMPAIRMENTS AFTER TRAUMATIC BRAIN INJURY BY THE CLINICIAN : INTERRATER RELIABILITY AND CONSTRUCT VALIDITY OF THE REVISED NEUROBEHAVIORAL RATING SCALE. Mazaux JM*, Vanier M**, Lambert J**, Dassa C**, Levin HS***. *Bordeaux, France. **Montreal, Canada. ***Houston, USA Assessment of neurobehavioral impairments after traumatic brain injury (TBI) in context of clinical practise is difficult and controversial. The Neurobehavioral Rating Scale (NRS) has been developed in 1987 by Levin and associates to provide the clinician with a brief though comprehensive and specifically-designed for TBI patients assessment tool. The NRS consisted of 27 items scored according to a semi-structured interview. From 1990 to 1994 the Scale was revised in order to improve its reliability and make its rating easier and more sensitive. In this study we report on the interrater reliability and content validity of the Revised NRS. 286 patients aged 16 to 68 years refereed from 17 French hospitals were included in the validity study. Five per cent of the patients in sample suffered a mild TBI, 15% a moderate and 80% a severe TBI. A subset of 70 patients were randomly selected for the reliability study. Three ratings of video recordings were

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provided for each of these patients by three independent examinators blind from each others opinion. The results of the reliability study for items were very good. The percentages of agreement among the items varied from 47.1% to 92.8% (average 73.6%). The kappa statistics varied from 0.22 (item: Difficulty in planning) to 0.77 (item: Memory difficulties), with an average of 0.43. Exploratory factor analyses and orthogonal (varimax) and correlated (Oblimin) rotations were undertaken to identify the latent concepts of the Scale; they disclosed as best result a maximum likelihood extraction of five factors explaining 42.2% of the total variance. They were: (F1) Deficits in intentional behaviours and in memory, (F2) Lowering of emotional states, (F3) Emotional and behavioural hyperactivation, (F4) Lowering of arousal state and of attention, (F5) Speech and language problems. The reliability of these factors scores were found excellent. Statistical relationships between the factors and individual data were studied by mean of analysis of variance methods and regression techniques, and supported the concurrent validity of the factors. As a whole, the study confirms the clinical utility of the Revised NRS as a brief, reliable and valid screening instrument for TBI patients. P50 TEMPORO-SPATIAL WORKING MEMORY IN PATIENTS WITH PREFRONTAL AND STRIATAL LESIONS. M. Verin Objective. To investigate in human the involvement of the prefrontal cortex and the basal ganglia in temporo-spatial working memory. Background. Involvement of prefronto-striatal loops in Spatial Delayed Response paradigm has been recently demonstrated in human by our group. The respective role of spatial and temporal parameters remains to be determined. Design/Methods. We tested the involvement of the associative areas of the prefrontal cortex and the basal ganglia in the integration of both temporal and spatial coordinates of internal representations of environmental informations. A set of sequencing tasks was designed which incorporate the dissociation of (1) spatial and temporal parameters, (2) recall and recognition processes, and (3) analyses of the role of the delay. Performance of patients with prefrontal lesions (n = 8) and patients with striatal dysfunction (progressive supranuclear palsy, n = 13; and Parkinson’s disease, n = 12) was compared to that of a healthy control group, (n = 12). Results. In the spatial and the temporo-spatial recall tasks, the effect of the delay was significant in all the patient groups, whereas in the temporal recall task, the delay effect was evident only in the two groups with striatal dysfunction. Conclusion. These results in man confirm: 1) the role of the prefrontal cortex and the striatum in the processing of spatial informations during a delay and, consequently, in behavioral planning; 2) the implication of the striatum in the processing of temporal informations during a delay and, consequently, in the temporal structuring of spatial items and motor sequencing. P51 MODULARITY OF THE CONTROL FUNCTIONS OF THE PREFRONTAL CORTEX? O. Godefroy, J. P. Pruvo and M. Rousseaux (Lille, France) Lesions of the prefrontal cortex result in a wide variety of neuropsychological disorders but the possible unity of frontal control processes remains unsettled. This study assessed control processes operating in novel, conflicting and combined tasks in patients with focal lesion. The study group included patents with postaneurysmal frontal (n = 10) and vascular posterior (n =7) brain damage, and matched controls (n = g). Experiments used two-choice reaction time tests with similar stimuli, response mode and basic decision processes requiring to (1) perform novel decision, (2) combine two choice tasks previously performed in a single condition and (3) to transiently inhibit responses. It mainly showed (1) impairment of novel decision in the frontal group (p < 0.005), and (2) impairment of response inhibition (n = 2) and tasks combination (n = 2) in some frontal patients, (3) with the association of novelty and inhibition disorder being the most specific and sensitive criterion of frontal damage (p < 0.001). In addition, selective deficits with double dissociations were evidenced on novel, conflicting and combined tasks. This study provides additional evidence for the prominent role of the frontal lobes in control processes and demonstrated selective deficits of control processes suggesting that the frontal control functions depend upon different systems. Thus these results strongly support the need for subdividing the frontal syndrome in several syndromes. P52 CREUTZFELDT-JAKOB DISEASE: NEUROPATHOLOGICAL FINDINGS IN RETINA. J. de Seze, C. A. Maurage, C. F. Arndt, P. Vermersch, F. Pasquier, M. M. Ruchoux, A. Destée, J. C. Hache. Lille (France)

Recently, we described (de Seze et al., J Neurol 1997; 244 : S91) the interest of the electroretinogram (ERG) in the early diagnosis of Creutzfeldt-Jakob disease (CJD). However pathological examination of retina had been performed in a very few cases of CJD. Aim of the study: To report the neuropathological findings in the retina of 3 CJD patients with abnormal ERG. Methods: In 3 patients with definite CJD we studied retinal pathological findings. ERG of these patients showed a typical ERG impairement (b-wave and b/a ratio decreases with a-wave preservation). Results: Inner and outer photoreceptor segments were well preserved. Vacuolizations were located in the outer plexiform layer and Muller cells appeared to be swollen. Conclusion: The ERG abnormalities are well correlated to the neuropathological findings. The vacuolization of the outer plexiform layer without photoreceptor destruction confirms the importance of the neuroretinal impairment in CJD as well showed by the b-wave decrease and a-wave preservation. P53 A LEFT CEREBRAL BRAIN LESION CAUSING LEFT-SIDED NEGLECT DYSLEXIA. Slachevsky A1, 2; Bakchine S1; Guillaume S1; HenryAmar F1. 1Fédération de Neurologie, Hôpital Pitié-Salpétrière, Paris, France; 2Servicio de Neurologia, Hospital del Salvador, Santiago, Chile There are only a few reports of a left lesion causing a left-sided neglect dyslexia. The mechanism of such a disorder remains controversial. We will thus discuss the mechanism of neglect dyslexia in the context of previous case reports for a better understanding of this form of neglect dyslexia. We report the case of a 72 year old, left-handed woman who presented with a visual disturbance and an aphasia (anomia and semantic paraphasias), following a ischemic stroke. The main clinical feature was a prominent reading difficulty with failure to identify the beginning of words A full neuropsychological evaluation was undertaken. The absence of visuospatial neglect was demonstrated. However, in the reaction time task, she was slower to detect a stimulus on the right than on the left. A specific investigation focusing on this aspect of reading disorders showed 43% of errors in the reading of numbers (omission or substitution of the first number), 16% of errors in the reading of words (60% of which consisted of substitutions of the first letter) and 70% of errors in reading of non-words (60% of which consisted of substitutions of the first letter). Conclusions: This case is remarkable because of the presence of a left lesion causing a left-sided neglect dyslexia without a visuospatial neglect. The current theories on positional neglect dyslexia and neglect dyslexia are insufficient to explain the observations noted in the present case. However, theories on object representation may allow one to better understand this type of dyslexia. P54 SENSORY MONITORING DIFFERENTIALLY AFFECTS MOVEMENT SLOWNESS IN PARKINSON’S (PD) AND ALZHEIMER’S DISEASE (AD). M. Alberoni, M. F. Ghilardi, M. Rossi, N. Del Grosso, M. Franceschi, C. Mariani, F. Fazio. IRCCS S. Maria Nascente, INB CNR, H. S. Raffaele, Univ. Milano; Ist. Fisiologia, Univ. Ferrara, Italy We have previously shown that reaching movements of AD patients show abnormally increased duration. Here we compare AD motor slowness to parkinsonian bradykinesia. Subjects were: 16 PD patients (H & Y stage: 1–11) with bradykinesia as main sign and no cognitive impairment; 23 AD patients (mild to moderate) without extrapyramidal involvement; 20 normally aging control subjects. All subjects were instructed to make, when ready, single, uncorrected movements, as.fast and as accurate as possible by moving a cursor on a digitizing tablet without seeing their limb. Target and starting locations were always visible on a screen, while during movement cursor position was either visible (FB) or blanked (NoFB). With FB, prolonged movement times were found in AD vs PD ( p < 0.001), AD vs controls ( p < 0.001) and PD vs controls ( p = 0.0371). Extent covered by the transport phase was: 96.6 ± 2.5% in controls, 84.5±7.8% in PD and 75.1 ± 11.7% in AD. For NoFB, significant slowness and fragmented asymetrical velocity profiles were found in AD only. We conclude that: 1) movement slowness in AD results from impairment in feedforward mechanisms and, thus, from their substitution with continuous sensory monitoring of the moving hand; 2) feed-forward commands are preserved in our PD patients and can be used to minimize bradykinesia, which was detectable only when visual FB was available. P55 VALUE OF DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGE IN CREUTZFELDT-JAKOB DISEASE. H. A. Kretzschmar1, Stefan Kropp1, Michael Finkenstaedt2, Christoph Laske1, Walter Schulz-Schaeffer3, Inga Zerr1, Sigrid Poser1. Departments of Neurology1, Neuroradiology2 and Neuropathology3, Georg-August-University Goettingen, D-37075 Germany

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The definite diagnosis of Creutzfeldt-Jakob disease (CJD) depends on the neuropathological examination of brain tissue of suspected cases, obtained either by biopsy or autopsy. MRI is helpful to substantiate the diagnosis of CJD noninvasivly. In a recent study T2- and proton density-weighted magnetic resonance images showed high signal intensity changes in the basal ganglia (BG) in about 80% of CJD patients. We evaluated diffusionweighted images (DWI) in five patients with suspected CJD. DWI showed high signal abnormalities in the cortex as well as in basal ganglia in all cases. Two of these cases has been confirmed CJD by autopsy, the three remaining patients are still alive. The signal abnormalities of the cortical gray matter were more obvious in the diffusion-weighted images compared with the standard T2- and proton density-weighted studies. Because the aquisition time for the DWI is only four seconds, there were less motion artifacts compared to the standard sequences. In our experience, DWI studies are the most sensitive and fastest sequence to evaluate a patient with suspected CJD. P56 MEDIAL TEMPORAL ATROPHY, CT AND SPECT ASYMMETRY IN FRONTOTEMPORAL DEMENTIA. Lavenu I, Pasquier F, Jacob B, Lebert F, Petit H. Centre de la Mémoire. Clinique Neurologique. CHRU Lille. France Frontotemporal dementia (DFT) is a clinical syndrome corresponding to several histological syndromes including Pick’s disease so far it is not possible to distinguish clinically the different histological syndrome. However, a severe asymmetrical lobar atrophy with amnesic syndrome might predict Pick’s disease. To look for a link between asymmetric frontal or temporal lobar degeneration on CT and on SPECT and a medial temporal lobe atrophy (MTLA). SPECT and CT were performed in 20 DFT patients. A consistent asymmetry in SPECT and CT was shown in 3 patients. No asymmetry both on CT and SPECT was found in 10 patients. In 7 patients SPECT and CT data were inconsistent: asymmetrical atrophy with no uptake decrease (n = 2), asymmetrical uptake decrease without atrophy (n = 4), left > right uptake decrease and right > left atrophy (n = 1). In patients with MTLA (n = 5), data on SPECT and CT were always consistent: degeneration was asymmetrical in 3 and symmetrical in 2. These findings show that SPECT and CT data are not always consistent in DFT as well as in Alzheimer’s disease. However the combinaison of asymmetrical abnormalities both in SPECT and CT scan and MTLA and severe amnesic syndrome might predict Pick’s disease. P57 ROLE OF AGE, SEX AND EDUCATIONAL LEVEL IN PERCEPTION OF EMOTION. Lavenu I, Pasquier F, Lebert F, Henri Petit. Centre de la Mémoire. Clinique Neurologique. CHRU Lille. France Many studies try to find what are the nervous substrates of emotion which processing is impaired in many psychiatric and neurologic disorders. The aim of our study was to look for the influence of the age, the sex and the level of education of normal subjects on the perception of emotion. Subjects and methods: 56 subjects were enrolled in the study: 28 men and 28 women from 18 to 49 years (mean 29 years) and level of education: < 8 years of education (n = 7), > 8 years of education < 12 (n = 22) and > 12 years of education (n = 27). Subjects had to recognize and to point on a card which name of the seven fundamental emotion (anger, disgust, happiness, fear, sadness, surprise and contempt) corresponds to the facial expression shown on a set of 28 faces. Results: Men and women did not differ for the detection of an emotion that is the fact that a face with an emotion can be distinguished from a face without emotion (neutral). Subjects with highest level of education better recognized fear (F = 6.021, p = 0.0044) and surprise (F = 4.011, p = 0.0239). Performances decrease with age (r = – 0.264, p = 0.0435). Comments: The ability to recognize emotion depends on the educational level and decrease with age. P58 FATAL FAMILIAL INSOMNIA: THE GERMAN CASES. I. Zerr1, A. Giese2, O. Windl2, W. Schulz-Schaeffer2, S. Kropp1, C. Riedemann1, C. Laske1, H. A. Kretzschmar2, S. Poser1. 1Dep. of Neurology, 2Dep. of Neuropathology, Georg-August-University, Goettingen, Germany Fatal familial insomnia (FFI), a recently described rare prion disease, is associated with an aspartatic acid to asparagine mutation at codon 178 of PRNP and methionine at codon 129 (D178N-129M). Untreatable insomnia and dysautonomia followed by progressive neurological disorder were reported to be the typical manifestation, the selective degeneration of thalamic nuclei is the predominant pathological hallmark. Here we report the

clinical and pathological features of FFI cases in Germany. FFI cases were identified in the German Creutzfeldt-Jakob (CJD) surveillance between 1993 and 1997. The constellation D178N-129M was identified in 8 individuals. Three affected men and five women belong to seven unrelated families. A family history of a neurodegenerative disorder was recalled only in 4 patients. In contrast to the first reported FFI case, none of our patients complained of severe insomnia in the early stages. Dysautonomia was observed in varying degrees in most patients. The clinical course of these patients resembled sporadic CJD according to the criteria. In one case the neuropathological examination showed changes that were more reminiscent of forms of sporadic CJD, in the remaining four the histopathology was typical of FFI. The clinical picture in patients with FFI may vary to a great extend. Genotyping of the patients was crucial in providing laboratory confirmation of the diagnosis of FFI, even if there was no family history of prion diseases. P59 STUDYING CONTROLLED LANGUAGE PROCESSING IN BILINGUALS WITH fMRI. P. Calabrese1, H. F. Durwen1, A. Falk2, L. Heuser2 and W. Gehlen1. 1Dept. of Neurology Knappschaftskrankenhaus), University of Bochum, Germany. 2Inst. of Radiology (Knappschaftskrankenhaus), University of Bochum, Germany While there is enough clinical evidence for a left-hemispheric predominance of linguistic processing at least for the native language there is only scarce support concerning the anatomical organization of a language acquired later in life.The aim of our investigation was to study the anatomical implementation of a second language in normal volunteers by functional MRI using a standard verbal fluency paradigm. We therefore studied altogether 5 healthy right-handed adult volunteers of Russian decent. The subjects had to generate words subvocally according to a given category in German (1st condition, second language) as well as in Russian (2nd condition, first language). The activation patterns were recorded using a conventional Siemens Vision MRI scanner of 1.5 Tesla, with TR of 1.68 ms, TE of 64 ms, FOV of 220 mm and a Matrix of 114*128. All investigations were done with a circularily polarized head coil and using the EPI technique realizing a total of 14 slices at one time. Results and conclusion: In both conditions we could demonstrate a predominantly left-sided temporoparietal activity. In addition to this, it was also possible to demonstrate a particular activation of the right prefrontal region in the german-languagecondition. We conclude from these findings that effortful processing of a subsequently acquired language requires more – frontal lobe mediated – organizational guidance (“working memory”). P60 APOLIPOPROTEIN E GENOTYPE AND THE RATE OF CLINICAL PROGRESSION IN PATIENTS WITH PROBABLE ALZHEIMER’S DISEASE. A. Pfeffer, K. Czyzewski, M. Golêbiowski, E. Kida, M. Barcikowska, Warsaw, Poland Many studies have demonstrated an association between the apolipoprotein E (apoE) ε4 allele and Alzheimer’s disease (AD). Inheritance of the apoE ε4, a genetic risk factor for developing AD is associated with earlier onset of dementia and can be expected to influence progression of the disease, i.e. a more rapid decline. The aim of this study was to determine whether apoE genotypes can influence the rate of cognitive decline in AD. ApoE genotypes were identified in 54 persons with clinically diagnosed probable AD. Patients were divided into two groups, those without and with at least one apoE ε4 allele. We determined the rate of disease progression by using Mini-Mental State Examination (MMSE) and Global Deterioration Scale (GDS) in 45 patients (16 men and 29 women) who were followed up longitudinally for 2 years. Statistically significant differences were exclusively observed among women between ε4 allele carriers and not-carriers regarding measures of cognitive decline. The females without apoE ε4 alleles progressed more rapidly (6.0 points per year on the MMSE, –0.85 points per year on the GDS). The rate of decline for females with other genotypes was slower, at 0.92 points per year on MMSE and –0.5 points on GDS ( p < 0,01 and p < 0,05 respectively). We suggest that apoE ε4 allele is not associated with a more rapid course of AD, and in female AD patients it may even indicate a better prognosis. P62 INDUCTION OF TNFα BY β-AMYLOID PEPTIDE MEDIATES MACROPHAGE NITRIC OXIDE PRODUCTION. M. Huberman*, B. Sredni^, F. Shalit^. *Department of Neurology, Meir Hospital, Kfar Saba, Israel. ^C.A.I.R. Institute, Department of Life Sciences, Bar Ilan University, Ramat Gan, Israel

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Amyloid β peptide (βA4) is the major proteinaceous component of the amyloid plaques found in the brains of Alzheimer’s Disease (AD) patients. Recent studies show that βA4 is responsible for activation of microglia cells in vivo. The neurotoxicity of βA4 has been attributed, in part, to the induction of nitric oxide (NO) production. In this study we investigated the mechanism by which βA4 induces NO production. For this purpose we used the murine-derived monocyte/macrophage S774 cell line. βA4 induces the secretion of tumor necrosis factor-α (TNFα) in these cells in a dose-dependent manner. Incubation of cells with βA4 slightly increased nitric oxide (NO) production, which effect was further enhanced by the addition of interferon-γ (IFNγ). Substitution of βA4 with TNFα and incubation of the cultures with IFNγ resulted in significant NO production, although lower than that obtained in the presence of the peptide. Incubation of cultures with a monoclonal antibody (mAB) against TNFα abrogated NO production. Our results suggest that βA4-induced TNFα production is a crucial event in the activation of peripheral macrophages, which then mediate neuronal cell injury via a NO mechanism. Analogously, βA4 might play a key regulatory role in the induction of NO secretion by microglia, thereby aggravating neurodegenerative processes accompanying Alzheimer’s disease.

P63 POLYMORPHISM IN THE REGULATORY REGION OF GENE APOLIPOPROTEIN E (APOE) AND CLINICAL EXPRESSION IN ALZHEIMER’S DISEASE. A. Frank; B. Yagüe; F. Valdivieso*; M. J. Bullido*; E. Díez-Tejedor; P. Barreiro. Department Neurology. Hospital Universitario “La Paz” Universidad Autónoma de Madrid and *Department of Molecular Genetics Severo Ochoa, Universidad Autónoma de Madrid, Spain A new polymorphism in the regulatory region of the APOE gene has been recently described and the homozygosity of the common variant (– 419A) seems to be associated with increased risk of developing late-onset Alzheimer’s disease (AD), independently of the APOE genotype. Patients/ Methods: To assess if this new polymorphism influences not only in the risk of developing AD, but also on the expression and severity of the cognitive impairment, we have analyzed its relation with neuropsychological tests in a series of 62 late-onset AD patients. Statistical analysis (Student’s t, χ2 and ANOVA) was done. Results: The frequency of – 419AA in the whole series was 74%. Percentajes of – 419AA for each APOE genotype group were similar (APOE 4.4 = 80%; APOE 3.4 = 71%; APOE 3.3 = 75%) (NS). No statistical differences were found in memory tests, picture recognition, Folstein’s Mental State Examination, Blessed’s scale and CDR severity scale between homozygotic and non-homozygotic – 419A late-onset AD patients. Conclusions: These results indicate that the new polymorphism seems not to exert relevant influence on the clinical expression of the cognitive impairmet in late-onset Alzheimer’s disease.

P64 RAPID ONSET DEMENTIA IN PATIENTS WITH MICROSCOPIC POLYANGIITIS. Capra R, Gregorini G, Mattioli F, Santostefano M, Galluzzi S. Dpt. of Neurology and Nephrology, University of Brescia, Italy The real incidence of CNS involvement in systemic vasculitis is largely unknown and a direct aggression to the CNS small vessels must be differentiated from its general involvement due to metabolic (renal and pulmonary) failure or to degenerative atherosclerotic disease. Of a large series of 122 patients harboring an ANCA+ vasculitis, 29 were diagnosed as having a Wegener Granulomatosis and 91 a Microscopic Poliangitis Rapidly Progressive Glomerulonephritis. Among these patients, 11 (9 females, 3 males, mean age 75 years), who were referred to be fully active and independent before the onset of the disease, exhibited during the acute phase of the systemic vasculitis, a rapidly developing severe dementing illness (Barthel index ranging from 0 to 45, IADL = 0) without focal signs. The neurological examination showed also a peripheral involvement in all the patients and extrapiramidal signs in two. CT scan revealed leukoaraiosis in all but three patients, who had multiple infarcts. All the patients were submitted to immunosuppressive therapy with steroid and cyclophosphamide for 18 months. At the end of therapy five were died (two due to uraemia, three to cardiac arrest), one partially improved but was admitted to hemodialytic treatment. The remaining dramatically improved both in the systemic and the cognitive disease, gaining functional indexes similar to the premorbid ones. The characteristic of a rapidly developing and possibly reversible dementia suggest a major role of a direct small vessels involvement in the CNS in the genesis of the brain organic syndrome.

P65 MELANOCORTIN PEPTIDES INHIBIT PRODUCTION OF NITRIC OXIDE BY B-AMYLOID ACTIVATED MICROGLIA. D. Galimberti, P. L. Baron, L. Meda, E. Prat, P. Agazzi, M. Raimondi, G. Ardolino, G. Conti, E. Scarpini and G. Scarlato. University of Milan, IRCCS Policlinico, Milan, Italy α-Melanocyte stimulating hormone is an ancient tridecapeptide (α-MSH [1–13]) with potent inhibitory activity in all major forms of inflammation. The antiinflammatory message sequence of α-MSH[1–13] resides in the COOH-terminal tripeptide α-MSH[11–13]. Previous studies have shown that amyloid-β (Aβ) peptides trigger production of proinflammatory mediators by cultured microglia, suggesting that Aβ/microglia interaction may play a role in the pathogenesis of senile plaques in Alzheimer’s disease (AD). We tested the effects of α-MSH[1–13] and of α-MSH[11–13] on production of nitric oxide (NO2–) in cultured murine microglia stimulated with Aβ[1–42] or Aβ[25–35]. Release of NO2– in cell free supernatants was determined by Griess reagent whereas mRNA expression of inducible Nitric Oxide Synthase (iNOS) was examined by Northern blots. In Aβactivated microglia, α-MSH[1–13] as well as α-MSH[11–13] significantly inhibited production of NO2– and of iNOS mRNA. Our study demonstrates that melanocortin peptides inhibit production of NO2– from Aβ-activated microglia. These data, together with the finding of reduced levels of αMSH in the CSF of AD patients (Rainero et al. 1988), suggest that impairment of endogenous α-MSH might promote the progression of neurodegenerative and inflammatory changes in senile plaques of AD brain. P66 PROGRESSIVE VERBAL DEAFNESS: A RARE NEURODEGENERATIVE DISORDER. Ivan Mari, Jean-Luc Houeto, Gael Gallouedec, Serge Bakchine et Marie Vidailhet Progressive focal cortical atrophies have recently been described as a rare forme of neurodegenerative disorders, the “focal dementias”. The most frequent forms are the fronto-temporal dementia, the progressive cortical blindness, the progressive aphasia and the progressive anarthria. We report the case of a 51-year-old man who complained of difficulties understanding single words or sentences in the everyday life. His ability to write or read was preserved. During the following months appeared difficulties in the recognition of familiar noises (as the door bell, the telephone ring ...). Neurological examination showed brisk pyramidal reflexes with a bilateral Babinski sign. The neuropsychological assessment showed a verbal deafness and a complete agnosia for common noises. In contrast, audiometry was normal. MRI revealed a mild bilateral atrophy. SPECT studies and PET scan showed bilateral hypometabolism of temporal poles, of the anterior half of the left lateral temporal cortex and of the left hypocampic cortex. The association of noise agnosia and focal temporal hypometabolism suggest the diagnosis of progressive verbal deafness, a rare neurodegenerative disorder that has been rarely reported. This is a new variant of focal dementia. P67 REDUCED DENSITY OF DOPAMINE D3 RECEPTORS ON LYMPHOCYTES IN ALZHEIMER’S DISEASE. P. Barbanti, G. Fabbrini, R. Cerbo, M. P. Pascali, A. Ricci*, B. Caronti, G. Bruno, G. L. Lenzi. Depts. of Neurosciences and of *Cardiovascular and Respiratory Sciences, University “La Sapienza”, Rome, Italy Clinical and pathological evidence points to an involvement of dopamine in Alzheimer’s disease (AD), the most common form of cognitive decline in elderly. Human peripheral blood lymphocytes (PBL) express dopamine D3 and D5 receptor subtypes which belong to D1-like and D2-like receptor superfamily, respectively. We assayed dopamine D3 and D5 receptors on peripheral blood lymphocytes (PBL) in 20 patients with AD and in 25 healthy controls, by radioligand binding assay techniques using [3H]7OHDPAT and [ 3H]SCH 23390 as ligands. AD patients revealed a lower density (Bmax) of dopamine D3 receptors on PBL than controls ( p < 0.001), while the density of dopamine D5 receptors and the affinity (Kd) of both [ 3H]7OH-DPAT and [ 3H]SCH 23390 bindings to PBL were similar in both groups investigated. The reduced density of dopamine D3 receptors on PBL is in keeping with the changes in the expression of D2 receptors in the striatum, hippocampus, amygdala and olfactory bulb in AD and represent a further support of the involvement of dopamine D2-like receptors in AD, even in those patients with no evidence of parkinsonism, behavioural abnormalities and psychosis. Although their functional role is still unknown, it seems reasonable to assume that the reduced expression of dopamine D3 receptor in AD represents a peripheral sign of the involvement of the dopaminergic system in the disease.

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P68 MEMORY STATUS IN MULTIPLE SCLEROSIS PATIENTS WITH BATTERIE REDUITE 84. Mª Angeles Maurel, Cristina Iñíguez, Luis F. Pascual. Servicio de Neurologia. Hospital Clínico Universitario, Zaragoza, Fundación Nacional Esclerosis Múltiple, Spain

P71 NEUROPSYCHOLOGICAL EVALUATION OF HOMOZYGOUS BETATHALASSEMIA. Roberto Monastero, Gaia Monastero, Marco D’Amelio, Alessandro Padovani* and Rosolino Camarda. Institute of Neuropsychiatry, Palermo and *Clinic for Nervous Diseases, Brescia, Italy

Objective: evaluation of memory status and specific memory processes in MS patients. Methods: 48 patients with MS, 31 women, 17 men were included. Patients with severe cognitive impairment were excluded. Mean age was 40 ± 2. Mean disease duration and mean EDSS score were respectively 11 ± 1 and 3.4 ± 0.31. A relapsing-remitting course was present in 38 patients, a progressive course in 3 and a relapsing progressive course in 7. By Cultural level: low 33, medium 10, high 5. All subjects were explored with Batterie Reduite 84 and other neuropsychological assessment. Results: The Z score of Batterie reduite 84 was classified according to Lezak in Very Superior n = 0 patients; Superior n = 2 patients (4%); High average n = 2 patients (4%); average n = 7 patients (15%); low average n = 6 patients (13%); Borderline n = 9 patients (19%); Retarded n = 22 patients (46%). A positive correlation was observed with EDSS score (Rho = 0.42, p = 0.003). No correlation was seen by sex or age. No differences were observed between verbal or visual encoding, retrieval or retention. Recognition was better preserved, but declined in retarded group. Conclusions: only the 35% of MS patients had a normal memory. The 65% was in the pathological (46%) or borderline (19%) ranges. Visual and Verbal memory were affected in a similar extent.

Homozygous beta-thalassemia (ß-Th) is a genetically determined chronic hematological disorder characterized by ineffective erytropoiesis, peripheral hemolysis and a severe anemia. This condition requires regular blood transfusions leading to secondary iron overload which is controlled by intensive iron chelation therapy with subcutaneous administration of desferrioxamine (DFO). The aim of our study is to determine whether there is an impairment of higher cognitive functions in ß-Th patients who are exposed, in addition to periodically hypoxic state, to both permanent risk of iron overload and chelation agent’s neurotoxicity. Forty-seven patients (28 male and 19 female) with ß-Th (age range: 16 through 35 years old) and 47 normal age, education and sex matched controls partecipated in the study. All subjects underwent laboratory blood examination and were evaluated by an extensive neuropsychological test battery for the assessment of general intellectual ability, attention, abstraction, executive functions, language, visuo-spatial skills, short and long term memory. In all tests, ß-Th patients showed a significative impairment compared to controls ( p < .01 to p < .0001). The performance of ß-Th patients was not correlated to neither duration of illness nor duration of DFO treatment nor depression scores. Our data suggest that ß-Thalassemia is associated to global cognitive dysfunction likely due to either iron overload or periodically hypoxic state but not to DFO neurotoxicity.

P69 THE VISUAL VARIANT OF ALZHEIMER’S DISEASE (AD). R. Deschamps, S. Cchokron, A. Moulignier, Fondation Rothschild, Paris, France Visual impairment may be the initial complaint and the dominant manifestation of AD. Such cases are very infrequent. A 54-year-old righthanded accountant man developed difficulties reading and writing numbers in tables in 1992, and was obliged to slide an index card down the page to help keep the right place. Dismissed in 1993, he gradually developed simultagnosia in 1995. On first admission on June 1996, we noted optic ataxia, gaze apraxia and disturbance of visual attention, principally in the left visual field, with intact vision (Balint syndrome), whereas memory, judgement, verbal reasoning and intellectual efficiency were preserved. On September 1996 we noticed a finger agnosia, with right/left disorientation, dysgraphia and spatial dyscalculia, indicating a Gerstmann’s syndrome. The Mini-mental Status (MMS) was 22/30. Magnetic resonance imaging (MRI) of the brain was normal in 1996 but 99 Tc Single Photon Emission Computed Tomography disclosed bilateral parieto-occipital hypofixation. All investigations ruled out curable dementia. The patient progressively worsened in 1997 (MMS = 18) with mild memory impairment and in the daily-life activities. MRI showed bilateral occipitoparietal atrophy. Tacrine was ineffective, and substituted for a new MonoAmine Oxydase-B’s inhibitor, with relative stabilisation of AD, confirmed on tests. The consistent findings in this focal form of AD are: younger age at onset, retained insight, rarely family history of dementia and prominent bilateral occipitoparietal pathological changes. We emphasised the pitfalls of such feature of AD, frequently referring patients to ophtalmologists. P70 VASCULAR RISK FACTORS IN ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEMENTIA. D. DeplanqueA, F. PasquierA, D. LeysB, B. JacobA, H. HenonA–B, I. LavenuA, F. LebertA, H. Petit A. Department of Neurology. Memory ClinicAa and Stroke Unit B. University of Lille, France There is evidence for a link between vascular risk factors and Alzheimer’s disease (AD) but no data are available in others degenerative dementias. The aim of our study was to determine the prevalence of vascular risk factors in age and sex-matched patients with AD or frontotemporal dementia (FTD) selected from 675 consecutive patients refered to the Lille Memory Clinic. Vascular risk factors or vascular events including arterial hypertension, diabetes mellitus, hyperlipemia, tobacco and alcohol consumption, previous stroke, coronary heart disease, history of atrial fibrillation and peripheral artery disease were prospectively collected at the first followed-up visit. We included 131 patients (76 women and 55 men), mean-age 61 ± 4 years. Clinical diagnosis was probable AD in 92 and FTD in 39. There was no difference for the presence and the number of vascular risk factors and for the vascular events between the 2 groups. However, hyperlipemia was significantly more frequent in AD than in FTD (60% vs 15%; Chi2, p < 0,0001). This result confirms the possible link between hyperlipemia and AD.

P72 β-AMYLOID DEPOSITS WITHIN BRAIN OF VERY OLD ANIMALS. M. Barcikowska, Z. Soltysiak. 1. Medical Research Centre Polish Academy of Sciences, Institute of Biostructure, Department of Pathological Anatomy University Medical School of Warsaw. 2. Academy of Agriculture Wrocław, Poland The aim of study was to search for β-amyloid in various very old animal brains. Examined group consist of: six european cats aged: 11–22 years, ten dogs 14–22 years old, six monkeys 7–33 years old, one fox (15 years) 5 carps 7 to 13 years old, two old birds (12 and 39 years old), one snake (17 years old), two deers (aged 15 and 17 years), one horse (24 years) two goats (6 and 9 years old) and two sheep (6–13 years). Five standard specimens for each brain were taken and immuhistochemistry with mAb. 4G8 antibody and thioflavine S stainings were used for β-amyloid visualization. To the best of our knowledge, we are the first to find positive for βamyloid antibody accumulations within brain of a 21 years old european cat, a panther (12 years old), a 15 years old fox and a goat (6 years). No βamyloid deposites were found in non-mammals: old fishes, birds, snake. Not surprisingly nine of the ten dogs’ brains and four of the six monkeys’ brain were positive for anti β-amyloid immunohistochemistry. 4G8 mabb labelled mostly diffuse and primitive deposits and walls of vessels. Some of them were very delicate and scanty but in some species they were abundant in neuropil, mostly in neocortex and hippocampal and parahipocampal areas. Very rarely so called classic plaques were observed. In very few animals brain congophilic angiopathy was labelled without β-amyloid staining in neuropil. P73 DIFFERENTIAL PROFILES OF NEUROPSYCHOLOGICAL DEFICITS IN VIRAL AND BACTERIAL MENINGOENCEPHALITIS. Sittinger HA, 1Merkelbach S, 1Müller M. Departments of Psychiatry and 1Neurology, 66421 Homburg/Saar, Germany We studied the neuropsychological long-time sequelae (33 ± 12 months after acute infection) in unselected patients with viral meningoencephalitis (VM; 22 patients, mean age 37 ± 15 years) and bacterial meningoencephalitis (BM; 19 patients, 51±18 yrs) to compare cognitive and affective symptoms. Methods: All patients were administered the following neuropsychological tests: Multiple-choice-vocabulary-test (MWT-B); short version of the Wechsler Intelligence Scale (WIP); Wechsler Memory Scale (WMS); Benton-Test (BT); Number-Connection-Test (ZVT); d2-Test (d2); BeckDepression-Inventory (BDI). Results: There were no significant differences in education and premorbid intelligence between VM and BM (MWT-Bpercentiles: 63.9 ± 25.1 vs. 70.6 ± 20.9), in general intelligence (WIP-percentiles: 67.1 ± 23.0 vs. 68.0 ± 25.0), or subtests of the WIP (semantic memory, verbal reasoning, visuoperceptive and visuoconstructive functioning), memory (BT, WMS) and in concentration (d2). Velocity in perception, information processing and psychomotor performance (ZVT) was

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significant higher in the VM (percentiles: 48.1±32.2 vs. 20.6±23.4; p = .009), even when corrected for age-differences. There were lower BDIscores in the VM (4.2 ± 4.4 vs. 6.4 ± 5.0; p < .05) especially because of diminished drive ( p = .008) and premature tiredness (p = .08). Conclusion: The profile of neuropsychological deficits was similar for VM and BM. Clear differences concern the velocity of performance and subjective level of energy which were lower for the BM and may be due to the more severe acute disorder in BM. P74 THE EFFECT OF TACRINE ON PATIENTS WITH PARKINSON’S DISEASE AND DEMENTIA. Werber AE, Mildorf B, Perlov S, Rabey LM, Department of Neurology, Assaf Harofeh Med. Ctr.’ Zerifin, Israel Patients with Parkinson’s disease (PD) often suffer from dementia (PDD). Apart from ´´cal PD changes, their brain histology reveals Alzheimer’s disease (AD)-like changes and decreased cholineacetyl transferase (Chat) activity in the cortex and hippocampus. This cholinergic deficiency has been attributed to the intellectual decline. Since tacrine, a centrally acting cholinesterase inhibitor, had been reported to improve cognition m AD, we hypothesized a similar effect in PD1). The aim of this work was to assess the effect of tacrine in PDD patients, by evaluating cognitive and motor influence of the drug. We conducted an open study involving 7 PDD patients; 4 men and 3 women, mean age 75 y, mean PI) duration 11. 5y, mean PDD duration 4y, Yahr staging Ill (5 patients) and IV (2 patients). AB patients have been evaluated for cognitive part by the Folstein Mini-Mental State Evaluation (MMSE) and ADAS COG, at baseline and on maximal dose of tacrine adjusted for each person (mean maximal daily dose 100 mg mean treatment period 6 months). The motor part of Unified PI) Rating Scale (UPDRS) and Short Parkinson’s Evaluating Scale (SPES) applied for testing motor function before treatment and under tacrine. The results show improvement in the cognitive state of our PDD patients under tacrine: ADS-COG mean score improved by 7.9 points, and MMSE mean score improved by 2.4 points, however, statistical analysis failed to reach significance. Assessment of motor function by UPDRS and SPES did not show any deterioration at baseline and under tacrine. In one patient we observed marked improvement of motor function under the drug. We conclude that tacrine seems to have a beneficial effect on cognition in in PDD patients without adverse motor influence. Double blind controlled studies are necessary to confirm our results. P75 PURE PROGRESSIVE AMNESIA: A FURTHER TYPE OF FOCAL ATROPHY? M. Didic1, A. Ali Chérif1, 2, D. Gambarelli3, M. Poncet1, 4,, J. Boudouresques2. 1Laboratoire de Neurophysiologie et Neuropsychologie (INSERM CJF 9706), Faculté de Médecine, Marseille, 2Service de Neurologie, 3Service díAnatomie Pathologique et Neuropathologie,4Service de Neurologie et Neuropsychologie, Hôpital de la Timone, Marseilles, France Over the past years, there has been growing interest in degenerative diseases with progressive isolated monosymptomatic deficits or “focal atrophies”. Cases with isolated deficits in the domain of language, behaviour, semantic memory, visuo-spatial skills, perception and praxis have been reported. Recently, isolated progressive deficits of episodic memory have been reported in several patients. PET studies indicated focal involvement of the mesial temporal lobe. In the absence of neuropathological data the aetiology of the disorder remained unresolved. We report on a further case with a progressive amnestic syndrome of insidious onset that worsened progressively and remained stable over a period of 8 years. Her severe amnestic syndrome of bihippocampal type contrasted with normal performance in other cognitive domains and behaviour. She ultimately developed more widespread cognitive decline and terminal dementia. Post-mortem examination 18 years after the onset of her memory problem revealed generalised atrophy, clearly predominating on the mesial and inferior temporal lobes. Histologically, numerous senile plaques and neurofibrillary tangles, consistent with neuropathological criteria of Alzheimer’s disease, were observed. This case illustrates that degenerative disease can selectively affect episodic memory over a prolonged period of time and that the syndrome of pure progressive amnesia may represent a further type of focal cerebral degeneration with an isolated monosymptomatic neurological deficit. P76 DEGENERATIVE AND SLOWLY PROGRESSIVE LIMB-KINETIC APRAXIA WITH ATROPHY AND HYPOPERFUSION OF THE LEFT HEMISPHERE. A THREE YEAR FOLLOW-UP. P. J. Modrego, R. Montoya, M. A. Pina, J. M. Pérez. Trullen, Alcañiz and Teruel, Spain

The lesions responsible for limb-kinetic apraxia (LKA) have been ascribed to the central region between the precentral and postcentral gyrus, but its mechanism remains obscure. LKA may be seen in stroke or in other focal lesions but only a few cases of slowly progressive LKA without dementia have previously been published. In some cases it may be an early manifestation of corticobasal degeneration. We present an exceptional case of pure and slowly progressive LKA. A 60 year right-handed woman was admitted to our hospital because of a progressive clumsinesss of the right hand, especially in manipulating objects or in doing daily living activities. We did not detect dementia, ataxia, rigidity, tremor or paresis. The language was grammatically correct with normal performance in writing and reading. The right arm was hypokinetic in walking. These symptoms did not respond to L-Dopa. The CT and MRI scans showed atrophy in the frontal, parietal and temporal areas of the left hemisphere. A single photon emission computed tomography (SPECT) was performed after two years of the initiation and revealed a significantly decreased cerebral blood flow in the whole left hemisphere. Three years after the first consultation, the right-hand clumsiness had worsened without other neurological abnormalities. Our case represents a pure and degenerative form of LKA which remained isolated after 3 years. The extensive atrophy and decreased perfusion of the left hemisphere reflect the complexity of this syndrome and support the hypothesis of the impaired interaction between the motor and somatosensory cortices. P77 NEUROPSYCHOLOGICAL REHABILITATION IN PROGREDIENT DISEASE: EXPERIENCES WITH MULTIPLE SCLEROSIS PATIENTS FROM THE BOCHUM MODELL. Haupts M, Calabrese P, Gehlen W. Ruhr-Universität Bochum, Dept. of Neurology/Knappschaftskrankenhaus, D-44892 Bochum, Germany Whether successful neuropsychological intervention for memory impairments of the type also seen in multiple sclerosis is possible, has been an attempt under debate for the last years. Especially complicating for rehabilitation is the progredient nature of the disease. Young age and potential impact of neuropsychological handicaps in multiple sclerosis (MS) patients however call for initiative. We report experiences in 8 multiple sclerosis patients (6 females/2 males, mean age 42 years, median Extended Disability Status Scale 5.0) undergoing a structurized outpatient programme for 4 months, in comparison to 10 matched MS patients without formal intervention. Opposing the natural course of the disease, improvements of mnestic functions could be demonstrated in close correlation to interventions. Also at follow-up after 2 years sustained effects could be found. This study was granted by Gemeinnützige Hertie-Stiftung GHS 231/91. P78 ANALYSIS OF FAST SEQUENTIAL FINGER MOVEMENTS IN A PATIENT WITH MULTIPLE SYSTEM ATROPHY: APRAXIA OR ATAXIA? 1B. Legros, 2J. Jacquy, 1J. Hildebrand, 1M. Manto. 1Neurologie, Hôpital Erasme (B); 2Neurologie, CHU-Charleroi (B) When patients with multiple system atrophy (MSA) exhibit apraxia, the differential diagnosis with cerebellar ataxia is a challenge for the clinician, particularly for fast finger movements. We analysed fast sequential finger movements in a 52-year-old patient with a 2 years history of gait disorder followed by cognitive deficit. Neurological examination showed a MMSE of 20/30, ideomotor apraxia, pyramidal signs and cerebellar ataxia. Brain MRI revealed a pancerebral atrophy. Kinematics were compared with those obtained in 8 healthy subjects (8 male; mean age of 52 years; range: 37–64). Kinematic analysis of fast sequential opposition movements demonstrated: (1) loss of independent finger movements between thumb and index, (2) delayed initiation of extension movements, (3) asymmetry in kinematics of index movements characterized by triangular shapes of movements with a ratio of extension phase/flexion phase up to 3.70 (controls: 1.03 ± 0.06) and a ratio of the largest extension/the smallest extension up to 6.28 (controls: 1.31 ± 0.10). Loss of independent finger movements and delayed initiation of extension finger movements have been previously described in cerebellar patients. The triangular shapes of movements in our patients were indicative of a disrupted motor planning in cerebral cortex. Kinematic study of fast finger movements is a useful tool to estimate the respective contribution of cerebral cortex involvement and cerebellar involvement in the defects of fast finger movements in patients with MSA. P79 FREQUENCY OF APOE4 ALLELES IN DIFFERENT ETHNIC GROUPS IN ISRAEL. Hilkevich O, Chapman J, Bonne Bat-Sheva T, Korczyn AD. Department of Neurology, Sackler Faculty of Medicine, TelAviv University, Ramat-Aviv, Tel-Aviv, Israel

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The aim of the study was to compare the frequency of APOE 4 alleles in different ethnic groups in Israel. Alzheimer’s disease (AD) in elderly patients is linked to the APOE 4 allele. This allele was the first gene to be linked to AD in a large group of patients. The frequency of this allele in different ethnic groups was not yet examined. The ethnic variety in Israel provides such an opportunity. In order to genotype for APOE alleles, we utilized a modified method. The relevant portion of the APOE gene is amplified by PCR and then digested with either Hae II, which doesn’t cut E2 alleles and Afl III which doesn’t cut E4 alleles. A combination of these digests enables identification of all possible alleles combinations, such as 2/2, 2/3, 2/4, 3/3, 3/4 and 4/4. We examined 68 non-demented Jews of Ashkenazi origin, 20 of Sephardi origin and 30 each of Bucharian, Libyan and Ethiopian Jews origin, using this method and analyzing only E4 allele carriers. Results: The lowest E4 frequency was found in Libyan Jews (6.7%) and was similar in all other groups except Ethiopian Jews where a higher frequency of 27% was found, which is statistically significant (p < 0.002). Conclusions: In most ethnic groups we examined, there was an E4 frequency of about 10%. In contrast, the Ethiopian Jews had a significantly higher allele frequency. A question for future study is whether in this specific population the E4 allele is also a risk factor for AD. P80 THE MANAGEMENT OF “DYSCONTROL SYNDROME” DURING REHABILITATION. S. Reinbott, M. G. Griese, Rheinische Kliniken Düsseldorf, Kliniken der Heinrich-Heine-Universität, Dept. Psychiatry/Neurology. Germany The present discussion focuses on those neurobehavioral syndromes following neurological diseases that most frequently challenge the rehabilitation team: defects in orientation, memory and aggressiveness. The aim of this study was to evaluate the outcome in a sample of 104 patients suffering from organic mental disorder leading to an acute “dyscontrol syndrome”. From 1995 to 1997 544 patients with psychiatric complications of neurological diseases were admitted to a specialised neuropsychiatric ward of the Psychiatric Department of the Heinrich-Heine-University. Retrospectively 104 patients fulfilled the including criteria of a neurological and psychiatric indication for intensive treatment. The most frequently reason for admission were disorientation, agitation and aggressiveness. As etiologic causes were found: vascular (22%), toxic-metabolic (16%), degenerative (13%), Epilepsy (10%), inflammatory (8%), neoplastic (6%), traumatic (4%) in 15 cases a primary psychiatric disorder (neurosis, personality disorder, psychosis) was underlying. Being able to continue neurological rehabilitation on a closed ward as well as administer psychopharmacotherapy and establishing a psycho- and sociotherapy by a well trained team of nurses, physiotherapists, social workers and physicians early in the course of rehabilitation improved the outcome and shortened duration of hospitalisation. More than 50% of our patients could be discharged home. Only eight patients had to be sent to a home for the elderly. We conclude that patients with psychiatric complications of neurological diseases can be rehabilitated successfully on a specialised neuropsychiatric ward by a multiprofessional team. P81 PRIMARY SJÖGREN’S SYNDROME: SUBACUTE ENCEPHALOPATHY, HAEMORRHAGE SUBARACHNOID AND CEREBRAL ISCHEMIA. A. Miralles; R. Soler; E. Diez Tejedor; A. Frank; F. J. Mora; P. Barreiro. Department of Neurology. Hospital Universitario “La Paz”. Universidad Autónoma de Madrid. Spain Primary Sjögren syndrome is a common rheumatic disorder. Central nervous system (CNS) complications are infrequent. We analyze one particular case with CNS involvement, focal and non focal simultaneously, and significant progressive neurologic dysfunction. Case report: Female, 47 years old, studied by arthritis and positive rheumatoid factor. The initial manifestations were focal motor seizures secondarily generalized, fever, left hemiparesis-hemi-hypoesthesia and consciousness diminution. These symptoms remitted but appeared rapidly progressive cognitive dysfunction. Diagnostic studies: GSV 73 mm/h. CT scan: cerebral oedema in the right hemisphere. MRI scan: increased signal intensity on T2 weighted and proton density weighted images. Cerebral angiography: abnormalities of small cerebral arteries. CSF analysis: xanthochromia, no evidence of infection. EEG: initially spikes and focal slow wave activity on right hemisphere, finally diffuse slow wave activity. EMG: normal. Autoantibodies: antinuclear antibodies 1/80, rheumatoid factor 301 UI/ml. Positive Schirmer’s test. Positive minor salivary gland biopsy. Brain biopsy: aseptic meningoencephalitis. Nerve and muscle biopsy: normal. Treatment with corticosteroids and monthly intravenous pulse of cyclophosphamide stopped

progressive dysfunction. Conclusion: CNS involvement in primary Sjögren syndrome rarely appears in acute and extensive way; this must be considered because early diagnostic and early therapy making use of corticosteroids and intravenous pulse cyclophosphamide can be useful. P82 CEREBELLAR ROLE IN MODULATING HIGHER CEREBRAL FUNCTIONS: CASE REPORT. R. Raffaele, I. Vecchio, C. Tornali, D. Geraci*, L. Rampello. Department of Neurology, *Department of Forensic Sciences. Catania, Italy Some reports suggest a cerebellar role in modulating higher cerebral functions. We describe a 50-year-old man affected by cerebellar atrophy, without evidence of supratentorial lesions, who presented ataxia and motor problems due to dismetric movements associated to motor handwriting problems characterized by the difficulty to maintain horizontal lines, involving a spatial dysgraphia, without evidence of language or written spelling deficits. Dysgraphia is a disorder of writing in patients with supratentorial damage. Our report favors the hypothesis of a functional interrelation between supratentorial structures and cerebellum in modulating cognitive functions. P83 WEIGHT LOSS PREDICTS “MALIGNANT” COURSE OF ALZHEIMER’S DISEASE: RESULTS OF TWO-YEARS FOLLOW-UP STUDY. Alexander Tsiskaridze, Roman Shakarishvili, Tamara Vashadze, Marina Janelidze. Sarajishvili Institute of Neurology, Tbilisi, Georgia Weight loss (WL) traditionally is considered as a typical finding in patients with Alzheimer’s disease (AD). We endeavoured to reveal whether this symptom predicts the rapid decline of cognitive and functional capabilities of patients with mild AD. Methods and results: Cohort of 72 patients with mild (baseline Clinical Dementia Rating (CDR) of 0.5 and 1) probable AD were followed-up. Among them 23 patients had significant WL (loss 15% or more of body mass during the initial stage of the disease). The following end-points were identified: CDR 2, which corresponds to the moderate stage of the disease, and death. During the subsequent 2 years, 18 subjects among the patients with WL had reached the end-points (3 patients had died), while in the group of patients without WL only 20 had reached the end-points (4 patients had died). On multiple regression model WL was independently associated with the above-mentioned end-point (CDR 2): Odds Ratio (OR) = 3.6, 95% Confidence Interval (CI) = 1.3–8.0; as well as an age of the disease onset less than 65 year OR = 2.3, 95%CI = 1.2–11.7. Though the prevalence of extrapyramidal syndrome (ES) and psychosis (P) (known predictors of the rapid deterioration) on baseline were higher in patients with faster decline, the association between these syndroms and rapid progression of the disease failed to reach the level of significance OR = 2.5, 95%CI = 0.8–3.9 and OR = 1.9, 95%CI = 0.6–12.3 respectively. This fact might be explained by small number of cases with ES and P in the beginning of the disease in our series. Conclusion: Significant WL (more than 15% of initial weight) in the early stage of AD predicts rapid progression of the disease. Such WL in our survey was not caused by changes of appetite or eating habits. It is likely that in cases of “malignant” course of AD the dystrophic and the brain atrophic-degenerative processes are parallel. P84 HUMAN BRAIN THETA ACTIVITY AND HABITUATION: EVENTRELATED SPECTRAL PERTURBATION. Thomas Dietl, Gerhard Dirlich, Luise Vogl, Christian Lechner and Friedrich Strian The EEG theta activity is enhanced during cognitive demands. In particular it is related to episodic and recognition memory. We studied stimulusinduced alterations of the theta activity in a traditional paradigm in event related potential (ERP) habituation research. The paradigm appears suitable for studies on patients with memory disorders because of its independence of specific instructions. The computation of event-related electric brain responses requires multiple repetitions of the stimulus for the averaging procedure. Therefore, short trains of somatosensory stimuli (48 stimulus trains with 27 stimuli each at 0.9 Hz) are separated by stimulusfree intervals (30 s). The stimulus free interval causes at least a partial reset of the habituation occuring during the stimulation trains. This paradigm allows the selective averaging of the events at different positions within the stimulus train. In addition to traditional ERPs, event-related power spectra were computed. The spectral information was complemented by an analysis of the theta band-pass filtered EEG epochs. This approach allows

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a discrimination between “phase-locked” and “freerunning” theta components. The main result on the stimulus related spectral perturbation is the finding of a transient increase of the theta activity over frontal midline regions after the first stimulus (20 %). The second stimulus leads to a reset of the theta activity to the prestimulation baseline. P87 PLATELET HYPER-AGGREGABILITY AS A CAUSE OF CHRONIC HEADACHE, DIZZINESS, VERTIGO, AND LEUKO-ARAIOSIS. S. Fujita. Department of Neurosurgery, Hyogo Brain and Heart Center at Himeji, Japan Cause of leuko-araiosis is assumed to be systemic hypertension, but through this study platelet hyper-aggregability revealed to be an another important cause. Methods and results: Serial one hundred and seventy-three outpatients who are suffering from frequent vertigo, continuous dizziness and chronic headache were analyzed in connection to platelet aggregability and MRI findings. Level of platelet aggregation is determined by aggregation-size analytic method using aggregation reagents (two different concentration of each ADP and collagen are used) into 9 classes. Class 9 or 8 is defined as hyper-aggregability. Incidence rate of platelet hyper-aggregation is found to be very high in these cases, 84% in the headache, 73% in the dizziness and 71% in the vertigo. Cases who show platelet hyper-aggregability, symptom of them disappeared by administration of antiplatelet agents, as to the platelet aggregability becomes to normal level. Among platelet hyper-aggregability cases, incidence rate of leuko-araiosis is significantly high ( p = 0.0013) in comparison to non platelet hyperaggregability cases. Conclusion: From these results, it might be concluded that the cause of vertigo, dizziness and chronic headache, and even leukoaraiosis are attributable to the platelet hyper-aggregability.

Motor Neuron Disease P88 AMYOTROPHIC LATERAL SCLEROSIS (ALS) MIMIC SYNDROMES: FINDINGS OF THE IRISH MOTOR NEURON DISEASE REGISTER OVER A THREE-YEAR PROSPECTIVE STUDY PERIOD. B. J. Traynor, B. Corr, E. Frost, O. Hardiman It is estimated that 5 to 10% of patients diagnosed with motor neuron disease (MND) have a MND mimic syndrome. There have been few published reports that have prospectively established the prevalence of MND mimic syndromes. The Irish Motor Neuron Disease Register is an ongoing study of the incidence and prevalence of MND in Ireland, which has prospectively accumulated data since January 1st, 1995. We present data on patients initially diagnosed with MND and informed of their diagnosis, who had a mimic syndrome. We reviewed our records of 419 patients on the register with a presumptive diagnosis of MND. Of these, 14 patients (representing 3.4% percent of the total) were found to have diagnoses other than MND, including six patients with multifocal conduction block motor neuropathy, four male patients with Kennedy syndrome, and four patient with other conditions. Lack of progression of symptoms over a relatively long period of time often provided the first clue to the correct diagnosis. Ultimately the correct diagnosis relied heavily on awareness on the part of the neurologist of the diagnostic pitfalls and the application of appropriate diagnostic procedures, such as neurophysiological testing in the example of multifocal conduction block motor neuropathy and blood tests in Kennedy’s disease. Misdiagnosis of MND mimic syndromes remains a difficult clinical problem despite increased neurological awareness and improved diagnostic tests. P89 MRI ABNORMALITIES IN MOTOR NEURON DISEASE: STUDY OF 24 PATIENTS. M. Corbo°, E. Munerati°, F. Triulzi*, F. Scomazzoni*, L. Strada*, R. Nemni°, G. Comi°, N. Canal°. °Dept. of Neurology and *Dept. of Neuroradiology, IRCCS H.S. Raffaele, University of Milan, Italy Degeneration of the corticospinal tracts is a necessary condition for the diagnosis of Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). Magnetic Resonance Imaging (MRI) is primarily used to identify or rule out diseases that simulate symptoms and signs of those Motor Neuron Diseases (MND). However the sensibility of this technique to disclose a degenerative upper motor neuron involvement and its correlation to the clinical picture of MND is still uncertain. A total of 24 patients had brain MRI using T2-weighted slices to visualize high signal ar-

eas along the course of pyramidal tracts. FLAIR sequences have also been performed. 18 patients had probable or definite ALS (average age: 62 + 11 yrs, duration of disease: 13.4 + 10.4 months) and 6 had PLS (average age: 52.3 + 5.2 yrs, duration of disease: 50 + 34.6 months). All the patients had clinical and neurophysiological evaluation. In 4 patients with PLS we observed an hyperintense signal on both T2-weighted and FLAIR sequences along the course of cortico-spinal pathway (CSP), whereas the remaining 2 studies were normal. Differently, in SLA patient group only 1 case exibithed the typical signal intensity alteration of CPS. However, in another case a striking hypointense signal of primary motor cortex on T2-weighted images was detectable, even in absence of abnormalities of CSP. 10 of the remaining patients showed non specific multiple foci of T2-hyperintensity in subcortical white matter, 5 showed non selective cerebral atrophy, and 6 had a normal exam. The study shows that PLS patients have abnormalities of CSP more commonly detectable by MRI technique than ALS patients. This might be due to the selective and severe involvement of CSP and to the longer duration of disease in PLS. P90 EARLY DIAGNOSIS OF MOTOR NEUROPATHY AND LOWER MOTOR NEURON DISEASE. Sferrazza B, Marchettini P, Lazzerini A*, Quattrini A, Nemni R, Iannaccone S. Dpt. of Neurology and Orthopedics*, IRCCS H. San Raffaele, Milan, Italy We studied 20 consecutive pts with progressive muscular weakness, wasting, atrophy and/or fasciculations, normal nerve conduction velocities (NCV) and absence of conduction blocks or slowed NCV ruling out demyelination and without sensory or upper motor neuron involvement. All pts underwent motor nerve biopsy of the obtutaror nerve. We made the pathological diagnosis of suspected Motor Neuropathy (MN) in 8 pts on the basis of the presence of nerve regeneration (7 pts), nerve demyelination (3 pts), inflammatory cells (1 pt) or abnormal deposits (1 pt). In 12 pts the pathological finding of poor nerve regeneration associated to chronic axonal involvement suggested the suspected diagnosis of Motor Neuron Disease (MND). At one year follow up,by clinical and electrophysiological criteria, we confirmed the diagnosis for 10 pts: 3 pts affected by MN (1 pt with sensory signs, 2 pts improved by IVIg therapy), 7 pts affected by MND (2 pts with upper motor neuron signs, 5 pts complained of respiratory failure). At two years follow up we confirmed by clinical and neurophysiological criteria all the diagnoses.This study confirms that biopsy of motor branch of the obturator nerve is an effective diagnostic criteria for an early diagnosis MND or MN. P91 RESPIRATORY FUNCTION DURING WAKEFULNESS AND SLEEP IN AMYOTROPHIC LATERAL SCLEROSIS. SIS. Iannaccone S, Zucconi M, Sferrazza B, Golzi V, Fumagalli A*, Bianchi A*, Landi C, FeriniStrambi L. Dpt. of Neurology and Pneumology*, IRCCS H. S. Raffaele Milan, Italy The aim of this study was to evaluate the time course of breathing pattern and respiratory mechanism in 11 pts with Amyotrophic Lateral Sclerosis (ALS). All pts underwent to neurological status, arterial blood gases analysis, spirometry, nocturnal polysomnography every two months. A progressive decline in all spirometric parameters (Forced Vital Capacity (FVC), Forced Expiratory Volume 1, Max Respiratory Pressures) has been found with a significant correlation with Norris Scale ( p = .001). Arterial blood gases were normal during the follow-up study. After one year 3 pts complained of respiratory failure (RF). Literature data suggest that FVC < 50% of predicted indicates an increased likelihood of RF.Out of our three pts affected by respiratory failure two had FVC < 50% of predicted (one had a severe central sleep apnea while the other had sporadic nocturnal obstructive apneas) and the third had FVC 70% of predicted but nocturnal hypoventilation with tonic oxygen desaturations. Besides this, one of the other ALS pts who did not complain of RF had FVC < 50% of predicted. In conclusion our data suggest that FVC is not the best index to follow throughout the course of the illness but it may be useful only in association to polysomnograhic respiratory parameters. P92 RILUZOLE RESTORES IMPAIRED INTRACORTICAL INHIBITION IN PATIENTS WITH ALS. Stefan K, Kunesch E, Benecke R, and Classen J. Neurologische Klinik, Universität Rostock, Germany Glutamate-related excitotoxicity likely plays a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the glutamate-antagonist riluzole

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is effective in slowing the progression of ALS. Using transcranial magnetic stimulation (TMS) in a paired-pulse paradigm, we investigated intracortical inhibition (ICI) and facilitation (ICF) and the effect of riluzole on ICI and ICF in patients with ALS. Additionally, resting motor threshold (RMT), ratio of TMS-evoked to peripherally evoked motor potentials (MEP%), and cortically evoked silent period (SP) were determined in the extensor digitorum communis muscle. Data were compared to age-matched disease (spinal muscular atrophy) and healthy controls. Of eight consecutive ALS patients (mean age, 60.1 ± 15.6 years), in four patients ICI and ICF could not be investigated because RMT was too high. In the four remaining patients, MEP%, and ICI were decreased (p < 0.01), and ICF, SP and RMT were unchanged as compared to controls, in agreement with recent findings by other groups. Riluzole partially restored ICI (before 127.3 ± 15.6%; after 85.5 ± 26.4%; p < 0.03) and left ICF essentially unchanged (before 143.9 ± 33.2%; after 139.7 ± 27.4%; n.s.). Additionally, we found a previously undescribed linear relationship (r = 0.67; p < 0.02) between ICI and ICF in 12 controls challenging current views that the two phenomena are independent of each other. Riluzole modulates favourably deficient ICI in patients with ALS. Furthermore, these data suggest that glutamatergic mechanisms, possibly separable from those producing ICF, are active during ICI induced by TMS. P93 CORRELATION OF CLINICAL SYMPTOMS AND MR SPECTROSCOPY IN CORTICOBASAL DEGENERATION. C. Kornblum, W. Block*, Ch. Pohl, H. Schild*, F. Ries. Departments of Neurology and *Radiology, University of Bonn The diagnosis of corticobasal degeneration, a neuro-degenerative disease with involvement of the fronto-parietal cortex and basal ganglia, is mainly based on clinical symptoms (extrapyramidal syndrome and cortical signs including “alien limb phenomenon”, parietal lobe apraxia, pyramidal signs) and neuropathological findings with a loss of neurons and gliosis in the cerebral cortex and basal ganglia. Brain MRI and CT-scan show normal results or asymmetrical or global cortical atrophy mainly affecting the fronto-parietal lobes. Case report: A 63 year old male patient observed over a period of two years presented with a left-sided “alien limb phenomenon” and akinetic-rigid syndrome initially. Further clinical follow-up showed progression of complaints with apraxia, dysarthria, movement disorders concerning the left arm and leg including rigidity, loss of fine motor skills with involuntary movements, dystonia and tremor. Additionally, signs of neuropsychological disorders and gait problems developed, resulting finally in a spreading of symptoms to the contralateral limbs. Technical examinations: MRI of the brain showed a diffuse cortical supratentorial atrophy accentuating the right hemisphere. 1H-MR spectroscopy (MRS) of the primary motor cortex ipsi- and contralateral and basal ganglia showed a severe decrease of the NAA (N-acetylaspartate)/Cho (choline)-ratio mainly of the right central region, associated with a normal Cho/Cr (creatine)ratio. MRI- and MRS- Follow-up after one year lead to a progression of the asymmetrical cortical atrophy and further reduction of the NAA/Choratio in the motor cortex and basal ganglia of the right hemisphere. Initially normal neuropsychological testing showed severely reduced psychomotor and visuo-constructive functions after one year. Somatosensory evoked responses were pathological, magnetic stimulation of the motor cortex was normal. Conclusion: This case represents a rapidly progressive corticobasal degeneration and illustrates the usefulness of MRI and MRS in this setting. (Shortened by the editor). P94 ABNORMAL THRESHOLDS OF MOTOR AND SENSORY NERVES IN AMYOTROPHIC LATERAL SCLEROSIS (ALS). U. Hoffmann, S. Horn, J. Großkreutz, M. Hofmann, S. Quasthoff. Dept. of Neurology, TU, Munich, Germany Threshold electrotonus measurements have shown an axonal ion channel dysfunction in peripheral motor nerves of ALS Patients (Bostock et al., Brain 1995). The aim of the present study was to investigate whether this abnormality is related to a change in threshold current. We measured the threshold current needed to produce 40% of the maximal compound action potential amplitude (CAPA) of the median nerve with a 1 ms lasting testpulse. Threshold current for the 40% CAPA of 75 motor nerves in ALS Patients were significant higher compared to 48 controls (12.5 ± 0.08 mA versus 10.1 ± 0.02 mA; p = 0.01). Additionally, threshold current for 40% CAPA of sensory nerves of 20 ALS patients was also increased compared to 25 controls (12.2 ±. 0.16 mA; 6.8 ±. 0.06 mA; p = 0.0008). After treatment with Riluzole (100 mg/die) the threshold of motor (42) and (15) sensory nerves was furthermore increased in ALS patients (16.2 ±. 0.1 mA;

13.2 ± 0.016 mA). Motor nerves of 57 diabetic neuropathy patients also exhibited an increased threshold. However, the increase in threshold of sensory nerves of 25 diabetics was not significant compared to controls. Our results show that ion channel dysfunction in ALS patients are associated with an increased threshold current for the 40% CAPA of the maximum amplitude. This abnormal behaviour is not restricted to motor nerves, but could also be observed in sensory nerves of ALS patients. This observation is an additional element in favour of the involvement of the sensory tracts in ALS. The increase in threshold during Riluzole treatment might indicate the previously reported ion channel blocking activity of the drug. Another explanation could be the unchanged progression of the disease. Supported by the W. Sander Stiftung. P95 CYSTINE DEPRIVATION-INDUCED APOPTOSIS IN IMMATURE CORTICAL NEURONS. EFFECTS OF EXCITATORY SULFUR AMINO ACIDS ON CYSTINE TRANSPORT. Y. Tsukamoto1, H. Homareda2 and Y. Yoshino1. 1The First Department of Internal Medicine and 2 The First Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan In the neuronal tissue of patient with amyotrophic lateral sclerosis(ALS), the elevation of taurine, the final product of the metabolic pathway of sulfur amino acids (SAAs), has been reported, suggesting that excitatory SAAs, the intermediates of this pathway, could also be increased. This study was undertaken to evaluate whether excitatory SAAs have the ability to inhibit cystine uptake. Since immature neurons have not yet expressed the receptor channels, they are not susceptible to excitotoxicity. Inhibition of cystine transport leads to a depletion of glutathione, and results in cell death due to oxidative stress. Cell cultures were obtained from the cerebral cortex of foetal Wistar rats. Cytotoxicity studies were performed 48 hours after plating by addition of media containing SAAs; cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfocysteine. Cell death was quantified by the release of the cytosolic enzyme lactate dehydrogenase, and single cell assessment of apoptosis was carried out by staining cells with acridine orange. HCA and HCSA showed cytotoxicity, the morphology of which was compatible to apoptosis. It will be a subject for future study to examine whether this mechanism of cell death is primarily present in ALS. P96 24-HOUR URINARY CREATININE EXCRETION AS A MEASURE FOR MUSCLE MASS IS UNRELIABLE. Van der Kooi EL1, Vogels OJM1, Dicke HC 2, De Keijzer MH 3. 1Department of Neurology, 2Department of Dietetics, 3Central Clinical Chemical Laboratory, University Hospital Nijmegen, The Netherlands In neuromuscular trials reliable estimates of skeletal muscle mass are important. Although reliable and accurate neuroradiologic measurements are available now, the 24-hour urinary creatinine excretion (24h-UCE) method is still considered the golden standard. This method knows many pitfalls, including dietary, physiological factors and collection errors. To investigate the influence of diet on 24h-UCE and the practical difficulties collecting urine two healthy researchers collected 24-hour urine specimen during 4 weeks of respectively normal, meat-free and meat-enriched diets. In the meat-free diet weeks slight stabilization of considerable varying 24h-UCE measurements was reached at an 5% lower level (range 0–12%). Although both researchers were highly motivated and aware of the pitfalls, ordinary errors (causing up to 28% lower values) occured. Surprisingly, the non-dietary errors were more pronounced than the dietary influences. Not-foreseen pitfalls were the practical difficulties handling the containers as experienced by the female researcher. These problems will certainly be more pronounced in the neuromuscular patient. Considering the effort, pitfalls and the fact that the used equations are indirect and population-based, we must conclude that the 24h-UCE method to estimate skeletal muscle mass in neuromuscular patients is unreliable, and should be replaced by neuroradiological methods. P97 HIGH INCIDENCE OF FRONTAL LOBE IMPAIRMENT IN MOTOR NEURON DISEASE WITH BULBAR ONSET. Tarodo F, Cadilhac C, Touchon J, Camu W. Service de Neurologie B, Hôpital Gui de Chauliac, Montpellier, France In some cases of motor neuron disease (MND), the neurodegeneration is not restricted to the motor neurons and fronto temporal (FT) lobe demen-

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tia is frequently associated with MND, making it likely that both disorders are part of a common spectrum. As both bulbar MND and dementia have been associated with the apolipoprotein E (ApoE) allele E4, we studied the incidence of dementia in bulbar MND. 23 patients with bulbar onset of MND, were studied with the following: 1) A neurological examination; 2) A neuropsychological series of tests; 3) SPECT-HMPAO. 4) P3 wave study. Cognitive impairment was classified in three groups: 1) Clinical and functional abnormalities; 2) isolated functional impairment; 3) no cognitive impairment. There were 8 patients in the first group. The dementia is in all of the cases of the FT lobe type; 5 patients were classified in group 2 with also a FT lobe type impairment. In group 3, without abnormalities, there are 10 subjects. All were genotyped for ApoE, and dementia is not associated with the presence of the allele E4. This study supports the hypothesis of a continuum, or a common spectrum, between bulbar MND and dementia of the FT lobe type. Prospective studies both in spinal and bulbar MND are warranted to try to refine the nosology of the disease. P98 QUANTITATIVE ANALYSIS OF STRIATAL DOPAMINE D2 RECEPTORS USING 123I-IODOLISURIDE SPECT: CHOICE OF REGIONS OF INTEREST DEPENDING ON PERFUSION SPECT. PrunierLevilion C*, Tranquart F**, Cottier JP***, Corcia P*, Guilloteau D**, Autret A*, Chossat F****, Bekhechi D****, Baulieu JL**. *Neurology, **Nuclear Medicine, ***Neuroradiology, CHU Tours, France; ****CISBioInternational Gif sur Yvette Quantitative analysis of dopamine D2 receptors (RD2) in striatum with specific radioligands can be valuable to differentiate PD from other extrapyramidal diseases. The parameters currently used for semi-quantitative assessment of density of RD2 are ratios between specific activity in striatum and non specific activity of reference regions of interest (ROI). We decided to take perfusion SPECT images as anatomical guides to draw striatal, thalamic, frontal and occipital ROI. 15 patients (2 females, 13 males) with isolated extrapyramidal syndrome were studied and followed during 18 months to revise the initial diagnosis using UKPDSBB criteria (1988) for PD, NINDS-ADRDA criteria (Litvan,1996) for PSP and Quinn’s criteria (1994) for MSA: 8 patients were classified as PD, 4 as MSA and 3 as PSP. They had stopped all dopaminergic treatment during 7 days and all had perfusion SPECT with 99mTc ECD and 123I-Iodolisuride (123I-ILS) SPECT 2 days interval. We chose the occipital lobe (O) as the reference ROI. The perfusion SPECT images allowed us to determine putamen and caudate nucleus areas within the striatum. We calculated the following ratios to evaluated semi quantatively the density of RD2 in the striatum (S), the caudate nucleus (C) and the putamen (P): S / O, C / O and P / O. The results were significantly different between both populations (8 PD, 7 non PD) for S/O (1.97 +/– 0.34 vs 1.62 +/– 0.21; p < 0.02), C/O (1.91 +/– 0.38 vs 1.53 +/– 0.24; p < 0.02) and P/O (2 +/– 0.34 vs 1.67 +/–- 0.22; p < 0.02). We conclude that 123I-ILS seems to be an interesting approach for classification of extrapyramidal diseases between PD and PD plus syndromes. P99 NEUROPHYSIOLOGICAL CORRELATION BETWEEN UPPER AND LOWER MOTOR NEURON (MN) ABNORMALITIES IN ALS PATIENTS. Alberto Cappellari, Vincenzo Silani, Andrea Brioschi, Sergio Barbieri, Massimiliano Braga, Guglielmo Scarlato. Institute of Neurology, IRCCS Maggiore Hospital, Milano This study illustrates the neurophysiological correlation between upper and lower MN impairment in amyotrophic lateral sclerosis (ALS). Two patients with long lasting focal impairment, the first with left lower limb onset three years before and the second with right lower limb onset one year before, underwent EMG examination and motor evoked potentials study. In the first patient the degree of denervation was: left lower limb > right lower limb > left upper limb > right upper limb. Cortical latency and central conduction time (msec) were for lower limbs 36.3–20.7 (left) and 28.4–16.8 (right) and for upper limbs 18.3–7.0 (left) and 17.4–6.0 (right). In the second patient denervation was more evident in the right lower limb, followed by the left lower limb and right upper limb. Cortical latency and central conduction time (msec) were for lower limbs 39.5–25.5 (right) and 28.8–16.4 (left) and for upper limbs 18.8–5.8 (right) and 19.0– 4.8 (left). The asymmetrical slowing of central motor conduction was positively correlated with the degree of peripheral denervation, suggesting that ALS patients with long lasting focal clinical deficit needs to be further investigated to shed light on the controversial issue of upper and lower MN correlation in ALS.

P100 FUNCTIONAL ABNORMALITIES AND NEUROPSYCHOLOGICAL FINDINGS IN THE EARLY COURSE OF ALS. T. Lauter, P. Calabrese, H. F. Durwen, S. Wierzba and W. Gehlen. Dept. of Neurology (Knappschaftskrankenhaus), University of Bochum, Germany We report the clinical data of a 57-year-old female patient who presented with marked atrophy of the shoulder girdle, dysphagia and dysarthria which together with other clinical signs prompted the diagnosis of ALS. The mnestic deficits were reported before any neurological symptoms developed, thus leading to a dementia-like picture. At time of admission the patient was also tested with a variety of neuropsychological tests including attention/concentration, working memory, learning, visuoconstruction, fluency, execution, language and speech. The neuropsychological profile was characterized by a combination of impairments in the domains of working memory, fluency and execution. While the MRI-imaging was unconspicious SPECT findings indicated a marked hypometabolism with a preponderance of the frontal lobes. We conclude from these findings that functional metabolic changes which themself are mirrored by substantial behavioural alterations may precede structural damage in the course of amyotrophic lateral sclerosis. This case also illustrates that mnestic deficits can be the leading symptom of an ALS-dementia-complex. P101 ACTIVATION OF GROUP I AND GROUP III METABOTROPIC GLUTAMATE RECEPTORS DELAYS APOPTOSIS OF CULTURED CHICK MOTONEURONS. J. M. H. Anneser, S. Horstmann and G. D. Borasio. Department of Neurology, University of Munich, Klinikum Grosshadern, Munich, Germany Glutamatergic excitotoxic mechanisms mediated by the activation of ionotropic glutamate receptors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). On the other hand, there are indications that activation of metabotropic glutamate receptors (mGluRs) may actually exert neuroprotective effects. We therefore tested the effect of group-selective mGluR agonists on chick embryonic motoneurons in vitro. Activation of group I receptors with (s)-3,5-dihydroxyphenylglycine (DHPG) or group III receptors with L-2-amino-4-phosphonobutanoate (L-AP4) delayed apoptosis in a dose-dependent fashion. DHPG at 200 µM increased the survival rate to 53% after 24h (control 29%) and 44% after 48h (control 23%). L-AP4 was most effective at 100 µm (43% survival after 24h and 38% after 48h). These effects could be blocked with specific antagonists. The group II agonist (2S,2´R,3´R)-2-(2´,3´-Dicarboxycyclopropyl)glycine (DCG IV) showed no survival-promoting activity. These findings are paralleled by the results of our in situ hybridisation studies in human motoneurons: Using sets of three different oligonucleotides directed against the mRNAs coding for mGluR1–7, expression of group I (mGluR1) and III receptors (mGluR4,–7) but not of group II mGluRs could be detected. The observed survival-promoting effect of mGluR agonists underscores the complexity of glutamatergic actions on motoneurons. The dissection of neurotoxic and neuroprotective pathways triggered by GluRs in motoneurons may help to further elucidate the pathogenesis of ALS. P102 UTILITY OF GLUTATHIONE AND LIPID PEROXIDATION PRODUCTS (LPO) AS MARKERS OF DISEASE PROGRESSION IN ALS. Gámez J, Dominguez C, Martin P, Cervera C. Barcelona, Spain Objective: To determine the existence of correlation between the measurements of Glutathione (GSH), and Lipid Peroxidation products (LPO) in blood with the clinical progression of the disease. Background: Amyotrophic Lateral Sclerosis (ALS) is caused by degeneration of motor neurons in cortex, brainstem and spinal cord. Patients generally die of respiratory failure within a median of 3-5 years. Functional rating scales, isometric muscle testing, electrophysiologic studies, and pulmonary function are used as markers of disease progression. However blood test don’t provide enough information of disease progression. The free-radical-mediated mechanisms might be implicated in the pathogenesis of ALS. Protection against oxidative damage is provided by antioxidants agents: Superoxide Dismutase, Glutathione, Glutathione-peroxidase, catalase, tocopherol, vitamin C. Materials and methods: We report 41 patients with ALS: 35 SALS and 6 FALS. GSH activity was measured in erythrocytes. LPO were evaluated in plasma and erythrocytes. Measures of disease progression were: Manual muscle strength loss, ALS Functional Rating Scale and decline in pulmonary function. Results: LPO, ending products of lipid peroxidation, were significantly increased in the group of patients with faster/bad progression. GSH, the principal antioxidant, was significantly decreased in

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patients with fast progression. It suggests the existence of cellular oxidative damage expressed at systemic level. Conclusions: Measurement of GSH activity and LPO could help to know the progression of disease. It could perform a biochemical test useful in the control of the natural history of the ALS. In the future, these parameters could be useful in the evaluation of new therapeutic agents. P103 SPORADIC AMYOTROPHIC LATERAL SCLEROSIS WITH EARLY ONSET CLINICAL OBSERVATIONS IN EIGHT PATIENTS. S.VlaskiJekic. Clinic of Neurology, Skopje, Macedonia The average age of the clinical onset of Amyotrophic Lateral Sclerosis (ALS) is in the mid-fifties, but it can occur anytime after the teen years. We present the clinical observations in eight patients with sporadic ALS occurring before 45 years of age, diagnosed according to the World Federation of Neurology criteria for ALS. Three patients are females 40–44 years old at the time of the disease onset. Five patients are males with ALS occurring between 29–43. The time from the first symptoms to diagnostically recognition of the disease varied form 6 months to 3 years. The following-up period ranged from one to four years. All patients showed a classical clinical type with limb-onset ALS. The upper motor neuron syndrome (UMN) dominated a clinical picture for a long time during the clinical course of the disease. The lower motor neuron syndrome (LMN) occurred early, but it developed slowly. The muscle atrophies evolved with the same successive spreading pattern as the pattern in the older onset ALS. They expanded along the limbs but were rather moderate. The associated prominent fasciculations were long-term persistent. The bulbar symptoms of a supranuclear type appeared later in the clinical course: two to five years after the first clinical symptoms of the disease. Their progression was slow. All patients are still alive. Four patients survive 5 years after the onset of disease. The earlier onset of ALS was associated with a slower clinical course and a longer survival of affected individuals. It seems that the age of onset of ALS has no important role to the characteristics of clinical presentation and successive evolutionary pattern of disease, but it can model its evolutionary dynamics and survival prognostics. Prognosis is better if the time between the onset of symptoms and diagnosis of the disease is longer.

Sleep Disorders P104 NARCOLEPSY: CLINICAL, POLYSOMNOGRAPHIC AND IMMUNOGENETIC DATA IN 24 NARCOLEPTIC SUBJECTS NATIVE OF MARTINIQUE (FRENCH WEST INDIES). Dauvilliers Y1, Ondzé B1, Billiard M1, Bazin ML2, Cesaire R3, Bera O3, Bazin M2. 1Service de Neurologie B, Hôpital Gui-de-Chauliae, Montpellier. 2 Service d’Exploration Fonctionnelle du Système Nerveux, Hôpital Pierre Zobda-Quitman, 3 Centre de Transfusion sanguine, Hôpital Clarac, Fort-de-France The haplotype found in almost all Caucasian and Japanese narcoleptic patients has the serological specificity HLA DR2-DQwl. At the gene level this corresponds to DRB 1 * 1501, DQA 1 *0 102,13QB 1 *0602. Because the linkage disequilibrium between DR and DQ is very high in Caucasians and Japanese, DRB1*1501 is almost exclusively associated with DQAl*01.02 and DQB 1 *0602. One of the ways to further narrow the susceptibilty region is to study the disorder in different ethnic groups. This approach has shown that all North American Black patients had the DQB1*0602, but only 60% had DR2 (Matsuki et al. 1992). We were interested in narcolepticc subjects native of Martinique, an island with a highly half-breed population. Our population included 24 subjects, 14 (6 male and 8 female) with full blown narcolepsy and 10 (8 male and 2 female) with narcolepsy without cataplexy. Irresistible sleep episodes were severe in both groups but cataplexies were rare in the first group. Mean sleep latencies in the multiple sleep latency test were short in both groups (3.36 ± 2.01 and 3.3 ±1.91). All subjects were DQw1 positive but only 64.2% of subjects with narcolepsy and 70% of subjects with narcolepsy without cataplexy were DR2 positive. Conclusion: These data further extend the results obtained in North American Black narcoleptic patients. P105 SLEEPINESS AND FATIGUE IN THE UPPER AIRWAY RESISTANCE SYNDROME (UARS). B. Ondzé, F. Espa, Y. Dauvilliers, B. Carlander, A. Besset, M. Billiard. Department of Neurology B, Gui-de-Chauliac Hospital, 34295 Montpellier

The UARS was first reported by Guilleminault et al. (1993) in patients complaining of sleepiness or fatigue. Patients often present with morphological abnormalities such as malocclusion of the jaw type 2, micrognatia, temporo-mandibular instability and high arched palate. Their sleep is frequently fragmented by arousals provoked by non apn’eic respiratory events corresponding to an increase of airway resistance during sleep. We diagnosed 30 cases of UARS in our sleep laboratory: 21 men an 9 women, aged 45 ± 14 years, with a body mass index of 24.5 ± 4.2 kg/m2. 27 complained of sleepiness, 15 of fatigue and 18 were habitual snorers. Subjects spent two nights and one day in the laboratory. Night 1 was followed by a multiple sleep latency test (MSLT) and night 2 served to monitor eosophageal pressure. Sleep was scored according to Reschtschaffen and Kales and the arousals according to criteria defined by the American Sleep Disorder Association. Arousal index was 24.7 ± 4/hour, wake time after sleep onset: 89.7 ± 54.5 minutes and total sleep time: 368.6 ± 97 minutes. In all cases, an increased respiratory effort was demonstrated. In 25 cases, the Epworth Sleepiness Scale(ESS) showed a score > 11 but in only 5 cases did the MSLT show a mean sleep latency t ~ 7 minutes. No significant relation was found between MSLT and ES S ( p > 0.05). Conversely, a significant correlation was found between the MSLT and the arousal index ( p < 0.05). In UARS, EDS is related to sleep, fragmentation which is caused by an increased respiratory resistance. P106 IDIOPATHIC HYPERSOMNIA: THE POLYSYMPTOMATIC FORM. Dauvilliers Y, Merle Q, Ondzé B, Carlander B, Besset A, Billiard M. Service de Neurologie B, Hôpital Gui-de-Chauliac Montpellier Idiopathic hypersomnia was first discribed by Roth (1976). In his initial description he reported a polysymptomatic form characterized by nocturnal sleep of abnormally long duration, great difficulty waking-up, more or less constant excessive daytime sleepiness and daytime nap(s) typically of long duration and not refreshing; and a monosymptomatic form with nocturnal sleep of normal or long duration, no difficulty waking up, constant or recurrent excessive daytime sleepiness and refreshing or not refreshing daytime naps. We report 12 cases of polysymptomatic idiopathic hypersomnia (5 male and 7 female). Age of onset was during childhood in 3 cases, adolescence in 7 cases and early adulthood in 2 cases. Polysomnography was performed according to the following schedule: an all night polysomnographic session followed by a multiple sleep latency test (MSLT) and then, from 7:00 p.m. onward, a 24 hour continuous polysomnography. Total sleep time (TST) was 518.6 ±41.06 min, wake after sleep onset (WASO) 32.3 ± 34.9 min and number of awakenings 6.9 ± 7.01 on night 1. Mean sleep latency on the MSLT was 9.54 ± 3.64, TST was 598.25 ± 128.39 min, WASO 43.1 ± 38.28 and number of awakenings 10.81 ± 6.49 on night 2.TST was 151.27 ± 94.51 min during day 2. TST was 837.22 ± 11.39 min on night 2 + day 2. Conclusion: The polysyrntornatic form of idiopathic hypersomnia is characterized by an enormous quantity of 24 hour sleep (13h57 min ± 1h51). P107 A SPECIAL TYPE OF REM SLEEP PARASOMNIA IN A NARCOLEPTIC PATIENT. Ondzé B, Espa F, Besset A, Billiard M. Sleep and Wake Disorders Unit, Department of Neurology B, Hôpital Gui-de-Chauliac, Montpellier, France Sleep paralysis (SP) is an incapacity to move limbs and head and to breath correctly, occurring either at sleep onset or on awakening, accompanied by a high degree of anxiety. REM sleep behaviour disorder (RBD) is characterized by intermittent loss of REM sleep atonia and the appearence of elaborate motor activity associated with dream mentation. Case report: This 48 year old narcoleptic subject was referred for repeated sleep paralysis. During polysomnography followed by an MSLT, 3 episodes during the night and 2 episodes during the MSLTwere observed. The subject had head jerks, lip movements and groaned words such as: “I cannot”, “I am frightened”. On polysomnography, muscular bursts, ocular movements, theta waves and saw-tooth-waves were evidenced. The first three episodes occurred during the second REM period of the night; the first beginning 27 min. after the onset of the period and the last one ending 11 min. before the end of the period. The fourth episode and the fifth occurred during the second and the third MSLT sessions respectively after 12 min. of light sleep and 10 min. of REM sleep; 9 min. of light sleep and 10 min. of REM sleep. The fourth episode was interrupted by the technician and the patient was hard to wake up. The awareness of the paralysis and the difficulty to wake up are trivial in SP. On the other hand, the incomplete muscle atonia, the head and lip movements and the occurrence of the episodes not at sleep onset or at sleep offset, but within REM sleep, are suggestive of a RBD.

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The reported condition is probably a transitional form of REM sleep parasomnia between RBD and SP. P108 FAMILY STUDIES IN NARCOLEPSY. Dauvilliers Y, Pasquié-Magnetto V. Carlander B, Billiard M. Service de Neurologie B, Hôpital Gui-de-Chauliac, Montpellier A family tendency for narcolepsy has long been recognized. Several studies have attempted to define the proportion of probands with a family history of the condition. Results were extremely heterogeneous until recent studies by Honda (1988) and by Guilleminault et al. (1989). Based on Honda’s clinical criteria, 316 subjects were diagnosed as narcoleptics. A pedigree at the second degree was obtained in 233 probands. Relative with either narcolepsy or isolated daytime naps and/or lapses into sleep occurring almost every day were indicated by the probands. Next an Epworth sleepiness scale was given by the proband to all his first and second degree relatives (whether or not affected with excessive daytime sleepiness). Ultimately a Standford Narcolepsy Questionnaire was mailed to subjects with a sleepiness score > 10 in order to confirm narcolepsy in the suspected subjects and to rule out another cause of sleepiness in those subjects with isolated daytime naps and/or lapses into sleep only. Results: A positive family history of narcolepsy was found in 18 subjects (7.72%) and a positive family history of isolated daytime naps and/or lapses into sleep in 42 sujects (18%). The empirical risk for narcolepsy was (1.25/0.026), 48 times greater in family members of a narcoleptic proband than in the general population. The segregation ratio for narcolepsy and isolated daytime naps and/or lapses into sleep was 0.24. The Epworth sleepiness scale was given to first and second degree relatives of 67 probands, namely 308 first degree relatives and 423 second degree relatives. 36 first degree relatives experienced excessive daytime sleepiness. Out of these 36, 16 were given the Standford Narcolepsy Questionnaire. Among these subjects, 3 were narcoleptics while 6 experienced isolated excessive daytime sleepiness only. P109 SEVERITY OF NARCOLEPSY. Dauvilliers Y Carlander B, Billard M. Service de Neurologie B, Hôpital Gui-de-Chauliac, Montpellier According to the French ministerial order dated 7. 5. 1997 listing the physical disabilities incompatible with obtaining or keeping a driving license, narcolepsy is theoretically a contra-indication to car driving. However the ministerial order mentions the possibility of car driving according to the clinical state, the results of laboratory tests and the results of treatments. We decided to evaluate the range of severity of the condition in 300 narcoleptic subjects with full blown narcolepsy, clinically in 300 subjects, by means of the Epworth sleepiness scale (ESS) in 86 subjects (abnormal, 10 to 24) and by means of a multiple sleep latency test (MSLT) in 216 subjects (abnormal ≤ 7). 100 subjects experienced irresistible sleep episodes and cataplexy, 102 irresistible sleep episodes, cataplexy and either hypnagogic hallucinations or sleep paralysis and 98 subjects the complete tetrade. 5 subjects scored 10 to 12 on the ESS; 11.13 to 15; 24.16 to 18; 28.19 to 21 and 14.22 to 24. Mean sleep latency was < 2 min in 29 subjects, ≥ 2 and < 4 in 65 subjects, ≥ 4 and < 6 in 70 subjects, ≥ 6 and < 8 min in 26 subjects and ≥ 8 in 36 subjects. 18 subjects were rated 1 (less than 1 cataplexy per year) on the cataplexy frequency scale, 63,2 (more than 1 per year); 92.3 (more than 1 per month); 50.4 (more than 1 per week) and 78.5 (more than 1 per day). 8 subjects showed no SOREMP on the MSLT; 25.1; 45.2; 58.3; 42.4 and 39.5. Conclusion: The severity of narcolepsy varies within large margins. A severity scale deserves to be designed to help general practitioners and neurologists in charge of narcoleptic subjects.

eral cognitive ability of PD patients. Twenty-nine non-demented PD patients, under optimal L-dopa treatment, were studied. They were at stage II and III of the disease and their mean age + SD was 63.9 + 5.3 yrs. A standard auditory “oddball” paradigm was used to elicit P300, while rCBF was evaluated by 99mTcHMPAO SPECT. General cognitive ability of PD patients was assessed by means of the a) Raven’s Coloured Progressive Matrices (RCPM) and b) Test of Non-verbal Intelligence (TONI-2). Statistical analysis of our findings showed that lower rCBF in right temporal lobe areas was related to inferior performance in RCPM (r = 0.42, p = 0.02) and TONI-2 (r = 0.44, p = 0.01), while there was no relationship between RCPM or TONI-2 scores and P300 parameters. Our findings indicate that SPECT is a much more sensitive index of general cognitive ability of PD patents than P300. P111 HANDWRITING TRAINING FOR PATIENTS WITH WRITER’S CRAMP. Mai N, Marquardt C, Schenk T. Munich, Germany Patients with writer’s cramp show a movement disorder that is restricted to writing. They generally have no other neurological abnormalities. Spontaneous recovery is rare. Treatments that lead to a sustained improvement of this condition are still not available. Thus, writer’s cramp constitutes a challenge for researchers in the field of motor rehabilitation. The aim of the present study was to develop and evaluate new training procedures for the treatment of handwriting disorders in writer’s cramp. Handwriting movements of 70 patients were recorded with a digitizing tablet. Performance was assessed by analyzing the velocity profiles of single up or down strokes. All patients showed abnormal velocity profiles when writing individual letters. However, 80% of the patients showed normal or almost normal velocity profiles under altered writing conditions (e.g., writing with a modified pen-grip posture, writing while standing). A training procedure was developed which started from a condition under which good writing was possible and proceeded toward conditions more like those of standard writing., The training of 30 patients has been completed. Handwriting performance was measured before and after training with the digitizing tablet. Handwriting was clearly improved after the training of most patients. These results show that the handwriting disorder of patients with writer’s cramp can be reduced even in cases with long-standing disorder by such training. This raises doubts about the widespread notion that writer’s cramp is a form of focal dystonia. P112 LONG-TERM TREATMENT WITH α-DIHYDROERGOCRYPTINE IN DE NOVO PARKINSONIAN PATIENTS: EIGHTEEN-MONTH FOLLOW-UP. Dihydroergocryptine Parkinson’s Disease Italian Study Group

P110 RELATIONSHIP BETWEEN EVENT-RELATED POTENTIALS, HMPAO SPECT AND COGNITION IN PARKINSONIAN PATIENTS. Z. Katsarou, S. Bostantjopoulou, A. Alevriadou, G. Gerasimou, G. Georgiadis, G. Kiosseoglou, A. Kazis, G. Mentenopoulos. Thessaloniki, Greece

In 1994 a multicenter, randomized, double-blind, placebo-controlled, parallel-group study was carried out to confirm the effectiveness and safety of a long-term treatment with α-dihydroergocryptine (α-DHEC) in newly diagnosed Parkinsonian patients. The long term treatment with placebo suggested close together clinical observations and intermediate analyses to prevent unnecessary prolongation of the trial, should there be clear clinical differences between the treatments. The first of the two intermediate analyses, undertaken three months after the randomisation of the patients, showed statistically significant differences between the treatments, with a cautionary check of the false positive results. This experimental evidence led to suspension of the trial to open the experimental keys and recourse to treatment with an active drug of all the patients who, according to the randomisation list, had been assigned to the placebo group. In the interests of assuring the safety of long term use of α-DHEC, a further phase of study was planned, during which all the patients under observation were treated with α-DHEC for the 18-month period specified in the protocol. The aims of the open phase were pursued separately considering the two randomised groups, made up of patients previously treated with α-DHEC (23 patients) and with placebo (23 patients). The statistical analysis of the open phase, using the value at the beginning of the open phase and the duration of the open phase as covariates, showed a significant decrease of the UPDRS total score (P = 0.015) without difference between groups (P = 0.096). These results showed the adequacy and safety of long term monotherapy with αDHEC, after adjusting the dosage to the clinical conditions.

Event-related potentials and regional cerebral blood flow (rCBF) are two techniques employed in the investigation of cognition in patients with Parkinson’s disease (PD). However it is controversial, whether abnormality in each one of them is a reliable index of cognitive impairment. The purpose of our study was to investigate whether auditory P300 event-related potentials (P300) and rCBF, assessed by SPECT, are related to gen-

P113 TREATMENT OF RESTLESS LEG SYNDROME (RLS) WITH CABERGOLINE. Karin Stiasny, Julia Roebbecke, *Peter Schüler, Wolfgang H. Oertel, Dpt. of Neurology, Univ. Marburg, *Pharmacia & Upjohn, Erlangen, Germany

Extrapyramidal Disorders

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Objective: To define the effective doses of cabergoline and to evaluate the tolerability and efficacy of cabergoline in idiopathic restless legs syndrome (RLS) in a 12-week open label pilot trial. Background: Dopaminergic treatment with L-Dopa (plus dopa-decarboxylase-inhibitor) has been proven as efficient therapy in RLS. However, augmentation (e.g. occurrence of symptoms at daytime, increased intensity) may be a limiting factor. Dopamine agonists are an alternative treatment option although the duration of action is also limited. The long acting (D1)/D2 -dopamine agonist cabergoline might overcome these problems. Method: Eight patients (age 38 to 64 years, mean 55.5 years) with idiopathic RLS (duration of disease 4 to 47 years, mean 27.5 years) were diagnosed according to the criteria of the Int. RLS Study Group. All patients had previously been treated with LDopa. At the beginning of the study 3 patients were no longer on L-Dopa because of side effects or inadequate response. Five patients were still on L-Dopa (400–800 mg/day) of whom 4 had developed augmentation. Patients received domperidone 20-mg t.i.d. Cabergoline was then started with 0.5 mg and was increased in steps of 0.5 mg until RLS symptoms improved sufficiently or disappeared in the patients’ opinion. In L-Dopa treated patients, L-Dopa was gradually reduced and discontinued if possible. Efficacy parameters were polysomnography, subjective rating of RLS-symptoms and sleep by a questionnaire, Patients and Clinical Global Impression. Results: 6 of 8 patients (follow-up period 23 to 139 days, mean 78 days) became free of RLS-symptoms under cabergoline-monotherapy (1 to 2 mg, mean 1.6 mg) as a single evening dose. The remaining two patients report a significant relief of RLS-symptoms. Both of them continue to take 2mg cabergoline (for 23/105 days), one additionally taking 300 mg L-Dopa. Tolerablity was excellent in 7 pts. One patient reported possibly drug-related nausea. However, in all 8 patients, domperidone was stopped after 2-8 weeks. Conclusion: Cabergoline as a single evening dose (1–2 mg) is effective and well tolerated in RLS.

P114 PARKINSONIAN TREMOR AFTER UNILATERAL PALLIDOTOMY. Valldeoriola F, Tolosa E, Nobbe FA, Rumià J, Molinuevo JL. Barcelona, Spain Pallidotomy improves levodopa-induced dyskinesias and parkinsonian symptoms but previous studies on pallidotomy have not been focused on its effects on tremor. We evaluated the effect of unilateral stereotactic pallidotomy with microrecording guidance on contralateral tremor in 23 consecutive patients who underwent pallidotomy. Patients scoring less than three in a twelve points scale based on UPDRS, were excluded. Tremor was classified as moderate (group A; score 3–6, n = 9) or severe (group B; score 7–12, n = 5). Clinical evaluation was done in overnight off condition, 3 days before and 4 months after surgery. Levodopa intake remained stable during the study. Mean age and disease duration of patients was 59 (± 6.3) and 14.5 (± 6.6) years. Mean Hoehn & Yahr and Schwab & England scores while off were 3.68 and 36.4 %. There were no differences in the distribution of age, sex, duration and severity of the disease among patients with moderate or severe tremor. Bradykinesia and rigidity contralateral to pallidotomy improved similarly in group A and B of patients (respectively, bradykinesia improved 46% and 40% and rigidity 41% and 40%). Pallidotomy ameliorated contralateral dyskinesias by > 85% in both groups. Overall, contralateral tremor decreased by 54% ( p < 0.0001), but patients with moderate tremor improved by 68% (p < 0.0001) and patients with severe tremor only by 38% (p = 0.02). Pallidotomy is effective in reducing parkinsonian tremor more so than it is to improve bradykinesia and rigidity. Severe tremor, however, might respond better to other neurosurgical strategies.

P115 EFFECTIVENESS OF RISPERIDONE IN HYPERKINETIC MOVEMENT DISORDERS. C. Dallocchio, S. Cattaneo, L. Barletta, E. Rocci, V. Pellegrini, C. Buffa, P. Mazzarello*. Dipartimento di Neurologia e Riabilitazione, Ospedale S. Giacomo, Novi Ligure AL; * Istituto di Genetica, Biochimica ed Evoluzionistica, CNR, Pavia Objective: To determine the effect of the atypical neuroleptic risperidone in patients with hyperkinetic movement disorders (HMD); all patients had either failed to respond or failed to tolerate common medications used in these disorders. Background: Risperidone is an atypical antipsychotic agent with serotonine-5HT2 and dopamine-D2 receptors antagonism, producing fewer extrapyramidal side effects common to conventional neuroleptic drugs. Few open study suggest the potential role of risperidone in HMD. Recent literature suggest that the atypical neuroleptic clozapine ameliorates some abnormal movement desorders but clozapine can be used safely if weekly

white-cell counts are estabilished. Methods: Adequate follow-up information about the effects of risperidone (daily dosage 1–6 mg.) was available on 13 patients (8 women and 5 men, mean age 56.5 ± 10.7) with severe HMD. The response was rated on a scale of 1 to 5 where 1 = marked reduction in abnormal movements, excellent improvement in function; 2 = moderate reduction in abnormal movements, very good improvement in function; 3 = moderate improvement in abnormal movements, only mild or no improvement in function; 4 = poor or no response in abnormal movements or function; 5 = worsening of movement disorder, deterioration in function, or both. Patients were examined on admission and at regular intervals and the mean duration of risperidone treatment was 5.5 months (range 2 to 24 months). Diagnoses included Huntington’s disease (N = 4), tardive dyskinesia (N = 5), essential tremor (N = 2), parkinsonian rest tremor (N = 2). Results: The global response rating of 1 (marked improvement) was recorded in all the patients except for the two patients with essential tremor (global response rating of 3) and for one patient with parkinsonian rest tremor (global response rating of 4). The most common side effects included drowsiness (30 %) and akathisia (10 %); no kind of extrapyramidal side-effects were reported. Conclusions: Although this is not a comparative study, we feel that despite some temporary side-effects, risperidone is a useful drug in the treatment of chorea and tardive dyskinesia and that it could be effective for the treatment of a variety of HMD.

P116 LONG-TERM RESULTS OF PALLIDOTOMY IN PARKINSON’S DISEASE. Gorospe A, Linazasoro G, Ramos E, Guridi J, Rodriguez M, Obeso JA. Clínica Quirón. San Sebastián. Spain Objective: Evaluate the efficacy of microelectrode guided pallidotomy in Parkinson’s disease. Background: There are few publications about the long-term efficacy of pallidotomy. Methods: Twenty-eight patients with complicated Parkinson’s disease (severe fluctuations and dyskinesias) were summited to microelectrode guided pallidotomy. Assessments conducted in the basal OFF (12 h. without medication) and best ON states preoperatively and 1, 12 and 24 months postoperatively included: UPDRS motor subscale (total, each hemibody, tremor, bradikynesia, rigidity and axial symptoms) and Obeso’s dyskinesia scale. Results: Total motor UPDRS in OFF improved by 33.7% at 1 year and 23% at 2 years. This moderate loss of clinical benefit was related to a worsening of the parkinsonian symptoms in the non-operated side (28.5% at 2 years) and a sligth reduction of the effect on axial symptoms (38% and 21% of improvement in the first and the second year, respectively). Tremor, rigidity and bradykinesia on the operated side improved inmediately after surgery and this effect was sustained over the follow-up period. Contralateral dyskinesias dissappeared in all cases but in one. Conclusion: All parkinsonian symptoms improved after surgery either in the OFF and in the ON state. Levodopa induced dyskinesias were practically abolished. Much of the benefit was sustained at two years, although some improvements, such as those on axial symptoms decreased within the second year.

P117 LONG-TERM EFFECTIVENESS OF HIGH FREQUENCY STIMULATION OF THE GPi IN SEVERE PARKINSON’S DISEASE: A FOUR YEAR FOLLOW UP. Guehl D, Rougier A, Boraud T, Bioulac B, Gross C. Bordeaux, France Improved knowledge of pathogenesis of the Parkinson’s disease has underlined the role played by the subthalamic nucleus (STN), whose unbridled activity induced a consequent overstimulation of the Globus pallidus internalis (GPi). Since high frequency stimulation (HFS) can reversibly incapacitate a nervous structure, we proposed stimulation of ventro-posterolateral GPi to a parkinsonian patient who has now been followed up for four years. Clinical tests were carried out using the Unified Parkinson Disease Rating Scale. when HFS was started, the patient was 46 years old and had been suffering for ten years from akinesia, rigidity and mild tremor on the right side as well as speech and gait impairments. L-dopa therapy had subsequently induced dyskinesia on the right side and axial dystonia. HFS of the left GPi induced a dramatic decrease in contralateral rigidity and akinesia, particularly in the upper limb. Gait, right upper tremor, postural stability and speech were also improved; dyskinesia was considerably reduced. Despite the fact that the disease has progressed, HFS has maintained and even increased its effectiveness over the four year following period. These results confirm the long term action of HFS of the GPi on bradykinesia, rigidity and L-dopa induced dyskinesia. It seems to constitute an excellent -and reversible- therapy for severe akineto-rigid parkinsonism.

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P118 CLINICAL AND NEUROPHYSIOLOGICAL PROTOCOL FOR THE ASSESSMENT OF TREMOR. Pacchetti C, Mancini F, Bulgheroni M, Fundarò C, Martignoni E, Nappi G. Parkinson’s Disease and Movement Disorders Centre, Institute of Neurology, IRCCS “C. Mondino”, University of Pavia, Pavia, Italy Tremor is a rhythmical involuntary oscillatory movement of one body part; its phenomenological features (components, anatomical sites and times of presentation) are simply to describe but its etiologic and syndromic allotment is, sometimes, complex. Clinical classification supported by neurophysiological data (accelerometry and surface EMG) allows a correct diagnosis of tremor but these methods usually fail to reflect tremor’s effect on patients daily living. To this aim, we have realised a protocol for the clinical and neurophysiological assessment of tremor. The clinical part consisted in personal history, medical examination, the Activities of Daily Living Self-questionnaire (ADLSQ), the Handicap Self-questionnaire (HSQ) and the handwriting test. The neurophysiological session included accelerometry (Bruel & Kjaer) and surface EMG (8 channels telemetric system, BTS, ITALY), which data were acquired while patients performed standardised sequences of movements: relaxed arms, outstretched arms, slow hands’ movements, finger-to-finger test and execution of more disabling activities of daily living as emerged from previous rating scales. Applying this protocol we have identified the clinical and neurophysiological features of tremor in 50 patients with Parkinson’s Disease and 50 patients with Essential Tremor. In particular, we have described EMGraphic and accelerometric pattern of tremor both a time and frequency domain. These data were also correlated with the rating scales in order to associate the neurophysiological pattern and the degree of patients’ disability reflected by the scales.

P119 “APRAXIA OF LID OPENING”, A FOCAL EYELID DYSTONIA? EFFICACY OF BOTULINUM TOXIN. M. Borg, M. Chatel. Service de Neurologie. Hôpital Pasteur, Nice, France During the last three years, we have seen 10 patients with the so-called “apraxia of lid opening” (ALO) according to Lepore and Duvoisin’s clinical criteria; as an isolated condition (1 patient), with idiopathic blepharospasm (1 patient), with idiopathic Parkinson’s disease (4 patients), with progressive supranuclear palsy (3 patients), with multiple system atrophy (1 patient). In 3 cases, the features were transient and seen in Parkinson’s disease, improved by modification of Dopa-therapy. The 7 others patients were treated with botulinum toxin (BTX) therapy (Dysport). Injection of ALO, like in classical blepharospasm, was followed by lack of improvement in two cases. Because of this ineffectiveness, injections were realised according to method described, among others, by Krack and Marion (1994), medially and laterally in pretarsal parts of the palpebral orbicularis oculi (OO), in the upper and lower lid, close to the eyelash lines. A clinical and functional benefit was obtained in 6 patients out of 7. ALO is a syndrome which may be produce by several mechanisms, and in some cases chemical weakening induced by BTX, of the pretarsal OO, allows dramatic reduction of this disorder. These data provide clinical support to the suggested role of the pretarsal OO in the pathogenesis of some cases of ALO.

P120 SCHUHFRIED’S VIENNA TESTING BATTERY, AN OBJECTIVE TOOL TO EVALUATE NEW ANTIPARKINSON MEDICATION. C. N. Homann, K. Wenzel, K. Suppan, G. Ivanic, R. Schmidt, K. Petrovic, M. Feichtinger, R. Crevenna, M. Scala, E. Ott. Dept. of Neurology, KarlFranzens-Universität Graz, Austria The evaluation of the effects of antiparkinson medication with the current instruments always comprises a certain degree of subjectivity, be it on part of the patient or the physician rater. To increase objectivity we added to our standard evaluation repertoire the test series by Sturm & Büssing, a part of the Schuhfried’s Vienna Motor Performance Testing Battery, with subtests for steadiness, tracing, aiming and tapping. 9 patients, 3 female and 6 male, aged 53–72 (mean 61.5) received a new Dopamine Agonist over a 10 week study period and were tested at baseline and each consecutive visit. While L-Dopa could be reduced substantially parameters for bradykinesia, tremor and fine motor skills showed to remain stable. These findings were in accordance with the scores of the UPDRS part II and III and the stages by Höhn and Yahr. This reliable and fast method might be a good adjunct to further large scale drug trials.

P121 R- AND S-SALSOLINOL ARE NOT INCREASED IN PLASMA OF “DE-NOVO” PARKINSONIAN PATIENTS. Th. Müller, S. Sällström Baum*, P. Häussermann, D. Woitalla, H. Rommelspacher*, W. Kuhn. Department of Neurology, Ruhr-University of Bochum, * Department of Clinical Neurobiology, Benjamin Franklin Hospital of the Free University of Berlin, Germany An augmented synthesis of tetrahydroisoquinolines, such as salsolinol (SAL) or an increased N-methylation of these compounds has been addressed as putative pathophysiologic mechanisms in Parkinson’s disease (PD). Aim of this study was (1) to investigate relations between plasma levels of dopamine and R- and S-enantiomers of SAL and (2) whether these metabolic precursors of the neurotoxic N-methylated-SAL (NMSAL) are elevated in “de-novo” Parkinsonian patients compared to matched healthy controls. Plasma levels of R- and S-SAL and dopamine did not significantly (R-SAL: p = 0.61, S-SAL: p = 0.51, dopamine: p = 0.84) differ in both groups. Dopamine levels were not associated to R-SAL (p = 0.88, r 2 = 0.0008) and S-SAL ( p = 0.088, r 2 = 0.12) neither in Parkinsonian patients nor in controls. We conclude, that an upregulation of N-methylation of tetrahydroisoquinolines takes place in PD by enzymes such as neutral N-methyltransferase specific for R-SAL. The activity of this enzyme has been found elevated in parkinsonian lymphocytes. This increased Nmethylation by the N-methyltransferase specific for R-SAL leads to the known augmented levels of neurotoxic R-NMSAL in Parkinsonian patients compared to controls in the cenral nervous system. P122 COGNITIVE DEFICITS ARE DIFFERENT IN SPORADIC AND FAMILIAL PARKINSON’S DISEASE. Dujardin K, Grunberg C, Becquet E, Defebvre L, Destee A. Lille, France Some studies have demonstrated that sporadic and familial Parkinson’s disease (PD) were clinically completely similar. From a physiopathological point of view, and perhaps in the future from a therapeutic point of view, it seemed to us very important to study whether these two clinical forms were also similar with regard to cognitive impairment. The present study compared then cognitive function in two groups of treated patients with familial or sporadic PD to one group of matched control subjects. Executive functions (Wisconsin Card Sorting Test, word fluency test, spatial working memory task, Brown-Peterson paradigm and Luria’s motor dynamic sequences) were particularly investigated. The results showed that, compared to controls, both groups of PD patients presented executive dysfunction. However, the deficits were less important in patients with familial PD. Indeed, these patients performed significantly worse than controls only on a limited number of tasks, although patients with sporadic PD presented a significantly larger dysexecutive syndrome. Since the patients of both groups were matched as closely as possible for age, duration and severity of the disease as well as for intellectual function, these deficits are interpreted as consecutive to dysfunction of the dorsolateral striato-cortical loop. It is suggested that, in both patients groups, the deficits result from dopaminergic and non-dopaminergic deprivation but that the quantitatively larger impairments observed in sporadic PD patients may result from a larger participation of non-dopaminergic factors. P123 AFFECTIVE DISORDERS IN PATIENTS WITH MULTISYSTEM ATROPHY (MSA) AND IDIOPATHIC PARKINSON’S DISEASE (IPD). Fetoni V, Testa D, Genitrini S, Soliveri P, Monza D, Caraceni T, Girotti F. Istituto Nazionale Neurologico C. Besta, Milano In its initial phases, striato-nigral (SND) type MSA is difficult to distinguish from IDP. However as MSA progresses, autonomic, pyramidal and often cerebellar signs, as well as loss of initial response to L-Dopa, render differential diagnosis relatively easy. Both conditions are characterized by compromise of executive functions as a result of damage to striato-frontal circuits. However no studies have examined psychiatric disturbances in MSA, although these have been exensively investigated in IPD. We examined mood and psychiatric disturbances in 12 probable SND type MSA patients compared to 12 IPD patients with similar motor compromise. We evaluated the patients in the absence of L-dopa and after administering 250 mg L-dopa + carbidopa using the following scales: UPDRS for motor assessment, MMSE for mental state, BPRS for psychiatric disturbances and Hamilton scale for depression (HAM-D). At baseline the groups did not differ in age, motor compromise, BPRS or MMSE scores, while illness duration and depression were greater in the IPD group. After L-dopa UPDRS, HAM-D and BPRS scores improved significantly in IPD patients, while in

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MSA patients there was a significant improvement in motor state, a modest but significant improvement in HAM-D score and no change in BPRS. Analysis of depression subitems showed that MSA patients were more compromised than IPD patients on items assessing inhibition and emotional detachment.

Poster Session 2 Genetics P124 CLINICAL FINDINGS IN PROXIMAL MYOTONIC MYOPATHY (PROMM): ANALYSIS OF 80 FAMILIES. Schneider C1, Koch MC2, Meinck HM3, Reiners K1, Reimers C 4, Pongratz D5, Broich P 6, Schalke BCG7, Gonschorek AS8, Janzen RWC 9, Toyka KV1, Ricker K1. Departments of Neurology, Universities of Würzburg1, Heidelberg3, Göttingen4, Bonn6, Regensburg7, and Magdeburg8, Department of Human Genetics, Marburg2, Friedrich-Baur-Institut, München4, Krankenhaus Nordwest Frankfurt 9 PROMM is an autosomal dominantly inherited multisystem disorder similar to but distinct from myotonic dystrophy on clinical and genetic grounds. The core features of PROMM are proximal weakness, myotonia, cataracts and pain. The PROMM phenotype does not segregate with the trinucleotide repeat expansion at the myotonic dystrophy gene locus on chromosome 19q13.3. We evaluated clinical and laboratory data of 214 patients from 80 families with PROMM from Germany. Myotonia was found in 86%, weakness in 69% and cataracts in 74% of the patients. 67% of them suffered from pain, 23% from tremor and 17% from cardiac problems. Hypogonadism was present in 10% of the male patients. In all families CTG repeat expansion on chromosome 19q13.3 could be excluded by DNAanalysis. Conclusion: This extended study allows a better definition of the clinical features and the variability of the disease. In approximately 70% of families all four core features were seen whereas in single patients sometimes only one or two characteristic features of PROMM are present. Thus, the diagnosis of PROMM may often be missed. The molecular defect(s) remain to be discovered.

P125 NOVEL MUTATIONS IN 4 SPANISH FAMILIES WITH MYOTONIA CONGENITA. Gámez J, De Diego C, Cervera C, Plassart E, Lasa A, Baiget M, Fontaine B. Barcelona. Spain; Paris, France The aim of this study was to investigate the molecular genetic basis of autosomal dominant and recessive forms of Myotonia Congenita in Spanish families. Background: The skeletal muscle chloride channel gene (CLCN1) is localised on chromosome 7q35. The gene is composed of 23 exons. Different mutations in CLCN1 have been shown to cause Myotonia Congenita. Materials and methods: A total of 19 patients from 13 families (7 autosomal recessive, 5 autosomal dominant forms and 1 unrelated patient) were investigated. All patients underwent full neurologic examination with a particular attention to the neuromuscular system. The pattern of transmission was established whenever possible by examination of family members. Genetic analysis was performed using DNA isolated from leukocytes. The detection and identification was performed using PCR-SSCP analysis and direct PCR-sequencing. Genotyping was made with D7S684, D7S661 and D7S2513 microsatellites. Results: We have found 4 novel mutations (2 dominant and 2 recessive). One was a frameshift mutation due to a 4 bp insertion. The other 3 mutations were: 2 missense (A221T and R669C) and 1 nonsense (Q658X). We have found also 2 novel polymorphisms. In the remaining of families we were unable to find out any mutation, although they fulfilled the diagnostic criteria for the disease. Conclusions: These results in our Spanish patients confirm the existence of a large number of rare mutations in Myotonia Congenita. This hypothesis was previously suggested by Meyer-Kleine in 1994. Many additional mutations remain to be discovered in this gene.

P126 GAG DELETION IN THE DYT1 GENE IN EARLY LIMB-ONSET IDIOPATHIC TORSION DYSTONIA IN GERMANY. C. Kamm, E. Kastellon-Konkiewicz, M. Naumann, A. Ceballos-Baumann and T. Gasser Early limb-onset idiopathic torsion dystonia ( ITD) is a movement disorder, beginning in childhood and characterized by sustained involuntary

muscle contractions. It is transmitted as an autosomal-dominant trait with reduced penetrance of 30–40% and particularly high prevalence among Ashkenazi Jews. Recently, Ozelius et al. (Nat Genet 1997; 17 : 40– 48) identified the DYT1 gene on human chromosome 9q34 and found a unique 3-bp GAG deletion in heterozygous form in 261 obligate gene carriers in 68 families with early limb-onset ITD linked to chromosome 9q, including four non-Jewish families, as well as in 14 out of 19 families (= 74%) with typical early-onset dystonia of different ethnic backgrounds. To investigate the role of this deletion in various dystonia subtypes in our population, we have examined 56 patients with ITD for the 3-bp GAG deletion. Of four patients with typical early limb-onset ITD, one of them with positive family history, three (= 75%) tested positive for the mutation, as did one patient with multifocal (and most probably beginning generalized) dystonia, whereas five other patients with multifocal, 30 patients with focal cervical, 14 patients with segmental and two patients with atypical early-onset generalized dystonia beginning in cervical muscles did not. This suggests that the GAG deletion is responsible for the vast majority of cases of typical early limb-onset dystonia in our population, consistent with the findings of Ozelius et al. P127 THE FIRST STOP CODON POINT MUTATION IN THE HUMAN VOLTAGE GATED POTASSIUM CHANNEL Kv1.1 ASSOCIATES WITH DRUG RESISTANT EPISODIC ATAXIA TYPE I. Hanna MG1, Eunson L1, Panayiotopoulos CP2, Youroukos S3, and Wood NW1. 1Neurogenetics Section, Dept of Clinical Neurology, Institute of Neurology, Queen Square, London, UK; 2Department of Clinical Neurophysiology and Epilepsies, St Thomas’ Hospital, London, UK; 3Elpidos, Athens, Greece Episodic ataxia type I is a rare autosomal dominant disorder in which patients experience brief attacks of cerebellar ataxia and have continous interattack myokymia. Mutations in the human voltage gated potassium channel on chromosome 12p have been described in EA1 patients. We have identified a 20 year old Greek female who developed typical episodes of limb ataxia with dysarthria at the age of 10 years precipitated by sudden movement, startle and emotional stress. She experienced multiple attacks in a day but neurological examination was normal between attacks other than mild perioral myokymia. There was no family history. Although there was an initial improvement in attack frequency with acetazolamide this improvement was not maintained and carbamazepine was added to regime with little additional benefit. Genomic DNA sequence analysis of the entire voltage gated potassium channel (Kv1.1) on chromosome 12p was undertaken. A new heterozygous point mutation in codon 417 was identified. This C to G transition resulted in the introduction of a premature stop codon which would be predicted to result in the loss of the final 64 amino acids from the C terminal cytoplasmic loop. This mutation was not detected in 200 control chromosomes or in the patients parents suggesting that she represents a fresh dominant mutation. This is the first stop codon mutation to be reported in the human voltage gated potassium channel (Kv1.1). It may induce channel dysfunction by impairing C type inactivation and this may account for the severe drug resistant phenotype. This case illustrates that there may not always be a family history and that the treatment response in EA1 patients is heterogeneous and is likely to be mutation specific. P128 SCREENING OF DYT1 MUTATION IN BRITISH DYSTONIA PATIENTS. E. M. Valente, P. R. Jarman, T. T. Warner, O. Bandmann, N. W. Wood. Neurogenetics, Institute of Neurology, Queen Square, London, UK Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. DYT1 on chromosome 9q34 was the first PTD gene mapped. A three basepair (GAG) deletion in this gene was reported to account for almost all early limb-onset generalised PTD. No relationship has been found with DYT1 in patients with prominent cranio-cervical involvement. To elucidate the DYT1-associated phenotype, we analysed the DYT1 mutation in 85 PTD patients, either sporadic or index cases from small PTD families. Patients have been divided into three clinical subgroups: a) typical or probable DYT1 phenotype (early limb-onset generalised dystonia) (n =18): 13 patients (72%) carried the GAG deletion; b) uncertain DYT1 phenotype (cervical or cranial dystonia spreading to limbs, or isolated writer’s cramp beginning before age 45) (n = 12): only 1 patient (9%) (early arm-onset generalised dystonia) had the DYT1 mutation; c) atypical or unlikely DYT1 phenotype (focal or segmental cervical-cranial dystonia, writer’s cramp beginning after age 45) (n = 55): 2 patients (4%) (segmental dystonia starting in the right arm and in the neck, respectively) carried the GAG deletion. These data confirm the importance of the GAG

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deletion in PTD but indicate phenotypic and genotypic heterogeneity. This is the first study to identify the DYT1 mutation as causative in segmental dystonia. P129 FREQUENCY OF His1070Gln AND Gly1267Lys MUTATIONS IN POLISH WD PATIENTS’ POPULATION. B. Tarnacka, G. Gromadzka, M. Rodo, A. Czlonkowska, Institute of Psychiatry and Neurology, Warsaw, Poland The gene responsible for Wilson’s Disease (WD) encodes copper transporting ATP-ase. More than 30 mutations (M) have been described so far. 124 Polish WD patients from 109 families were analysed for His1070Gln M and Gly11267Lys M with regard to age and the clinical form of presentation. To identify these Ms single stand conformational polymorphism analysis was performed. The group consisted of 83 patients with neurological presentation (NP), 17 with hepatic presentation (HP) while 23 were asymptomatic. His1070Gln M, present on both chromosomes, occured in 34 cases – 27% [95% CI 19.6–35.3]: 26 were with NP (age of onset 29 ± 15.5), 4 with HP (age of onset 18 ± 8), 4 were asymptomatic. In 26 patients – 21% [95% CI 13.8–28.1] – we observed Gly1267Lys M on both chromosomes; 15 of these patients were with NP (age of onset 29 ± 15.5) and 5 with HP (age of onset 11 ± 1.5). We observed 8 patients (6.4%) with both Ms on their chromosomes. 24 patients were heterozygous for His 1070Gln M and 19 for Gly1267LysM; mutation on the second chromosome was unknown. In 13 cases the above Ms have not been found. Our conclusion is that His1070Gln M and Gly1267Lys M are most frequent mutations in Polish WD population (present on 72% of chromosomes). P130 EFFECT OF SIMVASTATIN IN ADDITION TO CHENODEOXYCHOLIC ACID IN PATIENTS WITH CEREBROTENDINOUS XANTHOMATOSIS. Verrips A1, Wevers R 2, van Engelen BGM1, Keyser A1, Wolters BG 4, Barkhof F 5, Stalenhoef A6, de Graaf R7, Janssen F2, Gabreëls FJM1. Departments of Neurology1, Internal Medicine 6, and Medical Statistics7, Laboratory of Pediatrics and Neurology2, University Hospital of Nijmegen, department of Clinical Chemistry4, University Hospital Groningen, Department of Diagnostic Radiology5, Free University Hospital, Amsterdam, The Netherlands Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease. The enzyme sterol 27-hydroxylase, active in the bile acid metabolism, is deficient. This enzyme deficiency leads to excessive production of cholestanol that accumulates in many tissues. CTX is characterised by premature bilateral cataract, atherosclerosis, neurological abnormalities and tendon xanthomas. The effects of the combination of chenodeoxycholic acid (CDCA) and simvastatin on serum cholestanol, cholesterol and lathosterol levels were investigated in seven adult patients with CTX, who had been on long-term treatment with CDCA. These patients were treated with the combination of CDCA and an increasing dose of simvastatin for a period of six months. We found a significant effect of this combination therapy compared with CDCA alone regarding the lowering of the serum cholestanol, lathosterol and LDL cholesterol levels. We conclude that, compared to CDCA as monotherapy, the combination of CDCA and simvastatin is effective in lowering serum cholestanol, lathosterol, and LDLcholesterol levels in long-term CDCA treated adult CTX patients. P131 MITOCHONDRIAL ALTERATIONS IN FRIEDREICH’S ATAXIA: COMPARISON WITH THE YEAST GENETIC MODEL. J. L. Bradley, J. Blake, S. Chamberlain*, P. K. Thomas, J. M. Cooper, A. H. V. Schapira. Royal Free Hospital School of Medicine and *Imperial College School of Medicine at St. Mary’s, London, UK The primary defect in Friedreich’s ataxia (FRDA) has been identified as an unstable GAA triplet repeat in intron 1 of the frataxin (X25) gene resulting in a deficiency of frataxin protein presumably by interfering with RNA processing. Frataxin has recently been localised to mitochondria (mt) and several theories have emerged regarding its primary function. These include a role in mtDNA replication or maintenance, oxidative phosphorylation, the antioxidant defence of cells and mitochondrial iron metabolism. To help determine the role of frataxin we have analysed a variety of tissues from patients with FRDA for mitochondrial respiratory chain (MRC) activities, mtDNA abnormalities, aconitase activity and iron accumulation in comparison with similar control samples. MRI activities were significantly reduced in FRDA heart and skeletal muscle but were no dif-

ferent from control in cerebellum or dorsal root ganglia. Aconitase activity, which is a marker of oxidative stress, was also found to be reduced in FRDA heart, DRG and skeletal muscle. Reductions in mtDNA levels were also found both in skeletal and cardiac muscle and iron accumulation seen in the heart, liver, and spleen of FRDA patients.

P132 FRIEDREICH’S ATAXIA AND CONGENITAL GLAUCOMA COSEGREGATING IN AN INBRED SPANISH FAMILY. O. Combarros, J. Berciano, A. Oterino, J. M. Polo, M. De Castro*, F. Palau*. Service of Neurology, Hospital “Marqués de Valdecilla”, Santander; *Service of Genetics, Hospital “La Fe”, Valencia, Spain We describe an inbred family in which three sibs had congenital glaucoma (CG) and two of them also fulfilled all the clinical diagnostic criteria of Friedreich’s ataxia (FA). Four other subjects in this family were affected by history, and all four had progressive ataxia in their first or second decade of life and severe visual failure in infancy (Combarros et al. J Med Genet 1988; 25 : 44–46). DNA was available from parents and proband’s siblings (proband was deceased), and we performed the analysis of the GAA trinucleotide repeat at the FA gene on chromosome 9. Both parents and the non ataxic sibling carried an expanded allele and a normal allele confirming that they were healthy carriers, whereas the ataxic sibling showed two expanded alleles of 1050 and 715 repeats which confirmed FA diagnosis in the family. The present concurrence of FA and CG has not previously been reported. The segregation together of neurological and ophthalmological defects in virtually all affected subjects within this inbred family (except in the non ataxic sibling with CG who represents a meiotic recombination), supports a linkage between FA and CG genes. So far, two loci mapping at 2p21 and 1p36 regions are known to be associated with CG. On the basis of this family, a new locus for CG is postulated on chromosome 9. P133 α1-ANTICHYMOTRYPSIN AA POLYMORPHISM (ACT-AA) AND THE SUSCEPTIBILITY TO PARKINSON’S DISEASE (PD). Esteban Muñoz, Víctor Obach, Mario Ezquerra*, Mercé Francés, Gabriel Salazar, María J. Martí, Rafael Oliva*, Francisca Ballesta*, Eduardo Tolosa. Neurology and * Genetic Services. Hospital Clínic, University of Barcelona. Spain In the last years, the role of genetic factors in the aetiology of PD have gained in importance. Recently, the ACT-AA genotype has been related to an increased risk for developing PD in the Japanese population. Objective: To determine whether the ACT-AA polymorphism is associated with an increased risk for developing PD in our population. Patients and methods: 71 patients with PD were compared to 109 age matched healthy control subjects. DNA was isolated from leukocytes. PCR products were digested with the enzyme MvaI and electrophoresed in a polyacrylamide gel. Statistical analysis were made using the Chi-square and Student tests. Results: The ACT-AA polymorphism frequency was not significantly increased in PD (31%) as compared to controls (28.4%). The ACT allelic distribution was similar for familial and sporadic PD, females and males, and the different types of parkinsonism. The ACT-AA frequency was higher in relatively early onset PD (41,6% in ≤ 50 years old versus 25.5% in > 50), but the same effect was found in control subjects. Conclusions: The ACT-AA polymorphism is not related to an increased risk for developing PD in the Spanish population. The ACT-AA overrepresentation in ≤ 50 years old subjects would suggest that this polymorphism could be associated to other life-threatening conditions different to PD. P134 CLINICAL AND MOLECULAR FINDINGS IN ITALIAN KINDREDS OF AUTOSOMAL DOMINANT CEREBELLAR ATAXIA (ADCA). L. Orsi, P. Mortara, A. Nardacchione, A. Franco, E. Pavanelli, S. Lucisano, A. Mauro, E. Grosso, G. Restagno, N. Migone, D. Schiffer. Torino, Italy Spino-cerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders. We tested for SCA type 1, 2, 3 and 6 mutations 22 unrelated Italian kindreds of ADCA and 40 sporadic patients to evaluate the frequency of the different mutations and the molecular and clinical features. SCA1 mutation was detected in 18% of the families, SCA2 in 36% and SCA6 in 5%. No sporadic cases tested positive for the investigated mutations. In SCA2 patients (N = 21) the expanded alleles ranged from 36 to 45 CAG repeats; a negative correlation between the size of CAG repeat and age of onset was observed with a significant difference between pa-

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ternal and maternal transmission in the anticipation of age at onset. The SCA6 mutation was detected in a large Italian kindred with 23 affected individuals: 23 CAG repeats were detected in all tested subjects, except 1 with 24 CAG. The clinical spectrum in SCA1 and SCA2 patients is wide, without significant differences, although slow saccades and hypo-areflexia are more frequent in SCA2 than in SCA1 patients. The greater phenotypical differences was found between SCA1 and SCA2 groups versus SCA6 patients, that presented a longer duration of disease, and a more homogeneous clinical picture with nystagmus, dysartria, dysphagia and psychic disturbances as more frequent findings associated to the slowly progressive ataxia.

P135 SOMATIC MUTATIONS OF THE (GAA)n TRACT WITHIN THE FRATAXIN GENE CAN BE TRACED BY TYPING SINGLE HAIRBULBS. Epplen C1, Frank G1, Miterski B1, Epplen JT1, Ristow M2, Vorgerd M3, Malin JP3, Amoiridis G4, Przuntek H4 and L Schöls4. 1Molecular Human Genetics, Ruhr-University Bochum, 2Department of Internal Medicine, University Köln, 3Department of Neurology, Kliniken Bergmannsheil and 4Department of Neurology St. Josef Hospital, Ruhr-University Bochum, Germany Friedreich ataxia (FA) is an autosomal recessive neurodegenerative disorder characterized by a trinucleotide expansion in intron 1 of the Frataxin gene on both alleles or, rarely, by point mutations within the coding region. In general, the shorter (GAA)n expansion of both alleles can be correlated with onset and severity of the disease. Intermediately sized alleles of (GAA) 38 were observed in mothers of two families with affected children. In the first family the (GAA) 38 allele expanded during transmission to at least (GAA) 66 and (GAA) > 400. In the second family the (GAA) 38 allele expanded to at least (GAA) 70 and (GAA) > 200. These data were obtained by DNA typing of peripheral blood cells. To test for somatic mutation single hairbulbs were investigated. Up to six distinct (GAA)n containing fragments were observed in single hair bulbs demonstrating somatic mutations. Whether or not single peripheral blood cells display similar heterogeneity is presently being tested. Our results offer explanations for the limited correlation between the genotype in lymphocytes and the variable clinical phenotype. P136 PROMOTOR AND CODING REGION POLYMORPHISMS IN TNF GENES REVEAL A COMPLEX PATTERN OF PREDISPOSITION FOR MULTIPLE SCLEROSIS. Epplen C1, Jäckel S1, Pöhlau D2, Sindern E3, Haupts M4, Weber F5 and Epplen JT1. 1Molecular Human Genetics, 2Departments of Neurology, St. Josef Hospital3, Kliniken Bergmannsheil4, Knappschafts-Krankenhaus, Ruhr-University Bochum, 6Department of Neurology, University Clinic, Göttingen Whether the HLA-DRB1 genes themselfes or genes in strong linkage disequilibrium predispose for MS is still a matter of debate. Whereas the association of the HLA-DRB1*1501 and HLA-DRB1*03 alleles with MS has been confirmed repeatedly in unrelated Northern Europeans, conflicting results have been obtained in family studies. Data obtained by the genome scanning approach point to the TNF region, rather than the HLA-D genes as predisposition factor. Therefore genes, of the TNF family (lymphocyte specific transcript, LST-1; lymphotoxin (LT) B, LTA and TNFA) have been screened by SSCP analysis and different alleles were sequenced. Polymorphisms were identified for the promotor region of the TNFA gene (position –862, –805, –733, –308, and –238), whereas the coding region lacks polymorphisms. Within the LTA gene alleles are defined by polymorphisms in the signal peptide (E-30G) as well as in the mature peptide (H17P, T26N). Four base exchanges in non-coding sequences were found in addition. So far no polymorphisms were identified within the promotor region or coding region of the LST-1 and LTB genes. Typing of MS patients (> 350) and controls (> 350) for HLA-DR, TNF and LTA reveals a complex pattern of haplotypes and genotypes. Distinct LTA alleles are found more often in HLA-DRB1*1501 patients than in HLA-DRB1*1501 control cohorts. P137 IMPLICATION OF A MISMATCH REPAIR OF MITOCHONDRIAL DNA (mtDNA) IN MITOCHONDRIAL CYTOPATHIES. Paul R, *Santucci S, **Rassoulzadegan M, *Paquis V, *Desnuelle C. *Laboratoire de Neurobiologie Cellulaire, Faculté de Médecine, Av. de Valombrose, Nice. **Unité 470 INSERM, Centre de Biochimie, Parc Valrose, Nice

Objective: To identify a post-replicative mismatch repair system of mtDNA in mammals. Background: Homologs of the Escherichia coli MutS mismatch repair protein have been detected in a wide variety of organisms. In Saccharomyces cerevisiae, the product of the MSH1 gene is imported into mitochondria and plays a role in stability of mtDNA. Mutations in yeast MSH1 gene causes a petite phenotype associated with rearrangements of mitochondrial genome. In mammals, such a mtDNA repair mechanism has never been reported. Material/Methods: A mutator phenotype as been evidenced when the human MSH2 gene, implicated in nuclear DNA repair, is expressed in E. coli. It seems that the human MSH2 protein binds to mismatches but is not able to interact with the other bacterial proteins of the MutHLS system. We have constructed a vector expressing the bacterial MutS protein into mammals mitochondria. This expression was analysed in transfected cells using immunohistochemistry methods and its effect was tested by mtDNA large fragment PCR. Results: Expression of the MutS protein was detected in mitochondria of the transfected cells and mtDNA deletions seem to be present. Conclusion: Data give indirect evidence for the presence of a MutHLS like repair system in mammalian mitochondria, raising the hypothesis of its implication in the determinism of mtDNA deletion in mitochondrial cytopathies.

P138 LINKAGE ANALYSIS OF A LARGE ENGLISH FAMILY WITH AUTOSOMAL DOMINANT CEREBELLAR ATAXIA TYPE III. Worth PF, Valente EM, Giunti P, Davis MB, Wood NW. Neurogenetics Section, Department of Clinical Neurology, Institute of Neurology, Queen Square, London. WC1N 3BG. UK The autosomal dominant cerebellar ataxias (ADCAs) are a group of heterogeneous disorders which are clinically classified as types I-III. Recently the genetic basis of some of these clinical subtypes has emerged. There are at least 4 genes which account for ADCAI, of which three have been cloned and are known as SCA1-3. ADCAII appears to be genetically and clinically homogeneous and the gene, SCA7, has been cloned. The molecular basis of the defect in these four genes is an unstable expanded trinucleotide repeat which codes for a polyglutamine domain and accounts for the phenomenon of anticipation. Clinically, ADCAIII is a ‘pure’ ataxia but is genetically heterogeneous. SCA6, the molecular basis of which has been shown to be a moderately expanded trinucleotide repeat in the α1A subunit of the voltage-gated calcium channel gene CACNL1A4, accounts for only 50% of ADCAIII families in the UK. We report a six generation family with ADCAIII comprising 18 affected subjects (Zmax 5.2). Detailed clinical assessment shows that the phenotype is of a late-onset, relatively benign, slowly progressive, pure ataxia and anticipation has not been observed. The family is negative for SCA1–3, 6–7 and is not linked to the other known ataxia loci. A genome-wide search using c.300 highly polymorphic microsatellite markers has been undertaken. To date, 25% of the genome has been excluded. By the time of presentation we hope to have completed the initial screen.

P139 IN VITRO AND IN VIVO ACTIVITY OF MCK REGULATORY SEQUENCES INSERTED IN LTRS OF RETROVIRUS VECTORS. A. Bardoni*, A. Fassati^, M. Sironi§, D. J. Wells†, N. Bresolin*§, G. Dickson^. *IRCCS Eugenio Medea, Associazione La nostra Famiglia Bosisio Parini, Lecco, Italy. ^ Department of Biochemistry, Royal Holloway College, University of London, UK. § Istituto di Clinica Neurologica, Ospedale Maggiore, Università di Milano, Italy. † Gene Targeting Unit, Department of Neuromuscolar Deseases, Charing Cross Campus, London, UK The use of retroviral vectors (RVs) for gene therapy is associated with the risk of malignant transformation of infected cells. Targeting RVs to specific tissues would increase their safety and clinical applicability. Indeed, it could be possible to modulate the enhancer function to construct RVs which can be turned on and off in particular stages of cell differentation or in the same cell in different physiological conditions. To explore the potential of targeting and modulating RV expression to tissue specific we constructed muscle specific vectors which present muscle creatine kinase (MCK) promoter-enhancer unit in place of the viral wild type in the LTRs (Long Terminal Repeats). In vitro the level of expression of these RVs were 30 fold higher in C2 myotubes than C2 myoblasts and the endogenous MCK gene was similarly dependent on the maturity of the muscle cultures. In vivo in regenerating muscle RV testing showed a delayed pattern of expression in myofibres compared to the RV containing the wild type LTRs. These data suggest that other biological components may be important for sustained and consistent tissue specific expression in vivo.

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P140 GENE ASSOCIATION STUDIES OF TRANSFORMING GROWTH FACTOR-BETA (TGF-β) POLYMORPHISMS IN MULTIPLE SCLEROSIS (MS). G. V. McDonnell, A. G. Droogan, C. W. Kirk, C. A. Graham, S. A. Hawkins. Belfast, Northern Ireland, U.K. Objective: To examine the influence of TGF-β genes on MS susceptibility. Background: TGF-β, of which three homologous isoforms exist (1, 2 and 3), is a strongly immunosuppressive cytokine-inhibiting expression of pro-inflammatory cytokines and blocking cytokine induction of adhesion molecules. TGF-β delays onset of EAE and TGF-β1 gene knockout mice develop fatal multifocal inflammatory disease. High TGF-β levels exist during MS remission and it is postulated that the unremitting course of primary progressive disease (PPMS) may be due to low TGF-β levels. Methods: Gene association studies using separate polymorphic microsatellite markers for TGF-β1 and TGF-β2 were performed, incorporating 151 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 104 PPMS patients and 159 normal controls (Nor). Forward primers were 5´ end-labelled with 6-Fam, PCR products were analysed on an Applied Biosystems 373A fluorescent fragment analyser and Genescan 672 software was used for allele sizing. Results: No significant differences existed in allele frequencies between either MS group and controls regarding the TGF-β1 marker: RR/SPMS vs Nor ( p = 0.48, df = 8); PPMS vs Nor ( p = 0.34, df = 8). Similarly there were no associations demonstrated with the TGF-β2 marker: RR/SPMS vs Nor ( p = 0.24, df = 2); PPMS vs Nor ( p = 0.53, df = 2). Conclusion: These data indicate that TGF-β1 and 2 genes are not loci influencing MS susceptibility, either RR/SPMS or PPMS, in this population.

P141 CONFIRMATION OF THE HEREDITARY NEURALGIC AMYOTROPHY (HNA) LOCUS TO CHROMOSOME 17q24–-q25 IN ONE SPANISH FAMILY WITH CHARACTERISTIC FACIAL DYSMORPHIC FEATURES. A. Pou-Serradell (1), J. Meuleman (2), G. Kuhlenbaeumer (2), C. Van Broëckhoven (2), V. Timmerman (2). Servei de de Neurologia (1), Hospital del Mar, Universitat Autònoma de Barcelona. Barcelona. Spain. Neurogenetics Department (2), Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Antwerpen, Belgium Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant inherited recurrent focal neuropathy characterized by episodes of brachial plexus neuropathy with muscle weakness and atrophy as well as sensory disturbances. Mild dysmorphic facial features including hypotelorism, long nasal bridge and upslanting palpebral fissures are present in some HNA pedigress but clear segregation of the dysmorphism with the disease has not been proven. To confirm the recently described HNA locus on distal chromosome 17q, we performed a genetic linkage study in an extended pedigree of Spanish origin in which the diagnosis of HNA was confirmed a genetic linkage study in an extended pedigree of Spanish origin in which the diagnosis of HNA was confirmed by accepted diagnostic criteria. Seventeen family members including 7 affected individual, with mild dysmorphic facial features, were available for linkage analysis. Defects in genes associated with various other inherited peripheral neuropathies were not excluded. Phenotypic information on all family members included in this study was obtained by both interview and physical examination. The results of genetic analysis in this HNA pedigree indicate that all the patients have a common disease haplotype. Our results confirm the presence of a locus on chromosome 17q. Further analysis in HNA pedigrees, including those with and without associated dysmorphic features, will also be needed to explore the possibility of genetic heterogeneity within HNA.

P142 AUTOSOMAL DOMINANT MYOFIBRILLAR MYOPATHY WITH ABNORMAL DESMIN ACCUMULATION. CLINICAL AND FOLLOW-UP STUDY OF ONE SPANISH FAMILY WITH INTRAFAMILIAL PHENOTYPE VARIABILITY. A. Pou-Serradell (1), J. Mª Corominas Torres (2), J. Lloreta i Trull (2). Servei de Neurologia (1), Unitat de Neuropatologia (2). Hospital del Mar. Universitat Autònoma de Barcelona. Barcelona. Spain The combination of distal as well as proximal weakness, cardiomyopathy, involvement of velo-pharyngeal muscles, respiratory disturbances and dominant inheritance, should strongly suggest a disorder with myofibrillar alter-

ations and foci of abnormal desmin positivity in muscle. This report concerns a family from southern Spain in which 2 sisters present an involvement of skeletal (distal more than proximal) and velo-pharyngeal muscles with onset at the third decade of life and with a rather severe progressivity, leading soon to the bilateral foot drops. Two other members, the mother and one brother, – the latter with hypertrophic cardiomyopathy, atrioventricular block and severe heart failure, – have already died. The mode of transmission is autosomal dominant. The electrophysiological study shows myogenic patterns with spontaneous activity but not myotonic discharges. Genetic studies have excluded myotonic dystrophy. Muscle biopsy in the sisters shows myopathic changes and a few rimmed vacuoles in one of them. We describe the light microscopic and ultrastructural findings in the 2 surviving patients and demonstrate a similar pattern of structural reactions of skeletal muscle in both of them. An intrasarcoplasmic (specially subsarcolemmal) accumulation of an electro-dense filamentous material arising from the Z-bands and a focal disruption of the myofibrils. Immunohistochemically the subsarcolemmal material stained positively for the intermediate filament protein desmin but other proteins as ubiquitin and actin were overexpressed. In conclusion, these very different intrafamilial phenotype into our family presuppose a disorder involving skeletal, cardiac and smooth muscle, confirming the multisystemic character of desmin myopathy. Nevertheless, since other proteins appear also accumulated in the sarcoplasm, we consider the term Myofibrillar Myopathy more appropiate to cover this spectrum of pathologic changes otherwise considered as desmin-related neuromuscular disorders.

P143 MELAS MUTATION PRESENTING WITH RHABDOMYOLYSIS. Sukumaran S, Droogan O, Duran S, Farrell MA, Harmey M, Murphy J, O’Connor K, Perryman R, Hardiman O. Neurosciences Division, Beaumont Hospital Dublin, Dept. Botany University College Dublin, Louth Hospital, Co. Louth, Ireland Rhabdomyolysis is associated with disorders of muscle metabolism in which there is a deficiency of substrate, and rarely with disorders of oxidative phosphorylation. A 26-year-old man presented with an acute leptospirosis manifesting as aseptic meningitis, followed by severe rhabdomyolysis, leading to acute renal failure. A muscle biopsy revealed ragged red fibres, and staining with cytochrome oxidase and succinic dehydrogenase revealed interfibre mosaicism. His past history was remarkable for exercise intolerance. Neurologic examination on recovery was normal with the exception of a mild myopathy including ophthalmoplegia. Family history was unremarkable. Mitochondrial DNA analysis from muscle mitochondria revealed a point mutation A3243G, commonly associated with MELAS syndrome. Neither the patient nor his family had any of the characteristic stigmata of MELAS. To our knowledge, this is the first reported case of rhabdomyolysis associated with this mutation. In addition to defects of substrate utilisation, oxidative phosphorylation defects should be sought in patients with unexplained rhabdomyolysis.

P144 FAMILIAL OCCURRENCE OF MENINGIOMAS: COINCIDENCE OR HEREDITY FACTORS? V. de Borchgrave*, M. Dupuis*, G. Dardenne**, M. Donnay***. Department of Neurology*, Neurosurgery** and Anatomopathology*** Clinique Saint-Pierre, Ottignies, Belgium There are a few reports of familial occurrence of meningiomas but the evidence for inheritance is unclear. We describe the case of a father and his daughter both with meningioma. The father was hospitalised for subacute confusion and the scanner showed a right temporal meningioma. Histological examination revealed a secretory meningioma. Five months later, the patient’s daughter was admitted for a first tonic-clonic seizure. She also presented a right temporal meningioma which was a transitional form. The ophtalmogical and dermatological examination of the two patients didn’t show any sign of neurofibromatosis type 2 (NF2), and no deletion of chromosome 22 in leucocytes was detected. Occurrence of meningiomas in at least two members of the same family without any sign of neurofibromatosis has been reported twelve times. Influence of genetics factors is suggested by recent linkage analysis which supported the hypothesis that there exist a familial meningioma locus, localised on the long arm of the chromosome 22, distinct and distal to the NF2 locus. The inherited occurrence of meningiomas is rare and therefore, doesn’t justify systematic familial research in isolated cases. However, if two members of the same family is affected, it is maybe helpful to examinate their relatives, perform a scanner or MRI and discuss genetics analysis.

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P145 DIAGNOSIS OF THE CMT1A DUPLICATION BY PCR-BASED DETECTION OF A NOVEL JUNCTION FRAGMENT. O. Combarros, A. Oterino, J. Berciano, A. Benito*, J. L. Fernández-Luna*. Services of Neurology and Immunology*, University Hospital “Marqués de Valdecilla”, Santander, Spain Charcot-Marie-Tooth type 1A (CMT1A) is associated with duplication of 1.5 Mb region on 17p11.2–p12. This rearrangement occurs after mispairing and unequal recombination event during meiosis between repeated and homologous sequences flanking the 1.5 Mb region (distal and proximal CMT1A-REPs). A recombination hotspot has been identified between the distal and proximal REP elements,and Southern blot detects a specific 1.7 kb EcoRI/NsiI junctional fragment in 75% of CMT1A duplication cases. A recent study (Haupt et al., Hum Genet 1997; 99 : 688–691), has introduced a PCR-based method that identifies directly the REP junction fragment by using a set of primers that flank the EcoRI (distal REP) and NsiI (proximal REP) restriction sites. This method allows a detection frequency similar to the one obtained by the Southern analysis. To better define the sensitivity of this PCR-based CMT1A-REP analysis, we have conducted a study (using the primers originally reported) in 40 control subjects and 16 unrelated patients with known duplications detected with either the RFLPs pVAW409R3/MspI (Southern) or microsatellite (RM11-GT and AFM191xh2) analysis (PCR). Only six patients (37.5%) displayed a novel 1.7 kb EcoRI/NsiI junction fragment that was not found in normal subjects. An explanation for the low sensitivity of this method in our experience is that the majority of our patients could be polimorphic at the restriction enzyme sites, or that the recombination could have occurred just outside the 1.7 kb hotspot region.

P146 MITOCHONDRIAL 3243A→G MUTATION (MELAS MUTATION) ASSOCIATED WITH PAINFUL MUSCLE STIFFNESS. M. Deschauer, MD, T. Wieser, MD, S. Neudecker, A. Lindner, MD, and S. Zierz, MD. Department of Neurology, Martin-Luther-University Halle-Wittenberg Ernst-Grube-Str. 40, D-06097 Halle, Germany The mitochondrial mutation A→G at nucleotide position 3243 is typically associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and less frequently with other mitochondrial encephalomyopathies like CPEO (chronic progressive external ophthalmoplegia), diabetes mellitus with deafness and MERRF (myoclonic epilepsy with ragged red fibers). We found this mutation in a 61year-old patient who developed at the age of 54 a myopathy with painful muscle stiffness as the main feature and who’s muscle histopathology showed ragged red fibers. The mutation was detected heteroplasmatically in DNA from muscle and blood by PCR (polymerase chain reaction) amplification and restriction enzyme digestion. The level of mutant DNA was higher in muscle tissue than in blood cells. Until now myopathy with painful muscle stiffness was not a known phenotype of the 3243 mutation. Therefore the reported case is a further example for the variable clinical expression of this mutation and illustrates the difficulty in classification of mitochondrial encephalomyopathies. It is likely that more myopathies are caused by mitochondrial mutations than known yet.

P147 X-LINKED DOMINANT CHARCOT-MARIE-TOOTH DISEASE WITH 10 CASES IN A FAMILY. Feng Lianyuan, Wang Xueli, Wu Yingchen, Zhang Sun, Zhou Jianbuo, Bethune International Peace. Hospital, Shijiahuang P. R. China At present, only one out of 178 pedigrees of Charcot-Marie-Tooth Disease found in China is X-dominant. We report on a large family with the X dominant CMT and late onset. 70% of patients first manifested the disease at age 20 or under while only 3. 2% of patients first manifested the disease at age 40 or over. The large CMT family investigated had 2 affected males and 8 affected females (altogether 22. 2%) of 45 members are male, 32 are female) in four generations. Of these, one first manifested the disease at less than 10 years old, one at less than 20 years old, two at less than 30 years old, and six at more than 45 years old (60%). The disease affected only the lower limbs, distally.The proband patient, a 48 year old male, felt his lower limbs become weakened about half a year ago. Neurological examination displayed the feet hanging down slightly, pes cavus, weakly bending and stretching toes, and bilateral ankle reflex decreased. Other superfical and deep sensations were present and normal except the vibra-

tion sense, which was decrease at the ankle level. Muscle biopsy showed neurogenic atrophy. The calf nerve biopsy showed dysmyelinating changes. EMG tests demonstrated slowness of motor and sensory conduction velocity of calf nerves. The results of these and Further clinical tests all accorded with HMSN-1 and was X-linked dominant inherited. Moreover, this family displayed other relevant characteristics: (1) the two deceased patients (one of the lst generation, another of the 2nd generation) and the living Patients (three from the second’generation) all had long life-spans (77–88 years), and only first showed signs of the disease at around age 50; (2) of the patients from the 3rd generation, the three female patient are between 20 and 30 years old while the one male patients is 48 years old; (3) in the 4th generation, there is only one patient, and she is 10 years old. These features may indicate that the gene of this family is different from the others reported. It may be a new gene point mutation. This hypothesis expects advanced evidence of’ gene inspection.

Immunology P148 DISABILITY IN MULTIPLE SCLEROSIS: POLYMORPHISM AT THE IL-1BETA, TNFα AND IL-1RN LOCI. C. L. A. Mann, M. B. Davies, M. Boggild, P. W. Jones, A. A. Fryer, R. C. Strange, C. P. Hawkins; Keele Multiple Sclerosis Research Group, North Staffordshire Royal Infirmary, Stoke on Trent, England. UK Multiple Sclerosis (MS) is a complex inflammatory disease involving many cytokines. The pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα) have been associated with blood barrier breakdown in MS. The genes for IL-1beta and IL-1 receptor antagonist (RN) are situated on chromosome 2q13, and TNFα on 6p. Polymorphisms at these loci were studied (IL-1beta –511, IL-1RN VNTR, and TNFα-308). 400 patients with Clinically Definite Multiple Sclerosis were studied. Disability was scored by the Kurtzke Expanded Disability Status Scale (EDSS). Genotyping was performed by standard PCR. Results were corrected for gender, disease duration and age of onset using logistic regression. Homozygosity for allele 2 of the IL-1beta –511 polymorphism was associated with more severe disease (EDSS 6–10) in patients with a disease duration of 10 years and greater (n = 194, p = 0.01, OR = 2.32, 95%CI = 1.23– 4.39). For the IL-1RN VNTR polymorphism, the carriage of allele 2 was associated with “benign” disease (EDSS 0–3, disease duration 10 years or more) (n = 194, p = 0.009, OR = 2.73, 95%CI = 1.28–5.81), and was less frequent in patients with severe disability (EDSS 6–10, disease duration 10 years and greater) (n = 194, p = 0.015, OR = 2.17, 95%CI = 1.16– 4.08). No association was found between TNFα-308 genotype and disease severity. We conclude that inherited variation in the control of IL-1 production/modulation may influence disability in MS.

P149 CD8 + T CELLS ARE PRIMARILY INVOLVED IN THE PATHOGENESIS OF THE ANTI-HU PARANEOPLASTIC SYNDROME. Raymond Voltz, Josep Dalmau, Jerome B. Posner, Myrna R. Rosenfeld, New York, USA The pathogenic role of the T cell infiltrates in the nervous system and tumor of patients with the anti-Hu paraneoplastic syndrome is speculative. Analysis of the T cell receptor (TCR) usage may establish whether these T cells primarily invade the nervous system or are secondarily attracted. Frozen blocks of tumor and nervous system tissue from 7 patients with the anti-Hu syndrome were examined by immunohistochemical analysis with all commercially available TCR VB family-specific antibodies and by RT-PCR with TCR VO family-specific primers, followed by subcloning and sequencing of the antigen- specific CDR3 region of the TCR VP chain. Of 63 tissue blocks from 7 patients, 22 blocks from 5 patients had > 100 CD3+ infiltrates enabling an immunohistochemical TCR VB screening. All 5 patients showed limited TCR VO family usage. In 3 patients, overrepresentation of certain TCR VP families (> 10% of total CD3+ cells) was identified (up to 45%). The overrepresented families were mostly CD8+ Sequencing of the TCR VO CDR3 region of an overrepresented family in one patient revealed evidence of clonal expansion. The demonstration of limited family usage with clonal expansion argues against a non-specific or superantigen-driven immune response. Our findings strongly support that a specific antigen-driven oligoclonal expansion of cytotoxic CD8+ T cells is primarily involved in the pathogenesis of the anti-Hu syndrome.

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P150 PIVOTAL ROLE OF TNF-α IN ANTIGEN-INDUCED APOPTOSIS IN EXPERIMENTAL AUTOIMMUNE NEURITIS (EAN) AND ENCEPHALOMYELITIS (EAE) OF THE LEWIS RAT. Ralf Gold1, Andreas Weishaupt1, Thomas Hartung2, Stefanie Gaupp1, David A. Hafler3, Klaus V. Toyka1. 1Department of Neurology, University of Würzburg, Germany; 2Biochemical Pharmacology, University of Konstanz, Germany; 3Laboratory of Molecular Immunology, Harvard Medical School, Boston, USA We investigated the role of TNF-α secretion in antigen-specific therapy of EAN and EAE in-vivo. Antigen therapy has been successfully employed for the treatment of these animal models. Possible mechanisms of action comprise T cell apoptosis, leading to termination of inflammation in-situ. When neural antigens were administered i.v. either with TNF-α binding protein or neutralizing TNF-α antibody, T cell apoptosis in inflamed nerve or spinal cord was reduced to levels observed in control animals. In longterm studies, neutralization of TNF-α partially abolished the protective effect of antigen therapy on disease course. Focal liver necrosis that had been observed in earlier studies after antigen therapy was prevented by passive immunization with neutralizing anti-TNF-α reagents. These results show that TNF-α has the dual potential to mediate beneficial apoptosis of inflammatory T cells or to induce liver damage as a severe side effect after antigen therapy. Optimal dosing of the antigen may be critical when using this approach for human therapeutic trials. P151 CEREBROSPINAL FLUID FINDINGS IN CEREBELLAR DYSFUNCTION ASSOCIATED WITH LAMBERT-EATON MYASTHENIC SYNDROME. Ian Sutton*, Tom Heafield*, Bethan Lang+ and John NewsomDavis+. *University Department of Neurology, Birmingham. +Neurosciences Group, Institute of Molecular Medicine, Oxford Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which antibodies induce down-regulation of P/Q-type voltage-gated calcium channels (VGCCs) at the presynaptic motor nerve terminal. Several reports have described the co-existence of sub-acute cerebellar degeneration (SCD) and LEMS. Antibodies from LEMS patients immunoprecipitate 125I-ω-conotoxin-MVIIC labelled (P/Q-type) VGCCs solubilised from human cerebellum. Furthermore, LEMS immunoglobulin (IgG) blocks Ptype calcium currents in cultured rat cerebellar Purkinje cells. Thus antiVGCC antibodies may be involved in the pathogenesis of cerebellar dysfunction occurring in association with LEMS. Methods: To investigate this we assayed serum and CSF samples for anti-P/Q VGCC antibodies from two patients with clinical and electromyographic evidence of LEMS. Patient 1 is a 68 year old male with a 13 month history of SCD and in whom histology of a hilar lymph node biopsy revealed an underlying small cell lung carcinoma. Patient 2 was a 73 year old male with a 12 month history of LEMS without CNS involvement or identifiable malignancy. Results: Both patients had elevated serum titres (> 30 pM) of antiP/Q-type antibodies (2288 pM and 2400 pM). CSF anti-P/Q-type antibodies were detected at a titre of 316 pM in patient 1, but not in patient 2. Conclusion: The finding of an elevated titre of anti-VGCC antibody in CSF may provide an explanation for the cerebellar dysfunction occurring in association with LEMS. P152 DIAGNOSTIC CRITERIA FOR DEMYELINATING POLYNEUROPATHY ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS). Notermans NC, Eurelings M, Franssen H, Hartman L, Wokke JHJ In order to propose diagnostic criteria for demyelinating polyneuropathy associated with MGUS, we compared 30 patients with CIDP without a monoclonal gammopathy, with 29 patients with polyneuropathy associated with MGUS. All patients fulfilled the accepted electrodiagnostic criteria for CIDP. If the clinician can ’reliably’ distinguish between CIDP and demyelinating polyneuropathy associated with MGUS, appropriate therapy might be started when the neuropathy progresses. Patients with a demyelinating polyneuropathy associated with MGUS were 59 years (SD 9), the median time to the peak of the disease was frequently more than 2 years, the clinical course was slowly progressive without relapsing and remitting periodes, there was no cranial nerve involvement, the neuropathy was symmetrical, sensory symptoms and signs were predominant and the legs were more affected than the arms. In CIDP patients the mean age was 48 years (SD 14), there was often a preceeding infection, the median time to the peak of the neuropathy was within one year, the clinical course was often relapsing and remitting or monophasic, with often cranial nerve in-

volvement and motor features predominate. On electrophysiological examination we also found differences between both groups. In patients with a demyelinating polyneuropathy there was more evidence of axonal degeneration in motor and sensory fibers as spontaneous muscle fiber activity and decreased SNAP amplitudes occurred significantly more frequently. In conclusion, although it can be difficult in an individual patient to differentiate between a CIDP and a demyelinating polyneuropathy associated with MGUS, certain differences in characteristics have enabled us to develop a proposal for diagnostic criteria, which will be presented. P153 AFFINITY STUDIES OF HUMAN ANTI-MYELIN-ASSOCIATED GLYCOPROTEIN-IgM-ANTIBODIES USING ELISA, WESTERN BLOT AND IMMUNOHISTOCHEMICAL STAINING. F. Fluri, F. Ferracin, B. Erne, A. J. Steck, Department of Neurology and Neurobiology, University of Basel, Switzerland Objective: To compare the affinity of anti-myelin-associated glycoprotein (MAG) antibodies to neural tissue. Background: Anti-MAG-monoclonalIgM antibodies are associated with a sensory-motor polyneuropathy. The antibodies seem to be sufficient to cause the disease but the mechanism of demyelination remains unclear. Design/Methods: We studied IgM affinity in 19 sera that reacted to central nervous system (CNS)-MAG by ELISA and CNS- and peripheral nervous system (PNS) MAG by Western Blot (WB). Immunohistochemical binding of IgM to nervous tissue was studied using the indirect peroxidase method. Results: All sera showed an affinity to MAG by ELISA and CNS-WB technique but only 8 sera reacted with MAG by PNS-WB. We observed different staining intensities and patterns by immunohistochemical staining. There was a significant correlation between the ELISA titers and the immunohistochemical staining ( p < 0.0001). The concordance between the results of PNS and CNSWB was only 42%. Conclusion: The different staining patterns and intensities are probably due to different ELISA titers and/or to a microheterogenity of the anti MAG-antibodies. The poor 42% concordance between PNS and CNS-WB results suggest that there may be different glycosylation patterns of CNS- and PNS-MAG. Whether these differences explain some of the clinical variabilities remains unclear. P154 TRANSFORMING GROWTH FACTOR-β AND CELL-CELL ADHESION MOLECULE EXPRESSION IN THYMUS OF MYASTHENIC PATIENTS. C. Marcozzi, P. Confalonieri, P. Bernasconi and R. Mantegazza, Department of Neuromuscular Diseases, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies to the acetylcholine receptor and frequently associated with thymic abnormalities: hyperplasia and thymoma. The contact between thymic epithelial cells (TEC) and thymocytes, involving MHC class I/II and adhesion molecules, is a critical event for immune activation and cell proliferation. Since desmosomal proteins on epithelial cells can be up-regulated by TGF-β, we analyzed 10 hyperplastic thymuses, 6 thymoma and 6 involuted thymuses from MG patients for the presence of TGF-β1 mRNA by RT-PCR and the expression of TGF-β1, desmosomal and classical cadherins by Western Blot and immunocytochemistry. We found a significant higher TGF-β1 mRNA expression in the hyperplasia versus thymomas or involuted thymuses ( p < 0.004 and 0.003, respectively). Its immunolocalization showed an intense and diffuse staining in the cortex in hyperplastic thymuses, mainly associated with cytokeratin+ cells; in thymoma the TGF-β1 staining was identifiable in patchy areas of cytokeratin+ cells whereas in the involuted thymus the signal was mainly associated with the connective tissue. Preliminary results showed an higher expression of desmosomal proteins and E-cadherin in hyperplastic than in thymoma and involuted thymuses, resembling the data observed for TGF-β1. These results demonstrate that human TEC can differently synthetize TGF-β1 depending on the pathological conditions. However, the functional role of TGF-β1 in thymus deserve further explanations. P155 IgG-MEDIATED CYTOTOXICITY OF ANTINEURONAL (ANTI-HU) ANTIBODY POSITIVE SERA TO MYENTERIC PLEXUS CULTURES. Blaes F, Klotz M, Mergner D, Schimrigk K, Schäfer KH1. Dpts. of Neurology and 1Anatomy, University of the Saarland, 66421 Homburg In paraneoplastic neurological syndromes (PNS) gut motility disturbances occurs as one symptom of these complex disorders. Since these syndromes

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are often associated with high-titre anti-neuronal antibodies, an autoimmune etiology has been suspected. However, the pathogenicity of these autoantibodies is yet unclear. In our study sera and IgG-fractions of 7 antiHu-positive PNS-patients and 7 healthy controls were tested for cytotoxicity to dissociated rat myenteric plexus cultures. All but one of the PNSpatients had a history of gut motility disturbances. Dissociated myenteric plexus cultures of the rat were incubated with the sera for 24 hours. Cytotoxicity was investigated using a double fluorescence staining (calcein green for living cells and ethidium homodimer [red fluorescence] for dead cells). 85% of the cells incubated with control sera, but only 65% of the cells incubated with PNS-sera survived (p < 0.05). Using the isolated IgGfractions of the sera, we found similar results. The IgG-free sera showed no significant cytotoxicity to the myenteric plexus cultures compared with the controls. Complement addition had no significant effect on the cytotoxicity. Our results implicate an complement-independent, antibody-mediated cytotoxicity to myenteric plexus may play a role in the pathogenesis of gut motility disturbances associated with paraneoplastic neurological syndromes.

with a decrease in systemic TNFα secretion. We have investigated the influence of IVIg on the TNFα secretion of cultured microglia, the main TNFα producing cell in the CNS. Microglia were isolated from neonatal rat mixed glial cell preparations and TNFα was measured in the culture medium using a bioassay. After the incubation with 12.5 mg/ml for 3 h, IVIg increased the spontaneous TNFα secretion nearly two-fold, but this was also seen with an albumin preparation. Additionally, this effect could be blocked by polymyxine B, suggesting that it is mediated by trace contaminations of endotoxins in these preparations. A similar effect was seen after stimulating the microglia with 100 ng/ml LPS. The stabilizing agent of this particular IVIg preparation, glycine, inhibited both the spontaneous and LPS stimulated TNFα secretion. Longer incubation with IVIg for 24 h had no effect on spontaneous and LPS stimulated TNFα secretion of microglia. After 48 h TNFα was slightly decreased, but the effect was even more pronounced with glycine alone. We conclude that polyclonal immunoglobulins have no direct influence on TNFα secretion of cultured microglia and the effects of stabilizing agents and contaminations have to be considered.

P156 HIGH DENSITY MARKER ANALYSIS CONFIRMED LINKAGE WITH THE MHC LOCUS IN ITALIAN MS FAMILIES. M. Eoli1, C. Gartioux3, F. Ribierre,3 M. C. Riggio1, M. Zaffaroni2, C. Milanese1, E. Seboun3. National Institute C. Besta1, Milan, San Antonio Hospital2, Gallarate Italy and Genethon3, Evry, France

P159 IN VITRO AND IN VIVO BYSTANDER SUPPRESSION OF ENCEPHALITOGENIC RESPONSES BY Th2 TYPE T-SUPPRESSOR CELL LINES AND CLONES INDUCED BY COPOLYMER 1 (COPAXONE®). R. Arnon, R. Aharoni, D. Teitelbaum and M. Sela, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel

Gene density of the MHC gene complex is one of the highest of the genome and that region contains multiple genes involved in the immune response such as HLA aand TAP genes. Several reports of linkage and association between MS and the HLA region have been controversial. Recently, the whole genome approach was undertaken to reveal the genetic basis of MS. Evidence of linkage with the MHC was found on British and American families. The Canadian study failed to detect linkage; however, a strong linkage disequilibrium was found with amarker located just outside of the MHC. To evaluate the role of the MHC in Italian families we analyzed 39 multiplex families (40 ASP) with 24 highly informative microsatellites markers spanning 15 cM within the MHC region. Multipoint linkage analysis was performed with MAPMAKERS/SIB. Two markers gave a 1.6 MLS, strongly supporting linkage with the MHC.

The synthetic amino acid copolymer, Copolymer 1 (Cop1, Copaxone®, Glatiramer Acetate) which is immunologically crossreactive with myelin basic protein (MBP) suppresses experimental allergic encephalomyelitis (EAE) and shows beneficial effect in relapsing multiple sclerosis (MS). We have recently demonstrated that Cop1 induced T suppressor (Ts) lines and clones which were confined to the Th2 pathway and crossreacted with MBP on the level of Th2 cytokine secretion. Injections of these Ts cells into mice resulted in inhibition of EAE induced by whole spinal cord homogenate, in which several autoantigens may be involved. We have now demonstrated that the Cop1 Ts lines/clones did not crossreact with other myelin antigens of EAE and MS besides MBP, i.e. proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) and αB crystalline. Nevertheless, the Cop1 Ts cells inhibited in vitro the IL-2 secretion response of PLP specific T cell line to PLP p139-151. This inhibition was demonstrated by supernatants of Cop1 Ts cells stimulated with either Cop1 or MBP but not with the PLP peptide. Furthermore, the Cop1 Ts lines/clones ameliorated EAE induced by two unrelated encephalitogenic peptides of PLP: PLP p139–151 and PLP p178–191. These results indicate that the therapeutic effect of Cop1 in EAE and MS is associated with the induction of Th2 cells that mediate bystander suppression.

P157 STUDIES OF THE β1 AND β2 INTEGRINS AND THEIR ADHESION RECEPTORS IN INFLAMMATORY MYOPATHIES. Cristina SeminoMora and Marinos C. Dalakas. NINDS, NIH, Bethesda, MD, USA Integrins are surface molecules that mediate cell-cell adhesion events. We examined the expression of β1 and β2 integrins and their adhesion receptors (VCAM and ICAM) on the activated T cells and the invaded muscle fibers in the muscle biopsies of 3 patients with inclusion body myositis, 3 patients with dermatomyositis, 3 patients with polymyositis and disease controls. Serial, frozen muscle biopsy sections were examined with double immunocytochemistry and confocal microscopy using monoclonal antibodies against the pairs of β1 integrin-VCAM and β2 integrin-ICAM. The identification of the cell type was examined in serial sections using monoclonal antibodies against CD 8+ cells, CD 4+ cells and macrophages. There was upregulation of the β2 integrin-ICAM pair on the infiltrating T lymphocytes surrounding or invading the muscle fibers indicating that extracellular matrix proteins and their cell surface receptors are overexpressed in the areas of inflammation in all types of inflammatory myopathies. The mRNA expression of β2 integrins is under study. Because in experimental models we have found that fibronectin peptides can supress inflammation by interfering with β2 integrins (unpublished observations), the information may be useful for designing more specific therapeutic strategies not only in inflammatory myopathies but also in other autoimmune inflammatory PNS and CNS conditions. P158 INFLUENCE OF INTRAVENOUS IMMUNOGLOBULINS ON THE TNFα SECRETION OF MICROGLIA IN VITRO. M. Stangel, C. Kovats, F. Boegner, P. Marx. Dept. of Neurology, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany TNFα is a proinflammatory cytokine that is involved in the pathophysiology of inflammatory diseases including multiple sclerosis and the animal model of experimental allergic encephalitis (EAE). The successful treatment with intravenous immunoglobulins (IVIg) of EAE was associated

P160 PULSED HIGH-DOSE DEXAMETHASONE THERAPY FOR MYOSITIS; AN UNCONTROLLED PILOT STUDY. M. F. G. van der Meulen1, J. E. Hoogendijk1, J. H. J. Wokke1, M. de Visser2. University Hospital Utrecht, Dept. Neurology1; Academic Medical Centre Amsterdam, Dept. Neurology2, The Netherlands Prednisone treatment for polymyositis (PM) and dermatomyositis (DM) is seriously hampered by adverse effects, especially in the long term. An alternative dose schedule may reduce side effects. Before considering a longterm controlled trial, however, it is necessary to have an indication of the initial, intended effects. In the present study eight patients with a newly diagnosed PM, DM, or non-classifiable myositis were treated with three cycles of dexamethasone (40 mg per day on four sequential days every 28 days). Primary outcome measures were muscle strength (by MRC sumscore and dynanometry), a visual analogue scale for pain and stiffness, and serum creatine kinase (CK) activity. The pilot study was considered succesfull if at least six out of the eight patients responded. A patient was defined as a responder if muscle weakness or pain, and CK activity were improved with at least 50% three weeks after the third cycle. Six patients responded (3 PM and 2 DM and 1 non-classifiable myositis). Side effects were mild, and included nausea and slight agitation. In one DM patient, muscle strength and CK activity almost normalized, but the severe skin abnormalities urged the neurologist in charge of the patient to start “standard” prednisone treatment after two dexamethasone cycles. In one non-classifiable myositis patient, weakness and pain almost disappeared, but the CK activity increased. Both responded favourably on administration of prednisone. In conclusion: The short-term effects of dexamethasone pulse therapy seem beneficial in the majority of patients. A larger, controlled trial is justified to determine long-term efficacy.

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P161 COMBINED ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM) AND ACUTE MOTOR AXONAL NEUROPATHY (AMAN) AFTER VACCINATION FOR HEPATITIS A AND INFECTION WITH C. JEJUNI. Huber S, Kappos L, Fuhr P, Wetzel S, Steck AJ. Departments of Neurology and Radiology, University of Basel, Switzerland After a phase with diarrhea for about three weeks a 23-year-old man received a vaccination with a recombinant vaccine for Hepatitis A. Three days later he complained about malaise, headache and fever and developped urinary retention and a stiff neck with mononuclear pleocytosis (60/mm3) and elevated protein. A week later he complained about weakness and double vision. On admission the patient was somnolent and had a supranuclear gaze palsy, dysarthria and a tetraparesis with brisk proximal and weak distal tendon jerks. MRI showed multiple lesions in the white matter, one of them only slightly Gd-enhancing. When signs of peripheral neuropathy became more prominent electro-neuro-myography established the diagnosis of an axonal motor polyneuropathy. Titers for C. jejuni and anti-GM1-antibodies were elevated. Central nervous symptoms subsided after a course of highdose intravenous steroids whereas a mild distal paresis of the lower extremities without pyramidal signs persisted at follow up 6 months later. Conclusion: To our knowledge this combination of ADEM and AMAN has not previously been described. The immunological attack must have been directed against two different antigens possibly because of a double stimulation with C. jejuni and the vaccine. P162 NEUROENDOCRINE-IMMUNE-SYSTEM INTERACTIONS: DHEA PLASMA-LEVELS IN RESPONSE TO THE COMBINED DEX-CRH TEST IN PATIENTS WITH MULTIPLE SCLEROSIS. T. Kuempfel, MD, F. Then Bergh, MD, E. Friess, MD, C. Trenkwalder, MD, F. Holsboer, MD, PhD. Max-Planck-Institut fuer Psychiatrie, Neurologie, 80804 München, Germany Neuroendocrine dysfunction may contribute to the pathogenesis of autoimmune diseases including multiple sclerosis (MS). DHEA has various immunological effects and low levels of dehydroepiandrosterone (DHEA) have been reported in chronic inflammatory diseases. We have previously reported lower DHEA plasma levels in the ACTH-stimulation test in patients with chronic progressive (CP) MS compared to relapsing remitting (RR) MS or controls. To further investigate the role of DHEA in MS, we used the combined dexamethasone-corticotropin releasing hormone (DEXCRH) test, a sensitive marker of hypothalamo-pituitary-adrenal (HPA) axis function and measured DHEA and cortisol plasma levels in 20 MS patients with active disease (11 females, age 39 ± 14 years, acute relapse in 10, chronic progression in 10, EDSS 3.6 ± 1.3, mean ± SD) and in 8 matched controls. MS patients had slightly lower DHEA plasma concentrations than controls, both before (2.1 ± 1.2 ng/ml vs. 3.2 ± 1 ng/ml) and after (3.6 ± 3.4 vs. 5.4 ± 2) CRH stimulation. CP patients had lower DHEA levels than RR patients (1.9 ± 1 vs. 2.3 ± 1.4 ng/ml) and the DHEA-rise after stimulation with CRH was less in CP patients than RR patients (2.9 ± 1.5 vs. 4.3 ± 4.5 ng/ml). Cortisol/DHEA ratio was higher in CP patients (31.8 ± 24.2 ng/ml) than in RR patients (12.7 ± 13.4 ng/ml). As with HPA axis activity, our results suggest mild dysfunction in the neuroendocrine system in MS. Low DHEA plasma levels may be an indicator of chronic disease progression in MS. P163 TCR V GENE USAGE OF A T CELL LINE ISOLATED FROM THE PERIPHERAL NERVE OF A PATIENT WITH GUILLAIN-BARRÉ SYNDROME. J. C. Cooper, A. Ben-Smith, C. O. S. Savage, J. B. Winer*. Centre for Clinical Research in Immunology and Signalling, The Medical School, and *Department of Neurology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Thymocytes bearing the γδ T cell receptor have been found in association with the demyelinating lesions in Multiple Sclerosis, Experimental Allergic Encephalomyelitis and Guillain-Barré syndrome (GBS). γδ T lymphocytes from the normal human intestine preferentially express a Vγ8/Vδ1 phenotype and have been reported in the peripheral blood of patients with inflammatory bowel diseases. Here we report that peripheral blood lymphocytes isolated from a patient whose GBS was preceded by a Campylobacter jejuni gastrointestinal infection, proliferated well to C. jejuni but exhibited a normal frequency of γδ T cells by immunofluorescence and flow cytometry (2–3%) upon stimulation with this antigen, with normal peripheral blood TCR V gene usage. T cells generated from a sural nerve

biopsy performed on this patient exhibited an increased frequency of γδ T cells (25%) which were positive for the Vγ8 TCR V gene segment using monoclonal antibodies and flow cytometry. Further work has focused on the generation of a C. jejuni specific nerve derived T cell line to study the extent of γδ T cell involvement and their specificity. This finding further strengthens the belief that γδ T lymphocytes derived from the gut may play a role in the pathogenesis of GBS. P164 INDUCTION OF TGFβ1- AND REDUCTION OF TNFα- MRNA-EXPRESSION IN CULTURED PERIPHERAL BLOOD LYMPHOCYTES STIMULATED BY INTERFERON-BETA1B IN VITRO. L. M. Ossege1, E. Sindern1, B. Voss2, J.-P. Malin1. 1Institute of Neurology, Ruhr-University, BG Kliniken Bergmannsheil, and 2Professional Associations’ Research Institute of Occupational Medicine, Ruhr-University, Bochum, FRG Until 1996 the treatment of the relapsing-remitting form of multiple sclerosis (MS) with interferon-beta1b (IFNβ1b) is established in Germany. Effects on the expression of HLA-class-I and -II antigens by IFNβ1b and on the synthesis of interferon-gamma, interleukin-6 and -10 are described, but all mechanisms of action are not known. We investigated the influence of IFNβ1b on the expression of transforming-growth-factor-beta1 (TGFβ1)and tumor-necrosis-factor-alpha (TNFα)-mRNA in an in vitro model. Peripheral blood lymphocytes were isolated from 8 patients with relapsingremitting form of MS during remission and from 5 healthy controls. They were stimulated with IFNβ1b in different concentrations (10 U/ml, 10 2 U/ml, 10 3 U/ml, 10 4 U/ml, 10 5 U/ml) for 24 hours. To examine the expression of TNFα-mRNA the lymphocytes were stimulated with lipopolysaccharid (LPS, 1 µg/ml) in parallel. The mRNA-expression was investigated by the method of non-radioactive in situ hybridization. In both groups, patients and controls, a dose-dependent increase of the TGFβ1-mRNA ( p < 0.01) and decrease of the TNFα-mRNA-expression ( p < 0.05) was demonstrable in the cultured blood lymphocytes. These effects were even detectable after stimulation with IFNβ1b in low concentrations (10 U/ml and 10 2 U/ml), which corresponds to the applied dose in vivo. Summarised these data show an induction of the TGFβ1-mRNA expression and a reduction of the TNFα-mRNA expression by IFNβ1b in vitro. These might be further mechanisms of action during the IFNβ1-treatment of relapsing-remitting MS. P165 THE SUPPRESSION OF INTERFERON GAMMA PRODUCTION BY INTERFERON β THERAPY IS ANTAGONIZED BY HIGH-TITERED NEUTRALIZING INTERFERON β ANTIBODIES IN MULTIPLE SCLEROSIS PATIENTS. Petereit HF, Bamborschke S, Richter N, Schoppe S, Türkmen N, Heiß WD. Department of Neurology, University of Cologne, Cologne, Germany In the treatment of relapsing remitting multiple sclerosis (MS) interferon β has turned out to be effective in terms of reducing disease activity. Reduction of proinflammatory cytokines such as interferon gamma, tumor necrosis factor alpha and others under therapy has been documented and may partially be responsible for the clinical effects. Whether neutralizing antibodies against interferon β are capable to antagonize immunological and clinical effects of therapy or not has recently been discussed controversely. The aim of this study was to evaluate the frequency of interferon β antibodies and their implications on exacerbation rate and interferon gamma production in blood lymphocytes in MS patients under interferon beta therapy. We present a group of 21 patients with relapsing remitting MS treated with interferon beta-1-b for 6 to 18 months (mean 14 months). We found interferon β antibodies in 3 of 21 patients (14%). High titers of interferon β antibodies (> 100, in a bioassay performed by Meditest) were seen in one patient (4.8%). An increase in interferon gamma production in blood lymphocytes (measured by FACSscan) and in exacerbation frequency was seen in the patient with high titers of neutralizing antibodies only. We conclude that high titers of neutralizing antibodies are able to counteract the immunological and clinical effects of interferon beta therapy in multiple sclerosis. P166 INTERLEUKIN-6 AND INTERLEUKIN-10 LEVELS DURING INTERFERON BETA-1B THERAPY IN MULTIPLE SCLEROSIS PATIENTS. E. Lensch, Ch. Wilke, F. Thömke1, C. Peschel2. Department of Neurology, Deutsche Klinik für Diagnostik, Wiesbaden. 1Department of Neurology, University Clinic Mainz, Mainz; 2Department of Internal Medicine III, University Hospital of the Technical University, München (Germany)

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Interferon beta-1b therapy reduces attack frequency and stabilises total MRI lesion area in multiple sclerosis patients. Its mechanism of action is still unknown. The aim of our study was to investigate whether proinflammatory interleukin-6 (IL-6) or antiinflammatory interleukin-10 (IL-10) serum levels changed during the first three months of therapy. Plasma samples were obtained from 23 multiple sclerosis patients starting interferon beta-1b (Betaferon) therapy. IL-6 and IL-10 levels were measured by specific ELISA at baseline, 10 h and 24 h after the first injection, 10 h after the third injection and after 1 and 3 months (24 h post injection). Both IL-6 and IL-10 concentrations showed highest amounts 10 hours after the first injection (IL-6: 29.6 pg/ml, IL-10: 4.8 pg/ml). IL-6 could only be detected again 10h after the third injection. IL-10 levels dropped close to baseline level after the third injection but increased again after one month. Our results show that interferon beta-1b administration stimulates both IL-6 and IL-10 production. While IL-6 is only produced transiently in response to interferon beta-1b therapy, IL-10 production outlasts the initial phase and may represent a possible mechanism of therapeutic action. Supported by: Schering AG Berlin, Germany.

P167 ACUTE SELF-LIMITING ATAXIC NEUROPATHY (“SENSORY GUILLAIN-BARRÉ SYNDROME”): LOOKING FOR ANTIGANGLIOSIDES ANTIBODIES. Carme Serrano-Munuera, Francesc Graus, Eduard Gallardo, Isabel Illa. Barcelona. Spain Objective: To identify antigangliosides antibodies specifities in a large serie of Acute Self-Limiting predominantly Ataxic Neuropathy (ASLAN). The pattern of antiganglioside antibodies in ASLAN, a rare clinical syndrome, is not known. Recently, a single case with GD3 and GD1b reactivity has been reported. Patients/Methods: 10 patients with ASLAN were studied for IgM and IgG antibodies to GM1, GM2, GM3, aGM1, GD1a, GD1b, GD3, GT1b,GQ1b by standard ELISA and Thin Layer Chromatography (TLC). The results were compared with those found in: 53 patients with classical GBS, 8 with GBS post-parenteral gangliosides (gangl-GBS) and 5 patients with cis-platinum sensory neuropathy. Results: ASLAN. Patients: 9/10 were negative for all the antibodies tested. In 1/10 patient, anti-GD3 IgG and antiGQ1b IgG were found. Controls: Antiganglioside antibodies with various previously described specificities were found in 26/53 patients with classical GBS and 8/8 patients with gangl-GBS. 1/5 patient with cis-platinum neuropathy was antiGM2 positive.TLC confirmed the results. Conclusions: In patients with ASLAN there is no pattern of antiganglioside antibodies specifities, indicating that immunoreactivity in ASLAN/“Sensory GBS” is different from that found in classical GBS. Supported by: Fondo de Investigación Sanitaria. FIS BAE 97/5283, FIS 96/2190E. Spain.

P168 INCREASED TENDENCY OF T-HELPER CELLS TO UNDERGO APOPTOSIS AFTER IN VITRO STIMULATION IN PATIENTS WITH STABLE MULTIPLE SCLEROSIS COMPARED TO CONTROLS. Orhan Aktas, Volker Hoffmann, Maike Rieks, Sebastian Schimrigk, Horst Przuntek, Dieter Poehlau*. Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, D-44791 Bochum, Germany. *Sauerlandklinik Hachen, Sundern-Hachen, Germany In patients with relapsing-remitting multiple sclerosis (RRMS), treatment with Copolymer-1 (COP-1; Copaxone™), as an analogon of human myelin basic protein (MBP), reduces relapse rate and progression. A possible mechanism of action is the induction of T-cell apoptosis which has been shown after high-dose antigen application in an EAE model. Patients: 15 age- and sex-matched healthy controls and 15 patients with RRMS in a stable phase of the disease for at least 6 weeks were compared crossectionnally. Immunomodulating therapy, acute infections or concomitant disease was not allowed during 6 weeks before study entry. Methods: We stimulated 2 × 10 5 peripheral blood mononuclear cells (PBMC) per ml for 48 hours with COP-1 (1 µg/ml), MBP (2 µg/ml) or bovine serum albumin (BSA) (2 µg/ml) or without protein. The percentage of apoptotic T cells was measured using the Annexin V/propidiumiodide method (Boehringer Ingelheim). Lymphocytes were gated and CD4-subpopulations were identified using a PE-Cy5-conjugated anti-CD4-monoclonal antibody from Coulter-Immunotech. Flow cytometric analysis was done by FACScan™ and CellQuest software (Becton Dickinson). Groups were compared using Mann-Whitney U-Test. Results: After in vitro stimulation we found increasing percentages of apoptotic T-helper cells in patients with stable RRMS compared to healthy controls. The difference was significant for COP-1 ( p = 0.029), for MBP ( p = 0.03) and for BSA ( p = 0.05); and less

obvious for incubation with pure buffer (p = 0.08). No difference could be shown for CD4 negative- lymphocytes. Discussion: Our results suggest a non-antigen-specific increased tendency of T-helper cells from stable MS patients to undergo apoptosis.

P169 RELAPSING AND REMITTING CEREBELLAR SYNDROME IN COELIAC DISEASE. M. Baecke1, F. Setta2, J. Jacquy3, J. Hildebrand 4, P. Seeldrayers3, 4, M. Manto4. 1Faculté De Médecine, ULB (B); 2Universita La Sapienza, Roma (I); 3CHU-Charleroi, Charleroi (B); 4Hôpital Erasme, Ulb (B) A clinical history of relapsing and remitting neurological deficits occurring in a young adult is strongly suggestive of multiple sclerosis. We describe an exceptional cause of relapsing and remitting cerebellar syndrome occurring in association with coeliac disease. This 32-year-old man had a 5 years history of coeliac disease proven by intestinal biopsy. He presented 3 episodes of subacute cerebellar syndrome in a period of 3 years, with scanning speech, intention tremor and gait ataxia. The cerebellar syndrome recovered after a delay varying from 3 days to 1 week. There was no extra-cerebellar sign. While symptomatic, lumbar puncture showed 9 lymphocytes/mm3 and a protein level of 94 mg/dL (N < 50). No oligoclonal banding was found. Extensive search for infections or malignancy was negative. Brain MRI and brain CT were normal. EEG, somatosensory, visual and motor evoked potentials were normal. Fast wrist movements were dysmetric. Although coeliac disease has been associated with cerebellar ataxia, a relapsing and remitting course of cerebellar syndrome has not been described so far as a complication of the disease. Moreover, our patient did not exhibit epilepsia or myoclonus, which are usually present in patients developing neurological complications in association with coeliac disease. The ataxia was probably due to an auto-immune involvement of cerebellar structures.

P170 SELECTIVE INDUCTION OF OXIDATIVE BURST AND APOPTOSIS IN LEUCOCYTE SUBPOPULATIONS BY ULTRAVIOLET A RADIATION. T. Böttcher1, E. Mix1, V. Wolf 2, G. Gross2, R. Benecke1, U. K. Zettl1. Dept. of Neurology1 and Dept. of Dermatology2, University of Rostock, Germany Apoptosis, as a mechanism for selective cell elimination, plays an important role in the pathogenesis of autoimmun diseases. Ultraviolet A (UVA) radiation induces liberation of reactive oxygen species (ROS), which can promote apoptosis. We aimed to investigate the influence of UVA radiation on respiratory burst and apoptosis of human leucocyte subpopulations. Leucocyte rich plasma, harvested from blood of 10 sex matched, healthy volunteers was either treated with UVA (10 Joule/cm2 ) for 10 minutes or left untreated for control. While respiratory burst activity was measured by flow cytometry immediatly after UVA radiation or shame treatment, another part of the cells was fixed and permeabelized 8 hours later for in-situ tailing and flow cytometric measurement of apoptosis. Monocytes showed the highest level of spontaneous ROS production. UVA radiation lead to a significant increase of ROS production in granulocytes (treated 51% ± 11.1 vs. untreated 44.8% ± 11.8; p < 0.01) but had no effect on lymphocytes and monocytes. However, apoptosis was significantly increased in lymphocytes (treated 2% ± 0.4 vs. untreated 1.3% ± 0.2; p < 0.05), whereas monocytes and granulocytes were not affected. The results show a selective influence of UVA radiation on leucocyte subpopulations. Under UVA radiation, activated granulocytes and spontaneously active monocytes obviously act as donors of ROS, which induce apoptosis in lymphocytes. Though these interactions have to be analyzed in detail, we conclude that UVA radiation could be a therapeutical option in lymphocyte mediated autoreactive neurological disorders.

P171 A METHOD FOR THE ANALYSIS OT THE CYTOKINE PATTERN OF CEREBROSPINAL FLUID (CSF) CELLS BY FLOW CYTOMETRY. K. Hellwig, V. Hoffmann, M. Rieks, S. Schirnrigk, U. Theodoridis, H. Przuntek, Dieter Pöhlau*. Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, D-44791 Bochum, Germany. *Sauerlandklinik Hachen, Sundern-Hachen, Germany The cytokine network is essential for the pathogenesis of autoimmune diseases. The analysis of the cytokine pattern of peripheral blood cells with

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intracellular cytokine staining and flow cytometrical analysis is already a well established method. In inflammatory diseases of the central nervous system, the analysis of cells in the CSF is of interest. We adapted the method for intracellular cytokine detection in CSF cells. Method: After sterile lumbar puncture with a non traumatic conic needle, 5–10 ml of CSF are collected and immediately centrifuged for 10 min at 1200 rpm. After decantation of the supernatant, the cell pellet is washed with culture medium (RPMI + 5% foetal bovine serum). After resuspending in 200 ul culture medium the cells are incubated for five hours at 37° C with PMA and ionomycin for cytokine stimulation and with monensin for secretion inhibition. Afterwards fixation and permeabilisation with saponin buffer for two hours. In the last step the cells are incubated with Interferon-γ- and Transforming Growth Factor P-specific fluorescence-conjugated monoclonal antibodies for 20 minutes. For analysing we use a FACSscan™ and cellquest software from Becton Dickinson. Results. Using this method we found fluorescence signals in CSF cells qualitatively comparable with those found in peripheral blood cells. Due to the simultaneous analysis of the T-cell subset by surface markers (CD4, CD8), it is possible to identify the cytokine producing cell subpopulations. The most important problem of analysing CSF cells is the often small amount of cells and therefore the problem of fast subsequent treatment of the sample. This method can hopefully be adapted for other intracellular proteins and it may be a useful tool to evaluate the role of immune mediators secreted by CSF cells for the pathogenesis and disease activity of different neurological disease.

P172 A SINGLE CASE OF GUILLAIN-BARRÉ SYNDROME IN A FAMILY WITH CAMPYLOBACTER JEJUNI ENTERITIS. C. W. Ang, P. A. van Doorn, H. Ph. Endtz, I. S. J. Martina, B. C. Jacobs, R. van Koningsveld, F. G. A. van der Meché. Departments of Neurology, Immunology and Bacteriology, Erasmus Medical Center Rotterdam, The Netherlands We describe a family in which three members suffered from Campylobacter jejuni (CJ) enteritis but only one developed Guillain-Barré syndrome (GBS). This 10-year-old boy had diarrhea that resolved during a period of 2 days. One week later he developed GBS. Both his younger brother and father had also experienced a period of diarrhea, respectively 1 and 1.5 week before the patient. There was no difference in duration or severity of the diarrhea between the patient and his family members. CJ was isolated from the stools from his father and brother but not from the patient. Serological studies confirmed that the patient had also experienced a recent infection with CJ. Typing showed that the two CJ strains belonged to the same serotype. In ELISA and TLC the patients’ serum reacted with the gangliosides GM1, GD1b and asialo-GM1 and with the lipopolysaccharide (LPS) fractions from the CJ strains isolated from his family members. Only IgM in the serum from the brother reacted with ganglioside GM2, the serum from neither his father nor brother contained reactivity against other gangliosides or LPS fractions. HLA-typing revealed no absolute homology between the patient and his brother. This case enables us to study the relative contributions of both CJ and host factors in the development of GBS. Induction of cross-reactive antibodies against LPS and gangliosides is crucial in the pathogenesis of GBS and is not solely dependent on ganglioside mimicry. Comparing the immune response in GBS patients and CJ enteritis patients can be of great value in determining the additional factors that lead to GBS following CJ infection.

P173 A CAMPARISON OF POLYNEUROPATHY ATTRIBUTES BETWEEN PATIENTS WITH ANTI-MAG AND ANTI-SULFATID ANTIBODIES. S. Erb, F. Ferracin, E. Nardelli, A. Steck. Basel, Switzerland and Verona, Italy Thirty-nine patients with a peripheral neuropathy were tested for IgMantibodies against MAG and sulfatide using ELISA test. Fifteen patients (38%) demonstrated increased anti-sulfatide IgM antibodies. Five patients (13%) had-high anti-sulfatide antibody titers: all except one had similar clinical symptoms with weakness, sensory impairment, ataxia, hyporeflexia and presented an axonal neuropathy; one patient had only paresthesias and a normal electrophysiological exam. Thirteen patients (31%) showed increased anti-MAG antibodies. They had similar clinical polyneuropathy attributes but presented a demyelinating neuropathy. A weak cross reactivity between anti-MAG and anti-sulfatide antibodies was present in four patients. In conclusion, although both neuropathy groups clearly differed in their electrophysiological features, their clinical presentation were rather similar.

P174 ACUTE DEMYELINATINATING ENCEPHALOPATHY (ADEM): CLINICAL AND MRI RESPONSE TO STEROID THERAPY. Farsin Hamzei, Fritz Haverkamp*, Alexander Hartmann, Peter Leonhardt, Sabine Leutner**. Neurologic, Pediatric* and Radiologic** Clinic, University of Bonn, FRG Aim: To underline the importance of diagnosis and treatment in this type of immunologic disease Cases: We report on 3 adult cases and 2 infants with ADEM, who have been observed in our service and followed up to 8 years. All patient started with either changes of level of consciousness or psychomotor behavior. In 2 adults these symptoms started acutely with acute psychosis and in the other patients slowly and progressively. In 1 of these patients initial workup led to the diagnosis of a glioma. Bioptic investigation showed signs of acute inflammatory disease of the CNS in accordance with ADEM. All patient presented with change in the CSF with elevation of cell count up to 200 cells/ml and increase of protein up to 200 mg/dl. EEG showed signs of diffuse slowing and focal abnormalities. MRI investigation revealed changes of the white matter of both confluenting and large focal character. Steroid therapy of different dosage (100–10 000 mg/day) and repeated administration led to complete clinical remission in 2 adult cases and partial improvement in one case. Clinical course was different from course of the MRI changes with significant lower changes in the neuroradiologic appearance. Summary: ADEM is a rare diagnosis. However, it may occure more often than assumed previously. In some cases a rapid recovery is possible using steroid therapy. Some cases, however, are resistant to steroid therapy and other therapeutic regimes must be considered. P175 THE EFFECTS OF IMMUNOSUPPRESSION ON GENERALIZATION IN OCULAR MYASTHENIA GRAVIS. S. Huned, S. Patwa, MD, Steven P. Novella, MD, Jonathan M. Goldstein, MD. Yale University, Department of Neurology, New Haven CT USA Patients with untreated myasthenia gravis (MG) have been shown to generalize in approximately 45% of cases. There has been suggestion that treatment with immunosuppressive therapy reduces the conversion rate. Objectives: To determine the frequency of conversion from ocular to generalized myasthenia gravis in patients treated and not treated with immunosuppression. Methods: A retrospective analysis of 32 patients presenting to a university neuromuscular clinic or academic private office with documented ocular myasthenia gravis. Generalized MG was diagnosed in patients who developed other than ocular weakness. Results: Twenty-seven percent of treated patients and 60 percent of untreated patients converted from ocular to generalized myasthenia gravis. Conclusion: Immunosuppressive therapy reduces the frequency of conversion from ocular to generalized myasthenia gravis. This suggests that the use of early immunosuppression may be warranted in patients with ocular myasthenia gravis. A larger, randomized prospective study is indicated. P176 AUTOIMMUNE CONTRALATERAL VESTIBULOPATHY FOLLOWING RIGHT RAMSAY-HUNT SYNDROME. P. Schulz, V. Arbusow, M. Strupp, M. Dieterich, W. Sautier, T. Brandt. Munich, Germany We report on a unique case of initially right-sided, varicella zoster virus (VZV) induced Ramsay-Hunt syndrome that resulted in loss of function of all three right semicircular canals (SCC), facial palsy, and anakusis of the right ear. The cerebrospinal fluid contained 220 units/ml of VZV-specific IgG. Three months after antiviral therapy with acyclovir vestibular symptoms (spontaneous nystagmus, skew deviation, and unsteadiness of gait) had disappeared. At that time, the function of the left labyrinth was normal. Another 2 months later, the patient developed vestibular loss on the left side, as evidenced by the absence of caloric excitability of the left horizontal SCC and a residual post-rotatory nystagmus (< 5 s), while the left facial nerve and hearing in the left ear remained intact. An autoimmune pathogenesis of the left vestibular failure rather than bilateral VZV infection was suggested by the following data and observations: (1) no evidence of vesicular eruptions on the left auricle and virtual absence of antiviral IgG (0.023 units/ml) after onset of bilateral vestibulopathy; (2) prompt response of the left labyrinth to immunosuppressive therapy (gait disturbances significantly improved, per- and post-rotatory nystagmus to the left reappeared); and (3) presence of atypical nervous tissue-specific autoantibodies against a 45-kD protein which were clearly reduced following corticosteroid administration. We believe that a cellular immune process against the vestibular nerve (1) caused the left vestibular failure and (2) triggered the synthesis of the autoantibodies against a 45-kD nervous tissue-specific protein.

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Multiple Sclerosis P177 INCREASE IN CD4+CD29+CD45RA+ CELLS AND DECREASE IN CD4+CD29+CD45RA– CELLS IN MULTIPLE SCLEROSIS (MS) PATIENTS. INCREASE OF CD4+CD29+ CELLS IN PROGRESSIVE PATIENTS. M. Carreño, P. de Castro, M. L. Subirá. Departments of Neurology and Immunology. Clínica Universitaria de Navarra. Pamplona, Spain Peripheral blood lymphocyte subsets (PBLS) have often been studied in MS. An increase in T4/T8 ratio and a decrease in CD4+CD45RA+ cells in progressive disease have been reported. Objective: To find out if PBLS differ in MS patients and healthy subjetcts. To find out if they vary according to the clinical form. Forty-six clinically definite MS patients, without treatment. 16 men, 30 women. Mean age: 39.2 years. Mean EDSS: 3.2. Mean time of evolution: 9.4 years. 30 healthy subjects age and sex-matched. PBLS determined by three-colour flow cytometry Coexpression of CD29 and both isoforms of CD45 (CD45RO and CD45RA) studied on both CD4+ and CD8+ cells. Results: CD3+ ( p = 0.02), CD3+CD4+ ( p = 0.02), CD3+/CD4+ ratio ( p = 0.02) and CD4+CD29+CD45RA+ cells ( p = 0.001) were significantly increased in MS patients. CD4+CD29+CD45RA– cells ( p = 0.0008) and CD4+CD29+CD45RA–/CD4+CD29+CD45RA+ ratio ( p = 0.003) were significantly decreased. Progressive patients displayed significantly increased percentages of CD4+CD29+ cells respect to relapsing-remmitting patients. Conclusions: Percentages of several lymphocyte subsets differ in healthy subjects and MS patients. Triple labelling including coexpression of CD29 and CD45RA/CD45RO is useful to study MS patients The increase percentage of CD4+CD29+ in progressive patients could serve as an indicator of disease activity. P178 MITOXANTRONE – A WELL TOLERATED DRUG IN THE TREATMENT OF MULTIPLE SCLEROSIS. J. Reeß, S. Eisenmann, E. Mauch. Neurological Hospital Dietenbronn, Schwendi, Germany From April 1990 to December 1997 75 patients (mean age 37.7 years) with relapsing-remitting or secondary progressive multiple sclerosis were treated with mitoxantrone i.v. (12 mg/m2 body surface). A total number of 402 single doses were given, average time between the courses was 4.4 months. Mean cumulative dosage was 101 mg (min 30 mg, max 305 mg). Seven days after the first course no severe leucopenia or lymphopenia was seen. γ-GT increased slightly (mean 4.1 U/l), kidney function was not affected. As expected, major side effects were nausea and vomiting. In 23% of the courses supplementary antiemetics were needed. No patient refused further therapy due to these complaints. 27 patients developed ECG alterations. Echocardiography showed only in three cases pathological findings. A clear link to our therapy couldn’t be proofed but nevertheless therapy was stopped for safety reasons. In 8 other cases therapy was finished due to other side effects (1 alopezia, 1 ongoing leucopenia, 4 ongoing deterioration, 2 bad general condition). 1 patient got pregnant. Due to their stable neurological status 9 patients could also stop the treatment. Apart from the good clinical results (will be presented elsewhere) we think that mitoxantrone is a safe and well tolerated therapy for patients with multiple sclerosis. Therefore 13 of our 75 patients are treated actually on a outpatient basis. The evaluation of a quality of life questionnaire is still ongoing. P179 DELAYED-TYPE HYPERSENSITIVITY TO GLATIRAMER ACETATE (COPAXONE®): REPORT OF THREE CASES. Hofstadt U1, Leclaire J1, Raguz JM 2, Hilker O 2, Haneke E 2, Jörg J1. Kliniken für Neurologie1 und Dermatologie2, Universität Witten/Herdecke, 42283 Wuppertal, Germany Glatiramer acetate is a mixture of synthetic random polypeptides composed of 4 amino acids. Placebo-controlled trials in patients with relapsing remitting multiple sclerosis (RR-MS) showed significant effects on relapse rate leading to the approval of this drug for the treatment of RR-MS in several countries. We participated in a multicenter phase-III-trial in Germany. Methods: 33 patients with RR-MS were treated with glatiramer acetate 20 mg s.c. daily. Cutaneous sideeffects were reported by 90% around the injection sites, which was as frequent as in previously reported trials. Local erythema, itching and slight subcutaneous induration resolved without sequelae in less than three days in most of them. 3 patients reported subcutaneous masses of a diameter of 5 cm or more lasting for longer than a week. Allergologic testing including skin biopsy was done. Results: Epicutaneous tests were negative, prick, scratch and intracutaneous tests were positive in a dilution of 1 : 1000 in a crescendo reaction until 72 h. Skin biopsies showed lymphocytic and eosinophilic infiltration. Discussion:

This previously unreported reaction seems to be compatible with a delayed-type hypersensitivity (type IV-allergy). Patients treated with glatiramer acetate showing cutaneous reactions lasting longer than 3 days should be allergologically tested including skin biopsy. Because there is no experience with this reaction discontination of the drug should be considered in affected patients. P180 ENDOTHELINS AND MULTIPLE SCLEROSIS. Irkeç C, Nazliel B, Koçer B. Gazi University Medical Faculty Department of Neurology Ankara, Turkey Unfortunately the etiopathogenesis of M.S. (multiple sclerosis) is still not fully understood. In the last few years numerous studies were performed with otokoids in order to determine the ethiopathogenesis of M.S. Endothelins in the otokoid subclass were first obtained from cultered endothelial cells in 1985. In 1988 they were showned to be formed of 21 amino acids. Endothelins are known to be of 3 different forms. ET1 (endothelin 1) originates from endothelial cells while ET3 originates from neuronal tissue. ET1 shows the strongest vasoconstrictive properties. Because they have a strong vasoconstrictive property they can increase neuronal distruction. The study involved 24 patients of which 10 were male and 14 were female. Their mean age was 28. 3 times 3 cc. serum and serebrospinal fluid samples were taken from the patients. First in the first 24 hours of the acute attack and later on 3rd and 6th days. The control group consisted 10 male and 10 female from whom only a single 3 cc. serum sample was taken. The specimens were centrifuged in 5000 IU/ml edetic acid and aprotimin for 15 minutes with 3000 cyles and stored at –70° C. The sera were first processed with % 0.5 triofloroacetic acid. The endothelin was diluted in 0.1 M sodium sulphate, 0.05 M Na Cl, % 0.01 triton X-100 and % 0.01 sodium acid buffer, then incubated at 4 C for 24 hours with rabbit antiserum. The free and attached endothelin were seperated by precipitation in normal rabbit antiserum. The free fraction was aspired off and the attached fraction was counted with gamma counter and compared against the curve of free fraction. Serum ET1 values in the first and 3th day of the acute attack were significantly different from those of normal controls ( p > 0.0001). But after the 6th day the difference between M.S. patients and normal controls were not statistically significant ( p > 0.005). ET1 values in cerebrospinal fluid in the first 24 hours of an acute attack are significantly higher when compared to the values on the 6th day in M.S. patients. Alternation in vascular permeability during acute attacks may be the cause of ET1 rise in M.S. and this may stimulate the formation of periventrikuler plaques. P181 VALIDATION OF A HEALTH RELATED QUALITY OF LIFE AUTOQUESTIONNAIRE AMONG MULTIPLE SCLEROSIS PATIENTS. Biolay S, Gerbaud L, Vernay D, Aufauvre D, Millet F, Clavelou P. Clermont-Ferrand, France Objective: We conducted a prospective study among 166 multiple sclerosis (MS) patients (103 from an university hospital, 63 from an MS rehabilitation center) to assess the properties of the French version of the Multiple Sclerosis Quality Of Life- 61 items (MS QOL-61). Methods: The MS QOL-61 is an autoquestionnaire combining the RAND SF-36 and 25 items exploring specific dimensions of MS. It had been built by B. Vickrey at the University of California in Los Angeles, and a shorter form (MSQOL54) was published in 1994. The translation into French has one item less (MS QOL-60). Results: Acceptability is excellent with a response rate over 90%. Test-Retest reliability is good except for the “role limitationemotional” scale of the RAND SF-36. Construct validity, based on factor analysis, shows 9 factors and the introduction of specific items does not change the SF-36 internal consistency. “Sexual function” was the only scale not represented in one factor. External validity, tested against medical (Expanded Disability Status Scale, Kurtzke scale, Mini-Mental-State and disease stage) and rehabilitation (Functional Independence Measure) parameters is excellent. Conclusion: We concluded that this autoquestionnaire can be used to assess health related quality of life among French speaking MS patients. P182 DECREASED MRI LESION BURDEN CORRELATES WITH INCREASE SERUM SELAM-1 IN MULTIPLE SCLEROSIS PATIENTS TREATED WITH INTERFERON BETA-1b. G. Izquierdo, L. Dinca, M. A. Muñoz, O. Sanchez-Soliño, J. M. Garcia Moreno, J. M. Gata, M. A. Gamero, M. Lucas. Neurology Department, Macarena Hospital, Seville, Spain

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Interferon-beta-1b (IFNb-1b) lessens the attacks rate in relapsing-remitting multiple sclerosis (RRMS) by a mechanism which could be related to the decrease of migration into central nervous system. We studied MRI changes and soluble ELAM-1 (sELAM-1) in serum of treated and nontreated RRMS patients. Material and Methods: We studied 10 women and 6 men with RRMS which fulfilled the criteria for IFNb-1b treatment (mean years of evolution 5.6 ± 3; mean EDSS score 2.5; mean attack relapses 5.6 ± 2.8). Eight of them were treated with IFNb-1b and 8 nontreated patients were used as controls. Patients were checked up every 3 months; at the same time we performed MRI (T2 weighted slices and T1 enhanced with gadolinium) and we measured sELAM-1(ELISA). Results: Five of the treated patients and 6 of controls had constantly high levels of serum sELAM-1. At 6 months, sELAM-1 increased with respect to baseline levels in treated group (44.37 ± 6.15) versus (1.20 ± 2.32) in controls. sELAM-1 at 3 months (r2 = 0.64, p = 0.016), 6 months (r2 = 0.41, p = 0.08), 12 months (r2 = 0.58, p = 0.026), correlated inversely with MRI T2 burden lesion. Conclusions: IFNb-1b increased sELAM-1 in RRMS and the augmentation was correlated with the decrease in MRI burden lesion at 12 months of treatment. P183 LEVAMISOL DETERIORATES RELAPSES IN CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS. I. Milonas, N. Grigoriadis, C. Simeonidou*, D. Karussis**, O. Abramsky**. B’ Dept. of Neurology and Laboratory of Experimental Neurology, AHEPA Hospital, *Laboratory of Experimental Physiology, Faculty of Medicine, Aristotle University of Thessaloniki, Greece. **Dept of Neurology and Laboratory of Neuroimmunology, Hadassah-Hebrew University Hospital, Jerusalem, Israel Levamisol (LE) stimulates cell-mediated immune responses and was administered to patients with multiple sclerosis (MS) as part of several clinical trials in the past. The benefit from this treatment was either modest or absent. In this study the effect of LE on Chronic Relapsing Experimental Allergic Encephalomyelitis (CR-EAE) in Lewis rats, was investigated. CR-EAE was induced in 20 male animals, as described by Polman et al. (1988). LE was administered in 10 rats at doses of 20 mg/kg/day, i.p., for three consecutive days, commencing on day three postinoculation (PI). Control animals were treated with vehicle. Severe relapse commenced 12– 13 days PI and then transformed to a chronic course (8 animals), sometimes fatal (2 rats). Control rats exhibited a first episode at the same time as LE treated animals did, lasting up to 3–5 days, with almost no residual deficit. The mean maximum clinical score of the first episode was half the score of LE treated animals at the same time. A second relapse was noticed in 7 rats at days 19–24 PI and all but one recovered almost completely. Although previous clinical trials with LE in MS did not mention a worsening of the undelying disease, our results indicate a transform of CR-EAE to a more progressive form. Consequently, this agent may contribute to a more reliable experimental model for primary progressive MS. P184 CLINICAL PROFILE OF NEW PATIENTS ADMITTED TO A MULTIPLE SCLEROSIS UNIT IN ONE YEAR: A PROSPECTIVE STUDY. Mefkure Eraksoy, Gülsen Akman-Demir, Yüksel Kaplan. Department of Neurology, Istanbul Faculty of Medicine, Turkey This study was designed to determine the clinical and laboratory findings and final diagnosis of new patients at their initial admission to a multiple sclerosis (MS) unit in one year. Between January 1 and December 31, 1997, 1549 examinations were performed in our MS unit and 218 patients were admitted firstly. Of 218 new patients, 177 had definite, probable or suspect MS whose initial manifestations began before 1997. Forty-one (19%) of 218 patients had developed initial manifestations in 1997. Among these 41 cases, final diagnoses of nine patients were acute disseminated encephalomyelitis (5), somatization (2), complicated migraine (1), neurofibromatosis (1) and two patients were lost to follow-up. Thirty (19 female, 11 male) of 41 new patients were suggestive of MS symptomatology and presented with sensory-motor (29%) and brain stem (22%) manifestations, isolated unilateral optic neuritis (15%), bilateral optic neuritis (2%), left internuclear ophtalmoplegia (INO) (2%) and pure sensory symptoms (2%). The age at onset ranged from 16 to 50 years. Cranial MRI findings were consistent with MS in 25 patients.Four patients with unilateral optic neuritis had normal cranial MRI and one patient with INO had a single lesion in upper pons. Oligoclonal IgG bands were detected in 8 of 10 patients. Neurologic manifestations improved spontaneously or with steroid therapy. Only two patients developed clinically definite MS (CDMS) during this period.

This study reveals that 5% of patients admitted to an MS unit with initial manifestations developed CDMS in the same year and emphasizes that in order to ensure a clinical diagnosis of MS at all ages a long term meticulous follow up of patients is essential. P185 CONTROLLED STUDY ON DISEASE ACTIVITY AND QUALITY OF LIFE IN RR MS PATIENTS TREATED WITH AZATHIOPRINE OR β IFN-1b. Palumbo R, Fontanillas L, Salmaggi A, La Mantia L, *Mendozzi L, *Caputo D. Milanese C. Istituto Nazionale Neurologico “C. Besta”, Milan, Italy. *IRCCS Fondazione Don Gnocchi, Milan, Italy Both beta-interferon 1b (IFNb) and azathioprine (AZA) have been shown to reduce relapse frequency in RR MS (The IFNB MS study group, 1995) (Yudkin 1991). However, no comparative data are avalaible obtained in patients’ cohorts followed in the course of a controlled trial. We started a controlled trial in which patients fulfilling the criteria for IFNb treatment (RR disease, EDSS lower than or equal to 3.5, age 18–50, at least 2 relapses during the previous 2 years), were allocated to either azathioprine treatment or to IFNb treatment; a third group of patients, who did not consent to be actively treated, were followed with the same protocol. The protocol included: standardized neurological evaluation with EDSS scoring, quality-of-life (SF-36) questionnaire, Hamilton Depression Rating Scale and Beck Depression Inventory, standardized psychiatric anamnesis based on DSM-IV definitions (with a focus on mood disorders) at enrolment and every 3 months thereafter. Evaluation of cognitive function by Wisconsin Card Sorting test and memory test (short story recall) at enrolment and at 12 months. Up to now, 11 patients have been allocated to IFNb, 8 to AZA and 9 no treatment. Pre trial clinical features do not show significant differences among subgroups, except for a lower pre-study relapse frequency and lower score in mental health perception in the patients subsequently treated with AZA. Relapses during the follow-up are treated in all groups with a similar i.m. dexamethasone schedule. By June, 1998, follow-up will be available on 7 AZA, 10 IFNb and 9 no-treatment patients followed for at least 9 months, enabling a preliminary evaluation of the comparative efficacy and impact on quality of life of these 2 widespread chronic treatments of MS. P186 PSEUDO-TUMORAL MULTIPLE SCLEROSIS: 9 CASES WITH GOOD RESPONSE TO TREATMENT. C. Lebrun*, S. Chanalet**, P. Thomas*, M. Chatel*. Services De Neurologie*, De Radiologie**, Nice, France Pseudo-tumoral multiple sclerosis is a rare demyelinating disorder. It was first described as “acute multiple sclerosis”. Usually, disease is revealed by an acute sensory motor hemiplegia mimicking stroke-like syndrome, as in Balo’s concentric sclerosis, associated with a poor prognosis. Patients/ Methods: We report 9 cases (3 women and 6 men; mean age 26.7 years) treated over a period of 2 years duration, with a 2 to 4 years follow-up. Diagnosis was assessed within 1 month delay after first symptoms. Brain MRI (spT1 with and without gadolinium, SpT2, FLAIR) was performed before corticosteroid treatment. Visual evoked potentials, biological and immunological analysis of CSF, serological and immunological screening was also studied. Stereotactic biopsy was performed in one case. Results: The clinical features, results of the laboratory screening, and MRI findings suggest the diagnosis of the so-called pseudo-tumoral multiple sclerosis, despite the absence of pathological confirmation, excepted in one case. All cases were characterized by their acute onset and regression of symptoms following corticosteroid therapy (Methylprednisolone; 1 gm/q/d-5 days. Only 3/9 had neurological symptom before. On CSF studies, 6/9 had more than 5 lymphocytes/mm3, but only 3/9 had oligoclonal immunoglobulin production. MRI showed a solitary hypersignal in 6/9 cases. Finally, 7/9 accepted an immunomodulatory treatment: 4/9 needed an intravenous treatment by cyclophosphamide and 3/9 were treated with interferonß-1b. 2/9 refused further therapy. None of them relapsed. Conclusion: Clinical status of pseudo-tumoral multiple sclerosis can be improve with corticosteroid and immunomodulatory treatments. By this way, this rare type of demyelinating inflammatory disease seems to have a better prognosis. P187 CLINICAL AND MAGNETIC RESONANCE IMAGING (MRI) CHANGES IN MULTIPLE SCLEROSIS (MS) PATIENTS DURING INTRAVENOUS IMMUNOGLOBULINE (IVIg) TREATMENT. Aco Jovicic, Dragana Djordjevic, Slobodan Cirkovic*, Evica Dincic, Ranko Raicevic. Department of Neurology, Department of Radiology*, Military Medical Academy Crontrayska 17, Belgrade, Yugoslavia

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IVIg treatment is rather new mode of immunomodulatory therapy in MS patients. It was our aim to evaluate clinical and MRI changes in 10 MS patients, during 2 years follow-up. All patients were treated with IVIg, 0.4 g/ kg, during 5 days initially, and than with a single dose every 3 months. Clinical and MRI evaluation (Gd-enhanced) were performed each time. There were 7 remitting relapsing (RR), 1 secondary progressive (SP), 1 primary progressive (PP) and 1 newly diagnosed MS patient. In PP patient there wore constant increase in number of lesions and presence of Gdenhanced lesions, followed by minimal clinical improvement; in SP patient absence of clinical deterioration was followed by decrease of Gdenhanced lesions, and decrease of the number of total lesions; in newly diagnosed patient clinical improvement was followed by absence of Gdenhanced lesions after 6 months of treatment and their reappearance after 6 months wash-out period; 3 RR patients were clinically stable with decrease in total number of lesions and absence of Gd-enhanced lesions, in 3 clinical deterioration was followed by presence of Gd-enhanced lesions and increase in total number of lesions while 1 was clinically stable but with presence of Gd-enhanced lesion. According to our data, IVIG is potent immunomodulatory therapy in MS patients. P188 HIGH-DOSE METHYLPREDNISOLONE TREATMENT IN SUBGROUPS OF MULTIPLE SCLEROSIS (MS) PATIENTS. S. J. de Pijper, B. M. J. Uitdehaag, J. B. Boringa, C. H. Polman. Department of Neurology, “Vrije Universiteit” Hospital, Amsterdam, The Netherlands Objective: To investigate the association between course of disease and response to intravenous (i.v.). methylprednisolone (MP) treatment in MS patients. Material and methods: We analysed data of 136 patients admitted between March ’85 and April ’95 to our hospital with a diagnosis of MS, to be treated with a first course of i.v. MP. Patients were in a relapsing remitting (RR) (64), secondary progressive (SP) (52) or primary progressive (PP) (25) phase of the disease. Almost all patients received 5 × 500 mg i.v. MP. Response to treatment was scored as “no response”, “moderate response”, “response with improvement of every day activities”. Also duration of response (in months) to i.v. MP was measured. Results: 28 (20.6%) (6 RR, 16 SP, 6 PP) patients did not respond to treatment, 55 (40.4%) (23 RR, 22 SP, 10 PP) patients responded moderately, 53 (39%) (32 RR, 12 SP, 9 PP) patients responded with improvement of daily activities. Response to treatment in RR MS patients was significantly better than in SP or PP MS patients ( p < 0.05). Response in PP MS patients was slightly better than in SP MS patients although not statistically significant. Duration of response (> 6 mnd) in RR MS patients was significantly higher compared to PP or SP MS patients. We correlated the magnitude of the response to steroids with disease type and phase, age, duration of symptoms, disability score, dosage of steroids, symptomatology, number of previous relapses. The only factor having predictive value wasfound to be the presence of a real relapse in the RR phase of the disease. Conclusion: This retrospective study provides evidence that the only factor having prognostic value with regard to the effect if i.v. steroids is the phase of the disease. P189 IMMUNOLOGICAL EVALUATION OF OPTIC NEURITIS. Irkeç C, Nazliel B, Irkeç M. Gazi University Medical Faculty Department of Neurology & Hacettepe University Medical Faculty Department of Ophthalmology Ankara, Turkey It has been reported that 20–35 % optic neuritis patients acquire M.S. (multiple sclerosis) between 1–5 years. Optic neuritis can be unilateral or bilateral. Ischemic and demyelinated lesions are often seen in the optic nerve pathology of these patients. Optic neuropathy seen together with M.S. can remits even if it is not treated. However optic neuropathy seen in collagen vascular diseases proceeds with loss of sight and can only be controlled by using high dose steroids. Between 1990–1995 50 optic neuritis patients between 25–42 years of age (medium 31.5); of which 22 were bilateral; have been followed for 5 years using neurological, neuroimmunological, neuroradiological and electrophysiological tests. We have seen that among the 50 patients that we followed during the 5 years, 22 (44%) developed M.S.;10% during the first year, 18% during the second year, 7% during the third year, 4% during the fourth year. In this study while bilateral optic neuropathy cases showed oligoclonal band in cerebrospinal fluid (c.s.f.), unilateral and control cases did not show any sign of oligoclonal band. In this series unilateral and bilatreal optic neuoropathy group showed significant increase of IgG in their CSF and serum when compared with controls, while there was no sign of IgM in the CSF of the patients and controls. The patients evoked potentials were examined, they showed an increased latency of P100 when compared to controls. It was

significant that the cranial MRI of the patients showed the presence of demyelinated plaques. Leukotrien C4 (LTC4) in the c.s.f. in both unilateral and bilateral optic neuropathy group was significantly different from that of normal control group ( p < 0.0001). P190 CONTRALATERAL SUPPRESSION EFFECTS OF TRANSIENTLY EVOKED OTOACOUSTIC EMISSIONS (TEOAEs) IN ASSESSMENT OF BRAINSTEM MULTIPLE SCLEROSIS. P. Lalaki*, Ch. Bairaktaris, S. Tsounis, M. Tsalighopoulos*, I. Milonas, I. Daniilidis*. B’ Univ. Dept. of Neurology, AHEPA Hospital, Thessaloniki, Greece. *Univ. Dept. of Otorhinolaryngology – Head and Neck Surgery, AHEPA Hospital, Thessaloniki, Greece TEOAEs can be suppressed with simultaneous contralateral sound stimulation. This phenomenon is considered to be mediated via the efferent auditory pathway. The aim of the study was to evaluate the TEOAEs suppression test as clinical tool for the assessment of brainstem located multiple sclerosis. Contralateral sound activated suppression of TEOAEs has been studied in 19 patients (38 ears) suffering MS. 13 out of them had brainstem MS lesions. A group of 10 healthy volunteers (20 ears) was used as a control group. Middle ear pathology was ruled out in all subjects. TEOAEs recording and the emission suppression test have been performed in all subjects, by means of ILO 92 Analyzer. For the emission suppression test the protocol suggested by Prasher et al. (1994) was used. Acoustic reflex threshold (ART) measurements and auditory brainstem response (ABR) were performed in all patients and a MRI as well. Control group’s TEOAEs suppression ranged from 6.9 to 1.1 dB SPL (x = 2.86 dB SPL), 1.8 being the most constant value. 12 patients (17 ears) showed suppression less than 1.1 dB SPL or no suppression at all. Only 5 patients (6 ears) of them showed abnormal ABR findings suggestive of demyelination in the brainstem. 8 patients of them showed MRI findings suggestive of demyelination at the posterior fossa structures and 4 had MRI scans with no lessions at the bain stem structures. 4 patients with lesions at the medulla or cerebellum showed normal TEOAEs suppression. This study provides further evidence that the assessment of TEOAEs suppression may be a useful addition to the battery of tests employed in the ivestigation of suspected brainstem pathology as demyelination lesions. P191 CORRELATION BETWEEN MRI AND TNF-α, IL-4, IL-10 AND TGF-β LEVELS IN MULTIPLE SCLEROSIS. D. Djordjevic, A. Jovicic, S. Cirkovic*, M. Jovanovic**, M. Kataranavski*, B. Magdic, R. Miliajlovic**, E. Dincic, R. Raicevic. Department of Radiology*, Department of Neurology, Department of Medical Research**, Military Medical Academy, Belgrade, Yugoslavia Cytokines are potent mediators of pathophysiological events in MS. It was our aim to evaluate clinical presentation, MRI and cytokine CSF levels in 22 MS patients – 13 remitting-relapsing (RR), 2 primary progressive (PP), 4 secondary progressive (SP), 3 newly diagnosed. Our group was consisted of 16 female, 6 male patients, aged 24–41 years. Functional disability was measured according to extended disability status scale (EDSS) and in our group it ranged between 3 to 5 (average 3.6). Most of our patients – 17, were presented in a phase of clinical exacerbation. By using ELISA test we measured TNFα, IL-4, EL-10 and TGF-β in CSF (obtained by lumbar puncture within 7 days of clinical exacerbation), while MRI (Gdenhanced) were performed within the same period. The highest level of TNFa were in patients with Gd-enhanced lesions, markedly in RR exacerbation phase and a bit less ´m PP and SP. At the same time, those patients had lower level of IL-4 IL-10 and TGF-β, known as immunomodulatory cytokines. In conclusion, CSF levels of inflammatory cytokine TNF-α correlate with presence of Gd-enhanced lesions and might be used as a fine marker of inflammation severity in MS, as well as MRI. P192 INTERFERON BETA 1b (IFNβ1b) THERAPY DIFFERENTIALLY AFFECTS THE LYMPHOCYTE SUBSETS IN RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS). Gallo P, Ferrarini AM, Sivieri S, Perini P, Tavolato B. Department of Neurological and Psychiatrical Sciences, Second Neurological Clinic, University of Padova, via E. Vendramini 7, 35137, Padova, Italy The lymphocyte subsets were longitudinally analysed in IFNβ1b-treated RRMS patients. Before therapy (T0), and after one (T1), two (T2), three (T3), six (T4), and twelve (T5) months after therapy initiation, the following

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lymphocyte subsets were studied by FACS: CD3+, CD4+, CD8+, CD19+, CD3+HLA-DR+, CD4+CD25+, CD3-CD16+(CD56+), CD3+CD8+CD57+, CD4+CD45RO, CD4+CD45RA. While the majority of the T cell subsets and B cells (CD4+, CD8+, CD3+HLA-DR+, CD4+CD25+, CD19+) were only transiently affected by the therapy (generally, a signicant reduction was observed during the first 3 months, with a return to pre-treatment values after 6 months of therapy), the natural killer cells (NK, CD3–CD16+) showed a marked and long-lasting reduction, that was still significant after one year of treatment. Interestingly, four patients who had clinical relapses during the first three months of therapy showed an increased expression of CD25 on CD4+ cells.

P193 SERUM β2-MICROGLOBULIN AS BIOLOGICAL MARKER OF INTERFERON β ACTIVITY. Sola P, Bedin R, Cavazzuti M, Tizzanini W*, Merelli E. Neurological Department, University of Modena, Italy; *Laboratory of Chemical-Chemistry Analysis, Azienda Policlinico, Modena, Italy Serum β2-microglobulin, part of the HLA class 1 molecule, is increased after interferon (IFN) α, β, γ, administration; this increase represents increased turnover, increased surface concentration, or both. To test the biological activity of IFN β-1b and IFN β-1a, we determined the level of serum β2-microglobulin in 2 groups of patients affected by multiple sclerosis (MS), treated with IFN therapy. In the first group of 21 patients, treated with IFN β-1b (8 MIU s.c. every other day), we determined serum β2-microglobulin levels by nephelometry (N-Latex β2-microglobulin, Behring Diagnostics GmbH, Marburg) every two months, for 18 months during the patients’ follow up. The baseline mean β2-microglobulin value was 1.4 mg/l, and at 18 months was 1.6 mg/l, with little variations during the whole period. These data suggest that the protein does not accumulate over the time in course of the therapy. In 3 MS patients treated with weekly 6 MIU i.m. of IFN β-1a, we determined the β2-microglobulin levels after a single IFN injection at 0, 12, 24, 36, 48, 72 hours after the injection. The protein peak level was reached at 24 hours, while returned to the baseline in 72 hours. Our data suggest that: 1) single β2-microglobulin measurements every two months, in the course of the patients’ follow up, is not recommended as indicator of IFN activity; 2) on the contrary, serial measurements after a single injection, showing the level of serum β2microglobulin concentrations, appear to be a suitable biological marker of IFN activity. P194 MULTIPLE SCLEROSIS AND OLIGOCLONAL IMMUNOGLOBULINES G IN TEARS AND CSF. D. Devos, G. Forzy, Ph. Gallois, P. Hautecoeur Evidence of oligoclonal bands (OB) of immunoglobulins G (IgG) in cerebro-spinal fluid (CSF) is more important biological criteria to disclose inflammation and to attest diagnosis of multiple sclerosis (MS), than quantitative methods such as Delpech ratio. These bands are defined as discrete population of IgG. Tears are an accessible external secretions. We compare OB in CSF and tears in a population of 54 MS patients and 45 with other neurological diseases. We used a simple strip to collect tears which was run on agarose isoelectric focusing gel. In tears we found a sensitivity of 63%, a specificity of 73%, and a predictive positive value of 74%. Evidence of OB in tears were found in two third MS patients. We demonstrated a concordance of 77% between tears and CSF. Leading to the hypothesis that MS is an autoimmune disease induced by T lymphocytes activated in blood, so all the immunological events could also be initiated in tears as in CSF. The second result concerned the low percentage of false positive in tears, about 20% which is the same percentage as in CSF meaning that if we find OB in tears we won’t have much more information using CSF; but if tears analysis is negative, it would be necessary to practice a lumbar puncture, because of the lack of sensitivity of tears compare to CSF. P195 CORTICOID THERAPY IN MS: TO TAPER OR NOT TO TAPER OFF? Haupts M, Schlüter Th, Lauter Th, Gehlen W. Ruhr-Universität Bochum, Dept. of Neurology/Knappschaftskrankenhaus, 44892 Bochum, Germany High-dose corticosteroid pulses given intravenously have been established as a standard therapy for multiple Sclerosis (MS) exacerbations. Rapid resolution of clinical symptoms and gadolinium-enhancing active lesions in magnetic resonance imaging scans have been documented as well as pro-

phylactic potentials for following episodes after optic neuritis with doses of 3 × 1000 mg. Clinical experience however shows cases with recurrence of symptoms after such short corticoid pulses. Whether this may be due to reactivation of inflammation, psychotropic or metabolic effects of steroid letdown or other reasons, is not quite clear. Several clinicians prefer to “taper off” therefore after high intravenous doses with different regimens of low-dose parenteral or oral corticosteroids; on the other hand, prolongation of therapy increases costs and risks of side effects. Pharmacological actions of corticosteroids include inhibiton of cellular aggression against myelin, induction of apoptosis and reduction of proinflammatory cytokines. Hypophysal function is usually suppressed for some days after i.v.megadose therapies; we could demonstrate a suppression in 75% of 50 investigated patients. For both pharmacological and clinical considerations we use tapering schemes in daily routine without relevant increases in side effects. Corticoid tapering should be considered in MS therapy studies’ protocols. P196 TINNITUS AS THE PRESENTING SYMPTOM IN MULTIPLE SCLEROSIS. A. Gass, A. Schwartz, M. G. Hennerici. Dept. of Neurology, Klinikum Mannheim, FR Germany Tinnitus is an uncommon symptom in multiple sclerosis (MS). It may be due to lesions of the labyrinth, eighth nerve, or CNS, but the pathophysiology is uncertain. One of the hypotheses is that damage to the myelin sheath may allow ephaptic transmission between nerve fibres, which results in derangement of the temporal pattern of auditory nerve discharges causing tinnitus. A 24 year old young man presented with the first clinically isolated syndrome of subacute onset tinnitus on the left and left sided facial sensory disturbance. Somatosensory, visual and auditory evoked potentials showed no definite abnormality. CSF analysis revealed an elevated cell count and positive oligoclonal bands. Magnetic resonance imaging (MRI) demonstrated a circumscribed contrast enhancing midbrain lesion at the level of superior colliculus involving the left brachium of the inferior colliculus. This fiber tract of the auditory pathway connects the colliculus inferior with the medial geniculate. It is located at the surface of the mesencephalon. No further lesions were detected at that point. Symptoms resolved after high dose i.v. methylprednisolon treatment. Clinically definite laboratory supported MS was diagnosed 2 years later when the patient presented with new sensory symptoms. Cranial MRI showed several new lesions in deep white matter supratentorially and further new cerebellar lesions. To our knowledge this is the first report of tinnitus as a presenting symptom in MS. It appears likely that the lesion involving the brachium of the inferior colliculus caused symptomatic tinnitus.

P197 SIALIC ACIDS AND THEIR FRACTIONS IN ERYTHROCYTES OF PATIENTS WITH MULTIPLE SCLEROSIS (MS). Z. Stelmasiak*, B. Jakubowska-Solarska**, J. Solski**. *Department of Neurology, **Department of Clinical Analytics, School of Medicine, Lublin, Poland The investigations were performed in 30 patients (16 women and 14 men in age of 26–67; 44 years on average) with definite MS in different clinical stage according to Kurtzke EDSS: 1–3 (9 pts), 4–5 (12 pts), 6–8 (9 pts). The control group consisted of 30 healthy patients (17 women and 13 men in age 18–58 years; 42 years on average). Erythrocytes membranes were isolated with help of Fairbank’s method. Total proteins in membranes were determined with help of Lowry’s method and sialic acids with help of Plucinski’s method. Statistical analysis was performed on IBM PC with Statistica Versus 5.0 programme. In erythrocytes membranes of MS patients decrease of total sialic acids (TSA) and protein-bound sialic acids (PSA) in all clinical stages ( p < 0.05) and decrease of lipid-bound sialic acids (LSA) only in mild and moderate clinical stage (p < 0.05) were found. The results obtained show for changes in erythrocytes membranes of MS patients. P198 PREDOMINANCE IN THE AFFECTION OF THE DOMINANT HEMISPHERE AND EYE IN PATIENTS WITH FIRST CLINICAL ATTACK OF RETROBULBAR NEURITIS. Flabouriari K, Katsibris J*, Michael A, Papapetropoulos Th, Papathanasopoulos P, Neurologeurologos P. Neurological and Ophthalmological* Clinic,University of Patras Greece 20 patients with first clinical attack of RN have been examined at presentation with MRI of the optic nerve and MRI of the brain. The load

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volume of the demyelinating plaques has been calculated with semi automated method in the MRI of the brain separately for the two hemispheres (dominant and non dominant). The length of the demyelinating plaque (s) has been measured in the MRI of the optic nerve. 14/20 (70%) revealed demyelinating plaques in the MRI of the brain. All showed predominance in the distribution of the plaques in the left hemisphere (all were right handed). 12/20 (60%) had the right eye affected. and 4/20 had bilateral affection of vision. In this group of patients the load volume was equal in both sides (more than 600 mm). In 4/20 the left eye was affected. Results: i) The most common affected eye in our study is the right one (dominant one) (12/20 = 60%). .ii) Independendly which eye was affected, there is a predominance in the distribution of the demyelinating plaques in the MRI of the brain in the dominant hemisphere. Further study may establish the vulnerability of the dominant hemisphere and the dominant eye to MS pathology in the early stages of the disease.

P199 IS THERE A CONCORDANCE FOR THE AGE AT ONSET, THE SEVERITY AND THE COURSE OF THE DISEASE IN FAMILIAL MULTIPLE SCLEROSIS (MS): A STUDY OF 92 FRENCH SIBLING PAIRS? D. Brassat1, C. Azais-Vuillemin1, P. Charlet1, G. Semana2, G. Edan2, O. Lyon-Caen3, M. Clanet1, B. Fontaine3 and the French Multiple Sclerosis Genetics Group. 1Services de Neurologie et d’Epidémiologie, CHRU Purpan, Toulouse, 2Services de Neurologie et d’Immunologie, CHRU Pontchaillou, Rennes, Fédération de Neurologie et INSERM CJF 9608, Groupe Hospitalier Pitié-Salpêtrière, Paris, France The French Multiple Sclerosis Genetics Group collected 92 sibpairs concordant for Multiple Sclerosis (MS). Diagnostic criteria were those published by Goodkin and coll (1991). Each participating individual, either affected or not affected, was examined by a neurologist. An informed consent was signed by participating individuals and DNA was prepared from blood samples from all participating individuals. All affected individuals were haplotyped for HLA. Clinical informations were obtained for each participating individual: age at onset, course of the disease (remittent, remittent-progressive or progressive), duration of the disease and handicap (EDSS). Using appropriate statistical methods, clinical characteristics of this population of familial MS was compared to a population of sporadic MS. The possibility of intrafamilial concordance for clinical parameters was carefully analyzed. The influence of HLA on the course of the disease was also examined. The results will be presented at the meeting.

Muscle Disorders P201 MARKED PHENOTYPIC HETEROGENEITY ASSOCIATED WITH THE THE C7472 INSERTION MUTATION IN THE MITOCHONDRIAL TRNA SERINE GENE – THE POSSIBLE ROLE OF AN INTRAGENIC POLYMORPHISM. Hanna MG1, Nelson IP1, Eunson L1, Rahman S2, 5, Rose M3, Cooper JM2, Debono AG4, Aquilina J4, Schapira AHV1, 2, Wood NW1 and Morgan-Hughes JA1. 1Department of Clinical Neurology, Institute of Neurology, Queen Square, London, UK; 2Department of Neurosciences, Royal Free Hospital, London, UK; 3Department of Neurology, Kings College Hospital, London, UK; 4Department of Neurology, St Luke’s Hospital, Guardamangia, Malta; 5Institute of Child Health, Great Ormond Street Hospital, London, UK We have identified two patients harboring a recently described insertion mutation in the mitochondrial tRNA gene for serine (C7472) exhibiting striking clinical diversity not previously reported. Case I was an 18 year old female with a mild symmetrical proximal limb myopathy since her early teens. Case II developed photosensitive generalized epilepsy at the age of thirteen. He subsequently developed myoclonus, deafness, cerebellar ataxia and dementia and was diagnosed as MERRF. Muscle biopsy in both cases showed ragged red fibres and over 80% of fibres exhibiting absent COX activity. Immunocytochemical studies in both patients were consistent with impaired COX holoenzyme assembly or increased degradation in the COX negative fibres. The C7472 mutation was detected in heteroplasmic form in muscle and blood. Single fibre PCR and in vitro mitochondrial translation studies provided direct evidence for an association of the C7472 mutation and impaired respiratory chain function and indicate that this is a pathogenic mutation. A second intragenic change in the serine tRNA was identified at position 7472 (T to G) in case I with the milder phenotype. This second change was not detected in 100 control subjects and it was not heteroplasmic and therefore is unlikely to represent a pathogenic mutation in its own right. However, it is possible that the T7472G change may ameliorate the effects of the primary mutation and account for the milder phenotype observed in case I. This study confirms that the C7472 mutation is likely to be pathogenic and demonstrates that it can associate with myopathy as well as the MERRF syndrome. The striking histological findings indicate that this mutation has a particular propensity to affect COX function. The second change observed may represent an intragenic suppressor which may account for the lack of CNS disease in case I.

P200 LONG-TERM OUTCOMES OF RADIOLOGICALLY PLACED ARM PORTS: PROSPECTIVE STUDY IN A MULTIPLE SCLEROSIS POPULATION. PRELIMINARY RESULTS. S. Chanalet*, C. Lebrun**, Cp. Raffaelli*, B. Padovani*. Services De Radiologie*, De Neurologie**, Nice Cedex 1, France

P202 GENETIC HETEROGENEITY IN MIYOSHI-TYPE DISTAL MUSCULAR DYSTROPHY. W. H. J. P. Linssen*, N. C. Notermans$, J. H. J. Wokke$, J. P. Vreyling#, P. A. Van Doorn@, F. Baas# and M. De Visser#. The Departments of Neurology of the St. Lucas Andreas Hospital* and of the Academical Medical Center #, Amsterdam, the Department of Neuromuscular Diseases, Academic Hospital Utrecht $ and the Department of Neurology, Academic Hospital Dykzigt, Rotterdam@, The Netherlands

Purpose: To evaluate outcomes of long-term central venous access devices in patients with multiple sclerosis (MS) needing long-term chemotherapy by cyclophosphamide, mitoxantrone monthly associated with methylprednisolone or not. Patients/Methods: Since June 1996, we prospectively evaluated the follow-up of 37 arm ports placed in 36 patients with MS. Data on port complications and function were recorded. All catheter dysfunction and related complications were systematically investigated, and treated by the interventional radiologist when needed. Samples of blood or venous infusions were all performed by arm port. Results: Technical success for placement was 100%. Follow-up was obtained in all patients. Mean days of catheter use was 319 days (total: 11497 d; range: 10–592 d; median: 372 d). Complications occurred in 6 patients. Two arm phlebitis resolved with subcutaneous heparin. One ruptured catheter migrated in the right pulmonary artery. One patient had local infection, requiring removal of the device. Two patients with highdose corticotherapy at time of intervention had a delayed skin closure with exteriorisation of the chamber through the skin, requiring a replacement of the port in one case. No central venous thrombosis was observed. Conclusion: Radiological percutanaeous placement of long-term arm ports is an effective, low-cost alternative to surgical placement. In a MS population, a low rate of central venous thrombosis and infections can be expected associated with long-term immunosuppressive treatments. Mechanical complications can all be managed by the interventional radiologist.

Miyoshi-type distal muscular dystrophy (MMD) is an autosomal recessively inherited progressive disorder. Classically, MMD is characterised by an early adult onset of symmetrical weakness and atrophy of the calf muscles, preventing these patients to stand on tip-toe.The serum CK level is highly (10–100 times) elevated and the muscle biopsy shows muscle dystrophy. Recently, in a series of 24 Dutch MMD patients we showed clinical heterogeneity and an unfavorable progressive course. The putative locus of MMD is linked to the limb-girdle muscular dystrophy 2B locus on chromosome 2p12–14. Study purpose: To analyse Dutch MMD patients for linkage to chromosome 2p12–14 and to perform a genome wide screen in apparently non linked families. Design: Four families, comprising 10 patients were large enough for linkage analysis. Four highly polymorphic microsatellite markers (D2S134, D2S358, D2S145, D2S291) were used for genotyping individuals. Two-point lod scores were obtained (MLINK subprogram of the LINKAGE software package). MMD was considered to be autosomal recessive with complete penetrance and an estimated gene frequency of 0.007. Results: Three of 4 MMD pedigrees showed non-linkage to the region spanned by D2S134-D2S358-D2S145 on chromosome 2p. In two families recombinations with marker D2S291 were found. Other markers from the candidate region (D2S134, D2S358 and D2S145) also showed recombinations in 3 of the four families, whereas in one family MMD segregated with these markers (lod score: 0.98, with D2S134 (at θ = 0)). A genome wide screen showed linkage to a chromosome 10 marker (D10S2325) in two of the non chromosome 2 linked families. Of the ad-

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ditional chromosome 10 markers, nine markers, covering a 23 cM region, segregated with MMD resulting in maximum positive lod scores of 2,578 (at θ = 0). One family appeared not to be linked to either chromosome 2 or 10. Discussion and Conclusions: Our results exclude the locus 2p12–14 in three of 4 MMD families and indicate genetic heterogeneity. However, our pedigree sizes were small. The results on chromosome 10 suggest a third locus for MMD.

P203 MUTATION ANALYSIS IN CARNITINE PALMITOYLTRANSFERASE II GENE IN PATIENTS WITH DECREASED MUSCLE CPT ACTIVITY. Corti S, Bordoni A, Comi GP, Corti S, Bordoni A, Comi GP, Toscano A, Agennouz M, Tancredi L, Scarlato G. Milano, Messina, Italy Carnitine palmitoyltransferase II deficiency is an inherited disorder of muscle lipid metabolism. CPT II gene was analyzed in patients with decreased muscle CPT activity: group 1: < 100 pmol/min/mg (9 patients), group 2: < 250 (25 patients) (nv: forward 367 + 110; isotope 452 + 160 pmol/ min/mg). The point mutations C439T and C1992T and the polymorphisms G1203A and A2040G were analyzed. Group 1 included 4 familial and one sporadic case: age at onset was 15 + 8 years (exercise-induced muscle pain and myoglobinuria), two patients had infantile seizures. Group 2 patients were heterogeneous (age: 32.2 + 11 years); most patients had episodic myalgia and muscle weakness; five patients had persistent weakness; three had increased CK levels; two partial seizures. The C439T mutation was present in a heterozygous form in 7/9 group 1 patients, representing 4 independent mutations. All of them were positive for the polymorphisms defining the ILV CPT II allele. The same mutation was found in 1 patient of group. None had the C1992T mutation. Our study confirms the pathogenic role of CPT IISer439Leu mutation in CPT deficiency. It may further indicate the usefulness of CPT II gene analysis in symptomatic patients with intermediate CPT values.

P204 SYMPTOMATIC CARRIERS OF DUCHENNE AND BECKER MUSCULAR DYSTROPHY. E. M. Hoogerwaard1, E. Bakker2, P. F. Ippel3, J. C. Oosterwijk2, D. F. Majoor-Krakauwer4, N. Leschot5, A. van Essen6, H. G. Brunner7, G. J. B. van Ommen2, M. de Visser1. Dpts. of 1Neurology and 5Human Genetics, Academic Medical Centre Amsterdam; Dpts. of Human Genetics of 2Leiden, 3Utrecht, 4Rotterdam, 6Groningen, 7Nijmegen, The Netherlands Objectives: 1) to estimate the prevalence of symptomatic Duchenne (DMD) and Becker (BMD) muscular dystrophy carriers in a population of definite carriers, 2) to establish the clinical profile of symptomatic carriers. Methods: Definite carriers in the age of 18–60 years who were registered at the Department of Human Genetics in Leiden, were invited to participate in a cross-sectional study. Investigations included a full medical history, muscle strength assessment by hand-held dynamometry (mild weakness) and manual muscle testing (MRC 4, moderate weakness) and a cardiological work-up consisting of electrocardiographic and echocardiographic examination. Results: 129 carriers (85 DMD, 44 BMD) participated in the study. 72% had no symptoms or signs. 22 % of carriers were symptomatic: 7% had mild weakness; 9% had moderate weakness; 5% had DCM (only DMD); one carrier had DCM with muscle weakness. In addition 5% had regular muscle pain and cramps, affecting daily activities. Of the carriers with muscle weakness, 82% was predominantly asymmetric, shoulder girdle muscles more affected than pelvic girdle. None of the carriers was wheelchairbound. BMD carriers were less frequently and less severely affected in comparison to DMD carriers, 13.6% versus 18.8% for muscle weakness and zero versus 8% for DCM. Conclusion: This study shows that clinical manifestation of muscle and cardiac involvement can be found in one-fifth of carriers of the dystrophin gene. DMD carriers are more often affected than BMD carriers.

P205 MYOBLAST TRANSENDOTHELIAL MIGRATION: AN IN VITRO ASSAY. S. Corti, M. G. D’Angelo, M. Colucci, Y. Torrente, A. Larovere, S. Salani, M. Sironi, G. P. Comi, N. Bresolin, G. Scarlato. Milan, Italy Intravascular administration of myoblasts is a possible approach in gene therapy for muscular disease. To test the interactions between myoblasts

and endothelium we used culture wells where H5V cells (a murine endothelial cell clone) are seeded on microporous membrane separating an upper from a lower chamber. Murine muscle cell lines G8, C2C12, L6 and murine muscle cells derived from primary culture were added to the upper chamber. After 2, 24, 48 hours, the transmigrated and the nonadherent cells were counted at the microscope. The assays were also repeated after stimulation with TNFα, inducing expression of several adhesion molecule on endothelial cell surface. The myoblast migration in some experiments was enhanced adding growth factor as EGF and a supplement derived from bovine brain to the lower chamber. Only few cells were counted in the lower chamber after 2 hours incubation and a minor increase was observed after 24 and 48 hours. The mean of cellular adhesion was 60–70%; after endothelial stimulation with TNFα there was a nonsignificant increase in adhesion.The assays repeated with a source of chemoactractant factor showed a few increase in migration. The myoblasts showed a high adhesion to endothelial monolayer, but minimal ability in transmigration. This in vitro assay of myoblast endothelial interaction might help identify factors involved in the enhancement of myoblast migration.

P206 SOMITE-DERIVED CELL LINES: MYOGENIC POTENTIAL IN MYOBLAST MEDIATED GENE THERAPY OF DUCHENNE MUSCULAR DYSTROPHY. M. G. D’Angelo, Y. Torrente, S. Corti, M. Colucci, R. Del Bo, V. Basso, S. Strazzer, A. DeLiso, G. P. Comi, N. Bresolin, G. Scarlato; Milan, Italy Vertebrate skeletal muscle derives from somites that develop by segmentation of the paraxial mesoderm. In the mouse, somites begin to form at 8 days p.c. and develop caudally over a period of several days. Newly formed somitic cells from the thoracic and caudal levels of 11.5 day mouse embryos were isolated and transfected with pCMVlacZ. Somite-derived transfected cells were transplanted into a pregnancy mouse by uterine extracorporeal circulation technique and Xgal stain was performed in embryos “in toto” 24 hours after the injection and in 2-day-old newborn mouse. Following cellular injection (E 11.5) into mouse embryos (11.5 dpc), clones of lacZ-positive cells were detected in intercostal, proximal hindlimb, dorsal neck and head muscles. In addition, when somites of 11.5 days embryos were assessed into non corresponding older staged, bone tissues and cartilaginous skeleton were positive for lacZ stain. No LacZ positive embryonal tissues were observed after the injection of fibrogenic and myogenic cell line, previously transfected with CMV lacZ. These results demonstrated the possibility of Xgal labelled cells to invade several muscular tissues during embryonal development. The understanding of interactions between cellular intrinsic factors and signals from developmental tissues during somitic cells migration in the host muscle tissue could open new perspectives in gene therapy.

P207 INCLUSION BODY MYOSITIS WITH LEUKOENCEPHALOPATHY AND PARTIAL LAMININ α2 (MEROSIN) DEFICIENCY. Pareyson D, Morandi L, Mora M, Fallica E, Farina L, Sghirlanzoni A. Milan, Italy We report a case of leukoencephalopathy associated with myopathy characterized by the presence of inclusion bodies and merosin deficiency. The patient was a 29-year-old man who came to medical attention because of electrocution. He had slightly delayed motor milestones but normal subsequent development. Family history was unremarkable. Neurological examination disclosed pes cavus, mild muscle weakness and wasting, slight limb incoordination, nystagmus, retained deep tendon reflexes. Serum CPK was high. Electrophysiological examination showed EMG myopathic abnormalities and prolongation of F-latencies. Visual and auditory brainstem potential studies were normal, whereas somatosensory potential latencies were prolonged. CSF protein content was increased. IQ was 85 (WAIS). Brain MRI revealed a diffuse and symmetrical increase in signal intensity of the supratentorial white matter in T2-weighted images with some broadening of the gyri. Muscle biopsy showed myopathic features, a mononuclear cell infiltrate, autophagic vacuoles and filamentous nuclear inclusions. Immunocytochemical analysis revealed reduced positivity to laminin α2 (merosin) immunostaining. There is a previous report of familial inclusion body myositis with leukoencephalopathy (Cole et al., Brain 1988; 111 : 1025–1037). To our knowledge, this is the first case associated with partial laminin α2 (merosin) deficiency. The relationship between these different abnormalities is still to be defined.

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P208 MYASTHENIA GRAVIS, CASTELMAN’S TUMOUR AND PARANEOPLASTIC PEMPHIGUS. C. Heroum, M. Pages, N. Raison-Peyron, J. M. Quiquempois, J. M. Blard. Departments of Neurology and Dermatology, CHU Gui de Chauliac, Montpellier (France) Autoimmune diseases such as pemphigus vulgaris are frequent in patients with myasthenia gravis (MG) but Castelman’s tumour (CT) is rare. We report a case of myasthenia gravis associated with CT and paraneoplastic pemphigus (PP). In May 1995, a 47-year-old woman presented with diplopia, ptosis and muscular weakness. Diagnosis of MG was confirmed by electromyography and a positive pyridostigmine test. Computerized tomography revealed a posterior mediastinal tumor. The patient was operated on and pathological examination showed angiolymphoid hyperplasia characteristic of CT. After surgery, respiratory insufficiency required tracheostomy and long lasting mechanical ventilation. The patient developed painful and extensive oral and vulval erosions, and mucosal biopsy revealed pemphigus lesions. Plasma exchanges and intravenous immunoglobulins were ineffective. With a treatment including high doses of prednisone and aziathioprine, the patient slowly improved. There was no recurrence of pemphigus and myasthenia. Laboratory findings showed high level of antibodies against acetylcholinesterase receptors and striated muscles, circulating antibodies against intercellular spaces of human epidermis, rat epithelial and non epithelial tissues. Two epidermal polypeptides of 210 and 190 kDa were identified by the patient’s serum on immunoblot analysis. Our patient fullfills all the criteria of PP. To our knowledge, 3 cases of MG and only one case of PP associated with CT have been reported. This is the first case of MG, CT and PP. P209 ABNORMAL CYTOKINE AND CORTISOL LEVELS IN DYSTROPHIA MYOTONICA. Å. Johansson, H. Forsberg, E. Krylborg, T. Olsson. Departments of Medicine and Clinical Chemistry, Umeå University Hospital and Department of Medicine, Boden Hospital, Sweden Dystrophia myotonica (DyM) is the most common inherited muscular dystrophy. Hyperinsulinemia/insulin resistance and cognitive dysfunction are common features of DyM. We have previously reported abnormal adrenal steroid hormone levels in DyM. Cytokines may influence cortisol secretion at several levels. Our aims were to study cytokines levels in DyM and their relation to the cortisol axis, and if the disturbances relate to cognitive function. Eighteen men with DyM (41.3 ± 13.8 years; mean ± SD) and 18 healthy men (41.2 ± 14.5 years) were included. Blood samples drawn at 07.00, 11.00, 16.00 and 22.00 hours were analysed for cortisol, adrenocorticotropin (ACTH), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α ). Mini Mental State Exam (MMSE) was perfomed. IL-6 levels were significantly increased at all timepoints (p < 0.05; p < 0.001; p < 0.05 and p < 0.05), and all cytokines/homones showed abnormal diurnal rhythm. Patients had higher evening levels of cortisol (p < 0.001), and increased levels of ACTH at 16.00 and 22.00 hours (p < 0.01 and p < 0.001). Among patients, significant correlations were found between MMSE results and evening levels of cortisol ( p < 0.05), ACTH ( p < 0.01) and TNF-α ( p < 0.05), and between TNF-α and cortisol at 11.00 and 16.00 hours (p < 0.05 for both). Profound abnormalities in cytokine/cortisol levels found in this study in DyM may be causally related to the metabolic and cognitive dysfunctions in this disease. P210 EMERIN APPEARANCE AND EXPRESSION IN NORMAL HUMAN FETAL SKELETAL AND CARDIAC MUSCLE. A. Gallanti, P. Ciscato, A. Prelle, M. Sciacco, S. Messina, P. Bazzi, E. Conti, G. Scarlato and M. Moggio, Milan, Italy It has recently been demonstrated that Emerin, the protein lacking in Xlinked Emery-Dreifuss muscular dystrophy (EDMD), is localized at the nuclear rim in adult human skeletal and cardiac muscle and in other tissues. We studied the appearance and development of Emerin in normal human fetal skeletal and cardiac muscle at different weeks of gestation (from 9th to 22nd for muscle, from 15th to 18th for heart tissue) by immunoistochemistry with monoclonal antibodies against a 222 aminoacid fragment near the protein n-terminus. Our results show that 19% of nuclear rims are positive in muscle at the 9th week, and that this positivity progressively increases up to 40% at the 22nd week. In heart tissue nuclear rim positivity increases from 31% at 15th week to 50% at 18th week. These data suggest that Emerin espression is a time-related phenomenon and that, given the same time conditions, this protein is more extensively expressed in heart than in muscle tissue.

P211 MULTISYSTEM TRIGLYCERIDE STORAGE DISEASE (CHANARIN DISEASE): CLINICAL, BIOLOGICAL AND HISTOPATHOLOGICAL FEATURES OF FOUR CASES. B. Eymard*, P. Laforet* G. Bassez*, T. Maisonobe**, C. Lacroix***, A. Leroy-Willig*, R. Dournith****, E. Bruckert****, M. Jouas*, M. Fardeau*. *Institut de Myologie, Hôpital de la Salpétrière, Paris. **Service d’Explorations Fonctionnelles Neurologiques, Hôpital de la Salpétrière, Paris. ***Laboratoire de Neuropathologie, Hôpital Bicêtre, Kremlin-Bicetre. ****Services de Diabétologie et d’Endocrinologie, H6pital de la Salpetrière, Paris Chanarin disease is a rare lipid storage myopathy inherited as an autosomal recessive trait. We report the observations of 4 patients affected by this disease. All patients were female, aged 28 to 48 years. Three patients were of Mediterranean origin, and apparently no consanguinity was demonstrated. Muscle weakness began in the third decade (mean age at onset was 28.5 ± 2.1 years), and mean duration of evolution was 9.5 ± 12 years. Three patients had a severe shoulder girdle weakness, associated with milder pelvic girdle weakness. Important distal upper limbs weakness was also present in all patients. Hypertrophic cardiomyopathy was detected in two cases. Muscle biopsies showed in all cases a major lipid accumulation with micro-vacuolisation of muscle fibers. Diagnosis was made on the following features: normal serum carnitine assays, and detection of lipid storage on granular cells (Jordan’s anomaly). A short duration medium-chain triglyceride diet did not lead significative improvement in one patient; and the same diet was recently prescribed in a second patient one year after onset of the disease (preliminary results are reported). P212 CONGENITAL MYOPATHY WITH TUBULAR AGGREGATES – A CASE REPORT. C. Kosubek1, M. Bergmann2, U. Beck1, G. Gerfelmeyer1. Departement Of Neurology Bremerhaven1 and Institute Of Neuropathology Bremen2, Germany Tubular aggregates (TA) are observed in diverse disorders including myasthenic syndromes, chronic exposition to drugs or toxins and periodic paralysis. There are rare cases with TA without a known underlying condition, which are thought to be congenital. Clinically these myopathies present as isolated progressive muscle weakness, weakness with exercise-induced pain and stiffness or weakness with myasthenic features. We present the case of a 38 year old man, complaining of myalgia in both arms and in the proximal left leg for six months. The neurological examination showed normal reflexes and sensibility. There was an isolated weakness of the hand flexion muscles of the right hand whereas muscle strength was normal in the other muscles. There were reduced involuntary movements of the arms while walking. The muscle tone was normal. Laboratory tests showed a small persistent elevation of the creatine kinase (between 77 and 102 U/l) and small elevation of the liver enzymes. All other tests including hormones, antibodies, investigation of the cerebrospinal fluid and lactatischemia-test remained normal. Electromyography including tests for myasthenia showed no pathological findings. A histological, histochemical and electron-microscopical analysis (left m. vastus lateralis) showed many TA. There was no history of periodic paralysis and no family history of muscle disorders. Exposition to drugs and toxins could be excluded. Conclusion: this case represents a congenital myopathy with TA. P213 SEVERE MYASTHENIA GRAVIS – LONG-TERM FOLLOW UP AFTER TREATMENT WITH IMMUNOADSORPTION. Bucka C, Köhler W, Hertel G. Moabit Hospital Berlin, Germany Immunoadsorption (IAD) is a successful therapeutic treatment in severe Myasthenia Gravis (MG). In a seven years period 26 patients were treated with 140 series of IAD (1 to 7 IAD in 3 to 14 days, 302 IAD in total). All patients showed severe generalized MG (modif. Osserman classification group IIb, III or IV). 26/26 improved after each IAD series. 18/26 achieved stable clinical conditions (Osserman IIa) in a period from 1 year (y) 1 months (m) to 6y 4m. 2/18 remitted completely (follow up 4y 10 m and 4y 8 m). 14/18 improved outlasting after a single IAD series (2 to 7 IAD): 2 patients > 6 y, 4 > 5 y, 3 > 4 y, 3 > 3 y, 1 > 2 y, 1 > 1 y. 2/18 relapsed after 1y 5m and 3y 6m, both achieved stable conditions after a second IAD series (1y 5 m and 6m). 2/26 underwent a relapsing course, one had 5 exacerbation’s within 3y 6m with clinical improvement after each of 5 IAD series and died 1y 3m later due to myasthenic crisis. The second one had 9 relapses within 4y 8m with stable intervals from 1m to 1y 1m. 2/26 received ongoing regular prophylactic treatment after frequent myasthenic crisis, one during a period of 4y 8 m every 3 weeks (126

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IAD in 81 Series), the other during a period of 3y 6m with increasing intervals from 1m to 5m (27 IAD in 15 series) up to now. 3/26 died within one years follow up, due to lung cancer, malignant thymoma and anterior spinal artery syndrome. Finally IAD is a safe and highly effective treatment in severe MG, even in long-term application. All of our patients improved after IAD, most of them with outlasting effect in combination with chronic immunosuppressive medication. Clinical efficacy is well comparable to that of treatment with plasmapheresis, but is achieved with a significant lower risk of side effects, mainly because of patients own plasmaproteins are preserved. Nevertheless, controlled clinical studies are necessary to clarify whether IAD or plasmapheresis is the most effective procedure in treatment of severe MG. P214 A DEFECT IN THE PHOSPHORYLASE KINASE ACTIVATING SYSTEM – A RARE CASE OF METABOLIC MYOPATHY. C. Kayser, D. Heuss, B. Neundoerfer. Erlangen, Germany Type VIa glycogenosis comprises rare disorders in the activation of phosphorylase kinase which in return is responsible for the activation of phosphorylase ‘b’ resulting in phosphorylase ‘a’. We are presenting a case of an otherwise healthy 32 year old male who suffered from severe muscle cramps in both of his thighs after strong exercise. Subsequently he developed rhabdomyolysis with increased serum creatin phosphokinase levels. Family history is negative. Muscle biopsy revealed few subsarcolemmal accumulation of glycogen. Biochemical investigation showed moderately increased amounts of glycogen, normal total phosphorylase activity, normal phosphorylase kinase activity and normal activity of the branching enzyme. The active form ‘a’ of the phosphorylase was 6% of normal. This case is an interesting presentation of clinical heterogeneity in type VIa glycogenosis. P215 A LONG-TERM FOLLOW-UP STUDY OF EARLY ADULT ONSET DISTAL MYOPATHIES IN SPANISH PATIENTS. Gámez J, Navarro C, Codina A, Cervera C. Barcelona, Spain Objective: To describe the clinical evolution characteristics over a 10 years period in 5 patients with early adult onset distal myopathy autosomal recessive (EAODM) types I and II, belonging to 4 Spanish families. Background: EAODM occurs predominantly in the Japanese population. It is suggested that the prognosis is generally good with a relative benign course and not aggressive in most patients. Material and methods: 5 patients with EAODM (3 type I or Nonaka myopathy, 2 type II or Miyoshi myopathy), were followed over 10 years with serial neurological examinations. Results: Clinical onset was between ages 16 and 19. All patients presented progressive muscular weakness. Although initially, wasting and weakness affected the distal muscles in lower limbs, the disease progressed with involvement of proximal and paravertebral muscles (4–8 years after the onset). In the advanced stages (> 8 years from onset) there was a severe generalised wasting and weakness of proximal muscles of the upper limbs. Two patients needed ambulatory assistance. Facial, extraocular, bulbar and respiratory muscles were spared in all cases. Conclusions: The clinical features are: (1) Initial symptoms appeared at the end of the second decade. (2) The distal leg muscles were predominantly affected; (3) CK elevation was 10–150 times normal values; (4) Proximal muscles were involved 5–7 years after onset, resembling in this stage a limb girdle syndrome. (5) The clinical course of these patients indicates that the disease is more aggressive than previously supposed. (6) Differences were not observed between the two subtypes of EAODM.

to be significantly reduced to 41, 48, 43 and 45% respectively in comparison to the controls. Atractylate inhibited respiration was reduced in the same manner (55%) indicating that oxidative phosphorylation is diminished but not uncoupled. These changes correlate with decline of activity of the complexes I, II, III and IV of the mitochondrial respiratory chain to 38, 57, 61 and 43% of the controls. Additionally, the activities of glycolytic enzymes phosphofructokinase, phosphoglucomutase, and lactate dehydrogenase were found to be diminished to 64, 57 and 34%. Since the mitochondrial matrix enzymes citrate synthase and succinate dehydrogenase are not affected, a selective inactivation of the complexes of the respiratory chain and of the soluble cytosolic enzymes by the septic mediators including NO and reactive oxygen species can be assumed. The detected disturbances in energy metabolism could explain the severe muscle failure of the patients at least in part. P217 GLUCOCORTICOID RECEPTOR CONCENTRATIONS IN MUSCLE BIOPSIES FROM PATIENTS WITH NEUROMUSCULAR DISEASES. H. J. Stuerenburg, C. Buhmann, G. Winkler, B. Schoser, K. Kunze. Neurological Department, University Hospital Hamburg-Eppendorf, Germany Increases in circulating glucocorticoids promote catabolism, particularly in skeletal muscle. Due to stress resulting from illness, or during therapy with glucocorticoids (in particular for inflammatory myopathies), serum concentrations of glucocorticoids can be elevated in patients with neuromuscular diseases. The sensitivity of the muscle to glucocorticoids can be altered by a change in the number of glucocorticoid receptors in the muscle, or by a change in the proportions of activated receptors (between binders IB and II). For this reason we have investigated the concentration of glucocorticoid receptors, and the proportions of the two types (IB and II), in healthy and diseased muscle. We found significantly reduced concentrations of glucocorticoid receptors in the group of inflammatory myopathies (51% reduction; p < 0.05, Wilcoxon signed rank test); the concentrations in diabetic polyneuropathy, polyneuropathy associated with vasculitis, amyotrophic lateral sclerosis and metabolic myopathies also tended towards lower values, although the differences were not statistically significant. No significant changes in the proportions of activated receptors were found in pathological muscle, although the proportion of binder IB tended towards elevated values (especially in the diabetic neuropathies, with a 17% increase). We conclude that the sensitivity of muscle to glucocorticoids can be reduced in neuromuscular diseases by a reduction in the number of glucocorticoid receptors in the tissue, but that no relevant shift in the relation between activated receptor types is present. This is especially important in relation to the risk of a secondary steroid myopathy and catabolism of skeletal muscle in the treatment of inflammatory myopathies with glucocorticoids. P218 IMAGING OF RHABDOMYOLYSIS USING BONE SCINTIGRAPHIC AGENTS. A. Collier, R. Denays, M. Rubinstein, P. Wulleman*. CH Etterbeek-Ixelles, *Clinique St-Etienne, Bruxelles, Belgium

P216 IMPAIRED ENERGY METABOLISM IN SKELETAL MUSCLE OF PATIENTS WITH CRITICAL ILLNESS NEUROPATHY AND MYOPATHY: INVESTIGATION OF MITOCHONDRIAL FUNCTION IN SKINNED MUSCLE FIBERS. F. N. Gellerich, K. Hertel, S. Trumbeckaite, K. Kappen, S. Neudecker, A. Lindner and S. Zierz. Muskellabor der Neurologischen Klinik, Martin-Luther-Universität Halle-Wittenberg, Halle/ Saale, Germany

Rhabdomyolysis is a potentially fatal disorder that may complicate a variety of diseases or conditions: exhaustive exercice, infections, metabolic disorders, intoxications, deficiency states, trauma, ... Etiological diagnosis may be difficult when several of these factors are present in combination, as it is often the case in alcoholic or psychiatric patients. We performed bone scan with 99mTc methylene diphosphonate (MDP) in 18 cases of rhabdomyolysis admitted in our hospital during the last 5 years. Accumulation of the radioactivity in the skeletal muscle was revealed in 14/18 patients. Pattern of tracer captation was suggestive of a traumatic/prolonged pressure origin in 4 patients (mild focal or multifocal tracer uptake in 3 cases, moderate bilateral posterior buttock tracer uptake in 1 case) and of a non-traumatic origin in 10 cases (moderate to severe symmetrical or asymmetrical diffuse muscle tracer uptake). Final etiological diagnosis of rhabdomyolysis in these 10 patients were: septicemia (n = 4), polymyositis (n = 3), alcohol intoxication (n = 2), hypothyroidism (n = 1). These results suggest that 99mTc MDP bone scan can be useful in rhabdomyolysis to localize and quantitate the muscular involvement and to differentiate between traumatic and non-traumatic cases.

Using high resolution respirometry in combination with skinned fiber technique and multiple substrate-inhibitor titration, muscle biopsies (m. tibialis anterior, m. biceps brachii) were investigated of patients with clinically and electrophysiologically verified critical illness myopathy and neuropathy. Results were compared with controls of 27 patients without myopathies or neuropathy. Maximal mitochondrial respiratory rates for the substrates pyruvate, palmitoylcarnitine, glutamate, succinate and ascorbate were found

P219 CARDIOMYOPATHY IN SARCOGLYCANOPATHIES: POLYMORPHIC CLINICAL ASPECTS. Salandi A, Felisari G, Scarpazza P, Prelle A, Turconi AC, Marchi E, Valagussa G, Bresolin N. IRCCS E. Medea, Bosisio Parini, IRCCS Ospedale Maggiore Policlinico Milan; Italy

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Sarcoglycanopathies are autosomal recessive limb girdle dystrophies caused by a deficit of four proteins (α, β, γ and δ sarcoglycans) that constitute a complex functionally associated with dystrophin in all muscular tissues. The clinical spectrum is variable and can account for very severe phenotypes (SCARMD). Cardiac impairment has been reported in sporadic cases with features of dilative cardiomyopathy; no correlation has been found with the absence of a specific sarcoglycan. Five patients (4 males, 1 female) aged 10, 16, 22, 23 (SCARMD) and 32 years (mild phenotype) previously diagnosed as sarcoglycanopathies following clinical and immunohistochemical criteria showed: case 1 complete absence of testable sarcoglycans (α-, β- and γ-), cases 2 & 3 lacked α- and γ- and partially β-, case 4 showed complete absence of β- and partial of α-; case 5, the clinically milder one, presented a partial deficit of α-. No genetic analysis was so far performed in all but case 4 (β-sarcoglycanopathy). We focused our attention on cardiac aspects by means of instrumental investigations (ECG, Echocardiography and 24-hours ECG). In three out of five patient we found a polymorphic cardiac involvement: one severe dilative cardiomyopathy, one pure ventricular arithmic pattern and one with a mixed compromission. Cardiac impairment in sarcoglycanopathies seems more common and polymorphic than previously reported independently by the primary deficit. P220 RETROSPECTIVE STUDY OF A LARGE POPULATION OF PATIENTS WITH ASYMPTOMATIC OR PAUCISYMPTOMATIC ELEVATION OF CREATINE KINASE SERUM LEVELS. Tancredi L, Prelle A, Battistel A, Sciacco M, Comi GP, Ciscato P, Bordoni A, Fortunato F, Robotti M, Chiveri L, Napoli L, Bresolin N, Scarlato G and Moggio M. Milan, Italy We evaluated 119 patients who came to our observation in the last years because of occasional, but persistent high serum CK (at least twice the upper normal level). All patients are either asymptomatic or paucisymptomatic (myalgia or muscle cramps). Clinical evaluation of muscle strength was made according to the MRC scale and a number of laboratory tests were performed: routine blood examination, EMG, EKG, Munsat test, exercise testing, urine aminoacids and organic acids. Family members were also tested for blood CK levels. All patients underwent muscle biopsy which was examined with routine histological and histochemical methods along with histochemical reactions for myoadenilate deaminase, myophosphorilase and phophofruktokinase and immunohistochemistry with antibodies against dystrophin. Immunohistochemical studies with antibodies against sarcoglycans, merosin and desmin as well as ultrastructural examination were performed when necessary. Proper biochemical investigations (CPT, acid maltase, glycolitic pathway and β-oxidation essays) were performed following the diagnostic clues offered by morphological analyses. In a few cases genetic studies were necessary to achieve final diagnosis. So far, our investigations allowed us to make a definite diagnosis of neuromuscular disorder in 15% patients. We will discuss whether remaining patients may be considered affected with essential hyperCKemia or whether different diagnoses can be looked for. P221 MITOCHONDRIAL DYSFUNCTION IN INFLAMMATORY MYOPATHY. P. Shanahan*, O. Droogan, F. Brett, P. Gallagher, O. Hardiman* and M. Farrell. Departments of *Neurology and Neuropathology, Beaumont Hospital, Dublin 9, Ireland Mitochondrial dysfunction may arise as a result of inherited or acquired mutations in mitochondrial (mtDNA) and nuclear DNA). Mitochondrial dysfunction may also occur in the absence of mutations involving DNA from either source. There is increasing evidence that mitochondrial dysfunction may play a part in the pathogenesis of non-inherited inflammatory muscle disorders but the importance of mitochondrial dysfunction in this context is uncertain. Additionally it has not been determined whether such acquired mitochondrial dysfunction is associated with defects in mitochondrial or nuclear DNA. Muscle tissue from three patients (two with dermatomyositis (DM) and one with angiocentric intramuscular sarcoidal granulomas) exhibited interfibre mosaicism for cytochrome-oxidase (COX) and succinic dehydrogenase (SDH). Southern blotting and long PCR were used to search for deletions in muscle derived mtDNA. The common 4977bp mtDNA deletion together with additional smaller mtDNA deletions was present in muscle derived DNA obtained from a 44 year old male with DM. MtDNA deletions were not demonstrated in muscle derived DNA obtained from a 4 year old child with DM or in an elderly patient with sarcoid myopathy. These finding indicate that whilst mitochondrial dysfunction is present in inflammatory myopathy, a mitochondrial

DNA defect is not consistently associated with mitochondrial dysfunction in this context. We cannot, at this stage, exclude a defect in nuclear DNA. Supported by a grant from the Irish Brain Research Foundation. P222 POLYMYOSITIS WITHOUT INFLAMMATION IN MUSCLE BIOPSY. M. F. G. van der Meulen, MD1, J. E. Hoogendijk, MD1, M. de Visser, MD2, J. H. J. Wokke, MD1. Departments of Neurology, University Hospital Utrecht1 and Academic Medical Centre Amsterdam2, The Netherlands Mononuclear cell infiltrates form a histopathological key feature of polymyositis (PM) and dermatomyositis (DM). Here, we report four patients with severe polymyositis, without inflammation in repeated biopsies. Two men and two women, aged 37–64 years, presented with weakness of neck flexors and limb-girdle muscles (MRC grade 3–4) of subacute onset, and creatine kinase (CK) activity of 3600, 9400, 14.000, and 6400 U/L, respectively. There were no skin abnormalities. Biopsies taken from symtomatic muscles before the initiation of prednisone treatment showed scattered necrotic and atrophic fibres, but no inflammatory cells other than phagocytic cells at sites of necrosis. In all four patients CK-activity decreased quickly on high-dose prednisone, but increase in muscle strength took at least three months to become obvious. All four patients relapsed during slow tapering of the medication, resulting in MRC grade 2–4 weakness of facial, pharyngeal, axial, and proximal limb muscles, and, in one patient, a temporary dependence on artificial ventilation. Repeated biopsies, taken during or following immunosuppressive medication, showed severe “dystrophic” abnormalities in all four patients, but again no mononuclear cell infiltrates. Acid-maltase deficiency, dystrophinopathies, and sarcoglycanopathies were excluded. In none of the muscle biopsy specimens perifascicular atrophy, MAC-positivity, capillary depletion, or endothelial microtubular inclusions were found. A sampling error could explain the absence of inflammation in the biopsies of these patients, but, in view of the uniformity and unusual severity of clinical, laboratory, and histopathological abnormalities, it is also conceivable that the immunopathogenesis in these patients is different from the T-cell mediated processes usually underlying PM. P223 ABNORMAL SERUM LIPID METABOLISM IN MYOTONIC DYSTROPHY. Juan J. Vílchez, M. Bretó, T. Sevilla, Carlos Perla, María D. Cherma and Ignacio Dobón. Hospital Universitario La Fe. Valencia Myotonic dystrophy is a genetic affection due to a CTG expansion causing an abnormal protein-kinase and cell membrane dysfunction. Myotonia and muscle weakness are main clinical features but the disease may express a multisystemic profile. Endocrine and others metabolic derangement due to receptor insensitivity are frequent Lipid metabolism is not well known in this disease. We have investigated a serum lipid profile including triglicerides (TGC), total cholesterol (Chol) and cholesterol-linked to high, low and very low density lipoprotein (HDL, LDL and VLDL), as well as apolipoprotein A and B (apoA and apoB) in 45 MyD patients and 60 matched control. A fully enzymatic cholorimetric method for lipids and immunologic nephelometric method for lipoproteins were applied. A full biochemical serum profile was also obtained by a standard autoanalizer. Two abnormal lipid profile appeared in the MyD group: 1) An increased TGC level ( p = 0.001) and 2) reduced VLDL ( p = 0.001) and increased apoB ( p = 0.004) with preserved total Chol and their fractions. In conclusion an abnormal lipid metabolism is part of the MyD picture. This abnormality may be primary or secondary to other disturbances like the glucose metabolism or liver dysfunction.

Neurobiology P224 REGENERATION OF MOTOR AND SENSORY FIBERS IN THE CAT. M. Moldovan, J. Sørensen, C. Krarup. Department of Clinical Neurophysiology, the Neuroscience Centre, Rigshospitalet and the Department of Neurophysiology, Institute of Medical Physiology, University of Copenhagen, Copenhagen, Denmark Regeneration after crush or section of 18 tibial nerves was monitored electrophysiologically using implanted cuff electrodes placed at the sciatic and tibial nerves and wire electrodes at plantar muscles. Recordings were carried out from ventral (V) and dorsal (D) L6-S2 roots in terminal experiments at different distances of regeneration as determined by the location

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of the front of regenerating fibers within the tibial cuff electrode or the recording of plantar motor potentials. Root recordings were obtained in 6 control cats in which compound nerve action potentials of varying amplitudes (2-800 µV) were recorded at L6V-S2V and at L6D-S1D at stimulation of the tibial nerve. The dominant root representing motor fibers to the tibial nerve was S1V (80% of the summed electrical responses) whereas L7D was the dominant sensory root (60% of the summed electrical responses). During growth through the tibial nerve elongation in motor fibers was as fast or faster than sensory fibers except in one nerve. The motor elongation front was established by the S1V root while sensory fibers showed no dominant root pattern. At later regeneration after crush all roots were represented in the fiber population whereas a less homogenous pattern was seen after nerve section. However, all nerves after section or crush regained a dominant S1V and L7D root pattern. In control nerve, the sensory conduction velocity was about 20% higher than the motor conduction velocity, whereas no difference was present in regenerated nerve. This may suggest that maturation was more complete in motor than in sensory fibers. P225 REGIONAL POTENTIAL FOR OLIGODENDROCYTE GENERATION IN THE RODENT EMBRYONIC SPINAL CORD FOLLOWING EXPOSURE TO EGF AND FGF-2. S. Chandran, C. Svendsen, A. Compston and N. Scolding. University Department of Neurology, Cambridge, U.K. The origin of oligodendrocytes in the developing rodent spinal cord has not been established. Several lines of evidence suggest that oligodendrocyte progenitors arise exclusively from the ventral neuroepithelium and that the dorsal spinal cord develops the capacity for oligodendrocyte formation as a result of ventral to dorsal migration of these cells. One way of exploring this issue is to study more primitive oligodendrocyte precursors in the cord. Although specific markers are not available, their presence may be inferred using mitogens such as EGF and FGF-2, which stimulate the proliferation of immature neuroepithelial cells, and subsequently studying their differentiation into lineage restricted cells. We used this approach to assess whether the dorsal embryonic rodent spinal cord has the intrinsic potential for oligodendrocyte formation at E14. We confirm that oligodendrocytes and their immediate (A2B5+) precursors are confined to the ventral spinal cord of the E14 rodent; but, following exposure to EGF and FGF-2, significant numbers of oligodendrocytes and A2B5+ precursor cells also develop from isolated E14 dorsal derived cells without interaction from the ventral spinal cord. The observation that from E14, the dorsal cord already has latent oligodendrogenic potential provides an alternative mechanism for oligodendrocyte formation to ventro-dorsal migration of oligodendrocyte precursors. P226 DOPAMINE UPTAKE IN RAT STRIATAL SLICES: A MODEL FOR STUDY DOPAMINERGIC TRANSMISSION. G. Page, L. Barrier, S. Chalon, A. Piriou and F. Huguet. Centre d’Etudes et de Recherche sur les Xénobiotiques, EA 1223, Faculté de Médecine et de Pharmacie, Poitiers, France In a previous study1, we have shown that spontaneously free radicals production in rat striatal slices altered the two dopamine (DA) uptake systems. In fact, kinetic analysis of [3H]-DA uptake indicated two saturable mechanisms, one representing a high (uptake 1) and the other a low (uptake 2) affinity uptake system. However, the uptake 2 seemed to be less accessible to antioxidants (ascorbate and trolox) than uptake 1. The present experiments were also undertaken to determine whether one or two kinetically distinct uptake sites exist. Both of these uptake systems were absent after destruction of the nigrostriatal dopaminergic nerve-endings by 6-hydroxydopamine injected in Locus niger. A pretreatment of animals by reserpine or tetrabenazine did not modified uptake1 and uptake 2. In addition, the two processes of DA accumulation were sodium- and temperature-dependent. Different monoamine uptake inhibitors were tested. GBR 12935 and PE2I (specific dopamine uptake inhibitors) were respectively about 100 and 1,000 times as potent as nisoxetine and fluoxetine (specific noradrenaline and serotonin uptake inhibitors respectively) on these two [3H]-DA uptake processes. However, the concentrations of all these products inhibiting 50% (IC50) of uptake 2 were largely higher than those for uptake 1. Our data suggest that there is one neuronal and dopaminergic uptake system. The biphasic kinetic of DA uptake in rat striatal slices seems to be related to the existence of a diffusional barrier between DA transporters at the surface and those in the center of the slice. These results confirmed that striatal slices, an integrated neuronal network could be used to study dopaminergic transmission after different neurodegenerative treatments.

P227 THE ANTI-APOPTOTIC PROTEIN Bcl-2 IS OVEREXPRESSED IN RESTRICTED AREAS OF BRAINSTEM IN INFANTS AND ADULTS. Coquerel A*, Lemeur N*, Joly G¤, Dorandeu A#, Chevallier F*, Zsürger N°, Heurteaux C°. *Neurobiology and ¤ Histology, University Hospital, Rouen, # Forensic Medicine, CHU Montpellier °CNRS, Sophia-Antipolis, Nice, France Apoptosis, or programmed cell death, can be induced by various physiological (differentiation, selective maturation) or pathological (radiations, oxygen stress, …) agents. At extracellular level growth factors are able to counteract the proapoptotic effects of ligand-receptor complexes with death domain (FAS, TNF). Intracellular proteins are also inductive of apoptosis cascades by enzymes like “caspases” and mitochondria coupled proteins (Bax, Bag, Bad …). They induce membrane potential extinction via mitochondria megapore (MM) openness which leads to cytosolic Ca++ release, ATP and energy failures. The main origin of MM paralysis is superoxides, which are induced by hypoxic stress or by other ways (e.g. during dopamine [DA] synthesis and storage).The Bcl-2 protein family blocks apoptosis by stabilising MM properties. We tested (i) whether in DA enriched regions (Substantia nigra [SN], ventral tegmental area [VTA]), and in large cells of the Olive, Bcl-2 is more expressed than in small and non-neuronal-cells. (ii) if Bcl-2 is more expressed during infancy and especially in ventilatory control areas in sudden infant death? We found Bcl-2 is only overexpressed in restricted brainstem areas i.e. SN, VTA and olive. The labelling in only observed in large neurons, in infants like in 70 y.o. adults. Finally, this expression is more intense in VTA and SN and in aged adults than during infancy. The Olive and the DA+ regions are also well known to overexpress the neurotensin receptor which trophic role could be here confirmed by an anti-apoptotic effect. P228 THIOL-METHYLTRANSFERASE ACTIVITY IS NOT A MARKER OF SPORADIC OR FAMILIAL PARKINSON’S DISEASE IN FRANCE. Mastain B, Brique S, Vinner E, Brique-Becquet E, Lhermitte M, Destée A. Centre Hospitalier Universitaire, Lille, France Genetic predisposition to enhanced susceptibility to environmental neurotoxins is one major hypothesis regarding the pathogenesis of Parkinson’s disease (PD). The detoxifying enzyme thiolmethyltransferase (TMT) has been reported to be reduced in membranes of red blood cells from patients with PD in some European countries. These results have not been replicated in North-America and Japan studies. Aim of the study: To confirm TMT defect in French caucasian sporadic PD and to determine TMT activity in familial cases. Methods: TMT activity was assayed from 41 subjects: 14 sporadic PD, 13 familial PD and 14 controls (groups 1, 2 and 3 respectively). Mean of age was comparable between the three groups. Variances and means were compared between groups 1 and 3 and groups 2 and 3 (F and t tests). Results: group 1: TMT = 1.68 ± 0.36 nmol/h/mg; group 2: TMT = 2.01 ± 0.45 nmol/h/mg; group 3: TMT = 1.53 ± 0.35 nmol/h/mg; No difference was observed for variances or means comparisons between groups 1 and 3 ( p = 0.95 and 0.17 respectivly) and between groups 2 and 3 ( p = 0.83 et 0.08). Conclusion: We failed to confirm TMT defect as a marker for sporadic PD in Europe and TMT activity does not appear to be different in familial PD. P229 NO ACUTE EFFECTS OF GBS CEREBROSPINAL FLUID ON ELECTRO-PHYSIOLOGICAL PARAMETERS OF PERIPHERAL NERVES IN VITRO. M. Hofmann, S. Quasthoff. Dept. of Neurology, TU, Munich, Germany There is an ongoing discussion about blocking factors in the cerebrospinal fluid (CSF) of GBS patients. Such factors have been blamed to rapidly block sodium channels in muscle cell preparations as well as compound action potentials of rat sciatic nerves in vitro. However, there are also reports about the failure of factors in GBS CSF such as anti-GM1 proteins to induce conduction block in an animal model in vivo. The aim of the present study was to evaluate the acute effects of native CSF from GBS patients on electrophysiological parameters such as compound action potential amplitude (CAPA), latency (L), DC-potential (DC) and electrotonic responses (ER). The in vitro experiments were carried out in a “marsh-chamber”, compartmentalised into three electrically isolated compartments. The central compartment was continuously perfused with the substances to be applicated. In total 8 rat ventral roots, 3 rat sural nerve preparations and 1 rat vagus nerve were used to investigated the effects of GBS CSF of 6 different patients. CSF (2-5ml) was diluted in 50 ml normal Krebs ringer solution. The

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average application time was 60 min. As controls we also applied 10 ml CSF from patients with normal pressure hydrocephalus (NPH) to avoid unspecific effects of proteins in the CSF. Anti-Galactocerebroside (0.5 ml [Sigma] in 50 ml Krebs-Ringer), which is known to have an acute effect on CAPA was applied as a positive control in our experimental setup. In summary, none of the GBS CSF samples had an acute and significant effect on CAPA, L, DC shift or ion inward or outward currents evaluated by the ER. Possible slow and late effects of the GBS CSF could not be separated from the run down of the preparation. Supported by the W. Sander Stiftung. P230 BIOCHEMICAL PREDISPOSING PATTERN IN POST LUMBAR PUNCTURE HEADACHE (PPH). H. Alchaar, M. Lantéri-Minet, N. Memran, M. Chatel, and J. Weil-Fugazza**. Département Douleur, *Service Neurologie/CHU de Nice, France. **INSERM 161, Paris, France PPH occurs in 15 to 30 % of patients who undergo lumbar puncture (LP). No predisposing factors but sex, age and needle size have been shown to influence its incidence. The primary objective of our clinical research program is to study the constitutive biochemical pattern of patients who undergo LP in order to draw a predisposing pattern in patients suffering from PPH. Methods: Using high-performance-liquid-chromatography with electrochemical detection, we measured eighteen amino acids (glutamate, glutamine, aspartate, asparagine, glycine, ethanolamine, o-phosphoryl-ethanolamine, citrulline, arginine, histidine, alanine, taurine, cysteine, valine, GABA, phenylalanine, serine, methionine) in CSF and plasma of nine patients suffering from PPH (after diagnostic procedure) according to the IHS diagnostic criteria. A control group consisted of nine patients sex and age-matched who did not suffered from PPH after LP done in identical conditions. Results: PPH suffering patients had both significant higher constitutive aspartate-like compound plasma level (5.0 ± 1 vs 1.9 ± 0.6 nmol/l, p < 0.05) and significant higher constitutive glutamate plasma level (54.2 ± 5.6 vs 40 ± 5.2 nmol/l, p < 0.05). Conclusions: Although results must be interpreted with caution, such an approach could allow to discuss the hypothesis of a predisposition for either headache or pain related to a neurobiological substrate. Supported by Institut UPSA de la Douleur. P231 CYTOTOXICITY OF ANNONACEOUS TETRAHYDROISOQUINOLINES FOR PC12 CELLS AND ITS RELATION WITH THE HIGHLY PREVALENT PROGRESSIVE SUPRANUCLEAR PALSY (PSP) IN CARRIBEAN ISLANDS. A. Lannuzel, R. Hocquemiller, C. Sengler, J. V. Barnier, M. Tardieu, D. Caparros-Lefebvre. CHU de Pointe à Pitre; Laboratoire de Pharmacognosie, Faculté de Pharmacie de Chatenay Malabry; Laboratoire Virus, Neurone, Immunité, Le Kremlin Bicêtre; Institut Alfred Fessard, CNRS, Gif-sur-Yvette; France Objective: To assess the cytotoxicity of Annonaceous Tetrahydroisoquinolines for PC12 cells. Background: High percentage of levodopa-resistant parkinsonism, resembling to PSP in French West Indies (FWI) has been suggested to be due to dietary habits including fruits and herbal tea of tropical plants: annonaceous. Annonaceous contain alkaloids: the benzyl-tetrahydro-isoquinolines (13THQ) which may be neurotoxic and have induced parkinsonism in animals. Methods: We evaluated in vitro the toxic effect of annonaceous 13THQ for PC12 cells. The extraction of 1.2 gr of totum alcaloïdum, containing 5 alcaloids was obtained from 1350 gr of annona muricata leaves produced and dessicated in Guadeloupe. Reticuline represents 50% of the whole alcaloids. PC12 cells were overnight incubated in the presence of 1 pM to 1 mM BTHQ. The percentage of induced cell death was assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyitetrazolium bromide] colorimetric assay. Results: 13THQ were detected by high performance liquid chromatography in both seeds of annona fruits and herbal tea of annona muricata. Treatment of cultures with 1 mM totum alcaloïdum induced the death of about 70% of the cells. Discussion: These data suggest a relationship between the ingestion of weekly or daily herbal tea of annona muricata containing 13THQ and the high prevalence of PSP in W. This hypothesis is supported by the recent literature on parkinsonism induced by 13THQ in monkeys. P232 MAGNETIC RESONANCE IMAGING AND CYTOLOGICAL ALTERATIONS IN THE RAT BRAIN AFTER CHRONIC ALUMINIUM LGLUTAMATE INTOXICATION. Deloncle R1, 2, Barantin L3, Quellard N4, Fernandez B4, Babin P4, Séguin O3, Huguet F2, Akoka S3, Guillard O2. 1Université de Tours, 2Institut des Xénobiotiques Poitiers, 3Plateforme pluriformation RMN Université de Tours, 4Service d’Anatomopathologie CHR Jean Bernard Poitiers, France

Young mature rats weighing 300 ± 10 g received during 10 weeks, five days a week, intraperitoneal injections (1 ml/kg) of Al-L-glutamate (Al = Lglu = 0.1 M). Controls received sodium L-glutamate (0.1 M) or physiological saline. Animal brains were investigated by transverse relaxation magnetic resonance imaging with a resonator especially designed for this application. Sagittal scanning was first carried on, to select slices for transverse and coronal examinations. For these two experiments, a multi slice and multi echo technique was used. A qualitative examination of collected echoes was first done. A T2 parametric image was then calculated for a quantitative visualisation of global brain structural alterations. In Altreated rats, electron micrography of hippocampus demonstrate perivascular oedema, lipofuscin deposits, mitochondrial swelling and failures in myelin tube, similar to those observed in non treated ageing rats. These results support the hypothesis of a pathological accelerated ageing process aluminium-induced.

Cerebrovascular Disorders P233 ONCOGENIC CEREBRAL ANEURYSM FROM METASTATIC LUNG ADENOCARCINOMA ASSOCIATED WITH CEREBRAL THROMBOSIS AND RECURRENT SUBARACHNOID HEMORRHAGE. Gliemroth J1, Nowak G1, Gaebel C2, Kehler U1, Arnold H1. 1Department of Neurosurgery, 2Institute of Radiology, Medical University of Lübeck, Lübeck, Germany Intracerebral neoplastic aneurysms due to metastatic tumor embolization are rare and usually originate from cardiac myxoma or choriocarcinoma. Only three neoplastic aneurysms from bronchogenic carcinoma have been reported. We report a case of a fusiform proximal anterior inferior cerebellar artery aneurysm from a histopathologically confirmed bronchogenic adeno-carcinoma in an 38-year-old female. The course with vertebral artery occlusion and left posterior inferior cerebellar artery infarction, subsequent aneurysmal formation, recurrent subarachnoid hemorrhage (SAH), and development of a cerebellar metastasis is well documented by angiography, magnetic resonance imaging, and histopathologically examination. Conclusion: In this case there are some exceptionally features which differ from the previously reported cases. Firstly, the aneurysm was associated with the vertebrobasilar artery system in contrast to the other cases of bronchogenic neoplastic aneurysm. The aneurysm led to recurrent SAH without appearance of an intracerebral hemorrhage, which was the first sign of cerebral involvement in the other cases. Secondly, the aneurysm formation took place in the proximal portion of a major infratentorial branch. This is in difference to the more typically location of neoplastic aneurysm in the peripheral branches of supratentorial arteries. Thirdly, the histological examination of the aneurysm confirmed the diagnosis of metastasis from adeno-carcinoma of the lung, which differ from all before described pathological diagnosis. P234 CLINICAL SYNDROME AND ULTRASONOLOGICAL PATTERNS IN PATIENTS WITH DISTURBANCES IN VERTEBROBASILAR SYSTEM CAUSED BY CERVICAL SPONDYLOSIS. G. Enina, G. Baitgaile, T. Timofejeva, D. Jegere. 3. Puripa. Latvian Medical Academy, Riga, Latvia The objective of this study was to clarify the clinical and ultrasonological features of vertebral artery (VA) syndrome caused by cervical spondylosis detected by radiological examinations. 209 patients from 15 to 66 y. o. (mean age 39 y. o.) participated in the study. Patients with occlusion or stenosis of VA confirmed by angiography were excluded. CT performed in 49 cases showed small atrophic lesions located in thalamus and posterior cerebral artery territory in 6 patients and was normal in 49 cases. Transcranial color-coded duplex sonography was performed in all cases. The typical symptoms were vestibular disturbances with secondary headache (82% of cases). In 54.5% of patients these symptoms were combined with the panic attacks including hypothalamic paroxysmal disturbances (45% of cases), non-epileptic attacks with muscular hypotony and "drop attacks (4.8% of cases). The most typical ultrasonic findings were curves of VA in extracranial part (74.7% of cases) and intracranial part (28.2% of cases) with vasomotor instability manifested as alteration of blood velocity and flow turbulence. The reduction of diameter of one or both VA was confirmed rarely – in 11.8% of cases. The different stages of cerebral venous disturbance sonographically proven as a increase of flow velocity in the deep neck veins (per 47.5%) in 75% of cases and dilation of basal cere-

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bral veins in 32% of cases were a common accompanying signs of headache and panic attack in patients with VA syndrome.

P235 LOCAL THROMBOLYSIS OF SUBACUTE DURAL SINUS THROMBOSIS. Claes F, Flandroy P, Dive D, and Franck G. C.H.U. Liege, Belgium We report our experience of direct thrombolytic therapy in two cases of intracranial subacute dural sinus thrombosis. The first patient was a 70year-old man presenting with a left hemiplegia occurring 7 days after progressive impaired consciousness. The second one was a 17-year-old girl with a Guillain-Barré Syndrome associated with a right VI cranial nerve palsy, followed by signs of intracranial hypertension. Brain CT and MRI scans were strictly normal. Venous MR angiography revealed the diagnosis. Systemic heparin therapy was inefficient in these two cases. Local catheter infusion thrombolysis were performed respectively 7 and 15 days after clinical onset. A total amount of 900 000 IU and 1 350 000 IU urokinase was infused respectively in 2 hours. This treatment was followed by oral coumarinic agents. Both patients had complete recovery. The first one after 2 days and the second one after 2 weeks. Conclusion: direct thrombolytic therapy of intracranial dural sinus thrombosis is safe and efficient even in the subacute phase and for patients who do not respond to heparin treatment. P236 DIAGNOSTIC POTENTIALS OF A NEW ECHOCONTRAST AGENT IN TRANSCRANIAL COLOR DOPPLER IMAGING. K. Schweikert, A. Marugg, J. B. Llull*, Ph. Lyrer. Neurology Department, University Hospital, Basel, *Bracco-Research, Geneva, Switzerland We investigated visualisation of basal cerebral arteries by transcranial color coded duplex sonography (TCCD) compared to angiography and magnetic resonance angiography (MRA) in patients with insufficient transtemporal insonation. BR1 (SonoVueTM, Bracco SpA-Milan, Italy) is an echocontrast agent, containing sulphurhexafluoride-microbubbles, withstanding pulmonary transit. Method: Twenty-one patients (60.4 ± 10.7 years) were enrolled, 14 had an extracranial artery disease. TCCD gain was set at the lowest level allowing vessel identification and kept constantly. BR1 was administered intravenously. For the 1.2 ml-dosage (1.2–7.5 × 10 8 microbubbles), videotape analysis was performed for the ipsilateral middle (M1, M2), anterior (A1), posterior cerebral artery (P1, P2), posterior communicating artery (PCoA), and compared to reference angiographies (11) and MRAs (17). Results: Agreement was reached for visualisation of M1, M2 and P2 with both reference modalities and for A1 with MRA, with angiography in one patient less (10% false positive). PCoA and P1 were identified in all cases with TCCD but both only in 9 angiograms (18% false positive), PCoA in 12 and P1 in 15 MRAs (30%, 12% false positive). Conclusions: In patients with insufficient transtemporal insonation, BR1 optimises noninvasively identification of basal cerebral arteries. Accuracy of visualisation in TCCD was high for basal cerebral arteries of the anterior circulation, but lower for PCoA and P1 compared to gold standards. Alteration of insonation angle, gain, and additional use of Doppler signal might correct false positive results. P237 CEREBRAL INFARCTION FOLLOWING VIPER BITE: A CASE REPORT. Polo JM, Alvarez de Arcaya A, Cid C, Muñoz R, Ceballos O, Berciano J. Santander, Spain A 42-year-old farmer was bitten by a Vipera seoanei on his left thumb while scything. On admission, two hours later, neurological examination was normal; two deep fang marks were seen on the left thumb, and the upper left extremity was markedly swollen. He was placed in a critical care unit, where he almost always kept his head turned to the left, being seriously worried about his injury. Six hours after being bitten he suddenly developed mild agitation and sensory aphasia. Initial and subsequent controls of hemostasia were normal. A brain CT scan on day 2 showed an illdefined low density left parietal area; MRI confirmed this as an ischemic area. Electrocardiogram and two-dimensional echocardiogram were normal. An arteriography showed elongation of the left internal carotid artery, describing a complete loop, with indirect signs of distal arterial obstruction. His general condition eventually improved and inconstant nominal dysphasia was his only sequel. Cerebral infarction caused by viperbite is a rare incident and no definite pathophysiological mechanism has been es-

tablished. In the five instances published previously, disseminated intravascular coagulopathy, vasculitis, thrombin-like action from the venom and hypotension had been implicated. We suggest that in this patient a preexisting asymptomatic vascular anomaly in combination with head rotation, perhaps with the presence of the venom, facilitated the cerebral infarction. P238 PRIMARY INTRAVENTRICULAR BLEEDING IN THE EARLY STAGE OF UNILATERAL MOYAMOYA DISEASE. C. Gaebel, E. Reusche2, J. Gliemroth3, H. Lorch, M. Zwaan, H. Arnold3, H.-D. Weiss. Neuroradiology, 2Neuropatholgy and 3Neurosurgery, Medical University, Lübeck, Germany Besides lacunar, territorial and hemodynamic infarctions advanced stages of moyamoya disease are known to seldom cause subarachnoidal and parenchymal bleedings in young adults, sometimes complicated by secondary intraventricular blood spread. We analyse clinical and neuroradiological findings in an autopsy case of primary intraventricular bleeding in an early stage (beginning Suzuki II) of unilateral moyamoya disease (hemimoyamoya) and demonstrate neuroradiological-neuropathological correlations. A 27-year-old hitherto healthy female acutely developed generalised convulsion and deep coma. Computed tomography (CT) revealed ventricular tamponade by fresh blood without evidence for parenchymal bleedings, infarctions or other pathological findings. Panangiography (selective i.a. DSA) demonstrated unilateral 50% stenoses of intracranial carotid artery bifurcation and proximal A1-/M1-segments, combined with a circumscribed network of fine basal collateral vessels. Although emergency craniotomy with hematoma evacuation and ventricular drainage were performed the patient died within three days. Postmortem in vitro MRI, gross pathology, light microscopy and immuno-histochemistry confirmed the diagnosis of moyamoya disease including typical fibrocellular intimal thickening and reduplicated elastic laminae. Parenchymal bleeding components and alternative bleeding causes could be excluded. Multiple microaneurysms of the intraventricular choroidal artery portions caused by choroidal participation to the collateral circulation were identified as the bleeding source. Moyamoya disease should therefore be considered as a possible differential diagnosis in primary intraventricular bleedings of young adults, even when angiography reveals only unilateral early stage findings.

P239 ENDOVASCULAR TREATMENT OF RUPTURED INTRACRANIAL ANEURYSMS BY GUGLIELMI DETACHABLE COILS (GDC). Ph. Paquis, A. Rogopoulos, M. Lonjon, A. Naraghi, T. Desjardins, E. Aguinet, P. Grellier. Nice, France 89 patients with subarachnoid hemorrhage were electively treated using GDC; 48 women and 41 men, mean age of 52 (19–85). In the same time, 151 patients were surgically treated. Hunt and Hess grading was: grade I–II 61%, grade III 13.5%, grade IV–V 24.5%. Angiography revealed 98 aneurysms (9 patients with multiple locations): anterior communicating artery 42%, carotid artery 26.5%, posterior circulation 18% and middle cerebral artery 13.5%. Large neck size in 36% and small in 64%. Aneurysmal occlusion was total in 77% of cases, > 90% in 11%, and partial 12%. Among partial embolization, 4 had to be treated surgically, 4 had additional endovascular embolization, and 3 had angiographic surveillance. 8 aneurysms were repermeated. The clinical results are given according to the Glasgow outcome scale (GOS): GOS I-II in 80%, GOS III-IV in 10%, and death in 10%. These results are similar to those of the literature (Guglielmi, Houdart, Vinuella). Technique Indication depends on clinical grade, hematoma compression, vasospasm presence, location and size of aneurysm, neck size, and presence of perforant vessels near the neck. Embolization is therefore indicated in the following cases: anterior communicating, carotido-ophtalmic and posterior circulation aneurysms with a small neck. The technique is not indicated if the neck is very large, or with perforant vessels nearby, or with a big hematoma as usual in middle cerebral artery. P240 PROGNOSTIC VALUE OF THE 1 MONTH CLINICAL ASSESSMENT AND MRI AND rCBF STUDIES IN ANTERIOR CHOROIDAL INFARCTS. M. Rousseaux, B. Bayle, V. Lahousse, J. P. Pruvo, M. Steinling. Services de Rééducation Neurologique et de Médecine Nucléaire. CHU Lille, France

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In patients presenting with selective anterior choroidal artery infarct (ACAI), previous authors have investigated the prognostic value of early assessment on the 6 months prognosis. However, deficits, disability and handicap are not stable at this time. The aim of this study was to more specifically investigate the relative interest and the prognostic value of the secondary clinical assessment (1 month, M1), in combination with the analysis of lesions (MRI) and of rCBF disorders (SPECT), on the 1 year (Y1) status. Patients and methods. Each of the 16 patient admitted in the rehabilitation unit were investigated using: (1) general informations: age, sex, hospitalization duration, side of the lesion; (2) M1 assessment of deficits (motor and somatosensory deficits, balance and gait (FAC), Orgogozo scale, orientation and MMS) and disability (Rankin scale, FIM); (3) assessment of lesions using MRI (0.5 T; T2 sequences) in 4 subcortical areas (internal capsule, lenticular and caudate nucleus, thalamus), and Fazekas index; (4) analysis of rCBF with SPECT (Tomomatic 564) and Xenon inhalation; flow and asymmetry indexes (AI) were quantified in 6 areas of each hemisphere and in the cerebellum; (5) Y1 assessment of the same deficits and disability, plus evaluation of handicap (Holbrook scale). We used multiple correlations analysis between the Y1 and the M1 variables, then stepwise variable selections ( p = 0.05). Results. The performance in the Orgogozo scale (Y1) was best explained (R2 = 0.950) by: Orgogozo scale (M1), lesion side (better in left injury), MRI lesions (volume, Fazekas index), and parietal AI. The MMS was explained (R2 = 0.786) by: MMS (M1), and upper frontal AI. The Rankin scale (R2 = 0.968) by: motor deficit (M1), MRI lesions (Fazekas index; lenticular), and cerebellar AI. The FIM (R2 = 0.709) by: motor deficit (M1), MRI lesions (Fazekas index; capsular), and frontal and temporal AI; The drop of performance in the Holbrook scale (R2 = 954) by: motor deficit (M1), hand dysfunction, MRI lesions (lenticular), and cerebellar AI. Discussion. This study shows that in ACAI patients, important informations on the late prognosis can be obtained using a combination of clinical assessment of motor deficits, MRI evaluation of the internal capsule and lenticular lesions, and SPECT analysis of cortical consequences. Furthermore, the same type of variables explains the three levels of deficits, disability and handicap, at the exception of cognitive disorders (MMS).

P241 ANALYSIS OF HYPERTENSION-TREATMENT IN PATIENTS WITH ACUTE ISCHEMIC BRAIN DISEASE BEFORE THE ONSET OF NEUROLOGIC SYMPTOMS. R. Raicevic, A. Jovicic, D. Tavciovski*, M. Krgovic*, D. Veljancic, D. Djordjevic. Military Medical Academy, Department of Neurology; Deparment of Cardiology; Belgrade, Yugoslavia Arterial hypertension (HTA) is one of the major risk factors for the development of atherosclerosis and consequently ischemic brain disease (IBD). The aim of this study was to analyse the adequacy of antihypertensive treatment approach before the onset of E31), concerning the antihypertensive drugs divided, by different mechanisms of action (beta blockers, ACE inhibitors, diuretics and calcium channel blockers). Materials And Methods: The study included 100 patients, 68 male and 32 female, 65 years of mean age, with (IBD clinically and radioIogically verified. Detailed anamnesis of a duration of HTA, therapy taken before neurologic onset, regularity of treatment and control check-ups, was taken. HTA was verified after a criteria accepted for this disease, and blood pressure was measured every four hours during the first 48 hours, and later, three times a day. Results: Analysis of various antihypertensive drugs, showed that calcium channel blockers appeared the only or in therapeutic combination in 34%, diuretics in 36%, ACE inhibitors in 32%, and beta blockers in 17% of patients. Also, it was observed that more than 50% of patients had to change therapy either by adding antihypertensive drugs from some other group or by increasing the dose of the same drug. More than 70% of patients took the therapy irregularly and only 18% of patients had regular medical check-ups. Conclusion: Results of this study indicate a need of redefining the antihypertensive treatment approach and on the other hand, point out the fact that significant number of patients with HTA do not respect their disease, even after its worse complications occurred.

P242 MECHANISM OF THE ANTIOXIDANT ACTION OF GREEN TEA TO THE STROKE PREVENTION. Jovic P, Kosanovic M, Jovicic A, Spasic S. Military Medical Academy and University School of Pharmacy, Belgrade, Yugoslavia Recently, extensive four-year study in Japan showed that regular consumption of green tea decreases risk for stroke. Non-fermented (green)

and fermented (black) tea contain many polyphenolic compounds with antioxidant activities. The purpose of this study was to investigate total antioxidant activity and the content of selenium in green and black tea. Dried samples of green and black tea (1 g) were digested in Tecator digestion system, model 40. Atomic absorption analyses were performed by means of Perkin-Elmer model 5000 atomic absorption spectrophotometer. For selenium determination MAS-10 mercury hydride system was used. decoction tea samples (2% w/v) were prepared. Total antioxidant activty of these samples was determined spectrophotometrically using kit from Randox, UK. The content of selenium green tea was 0.50 µg/g, while black tea contained 0.21 µg Se/g. Diluted decoction of green tea (1 : 10) inhibited oxidation of chromogen 100%, while the inhibition of this reaction by decoction black tea is very good and similar. However, green tea contains almost 2.5-fold more selenium than black tea. Because selenium is an essential component of antioxidative enzyme glutathione peroxidase, it could be one of the reasons that green tea has more effective antioxidant action, as shown by in vivo investigation. P243 BILATERAL POLAR THALAMIC TERRITORY INFARCTION. L. Mossuto-Agatiello, A. Lottarini. San Giovanni Battista Hospital SMOM. Rome, Italy The medial and lateral portions of the anterior thalamus are usually supplied by the tuberothalamic (polar) artery from the posterior communicating artery (PCoA). When a tuberothalamic artery is absent, the polar territory is supplied by the thalamic-subthalamic arteries. Bilateral paramedian thalamic-subthalamic infarcts are common whereas bilateral infarction in the polar territory is quite rare. We now report 3 patients with bilateral simultaneous polar thalamic infarcts documented by MRI. Patient 1, with emboligenic heart disease, suddenly developed an akinetic mutism. Infarcts involved the entire polar territory with slight extension to the posterior paramedian territory. Patient 2, with a history of atrial fibrillation, suddenly became lethargic and showed abulia and amnesia. Neuroimaging disclosed bilaterally two distinct noncontiguous ischemic lesions, the former involved the anterior lateral thalamus, the latter the territory of the thalamic-subthalamic arteries. The PCoA’s were not visualized on MR angiography. Patient 3 developed memory loss after the use of anticryptogamic substances. Asymmetric lesions were observed in the anterior medial thalamus. The PCoA’s were of fetal type. SPECT scans of the amnesic patients showed decreased metabolic activity in the frontal cortex. Since there is no anatomical evidence that the polar arteries on each side originate from 1 common trunk as occurs in the thalamic-subtalamic arteries, the exact stroke mechanism remains unclear. Case 1 probably had embolic occlusion of the thalamic-subthalamic arteries with an unusual pattern of infarction. In cases 2 and 3 was hypothesized a hemodynamic mechanism related to a rapid failure of perfusion pressure within the PCoA’s. P244 DUPLEX-SCAN SONOGRAPHY OF CAROTID ARTERIES IN PATIENTS WITH LACUNAR INFARCTS. Dragan Marjanovic1, Milan Savic1, Jovan Strikovic1, Helena Marjanovic2, Filip Ser 3. 1Hospital for Cerebrovascular Disorders “Sveti Sava”, Belgrade; 2 Pharmaceutical Association Panevo; 3City Departement for Skin and Venereal Diseases, Belgrade Occlusion of small penetrating branches of the cerebral arteries results in lacunar infarcts. Usualy lacunar infarcts are in strong correlation with hypertension and atherosclerosis has involved not just the large arteries, but has extented into their finest branches. Objective: Atherosclerotic lesions of carotid arteries examined by Duplex-scan sonography in this study is not in correlation with lacunar infarcts, and all lesions revealed by this examination can not significantly influence circulation in penetreting vessels. Methods: Randomly chosen group of 43 patients with lacunar infarcts revealed by CT-scan and hypertension in history was examined by Duplex-scan sonography. A study group was made of 23 males and females aged 50–77. Duplex-scan sonography of common and internal carotid arteries showed atherosclerotic changes and plaques wich made stenosis of these vessels ranging from 7% to 25% located unilateraly or billateraly. All plaques were with no signes of hemorrhage nor ulceration and were not hemodinamicaly significant. Conclusion: Atherosclerotic lesions of carotid arteries can not be cause of lacunar infarcts in hypertensive patients especially if there are no signs of ulceretion or hemorrhage in atheromathose lesion. The main cause seems to be hemodinamic influence of hypertension at the level of penetrating vessels and pecularities of circulation through them.

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Poster Session 3 Cerebrovascular Disorders P246 CEREBRAL BLOOD FLOW CHANGES IN PATIENTS WITH HYPOTHYREOSIS. Krystyna Mizan, Piotrlyczak, Piotr Lass. Medical University, Gdañsk, Poland Patients with hypothyreosis frequently show a cognitive impairment, in many cases little reversible after the return to euthyreosis. Little is known on cerebral perfusion in those patients. We performed brain SPECT (Single Photon Emission Computed Tomography) using 99mTc-HMPAO and a triple-head gammacamera in 20 patients before and after therapy with Lthyroxin. We analysed interhemispheric asymmetries and intrahemispheric variations of 99mTc-HMPAO uptake, as compared to cerebellar uptake. Control group were 27 healthy volunteers. Cerebral perfusion abnormalities were found in 16/20 untreated patients with hypothyreosis. This was seen as a multiple focal interhemispheric cerebral perfusion defects in 14/20 patients, mostly in frontal, occipital and parietal lobes. Diffuse hypoperfusion of frontal lobes was seen in 14/20 patients, of temporal lobes in 6/20 patients, comparing to cerebellar blood flow. The frontal lobes’ involvement correlated with severity and duration of disease. After the treatment the focal asymmetries returned to normal in 3 patients, frontal hypoperfusion in 5 patients, temporal hypoperfusion in 2 patients. Conclusions: our results indicate the high incidence of cerebral perfusion defects in hypothyreosis, predominantly in frontal lobes and occipito/parietal border, related to the duration and severity of illness. Those changes seem to be little reversible after the treatment. Those alterations may be attributed to two mechanisms: long-lasting hypocholesterolemia and persistent metabolic depletion; alternatively the degenerative changes of brain vessels might be considered. P247 A CASE WITH MULTIPLE OCCULT CEREBROVASCULAR MALFORMATIONS WHO PRESENTED WITH OCULAR MOTOR SYMPTOMS AND ISOLATED INTRAVENTRICULAR HAEMORRHAGE. Ayșe Bingöl*, Canan Togay-Ișkay*, Nermin Mutluer*, Ilhan Erden**, Umman Sanlidilek**, Serdar Akyar**. Ankara University, Medical Faculty, Departments of *Neurology and **Radiodiagnostic, Ankara, Turkey A 67 year-old female patient presented with sudden onset of headache, nausea, diplopia and left- sided ptosis. Neurological examination revealed neck stiffness, bilateral decrease in visual acuity, complete 3rd nerve palsy on the left, partial 6th nerve palsy and nystagmus on the right. The cranial computed tomography (CT) revealed blood in the 3rd and 4th ventricles, left parasellar hyperintensity and pin-point contrast enhancements in bilateral thalamic location. Four-vessels digital subtraction angiography (DSA) was normal except for a minimal rightward shift of right callosal and pericallosal arteries. Cerebral magnetic resonance imaging (MRI) revealed multiple millimetric lesions in the brainstem and basal ganglia compatible with capillary telangiectasia and another lesion in the peri-aqueductal grey matter of superior mesencephalon compatible with cavernous angioma. The location of the cavernous angioma was not suitable for operation and the symptoms resolved spontaneously within several months. Capillary telangiectasia and cavernous angioma are occult cerebrovascular malformations thought to be different forms of the same pathologic entity and found together frequently. While capillary telangiectasias are mostly asymptomatic, cavernous angiomas risk for haemorrhage is 0.5–1% annually. Patients with haemorrhage in the 3rd or 4th ventricle or in the brainstem with no vascular abnormality on cranial CT and DSA may have occult cerebrovascular malformation which reveals itself readily on cerebral MRI.

P248 CEREBRAL, 3RD, 4TH AND 6TH CRANIAL NERVES AND RETINAL ISCHEMIA DUE TO IPSILATERAL INTERNAL CAROTID ARTERY STENOSIS. Ayșe Bingöl*, Figen Batiog˘ lu**, Sedat Ulkatan*, Serpil Karaali**, Nezih Yücemen*, Tülay Kansu***, Ilhan Erden****, Umman Sanlidilek****. Ankara University, Medical Faculty, Departments of *Neurology, **Ophthalmology and ****Radiodiagnostic, Ankara, Turkey. ***Hacettepe University, Medical Faculty, Neurology Department, Ankara, Turkey A 58-year-old male patient with unilateral severe internal carotid artery (ICA) stenosis who developed ipsilateral ophthalmoplegia, contralateral hemiparesis and bilateral ischemic optic neuropathy is presented. The patient

had several risk factors (diabetes mellitus, hypertension, cigarette smoking, alcohol consumption) for development of atherosclerosis. The severe ICA stenosis which added on to atherosclerotic background had significant effect on cerebral perfusion and labile arterial blood pressure (orthostatic hypotension) increased the cerebral hypoperfusion. As the last step, thrombosis of intracavernous portion of ICA and the insufficiency of ophthalmic artery led to neuro-ophthalmologic signs of ischemic origin. The patient refused any invasive intervention and the symptoms resolved spontaneously within several months. The case is of interest because of its rarity, diagnostic difficulty and requirement of several different radiodiagnostic studies. P249 DURAL ARTERIOVENOUS MALFORMATION IN THE ANTERIOR CRANIAL FOSSA. REPORT OF TWO CASES AND REVIEW OF THE LITERATURE. Gliemroth J, Nowak G, Arnold H. Department Of Neurosurgery, Medical University Lübeck, Germany Dural arteriovenous malformations (AVM) comprise approximately 15% of all intracranial AVM’s. Most of them are located in the posterior fossa or in the region of the cavernous sinus. Dural AVM’s of the anterior fossa are rare. Only few cases have been reported. Two cases of anterior fossa dural AVM’s are described. A review of the pertinent literature is given. Cases: In both cases an intracerebral hematoma was the first indication of the disease. In the first case, the malformation was supplied by both the anterior ethmoidal artery and frontopolar artery draining into the superior sagittal sinus (SSS). In the second case, the anterior ethmoidal artery with draining veins into the SSS and sphenoparietal sinus was the feeding vessel. Evacuation of the hematoma and excision of the malformation was performed on both patients. Conclusion: These anterior fossa dural AVM’s represent a distinct subgroup of dural AVM’s with a high incidence of intracranial hemorrhage. They are mainly supplied by the anterior and/or the posterior ethmoidal arteries, sometimes in combination with feeding vessels from the external carotid arteries. The venous drainage usually occurred directly or via a cortical vein into the SSS. Associated venous aneurysm have been considered to be the source of the intracerebral hemorrhages. Surgical removal of the AVM is the treatment of choice. P250 NEUROLOGICAL SYMPTOMS IN HELLP-SYNDROME. REPORT OF OWN CASES AND OVERVIEW OVER THE LITERATURE. U. Knopp, J. Gliemroth, U. Kehler, G. Nowak. Dept. of Neurosurgery, University of Lübeck, Lübeck The Syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP-Syndrome) was considered as a unique variant of severe preeclampsia. Intracerebral complications occur less frequent, eclamptic convulsions and some cases of brain edema are described. Intracerebral hemorrhage as a complication in HELLP-Syndrome has been described only in single cases, often correlated with fatal maternal outcome. Material: Our cases illustrate the severity of these complications: In the first case a 36year-old woman gravida IV para II was admitted to hospital at a gestational age of 39 weeks 6 days, HELLP Syndrome was diagnosed and an uneventful Ceasarean section was performed. CT scan 32 hours after cesarean section revealed a large left-occipital intracerebral and intraventricular bleeding. After hematoma evacuation she regained consciousness over the following 48 hours, the symptoms of HELLP-Syndrome (hemolysis, low platelets, elevated liver enzymes) were declining. The postoperative course seemed to be uneventful, when on the 11th day after surgery the patients level of consciouness deterioriated rapidly. After an cerebral computer tomography revealed several areas of low density, a cerebral angiography showed diffuse cerebral vasospasm. This was confirmed by transcranial Doppler ultrasound. She didn’t regain consciousness and dided in the state of cerebral death. Conclusion: This case underlines the meaning of intensive observation and neurological examination even days after the cesarean section in patients with HELLP-Syndrom to avoid such complications as cerebral vasospasm. P251 BILATERAL THALAMIC INFARCTION FOLLOWING AORTIC VALVE ENDOCARDITIS – A CASE REPORT. M. Hahn, M. Nueckel, E. Stolz, F. Leweke, W. Dorndorf. Department of Neurology, JustusLiebig-University Giessen, Germany Bilateral thalamic infarction is infrequent and often of embolic nature. Coma of various depth, hypersomnia, amnestic syndrome, disorientation and vertical gaze palsy are common symptoms. We present a case of bi-

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lateral thalamic infarction following aortic valve endocarditis scattered from infected teeth. A 30 year old women presented with coma for a period of at least 36 hours. On neurological examination only hypersomnolence and vertical gaze palsy but no abnormal cardiac murmurs were found. Body temperature was 37.3° C, striking laboratory findings were slightly elevated CRP and ESR. Computed brain tomography and cerebral magnetic resonance imgaging showed bilateral paramedian thalamic infarction. Cerebral arterial and venous angiogram, sonogram of the cerebral arteries, cerebrospinal fluid, electrocardiogram and chest x-ray were inconspicuous. 24 hours later temperature reached 38° C, in blood cultures coagulase-negative staphylococci were detected. Transesophageal echocardiogram showed aortic valve failure and valvular bacterial vegetations. As septic focus two teeth were identified by x-ray (apical periodontitis) and were extracted. Beneath continuous antibiotic and antithrombotic therapy with aspirin and after rehabilitation for 6 weeks, an incomplete vertical gaze palsy and discrete disturbance of vigilance and short-term memory still remained. We conclude, that bilateral thalamic infarction rarely results from an underlying infectious valvular heart disease. Beside antithrombotic therapy identification of the scattering infectious focus and long-term treatment with antibiotics are important.

P252 STROKE LOCATION AND EFFECTIVITY OF ENIG-TRIGGERED ELECTROSTIMULATION IN THE TREATMENT OF SPASTIC HEMIPARESIS. Mokrusch T. Hedon-Klinik, Lingen, Germany EMG-triggered electrotherapy has proved to be effective in the therapy of spastic hemiparesis following stroke. It reduces spasticity and additionally increases muscle contraction force and thus improves voluntary movement. The question was if there is an influence of hemisphere location on therapeutical results. Methods: A series of 22 patients were treated for 4–16 weeks. Group I (N = 11) had a single ischemic brain infarction in the left hemisphere, group H (N = 11) in the right hemisphere, both with a consecutive mid-orade paresis on the contralateral side. Electrotherapy was performed about seven times a week with a duration of 30 minutes and 10–15 repetitions of the movement which was trained. Effects on spasticity were estimated by the modified Ashworth scale and measured by the pendulum test, an improvement of muscle strength was measured by a hand-held myometer, and mobility was measured by the Barthel-index and the F1M. The improvement of life quality was measured by the Bf-S. Results: Spasticity was reduced in both groups without significant differences, as well as in the upper extremity or in the lower extremity. There was a slightly higher increase of muscle contraction force in the patients with left hemisphere lesions, which, however, did not reach the level of significance ( p = 0. 12). There was also a slightly better improvement in the abilities of daily living in this group, which, however, also was not significant ( p = 0. 15). Patients with left hemisphere lesions stated a better improvement in their life quality ( p = 0.08). Discussion and Conclusion: According to the present data, there is some slight indication that a left hemisphere lesion may show a better prognosis during the therapy of EMG-triggered electrostimulation than a right hemisphere lesion does.

P253 CLINICAL AND NEURORADIOLOGICAL FINDINGS IN FIVE PATIENTS WITH CEREBRAL AMYLOID ANGIOPATHY: GOOD OUTCOME FOR THREE OF THEM AFTER STEROID THERAPY. Claes F, Deprez M, Dive D, Flandroy P, Franck G. C.H.U. Liege, Belgium We describe five patients with progressive mental impairment or strokelike events and the good outcome after steroid therapy for three of them. All patients but one had subacute clinical manifestations. Two of them showed well-known manifestations with macrohemorrhages on both CT and MRI scans. Three had only leucoencephalopathy with microhemorrhages in T2 gradient recalled echo MRI sequences and pseudo-tumoral masses without contrast enhancement for two of them. Angiography excluded other diagnosis for three of them. All underwent brain biopsy which revealed classical amyloid deposits within the small vessels in addition with lesions due to hematomas if present. Three patients without macrohemorrhage received high dose methylprednisolone (1 g/d.) therapy during one week followed by oral treatment during three months. Prompt recovery was observed after one week for the two patients with the acute form followed by complete symptoms resolution during respectively 18 and 6 months follow-up. The third one, with progressive dementia, had just been also treated with a good outcome. Conclusion: cerebral amyloid angiopathy is a rare diagnosis which has to be evoked in front of particular clinical and neuroradiological features. Brain biopsy has to be per-

formed to assess the diagnosis. High dose steroid therapy should be instituted in acute or chronic patients, leading to clear clinical improvement. P254 DIFFUSION-WEIGHTED MR IMAGING IN A CASE OF CEREBRAL VENOUS THROMBOSIS. J. C. Corvol*, R. Manai*, M. Logak*, C. Oppenheim***, L. Spelle**, X. Vandamme***, D. Dormont***, Y. Samson*, G. Rancurel*. *Urgences Cérébro-vasculaires, **Neuroradiologie Charcot, ***Neuroradiologie Marsault, Hôpital de la Pitié-Salpétrière, Paris, France Diffusion-weighted sequence is the most sensitive MR sequence in acute arterial ischemic stroke, but has not been evaluated in venous cerebral ischemia. Case report: A 64 year old woman, after headache for 8 days, was admitted for sudden right hemiparesis with aphasia. Three hours after the onset of the deficit, CT scan was normal; MRI showed extensive left fronto-parietal hyperintensities on FLAIR sequence, but only minor and doubtful abnormalities on diffusion-weighted images. The patient had a generalized seizure six hours after onset, and repeated FLAIR and diffusion MR images were almost unchanged 24 hours later. Digitalized angiography showed extensive thrombosis of the superior longitudinal and left lateral sinuses. Clinical outcome was rapidly favorable with heparinotherapy. Discussion: The finding of marked FLAIR abnormalities and subtle diffusion abnormalities is inconsistent with an acute arterial stroke, since early ischemic cytotoxic edema causes marked decrease in diffusion coefficient. Conversely, this contrast may suggest prominent vasogenic edema, and it may indicate venous cerebral ischemia, as confirmed here by conventional angiography. Conclusion: In the context of an acute stroke, the contrast between marked FLAIR and subtle diffusion abnormalities at MRI may reflect the venous mechanism of cerebral ischemia. P255 MORTALITY AND NEUROLOGICAL RECOVERY AFTER HEMICRANIECTOMY IN PATIENTS WITH MIDDLE CEREBRAL ARTERY INFARCTION: A PRELIMINARY STUDY. R. Manai*, A. Srour**, M. Logak*, Y. Samson*, S. Timsit*, P. Cornu**, G. Rancurel*. *Urgences Cérébro-Vasculaires, **Departement of Neurosurgery. Hôpital de la Pitié-Salpêtrière, Paris, France Introduction: The prognosis of severe or “malignant” middle cerebral artery (MMCA) ischemic stroke is very poor. The mortality is over 80% in most published series. Decompressive surgery by hemicraniectomy may improve the prognosis. The aim of this study was to determine the optimal time of hemicraniectomy and to evaluate the functional prognosis. Patients and methods: We prospectively studied 12 patients with MMCA. Mean age was 48.7 years (26–60). All had massive hemiplegia, conjugated head and eyes deviation, consciousness impairement (Glasgow.S.S < 7) and/or unilateral mydriasis and neurovegetative disorders. CT scan was performed at admission and after every clinical worsening. Hemicraniectomy was performed as soon as possible after clinical and/or CT scan deterioration. Results: Decompressive surgery was performed (32 h ± 12 h) after stroke onset, except one patient with late worsening (13 days). Ninety one percent (11/12) patients survived. Seven were operated more than three months ago. All were able to walk without assistance. Modified Rankin Scale was 1 for 1 patient, 2 for 1 patient, 3 for 5 patients. The four other survivors patients have been operated more recently and are still bedridden. One immuno-suppressed patient died of pulmonary infection. Conclusion: Early hemicraniectomy reduces substantially the mortality of malignant MCA infarction, and might be associated with acceptable neurological sequellae. P256 LEBER’S DISEASE AND HYPERTENSIVE ENCEPHALOPATHY IN A 46-YEAR-OLD WOMAN. Benoist L, Logak M, Manaï R, Samson Y, Rancurel G. Urgences Cérébrovasculaires, Paris, France We report the case of a 46 year old woman admitted for headache, nausea, toppling gait associated with severe hypertension (260/130 mm Hg) since one week. She suffered from a familial optic atrophy of Leber diagnosed in 1992 by DNA mutation analysis. Initial examination showed bradypsychia, temporospatial disorientation, right hemiparesis and hemiataxia. Ophthalmoscopic examination showed oedema and haemorrhages according to significant hypertensive retinopathy. Bilateral temporoparietal slow waves were seen on EEG. CTscan and T2 weighted MRI found very extensive symmetrical areas of hypodensities or hyperintensities involving the white matter of both hemispheres, brainstem and cerebellum non enhanced after

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gadolinium injection. A punctiform left thalamic stroke was associated. Echocardiogram. showed left ventricular hypertrophy. Two days after, when hypertension was controlled by nicardipine, fast clinical improvement was obtained. Two months later, MRI found nearly complete resolution of the lesions. The unusual location and extension of the lesions in this hypertensive encephalopathy could be explain by the association with a mitochondriopathy. Pathologic changes in the blood brain barrier, primary disturbances of cerebral autoregulation with perhaps endothelial damages could contribute to worsen the consequences of hypertension in Leber’s disease.

ferences were found statistically significant. The present methodology has already been tested and standardized upon one healthy sample and was decided to be used as a basis is for investigation of cerebral autoregulation impairment. P260 DETECTION OF PATENT FORAMEN OVALE IN PATIENTS WITH ISCHEMIC STROKE. I. Vastagh, A. Folyovich, *R. Asbóth, *K. Sugár, S. Ilniczky, I. Szirmai

Three patients with a severe symptomatic carotid stenosis developed headache, epileptic seizures and focal neurologic deficits several days after carotidendarterectomy (CEN). CT of the brain revealed hypodensities, indicative of cerebral edema with haemorrhagic components. This is caused by cerebral hyperperfusion, a complication after CEN as a result of increased cerebral perfusion ipsilateral to the operated carotid stenosis. Dysfunction of the cerebral autoregulation is believed to be the cause of this hyperperfusion. Sometimes these complications are incorrectly attributed to one of the better known causes of a stroke. Better recognition of this specific syndrome is necessary for further study of the risk factors and research of preventive measures.

Etiology of stroke among young adults remains unknown in 35–40% of patients. The paradoxical cerebral embolisation due to the cardiac right to left shunt (patent foramen ovale and other septal defects) may be a reason of stroke in young patients. The patent foramen ovale can be the source of paradoxical cerebral embolisation even without any clinical signs of deep venous thrombosis or pulmonary hypertension. In the majority of the cases the patent foramen ovale is diagnosed in elderly. The paradox cerebral embolisation due to right to left shunting is proved by transcranial Doppler sonography with intravenous saline-contrast (10 ml saline with agitating microbubbles – 0.5 ml air and 0.5 ml blood). Authors examined 110 ischemic stroke patients with Multi-Dop T transcranial Doppler device at the Department of Neurology of Semmelweis Medical University, between 1 April –15 September, 1997. Intraatrial right to left shunt was detected in 29 patients. Transthoracic echocardiography in all 29 patients, transoesophagal echocardiography in 27 patients were carried out. The right to left shunt was more frequent (43.6%) in stroke patients among young adults, whereas paradox cerebral embolisation was proved in 14% of the elderly. According to these results, authors recommend this method in the diagnostic procedure of stroke patients among young adults.

P258 CORRELATION OF CLINICAL SYMPTOMATOLOGY WITH THE TYPE AND ADEQUACY OF COLLATERAL CIRCULATION IN PATIENTS WITH UNILATERAL INTERNAL CAROTID ARTERY OCCLUSION. A TRANSCRANIAL DOPPLER SONOGRAPHY (TCD) STUDY. Th. Arida, N. Artemis, D. Karacostas, K. Gymnopoulos, K. Vadicolias, S. Giannopoulos, I. Milonas. B’ Univ. Department of Neurology, AXEPA Hospital, Thessaloniki, Greece

P261 [123I] β-CIT SPECT AND WORKING MEMORY DEFICITS IN PARKINSON’S DISEASE. T. Wächter1, U. Müller1, H. Barthel2, M. Reuter3, A. Thöne4, D. Y. von Cramon1, 4. 1Max-Planck-Institute of Cognitive Neuroscience, Inselstr. 22, 04103 Leipzig, Germany; 2Department of Nuclear Medicine, University of Leipzig; 3Neurological Clinic MarthaMaria, Halle/Saale; 4Day-Care-Clinic of Cognitive Neurology, University of Leipzig

Using TCD we investigated the type and the adequacy of collateral circulation in 126 patients with unilateral TCA occlusion. Our attempt was to find out a possible corralation between the hemodynamic disturbances and the clinical symptomatology in these patients. 45 of them had TIA’s (group A), 35 had mild stroke (group B), 20 had severe stroke (group C) and 26 were asymptomatic (group D). 50 age matched healthy subject were used as control group. In asymptomatic the mean blood flow velocity in the ipsilateral middle cerebral artery was higher than in symptomatic: 44 ± 10.6 versus 37.02 ± 13.23 ( p < 0.01) but it was lower when it was compared with mMCA velocity in the control group: 52.98 ± 10.9 ( p < 0.002). The higher difference was found between mMCR velocity in group D and group C: 3065 ± 11.62 ( p < 0.001). Both ACoA + PCoA were patients more frequently in group D (69.23%) than in group C (20%) ( p < 0.025). No significant correration could be found for the other group. Our results suggest that at least in patients with severe stroke the type and the adequancy of collateral circulation may play role in symptomatology.

Parkinson’s disease (PD) is caused by degeneration of nigrostriatal dopaminergic neurones and resulting disturbances within basal ganglia loops. The striatal deficit can be visualized by single-photon emission computed tomography (SPECT) using [123I] β-CIT as a marker for the presynaptic dopamine transporter. The severity of motor symptoms of PD correlates with [123I] β-CIT uptake in the putamen (Seibyl et al. 1995). PD patients without dementia show deficits of working memory and executive functions that are similar to those observed in patients with lesions of the dorsolateral prefrontal cortex. Methods: To investigate the relationship between functional deficits in the head of the caudate nucleus and cognitive deficits we examined 17 patients with idiopathic Parkinson’s disease (PD) and 17 matched controls with a neuropsychological test battery. All patients underwent a high resolution [123I] β-CIT SPECT. For semiquantitative evaluation regions of interest were placed over the putamen, caudate nucleus (anterior striatum), and cerebellum using individual magnetic resonance images. PD patients showed significant ( p < 0.01) deficits in the digit ordering test (DOT), a verbal working memory test that has been evaluated in PD (Cooper et al. 1991) and “frontal” (Wächter et al. 1998) patients. There was a significant ( p < 0.05) correlation between the DOT scores and the [123I] β-CIT ratios for the contralateral caudate nucleus. Conclusion: Our results support the hypothesis that verbal working memory deficits in PD patients are due to disruptions of the dorsolateral-prefrontal loop at the level of the head of the caudate nucleus.

P257 THE CEREBRAL HYPERPERFUSION SYNDROME AFTER CAROTID ENDARTERECTOMY. B. van Harten1, W. A. van Gool2 and D. A. Legemate3. Department of Neurology, Sint Lucas Andreas Hospital1 and Department of Neurology2 and Vascular Surgery3, Academic Medical Center, Amsterdam, The Netherlands

P259 CEREBRAL AUTOREGULATION IN UREMIC NEUROPATHY. S. Gianopoylos, N. Artemis*, G. Theodosiou, Ch. Kitkas, C. Chatziconstantinou, I. Milonas*. Dept of Internal Medicine, Prefectural Hospital of Edessa. *B’ Dept. of Neurology Aristotle Univ. Med. School, Thessaloniki, Greece We evaluated cerebral autoregulation with TCD patients suffering from numeric neuropathy by measuring blood flow velocity (CBFV) changes drying the response to a rapid change in arterial blood pressure. Throughout study 30 patients were successively transferred from the upright to the horizontal position,then to Trendeleburg position and back to upright position. The TCD transducer (2 MHz,EME Uberligen) was fixed in the temporal window and peak MCAV optimal signal was continuously monitored. The initial peak MCAV in the upright position was 64 + 11 cm/sec. After the first position change the mean + SD increase in peak MCAV was 10.4 + 4.2 cm/sec and after the second transfer 7 + 3 cm/sec and both terminated constant for less than 3.5 sec. Mean + SD end tidal CO2 partial pressure was 34 + 2 mm Hg and did not significantly change during the examination ABP did not significantly change during the transfers. These results were compared to measurements of 25 healthy volunteers and the dif-

P262 A CASE OF BILATERAL SUPERIOR CEREBELLAR ARTERY OCCLUSION CAUSED BY BASILAR ARTERY STENOSIS. Isik Ç. Nihal, Gürel Nesrin, Isik Nejat, Bayrak Cevat. Istanbul, Turkey Simultaneous bilateral superior cerebellar artery occlusion with subsequent bilateral cerebellar and right thalamic infarcts was described in a 17year-old male. He had a sudden onset of pain and a sharp voice in his head. On admission he presented with mild disturbance of consciousness and bilateral cerebellar symptoms. Computed tomography disclosed no abnormality except suspect diffuse edemateous parenchyma but Magnetic resonance imaging (MRI) revealed hyperintensity in both cerebellar hemispheres and in right thalamic reagon on T2-weighted images. Cerebral

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Magnetic resonance angiography (MRA) showed a stenotic segment on the distal part of basilar artery. Cerebral angiogram performed five days after MRA showed suspect irregularities on low basilar tip. Superior cerebellar arteries on both sides couldn’t be visulized in both MRA and angiograms. Eight weeks after the first angiography a second control one was performed. It revealed no abnormality which suggests recanalisation. During this period neurological symptoms were regressed. Our diagnosis was simultaneous bilateral superior cerebellar artery occlusion due to basilar artery stenosis possibly dissection. P263 FLOW-CYTOMETRIC DETECTION OF IN VIVO PLATELET ACTIVATION IN HIGH GRADE CAROTID ARTERY STENOSIS. E. Stolz1, P. Oschmann1, M. Hahn1, B. Pötzsch2, Ch. Braunlich1, W. Dorndorf 1. 1Department of Neurology, JLU Giessen, D-35385 Giessen, Germany. 2Max-Planck-Institute of Physiological and Clinical Research, D-61231 Bad Nauheim, Germany High grade carotid artery stenosis carries a high risk of arterio-arterial embolism due to platelet aggregate formation. The aim of our study was to demonstrate in vivo platelet activation by surface P-Selectin expression in patients with high grade carotid artery stenosis. Methods: P-Selectin expression on platelet surface was measured by flow cytometry in full blood samples from 15 patients with carotid artery stenosis above 70% and 10 healthy controls. 9 of the patients showed generalized atherosclerosis defined by the presence of peripheral occlusive or coronary artery disease and calcification of the abdominal aorta, whereas 6 did not. Results: Compared to the controls (7.4 ± 5.6%) the patient sample showed a significantly higher rate of P-Selectin positive platelets (38.5 ± 8.2%). There was no overt difference between the patients with more confined carotid artery disease (38.2 ± 8.7%) in comparison to more generalized atherosclerosis (38.8 ± 8.4%). Conclusion: We demonstrated enhanced in vivo platelet activation by measurement of surface P-Selectin expression in patients with high grade carotid artery stenosis. According to our preliminary results the enhanced platelet activation is dependent on the carotid artery stenosis and not on the extent of further atherosclerotic lesions. P264 SUPERFICIAL SIDEROSIS OF THE CENTRAL NERVOUS SYSTEM: 30 YEARS OF CHANGES. F. Bouliour*, J. Grimaud*, T. Moreau*, A. Jouvet**, J.-C. Froment*** and Ch. Confavreux*. *Department of Neurology, H6pital de I’Antiquaille; **Laboratory of Neuropathology and ***Department of Neuroradiology, H6pital Neurologique, Lyon, France We report 4 cases of superficial siderosis of the central nervous system (CNS) diagnosed in the same Department of Neurology between 1968 and 1996. Our series shows the broad spectrum of the clinical manifestations of this syndrome. It highlights the evolution of the diagnostic procedure over the last 30 years. Until the 70’s, superficial siderosis of the CNS was diagnosed post mortem only, which is also the case for two observations of our study. In fact, at that time, it could have been diagnosed from the CSF analysis. Nowadays, Magnetic Resonance Imaging (MRI) allows to establish the diagnosis during the patient’s lifetime. Hemosiderine deposit is revealed by the absence of signal in T2-weighted sequences. The CSF analysis is here only to confirm the limited but persistent hemorrhage in the sub-arachnoid space through the presence of siderophages. It has a predictive value, since the evolution of the cytochemical markers of the CSF is correlated with that of clinical manifestations. The MRI era has allowed the physicians to move from contemplation to action. As soon as siderosis of the CNS is diagnosed, it is essential to find out the source of the sub-arachnoid bleeding, even through a surgical exploration. Only the etiological cure allows to expect a clinical stabilisation or improvement.

Infection of the Nervous System P265 ACUTE DISSEMINATED ENCEPHALOMYELITIS FOLLOWING ACTIVE IMMUNISATION FOR EUROPEAN SPRING-SUMMER MENINGOENCEPHALITIS. G. Roob, K. Niederkorn, H. Offenbacher, H. P. Hartung, F. Fazekas, Graz, Austria Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the brain with lesions in a distribution frequently similar to multiple sclerosis but differing by its monophasic course. A history of preceding infection or of specific vaccinations may provide an im-

portant clue for early diagnosis. We report a patient with clinical and imaging findings of ADEM following active vaccination for European spring summer meningoencephalitis (ESSME). A 23-year-old woman experienced slowly developing non-fluent aphasia, tetraparesis and psychiatric disorders with memory impairment and confusion over the course of one week. Spinal tap was abnormal for 15–40 mostly mononuclear cells. Magnetic resonance imaging (MRI) showed multiple round to ovoid lesions up to a diameter of 2 cm which were located in the corpus callosum, deep and subcortical white matter bilaterally. There was marked perifocal oedema and contrast enhancement of almost all lesions. Three weeks before she had undergone active immunisation for ESSME. Because of these features ADEM was suspected and the patient was put on high dose steroids. After a short further deterioration with seizures symptoms began to resolve and the patient almost completely recovered. There was no further contrast enhancement or the appearance of new lesions at follow-up. This observation suggests vaccination for ESSMS as another potential trigger of ADEM and confirms a potentially good outcome with rapid institution of therapy. P266 THE POLYMERASE CHAIN REACTION IN CEREBROSPINAL FLUID. Bamborschke S, Petereit HF, Porr A, Heiß WD. Department of Neurology, CSF-Laboratory, University of Cologne, Cologne, Germany With the polymerase chain reaction (PCR) very small amounts of specific DNA or RNA sequences can be detected in clinical specimens. In CSF diagnostics the method is extremely useful in early diagnosis of herpes simplex encephalitis, varicella-zoster encephalitis, meningitis and myelitis, cytomegalovirus infections in immunocompromised patients, in detection of JC-polyoma-virus in patients with progressive multifocal leukoencephalopathy, in diagnosis of tuberculous menignitis and – with some limitations – in neuroborreliosis. Clinically not so important but possibly useful are PCR-methods detecting Epstein Barr virus (primary CNS-lymphoma in AIDS), HHV-6, enteroviruses, cryptococci, toxoplasma, listeria, treponema pallidum, and meningococci in CSF and the differentiation of gram negative or positive bacteria in bacterial meningitis of unknown aetiology by amplification of group-specific 16SrRNA sequences. Other diagnostic options are the detection of mRNA-sequences specific for cytokines, adhesion molecules or T-cell-receptor restriction in multiple sclerosis, the detection of tumor specific gene sequences in CSF-cells in the meningeal spread of T-cell or B-cell lymphoma and the diagnosis of neurogenetic disorders. The main advantages of PCR are high sensitivity and rapid results, disadvantages are lacking standardisation of most tests and the possibility of false positive results because of contamination. P267 ESTABLISHMENT OF FIVE COMPETITIVE INHIBITION ELISA’S FOR DETECTION OF BORRELIA BURGDORFERI ANTIGENS IN CEREBROSPINAL FLUID (CSF). Sebastian Rauer, Alf Conrad and Reinhard Kaiser. Department of Neurology, University of Freiburg, Germany Evidence of spirochetal components within CSF would provide direct proof of neurologic infection. It has been shown that a competitive inhibition ELISA was suitable for detection of borrelial antigens in the urine. Now, five competitive inhibition ELISA’s for the detection of borrelial antigens in CSF have been established. The cutoff for optical density readings was set 2 standard deviations below the mean OD of 113 CSF samples from patients with no history of Lyme disease. Detection limits of the ELISA’s varied depending on the borrelial antigen: whole borrelial cell extract < 200 ng/ml; 83 kDa-antigen < 12.5 ng/ml; internal flagellin fragment (14 kDa antigen) < 100 ng/ml; outer surface protein C (OspC) < 50 ng/ml; outer surface protein A (OspA) < 400 ng/ml. On testing 26 CSF serum samples from patients with clinical and serological diagnosis of neuroborreliosis (lymphocytic meningoradiculitis 15, encephalitis 2, myelitis 3, isolated cranial polyneuritis 6) none revealed a positive result. The amount of free detectable antigen in CSF may be lower than the detection limits of the inhibition ELISA’s for the following reasons: 1. Spirochetes may adhere at the meninges or at neuronal tissue. 2. Antigens might be bound in immunecomplexes. We conclude that the detection of borrelial components by a competitive inhibition ELISA is not a useful tool in the laboratory diagnosis of neuroborreliosis. P268 NIMODIPINE REDUCES INTRACRANIAL PRESSURE IN EXPERIMENTAL PNEUMOCOCCAL MENINGITIS. R. Paul, U. Koedel, H. W. Pfister. Department of Neurology, Univ. of Munich, Germany

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This study assessed the effect of nimodipine on intracranial pressure (ICP) during experimental pneumococcal meningitis. In a rat model, meningitis was induced by intracisternal injection of 10 7 cfu heat-killed pneumococci. Treatment with nimodipine (30 µg/kg/h i.v.) 5 h after pneumococcal challenge reduced the increase in ICP 3 h after start of infusion (∆ICP: 7.7 ± 1.5 mmHg vs 11.6 ± 0.7 mm Hg in untreated rats at 8 h; p < 0.05). To investigate whether the reduction of ICP was caused by the decrease in systemic arterial blood pressure (SAP) (1) blood withdrawl was performed and (2) sodium-nitroprussid (SNP, 20 µl/kg/min i.v.) was administered to lower SAP. Hemorrhagic hypotension significantly reduced ICP after 8 h (∆ICP was 4.4 ± 1.0 mm Hg) whereas SNP did not influence ICP (∆ICP was 12.9 ± 1.7 mm Hg at 8h). Since hemorrhagic hypotension but neither SNP nor nimodipine reduced cerebral blood flow (CBF) we assume that the effect of nimodipine on ICP may not be due to hypotension-induced reduction of CBF. To elucidate possible mechanisms of the nimodipine effect on ICP we investigated whether nimodipine influences pneumococciinduced reactive oxygen species (ROS) generation by leukocytes as measured by whole blood chemiluminescence. Similar to the ROS scavenger superoxide dismutase and NADPH-oxidase inhibitor acetovanillone, nimodipine markedly attenuated ROS production (inhibition was 95 ± 2%, 70 ± 11%, 75 ± 9%, respectively). In conclusion, we found that nimodipine attenuated the increase in ICP in experimental meningitis. One possible mechanism of the nimodipine effect may be a reduction of ROS production.

P269 SUBACUTE MENINGO-MYELITIS IN A PATIENT WITH NEUROBORRELIOSIS (LYME DISEASE). W. Blersch, B. Schalke, U. Bogdahn. Department of Neurology, University of Regensburg Case report: Three weeks before admission a 65-year-old housewife complained of shoulder weakness and burning neck pain. Neurological examination revealed hyperpathia with changing intensity mainly in the left C2 dermatoma. Arm elevation was not possible over 90°. Symmetric atrophy was seen in both deltoid muscles. Spinal MRI was performed two days after admission and showed meningeal contrast enhancement suggestive of meningeosis carcinomatosa between C1 to C7 level. Cerebrospinal fluid (CSF) revealed a lymphoplasma-cellular pleocytosis (480 cells per mm3) with an impaired blood-CSF barrier (130 mg/dl total protein). The CSF analysis was positive for anti-B. burgdorferi IgG (1 : 21) and IgM (1 : 39) in ELISA as well as in the Western Blot. After exclusion of other causes of spinal inflammation antibiotic therapy was started (4 g Ceftriaxon daily for three weeks). Symptoms cleared: neck pain and subfebrile temperatures disappeared. Five days later she was able to lift her arms above 90° and after 2 weeks there was no longer evidence of paresis in the deltoid muscles. Conclusion: Despite neurological evidence of meningeosis carcinomatosa, subacute meningo-myelitis caused by B. burgdorferi is an important differential diagnosis and has to be excluded by serology and CSF analysis.

P270 CLINICAL AND MRI CORRELATES: A CLUE IN THE DIAGNOSIS OF HERPES ZOSTER MYELITIS. A. Collier, R. Denays, M. Martinez, C. Sohy, J. Moreau*. Centre Hospitalier Etterbeek-Ixelles, *Hôpital Erasme, Bruxelles, Belgium Myelitis is a rare complication of herpes zoster (HZ) infection, that usually develops in the immunocompromized host. The diagnosis may be difficult because finding in the vesicles or the cerebrospinal fluid (CSF) of HZ genomic material by the polymerase chain reaction (PCR) may simply represent a reactivation of a latent infection. A 37-year-old HIV (stade IV) homosexual man developed an acute myelopathy (paraplegia, sensory level at D5–D6 with proprioception and tact senses more affected than pinprick sensation) in temporal proximity to right thoracic (D2 and D6–10) and left abdominal (D10–12) skin vesicular lesions suggestive of HZ. PCR performed on the CSF was positive for HZ and negative for herpes simplex I/II. At MRI of the spinal cord, the lesions were recognisable in the T2-weighted images as irregular zones of increased signal intensity, throughout D1–2 and D4–6 segments. Lesions were predominant in the posterior cords, except at D5–6 level where nearly complete transsection of the spinal cord was demonstrated by transaxial views. These MRI findings of irregular and multifocal lesions, with maximal severity at the segments of the spinal cord corresponding to the dermatomal rash, are in agreement with 2 previous MRI reports and with the results of neuropathological studies in HZ myelitis. They suggest that clinical/MRI correlates may be a clue in the diagnosis of HZ myelitis.

P271 ACUTE TRANSIENT PARKINSONISM AFTER MILD FEBRILE ILLNESS. S. Pappa, A. Tavernarakis, H. Koutra, C. Potagas, N. Balakas. Athens, Greece We report the case of an otherwise healthy 23-year-old student who, after two consecutive febrile episodes with sore throat of three days each, developed severe Parkinsonism with akinesia, rigidity, resting tremor and also hyperhidrosis, tachycardia, palor and arterial hypertension; consciousness remained normal. All symptoms resolved within one month. Initial MRI showed symmetrical lesions involving striatum and substantia nigra bilaterally. These lesions were considerably reduced but still present at the moment of complete clinical recovery. The syndrome was documented by videotape recording. P272 SIGNS OF INFLAMMATORY DISEASES IN NEURORADIOLOGIC EXAMINATION AND CERBROSPINAL FLUID MIMICKING NEOPLASTIC DISEASES OF THE CENTRAL NERVOUS SYSTEMPRESENTATION OF TWO CASES. R. Tröscher-Weber*, F. Reinhardt, M. Winterholler, F. Erbguth. Department of Radiology*, Department of Neurology, University of Erlangen-Nuremberg, Germany We present two cases with findings suspicious of inflammatory process in neuroradiologic examination and in cerebrospinal fluid (CSF) mimicking neoplastic diseases. The first patient had been hospitalized with headaches and psychoorganic disturbances. CSF showed a typical subacute inflammatory syndrome with plasmacells, elevation of protein and lactate. Magnetic resonance tomography showed hydrocephalus and enhancement of basal meninges after Gadolinium-contrast. The patient died with a clinically suspicious tuberculous meningitis after weeks of tuberculostatic therapy. Autopsy revealed a diffuse astrocytoma WHO III spreading in basal meninges. The second patient presented with atactic gait disturbance. CSF showed mild signs of inflammation and a high percentage of eosinophile granulocytes. Cranial computed tomography revealed multiple cystic lesions in cerebrum and cerebellum. After initial antibiotic and anthelmintic treatment the clinical condition of patient worsened, biopsy revealed malignant cells in the wall of a cyst. Bronchoscopic examination uncovered a bronchial carcinoma. In both patients, cytologic examination of CSF showed no malignant cells at any time. We learned, that in cases of suspicious atypical inflammatory processes in central nervous sytem a rare differential diagnosis consists in neoplastic diseases, even without typical neuroradiologic findings or malignant cells in CSF. P273 HTLV-I ASSOCIATED MYELOPATHY: A CAUCASIAN PATIENT WITH PROPRIOCEPTIVE ATAXIA. F. Simon, D. Felten, H. Taillia, Y. S. Cordoliani, D. Béquet. Hôpital Val-de-Grâce, Paris, France Clinical presentation of human T lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) is not always a progressive spastic paraparesis in afro-Caribbean people. We report the case of a 69-year-old white homosexual man. This HIV-negative patient had never been transfused and had a long history of travel in tropical areas. After many years of sphincter dysfunction, he complained in 1995 of increased dysuria, impotence and progressive gait disturbance. Neurological examination showed a severe loss of proprioception in the lower limbs with ataxia, hypoesthesia with a T-8 sensory level and mild spastic paraparesis. No extra-neurological clinical abnormality was found. Spinal cord MRI showed a posterior medullar atrophy, very focalised at T8 level. HTLV-I antibody was detected in blood and cerebrospinal fluid by immunofluorescence (IF) at very high levels and confirmed with western-blot in blood. No other cause of myelopathy was identified; screening for syphilis was negative; electromyography and nerve conduction were normal. HAM in white people is very uncommon in European countries. Sensory abnormalities (paresthesias, distal sensory loss) are sometimes described as minor signs compared to paraparesis. In our patient, proprioception loss was the major symptom responsible of balance and gait disturbances. This clinical feature and a MRI very localised atrophy are uncommon. Particularity and frequency of sensory features in HAM are discussed, as well as spinal cord MRI findings. P274 ACUTE MYELITIS IN THE POST-ERUPTIVE PHASE OF RUBELLA: A CASE REPORT WITH MRI FINDINGS. D. Felten, H. Taillia, J. S. Guillamo, Y. S. Nizou, J. L. Sarrazin, D. Béquet. Hôpital Val-de-Grâce, Paris, France

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Amongst neurological complications of rubella virus (RV) in adults, myelitis is rare. We report the case of a 24-year-old immunologically competent man who was admitted for urinary disturbances. During the last four days he had presented fever and an eruption located on the face and secondary on thorax and limbs. At admission, he complained of an isolated retention of urine. Neurological examination was normal as well as usual biological tests. Cerebrospinal fluid analysis showed 35 cells/mm3, increased protein level and an intra-thecal synthesis of immunoglobulins. Significant titers of IgM antibodies to RV was found. Other viral studies were negative. Spinal cord MRI showed an enlargement of the cervico-thoracic cord and high signal intensity on T-2 weighted images at C3–C7, T5–T6 levels and in the conus medullaris. Urinary disturbances improved spontaneously in eight days; one month later, MRI was normalized. An acute myelitis may be observed in many sorts of virus. The prognosis is often good as in our case, but it may be serious, related to spinal cord necrosis; that has been reported with herpes simplex (HSV), varicella-zoster virus (VZV) and cytomegalovirus, especially in case of immunosuppression. MRI is important for the follow up. Aggressive antiviral therapy is advised in HSV and VZV myelitis. In other cases, vaccination against selected viral infection, such as rubella, is the only way to prevent acute complications. P275 CLINICAL FEATURES OF NEUROBORRELIOSIS. P. Umicevic, A. Jovicic, M. Tomovic, T. Hic. Military Medical Academy, Department of Neurology, Belgrade,Yugoslavia Lyme disease represent multisystem disease caused by the spirocheta Borrelia Burgdorferi. First description dated from 1975 in clinical form of juvenile arthritis, in Lyme county, Connecticut, USA. Polymorphous neurologic manifestations were noted in 15–20% of patients with Lyme borreliosis(LB) during last few years. We conducted this study in aim to characterise clinical features of neuroboreliosis(NB),and to discuss diagnostic and therapeutic problems. Fifteen patients (five women, aged 22–45 years) who were presented to our clinic (Department of Neurology) with NB, were evaluated,during period from 1988–96. Durations, of disease were in range from a few months to three years. Untill the NB was diagnosed, they were treated as encephalitis (2), meningoencephalitis (4), encephalomyelitis (3), vasculitis (l), polyneuritis (3), intracraniale space occuping process (I), polymiositis (l). Epidemiologica1 data related to tick bite were obtained in 10 cases. Twelwe patients had positive indirect immunofluoroscence assays (1 : 40–1 : 160). Among nonspecific complaints and signs most common were fever (8 pts), severe headache (12 pts), vomiting (6 pts), meningeal signs (4 pts).Cranial nerves lesions were observed in 8 patients (Facial nerve in 6 pts). Painful radiculitis was noted in 5 pts, signs of upper motor neurone lesions in 7pts, and extrapyramidal manifestations in 2. All patients were treated with penicilline V or doxyciline, during three weeks, with significant reduction of neurological signs and symptoms. Based on above mentioned experiences we concluded that clinical features of NB were different and non-specific. This neurological disorder could be unrecognized for a longer period of time, in absence of appropriate epidemiological data. P276 DENGUE ASSOCIATED FATAL CEREBRAL EDEMA. Bienfait HP, Janssen HLA, Jansen CL, van Duinen SG, Schimmsheimer RJ, Vriesendorp R, Groen J, Osterhaus ADME A 25-year-old Dutch woman was admitted to our hospital with fever, headache, fatigue and dizziness. These symptoms had started 4 days earlier on a return flight from a holiday in Thailand. On admission she was well orientated and had a fever of 39.1° C. There were no abnormalities found at physical and neurologic examination. Laboratory investigation showed no abnormalities except for a platelet count of 53 × 10 9/l. Eight hours after admission she collapsed and lost consciousness. Neurologic examination revealed a deep comatose state. Computed tomography of the brain demonstrated massive cerebral oedema without focal abnormalities. Despite extensive treatment she died the next hour. Autopsy only revealed brain oedema with specific capillary changes, and a secondary hemorrhage in the pons, being the cause of death. Investigation of the visceral organs showed no signs of internal hemorrhage. Dengue virus was detected by several means in blood and brain tissue. Dengue associated encephalopathy usually occurs in children, the majority of the patients recover without neurologic sequelae. Severe neurologic complications can occur in patients with the complete syndrome of dengue hemorrhagic fever. This case demonstrates that severe neurological manifestations of dengue fever are not confined to children or those previously sensitised by the virus, and that fatal dengue induced cerebral oedema can occur in the absence of clear signs of dengue shock syndrome.

P277 CANDIDA ENCEPHALITIS AS THE CAUSE OF FEVER OF UNKNOWN ETIOLOGY (FUO) IN A NON IMMUNOCOMPROMIZED YOUNG WOMAN. S. Papageorgiou, D. Makris, I. Kosmidis, C. Karageorgiou. Neurology Department, and Department of Internal Medicine, Athens General Hospital, Greece Fungal encephalitis has been described in immunocompromized patients. However, its occurrence in immunocompetent patients is very uncommon. We describe the case of a 32-year-old woman who presented with prolonged FUO lasting for more than a month for which she was thoroughly investigated. General clinical as well as neurological examination were normal. Fifteen days later, she presented jerky tendon reflexes of the extremities and a left Babinski’s sign. The rest of the neurological examination remained normal. There was no signs of meningism and the patient reported no headache. MRI investigation revealed a diffuse hypersignal in the basal ganglia, thalamus and mesencephalon. CSF investigations showed a mild pleocytosis (58 cells/mm3, 50% of which were mononuclear), slight elevation of proteins and normal glucose values. PCR investigation of the CSF was positive for candida. Candida fungi were detected also to the direct examination as well as to the CSF cultures. The patient received prolonged intravenous treatment with flucytosine and liposomal amphotericine. Fever dissappeared 7 days after treatment initiation. One month later neurological and CSF examination returned to normal. MRI follow-up findings will be discussed. P278 OTOGENIC DIFFUSE INFLAMMATORY MENINGITIS. Jekic V, Filipce I, Vlaski-Jekic S, Gogusevski B, Kaya E. Clinic of Otorhinolaryngology, Clinic of Neurology, Skopje, Macedonia Diffuse purulent meningitis represents the potential intracranial inflammatory complication caused by inadequately treated chronic suppurative otitis media. 1490 patients with a chronic infection of the middle ear have been surgically treated in the Clinic of Otorhinolaryngology in Skopje, Macedonia, for the last 20 years. The otogenic intracranial complications were found in 168 cases (11.2%). The most frequently found one, was the diffuse purulent meningitis. It was present in 56 patients (33.3%). With this percent, the otogenic meningitis (OM) takes the first place among the otogenic intracranial complications. Otogenic meningitis in 38 cases (67.8%) was associated with other intracranial complications. Twenty-five patients manifested both otogenic meningitis and extradural abscess (48.1%). Six patients had OM and sinus sigmoideus thrombophlebitis (11.5%), four patients were with OM and brain abscess (7.7%), and in three there was an association of OM with both extradural abscess and sinus sigmoideus septic thrombosis (5.7%). Diffuse purulent meningitis is a serious otogenic inflammatory intracranial complication needing urgent surgical treatment of the chronic suppurative inflammation of the middle ear: radical trepanation of the temporal bone or mastoidectomy. The adequate antibiotic treatment of the acute otitis media and a surgical approach to the chronic suppuration of the middle ear on time, represent the only rational prevention for otogenic intracranial complications in general, and for the otogenic meningitis respectively. P279 MEDICALLY TREATED INTRASPINAL BRUCELLA GRANULOMA. Ayșe Bingöl*, Nezih Yücemen*, Oktay Meço**. Ankara University, Medical Faculty, Departments of *Neurology and **Clinical Microbiology and Infectious Diseases, Ankara, Turkey A 40-year-old female presented with urinary incontinence and 2 months history of progressive weakness of the right leg and numbness of the left leg. Four months prior, she had diagnosis of systemic brucellosis with a period of radiculomeningoencephalitis; she was treated succesfully with rifampicin, doxycycline, trimethoprim/sulfamethoxazole and streptomycin and discharged symptom-free and she was still on rifampicin and doxycycline medication. Neurological examination revealed spastic paraparesis, globally hyperactive deep tendon reflexes, sensory level at T6. Magnetic resonance imaging (MRI) of the spinal cord revealed an intradural-intramedullary mass lesion of 10 × 30 mm at T5 level with surrounding oedema and enhancement with contrast material. Cerebrospinal fluid (CSF) was xanthochromic with lymphocytic pleocytosis and elevated levels of albumin, immunglobulins and antibody titres for brucella. We modified her medication as rifampicin 1200 mg, doxycycline 400 mg and trimethoprim/sulfamethoxazole 480/2400 mg daily and methylprednisolone 100 mg in decremental doses for 6 weeks. After 2 months she was symptomfree and her medication was continued with lower doses. At the end of the

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6 months the mass lesion resolved completely. Despite one year of treatment, she still has high antibody titres for brucella in CSF. Most of the spinal brucella granulomas in the literature are operated upon. We advise to try medical treatment of brucella granuloma with adequate dosage for the adequate length of time before considering surgical intervention.

P280 NEURO-BEHÇET OF THE SPINAL CORD. Simri M, Manelis J, Sula M. Department of Neurology Western Galilee Nahariya Hospital, Israel Neurologic findings in Behcet’s disease are variable and include meningoencephalitis, cranial nerve palsies, dementia, cerebellar ataxia, corticospinal tract dysfunction. The most common CT findings in neurobehcet are low density parenchymal lesions, usually in the brainstem or basal ganglia, enhanced following contrast. MRI appear to be more sensitive than CT in detecting the brain lesions. We present a case with pyramidal sings due to lesions in the cervical spinal cord demonstrated by MRI. Case report: a 31 year old woman with Behcet’s disease since 1994. The patient was admitted in December 1996 with headache and fever. Neurological examination demonstrated nuchal rigidity and bilateral pyramidal signs, CT of brain with and without contrast – normal. Aseptic meningitis was diagnosed. The patient continued her previous treatment with cyclosporine and prednisone, the headache and fever subsided. Five months later she was admitted again with fever and nuchal rigidity. The neurological examination was the same as previously, recurrent meningitis due to Behcet’s disease was diagnosed. The clinical picture subsided within five days. Two months later the patient developed gait difficulty. On examination there was mild tetraparesis, with bilateral pyramidal signs. Mri of brain (without and with gadolinium) – was normal. MRI of cervical spine revealed diffuse hyper intense lesions at T2. The patient was given imuran. Prednisone and cyclosporin was discontinued. The tetraparesis disappeared after 10 days. Summary: we present a case of Behcet’s disease with lesions of the spinal cord demonstrated by MRI. Only two cases of spinal cord involvement in neurobehcet, verified by MRI, have been described to date.

P281 THE VALUE OF LOW FREQUENCY ELECTROSTIMULATION IN THE REHABILITATION OF GUILLAIN-BARRÉ SYNDROME (GBS). Mokrusch T, Lubinski R. Hedon-Klinik, Lingen, Germany The main therapeutical indication for’ he use of low frequency electrostimulation in neurological rehabilitation is its influence on paresis and pain. The value of any type of electrotherapy, in inflammatory diseases is discussed controversely. We present the results of a pilot study, as the effects on GBS is not known. Methods: A series of 15 patients with GBS in the post-acute stadium were investigated that underwent neurological rehabilitation. Group 1: 6 patients received electrotherapy (20 minutes daily, 7 times a week; impulse intensity above motor threshold, impulse duration 250 µsec, frequency range 10–90 Hz. Additionally, physiotherapy was performed 5–11 times a week with 30 minutes per session. Group III: 9 patients, as group L but without electrotherapy. Parameters of outcome were: GBS-scores following Richard and Hughes, van der Meche and Schmitz; Barthel-Index; nerve conduction velocity. Results: The BarthelIndex showed an overall improvement from 64 ± 25 to 84 ± 20 score. There was a slight indication for a better improvement in the electrotherapy- group, which, however, did not reach significance. Similar results were obtained with the other parameters. Discussion and Conclusion: According to the present data, no distinct difference can be seen in the therapy results of patients with or without electrotherapy. A follow-up study is going on, actual results will then be presented.

P282 TREATMENT OF ACUTE HERPES SIMPLEX ENCEPHALMS (HSV). Jovicic Aco, Raicevic Ranko, Djordjevic Dragana, Dincic Evica, Markovic Ljuba*. Department of Neurology, Department of Radiology*, Military Medical Academy, Cmotravska 17, Belgrade, Yugoslavia Since acute HSV encephalitis is severe and potentially fatal neurological disease, it’s been our aim to evaluate efficacy of antiviral (aciclovir) and immunomodulatory therapy (interferon a) concerning the extent of intlammation and the time of treatment initiation. In 6 patients (3 male and 3 female), aged 20–40 years, diagnosis of HSV encephalitis was made clinically, electrophysiologicaly (EEG), radiologically (CT and MRI) and in one patient even histopatologically. Patients were presented with consciousness

disturbances, headache, seizures, motor, sensor and speech impairment EEG recordmga m 4 patients showed theta-delta activity in temporal regions, in 1 in frontal region and in 1 patients diffuse slow activity was present. In 5 patients focal lesions were found neuroradiological examination and in 1 diffuse brain oedema. Scrological tests in all patients showed antiHSV antibody increase. All patients were treated with aciclovir, 5 mg/ kg intravenously, divided in 3 daily doses during 5 days, and interferon a in a dose of 6 million iu intramuseularly, on the second day, during 10 days. In 5 patients therapy was started within 48 hours of clinical presentation, and in patient with diffuse changes after 4 days. Those 5 patients recovered during 2 weeks, while the sixth patient deteriorated and died after 7 days of treatment. In conclusion, efficacy of applied treatment is dominantly dependent on intla amation extent and the time of treatment initiation.

Motor Neuron Disease P283 AUTOSOMAL DOMINANT SPINAL MUSCULAR ATROPHY WITH LATE ONSET AND RAPID PROGRESSION. Vos RM, van den Berg LH, Wokke JHJ. Department of Neurology, University Hospital Utrecht, The Netherlands Most cases of proximal spinal muscular atrophy (SMA) show an autosomal recessive mode of inheritance. Autosomal dominant (AD) forms are rare and may account for less than 2% of childhood onset proximal SMA and 30% of adult onset forms. The childhood forms show a relative benign disease course whereas in adult forms handicaps develop more rapidly. Median life expectancy after diagnosis of the latter is though reported to be 20 years. We present two families with rapidly progressive AD SMA. In family 1 the index case and his father presented with proximal symmetric muscle weakness. Both died from respiratory failure at the age of 40 respectively 49 years having had symptoms for one and three years. In family 2 the index case presented with asymmetric distal weakness. Both he and his father died from respiratory failure at the age of 64 respectively 77 after a symptomatic phase of five and four years. In all cases clinical signs of pyramidal tract or bulbar involvement were absent. No mutations in the survival motor neuron (SMN) gene were found. Pathological observations in three of four cases will be discussed. Adult onset proximal SMA is classified as SMA type IV and may, as the childhood forms, be caused by mutations in the SMN gene. The disease course in the four cases resembles that of familiar ALS with patients dying from respiratory failure after only a few years. Nevertheless the absence of signs of pyramidal tract involvement suggests genetic heterogeneity. The rapidly progressive disease course in these cases may have implications for genetic counseling.

P284 COMPUTER-ASSISTED MAXIMAL VOLUNTARY ISOMETRIC CONTRACTION (cMVIC) VERSUS HAND-HOLD DYNAMOMETRY (HH-Dyn) FOR MUSCLE STRENGTH TESTING IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS). Beck M, Würffel W, Giess R, Toyka KV, Ochs G. Department of Neurology, Julius-Maximilians-University Würzburg, Würzburg, Germany Objective: To study the reliability and feasibility of HH-Dyn compared to cMVIC for muscle strength in ALS. Background: cMVIC requires considerable effort, time and equipment but delivers well accepted data accuracy and reliability. It is a matter of debate whether HH-Dyn, which is less costly and much easier to perform, can yield data of comparable precision. Design/Methods: cMVIC was performed using an examining table, a strain gauge system and computer assisted real time A/D-data-collection system (MacAdios Analog to Digital System). A Chatillon Isokinetic Dynamometer was used for HH-Dyn with a standardised examination procedure. 360 measurements were performed by the same investigator in 43 consecutive ALS-patients, both by cMVIC and HH-Dyn. A recovery break was allowed between measurements. Results: As expected, the quantitative data analysis demonstrated a highly significant correlation (r = 0.85, Pearson) between the two methods. However, as a rule, we found a tendency to underestimate muscle strength above 10 kg by HH-Dyn as compared to cMVIC. The accurate positioning of the limbs and the preservation of isometric conditions was most essential when performing HH-Dyn, reflected in high correlation between measurements of identical muscle groups in different individuals. Conclusion: Accurately performed HHDyn can provide muscle strength data in close correlation with the time consuming and sophisticated cMVIC procedure.

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P285 INCREASED GDNF mRNA EXPRESSION IN DENERVATED HUMAN SKELETAL MUSCLE. Dieter Chichung Lie1, 2, J. Michael Schröder, MD1, Joachim Weis, MD3. 1Institut für Neuropathologie der RWTH Aachen, Germany; 2Neurologische Universitätsklinik Regensburg, Germany; 3Institut für Pathologie der Universität Bern, Switzerland Glial cell line derived neurotrophic factor (GDNF) is a very potent trophic factor for several subpopulations of neurons including dopaminergic midbrain neurons and motoneurons. Therefore, GDNF has been discussed as a therapeutic option for neurodegenerative diseases such as Parkinson’s disease and Amyotrophic lateral sclerosis (ALS). GDNF is expressed in many different organs including skeletal muscle in humans and rodents. A recent report on GDNF expression in muscle specimens of patients with endstage ALS described decreased GDNF expression in these cases. However, GDNF expression in mice is increased following denervation. To address the question, whether GDNF expression in human skeletal muscle is influenced by denervation or primary muscle disease we studied the expression of GDNF mRNA in denervated human muscle (18 cases including 4 cases of ALS) and in muscle from patients with Duchenne muscular dystrophy (DMD) (12 cases) by competitive RT-PCR and compared it with the expression in normal muscle (8 cases). GDNF mRNA levels were approximately 5-fold increased in denervated muscle compared to normal and dystrophic muscle. Higher levels of GDNF were expressed in cases of rapidly progressive neurogenic atrophy including the ALS cases compared to cases of chronic neurogenic atrophy. These results indicate that increased GDNF expression is part of the physiological reaction of human skeletal muscle to denervation. Therefore GDNF might indeed be of therapeutic value in the treatment of denervating neurodegenerative diseases such as ALS. P286 NEUROTOXICITY OF HIGHLY-HALOGENATED β-CARBOLINES ON DOPAMINERGIC CELLS IN CULTURE. G. Gille, B. Janetzky, H. Reichmann1, G. Bringmann, W.-D. Rausch3. 3Inst. Med. Chem., Vet. Med. Univ. Vienna, Austria, 2Inst. of Organic Chemistry, University of Würzburg, 1Dept. Neurology, University of Dresden, Germany Highly chlorinated β-carbolines may be formed under physiological conditions from endogenous biogenic amines and exogenous chloralhydrate. Similar structure to 1-methyl-4-phenyl-pyridinium ion (MPP+), in vitro neurotoxicity and inhibitory effects on mitochondrial respiration stimulated these investigations on neurotoxicity to the dopaminergic system. Effects of exposure of halogenated β-carbolines on mesencephalic dopaminergic cells were studied with morphometry, 3H-dopamine-uptake and enzymatic activity of complex I in mitochondrial preparations. Results: Effective toxic concentrations of 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) and related tested derivatives on cell viability and dopamine uptake were 10–100 µM. IC50 values of complex I inhibition of toxic compounds were 100–400 µM. Conclusions: Dopamine uptake and inhibition of complex I depend on the degree of halogenation. Toxicity can be further enhanced by methylation of N-2 suggesting that both, halogen and methyl groups contribute to the neurotoxic potential of substituted β-carbolines. P287 1H-MAGNETIC-RESONANCE-SPECTROSCOPY (1H-MRS) IN THE DIAGNOSIS OF MOTONEURON DISEASE. Giess R, Kenn W*, Scholz C, Pabst T*, Beck M, Ochs G. Dept. of Neurology and *Dept. of Radiology, University of Würzburg, Germany Objective: To evaluate diagnostic significance of 1H-MRS in motoneuron disease (MND). Background: Former studies with 1H-MRS in MND demonstrated conflicting assessment in detecting upper motoneuron degeneration. Patients and Methods: 1H-MRS was performed in ten patients with amyotrophic lateral sclerosis (ALS), two patients with primary lateral sclerosis and ten patients with neurological diseases not affecting the central nervous system. The peak integral for the signals of the metabolites Nacetylaspartate (NAA), choline (Chol) and creatinine (Crea) was determined bilaterally in the motor cortex by a single voxel technique (SV) in a volume of interest (VOI) of 20 × 20 × 20 mm and by chemical shift imaging (CSI matrix 16 × 16) in a VOI of 10 × 10 × 15 mm. Results: Statistical analysis of the metabolic ratios of NAA/Chol, NAA/Crea and Chol/ Crea failed to detect significant differences between the motoneuron disease patients and the control group both in CSI and SV. However, comparing the hemispheres within the same patient, a significant reduction of NAA/Chol contralateral to the clinically more affected body region could

be demonstrated in CSI but not in SV. Conclusion: Upper motoneuron degeneration can be detected by 1H-MRS, but resolution and evaluation of data with current technology needs further improvement. P288 AMYOTROPHIC LATERAL SCLEROSIS SERA INDUCE AN APOPTOTIC MOTOR NEURON DEATH. Hivert B, Quiquempois JM, Camu W. Laboratoire de physiopathologie neuromusculaire, INSERM CJF 97-02, Montpellier, France Amyotrophic lateral sclerosis is a devastative neurodegenerative disorder of the motor neuron of unknown origin. In the last years it has been suspected that environmental toxins or circulating antibodies could be present in the blood, leading to motor neuron degeneration. We tested this hypothesis, studying the influence of ALS sera on motor neuron survival. Embryonic rat motor neurons were obtained after enzymatic dissociation and purified either by a Metrizamide gradient or by panning (immunoaffinity). Dialysed ALS sera were applied after 24hrs at a concentration of 1%. Survival was assessed after another day by counting cells under microscope. In a second set of experiments, apoptosis was studied with the TUNEL technique. We found that 30% of the ALS sera were highly toxic for motor neurons inducing more than 70% of cell death. This toxicity was not inhibited by glutamate antagonists. The TUNEL technique showed that the mechanism of death for the motor neurons is apoptosis. This apoptosis was inhibited by benzamide and nicotinamide with a dose-response pattern. These data support the hypothesis of a circulating molecule responsible for motor neuron degeneration. However, it is not possible to determine whether this factor is unique or not and whether it a cause or a consequence of the disease process. Nevertheless, this may help to define new therapeutic agents in ALS. Supported by AFM and ARS. P289 NERVE GROWTH FACTOR CONCENTRATIONS ARE ELEVATED IN MUSCLE BIOPSIES FROM PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS. H. J. Stuerenburg, M. Oechsner, C. Eggers, H. C. Hansen, K. Kunze. Department of Neurology, University Hospital Hamburg-Eppendorf, Germany In order to investigate the possible influences of pathological processes on muscle NGF levels in human subjects, we measured the NGF concentrations in muscle biopsies from 35 male and 16 female subjects (controls, n = 14; amyotrophic lateral sclerosis, n = 20; inflammatory myopathy, n = 6; muscular dystrophy, n = 11). The NGF concentration in each group was as follows: controls, 1.73 ± 0.3 pg/mg protein (mean ± S.E.M.); muscular dystrophies, 1.73 ± 0.48 pg/mg protein; inflammatory myopathies, 2.28 ± 1.45 pg/mg protein; amyotrophic lateral sclerosis, 4.15 ± 0.79 pg/mg protein. The tissue NGF concentrations were significantly (140%) higher in patients with ALS than in the control subjects ( p < 0.05, Wilcoxon signed rank test). Age and gender had no influence on tissue NGF concentrations. We conclude that the NGF increases observed here in affected muscle in amyotrophic lateral sclerosis can best be explained in terms of rapidly progressing denervation processes, and could furthermore have an influence on regenerative processes in the musculature. P290 MOTOR NEURONE DISEASE AND PERCUTANEOUS GASTROSTOMY. N. J. Giffin, C. Russell, G. N. Fuller, D. L. Stevens. Gloucester, United Kingdom Dysphagia is a common problem in motor neurone disease (MND), percutaneous gastrostomy (PEG) provides symptomatic relief. A previous prevalence study reported 3% of patients had PEGs, but little is known on optimal use of PEG in MND. Gloucestershire Royal Hospital (catchment population 550,000) has a multidisciplinary team for patients with MND. Records kept by the team identified 77 MND patients. Annual incidence, since January 1989, is 1.57/100,000 (expected 1.5/100,000) and prevalence at 25/11/97 is 5.45/100,000 (expected 4–6/100,000). PEGs were offered when dysphagia caused distress or eating was unduly slow and other interventions insufficient. Median age of symptom onset was 60.3 years (range 24–88 ). In the 30 alive, 6 (20%) have PEGs. Of the 47 deceased, 24 (51%) had PEGs, (12/17 bulbar-onset and 12/30 limb-onset). Median duration of symptoms prior to PEG was 17.5 months (range 3–43.6) for bulbar-onset and 34 months (range 20.1–117.6 ) for limb-onset. 2 (6%) died within 3 days of the procedure, one of left ventricular failure (postmortem performed), one of respiratory failure (no post-mortem). Survival was no different with or without a PEG in the bulbar-onset group, but was

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10 months longer in the limb-onset group with PEGs than those without. However, median survival after the PEG in the latter group was only 2.5 months. Fifty one percent of MND patients in Gloucestershire are given a PEG, a higher rate than other series. Limb-onset patients with a PEG have a modestly prolonged survival, but the significance is uncertain as patients were not randomised. Our clinical impression is that PEGs are effective in relieving distressing symptoms and since they are being used increasingly frequently their impact on quality of life should be formally evaluated. P291 O’SULLIVAN-McLEOD SYNDROME AND HIRAYAMA SYNDROME: ONE OR TWO ENTITIES? C. Guiraud Chaumeil, J. Melki, J. L. Dietemann, C. Tranchant, J. M. Warter. Service des Maladies du Système Nerveux et du Muscle, Service de Radiologie II, Hôpitaux Universitaires, Strasbourg, France O’Sullivan-McLeod syndrome and Hirayama syndrome are very similar diseases resulting in distal muscular atrophy of the upper extremity. These two entities are clinically characterised by juvenile male occurrence, insidious onset, localised distribution of muscular atrophy, non evolutive course. Electromyography shows typical neurogenic pattern in the atrophied muscles indicating anterior horn involvement. Based on our clinical experience and on literature data, our objective was to investigate whether these syndromes are really different or not, and if there is some reasons to individualize them. We report four patients – 3 men and 1 woman – who developed juvenile muscular atrophy of distal upper extremity localized in hand and forearm. For each patient were performed a clinical and electrophysiological study and a cervical magnetic resonance (MR) in neutral and flexed positions. Survival motor neuron (SMN) gene was studied in all patients and did not carry any mutation. Electrophysological and MR findings support two distinct physiopathological hypothesis. As suggested by Iwasaki et al. in 1987, Hirayama’s disease could be due to a local compression of the spinal cord in flexed neck position, called flexion myelopathy. On the other hand, as suggested by more diffuse electrophysiological abnormalities O’Sullivan and McLeod syndrome could correspond to a localized form of progressive muscular atrophy. P292 HIV-ASSOCIATED MOTOR NEURON DISEASE. S. Contant, A. Moulignier, M. Baudrimont, O. Gout, P. Bakouche. Fondation Rothschild and Hopital Saint Antoine, Paris, France Objective: To describe unusual clinical and electrophysiological features of neurological complication in HIV-1 infection. Patients and methods: Six patients were enrolled in this retrospective study among approximately 2200 consecutive HIV-infected patients with neurological symptoms referred to one of us (AM) between 1987 to 1997, by numerous infectious diseases departements. El Escorial clinical diagnostic criteria for MND were used. Other causes than HIV-1 were ruled out. Results: Five patients were caucasian homosexual men, and one woman originated from Africa. The clinical feature at onset was that of a monomelic form of MND. MND was the first manifestation of HIV infection in all patients and revealed HIV seropositivity in one case. CD4 cell counts were low (Mean = 27/mm3) in all patients. P24 antigen in cerebrospinal fluid (CSF) and β2microglobuline were elevated in 5/6 patients and CSF viral load was high in 2/3 patients. All patients were younger (mean age = 36.6 years) than the MND’s usual age of onset. The evolution was subacute and all patients improved with antiretroviral therapy. Conclusion: These cases provide additional evidence that infection with HIV-1 should be considered in the differential diagnosis of apparent motor neuron disease, notably in young adults. HIV-1 might cause MND by several mechanisms, via abortive infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease (molecular mimickry mediated by antibody or cells). P293 PIEMONTE AND VALLE D’AOSTA AMYOTROPHIC LATERAL SCLEROSIS REGISTER: A PROSPECTIVE, POPULATION-BASED CLINICO-EPIDEMIOLOGICAL AND PROGNOSTIC STUDY. Terreni AA, for the Piemonte and Valle d’Aosta Amyotrophic Lateral Sclerosis Register. Torino, Italy The incidence of amyotrophic lateral sclerosis (ALS) shows some variations between different countries. In particular, all studies until now performed in Italy show incidence rates lower than most surveys from North-

ern Europe and the United States. Since 1/1/95 we have collected prospectively ALS cases incident in two Italian regions, evaluating the clinicoepidemiological features of ALS with the collaboration of the 28 Neurological departments of the area. After diagnosis, the cases were followedup and several prognostic parameters were assessed. The cases met the WFN criteria for diagnosis of definite ALS. During the study period a total of 186 patients with ALS were identified, corresponding to a mean crude annual incidence rate of 2.11 (95% confidence interval 1.83–2.44) and an adjusted incidence rate of 1.99. Men/women ratio was 1.25 to 1. The age-specific incidence rate showed an increase to the 60+ age-class, with a subsequent slight decrease. The mean age of onset of ALS was 63.2 years (SD 11.0). The most frequent site of onset of symptoms were upper limbs (32.5% of cases). The median survival time from onset was 36 months. Negative prognostic factors were bulbar onset and age over 60 years. The incidence and clinical characteristics of ALS in Piemonte and Valle d’Aosta are similar to those observed in Northern Europe and generally higher to that reported by other Italian studies. P294 SELECTIVE MOTOR NEURON DEGENERATION IN ALS. Silani V, Braga M, Fociani P*, Ermellino L*, Brioschi A, Ciammola A, Ferrero S*, Buffa R*. Scarlato G. Institute of Neurology. *Secondo Servizio di Anatomia Patologica-IRCCS Maggiore Hospital, Milano, Italy Markers of motor neuron (MN) injury (i.e., ubiquitin, c-Jun, apoptosis markers) represent useful parameter to document the differential MN damage in ALS. A patient with predominant lower motor neuron impairment with a caudal-rostral clinical progression has been treated with riluzole. Samples of motor cortex, corticospinal tract, brainstem, and from all levels of spinal cord as well as diaphragm and pectoralis muscles were processed. Staining for myelin (Kluver-Barrera), GFAP, p75-NGFr, Ubiquitin, NSE, and anti-MBP were performed. Apoptotic cells were detected on serial sections in brainstem and spinal cord by Apoptag kit. We observed MN loss in motor cortex layer V without gliosis. Cortico-spinal tracts showed bilateral demyelination. No MN loss was observed in facial and hypoglossal nuclei, but ubiquinated intracytoplasmic inclusions. Expression of MBP was normal. We observed a significant loss of MNs in the lumbar cord segment with a negative ascending gradient; a few in the brainstem, but no apoptotic cells in the cord (advanced cell death). Surviving MNs normally expressed NSE and p75-NGFR immunoreactivity. Denervation was shown in skeletal muscles. Specific cell markers for MN impairment appears useful to define stage and selectivity of MN degeneration and to correlate clinical to neuropathological findings. Molecular effects of riluzole on MN markers need to be further defined.

Multiple Sclerosis P295 LINKAGE ANALYSIS OF HLA CLASS II GENES IN JEWISH MULTIPLEX FAMILIES WITH MULTIPLE SCLEROSIS. C. Brautbar1, Y. Cohen2, C. Sofirman1. D. Karussis3, E. Kahana4, O. Abramsky3, A. Karni3. Tissue Typing Unit1, Department of Psychiatry2, Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem3, Department of Neurology, Barzilai Medical Center, Ashkelon4, Israël Multiple sclerosis is almost world wide associated with HLA-DR2 haplotype. Recently we showed that this association exist in Jewish MS patients. However, linkage studies of MS with the HLA genes did not disclose unequivocal results. Therefore, we performed a multipoint LOD score and Nonparametric linkage (NPL) analysis for the HLA class II genes in 11 MS multiplex families, by using the GENEHUNTER computer package. HLA class II genotypes were revealed by PCR-based typing of DRB1, DQA1 and DQB1 loci. The association of the MS patients and the healthy members (HMs) from these multiplex families with the HLA make up was also studied, by comparing them to 293 ethnically correlated healthy controls (HCs). The overall LOD scores for the loci DRB 1 ~ DQA1 and DQB 1 at 0 = 0.0 1, using a dominant model with 3% penetrance, were 0.25, 0.26 and 0.3 1 respectively; the P values for the NPL scores were 0. 10, 0.09 and 0.09, respectively. The association study revealed no significant differences between the MS patients and the HMs. The frequency of DRB 1 * 1501 haplotype in MS patients was low (4.3%) and without significant difference compare to the HMs and the HCs. However, a significant higher proportion of DRB 1 * 13 03 haplotype was found in the patients and the Ws of the MS multiplex families. Our results indicate a trend towards excess allele sharing of the HLA genes in MS patients. In contrast to Jewish MS patients from simplex families, the multiplex families pa-

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tients did not show any association with the DRB 1 * 1501 haplotype or allele. As was found in sporadic non Ashkenazi MS patients. positive association with DRB 1* 1303 haplotype was also found in multiplex family MS patients. P296 ERAZIMUS: EARLY AZATHIOPRINE VERSUS INTERFERON IN MULTIPLE SCLEROSIS. Thibault Moreau, Sandrine Blanc, George Riche, Jérôme Grimaud and Christian Confavreux. Department of Neurology, Hôpital de l’Antiquaille, Lyon, France As single therapies, both interferon beta-1a and azathioprine have shown proven efficacy in patients with relapsing multiple sclerosis. The combination of the two therapies however has not yet been studied. ERAZIMUS is a French single-center pilot trial designed to confirm the safety and tolerability of interferon beta-1a (AVONEX™) in combination with azathioprine (Imurel™) on a limited number of subjects (30) receiving azathioprine treatment for at least six months for relapsing-remitting multiple sclerosis. The safety profile of the combination of azathioprine and interferon beta-1a will be evaluated through clinical, hematology and biochemistry laboratory parameters performed at specific timepoints throughout the study. Blood samples will also be collected and analyzed to determine in parallel neopterin levels (a pharmacodynamic marker of interferon actions) and 6 thioguanine nucleotide (a metabolite of azathioprine) between three groups of patients distributed according to azathioprine daily doses (50 mg, 100 mg, 150 mg). Patients will receive a weekly intramuscular injection of 6 × 10 6 International Units interferon beta-1a for four months. Safety will be monitored throughout the study. Treatment and study discontinuation rates, serious adverse events, clinically relevant laboratory abnormalities and adverse events will be summarized by dosing group. If this current pilot trial confirms the safety and tolerability of the combination of the two therapies, a large, randomized, multicentre efficacy trial on several hundred patients will be proposed in Europe. Supported by grants from the Commission of the European Communities DG XII (Contracts N° BMH1-CT93-1529, N° CIPD-CT94-0227 and N° BMH4-CT96-0064), and by funds from the Ligue Française contre la Sclérose En Plaques (L.F.S.E.P.), the Association pour la Recherche sur la Sclérose en Plaques (A.R.S.E.P.), the Hospices Civils de Lyon and Glaxo Wellcome and Biogen Laboratories. P297 T1 HYPOINTENSE LESION LOAD ASSESSMENT IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS. J. I. O’Riordan, M. GawneCain, A. Coles, D. A. S. Compston, D. H. Miller. The Institute of Neurology, Queen Sq, London and Addenbrooke’s Hosp., Cambridge, UK Despite the fact that magnetic resonance imaging (MRI) has been shown to have only a weak correlation with clinical outcome measures it is been used increasingly as a surrogate marker of disease activity in multiple sclerosis (MS). T1 weighted lesion load (LL) may have a better correlation with disability than the more conventional T2 weighted lesion load. As a result we studied 25 patients with secondary progressive MS, mean EDSS 5.7 (4–7), in order to (a) evaluate different measurement techniques used to quantify T1 hypointense lesion load, and (b) to compare lesion load as measured using different parameters and disability. T2 LL correlated well with both the hypointense lesion load on T1 pre-gadolinium (r = 0.8, p < 0.0001) and T1 post-gadolinium (r = 0.8, p < 0.0001) but less so with the enhancing lesion load (r = 0.4, p < 0.05). When compared with the EDSS, however, there was no significant correlation with the T2 lesion load (r = –0.27, p = 0.2), T1 pre-gadolinium (r = –0.3, p = 0.1), T1 post-gadolinium (r = –0.4, p = 0.7) and enhancing volume (r = –0.28, p = 0.2). There was a very strong correlation with T1 hypo-intense lesion volume pre and post gadolinium (r = 0.96, p < 0.001). Following histogram matching there was a strong correlation between the degree of hypointensity at all levels greater than 200 and both overall T1 lesion and T2 LL (r = 0.7, p < 0.001). There is a strong correlation between T1 and T2 lesion volume providing some concern about the value of T1 volume as a separate predictor of disability. These observations are cross sectional and it is possible that the longitudinal changes of T1 and T2 lesion load and EDSS are more important. P298 SHORT-TERM MRI FOLLOW-UP OF NEW MS LESIONS WITH DIFFERENT PATTERNS OF GADOLINIUM ENHANCEMENT. M. Rovaris, G. Mastronardo, M. A. Rocca, C. Gasperini, V. Martinelli, F. Prandini, M. Filippi. MS Biosignal Analysis Center, IRCCS H. San Raffaele, University of Milan, Milan, Italy

Several magnetic resonance imaging (MRI) studies demonstrated that a triple dose (TD) of Gd detects about 70% more lesions than the standard dose (SD) in patients with multiple sclerosis (MS). Aim of this longitudinal study was to investigate the pathology underlying MS lesions enhancing after either SD or TD of Gd by comparing their short-term evolution. For 3 months, 30 relapsing-remitting MS patients underwent two monthly MRI sessions, consisting of Gd-enhanced T1-weighted scans (TR = 560 ms, TE = 15 ms, 24 axial contiguous interleaved 5-mm thick slices), after SD (e.g., 0.1 mmol/Kg) in one session and TD (e.g., 0.3 mmol/Kg) in the other. New enhancing lesions on month 1 and month 2 follow-up scans were studied and for them any persistence of enhancement was evaluated on the next month scans. Two-hundred and forty-two lesions entered the analysis; 151 lesions were enhancing after both SD and TD, 91 lesions only after TD. After 1 month, 134/242 lesions (56%) were not enhancing, 66/242 lesions (27%) were still enhancing when giving the same Gd dose and 42/242 (17%) changed their pattern of enhancement. For the 151 lesions enhancing after both SD and TD, 73 (48%) were not enhancing, 50 (33%) were still enhancing after both SD and TD and 28 (19%) were enhancing only after TD. For the 91 lesions enhancing only after TD, 61 (67%; p < 0.005) were not enhancing, 16 (18%; p < 0.01) were still enhancing only after TD and 14 (15%; p = n.s.) showed enhancement after both SD and TD. MS lesions enhancing after either SD and TD or TD only may have distinguished pathological characteristics, since only a minority of them changes the pattern of enhancement on follow-up scans. Lesions enhancing only after TD may have a less severe inflammatory damage, as demonstrated also by the shorter duration of their enhancement period.

P299 DEVELOPMENT OF A QUALITY ASSURANCE PROTOCOL FOR MAGNETIZATION TRANSFER IMAGING. Silver NC, Mottershead JP, Green A, Hughes E, Tofts PS, Miller DH. NMR Research Unit and Department of Neuroimmunology, Institute of Neurology, London, UK Magnetization transfer (MT) imaging may provide quantitative measures relating to brain white matter structural integrity. In multiple sclerosis (MS), MT ratio (MTR) measurement may be useful to monitor putative therapies. For longitudinal studies, it is important to have stable scanner performance. We have designed a pilot study to monitor quality assurance for MTR changes in phantoms and control subjects. Two identical gelatin phantoms were studied at 1–2 weekly intervals over 6 months. In addition, 7 healthy volunteers were studied 4 times over a 9 month period with scanrescan at study onset. An interleaved spin echo sequence was used for measuring MTR at 1.5 Tesla. For phantoms, we observed good stability [phantom A: mean MTR = 24.7 percent units (pu) (range = 23.0–25.6, SD = 0.5); phantom B: mean MTR = 24.6 pu (range = 23.0–25.2, s.d. = 0.5). In healthy volunteers, mean MTR values remained stable over all 4 time points (38.2, 38.0, 38.2 and 38.1 pu). The follow-up values were compared with those at baseline to assess values for coefficient of variation (baseline scan : baseline rescan = 0.8%; baseline scan : follow-up 1 = 0.8%; baseline scan : follow-up 2 = 0.9%, baseline scan : follow-up 3 = 1.1%), thus showing stable scanner performance over time. In conclusion, it is possible to implement a useful quality assurance protocol to monitor scanner performance over time. In particular, we have shown reproducible and stable of brain MTR measurements using this particular sequence.

P300 MEASURING DISEASE ACTIVITY IN MULTIPLE SCLEROSIS: A CORRELATIVE STUDY OF SERIAL WEEKLY GADOLINIUMENHANCED MRI AND IMMUNOLOGICAL MARKERS. N. C. Silver, C. D. Good, G. Giovannoni, M. Lai, E. J. Thompson, D. H. Miller. NMR Research Unit and Department of Neuroimmunology, Institute of Neurology, London, UK Gadolinium-enhanced MRI provides a marker of disease activity in multiple sclerosis (MS). We studied 5 patients with relapsing-remitting or secondary progressive MS to determine the relative sensitivities of weekly versus monthly enhanced imaging. We also correlated such MRI activity with potential immunological markers. Weekly brain T1-, T2- and proton density-weighted spin-echo images were obtained at 1.5T following intravenous Gd-DTPA (0.1 mmol/kg) over 3 months. Serum C-reactive protein (CRP) and intercellular adhesion molecule 1 (sICAM-1) and urinary neopterin : creatinine ratio (UNCR) were also measured. Overall, weekly imaging detected 33% more new enhancing lesions than would have been seen with monthly study (52 vs. 39 enhancing lesions, p = 0.04). Mean duration of enhancement was 3.8 weeks and 7 lesions (13.5%) were seen to enhance for only 1 week. Studies showing Gd-enhancement showed higher

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UNCR and CRP levels (median UNCR = 359 vs. 253, p = 0.02; median CRP = 752 vs 161, p = 0.05). No correlation was seen for sICAM-1. In conclusion, the benefits of weekly versus monthly Gd-enhanced MRI appear small in relation to the increased commitment required for MS treatment trials. Individual lesions appear to have a definable inflammatory time course with early production of pro-inflammatory markers, perhaps explaining the poor correlation between such markers and MRI activity when studied at monthly intervals. Shorter temporal profiles of Gd-enhancement should be considered when attempting to correlate inflammatory markers with disease activity.

P301 A MULTI PARAMETER MRI STUDY OF CLINICALLY ISOLATED SYNDROMES SUGGESTIVE OF MULTIPLE SCLEROSIS WITH 3 MONTH FOLLOW-UP. P. A. Brex, J. O’Riordan, K. A. Miszkiel, G. J. Barker, D. G. MacManus, I. F. Moseley, W. I. McDonald, G. T. Plant, D. H. Miller. NMR Research Unit, Institute of Neurology, London, UK We studied 60 patients with clinically isolated syndromes suggestive of multiple sclerosis with the following sequences: (i) T2-weighted fast spinecho (FSE) of the brain and spinal cord, (ii) fast fluid-attenuated inversion recovery (fFLAIR) of the brain and (iii) T1-weighted images of the brain and cord looking for both gadolinium enhancement and hypointense areas. Follow-up brain MR studies were performed on 39 patients after 3 months to look for new lesions. At presentation, brain FSE and fFLAIR were abnormal in 73% of patients, T1 hypointense areas were seen in 50%, and enhancing lesions in 35%. Spinal cord FSE abnormalities were present in 42%, enhancing lesions in 10% and T1 hypointense lesions in 0%. At follow-up, new FSE brain lesions were seen in 46% and new enhancing lesions in 28%; 23% had enhancing lesions on both studies. In summary, there is a high frequency of brain T1 hypointense areas and FSE cord lesions at presentation and recurrent blood brain barrier leakage after 3 months. Further follow-up is needed to determine the clinical predictive value of these early pathological features.

P302 LATE ONSET MULTIPLE SCLEROSIS. S. Cordera, A. Cucatto, C. Juenemann, P. Schiffer, A. Calvo, D. Schiffer. Dept. Neuroscience, Div. Neurology, University of Turin, Italy Multiple sclerosis (MS) is a disease of young age; in the literature, few series considered patients with age at onset over 50 years. In the period 1987–1997, 202 first diagnoses of MS were performed in our Department. Out of these, 79 (39%) referred to patients older than 50 years. In 41 of these cases (52%) the disease was already clinically evident before the diagnosis; in the other 38 cases (48%) the symptomatology at the diagnosis was the first manifestation of the disease. This group was compared to a control group of 75 cases. Signs at diagnosis in the late onset group were: 36.8% motor impairment, 39.5% multifocal involvement with cranial nerve deficit associated with parestesia or cerebellar signs, 13.2% motor deficit with parestesia, 1 case optical retrobulbar neuritis, internuclear ophthalmoplegia and 2 urinary incontinence. In the control group the principal pattern at diagnosis was a multifocal involvement (48%), motor impairment (13.3%), 4 cases optical retrobulbar neuritis and 4 cases cranial nerve palsy, urinary incontinence in 1 case. MRI lesions distribution was similar in the two groups. There was no significant difference in the interval between onset and diagnosis in the two groups. In our experience MS diagnosis is not unusual in patients with non conventional age for the disease; the main clinical feature is motor deficit and all the diagnostic procedures are necessary for the diagnosis.

P303 CORRELATION OF HYPOINTENSE T1 LESIONS WITH CEREBRAL VOLUMES IN MULTIPLE SCLEROSIS. B. P. Turner, C. Liu, S. Edwards, Q. Gong*, N. Roberts*, L. D. Blumhardt. Division of Clinical Neurology, Nottingham University; *MRR Centre, Liverpool, UK Axonal loss is considered to be a factor underlying fixed neurological deficit in multiple sclerosis (MS). T1 hypointense lesions (T1-HL) are thought to represent areas of axonal loss and gliosis within chronic plaques. We aimed to investigate the relationship between T1-HL and brain atrophy. T1-weighted spin echo and 3-dimensional magnetisation prepared rapid acquisition gradient echo images were performed on 40 MS patients (20 relapsing-remitting, 20 secondary progressive). Supratentorial and infra-

tentorial T1-HL number and area (‘lesion load’) were measured with a semi-automated method. The volumes of ventricles (VEN), corpus callosum (CC) and infratentorium were obtained with stereology. EDSS and Ambulation Index (AI) scores correlated with infratentorial T1-HL number (EDSS: r = 0.4, p = 0.014; AI: r = 0.42, p = 0.009) and load (EDSS: r = 0.42, p = 0.009; AI: r = 0.45, p = 0.006). Supratentorial T1-HL number and load correlated positively with VEN (no. r = 0.37, p = 0.024; load r = 0.4, p = 0.014) and negatively with CC volume (no. r = –0.43, p = 0.0077; load r = –0.47, p = 0.0036). Infratentorial T1-HL correlation with EDSS and AI is consistent with the bias of these scales towards brainstem and spinal cord and the lack of correlation with infratentorial volumes suggests that atrophy of these structures is due in part to Wallerian degeneration. Ventricular enlargement and corpus callosum shrinkage are modestly correlated with supratentorial T1-HL implying a contribution to supratentorial atrophy by T1-HL.

P304 T1 HOLE/TOTAL AREA RATIO: A POSSIBLE NEW MRI MEASURE OF CLINICAL DISABILITY IN MULTIPLE SCLEROSIS? Keele Multiple Sclerosis Research Group. M. B. Davies, R. Williams, N. Haq, C. P. Hawkins. Department of Neurology, Royal Infirmary, North Staffordshire Hospital and MRI Unit, Cornwall House, Stoke-on-Trent, England, UK Magnetic resonance imaging (MRI) is considered a possible surrogate marker of clinical disability in multiple sclerosis (MS). Abnormality on T1 weighted MRI sequences may be a useful measure of irreversible tissue disruption and axonal loss. We studied a new MRI measure using T1 sequences in 10 patients and compared it with conventional T2 and proton density (PD) weighted sequences in established MS. A Phillips (0.5 T) scanner was used. MRI lesion area was calculated independently in each patient (NH, MBD). Posterior fossa T1 hole area (SE 550/10, slice thickness 5 mm), and T2 and PD (SE 2760/80 and 20, slice thickness 5 mm) hyperintensity lesion area was measured manually using an Allegro© workstation (MBD). The total area of posterior fossa brain tissue on T1 weighted images was measured. The ratio of T1 hole area to total area of brain tissue in the posterior fossa was calculated. Clinical disability was measured using the EDSS and a posterior fossa FS (cerebellum and brainstem) in all patients. Preliminary results suggest a stronger relationship between T1 hole/total area ratio1 and clinical disability in the patients studied compared to conventional T1 hole2, T23 and PD4 lesion areas (EDSS r1 = 0.23 c.f. r 2 = 0.16, r 3 = –0.09, r 4 = –0.2; FS r1 = 0.31 c.f. r 2 = 0.27, r 3 = 0.30, r 4 = 0.27, p > 0.05). T1 hole/total area ratio may allow a better correlation between MRI abnormality and clinical disability in MS.

P305 DISEASE DURATION DETERMINES THE EFFECT OF AMANTADINE ON COGNITIVE PROCESSES IN PATIENTS WITH MULTIPLE SCLEROSIS AND FATIGUE. A DOUBLE-BLIND PLACEBO CONTROLLED CROSSOVER STUDY. Sailer M, Heinze H-J, Hauser U, Schoenfeld MA, Smid HGOM. Dept. Of Neurophysiology, MS-Unit, 39120 Magdeburg, Germany Treatment with amantadine was reported to be of beneficial effect on the overall daily performance in a number of patients with multiple sclerosis and fatigue. We investigated the effects of amantadine on cognitive processes with event related brain-potentials (ERP) and behavioral methods. Patients and Method: 24 patients with MS and fatigue were randomized in the verum and placebo groups. At two different times, the stimulus selection/response-choice task was performed in a double-blind, placebocontrolled cross-over, within-subjects design. Two different measures that make it possible to infer the timing of two major cognitive processes in the brain: i) stimulus selection and ii) response selection were applied. Results: Patients with a long disease duration (median > 7 years) had significantly reduced amplitudes in the ERP measures of stimulus selection and response selection, and their reaction times were significantly delayed compared to patients with a shorter disease duration. In the former group amantadine exerted a highly significant treatment by group interaction on the ERP measures and the reaction times. The degree of the fatigue had no influence on the task-directed processing or selective motor response. Conclusion: The present findings suggest that amantadine improves information processing in patients with a relatively long history of MS and not in patients with a relatively short disease duration. This improvement seems to be associated with an increase of available general resources, that is, an increase of information processing capacity.

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P306 ACTIVITY PARAMETERS IN MULTIPLE SCLEROSIS (MS) – CLINICAL COURSE, MAGNETIC RESONANCE IMAGING (MRI) AND INTERCELLULAR ADHESION MOLECULES. C. Schiel°, J. Kraus°, A. Kern*, P. Oschmann°, B. Engelhardt +, R. Bauer°, C. Hornig°, H. Traupe*, W. Dorndorf°. Department of Neurology° and Neuroradiology*, University Gießen, Max-Planck-Institut, Bad Nauheim+ The present study was performed to determine possible correlation between clinical course, contrast enhancing lesions in MRI and the soluble and cell bound form of the intercellular adhesion molecules in CSF and serum of 25 patients (11 male, 14 female, age 19–60) with relapsing-remitting MS for 2 yrs. In all patients MRI, clinical examination and determination of immunological markers were performed twice in between 90 days. Results: Classifying patients concerning remission and relapse significant differences were found regarding the expression of ICAM 1 on CD 3+ T-cells (9.76 ± 1.76 versus 18.92 ± 4.81; p < 0.001) and on CD 14+ monocytes (65.36 ± 14.9 versus 101.08 ± 33.75; p < 0.03) in CSF. On blood cells this difference occurred only on CD 3+ T-cells (4.78 ± 1.25 versus 6.53 ± 1.94; p < 0.1). No statistical difference regarding the immunological markers between patients with and without Gadolinum enhancing lesions could be obtained. We thus correlated solely the amount of contrast enhancing lesions with the soluble and cell bound adhesion molecules. This revealed an inverse correlation between the MRI lesion load and the ICAM-1 expression on monocytes in CSF. Conclusion: We conclude that c-ICAM-1 on CD3+ cells and CD 14+ monocytes seems to correlate better with the clinical activity of MS patients than MRI. 19 patients were showing acute clinical symptoms at the beginning of the study (76%), 8 of them having MRI activity (8%). 6 patients (24%) were clinically in remission. Their MRI was showing no activity. There was a possible relationship concerning 8 patients with active MRI lesions between planimetric amount of disease burdon and ICAM 1 expression on monocytes in CSF. (abstract shortened by the editor). P307 LONG-TERM PROGNOSIS IN MULTIPLE SCLEROSIS (MS). Kohler A, Merkelbach S, Müller M, Blaes F, Schimrigk K. Department of Neurology, 66421 Homburg/Saar, Germany Prognosis in MS has been reported to depend on various epidemiological and clinical factors. Overall, a progress over time can be expected, but the speed of progression varies within a large range. We studied the long-term courses of 300 patients (67% women, 33% men; mixed ambulatory and hospital series) retrospectively assessing the Expanded Disability Status Scale (EDSS) and the Progression Index (PI). Both parameters were correlated with clinical and epidemiological data. 56% of the patients were categorized as relapsing-remitting MS (mean age at onset 28.5 years, mean duration of disease 10.1 years, PI 0.26); 25% were secondary progressive (age 30.4 ys, duration 17.5 ys, PI 0.29, respectively), 19% were primary progressive (age 36.6 ys, duration 12.8 ys, PI 0.38). Mean EDSS after 10 years was 3.9 (n = 186), after 20 ys 5.6 (n = 63). The speed of progression accelerated continuously with increasing age at onset. Additionally, PI was higher in males than in females. Concerning initial symptoms, best prognosis was calculated with PI 0.25 for opticus neuritis, whereas the highest progression speed was found for pyramidal tract symptoms (PI 0.35). With increasing duration of the disease, PI decelerated. Our data confirm the evidence, that best prognosis can be expected in relapsing-remitting MS, especially with visual disturbances at the onset. Even if PIs are lower in the late time course, MS progresses dynamically throughout live. However, the progression speed of MS seems lower than reported previously. P308 INTERFERON-BETA-1b MODIFIES IL-10/IL-12 BALANCE IN PERIPHERAL BLOOD OF MULTIPLE SCLEROSIS PATIENTS. L. Dinca, M. A. Quesada, M. Lucas, J. M. Gata, O. Sanchez-Soliño, G. Navarro, J. M. Garcia-Moreno, G. Izquierdo. Neurology Department, Virgen Macarena Hospital, Seville, Spain Interferon-beta-1b (IFNb-1b) reduces attacks in relapsing-remitting multiple sclerosis (RRMS) by an unknown mechanism which could be related to the modification of the proinflammatory/antiinflammatory cytokine balance. We study proinflammatory (IL-12) and antiinflammatory (IL-10) cytokine in the serum of treated and non-treated RRMS MS patients. Material and methods: We studied 10 women and 6 men with RRMS which fulfilled the criteria for IFNb-1b treatment (mean years of evolution 5.6 ± 3; mean EDSS score 2.5 range from 1 to 4.5; mean attack relapses 5.6 ± 2.8).

Eight of them were treated with IFNb-1b and 8 were used as controls. Patients were checked up at the beginning of the treatment and later at 3 and 12 months; at the same time serum sample were collected and IL-10 and IL-12 cytokine levels were measured by ELISA. Results: We observed an increase in serum IL-10 in treated patients (18.70 ± 10.6) vs. (6.44 ± 2.5) in the control group, after 12 months of treatment with IFNb-1b. During the 12 months of following up we detected no significant modification in the serum levels of IL-12 neither in the treated nor in the control group. Conclusions: IFNb-1b increased serum IL-10 and modified the balance between proinflammatory (IL-12) and antiinflammatory (IL-10) cytokine. P309 RAO VERSUS VESPAR: A COMPARISON OF TWO NEUROPSYCHOLOGICAL TESTS IN MULTIPLE SCLEROSIS (MS) PATIENTS. S. J. de Pijper, J. B. Boringa, R. H. C. Lazeron, Ph. Scheltens, C. H. Polman. Department of Neurology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands Our aim of this study was to compare the verbal and spatial reasoning test (VESPAR), a processing test, to the RAO test being a neuropsychological test to screen for cognitive impairment in MS patients. This was based on the hypothesis wether VESPAR is a test with additional value when measuring cognitive impairment in MS patients. Material and methods: We analysed data of 93 MS patients in the progressive phase of the disease, who visited our out-patients clinic from February ’96 until October ’97. Each patient was tested neuropsychologically using RAO’s standardised battery (adapted in Dutch) directly followed by the VESPAR test. Outcome was measured by standardised scores of the subtests of RAO (Paced Auditory Serial Addition Test = PASAT and Symbol Digit Modalities Test = SDMT) separately and by cumulative scores of both tests. Disability was expressed as described in the EDSS-score by Kurtzke. Results: RAO-total score and VESPAR-total score were highly correlated (r = 0.52, p < 0.003). A similar correlation was found when comparing VESPAR and PASAT (r = 0.50, p < 0.003) and SDMT (r = 0.54, p = 0.001) both subtest of RAO measuring attention and speed. Conclusion: RAO’s battery, a useful test for screening cognitive impairment in MS patients shows to be highly correlated to VESPAR a reasoning test. Although the VESPAR test which evaluates processing abilities, showed a certain amount of impairment in our MS patients, we are not fully convinced of the additional value of this test set because two subtests of the RAO (PASAT and SDMT) show comparable results. P310 EVALUED: EVALUATION OF THE EDMUS SYSTEM. The EVALUED Study Group: Amato MP, Bartolozzi ML, Dipartimento di Scienze Neurologiche, Firenze – Confavreux Ch, Cortinovis P, Hours M, Hôpital Neurologique, Lyon – Hartung HP, Morrisey S, Flachenerecker P, Neurologische Universitätsklinik, Würzburg – Kappos L, Huber S, LechnerScott J, Neurologische Universitätspoliklinik, Basel – Livrea P, Trojano M, Avolio C, Cattedra di Neuropathologia e Psicopatologia, Bari – Thompson AJ, Hobart J, Grimaud J, Institute of Neurology, London The EDMUS is a concise and descriptive registration system developed for clinical and reseach purposes to document clinical and laboratory data in patients with multiple sclerosis (MS). The reliability of the EDMUS system has been evalued both within each participating centre and across 6 European centres (Bari, Basel, Firenze, London, Lyon, Würzburg). 12 observers have completed the EDMUS system after having independently examined 30 subjects each and analysed 36 written records. Statistical analysis assessed selected key-items: duration, course, severity of the disease, diagnosis level of the patient, date, type and symptoms of events, the Kurztke’s DSS and EDSS, 1 the EDMUS Grading Scale (EGS) (a simplified version of the EDSS). 2 A high degree of reliability (repeatability and reproducibility) of clinical data is achieved and closer examination of the sources of disagreements or inconsistencies among examiners will allow further improvements. The EDMUS system is a promising tool when reliability is essential, e.g. in studies involving serial follow-up examinations and multicentre studies in MS. 1. Kurtzke JF, Neurology 1983, 33 : 1444–1452. 2. Confavreux Ch et al., J Neurol Neurosurg Psychiat 1992, 55 : 671–676. P311 MODULATION OF CYTOKINE-INDUCED HLA-DR, ICAM-1 AND VCAM-1 ON HUMAN CEREBRAL MICROVESSEL ENDOTHELIAL CELLS BY COP-1. Corsini E, Dufour A, Gelati M, Massa G, Milanese C, Nespolo A, Giombini S, Salmaggi A. Istituto Nazionale Neurologico “C. Besta”, Milan – Italy

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Copolymer-1 (Glatiramer acetate) (Copaxone®) has been found to reduce relapse rate and slow progression of disability in multiple sclerosis (MS); the postulated mechanisms of action include the generation of a Th2 response by Copolymer-1-specific cells which cross-react with MBP, and competiton for MBP for binding to HLA-Class II on APC. The aim of the present study was to investigate whether Copolymer 1 can modulate the expression of adhesion molecules on endothelial cells, thus inhibiting in an antigen non-specific manner the infiltration of PBMNCs into the brain. Human umbilical vein endothelial cells (HUVECs) and human cerebral microvessel endothelial cells (HCMECs) were isolated and cultured according to standard techniques. Cells were then stimulated for 72 hours with ?-IFN, TNF-? and LPS with or without either L-Copolymer-1 (25 mg/ ml) or D-Copolymer-1, (the non encephalitogenic ineffective enantiomer provided by TEVA Pharmaceutical Industries). The effects of D-Copolymer-1 were only investigated in HCMECs. The expression of cell surface HLA-DR, ICAM-1 and VCAM-1 was evaluated by direct immunofluorescence with FITC- or PE-conjugated monoclonal antibodies and analysis of fluorescence histograms with cytofluorimeter (FACStar Plus, Becton Dickinson). The results did not show differences in the response to the applied stimuli between HUVECs and HCMECs. ?-IFN was able to significantly increase the expression of HLA-DR, TNF-? enhanced ICAM-1 and VCAM-1 while LPS slightly increased ICAM-1. Copolymer-1 treatment, either alone or in combination with TNF-?, ?-IFN and LPS, had no detectable effect on of HUVECs and HCMECs. No significant differences between D-Copolymer-1 and L-Copolymer-1 treatment were found on HLA-DR, ICAM-1 and VCAM-1 expression on HCMECs. The lack of in vitro effects of Copolymer-1 treatments on adhesion molecules suggest that a non-specific reduction of adhesion molecules on the blood-brainbarrier endothelium is not a major part in the mechanism of action of Copolymer-1. P312 ACUTE MYELOPATHY REVEALING MULTIPLE SCLEROSIS: 20 CLINICAL CASE STUDIES OF EARLY PROGRESSION. G. Borthiry*, C. Lebrun*, S. Chanalet**, M. Chatel*. Services De Neurologie*, De Radiologie**, Nice, France Acute myelitis (AM) revealing multiple sclerosis (MS) can be associated with a poor prognosis. We tried to define the risk of early progression or some pronostic factors of this type of MS. Patients/Methods: In a combined clinical and magnetic resonance imaging follow-up study, we report 20 cases (14 women and 6 men; mean age 34 years) of AM revealing MS over a period of 2 years duration, with a 2 to 4 years follow-up. Studies for each patients were: Brain and spinal MRI performed before corticosteroid treatment, visual evoked potentials, biological and immunological analysis of CSF, serological and immunological screening. Results: Previous neurological symptoms were found in 25% of patients; family history of MS in 10%. The clinical presentation was: sensitive signs:100% (80% dysesthesia; 55% proprioceptive ataxia); motor signs: 40%; Lhermitte’s sign: 25%; Brown-Sequard syndrome: 25%; bladder signs:25%. Spinal cord MRI showed myelitis in cervical (60%) or thoracic areas (40%), with 6% of contrast enhancement. Brain MRI was strongly suggestive of MS in 65% and normal in 25%. Visual potentials were abnormal in 56% and CSF studies showed lymphocytosis in 40% with oligoclonal bands in 47%. At the follow-up term, diagnosis was performed in 85% of patients and relapse occurred within one year. Progression form was for 40% relapsing remitting MS, 30% progressive remitting and 15% progressive. Conclusion: Initial clinical and biological status of AM revealing multiple sclerosis can determine the risk of early progression. In our study, 2 sub-group can be distinguished: a group of severe prognosis: age > 35 yrs; incomplete recovery of neurological signs with methylprednisolone; multiple hypersignals on brain MRI; CSF oligoclonal bands. Other patients seem to have a better prognosis. P313 FACTORS INFLUENCING THE QUALITY OF LIFE (QOL) IN MULTIPLE SCLEROSIS (MS). D. Buljevac1, P. A. van Doorn1, J. B. de Boer2, J. Paschier2, F. G. A. van der Meché1. Dpts. of Neurology1, University Hospital and Medical Psychology2, Erasmus University, Rotterdam, The Netherlands Aim: To analyze the influence of different factors on the QoL in the group of 40 patients with moderate relapsing-remitting MS (23 F/17 M, mean age 37 yrs., range 19–55 yrs; mean EDSS 2.65, range 0.0–6.5) Method: In a prospective study, three self-report QoL questionnaires were used: the RAND Short Form-36 (SF-36), the Activities of Daily Living and MS-Related Symptoms (ADL-MS/RS-MS) questionnaire and the Multifactorial

Fatigue Index (MFI). At week 0, 6, 12, 24, and 36 the questionnaires were filled in and the neurological examination was performed. The multivariate model included age, gender, disease duration, marital, educational and employment status and neurological impairment. Results: A low EDSS score, having a job and living with somebody were the most significant elements for a good QoL at this stage of MS. It positively influenced physical and social functioning, mental health, general health perception, ADL total score, intimacy, recreational activities etc. Age, disease duration and education appear to be less influential. Among the EDSS functional scores (FS), the intensity of sensory symptoms appeared to be the most important for the QoL. Cerebral/cognitive functioning significantly contributed to the reduction in activity, motivation and mental fatigue. Conclusion: The QoL of patients with moderate MS benefits most from a low impairment level, absence of sensory symptoms and full social functioning (work, relationship). P314 ETOMS STUDY: BASELINE CHARACTERISTICS OF THE INCLUDED POPULATION. G. Comi, M. Filippi, F. Barkhof, L. Durelli, G. Edan, O. Fernandez, H. P. Hartung, P. Seeldrayers, P. Soelberg-Sorensen, F. Martinelli, M. Rovaris, O. Hommes and the ETOMS Study Group We present the clinical and paraclinical findings of patients included in the ETOMS clinical trial, which was undertaken to assess the effects of treatment with Interferon beta-1 a (Rebif, Serono) in Multiple Sclerosis (MS) patients at the onset of the disease. Patients presenting with a first episode suggestive of MS and a typically abnormal brain magnetic resonance imaging (MRI) scan were recruited for the study in 54 centres from 14 European countries. The average time between the onset of symptoms and the screening procedure was 46 days (range: 4–98 days). A neurological examination, dual-echo and post-contrast T1-weighted brain MRI were obtained from all the patients. Cerebrospinal fluid examination was performed in a subgroup of patients. Three hundred and eleven patients entered the study; mean age was 28.7 years (range 18–46 years). The commonest symptoms at presentation were (in decreasing frequency): sensory, motor, visual and oculomotor. Clinical findings suggestive of multifocal CNS involvement were observed in 14% of the patients. CSF examination was positive in 180/220 cases (82%). The median numbers (range) of total brain T2-weighted lesions, infratentorial T2-weighted lesions and enhancing lesions were 25 (3–159), 1 (0–13) and 1 (0–88), respectively. One or more enhancing lesions were present in 57.6% and two or more enhancing lesions in 37.7% of patients, respectively. A multifocal clinical presentation was associated with a higher MRI disease burden. Spinal cord MRI was positive in 84% of patients with isolated spinal cord clinical presentation. These data allow to better define the clinical and paraclinical findings for a large sample of patients in the earliest phases of MS. P315 LACK OF SPECIFICITY OF ANTIBODIES AGAINST MYELINOLIGODENDROCYTE GLYCOPROTEIN (MOG) IN MULTIPLE SCLEROSIS (MS) PATIENTS. Amon Karni, Ronit Baldmer-Kleiner, Avraham Ben-Nun and Oded Abramsky. Department of Neurology, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel Plasma cells, B Iymphocytes and IgG participate in the inflammatory reaction of MS, and in experimental animals demyelination can be mediated by anti myelin antibodies (Abs), particularly by anti-MOG Abs. We measured the anti-MOG and anti-myelin basic protein (MBP) Abs by, avidinbiotin enzyme linked immunosorbent assay (AB-ELISA) for CSF, and by standard ELISA for plasma. CSF was obtained from 31 MS patients (pts), 31 pts with other central nervous system disease (CND) and 28 with chronic headache (CH). Plasma was obtained from 33 MS pts. 28 CND pts and 31 healthy donors (HD). Positive CSF and plasma Abs were considered > mean + 2 S.D. of the CH or HD, respectively. CSF-IgG levels was measured by immunodiffusion plates (RETIRING). MS and CND patients had significantly higher anti-MOG and anti-MBP CSF levels than CH patients. The rate of positive anti-MOG was significantly higher in the first two groups. There were no significant differences in these Abs between MS and CND patients. There were no significant differences in the CSF-IgG levels between MS and CND patients with positive levels and those with negative levels. respectively. MS patients had significantly higher antiMOG and anti-MBP plasma levels than CND patients or HD, but there were no significant differences in the rate of positive levels. There were no correlation between these Abs and the severity or the disease course. A weak correlation was found between CSF-anti-MOG and long duration of MS.

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P317 INTER-SCANNER VARIATION IN BRAIN MRI LESION LOAD MEASUREMENTS IN MS USING CSE, RARE AND FAST-FLAIR. M. Filippi, M. A. Rocca, C. Gasperini, M. P. Sormani, S. Batianello, C. Pozzilli, G. Comi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan A previous study (Filippi et al., Neurology 1997; 49 : 371–377) demonstrated that brain magnetic resonance imaging (MRI) lesion volume measurements in multiple sclerosis (MS) using conventional spin-echo sequences (CSE) are influenced significantly by the use of different MR scanners. Recently, two other pulse sequences have been proposed to be used for lesion load measurements in MS, i.e., rapid acquisition relaxation enhanced (RARE) and fast fluid attenuated inversion recovery (fastFLAIR). In this study, we evaluated and compared the effect of inter-scanner variation on lesion load measurements in MS when using CSE, RARE and fast-FLAIR. We obtained MRI scans from 9 patients with relapsingremitting MS on two sessions separated by 24 hours. In both the sessions, we obtained dual-echo CSE, dual-echo RARE and fast-FLAIR, using a Siemens 1.5 T machine in one occasion and a Phylips 1.5 T machine in the other. Lesion load measurements were performed three times (each session was separated by 1 month) in a random order by a single observer using a semi-automated segmentation technique. Intra-observer coefficient of variation (COV) for the different sequences and scanners ranged from 3.0% to 4.2% (no statistically significant difference). As expected, the inter-scanner COV was higher than the intra-observer COV for all the sequences ( p < 0.0001): it was higher for fast-FLAIR (18.5%) than for RARE (9.5%) and for CSE (7.4%). The inter-scanner COV obtained for the machine to which the operator was used was lower than that obtained on the machine of the other centre (13.2% vs 28.7%). Our data confirm that the use of multiple scanners influences significantly lesion load measurement from MRI scans of patients with MS and indicate that this influence is higher for newer sequences. It also indicates that, in clinical trials, operators should be trained using images from a range of scanners involved in the trial and, if newer sequences are planned to be used, careful standardization is needed. P318 LONG-TERM CHANGES OF MAGNETIZATION TRANSFER RATIOS OF LESIONS FROM PATIENTS WITH RELAPSING-REMITTING AND SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS. M. A. Rocca, B. Colombo, G. Comi, M. Filippi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan We measured the magnetization transfer ratio (MTR) of newly enhancing lesions when they appeared and one year later from patients with multiple sclerosis (MS) to evaluate their changes and to correlate them with the presence of abnormalities on T1 and T2 weighted scans and to disease course. Seven patients with relapsing-remitting (RR) and 7 with secondary progressive (SP) MS were studied. Brain MRI were obtained at study entry, 28 days and 12 months later. In each session, dual echo conventional spin-echo (CSE), 2D gradient echo with and without a saturation pulse and pre- and post-contrast T1-weighted CSE were obtained. A single observer outlined the lesions identified at the time of their first appearance on a computer screen. These lesions were then mapped on to the co-registered MT images and their MTR measured. The MTR values of the same lesions on the corresponding co-registered follow-up MT scans were also measured. Forty-six (40 in the RRMS and six in the SPMS group) newly enhancing lesions were found. The mean MTR of these lesions was 45.2 % at entry and 43.0 % at follow up ( p = 0.01). The mean lesion MTR at entry was 45.9 % in RR MS patients and 40.4 % in SP MS patients ( p = 0.01). The mean lesion MTR at exit was 44.1 % in RR MS patients and 35.2 % in SP MS patients ( p = 0.00005). At entry, the MTR of newly enhancing lesions with no corresponding T2 and T1 abnormalities was significantly higer than that of newly enhancing lesions with corresponding T2 and T1 abnormalities ( p = 0.0005 and p = 0.0002, respectively). Our results suggest that a) the MTR of newly-formed MS lesions may be highly variable and strictly related to the presence of T2 and T1 abnormalities and b) it reduces as the time goes by, particularly in patients with a more severe disease course. P319 MAGNETIZATION TRANFER RATIOS OF MULTIPLE SCLEROSIS LESIONS WITH VARIABLE DURATIONS OF ENHANCEMENT. M. A. Rocca, M. Rovaris, V. Martinellli, B. Colombo, M. Filippi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan, Italy

We investigated, using magnetization transfer (MT) imaging, the characteristics of multiple sclerosis (MS) lesions enhancing for different periods. Ten patients with clinically definite MS and a relapsing remitting course were studied. MRI examinations were performed, using a scanner operating at 1.5 T, on all patients every 28 (+ 5) days on four separate occasions. On each scanning occasion, dual echo conventional spin echo (CSE), 2D gradient echo images with and without a saturation pulse, pre- and postcontrast T1-weighted CSE were obtained. We also obtained MTI scans from five sex- and age-matched healthy volunteers at the begininning and at the end of the study. The MT ratio (MTR) values obtained from grey matter, white matter and cerebro-spinal fluid were stable over the study period (scan-rescan variation < 3%). For each patient, the four monthly scans were evaluated by a single observer to identify the new enhancing lesions, which were then classified as enhancing on a single scan or on at least two consecutive scans. We then measured the MTR of new enhancing lesions on co-registered quantitative MTR images. A total of 40 postcontrast scans were obtained and analyzed. Fifty-four new enhancing lesions were seen with a mean MTR value of 33.6% (SD = 7.8%). The mean MTR values were 35.3% (SD = 7.0%) for the 39 lesions enhancing on a single scan and 29.3% (SD = 8.6%) for the 15 lesions enhancing on at least two consecutive scans ( p = 0.01). This study suggests that the amount of tissue disorganization in new MS lesions at the time of their appearance is variable and that it is greater in those lesions which will then enhance for longer periods of time. This confirms that the pathological substrate of enhancing lesions in MS is highly heterogeneous and may have implications for the understanding of how MS evolves.

P320 ASSESSMENT OF DISEASE SEVERITY IN MULTIPLE SCLEROSIS PATIENTS WITH MAGNETIZATION TRANSFER HISTOGRAMS. M. Rovaris, G. Iannucci, L. Minicucci, V. Martinelli, M. A. Rocca, G. Comi, M. Filippi. MS Biosignal Analysis Center, IRCCS H. San Raffaele, University of Milan, Milan, Italy Brain magnetization transfer ratio (MTR) histograms derived from MTcalculated magnetic resonance imaging (MRI) provide information about the amount of micro- and macro-microscopic tissue damage in patients with multiple sclerosis (MS). The aim of this study was to compare MRI measures obtained with this technique in MS patients with different clinical courses. One-hundred and one patients affected by clinically isolated syndrome (CIS) at presentation (i.e., laboratory supported MS, n = 21), relapsing-remitting (RR) MS (n = 44), secondary progressive (SP) MS (n = 28) and primary progressive (PP) MS (n = 8) and 20 age- and sex- matched healthy controls were studied. 2D gradient echo axial, 5-mm thick brain MRI scans, with and without a MT-saturation pulse, were obtained from all the subjects. Histograms of pixel intensity were created from the MTcalculated images, after a preliminary manual segmentation to exclude the extracranial tissues. For each histogram, the height and the location of the histogram peak with respect to the x axis and the mean MTR value of the brain volume were obtained. Mean brain MTR and histogram peak height values were significantly higher in controls (45.8%, 63.3%) than in MS patients (43.4%, 59.2%). Mean MTR and peak height were significantly higher in controls and in CIS (45.6%, 64.5%) than in RRMS (43.0%, 58.2%), SPMS (42.1%, 58.7%) and PPMS (43.9%, 52.4%). No significant differences were found between controls and CIS patients, between RRMS and SPMS patients and between SPMS and PPMS patients. Our findings confirm that the amount and severity of both macroscopic and microscopic brain damage can be assessed in MS patients by means of MTR histogram analysis and highlight that this technique may provide MRI measures related to the clinical evolution of the disease.

P321 VISUAL ATTENTION IMPAIRMENT IN MULTIPLE SCLEROSIS. M. Albereini*, M. F. Posso, V. Maitnell§, S. Blanchi$, C. Mariam*, G. Coin§. *Dept of Rehabilitative Neurology, IRCCS-Santa Mania Nascente and §Dept. of Neurology and $Ophthalmology IRCCS, H. San Raffaele, Milano, Italy We compared the performance of 15 patients with Multiple Sclerosis (MS) and 14 matched healthy control subjects on a series of computerized tests of visual attention. Patients selected had a history of optic neuritis, but no evidence of persistent relevant visual acuity defect or upper limb motor impairment. They were also submitted to Pattern Visual Evoked Potentials (PVEP), in order to correlate neurophysiological results and cognitive performance. The SM patients showed a significant impairment in tests of selective visual attention requiring to detect the presence/absence of a visual

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stimulus among an increasing number of distractors, both for simple ( p < 0.002) and complex patterns ( p < 0.001), and a significant slowing and altered profile of performance in a visual attention orienting task (p < 0.001). Their performance was instead unimpaired in comparison with the control group in neuropsychological tests of memory, abstract reasoning and visual perception. Our data extend to visual attention the evidence of attentional impairment in MS. Patients with and without a significant increase of the P100-VEP component latency showed a different degree of impairment in the attentional tasks, suggesting that persistence of conduction defects along the visual pathways can impair the parallel processing of elemental visual features.

P322 STUDY OF THE HUMAN T-CELL RESPONSE TO THE NEURONAL PROTEIN SYNAPSIN AND MYELIN BASIC PROTEIN (MBP) IN PATIENTS WITH MULTIPLE SCLEROSIS (MS). T. Polak, G. Schlaf, M. Mäder, S. Poser, F. Weber. Department of Neurology, University of Göttingen, Germany There is much evidence that MS is an autoimmune disease in which Tcells reactive against proteins expressed in the brain play a pivotal role. Although MS is considered primarily as a demyelinating disease, neuronal damage is frequently observed and correlates well with the neurologic deficit. Therefore we investigated the T-cell reactivity against synapsin – a neuronal protein highly conserved between species. Peripheral blood mononuclear cells were isolated from six MS patients (two relapsingremitting, four primary progressive), one patient with acute demyelinating encephalomyelitis (ADEM) and three healthy donors. Relative frequencies of synapsin, MBP and tetanus toxoid specific T-cells were compared in individual MS patients using the “split-well” primary limiting dilution technique. The frequency of synapsin and MBP specific short-term T-cell lines occurred in a range of 0–30 %, but differed in individual patients. The number of T-cell lines observed was high in two patients with malignant, primary progressive course, wherease the response of the other patients was in the range of the patient with ADEM and of the controls. In contrast, the frequency of T-cell lines specific for MBP was highest in a patient with relapsing-remitting MS. Proliferation indices of the T-cell response against synapsin and MBP were similar in all MS patients. This study demonstrates that short-term T-cell lines specific for a neuronal protein can be recovered from the immune repertoire of MS patients at a similar frequency as T-cell lines specific for a myelin autoantigen. Study supported by the DFG (We 1439/4-1).

P323 A NEW FINDING IN LARGE ACTIVE MULTIPLE SCLEROSIS LESIONS ON DIFFUSION WEIGHTED MRI. A. Gass1, J. Gaa2, W. Schreiber3, A. Schwartz1, M. G. Hennerici1. Dept. of Neurology1 and Radiology2, Klinikum Mannheim, Univ. Heidelberg, German Cancer Research Center 3, FR Germany Acute multiple sclerosis (MS) lesions frequently show a particular composition: A nodular contrast enhancing center (CEC) surrounded by an area of inflammatory oedema. Compared to the surrounding area the CEC of the lesion shows higher T2 signal and lower T1 signal and a lower magnetisation transfer ratio. Diffusion weighted (DW) magnetic resonance imaging (MRI) allows visualisation of water proton mobility. In acute MS lesions the apparent diffusion coefficient (ADC) is increased compared to normal appearing white matter indicating a higher mobility of water protons. Due to the lower image resolution of echo planar (EP) DW MRI the different elements (oedematous zone, cellular infiltration, demyelination) of acute MS plaques can only be visualised in large lesions. We report a new DW imaging finding in 6 large lesions (diameter 6–9 mm) in 4 patients relapsing MS. The MRI protocol consisted of conventional (T1-, PD-, T2-,T1-weighted + contrast) and EP DW MRI (EP-SE 4000/144/ 5 mm, b = 0/160/320/640/1000 s/mm2, diffusion gradients in 3 orthogonal directions, image resolution 5x1.8x1.8 mm). All lesions showed the above described composition with a nodular CEC. On the ADC map both, the core and the periphery of the lesion showed increased diffusion which was less pronounced in the center (ADC/3 = 0.93–1.02 × 10 –5 cm2/sec) than in the periphery (ADC/3 = 1.23–1.29 × 10 –5 cm2/sec) of the lesion. This is surprising as the higher degree of tissue destruction in the CEC should lead to a more pronounced ADC elevation (due to the lack of cellular barriers) than in the periphery of the lesion. Factors associated with contrast enhancement and demyelination (e.g. myelin breakdown products, cellular infiltration) may limit diffusion in the center of acute lesions.

P324 ECONOMIC IMPACT OF MULTIPLE SCLEROSIS (MS) ON THE PATIENT AND HIS FAMILY FROM A FRENCH STUDY ON 157 PATIENTS. J. P. Marissal, T. Lebrun, P. Hautecoeur, P. Gallois, Y. Castanet From an original methodology allowing a 2-year follow-up (1 year retrospective, 1 year prospective), we assess the cost of MS for the patient and his family, concerning professional outcome, income, healthcare use and consequences on daily living, housing and vehicle, from a sample of 157 French patients with MS defined according to Poser criteria, included from June 1995 to December 1996. MS consequences are analyzed according to MS form and degree of severity. Baseline statistics are: mean age, 42.9; onset of disease, 12.2 years; women, 66%; relapsing remitting, 52%; secondary progressive, 37%; primary progressive, 11%; mean EDSS score, 4.8 (± 2.2). Mean healthcare costs during the 12-month period prior to inclusion amounts to 6,900 US $: 76% hospital costs, 24% ambulatory costs. Mean 3-month prospective healthcare costs (N = 75) are 1,272 US $, 11.3% ambulatory medicine, 21.3% physiotherapy and nursing, and 62.3% hospital care. EDSS score and MS evolutive form are good predictors of MS impact on the patient and his family. Patients’ classification according to 3 medical criteria (EDSS, evolutive form and Kurtzke’s score per item) defines 4 differentiated groups as regards disability. Median 12-month retrospective healthcare costs vary between groups from 2,852 US $ to 7,617 US $. Estimation of intergroup differences concerning prospective healthcare costs will be provided. P325 MS-CANE: COMPUTER-AIDED NEUROLOGICAL EVALUATION OF MULTIPLE SCLEROSIS PATIENTS, BASED ON KURTZKE’S EXPANDED DISABILITY STATUS SCALE. Yael C. Cohen, Sharon Hassin-Baer, Raya Barishev, Yochanan Goldhammer and Benjamin Moses. Gertner Institute for Health Policy and department of Neurology, Sheba Medical Center, Tel-Hashomer, Israel Objectives: To introduce a computerized instrument, MS-CANE, for clinical evaluation and follow up of multiple sclerosis (MS) patients, and to determine it’s reliability compared to conventional EDSS assessment. Background: We developed a computerized instrument composed of a friendly user interface, which leads the examiner through a structured neurological interview and examination. MS-CANE was aimed to increase the reliability of clinical evaluations of MS patients, based on the following principles: a. Consistent collection of detailed data. b. Breaking compound notions into their basic components c. Using precise definitions and resolving ambiguities. d. Automated calculation of accepted scoring scales such as Kurtzke’s functional system scores and expanded disability status scale (EDSS). Methods: Content validity of MS-CANE was achieved by presenting it to a group of senior neurologists who reached a consensus on the definition of data items and scoring algorithm. Feasibility and acceptability of the tool was examined in a pilot study including 30 patients. To determine MS-CANE’s effect on reliability of EDSS assessment, 56 MS patients underwent paired conventional and MS-CANE evaluations. The interobserver agreement in both methods was compared using kappa statistic. Results: The senior neurologists judged MS-CANE to be compatible with Kurtzke’s EDSS. The tool was acceptable both to patients and examiners. The Kappa statistic was found to be 0.45 (i.e. poor agreement) for the conventional EDSS assessment and 0.71 (i.e. substantial agreement) for MS-CANE. Conclusions: MS-CANE was found to be a user-friendly, valid and reliable tool for clinical assessment of MS patients. P326 A LONGITUDINAL STUDY OF ICAM-1 AND TNF ALFA IN RELAPSING REMITTING MULTIPLE SCLEROSIS (RRMS): EFFECT OF RIFN BETA-1b THERAPY. Galgani S*, Rosengart L°, Gasperini C*, Madella C°, Fele MR*, Haggiag S*, Piazza G*. *Neurological Dept., S. Camillo Hospital, Rome; °Immunocitological Laboratory, S. Camillo Hospital, Rome, Italy The aim of this study was to investigate the effect of rIFNBeta-1b on serum levels of ICAM-1 and TNF alfa in RRMS patients, in a longitudinal study one year before and one year during rIFNBeta -1b therapy. We evaluated 15 patients RRMS by measuring serum levels of ICAM-1 and TNF alfa monthly for 12 months, before and during rIFNBeta-1b therapy. Moreover, a serum levels of ICAM 1 and TNF alfa were detected in case a clinical relapse. All serum samples of ICAM-1 and TNF alfa were measured by ELISA. Data were evaluated by Anova, with the EPI Info 6 (Database and Statistics Program for Public Health, WHO). A significant reduction in the mean levels of ICAM-1 was observed during rIFNBeta-1b

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therapy (206.3 ± 60.5 ng/ml) compared to mean levels before rIFNBeta-1b therapy (258.3 ± 67.2 ng/ml) ( p = 0.04). No statistical significance was observed comparing the TNF alfa levels before (20.7 ± 5.1 pg/ml) and during (18.3 ± 4.8 pg/ml) rIFNBeta-1b therapy (p = 0.2). 22.4% of patients showed a value of ICAM-1 higher than normal range, 35% before, and 9.5% during therapy. TNF alfa values higher than normal range was observed in 31.4% of patients, 27.6% before and 35.2% during rIFNBeta1b therapy. The mean serum values of ICAM-1 and TNF alfa during clinical relapses were not statistically significant, compared to those obtained in absence of clinical relapses. In conclusion our data suggest that rIFNBeta-1b therapy may influence the ICAM-1 expression. P327 ANTINUCLEAR ANTIBODIES AND MRI ACTIVITY IN MULTIPLE SCLEROSIS. Pozzilli C, Ciccarelli O, Giugni E, Paolillo A, Gherardi M, Mainero C, Gasperini C, Bastianello S. Dept. Neurological Sciences, University of Rome “La Sapienza”, Italy Multiple Sclerosis (MS) is associated with high frequency of antinuclear antibodies (ANA), which correlate with disease activity. Gadolinium enhanced Magnetic Resonance Imaging (MRI) is a powerful procedure for monitoring disease activity. Purpose: To determine whether MRI activity was related with ANA positivity. Methods: Fourthy-two Relapsing-Remitting MS (RRMS) patients treatment-free were monthly examined by enhanced MRI for a 6-month period. The volume of enhancing lesions was estimated by a semiautomated local thresholding technique on T1 weighted images after injection of gadolinium-DTPA. Sera collected at months 3 and 6 were analyzed for ANA by standard indirect immunofluorescence techique, using a 1 : 40 cut-off. Results: Nine (21.4%) patients showed ANA positivity at two time points, 11 (26.2%) patients presented only one positive sample and 22 (52.4%) patients were ANA negatives. The mean volume (SE) of gadolinium enhancing lesions in these groups was 547 mm3 (190), 273 mm3 (103), and 153 mm3 (59), respectively. The difference in mean volume was statistically significant ( p = .02 by KruskalWallis). Conclusions: These data suggest that the peripheral immune compartment is activated in MS. In combination with MRI and other markers of ongoing peripheral inflammation ANA may become useful in monitoring disease course. P328 USE OF DATA FUSION TECHNIQUES FOR THE AUTOMATED SEGMENTATION OF MULTIPLE SCLEROSIS LESIONS IN MAGNETIC RESONANCE IMAGES. Dromigny-Badin A1, Zhu YM1, Grimaud J 2, Pachai C1, Boudraa A1, Hermier M1, Gimenez G1, Froment JC1, Confavreux C 2. 1CREATIS, CNRS UMR 5515, INSAVilleurbanne, France; 2 Service de Neurologie, Hôpital d’Antiquaille, Lyon, France Image segmentation plays a key role in the automated quantification of multiple sclerosis (MS) lesions in magnetic resonance imaging (MRI). This is also a problem not yet completely resolved. The purpose of the present communication is to show how the segmentation of MS lesions can be achieved using bayesian inference based data fusion approaches. The idea of segmenting MS lesions through bayesian fusion stems from the remark that the combined use of complementary (and redundant) information from T2 or PD (Proton Density) sequences makes it possible to extract more pertinent and desired information. The algorithms classify the couples of pixels from (T2, PD) images (TR = 2500 ms, TEPD = 15 ms, TET2 = 90 ms) into different classes using the bayesian theory or DempsterShafer (DS) evidence theory. The segmentation is achieved at pixel levels. The number of classes in each fused image, which could not be fixed once for all couples of (T2, PD) images, is adapted to the current image couple. The class parameters and the number of classes are updated after each iteration until convergence. Both methods successfully detected and segmented almost all the lesions with respect to the manually obtained results. The DS evidence theory based method, however, gave finer results than the simple bayesian theory based method, and provided a higher confidence level of segmentation (> 90%). The methods are being evaluated for a larger image database. This work was granted by ARSEP and LFSEP. P329 ELECTROPHYSIOLOGICAL STUDY OF FRONTAL LOBE FUNCTION IN MULTIPLE SCLEROSIS. L. Leocanl1, V. Martinelli 2, G. Santuccio2, F. Possa 2, E. Terlizzi 1, G. Comi1. Clinical Neurophysiology1 and Neurology2, H. S. Raffaele, University of Milan Psychometric tests revealed frontal lobe dysfunction as one of the most frequent aspects of cognitive dysfunction ’m multiple Sclerosis (MS). In

order to study the pathophysiological correlates of frontal lobe dysfunction, we evaluated the modifications of bioelectrical activity during the Stroop color-word matching test, which is thought to explore executive functions, and during performance of self-paced movements. We compared 11 MS patients, who failed in three or more tests evaluating frontal functions, among an extensive neuropsychological battery. These patients were compared to 10 MS patients who did not fall at any tests. All patients were right-handed. EEG was recorded while patients performed self-paced extensions of the right thumb and, separately, during mental discrimination between congruent and incongruent color-word visual stimuli. Manual reaction time to the Stroop test was also measured. Reaction time to the Stroop test was significantly slower in patients with frontal cognitive impairment compared to the unaffected patients. The main components of the event-related potentials to the Stroop stimuli were modified both in latency and amplitude in patients with frontal cognitive impairment. Moreover, in this group, the movement-related EEG potential preceding and during movement execution was reduced over the fronto-central regions contralateral to the movement. These data suggest that frontal cognitive involvement in MS corresponds to a reduced bioelectrical activity during performance of tasks involving executive functions. P330 HYPOTHALAMO-PITUITARY-ADRENAL AXIS REGULATION AND CYTOKINE LEVELS IN MULTIPLE SCLEROSIS. F. Then Bergh, T. Kümpfel, A. Grasser, C. Trenkwalder and F. Holsboer. Max-Planck-Institut fuer Psychiatrie, Neurologie, München, Germany We have tested the reactivity of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS) patients and previously reported heterogeneity among patients, related to clinical characteristics. To directly investigate the relation of endocrine and immune parameters, we measured serum (S-) and cerebrospinal-fluid (CSF-) cytokine levels by high-sensitive ELISA and performed the combined dexamethasone/corticotropinreleasing-hormone (Dex-CRH-)test in 24 MS patients (12 male, age 38.3 ± 9.6 years, disease duration 7.41 ± 7.9 years, acute relapse in 15, chronic progression in 9, EDSS 3.6 ± 1.4, mean ± SD). With regard to the DexCRH-test result, patients were divided into normal (n = 7), hyper- (n = 9) or hyporesponders (n = 8) according to the maximum rise in cortisol, compared to 34 controls. Various cytokine levels differed among groups, significant ( p < 0.05) for the following comparisons: in abnormal vs. normal responders, lower S-IL-1β (normal 0.69 ± 0.17, hyper 0.20 ± 0.08, hypo 0.15 ± 0.04 pg/ml) and higher S-TNF-RI (normal 1.22 ± 0.08, hyper 1.45 ± 0.09, hypo 1.54 ± 0.11 ng/ml). In hypo- vs. hyperresponders, S-IL-6 was higher (4.18 ± 0.87 vs. 2.98 ± 0.65 pg/ml), as well as CSF-IL-1β (1.21 ± 0.51 vs. 0.06 ± 0.05 pg/ml). (All cytokine data: mean ± SEM). HPA axis dysregulation is thus associated with differences in immune function, and may contribute to the pathogenesis of autoimmunity. There was no clear evidence for HPA system activation by inflammatory cytokines. P331 LINKAGE ANALYSIS IN 2 FAMILIES WITH HSN I – EVIDENCE OF GENETIC HETEROGENEITY. E. M. Wicklein1, U. Orth2, A. Gal2, K. Kunze1. 1Dept. of Neurology and 2Dept. of Human Genetics, University Hospital Eppendorf, Hamburg, Germany HSN I (Hereditary sensory and autonomic neuropathy type I), also known as HSAN I, hereditary sensory radicular neuropathy,maladie de Thevenard or l`acropathie ulceromutilitante familiale, is inherited as an autosomal dominant trait. Onset is usually within the second or third decade. The syndrome is characterized by progressive sensory loss of the distal extremities, predominantly in the lower limbs. Perception of all sensory modalities may be affected, but pain and temperature sensation is usually more markedly impaired than perception of light touch. Painless ulcerations of the extremities develop, later leading to mutilations. Autonomic dysfunction is minor and in most cases confined to sweating abnormalities. Histopathological studies suggest a distal axonal neuropathy. Recently, the disease locus has been mapped by linkage studies between D9S318 an d D9S176 on chromosome 9q22.1–q22.3. We examined two unrelated German families with patients in three and four subsequent generations. Clinical and electrophysiological features of affected individuals were compatible with HSN I. All available family members were genotyped for a total of 4 DNA polymorphisms, D9S922, D9S257, D9S938/D9S310, and D9S930 which define a region, that harbours the HSN1 locus. During analysis, in both families, negative lod scores were obtained at all recombination fractions (e.g. z = between –1.26 and –2.89 at theta = 0.01), suggesting that a disease locus is unlikely in this chromosomal region. Clinical signs consistent with HSN I as described above have now been reported in patients

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with a mutation on chromosome 3q13–q22, a genotype known to cause Charcot Marie Tooth syndrome type II (CMT2B). Therefore, in our families analysis of this chromosomal region is currently undertaken. Results will be presented. Our data suggest that there is a non-allelic genetic heterogeneity in clinical HSN I. P332 CHANGES OF IL-4, IL-10, TGF-α, TGF-β IN CEREBROSPINAL FLUID (CSF) AND PLASMA AFTER INTRAVENOUS IMMUNOGLOBULIN (IVIg) IN MULTIPLE SCLEROSIS (MS) PATIENTS. D. Djordjevic, A. Juvicic, M. Jovanovic*, E. Dincic, R. Raicevic. Department of Neurology, Department of Medical Research*, Military Medical Academy, Belgrade, Yugoslavia Considering its immunomodulatory effect, IVIG therapy has proven beneficial in MS treatment. Modulation of cytokine production is proposed as possible role of action. The aim of this study was to evaluate cytokine profile in MS patients before and after IVIg therapy. In 9 patients (5 relapsing remitting, 1 primary progressive, 1 secondary progressive, 2 newly diagnosed) IVIg was administered during 5 days (0.4 g/kg), and after 3, 6, 9 months in a single dose. Clinical assessment (EDSS), magnet resonance imaging (MRI) and liquor analysis were performed during each visit. Following cytokines were measured in CSF and plasma samples: TNF-α, IL-4, IL-10, TGF-β, using ELISA method. Samples were obtained before and 3–7 days after IVIg therapy. We found decrease of TNF-α and increase of IL-4, IL-10 and TGF-β levels in CSF and decrease of all plasma cytokines’ levels after IVIg treatment. Cytokines’ changes correlated with clinical improvement, blood-brain barrier healing and increased intrathecal IgG synthesis. In conclusion, decrease of inflammatory TNF-α cytokine and increase of immunomodulatory cytokines IL-4, IL10 and TGF-β after IVIg therapy, confirm the role of cytokines in MS pathogenesis as well as one of possible modes of IVIg action.

Peripheral Neuropathy P333 THE MISDIAGNOSES OF UPPER BRACHIAL PLEXUS LESION. A. Belova, S. Shafit. N. Novgorod, Russia We analysed misdiagnoses in patients referred to the neurorehabilitation unit with diagnosis of upper brachial plexus lesion between 1995 and 1997. 27 consecutive patients (disease duration from 7 to 28 days) were evaluated. All patients had a history of sudden onset of upper arm weakness consequent to acute closed trauma of shoulder region. Routine X-ray examination didn’t reveal bone fractures or dislocations. Upper brachial plexus lesion was decided on the basis of clinical and electrophysiological data. Clinical findings included limited range of active motions and muscular atrophy in upper limb-girdle and proximal part of the arm; in 25 cases sensory disturbances and/or pain were discovered. Electrophysiological findings localized to the appropriate nerves and muscles (partial involvement of nerves supplied by C5–C7 roots with some decrease of nerve conduction velocity and/or EMG signs of degeneration of paretic muscles) were revealed in 20 cases; the absence of electrophysiological abnormalities in other 7 patients was suggested due to short period after trauma which was insufficient for development of peripheral nerve degeneration and denervation EMG signs. At admission in the neurorehabilitation unit isolated upper brachial plexus lesion was present in 19 (70.4%) cases, upper brachial plexus lesion in combination with rotator cuff rupture – in 4 (14.8%) cases, only rotator cuff rupture – in 3 (11.1%) cases, posterior shoulder dislocation – in 1 case (3.7%). Conclusion: Misdiagnoses of upper brachial plexopathy are mainly associated with rotator cuff rupture which can be combined with upper brachial plexus lesion but demands a different treatment. P334 PERIPHERAL NEUROPATHY AND MYOPATHY IN IDIOPATHIC HYPEREOSINOPHILIC SYNDROME. N. Tașçilar1, N. Yücemen1, A. Yig˘ it1, H. U˘gur2, E. Tan3. Departments of Neurology1 and Neurosurgery2, Faculty of Medicine Ankara University and Department of Neurology3 Hacettepe University Hospital, Ankara, Turkey Idiopathic hypereosinophilic syndrome is a rare disorder, characterized by overproduction of eosinophils and eosinophilic infiltration of multiple organs. The syndrome is most commonly associated with cardiac, hemato-

logical, pulmonary, cutaneous and neurological involvement. Muscles, ears, eyes and lymph nodes are less commonly involved. Neurological involvement ranges from the central to the peripheral nervous system, and can be associated with eosinophilic myositis. We report a 18-year-old man with sensorimotor polyneuropathy, peripheral eosinophilia, and laboratory evidence of bone marrow, heart, and muscle involvement. Because of long lasting (more than 6 months) peripheral eosinophilia (4900/mm3) without any identified cause, a diagnosis of idiopathic hypereosinophilic syndrome was made. Clinical and electrophysiological findings were consistent with axonal neuropathy. Pathological examination of sural nerve suggested axonal damage, endoneurial and perineurial eosinophilic infiltration. Clinical neurological signs and eosinophilia improved with oral methylprednisolone, 1.5 mg/kg daily. Muscle involvement was detected by magnetic resonance imaging and confirmed by muscle biopsy, which showed eosinophilic infiltration. The case draws attention to a treatable syndrome with polyneuropathy and myositis, and emphasizes the value of magnetic resonance imaging.

P335 POSITIVE RESULTS OF PHASE II RECOMBINANT HUMAN NERVE GROWTH FACTOR (rhNGF) TRIAL TRIGGERS TWO PHASE III TRIALS TO CONFIRM EFFICACY AND SAFETY IN DIABETIC NEUROPATHY. C. Rask1, C. Sanders1 and J. Häussler 2. 1South San Francisco, USA and 2Basel, Switzerland A 6-month Phase II study demonstrated the safety and preliminary efficacy of rhNGF in 250 patients with diabetic neuropathy (DN). Consistent with its postulated mode of action, rhNGF improved small sensory fiber function measures of the Neuropathy Impairment Score for the Lower Limb (NIS[LL]; p = 0.170), a standardized score of neurological examination abnormalities in the lower limbs which provides a sensitive, reliable clinical measure of DN severity. Similarly, improvement in the ability to detect cooling (CDT; p = 0.049) and heat as pain (HP: 5.0; p = 0.150) was also reported. The combined score for NIS[LL]+CDT+HP: 5.0 was superior for rhNGF versus placebo (p=0.0052). Two 12-month Phase III studies (n = 1,000 and 1,500) are underway to confirm these results. They are designed to compare the proportion of patients with a clinically meaningful response (according to the Peripheral Nerve Society Consensus 1995) to rhNGF versus placebo. Efficacy will be determined by ≥ 2 point change in the NIS[LL] score. Directed by the Phase II findings, the most important secondary efficacy tests (CDT and HP: 5.0) focus on the effect of rhNGF on small fiber sensory neurons. Nerve Conduction Studies, Neuropathy Symptoms and Change Questionnaire, foot ulcer occurrence and a Quality of Life Questionnaire explore the efficacy spectrum. Results are expected early 1999.

P336 INDUCTION OF HUMAN SCHWANN CELL APOPTOSIS BY PROINFLAMMATORY CYTOKINES. Conti GC, MD, Scarpini E, MD, Baron PL, MD, Clerici R, MD, Stucchi CM, MD, Piccio L, MD, Basellini A, MD, Scarlato G, MD. Dept. of Neurology, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milano Italy Embryonic rat Schwann cell precursors undergo apoptosis during early peripheral nervous system ontogenesis. During development, Schwann cell apoptosis is rapidly suppressed. Neonatal Schwann cell can undergo programmed cell death after nerve cut, but the presence of this process in normal adult nerve or during neuropathies is still controversial. The objective of the study is the detection of programmed cell death (apoptosis) of human Schwann cells in culture at basal conditions and after treatment with pro-inflammatory cytokines. Human Schwann cells were cultured and stimulated for 18, 48, 72 and 96 hours with TNF-α and INF-γ. At each time point, both untreated and stimulated Schwann cells were fixed and characterized with the S-100 antibody. Apoptosis was detected in the S-100positive cells by a FITC-TUNEL technique. Stimulation for 18 hours with TNF-α and INF-γ induces apoptotsis in approximately 15% of Schwann cells, whereas no TUNEL-positive cells are detectable in untreated cultures. No apoptotic cells are evident by 48 and 72 hours in both normal and stimulated cultures. After 96 hours in culture, both at basal conditions and after TNF-α stimulation, approximately 5% of Schwann cells are apoptotic. The finding that Schwann cells dye of apoptosis can be related to the revertion to an embryonic phenotype, promoting regeneration through the response to different cytokines and neurotrophins. Apoptosis of Schwann cells after a few days in culture might represent a system to control excessive proliferation of these cells in absence of the axon.

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P337 MAGNETIC RESONANCE IMAGING ABNORMALITIES IN PERIPHERAL NEUROPATHY. Sghirlanzoni A, Grisoli M, Costa A, Ciano C, Fallica E, Pareyson D. Milan, Italy Magnetic resonance imaging (MRI) may reveal increased signal intensity in degenerating fiber systems, e.g. the dorsal columns within the spinal cord in the course of sensory neuronopathy, and enhancement of nerve roots in acute and chronic demyelinating inflammatory polyradiculoneuropathy (AIDP and CIDP). In order to evaluate the role of MRI in the diagnosis of peripheral nerve disorders, we designed a pilot study and performed: a) cervical spinal cord MRI in patients with sensory neuropathy of different etiology; b) lumbar MRI with gadolinium in patients with AIDP and CIDP. Patients with sensory neuropathy also underwent somatosensory evoked potential studies. Eleven patients showed increased signal intensity of the dorsal columns. This finding indicates degeneration of the centripetal projection of the dorsal ganglia T-cell. The contemporary involvement of the peripheral and central projections of the dorsal ganglia suggests a primary neuronopathy, rather than an axonopathy, in these cases. Three patients with AIDP and 2 with CIDP (one with root hypertrophy) showed enhancement of the lumbar nerve roots, suggesting root inflammation. MRI is useful in the differential diagnosis of both sensory and inflammatory neuropathies.

P338 PERIPHERAL NERVE INVOLVEMENT IN NON-HODGKIN MALIGNANT LYMPHOMAS. 8 CASES. M. Herpe, T. Rousset, M. Pages, J. M. Blard. Departments of Neurology and Pathology, Centre Gui de Chauliac, Montpellier (France) Clinical, electrophysiological and pathological data of 8 patients with peripheral nerve involvement and non Hodgkin malignant lymphoma (NHML) were reviewed in order to determine the mechanism of peripheral neuropathy. Patients with drug-induced neuropathies were excluded from the study. Peripheral neuropathy is directly related to the NHML in 6 cases: – one patient had tumoral infiltration of oculomotor nerves by a centrocytic centroblastic follicular lymphoma of the retroorbital area; – in 3 cases, neurological manifestations were due to meningoradicular localization of NHML: palsy of left V, VII, IX and X cranial nerves in an acute Burkitt lymphoma; extensive meningoradiculopathy complicating a B cell centroblastic centrocytic testicular lymphoma or revealating a lymphoblastic NHML. – 2 patients had distal nerve lymphomatous infiltration. In the first case with a B cell lymphocytic lymphoma restricted to peripheral nerve and IgG Kappa monoclonal gammopathy, a sensory polyneuropathy was followed 5 years later by a sensorimotor multiple mononeuropathy. The second one had a sensorimotor neuropathy complicating a T-cell cutaneous lymphoblastic lymphoma. In two cases of multiple mononeuropathy, the mechanism of neuropathy is uncertain. Our data confirm the clinical and pathological heterogeneity of peripheral neuropathy in NHLM. The mechanism of peripheral nerve involvement may be difficult to demonstrate in some cases.

P339 CHRONIC MULTIFOCAL DEMYELINATING SENSORIMOTOR NEUROPATHY. J. P. Camdessanche, J. C. Antoine, J. F. Mosnier, L. Absi, D. Michel. Saint-Etienne. France Among 46 consecutive patients with chronic dysimmune demyelinating neuropathy, 10 (22%) had a sensory-motor multifocal neuropathy (SMMN). In 7/10, the deficit predominated in the upper limbs and 6/7 had hand muscle atrophy. None of the 3 patients with predominant lower limb involvement had amyotrophy. The motor deficit was purely distal in 8/10. All the patients had conduction blocks or temporal dispersions in several nerves. Ten/10 patients had pain, paresthesia, sensory loss, or abnormal SAPs. Nerve biopsy performed in 7 patients showed myelin changes in 6/7 with additional axonal degeneration in 2. The last patient had many sproutings suggesting axonal degeneration distally to demyelination. Epineurial non necrotizing vasculitis was present in two. CSF protein concentration ranged from 0.46 to 0.68 g/l. Three/9 patients had low to medium titer of anti-GM1 antibodies and one had a monoclonal IgM. Response to treatments varied. Two/7 improved with steroids (+ azathioprine) and 3/4 to IVIg. As a whole, patients with predominant upper limb involvement were poor responders to steroids. This study shows that SMMN is probably not rare. Features such as distal muscle involvement predominating in the upper limbs, muscle atrophy, and poor response to steroids occur in MMN suggesting links with this disorder. However as some patients respond to steroids like CIDP, SMMN may be heterogeneous.

P340 CHRONIC MULTIFOCAL DEMYELINATING NEUROPATHY PRESENTING AS A CHARCOT-MARIE-TOOTH DISEASE. T. Stojkovic1, B. Mastain1, J.-F. Hurtevent2, A. Engles1, E. Le Guern3, H. Petit1, P. Vermersch1. 1Department of Neurology, CHRU of Lille, France. 2Department of Neurophysiology, CHRU of Lille, France. 3 INSERM U 289, Hôpital de la Salpêtrière, Paris, France A 18-year-old male patient presented with weakness and diplopia. No family history was noted. His early development was normal. At 6-year-old he presented a horizontal diplopia with a complete remission within 6 weeks. Then he progressively developed bilateral foot drop gait and distal weakness of the four limbs. Vibratory sensory was decreased in all limbs. Tendon reflexes were abolished. He had marked bilateral pes cavus, scoliosis and on electrophysiological study a demyelinating polyneuropathy suggesting a Charcot-Marie-Tooth (CMT) disease. As he complained again of diplopia at eighteen, a brain MRI was performed showing demyelinating periventricular lesions. Nerve conduction study showed prolonged distal latencies and F-waves as well as conduction blocks on all nerves. Electromyography showed denervation in the upper and lower limbs. Haematological and biological screening revealed no abnormalities. Serum lipid, arylsulfatase A, B and phytanic acid were normal. CSF analysis showed a protein level of 2 g/l. All these data were consistent with chronic inflammatory demyelinating polyneuropathy (CIDP). Moreover genetic analysis revealed no PMP22 duplication, associated with CMT1A. We here emphasized that childhood CIDP can mimic a severe form of CMT. We discuss the pathogenic mechanism for both central and peripheral demyelinating lesions. P341 CLINICOPATHOLOGICAL STUDY OF HEREDITARY SENSORY AUTONOMIC NEUROPATHY WITH ANHIDROSIS. A CASE REPORT. Y. Parman1, G. Hüner, M. Dernirkol 2, T. Tukel 2, G. Said 3. 1Istanbul Faculty of Medicine, Department of Neurology, Istanbul; 2 Istanbul Faculty of Medicine, Department of Pediatrics, Istanbul, Turkey; 3 Bicetre Hospital, Department of Neurology, Paris, France Hereditary sensory autonomic neuropathy (HSAN) with anhidrosis, designated as (HSAN type IV) in the Dyck et al. classification, is a very rare autosomal recessive condition that leads to self mutilation, bone fractures, multiple scars, mental retardation and early death from hyperpyrexia during childhood. We report a 13-month old male infant with HSAN type IV. He was the first child of consanguineous (first cousins), healthy Turkish parents. He had perinatal asphyxia. Poor feeding, hyperpyrexia and anhidrosis were present soon after birth. Convulsions starting at four months, self mutilation after eruption of the teeth, frequent lower respiratory infections were observed. Physical evaluation disclosed severe malnutrition with height, weight and head circumference below the 3rd percentile. There was normal tear formation. The tip of the tongue was missing. He had severe psychomotor retardation. Neurologic examination showed normal muscle strength, preserved deep tendon reflexes, lack of reaction to painful stimuli. Sensory and motor conduction studies were normal. EEG was unremarkable. Sural nerve biopsy showed a normal density of myelinated fibers in semithin sections. In thin sections there was a moderate reduction of unmyelinated fibers (11330/mm2) M2). The actual pathophysiologic mechanism of this rare disorder which is separable from Riley-Day syndrome only on clinical grounds remains unknown. P342 QUALITY OF LIFE IN PATIENTS WITH CHRONIC AXONAL POLYNEUROPATHY. M. Eurelings, F. M. Van Hellemondt, L. L. Teunissen, J. W. Hop, J. H. J. Wokke, N. C. Notermans. Utrecht, The Netherlands The objective of this study was to determine if the Rand-36 questionnaire can be used in patients with chronic axonal polyneuropathy to measure quality of life and if it adds to the evaluation of the seriousness of the illness. The Rand-36 is derived from the SF-36 questionnaire and is translated into Dutch and validated in the Netherlands. The design of this study is descriptive. Ninety patients (33 HMSN type II and 57 CIAP) were investigated with the Rand-36 by telephone. The data of the neurologic disease, the handicap and the quality of life were compared. Patients with a chronic axonal polyneuropathy performed worse in all domains of the Rand-36 than the reference population. Patients with worse outcome of neurologic investigation or handicap had not only lower scores of physical domains but also of emotional and social domains. No difference was found between HMSN type II and CIAP. Our conclusion is that the Rand36 can be used in chronic axonal polyneuropathy patients to measure qual-

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ity of life and can usefully add to the neurologic investigation and handicap scale. P343 COMBINED INTRAVENOUS IMMUNOGLOBULIN AND HIGH DOSES OF PREDNISOLONE IN BOLUS IN A CASE OF CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY. Perini M, Zarcone D, Basso P, Bettini B, Carnicelli A, Zibetti A. Neurological Department, Gallarate Hospital, Italy The efficacy of steroid therapy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is documented; more recently plasmaexchange (P.E.), added to the initial prednisolone therapy, seems to diminish the time for improvement. It is reported 88% improvement with this therapeutical combination in three months. The role of intravenous immunoglobulin (i.v. Ig) is not well defined; usually this therapy is recommended in patients refractory or contraindicated to steroid therapy. We report the case of a 57 years old man, who complained in 5 years progressive distal weakness, up to inability to work and difficulty in walking. Severe distal atrophy with areflexia and loss of sensivity were present. There were marked elevated spinal fluid protein, reduction in nerve conduction velocities with prolonged distal and F wave latencies; autoantibodies to the gangliosides GM1 were found in serum. Sural nerve biopsy revealed a loss of nerve fibers with demyelination and “onion bulbs”. The good response to P.E. associated with prednisolone was evident only for the first three months. No result was obtained by substitution of prednisolone with cyclophosphamide for other six months. I.V.Ig were given with initial good response, but persistent clinical and neurophysiological improvement was obtained only by a combination of i.v. Ig and high doses of prednisolone in bolus repeated every four months. The patient, refractory to chronic steroid therapy, with periodic short time high doses of glucocorticoids and I.V.Ig, was able to return to work and walk without assistance.

P344 ON THE TREATMENT OF POEMS SYNDROME. H. Drac, W. Drozdowski, P. Golêbiewski, H. Kwieciñski. Warsaw and Bialystok, Poland POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a rare multisystem disorder usually associated with myeloma. The treatment of this syndrome is still unresolved, as it is illustrated by our two cases. Case 1: 36-year-old woman developed progressing severe painful sensory-motor polyneuropathy with cachexia, skin hyperpigmentation, hypertrichosis, scleroderma-like changes, white nails, amenorrhea, hepatomegaly and papilledema. Electrophysiological study was consistent with a mixed demyelinating axonal sensorimotor neuropathy. Sural nerve biopsy revealed endoneurial edema, profound loss of myelinated fibers without cellular infiltrates. CSF protein level was elevated (95 mg/dl). M protein was absent. Thyroid, adrenal and ovarian tests were abnormal. Biopsy of the pubic bone lesion was diagnostic for plasmocytoma. For two years before the diagnosis of plasmocytoma the patient was treated with repeated courses of prednisone (60 mg/day), cyclophosphamide (100 mg/day) and course of IVIg 0.4 g/kg/day for 5 consecutive days without any benefit. Local radiotherapy and chemotherapy resulted in marked improvement of polyneuropathy and other symptoms. Case 2: 41-year-old woman started with progressive sensory-motor polyneuropathy and other POEMS syndrome symptoms. Recurrent polyserositis, splenomegaly and anasarca were found. Results of electrophysiological studies, sural nerve biopsy and CSF examination were similar as in the case 1. Monoclonal IgA protein was present in the serum. Adrenal, parathyroidal, thyroid, ovarian tests were abnormal. As yet, a malignancy has not been found. In the treatment prednisone, cyclophosphamide and IVIg were tried. Conclusion: In the first case the only effective treatment was radiotherapy and chemotherapy of bone lesion; in the second case long term (2 years) immunosuppression ameliorated multisystem symptoms, but not neuropathy. Accordingly to our experience single courses of IVIg in POEMS syndrome are ineffective. P345 CARPAL TUNNEL SYNDROME: COMPARISON BETWEEN CLINICAL AND NEUROPHYSIOLOGICAL EVALUATION. Pentore R, Capone L, Schönhuber R. Department of Neurology, Regional General Hospital, Bolzano, Italy Background: Neurophysiological evaluation (EMG/ENG) is the gold standard to diagnose carpal tunnel syndrome (CTS). Hovewer, in some pa-

tients, despite of clinical symptoms suggestive of CTS, particularly at early stages, EMG/ENG is normal. Aim of the study: to compare frequency of signs and symptoms suggestive of CTS in patients with positive and negative EMG/ENG. Material and Methods: Occurrence of pain, paresthesias and numbness with median nerve distribution, awakening during the night, improvement of symptoms by flicking the hand (flick test) were investigated in 269 consecutive CTS patients attending our EMG laboratory, in whom other causes of symptoms had been excluded. Results: EMG/ENG resulted normal in 35 (13%) patients. No significant difference was found for each considered parameter between patients with and without EMG/ENG abnormalities: pain (84% vs 83%), paresthesias (77% vs 86%), numbness (55% vs 65%), awakening (80% vs 68%), flick test (56% vs 49%). Comment: Clinical examination seems sufficiently sensitive for the diagnosis of CTS. Our data disagree with the literature: particularly the sensitivity of flick test resulted decreased (Pryse-Phillips 1984: 93% of CTS). EMG/ENG might be useful to confirm the diagnosis before surgical treatment and to rule out other less frequent causes of arm and hand pain.

P346 CIDP AND MONOCLONAL GAMMOPATHY. Bosboom WMJ, Van den Berg LH, Notermans NC, Franssen H, Wokke JHJ Both humoral and cellular immune mechanisms may play a role in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP), while in patients with a demyelinating neuropathy associated with a monoclonal gammopathy (MG) antibody activity of the MG may lead to nerve damage. Immunological treatment in these neuropathies are different, as CIDP may respond to intravenous immunoglobulin (IvIg) or prednisone and polyneuropathy associated with MG to immunosuppression. We present 4 patients with a neuropathy associated with a MG who fullfill the criteria for CIDP and respond to IvIg treatment. The patients presented predominantly motor symptoms, the electrophysiological examination was compatible with the CIDP research criteria, the CSF protein was elevated and two patients had T cell infiltrates in their sural nerve biopsy. Two patients had a benign MG (IgGλ and IgMκ), one patiënt an IgMλ MG due to a non-Hodgkin-lymphoma and the fourth an IgAλ MG due to a morbus Kahler. There was improvement of the neuropathy after treatment with IvIg. Although CIDP and polyneuropathy associated with monoclonal gammopathy (MG) are seen as different entities, there are polyneuropathy patients with a MG who have a typical CIDP, which may have implications for the choice of immunological treatment in these patients.

P347 ANTI-GANGLIOSIDE AND ANTI-SULPHATIDE ANTIBODY ASSAY IN NEUROPATHIC AND EPILEPTIC PATIENTS. B. Ferrero, G. Isoardo, A. Ricci, G. Aimo, E. Rota, B. Bergamasco, L. Durelli. Torino, Italy Anti-ganglioside (GM1, GD1b and GQ1b) and anti-sulphatide antibodies (Ab) were tested (using a well-standardized enzyme-linked immunosorbent assay with a blocking solution of 1% w/v of bovine serum albumin) in 183 neuropathic patients (19 pure motor, 23 pure sensitive, and 141 motor/sensitive neuropathies; 34 axonal, 51 demyelinating, and 98 axonal/demyelinating neuropathies) and in 137 epileptic subjects (40 partial symptomatic, 36 partial cryptogenetic, 13 generalized symptomatic/cryptogenetic and 48 generalized idiopathic epilepsies). RESULTS. Neuropathic patients: 14/84 (16.7%) had anti-GM1 Ab titer ranging 1/800 ÷ 1/28,896 (mean 1/3,850) for IgM and 3/84 (3.6%) ranging 1/1,220 ÷ 1/2,400 (mean 1/1,850) for IgG; 11/64 (17.2%) had anti-sulphatide Ab titer ranging 1/2,232 ÷ 1/91,648 (mean 1/5,830) for IgM and 1/64 (1.6%) at title 1/4,550 for IgG; 3/21 (14.3%) had anti-GD1b Ab titer ranging 1/1,200 ÷ 1/3,200 (mean 1/2,220) for IgM; none had a significant titer of IgG antiGD1b, and IgG/IgM anti-GQ1b. Epileptic patients: 19/137(14%) had antiGM1 Ab titer ranging 1/800 ÷ 1/1,800 (mean 1/1,350) for IgM and 10/ 137 (7.2%) ranging 1/800 ÷ 1/2,000 (mean 1/1,420) for IgG; 4/137 (2.9%) had anti-sulphatide Ab titer ranging 1/2,000 ÷ 1/6,000 (mean 1/3,100) for IgM and 1/137 (0.7%) at title 1/2,400 for IgG; 18/77 (23%) had antiGD1b Ab titer ranging 1/800 ÷ 1/1,200 (mean 1/990) for IgM and 25/ 77 (32%) ranging 1/800 ÷ 1/1,600 (mean 1/1,150) for IgG; 13/77 (9.4%) had anti-GQ1b Ab titer ranging 1/800 ÷ 1/1,200 (mean 1/1,000) for IgM and 22/77 (28%) ranging 1/800 ÷ 1/1,200 (mean 1/950) for IgG. Conclusions. Anti-sulphatide Ab frequency and titers are higher in neuropathic than in epileptic patients, whereas anti-ganglioside Ab frequency is similar in both patient groups, with higher titers in neuropathics.

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Cerebrovascular Disorders P348 ISOLATED VASCULITIS OF THE VERTEBRO-BASILAR CIRCULATION: CLINICAL AND ANGIOGRAPHIC REGRESSION WITH IMMUNOSOPPRESSIVE THERAPY. Manara R, Baracchini C, De Biasia F, Monaco S, Meneghetti G. Department of Neurological Sciences, University of Padua, Italy Isolated vasculitis of the CNS is a rare, recurrent, idiopathic, inflammatory disease, which usually involves the leptomeningeal and parenchimal blood vessels of the encephalon. The prognosis is poor, unless early treatment is provided. A 31-year-old man was admitted to our ward for the sudden appearance of a left fronto-temporal throbbing headache, transient obnubilation, paresthesias and hypostenia on the right extremities, dysarthria and vomiting; a cerebral CT scan and the EEG at admittance were normal. Just after a few hours he became bradycardic and had a decerebrating posture which totally regressed with anti-oedema treatment. On the following day a neurological examination disclosed a right hemiparesis and hypoesthesia; a second cerebral CT scan showed an area of hypodensity between the thalamus and the posterior arm of the left internal capsule. On the third day of his hospital stay the patient was still obnubilated, disarthric, with right midriasis still respondent to the light. Transcranial Doppler Sonography showed a marked decrease in velocity of the vertebral arteries and a marked acceleration of the middle segment of the basilar artery; these findings were confirmed by angiography documenting a narrowed basilar artery with irregular profile and internal defects. A cerebral MRI showed ischemic lesions at the following sites: left thalamo-capsular, left occipital, left cortico-cerebellar, right paramedian pontine hyperintensities. Further examinations (TT and TE Ecocardiography, lumbar puncture, prothrombotic profile, flogistic indexes, anti-phospholipid antibodies, indexes for autoimmune disorders) were all normal. At this point an isolated vasculitis of the CNS was considered to be highly probable and consequently proper treatment was provided: steroids, immunosuppressor and anticoagulants. We observed a gradual but almost complete clinical recovery with a significant regression of the transcranial and angiographic alterations at 10 months from onset. P349 ACCURATE DETERMINATION OF HUMAN BRAIN ARTERIAL TERRITORIES USING A STANDARDIZED VASCULAR MAPPING: PRELIMINARY RESULTS OF A PROSPECTIVE STUDY. F. Vuillier for the Asterix Group. Departments of Neurology and Neuroradiology University Hospital Besançon, Grenoble, Lausanne, Lille Knowledge of arterial territories is needed to achieve accurate localization of ischemic lesions on CT or MRI. The aim of this study was to evaluate a practical vascular brain mapping in the location of infarcts. We prospectively studied 110 consecutive patients (pts) admitted with infarction. All pts were analyzed using a standard protocol for clinical data and neuroimaging techniques. CT (15.5%) and MRI (84.5%) were analyzed using the axial sections of our standardized brain arterial mapping (Tatu et al.). We distinguished the main territory of the qualifying infarct from its extended territories. The adaptability of our mapping was studied in such a way as to a precisely delineate the qualifying infarct. Infarcts were located in infra-tentorial territories (23 pts) and in hemispheric territories (87 pts). All territories depicted in our mapping were involved. For 110 pts, 352 territories were concerned in which 134 were defined as the main territory. On 498 neuroimaging slices showing infarct, the axial mapping were adapted in 426 (global adaptability 85.5%). For the 72 other slices, there were technical difficulties (slice thickness or gap) in 47 (65%) and a lack of axial mapping in 25 (35%). The main territory was with certainty in 88 pts, estimated in 20 pts and remained indetermined in 2. Precise determination of the main arterial territory was always possible for brainstem infarcts. For hemispheric infarcts, the cortical variability of the 3 major arteries always allowed us to determine the main territory. For thalamic and cerebellar infarcts, the main territories were found precisely in 8/11 and in 1/8 cases, respectively. For each arterial territory we have depicted the most frequent variations. Our standardized vascular mapping is a useful tool for determining the main and extended territories in stroke. This step is essential in order to establish accurate clinico-radiological correlations. P350 SEVERE DISABILITY AT HOSPITAL DISCHARGE IN ISCHEMIC STROKE SURVIVORS. Pierre Arnold, Maurizio Paciaroni, Guy Van Melle, Julien Bogousslavsky. Service de Neurologic, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Background The purpose of this study was to predict the functional outcome at discharge of first-time stroke patients included consecutively in the Lausanne Stroke Registry. Methods We studied 3,628 sequential patients with first-ever stroke who were admitted consecutively to the Centre Hospitalier Universitaire Vaudois. Functional status was evaluated using the Rankin disability scale at discharge. We studied the prognostic value of historical, clinical and instrumental variables related to functional outcome at discharge. The factors studied were age, sex, risk factors, ECG results, occurrence of transient ischemic attacks (TIAs), extension of cerebral infarction, presumed cause of stroke, clinical findings and demographic characteristics. Univariate analysis was performed on each variable by comparing the number of functionally independent- versus dependent-patients at the moment of discharge. The significant variables of the univariate analysis were subjected to multivariate analysis with a backward logistic regression procedure to find those with an independent effect on the outcome. Results 3,156 patients, excluding 117 patients with ischemic stroke who died during hospitalization, and 355 with brain hemorrhage, were included. 2,867 patients belonged to the nil, mild or moderate disability groups (modified Rankin score 1–4; functionally at least partially independent patients) while 291 patients belonged to the severe disability group (modified Rankin score 5; functionally dependent patients). Multivariate analysis showed that impaired consciousness on admission, limb weakness, progressive worsening, infarct in the superficial + deep territory of middle cerebral artery, ischemic heart disease and cardiac arrhythmia, were predictors of severe disability at discharge. Age was not an independent predictor of poor outcome. Hypercholesterolemia was significantly related to a better outcome. Conclusions Some prognostic indicators associated with functional outcome at discharge are available during the first few hours after onset of stroke. This is important for the management of the individual stroke patient and for organizing suitable rehabilitation planning. P351 ARE CLUSTERING TIA RELATED TO SINGLE PERFORATOR DISEASE? Falcão F, Crespo M, Ferro JM. Neurology Department, Hospital Santa Maria, Lisbon, Portugal Multiple TIAs are usually considered to be embolic, but repetitive attacks of hemiplegia are thought to be related to single perforator disease. Purpose: To test the hypothesis that clustering TIA (≥ 2 TIA with a symptomatic free internal of less than 24 h) are related to single perforator disease while non-clustering multiple TIA are associated with embolism. Method: Consecutive multiple TIAs (n = 194) from an hospital stroke registry, were grouped in clustering (n = 107) and non-clustering (n = 87). Demographic, and clinical variables, risk factors and results of ancillary procedures were compared between the two groups. Results: Aphasia/alexia (20 vs 6%, difference 13, 95% CI 4–23) and ocular or cortical symptoms (33% vs 14%, difference 19, 95% CI 8–31) were more common among non clustering TIAs, while motor plus/or sensory disturbances affecting at least two of face, arm or leg where more common among clustering TIAs (57% vs 38%, difference 19, 95% CI 57–32). Medium/high risk cardiac emboligenic disease were more frequent among non clustering TIA (8% vs 4%, difference 4, 95% CI 11–24). Proportions of > 50% stenosis in appropriate extracranial vessels were similar in the two groups (8 and 7%). Conclusion: Almost 2/3 of clustering TIAs are related to single perforator disease, while cortical symptoms and cardioemboligenic conditions are more frequent among non-clustering TIAs. However the two groups show considerably overlap. P352 THE ROLE OF COLLAGEN DISEASE IN ARTERY DISSECTIONS. A. Dunac, S. Blecic, S. Jeangette, J. C. Bier, P. Rosetti, J. G. Hildebrand. Service de Neurologie. ULB Hôpital Erasme, Brussels, Belgium Artery dissection (AD) is a frequent cause of stroke, especially in youngs. While traumatic injury is frequently suggested, an inherited condition such as collagen disease could play a role in genesis but also in recurrence of AD. The aim of this study was to evaluate the importance of collagen disease in AD. From 2293 patients (pts) admitted to our stroke unit from 1991 to 1997, 259 (11.3%) were under 50. Among the 45 pts (17.3%) who have had AD, 33 had cervical AD, 7 intracranial AD and 5 had both intraextracranial AD. In addition to the complete work-up including MRI, MRA and conventionnal angiography, all these pts also had skin biopsy to study both quality and proportion of collagen fibers. Among the 23 pts who had an history of traumatism before AD, only one had anomaly of collagen type III fibers (Ehlers Danlos syndrome). In the remaining 22 patients, 12 (54.5%) had anomaly of collagen fibers: 9 had Elhers-Danlos

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syndrome, 2 had Marfan syndrome and 1 had Grönblad-Strandberg Syndrome. All but one pts with multiple dissection had in fact collagen disease. Two pts had AD due to heterozygote hyper-homocystinuria and 2 had AD due to atherosclerosis. In 8 pts the cause of AD remained unknown. Conclusion: Collagen disease is a frequent cause of AD in youngs. We suggest that skin biopsy should be performed in all pt with AD in order to disclose collagen disease and when present to propose medical advice mainly to prevent recurrence. P353 LACK OF ABNORMALITY ON DIFFUSION WEIGHTED MRI IN SPONTANEOUS TRANSIENT GLOBAL AMNESIA. A. Gass1, J. Gaa2, W. Schreiber3, A. Schwartz1, M. Georgi2, A. Sommer1, M. G. Hennerici1. Dept. of Neurology1 and Radiology2, Klinikum Mannheim, Univ. Heidelberg, German Cancer Research Center3, FR Germany Transient global amnesia (TGA) is a temporary dysfunction of anterograde and recent retrograde memory with preservation of alertness, attention and self-identity without neurological symptoms. Although there is evidence that TGA might be related to a migrainous aetiology the results of numerous studies on the aetiology of TGA are conflicting. Diffusion weighted (DW) magnetic resonance imaging (MRI) is sensitive to ischaemic tissue changes that are not detectable with T2-weighted MRI. Recently it has been shown that in TGA after posterior circulation angiography embolic lesions can be identified in the posterior circulation territories (Stroke 1997; 28 (11) : 2311–14). Yet to date there is no definite evidence whether structural abnormality is detectable with DW MRI in spontaneous TGA (STGA). We investigated 7 patients (4 women, 3 men, 56–72 years) 1–12 hours after an episode of STGA with conventional and DW MRI (EchoPlanar (EPI)-SE 4000/144/5mm, b = 0/160/320/640/1000s/mm2, diffusion gradients in 3 orthogonal planes) in transverse and coronal planes. Although we used a DW MRI technique that is sensitive to detect even very small areas of ischaemic tissue change (The Lancet 1997; 349 : 772–772), we did not identify any abnormality on DW images or on calculated maps of the apparent diffusion coefficient in STGA. We suggest that in spontaneous TGA one usually can not detect structural abnormality with DW MRI. This would be in line with other evidence that favours a migrainous etiology in STGA. P354 A STANDARDIZED VASCULAR MAPPING FOR BRAIN ARTERIAL TERRITORIES. Laurent Tatu, Thierry Moulin, Julien Bogousslavsky, Henri Duvernoy. Services de Neurologie et Laboratoires d’Anatomie. Besançon (F), Lausanne (CH) A knowledge of arterial territories is needed to achieve accurate localisation of ischemic lesions on neuroimaging techniques (CT scan, The aim of this study is to provide a practical tool for reliable clinico-radiologic correlations in patients with ischemic stroke. Methods: 24 serial sections are developed (4 mm thick for the infra-tentorial region, 8 mm for the supratentorial region) based on a bicommissural plane passing through the center of the anterior and posterior commissures. Each section shows the anatomic structures and Brodmann’s areas on the right side, and the arterial territories on the left side. Results: The arterial territories of the brainstem are derived from the anatomic works (Duvernoy) in 4 main territories (anteromedial, anterolateral, lateral and posterior, and those of the cerebellum according to the anatomopathologic work (Amarenco). In the hemisphere, the arterial territories were drawn based on an extensive overview of anatomic studies. For the thalamic territories, vascular territories are completed with a special delineation derived from the most recent radioclinical studies. According to Van der Zwann et al., the variability of the cortical territories for the 3 cerebral arteries are described. Conclusion: Our vascular mapping has been established mainly for dominant arterial territories, taking into account the variability of cortical supplying, evaluated on a standard plane, and based on anatomic studies. All sections may be used as a practical tool to determine arterial territories and may help establish consistent clinico-anatomic correlations in patients with ischemic stroke. P355 VASCULAR LESIONS OF THE SUBSTANTIA NIGRA AND PARKINSONISM. U. Müller1, M. Reuter3, M. Hund1, H. Barthel2, T. BauerWittmund4, D. Y. von Cramon1, 4. 1Max-Planck-Institute of Cognitive Neuroscience, Inselstr. 22, 04103 Leipzig, Germany; 2Neurological Clinic Martha-Maria, Halle/Saale; 3Department of Nuclear Medicine, University of Leipzig; 4Day-Care-Clinic of Cognitive Neurology, University of Leipzig

The concept of vascular or arteriosclerotic parkinsonism was introduced by Critchley (1929) and has ever been a subject of controversy. Neuropathological and neuroradiological series found a 5–20% prevalence of vascular lesions in patients fulfilling the clinical criteria of idiopathic Parkinson’s disease (IPD). Most of these patients have lacunar infarctions in the pallidum that might, however, be coincidental (Inzelberg et al. 1994). There was only one patient with hemiparkinsonism and a histologically proven infarction of the substantia nigra (Hunter et al. 1978). Patients and Methods: We report on two patients with vascular risk factors and clinical signs of parkinsonism that were refered for high resolution magnetic resonance imaging (MRI) in our 3Tesla scanner (Bruker MedSpec 3T/100). Results: Both patients showed small bilateral lesions in the midbrain affecting the substantia nigra. Single-photon emission computed tomography (SPECT) with [123I] β-CIT demonstrated a bilateral loss of nigrostriatal dopamine neurons. Patient G.F. (71 years, female) had no further lesions in the basal ganglia, a good response to levodopa and was diagnosed as having vascular parkinsonism. Patient G.S. (58 years, male) had a severe arteriosclerotic cerebral small vessel disease with multiple lacunar infarctions (brainstem, striatum, etc.) and a dysexecutive syndrome without dementia (excluding Binswanger’s disease). Conclusion: High-resolution MRI enables the in vivo detection of small vascular lesions in midbrain structures. Therefore the diagnosis of vascular parkinsonism should be extended to cases with lesions of the substantia nigra that are clinically undistinguishable from IPD.

P356 ISOLATED DYSARTHRIA DUE TO LACUNAR STROKE IS FREQUENTLY ASSOCIATED WITH CORTICO-LINGUAL TRACT DYSFUNCTION. Urban PP1, Wicht S1, Hopf HC1, Fleischer S2, Nickel O3. 1Department of Neurology; 2 Department of Communication Disorders; 3 Department of Nuclear Medicine, University of Mainz, Germany The pathophysiology of dysarthria can preferentially be studied in patients with small singular ischemic lesions. This condition is perfectly fulfilled in isolated dysarthria which is a rare lacunar stroke syndrome. We investigated the supranuclear tracts involved in speech production in seven patients with isolated dysarthria due to a singular lacunar stroke. Magnetic resonance imaging revealed the lesion site in the corona radiata (n = 4) and internal capsule (n = 2). In one patient no morphological lesion was identified. We tested cortico-bulbar tract function using transcranial magnetic stimulation and demonstrated impairment of the cortico-lingual projections in all of the patients and additional impairment of the cortico-orofacial projections in four. HMPAO-SPECT imaging, performed in six patients, showed no cerebellar diaschisis, suggesting unimpaired cerebroponto-cerebellar tract function. Dysarthria observed in the four patients with additional cortico-orofacial tract dysfunction did not differ from that in patients with isolated cortico-lingual tract dysfunction. We conclude that interruption of the cortico-lingual pathways to the tongue is crucial in the pathogenesis of isolated dysarthria following lacunar stroke. This project was supported by the DFG (Ur 37/2-1).

P357 UNDERLYING ARTERIOPATHY IN TRAUMATIC CAROTID AND VERTEBRAL ARTERY DISSECTIONS. Mokri B, Sinaki M, Piepgras, DG. Rochester, Minnesota, USA In traumatic dissections of carotid or vertebral arteries, in contrast with spontaneous ones, an underlying arterial disease is rarely considered a contributory etiologic factor unless arteriograms show evidence of other arterial disease such as fibromuscular dysplasia. Since most patients recover, autopsy or surgical specimens uncommonly become available for histologic study. We report six patients age 22 to 47 years with traumatic dissections of internal carotid arteries (five patients), or vertebral arteries (one patient). All had suffered severe non-trivial trauma (motor vehicle accidents in three, fall in one, sports injury in two). Arteriography showed evidence of dissection in all patients but no evidence of other arterial disease. One patient had osteogenesis imperfecta type-1 due to a null mutation in the type-1 procollagen gene COL1A1 Two patients died and underwent autopsy, three patients underwent resection of residual dissecting aneurysms and thus tissues became available for histologic studies. In two patients there was cystic media necrosis and in three there was marked paucity of the elastic fibers. We conclude that even in traumatic dissections of the carotid or vertebral arteries, and even when the arteriograms do not show evidence of other arterial disease, still some patients may have a primary arteriopathy likely rendering the arteries more vulnerable to the affect of trauma.

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P358 G20210A PROTHROMBIN GENE MUTATION IN TWO SIBLINGS WITH CEREBRAL VENOUS THROMBOSIS. N. Kubis, G. Huberfeld, G. Lot, L. Ripoll, P. Chaine, L. Drouet, F. Woimant The mutation in the 3´-untranslated region of the prothrombin gene, the G20210A heterozygous mutation, is a recently identified cause of thrombophilia which increases the risk of peripheral venous thrombosis, but its association with CVT has not yet been described. We report the cases of two siblings who experienced CVT, in whom this heterozygous mutation was discovered. The pedigree analysis showed an autosomal dominant inherited pattern of venous thrombosis disease. The members of the family who were still alive were tested. We discuss the imputability of the mutation in the responsibility of CVT in our two patients, in relation to previous observations and to what is known in other protein coagulation disorders.

Poster Session 4 Cerebrovascular Disorders (1) P359 EPILEPTIC SEIZURES FOLLOWING SUBCORTICAL INFARCTS. Bentes C, Pimentel J, Ferro JM. Department of Neurology. Hospital Santa Maria, Lisbon, Portugal Stroke is one of the most important causes of seizures in adulthood. Although less frequently than cortical infarcts, subcortical ischemia has also been implicated on epileptic genesis. Purpose: To study the incidence, type and risk factors for epileptic seizures following a subcortical infarct. Method: From a hospitalar stroke registry we retrieved 106 patients with subcortical infarcts, examined between 1986 and 1997, and selected those with at least one year of follow-up (n = 76). Results: Were included 54 striatocapsular, 14 thalamic and 8 anterior choroidal artery territory infarcts. Four patients had an epileptic seizure (5.3 %), three in the first month and two in the first day after stroke onset. Seizures were partial in three, generalised in one and did not recurred. All four patients had striatocapsular infarcts and in two an emboligenic cardiac condition was detected. One patient was diabetic, two had arterial hypertension and were daily alcohol users. Conclusion: Epileptic seizures are infrequent following subcortical infarct. Seizures seems to be an early event associated with emboligenic cardiac disease. The one year risk of seizures is very low. P360 ANOSOGNOSIA FOR HEMIPLEGIA AFTER ACUTE ISCHEMIC STROKE. D. Chavot, J. Galmiche, T. Moulin, L. Tatu, E. Berger, F. Vuillier, L. Rumbach. Department of Neurology, University Hospital, Besançon, France Our objective was to analyse the clinical evolution of anosognosia in poststroke hemiplegia. We focused our attention on only the patients (pts) with ischemic post-stroke deficit and anosognosia. For each pt we analysed sensorimotor deficit, temporo-spatial orientation, spatial and motor neglect. The signs described as being associated with body schema disorders were assesed in time: hemiasomatognosia (HSG), anosodiaphoria (ADA), somatoparaphrenia (SPA), nosoagnosic overestimation (NON), misoplegia (MPA), personification of paralysed limbs (PPL). Intensity of anosognosia was measured using a modified Starkstein questionnaire. Pts were evaluated twice a week for 3 weeks during hospitalization. From the 200 pts admitted, 11 met the inclusion criteria; stroke was located in right MCA in 10 pts and in right PCA in 1 pt. In all 11 pts, sensorimotor deficit was great. Associated with anosognosia were spatial neglect in 10, ADA in 9, PPL in 1. Spatial neglect, SPA and NON appeared at the onset of stroke while anosodiaphoria, MPA and PPL appeared later. Anosognosia decreased progressively in 9 pts and rapidly in 2; these 2 pts had major sensory deficit and a small infarct. This preliminary prospective study shows that intensity of anosognosia varies during stroke-course, as well as the different symptoms linked to body schema disorders. This suggests that body schema disorders are related to only one syndrome. P361 IMPROVEMENT OF ACUTE STROKE MANAGEMENT BY ANALYZING PRE- AND IN-HOSPITAL LATENCIES. Stephan Behrens, Michael Daffertshofer, Thomas Luiz*, Klaus Ellinger* and Michael Hennerici. Department of Neurology and Anesthesiology*, University Heidelberg, Klinikum Mannheim, Germany

Efficacy of acute stroke therapies (e.g. thrombolysis) correlates with the interval between symptom-onset and start of therapy. Improvement of acute stroke management has been suggested, but its efficacy is unknown. Therefore we analyzed the latencies from symptom-onset until start of therapy in acute stroke patients (first emergency call < 12 h after symptom-onset) from an urban region (800.000 inhabitants) 3 months before and 3 months after a special stroke training of 1) paramedics, 2) emergency doctors and 3) the emergency room nurses. Initially (n = 97 pts) the interval between first emergency call and hospital admission was 47 ± 14 min and the in-hospital time from admission to the start of therapy was 80 ± 87 min. Therapy started ≤ 3 h in 9 patients and ≤ 6 h in another 11 pts. The rate of systemic thrombo-/fibrinolysis was 11%. 257 paramedics, 46 emergency doctors and the emergency stuff from 9 hospitals were trained. The training procedure covered 3–4 hours per week over a period of 3 months. After the training phase, the pre-hospital (28 ± 12 min) as well as the in-hospital (47 ± 17 min) latencies of 115 stroke patients decreased significantly ( p < 0.05). Start of therapy was possible ≤ 3 h in 22 pts. and ≤ 6 h in another 28 pts. The rate of systemic thrombo-/fibrinolysis was significantly (< 0.05) increased. The interval between onset of symptoms and the emergency call was 62 ± 54 min and did not significantly differ between both analyzed periods. Stroke education of professional health care personal is efficient in terms of a significant reduction in transportation and management latencies, therefore increasing the number of patients suitable for a specific acute stroke therapy. P362 HYPERTENSION, ISCHEMIC STROKE AND MITRAL ANNULAR CALCIFICATION: NEVER ENDING STORY? Henriques IL, Correia J*, Leitão AL. Neurology and Internal Medicine* Departments; Hospital Espírito Santo, Évora, Portugal Mitral valve annular calcification (MAC) is associated with an increased risk for ischemic stroke both in hospital and community populations. We studied the hypothesis that other factors could be associated with MAC in patients with isquemic stroke. Material and methods: We prospectively included all patients that were consecutively submitted to transthoracic echocardiography in our department (1/6/1995–31/12/1997). We considered MAC a band of dense high-intensity echoes between mitral valve and the posterior left ventricular wall. All stroke patients were studied according to a protocol including at least one CT-scan or MRI. We analysed the association of MAC with sex, age, diabetes, hypertension, hyperlipidemia, smoking history, left ventricular hypertrophy, left atrial enlargement, mitral valve prolapse, ischemic heart disease, non-rheumatic atrial fibrillation and ischemic stroke. We analysed the data using a statistical package, including logistic regression analysis. From 623 patients with median age 66 years, 280 were male. Results: MAC was present in 292 patients (47%) and recent ischemic stroke(less than 8 days) in 133(21.3%). Non-rheumatic atrial fibrillation (NRAF) was present in 55 (8.8%), ischemic heart disease in 77 (20%). MAC related with hypertension ( p = 0.0000, Odds Ratio: 3.09; 95% Confidence Interval: 2.21–4.32), age over the median (p = 0.017; OR: 1.50; 95% CI: 1.08–2.10) and isquemic stroke ( p = 0.0026; OR: 1.87; 95%CI: 1.24–2.81) but not with NRAF ( p = 0.3630; OR: 1.29, 95%CI 0.74–2.25) or any of the other factors. Conclusion: Hypertension, age over 66 years and ischemic stroke are independently related with MAC in this population. NRAF is defenatly not related with MAC. MAC increases with age and is related with isquemic stroke both in hospital and population based studies. Together with hypertension, MAC is highly related with ischemic stroke. The meaning of the relationship between MAC and hypertension in ischemic stroke patients needs further research. P363 MODELS FOR THE STUDY OF BRAIN BEHAVIOR RELATIONSHIP IN BRAIN DAMAGED PATIENTS. O. Godefroy, A. Duhamel, X. Leclerc, H. Henon and D. Leys. Lille, France The anatomy of brain functions has been mainly derived from the study of brain-damaged patients. However major uncertainties still persist on the exact delimitation of brain lesion involved in specific disorder which are mainly due to methodological drawback. This study put forward four modes of brain-behavior relationship consistent with neurological data (unicity: one deficit-one lesion; equivalence: one deficit-two possible lesions; association: one deficit-association of two lesions; summation: deficit intensity is related to the number of lesions). A preliminary study assessing the reliability of statistical procedures showed that classification tree analysis provided the best account. In the validation study we examined lesion locations associated with motor weakness in 29 consecutive stroke patients (23 with motor weakness). Lesion location was determined

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on Magnetic Resonance Imaging. Selected lesions were compared to the anatomy of the human motor system. It mainly showed that (1) motor weakness was only observed in patients with lesion including the pyramidal system (gyrus precentralis and central part of the centrum semiovale (n = 13), posterior arm of the internal capsule (n = 9), antero-lateral part of the mesencephalon and pons (n = 1)), (2) that the classification tree test provided a perfect agreement with motor weakness predicted by lesion locations ( p = l), and suggested an equivalence mode of brain-behaviour relationship. This study supports that motor weakness in stroke patients is mainly due to lesion involving the pyramidal tract at any location and provides models that allow to document more precisely the anatomy of brain functions and its pathology. P364 ISOLATED VASCULITIS OF THE CENTRAL NERVOUS SYSTEM (CNS) OR SYSTEMIC VASCULITIS PAUCISYMPTOMATIC? J. L. Bru, E. Díez-Tejedor, F. Vivancos, F. Palomo, P. Barreiro. Servicio de Neurología.Unidad Cerebrovascular. Hospital Universitario La Paz, Universidad Autónoma de Madrid, Spain The isolated vasculitis of the CNS is a granulomatous vasculitis or nongranulomatous vasculitis defined as limited at CNS, characterized for headache, encephalopathy and focal deficits. After to analyse our series we propose clarify this entity. Material And Methods: Patients with the diagnosis of isolated vasculitis of the CNS between 1986–1996 on basis at clinics criteria, laboratory (standard, serology, immunology, cerebrospinal fluid (CSF) ), computerised tomographic (CT), magnetic resonance imaging (MRI), angiography and histology. Results: We include 7 patients with mean ages 49 + 9.1 (35–62) (women 4, men 3). 4 (57%) with cerebral ischaemia, 1 tentorial infiltration. In 6 (85%) the CSF was inflammatory with mononuclear pleocytosis. Angiography positive in 5 (71%). The histopathology showed granulomatous cerebral vasculitis (1 case) and systemic necrotizing vasculitis (1 case). The whole of cases had been diagnosed the isolated vasculitis of the CNS, that after of the study were identified as: non-granulomatous vasculitis (3), although with incomplete study; and granulomatous vasculitis (4): 1 idiopathic (sarcoidosis), 1 sarcoidosis, 1 polyarteritis nodosa group, 1 herpes zoster infection. Conclusions: The isolated vasculitis of the CNS may be paucisymptomatic shape, or systemic vasculitis which first manifestation affect at CNS. We think necessary an exhaustive diagnostic study. They may be classified as: nongranulomatous, and granulomatous (idiopathic or associate at other entities). P365 MULTIPLE VERTEBROBASILAR INFARCTS AND CARDIOEMBOLISM. Verdelho A, Pereira J, Ferro J. Neurology Department. Hospital Santa Maria, Lisbon, Portugal Background: While multiple cortical infarcts are usually related to cardioembolism, the pathogenesis of multiple, simultaneous, vertebrobasilar (VB) infarcts is often obscure. Purpose: To compare the association of single and multiple, simultaneous VB infarcts with emboligenic cardiac conditions. Method: From an hospitalar prospective registry of stroke we retrieved acute non lacunar infarcts of the VB territory, without previous episodes of stroke in any territory or VB TIA. Two groups were compared: patients with single VB infarct (n = 49) and patients with multiple VB infarcts (n = 24) in respect to conventional risk factors for cerebrovascular disease, ancillary procedures performed, VB arterial abnormalities, associated emboligenic cardiac conditions, and possible infarct pathogenesis (TOAST criteria). Results: Proportions of risk factors and of ancillary procedures performed in the two groups were similar, except for hypercholesterolemia, (more frequent in the multiple infarcts group: 46% vs 22%, difference 23% 95% CI: 0.3–46.5), and transcranial doppler that was performed in 67% of patients with multiple infarcts vs 43% of patients with single infarcts (difference 24%; 95% CI: 0.4–47.2%). In the multiple infarct group, potencial cardioemboligenic conditions, cardiac diseases with medium-high emboligenic risk and atrial fibrillation were more frequent (respectively 53% vs 11%, difference 41% 95% CI: 15.9–65.8; 11% vs 6% difference 5%, 95% CI: –11,3 – 20.5 29% vs 16%; difference 13%; 95% CI: –8.1 – 33.8). Conclusion: Simultaneous multiple non lacunar VB infarcts are predictive of cardioembolism. P366 CENTRUM OVALE INFARCTION IN 129 PATIENTS: NEUROIMAGING AND CLINICAL PATTERNS. T. Moulin, C. Barisien, L. Tatu, F. Vuillier, D. Chavot, E. Berger, L. Rumbach. Departments of Neurology, Besançon F-25000, France

The natural course, etiologies and clinical patterns in centrum ovale (CO) infarction are still commonly discussed. Methods: Using Stroke Data Banks, all patients (pts) with a compatible CT or MRI infarction mainly involving the CO were analyzed. Infarcts were classified according to the depth of the extension: limited to CO in group 1, the upper part of internal capsule in group 2, or the basal ganglia or claustrum in group 3. The neuroimaging aspects of infarcts were also analyzed: forms, size, anteroposterior and lateral extension. Clinical syndromes, vascular risk factors, potential causes, infarct volume, early (1-month) outcome (Rankin scale) were also studied. Results: There were 70 males, with a mean age of 67.8 y. Clinical presentation were as follows: motor involvement in 91.5% of the pts (complete in 22.5%, proportional in 44.9%), sensory dysfunction in 42% (complete in 10%, proportional in 61%), hemianopia in 22.5% and cognitive dysfunction in 45%. The outcome was good (Rankin 1–3) in 76.8% of all pts. A cardioembolic source was found in 31% of the pts, small vessel disease in 15%, large vessel disease in 46% and the etiology remained undetermined in 16%. Large vessel disease was the most frequent etiology in group 2. Group 1 infarcts were smaller (0.9 ml), ovoïd, with a lateral extension, and with a better outcome (85%). Group 1 pts more frequently presented nonproportional motor and sensistive deficits and less often cognitive dysfunction and heminopia, except in the posterior location. Deep extension was associated with a poor outcome (33%) and a greater volume (5.7 ml). Conclusions: Our findings suggest that clinical findings in CO infarcts are heterogeneous and depend to the location and volume of the infarction. A precise delineation of the anatomy of the CO is necessary.

P367 SUBADVENTITIAL RUPTURE OF THE INTERNAL CAROTID ARTERY WITH DELAYED SYMPTOMS. J. M. Trocello, F. Gigou, L. Marcy, A. Azria, A. Améri, F. Chédru. Neurology Department, Centre Hospitalier de Meaux, France A 19-year-old man suffered, after a motorcycle accident, a cranio-facial injury with a mandibular fracture. After 4 months, he was admitted for a left hemiplegia of sudden onset. Examination disclosed, in an obtundated patient, a left sensory-motor deficit with a left-sided neglect. Computed Tomographic scan disclosed an infarct in the territory of the right middle cerebral artery. An initial Doppler ultrasound study was negative. Angiography demonstrated an aneurysm of the right internal carotid artery at the base of the skull with an intra-luminal image considered as an intimal flap. The patient was treated with anticoagulants for 1 month. Subsequently, given the risk of complete arterial disruption and further emboli, surgical management was decided. The aneurysm was resected and an interposition of venous graft performed. There was a fresh thrombus extending from the aneuvrysm into the arterial lumen. On histological analysis, the aneurysm appeared to correspond to a subadventitial rupture of the artery. The postsurgical follow-up was uneventful and the patient partially recovered. This case should remind neurologists that delayed symptoms may occur in blunt carotid injuries. Neurologic aspects of subadventitial rupture of the internal carotid artery are reviewed and the place of this entity among the various types of arterial injuries discussed.

P368 APOPLIPOPROTEIN E DEFICIENT MICE SHOW DECREASED NACETYL ASPARTATE IN CENTRAL BRAIN REGIONS FOLLOWING TEMPOPARIETAL CORTICAL INFARCTION: EVIDENCE FOR REMOTE NEURONAL DYSFUNCTION. Pendlebury ST, Liess C, Cassidy P, Styles P, Matthews P. Oxford, UK Introduction Apolipoprotein E (apoE) appears important in the response to brain injury. In humans, the E4 isoform has been associated with an increased risk of Alzheimer’s disease and poor outcome from head injury. Aims The current experiment was designed to test i) whether apoE deficient mice (transgenic knockouts) show larger infarcts following middle cerebral artery occlusion as compared to wild type mice and ii) whether central brain regions remote from the infarct show secondary neuronal metabolic dysfunction. Methods Strokes were induced in 15 apoE deficient mice and 14 wildtype adult mice via distal middle cerebral artery occlusion at day 0. T2 weighted magnetic resonance imaging and proton spectroscopy localised to the central brain were performed at baseline and days 1, 3 and 7. Results Coronal images revealed tempoparietal cortical infarction of similar volume in transgenic and wildtype mice. In contrast, Nacetyl aspartate (NAA) levels in the central brain showed a reduction with time in the apoE deficient mice but not in the wild type mice (anova p = 0.03, linear regression analysis, p = 0.03). Conclusion These results indicate that apoE deficiency causes neuronal dysfunction in remote central

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brain regions following cortical infarction presumably through a reduced neuronal resistance to secondary injury. P369 ELEVATED CHLAMYDIA PNEUMONIAE ANTIBODIES IN ACUTE HEMISPHERICAL STROKE – A STUDY IN 60 CONSECUTIVE PATIENTS. I. Blaeser, Th. Rotermund, J. Leclaire, J. Jörg. Department of Neurology, University of Witten/Herdecke, Klinikum Wuppertal, Germany In 1987 Saikku for the first time demonstrated an association of coronary heart disease and carotid atherosclerosis with elevated Antibodies against Chlamydia (Ch.) pneumoniae. More than ten years later the thesis of chlamydial infection as a new independent risk factor for atherosclerotic disease becomes more and more popular. Our aim was to investigate the seropositivity for specific chlamydial antibodies in our stroke patients. Methods: Antibody titers (IFT) against Chlamydia pneumoniae were measured in 60 consecutive patients with acute hemispherical stroke and in 20 control patients. Using routine diagnostics localization and pathogenesis of cerebral ischaemia were assessed. Results: There was seropositivity in 50/60 (83%) of the patients; 35/60 (58%) were positive for specific IgG, 5/60 (8%) for IgM and 45/60 for IgA. Control patients presented significant lower antibody titers especially for IgA. Discussion: We were able to confirm the association of cerebrovascular disease with elevated Ch. pneumoniae antibodies and conclude that chronic infection with Ch. pneumoniae may be a new independent risk factor. Clinical relevance in context of classical risk factors and routine diagnostics will be discussed. P370 BASIC FIBROBLAST GROWTH FACTOR IN HUMAN BRAINS AFTER ISCHEMIC STROKE. D. Dziewulska. Warsaw, Poland Basic Fibroblast Growth Factor (bFGF) is expressed in injured CNS tissue. We examined the time course and distribution of bFGF in the first 4 weeks of the disease and after 30, 50 and 90 days in patients with ischemic stroke at the age of 38–92 years. Material comprised of 35 brains with ischemic infarct in area supplied by the middle cerebral artery. Immunohistochemical analysis using antibodies against bFGF, GFAP and NSE showed that the first immunoreactive cells – a few neurons with features of ischemic damage – appeared on the 2nd day after the stroke onset and were present during the first week of the disease. First bFGF positive astrocytes were detected on the 3rd day. Then the number of bFGF immunoreactive astrocytes gradually increased reaching its maximum at the end of the 2nd week. Double staining revealed that only a part of GFAP positive astrocytes were also bFGF immunoreactive. They were observed only in tissue adjacent to the necrosis. From the 27th day we did not observed bFGF positive astroglial cells. The bFGF immunoreactivity was also shown by macrophages inside necrostic area between the 3rd and the 20th day and by endothelial cells in the area surrounding the infarct between the 5th and the 22nd day. Because bFGF expression was observed mainly and for the longest time in astrocytes, we conclude that astroglia may be the main source of bFGF in brain ischemia with subsequent influences on neovascularization and repair reactions. P371 C677T MUTATION ON METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE AND FACTOR V LEIDEN IN CEREBROVASCULAR PATIENTS. P. Bedoucha*, M. Candito**, D. Jambou***, F. Fischer***, E. Van Obberghen**, M. Chatel*. *Neurology Dept., **Biochemistry Dept., ***Hematology Dept., Hôpital Pasteur, Nice, France Hyperhomocysteinemia is a recognized risk factor for vascular events, favoring both arteriosclerosis and thrombosis. Factor V Leiden is a significant factor in thrombosis and is the most frequent cause of familial thrombophlebitis. The C677T mutation on the MTHFR gene is found in similar proportions (12%) in the homozygous state in patients who suffer a cerebrovascular event (CVA) of nonembolic origin and in controls. However, this mutation is correlated with a discrete increase in homocysteinemia. Previous studies limited to the role of factor V Leiden in CVA or myocardial infarction (MI) (Kontula) have failed to show any difference between patients and controls. We investigated the potential role of the association of these two mutations in a group of 40 patients (13 CVA, 27 MI). Fifteen of these 40 patients were homozygous for the C677T mutation. Factor V Leiden was found in 3 of the MI patients: 2 were homozygous for the C677T mutation while the third was heterozygous. Factor V Leiden was not identified in any of the CVA patients, one of whom had homocystin-

uria related to a defect in cystathionine beta synthase and a history of cerebral thrombophlebitis in childhood. Preliminary results require confirmation in larger series owing to the important role of factor V Leiden and hyperhomocysteinemia in thrombotic disease.

Extrapyramidal Disorders P372 THE RELATIONSHIP BETWEEN CLINICAL SIGNS, THE ATROPHY OF THE CAUDATE NUCLEUS AND CAG TRIPLETS REPEAT IN HUNTINGTON’S DISEASE. Jan Roth1, Jana Židovská 3, Šárka Rùzièková 3, Eva Havrdová1, Vladimír Línek1, Tereza Uhrová 2, Marek Preiss2. Clinic of Neurology1, Clinic of Psychiatry2, Department of Human Genetics3, Charles University, Prague, Czech Republic We evaluated clinical data from 33 patients with Huntington’s Disease (HD) and compared them with CAG triplets repeat and the planimetric measurement of caudate nucleus head area (CNHA) in CT scans. The mean age of patients was 48.2 yrs (SD: 9.8 yrs), the mean duration of HD 8.1 yrs (4.8), the mean age at the onset of HD 40.1 yrs (9.5). HD started with motor symptoms in 22 patients, and with psychiatric symptoms in 11 patients. The paternal transmission was observed in 21 patients, the maternal one in 11 patients, unknown in 1 patient. The mean CAG triplets repeat was 47.6 (6.7). The mean CNHA was 0.41 cm2 (0.1). We found statistically significant reversed correlation between CAG triplets repeat and the age at the onset of HD ( p < 0.0005). The earlier onset of HD in patients with the paternal transmission compared to the maternal one was found statistically significant (p < 0.001). No differences concerning the age at the onset of HD were found between subgroups starting with motor or psychiatric symptoms. We also observed the significant reversed correlation between the duration of HD and CNHA measurement (p < 0.001). Even in the earliest stage of HD patients showed the marked atrophy of CNHA. P373 MAGNETIC PULSE STIMULATION – AN ADDITIONAL THERAPY FOR PARKINSON’S DISEASE? I. Schöll and A. E. Henneberg. Hospital for Parkinson’s Disease, Bad Nauheim, Germany The etiology of Parkinson’s disease is still unknown. Since the begin of LDOPA treatment by Birkmayer and Hornykiewicz in 1961 many different pharmacological approaches have been developped for a symptomatic treatment, supported by physiotherapy. However, in advanced states of the disease patients are impaired by additional symptoms. In 1992, Sandyk described a magnetic field therapy of Parkinson’s disease. We tested this method as an additional therapy in 100 patients evaluated by UPDRS III before and immediately after treatment and controlled by video tape-records. One hundred patients after written informed consent underwent a 30 minutes’ treatment, 15 minutes’ rest and again 15 minutes’ treatment with pulsed magnetic fields of the picoTesla range. The intensity, frequency and form of the pulses was adjusted individually to the needs of the patients. UPDRS III was performed before and after the therapy. Medication and other additional therapies were applied as usual, EEG’s were controlled within the following two days after treatment to exclude a developping epilepsy (5%). The patients showed an individual answer to the magnetic pulse stimulation with a maximum improvement of 90.0%. The mean improvement of UPDRS data was 28.7% with a variance of 23.2%. The medication had to be continued. Magnetic pulse stimulation seems to provide a promising additional therapy of Parkinson´s disease. A longterm study to control the longitudinal effects of the therapy has been started. P374 QEEG FINDINGS IN PATIENTS WITH VASCULAR PARKINSONISM. J. C. M. Zijlmansa, J. W. Pasmanb, M. W. I. M. Horstinka, S. L. H. Notermansb. aDepartments of Neurology, bClinical Neurophysiology, University Hospital Nijmegen, The Netherlands The diagnosis of vascular parkinsonism has been challenged for decades. The goal of the present study is to investigate whether the quantitative EEG’s of patients with vascular parkinsonism (atypical parkinsonism and extended subcortical MRI lesions) differ from those of patients with Parkinson’s disease. Therefore the qEEGs of 12 patients with vascular parkinsonism and of 12 Parkinson’s disease patients are compared for previously established ischemic EEG parameters. Furthermore, occipital slowing, assessed as an increase of relative delta and/or theta bandpower in the parieto-occipital leads by neurometric evaluation, was taken into account

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as a potentially discriminating parameter for Parkinson’s disease. It appeared that the EEG’s of patients with vascular parkinsonism are different from those of patients who have Parkinson’s disease. Although these patients did not have significant more signs that can be associated with ischemia, they had significantly less occipital slowing than patients who had Parkinson’s disease. This means that patients with vascular parkinsonism are not patients with Parkinson’s disease and coincidental subcortical vascular lesions. P375 TETRABENAZINE IN HUNTINGTON’S DISEASE. D. Paleacu, N. Giladi, A. D. Korczyn. Tel Aviv, Israel Huntington’s Disease (HD) is an autosomal dominant inherited disease which is characterized by choreoathetosis, dementia and/or psychiatric disturbances. Objectives: To assess the influence of tetrabenazine (TBZ), a monoamine depletor and mild dopamine receptor blocking drug on HD patients. Methods: Over the past year and a half we have treated 10 HD patients (mean age: 49.3 ± 11.2 years and mean disease duration of 10.7 ± 6.5 years) with TBZ. The response was rated by a clinical global impression of change scale (CGIC) of 1 to 5 (1 = marked improvement, 2 = good improvement, 3 = very mild improvement, 4 = no improvement, 5 = worsening) which was assessed at the last clinical visit. An Unified Huntington Disease Rating Scale (UHDRS) was performed at baseline and during the last visit. Results: The average duration of TBZ treatment was 9.3 ± 5.2, range: 0.5 to 18 months)? The average dose of TBZ was 57.5 ± 20.6 mg daily. 50% of the patients rated their improvement as marked (= 1) on the CGIC while the mean CGIC score was 2.1 ± 1.3. Chorea was the main sign to be improved while the UHDRS showed a trend towards deterioration as disease progressed. The most common side effects of TBZ treatment were drowsiness, and parkinsonism which were effectively controlled with dosage reduction. Conclusions: TBZ is an effective and safe symptomatic drug for the treatment of chorea in HD and in contrast to typical neuroleptics TBZ has not been shown to cause tardive syndromes. P376 URINARY DYSFUNCTION IN IDIOPATHIC PARKINSON’S DISEASE. Krygowska-Wajs A, Szczudlik A, Wêglarz W, Dobrowolski Z. Depart. Neurol. and Depart. Urol. Jagiellonian Univ., Cracow, Poland Although urinary dysfunction in IPD are very common, the incidence of urinary disturbances and urodynamic dysfunction is not exactly known. The aim of the study was to evaluate the frequency of urinary disturbances in patients with idiopathic Parkinson’s disease and their relationship to stage of the disease. The investigation was carried out on 41 patients aged 37–84 (mean 61.6) years. The neurological examination, including evaluation of parkinsonism according to UPDRS scale was conducted together with the urogical one, including uroflowmetry and cystometry. Patients with the infection of the urinary tract and prostate hypertrophy were excluded from the examination. 32 (78%) patients had urinary symptoms: frequency in 27 cases (65%), urgency in 9 cases (21%), urge incontinence in 1 case and dysuria in 1 case. Disorders in urodynamic examination were found in 26 cases (63%). They were: detrusor hyperactivity in 21 cases (51%), prolonged time of micturition in 18 cases (43%) and decrease of maximum flow rate in 19 cases (45%).Detrusor hyperactivity was more frequent in patients with extent parkinsonian motor signs (III part of UPDRS). The results of the examination indicate frequent urinary disturbances which can be markedly improved with levodopa treatment. P377 NEUROTOXICITY OF SALSOLINOL – A REVIEW. F. Durif, 1P. Dostert, G. Dordain. Fédération de Neurologie, CHU Clermont-Ferrand, 1Biotral Laboratory, Rennes, France Salsolinol (1 methyl-6,7 dihydroxy 1, 2, 3, 4-tetrahydroisoquinoline) (SAL), a tetrahydroxy-isoquinoline derivative, is an endogenous compound which results from the condensation from dopamine with acetaldehyde or pyruvic acid. Several lines of evidence suggest that SAL and SAL derivatives are implicated in the pathophysiology of Parkinson’s disease, acting as specific cytotoxic compounds on dopaminergic neurons: 1) SAL and Nmethylsalsolinol are detected predominantly in the human brain as the (R)enantiomer, suggesting that these compounds are synthesized enzymatically from dopamine. 2) (R)-methylsalsolinol is increased in the cerebrospinal fluid of Parkinsonian patients compared to control subjects. 3) In vitro studies have shown that SAL and norsalsolinol elicit cytotoxic effects on PC 12 cells, and both compounds have been shown to be accu-

mulated in the mitochondrial fraction of PC 12 cells after 3 days in culture. 4) (R)-methylsalsolinol injected into the rat striatum induces behavioral changes similar to those observed in Parkinson’s disease, with a selective reduction of tyrosine hydroxylase containing neurons in the substantia nigra after continuous administration. The specific neurotoxicity of SAL and derivatives on dopaminergic neurons in substantia nigra is thought to result from the selective uptake of N-methylsalsolinol in dopaminergic cells by a dopamine transporter. Then, N-methylsalsolinol and the more cytotoxic 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion may cause cell death by generating oxygen radical species and/or inducing DNA damage. P378 TWO FAMILIES WITH FAMILIAL PARKINSONISM. M. Cenk Akbostanci, Halil Karabulut, Gamze Güngör, Sedat Ulkatan, Aytaç Yigit, ˘ Išk Bökesoy, Nermin Mutluer. Ankara University, Medical Faculty, Departments of Neurology and Genetics We present of two families with familial parkinsonism. Pedigree analysis revealed that there were five affected persons in two successive generations in the first family and four affected persons in the same sibship in the second family. In the first family the mean age at onset of the two patients from the second generation was 52.5, while it was 35.7 for the three patients at the next generation which might suggest anticipation. Mean age at onset in the second family was 36.7 (range 28–53). Patients had mild to moderate parkinsonism with symmetrical bradykinesia, rigidity, and postural instability, although the mean disease duration was 13 years (range 2–30). Except for a male who had a symmetrical mild resting and postural tremor, none of the patients had tremor. Two males from the first family had impaired saccadic movements of downgaze. Levodopa responses were excellent. All the patients had almost no disability with daily doses of 250–500 mg of levodopa, but they all had peak-dose dyskinesias with a mean dose of 368 mg (range 250–500) daily. Possible etiologies were ruled out by appropriate testing. The distinctive features of the presently reported patients from sporadic Parkinson’s disease are early mean age at onset, slow rate of progression, symmetrical parkinsonism without tremor, appearance of levodopa dyskinesias with low doses. P379 EFFECT OF DOPAMINE AGONISTS ON FREE RADICALS AND BRAIN BIOELECTRICAL ACTIVITY IN PARKINSONIAN PATIENTS (PD). Karaban I, Kucherjanu V*, Karaban N, Kapoustina M, Garkavenko, V. Institute of Gerontology, Kiev, Ukraine. *Institute of General Pathology and Pathophysiology, Moscow, Russia This investigation was primarily concerned with determining a neuroprotective action of Parlodel, used in minimal dosages, in treatment of I’D patients. In the group of 22 patients with PI) stage 1.5–3.0 of Hoehn a. Yahr scale, we carried out a course treatment with Parlodel (2.5 mg/daily for 30 days) against the background of basic therapy with levodopa/carbidopa (Sinemet-250). The effect of treatment was evaluated by means of UPDRS motor scale, EEG mapping and plasma malon dialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) measurements. We registered an improvement (by 12%) of the motor activity (UPDRS items 18–31) in study patients. In 34% of patients this paralleled the decrease of thetarhythm capacity (from 50.8 to 32.3 VtV2) and maximal power of alpha activity in frontal-central regions of the brain. There was a considerable rise of SOD (from 2.33 to 3.81 me/mg Hb, p < 0.001). The antioxidant factor (SOD activity × CAT activity / MDA concentration ratio) increased from 850.7 to 1077.1. It is suggested that Parlodel can be included as part of basic treatment for preventing the disease progression. P380 MYOCLONIC REACTION IN A PATIENT WITH FAMILIARY ESSENTIAL MYOCLONUS. C. Saft, P. Kraus, H. Przuntek and Th. Müller. Department of Neurology, Ruhr-University of Bochum, Germany About 150 members of a family including 25 persons suffering from a familiary essentiell myoclonus were studied since many years. It has not been possible to detect the gene locus. One male member of this family showed a myoclonic reaktion with flexion of the tous 2 to 4 (M. flexor digitorum longus), induced by a sensitive stimulus in front of the shinbone. Manual triggering of the reflex arc showed nerve conduction latencies of 33 to 38 ms in the electrophysiological examinations, which could be explained by a spinal site of the generator. But we also found latencies with 50 to 60 ms. These findings do not fit to a spinal site of the generator, neither to a cortical. We speculate, that these results may be explained by a

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reticular site of the generator. This strong effect is considered to be a form of myoclonic reaction. P381 CELLA MEDIA INDEX AND PARKINSON’S DISEASE. L. Markovic1, N. Prvulovic1, A. Beric2, R. Marinkovic1. 1Department of Anatomy, University of Novi Sad School of Medicine, Novi Sad, YU. 2Department of Neurology, Hospital for Joint Disease, New York University School of Medicine, New York, USA One of the numeric measure of central atrophy is Cella Media Index (CMI) (ratio between distances of walls of the lateral cerebral ventricles’ central parts and appropriate brain or cranial width). The aim of this study was to determine if there is a difference of CMI values in cases of Parkinson’s disease (PD) vs. health individuals, and according to the age and sex, too. Material and methods: CMI is the ratio between: the shortest (longest) distance between central part of lateral brain ventricles’ lateral walls and brain or cranial width at the appropriate level (CMI21 or CMI22; CMI11 or CMI12). Cerebral ventricular system was studied in 59 PD patients, and in 60 healthy voluntaries. 1.5T GE Signa MRI scanner and 1.5TE SP634000 Siemens were used. Measurements were made on axial MR images. A set of contages 5 mm thick were obtained with spin echo T2-w (TR/TE 2000/80) sequences and a set of contages 6 mm thick were obtained with turbo spin echo T2-w (TR/TE 3700/93). Results and Conclusion: Positive, significant correlation was obtained between CMI21 and CMI22 indexes and the age of both patients and healthy voluntaries. There was significant difference between CMI11, CMI21 and CMI22 in both investigated groups. There was no sexual dimorphism between determined values in both groups.

P382 APPLICATION OF MRI IN PATIENTS WITH EXTRAPYRAMIDAL SYMPTOMATOLOGY. D. Djilas, D. Kozic, D. Bogdanovic, B. Petrovic, K. Kopriv˜sek, M. Lucic, O. Adic, M. Prvulovic. Magnetic Resonance Center, Sremska Kamenica, Serbia The purpose of the study was to evaluate the sensitivity of MRI in revealing possible pathology in patients with extrapyramidal symptomatology as the chief complaint. Seventy-eight patients were examined on 1,5T imager (Magnetom SP 63 4000, Siemens). MR finding was negative in 47 patients (60%). In 15 cases multiple ischemic lesions involving basal ganglia were detected. Only 15% of patients with clinically typical Parkinson disease had positive MR finding (most obvious sign was narrowing of pars compacta of substantia nigra). Striatonigral degeneration was evidenced in 4 patients, non-specific lesion in basal ganglia unilaterally in 3 and diffuse cortical atrophy in 4 patients, respectively. In 3 patients typical lesons for Willson’s disease were documented and this diagnosis was later on confirmed biochemically. Computerized tomography was performed in majority of cases prior to MRI and all findings were negative apart from several cases with ischemic lesions, cortical atrophy and one patient with Willson’s disease. Our results suggest MRI as the useful diagnostic modality in revealing the possible pathology in patients with extrapyramidal symptoms. Unfortunately, sensitivity for confirming the diagnosis of Parkinson s disease is rather poor. Computerised tomography should not be performed in patients with extrapyramidal syndrome. P383 AN AUTONOMOUS DEVICE FOR MEASURING GRIP FORCE AND OBJECT MOVEMENT FOR THE STUDY OF MANIPULATIVE ACTIONS. J. Philipp, N. Mai. Dept. of Neurology, Ludwig-MaximiliansUniversity, Munich, Germany The investigation of grip force control is a unique method for investigating sensorimotor disorders of the upper limb. The control of grip force is a highly developed skill which requires precise coordination of sensory input and force output. Grip force is subtilely affected by the physical properties of grasped objects, such as weight or surface friction, as well as cognitive learning variables, e.g. familiarity with the object. Under the dynamic conditions of handling an object, grip force is perfectly attuned to the object motion. Sensory or motor deficits lead to characteristic disturbances of this skill. The practical investigation of dynamic grip force control has been limited by the fact that a typical measurement device connects the sensors inside the object to a computer via cable. We report on a newly developed device that allows cable-free measurement of grip force and all six degrees of freedom of movement. All sensors, controls, and storage systems are integrated in a can-shaped object, 90 mm in diameter

and 45 mm in height, which offers completely independent measurement and easy bedside investigation. Recording time is approximately 20 minutes when sampling data with 100 Hz/12 bit per channel. The complete data can later be transferred to a PC for further analysis. In addition to technical details the recordings of normal subjects and neurological patients are also presented.

History of Neurology P384 CONSTANTIN VON MONAKOW’S FORMING YEARS. Jürg Kesselring, MD. Rehabilitation Center, Valens, Switzerland Constantin von Monakow (1853–1930), the well known neuroscientist, first Professor of neurology in Switzerland and founder of the Swiss Neurological Society spent the first seven years of his long and successful career as assistant physician in the Psychiatric clinic in Pfäfers in the remote Tamina Valley. In this clinic, situated in an old Benedictine monastery, von Monakow completely on his own performed ablation experiments on cats and rabbits which allowed him to describe for the first time the connections between cortex and thalamus accurately and correctly. He described the rubro-spinal tract in these animals which now bears his name as eponym. And it was during these years that von Monakow laid the basis to the concept of what later became well known as “diaschisis”. Only in our days has it become possible through modern imaging techniques to prove this far-reaching concept to be a possible explanation for recovery mechanisms after brain injury and of neuroplasticity.

P385 Visual art in Duchenne’s practice. M.J Al-Aloucy. Hôpital Victor Hugo, 93380, Paris, France Although he was excluded from the Salpêtrière and the academic life in Paris, Duchenne had the courage to work alone in his private office. In his daily practice, physiological experiments, papers and textbooks, we see Duchenne not only as a neurologist but also as a great artist. He certainly was one of the first world neurologist who used photograph in his work. Later on, Charcot established the first clinical photography department in a hospital influenced by his friend. In the study of the facial muscles of expression, Duchenne considered art and neurology to be pivotally. Although his theory of human facial expression was criticised by many of doctors of his epoch, even from his friend Darwin,. his effort had a considerable impact on neurology,psychology and fine art. The paper examines the artistic talent of Duchenne de Boulogne, through his original photographs, his theory of emotions and human facial expression and its application to paintings and sculptures.

P386 ORIGIN OF STRIATONIGRAL DEGENERATION: A HISTORIAL REVIEW. J. Berciano, O. Combarros, J. M. Polo, J. Pascual and A. Oterino. Santander, Spain Objective: To revisit the papers by Scherer (Z ges Neurol Psychiat 1933; 145 : 335–405 and 406–419) describing four sporadic olivopontocerebellar atrophy (OPCA) cases thought to represent the earliest clinicopathological description of striatonigral degeneration (SND). Background: The original SND description is currently attributed to Adams, Van Bogaert and Van der Eecken (Psychiat Neurol [Basel] 1961; 142 : 219–259). Design/Methods: We reviewed Scherer´s aforementioned papers published in 1933. It is worth noting that then extrapyramidal rigidity associated with OPCA was considered as a type of “cerebellar” parkinsonism (Guillain et al., Rev Neurol [Paris] 1928; 50 : 590–595). Results: Two of the Scherer’s four patients had severe parkinsonism masking cerebellar semeiology. Pathologically both cases displayed marked degeneration of the striatum and substantia nigra and non-fully developed ponto-cerebellar atrophy. Cerebellar ataxia was the outstanding symptomatology in the other two, their pathological study showing severe ponto-cerebellar lesions and incipient striato-nigral atrophy. Scherer stated that the severity of extrapyramidal rigidity in OPCA correlates not with the degree of cerebellar degeneration but with that of striatum and nigra. Furthermore, he compared the observed striatal lesions with those reported in Huntington’s disease proposing that this disease, OPCA and Pick atrophy should be included under the same nosological umbrella. Although Van Bogaert was

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aware of Scherer’s papers (Traité de Medicine, vol XVI, Paris: Masson 1949 : 142–218) these were overlooked by Adams and colleagues. Conclusions: Scherer gave the first accurate description of SND. Moreover his contribution was essential in ruling out the prevalent concept of “cerebellar” parkinsonism in OPCA. Supported by “Fundación Marcelino Botín”, Santander, Spain.

Multiple Sclerosis P387 COMPARISON OF PROTON DENSITY/T2 (PD/T2) AND GADOLINIUM-ENHANCED T1 (GD-M1) MRI IN DEMONSTRATING A TREATMENT EFFECT AND DOSE DIFFERENCE IN PRISMS TRIAL OF INTERFERON ??1a (REBIF®). David Li1, Guojun Zhao1, Robert Hyde2, Florilene Dupont2, Ayad Abdul-Ahad2, Yan Cheng1, Xiuyu Wang1, Donald Paty1. The UBC MS/MRI Research Group, The PRISMS Study Group. 1UBC,Vancouver, Canada; 2Ares Serono, Geneva, Switzerland The PRISMS trial of interferon ??1a in relapsing remitting (RR) multiple sclerosis (MS) used MRI to demonstrate a significant reduction in burden of disease accumulation and disease activity, thereby supporting the positive clinical results showing reduction in disease progression and exacerbation. Here, the value of the different types of MRI activity were compared. 560 patients with RR-MS were randomised to: placebo (n = 187), 22 mcg (6 MIU) (n = 189) and 44 mcg (12 MIU) (n = 184), subcutaneously, three times weekly. All patients had biannual PD/T2 MRI (cohort 1), 198 patients (cohort 2) and 39 patients (cohort 3) had 11and 26 monthly scans, respectively, to determine PD-T2, Gd-T1 and combined unique (CU) activities. A highly significant decrease in mean number of PD/T2 active lesions per patient per scan was seen in cohort 1 between each treatment group and placebo (both p < 0.0001), and between treatment groups (p = 0.0003), favouring the 44 mcg group. In cohort 2, PD-T2, Gd-T1 and CU lesions were significantly lower (all p<0.0001) between both treatment groups and placebo. A significant dose difference was seen only with PD/T2 activity (p = 0.0443). Cohort 3 demonstrated a treatment effect between the 44 mcg group and placebo for all activity measures (PD/T2 p = 0.0120; Gd-T1 p = 0.0474; CU p = 0.0105), but in 22 mcg patients only with PD/T2 activity ( p = 0.0414). Thus, statistically, PD/T2 activity confirms treatment effect and dose-difference more effectively than GD-T1 in smaller patient cohorts.

P388 QUANTITATIVE VOLUMETRIC ANALYSIS OF BRAIN MRI FROM PATIENTS WITH MULTIPLE SCLEROSIS. G. Mastronardo, M. A. Rocca, V. Martinelli, G. Comi, M. Filippi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan We compared the volumes of the brain as a whole and of different cerebral structures from patients with multiple sclerosis (MS) and normal subjects. In the patients, we also correlated brain volumes with T2 and T1 lesion loads and disability. Dual echo scans and, after the i.v. administration of 0.1 mmol/kg gadolinium-DTPA, a magnetization-prepared rapid acquisition gradient echo (MP RAGE) sequence with subsequent reconstruction of axial 1 mm-thick slices were obtained in fifteen patients with either relapsing remitting (RR) or secondary progressive (SP) MS and fifteen sex-, age-, height- and weight-matched healthy volunteers. The brains and the different cerebral structures studied (cerebral hemispheres, cerebellum and brainstem) were then segmented manually by a single observer on reconstructed MP RAGE scans. The same observer also measured the lesions present on the proton density (PD) and on T1-weighted scans. Patients had significantly lower cerebral (p = 0.008), hemispheric (p = 0.01) and brainstem ( p = 0.03) volumes than the normal controls. Cerebral atrophy was detected in 7 (47%) MS patients, hemispheric atrophy in 6 (40%), brainstem atrophy in 3 (20%), and cerebellar atrophy in 1 (7%). No significant correlations were found between the cerebral volumes and the EDSS scores (SRCC = 0.30), the hyperintense (SRCC = 0.16) and the hypointense (SRCC = 0.22) lesion volumes. The degree of disability correlated significantly with the T1 hypointense lesion volumes measured on the MP RAGE scans (SRCC = 0.61, p = 0.02), but not with the hyperintense lesion volumes measured on the PD weighted scans (SRCC = 0.19). This study demonstrates that brain atrophy is a frequent finding in patients with MS and that mean volumes of the brain and different cerebral structures are significantly lower in the MS group compared to the normals. However, despite such reductions, no clear relationship between reduction of cerebral volumes and disability was found.

P390 PROTON MR SPECROSCOPY IN CLINICALLY ISOLATED SYNDROMES SUGGESTIVE OF MULTIPLE SCLEROSIS: EVIDENCE FOR AXONAL LOSS OR DYSFUNCTION. P. A. Brex, B. GomezAnson, S. M. Leary, G. J. M. Parker, G. J. Barker, D. G. MacManus, C. A. Davie, G. T. Plant, D. H. Miller. NMR Research Unit, Institute of Neurology, London, UK Using proton MR spectroscopy (MRS) we studied 11patients with clinically isolated syndromes suggestive of multiple sclerosis (CIS) and 10 controls. Single voxel spectra (mean volume 2.76 mL) were acquired from parietal or periventricular areas (General Electric 1.5T Signa Horizon EchoSpeed scanner, TR 3000ms, TE 30ms, PROBE PRESS). Thirteen spectra were obtained from controls, twelve from normal appearing white matter (NAWM) in patients and four from lesions. Absolute metabolite concentrations were measured using the LC Model. There was a significantly lower N-acetylaspartate (NAA) in the lesions compared with the control group ( p = 0.009). Patient NAWM NAA tended to be lower than control but this was not significant ( p = 0.10). Myo-Inositol was significantly raised in the lesions compared to controls (p = 0.009) and NAWM ( p = 0.0076). There were no other abnormalities. The reduction in NAA suggests axonal loss or dysfunction in demyelinating lesions at the earliest clinical stage of the disease. The prognostic significance of this finding will require prolonged follow-up.

P391 TNF-α DOWN-REGULATION IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS) TREATED WITH INTERFERON-BETA 1a (IFN-β 1a). Lodi Gogovska* #, Risto Ljapcev#. *Klinikum Groβhadern, Clinic of Neurology, Munich, Germany. # Clinic of Neurology, Faculty of Medicine, Skopje, Macedonia The aim of the study was to determine the influence of IFN-β 1a treatment on the serum levels of Tumor Necrosis Factor-alpha (TNF-α) in patients with RRMS. The mechanism(s) of action responsible for the immunomodulatory effects mediated by IFN-β in MS patients are still unclear, although suggestions include anti-viral effects, reduction of transcription of MHC class II molecules, opposition to the effects of proinflammatory cytokines, such as TNF-α which has been ascribed possible disease-promoting role in MS. Enzyme Immunoassay (EIA) was used for the quantitative determination of soluble TNF-α in the sera of 25 RRMS patients. The patients were assayed for the TNF-α before and six (6) months after initiating the treatment with IFN-β 1a administered subcutaneously in a dose of 6 MIU 3 ×/week. Patients had received no steroids or other drugs (with the exception of IFN-β 1a) at least during the last 2 months at the time of blood drawing. Blood samples from 40 healthy individuals served as a control group. RRMS patients after 6 months IFN-β 1a treatment had significantly lower TNF-α serum levels (mean ± SD; 14.2 ± 10.3 pg/ml) as compared to the base-line TNF-α (before initiating the IFN-β 1a treatment; 78.4 ± 28.2 pg/ml) and the control group (29.4 ± 11.9 pg/ml). Conclusion: IFN-β 1a reduces the TNF-α serum levels in RRMS patients. TNF-α down-regulation could be one of the possible mechanisms of action responsible for the immunomodulatory properties of IFN-β 1a in MS patients. TNF-α represents a promising tool to follow-up the effects of the treatment in MS.

P392 SOCIO-ECONOMIC IMPACT OF MONTHLY INTRAVENOUS IMMUNOGLOBULIN TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS (MS): THE AUSTRIAN IMMUNOGLOBULIN IN MS STUDY (AIMS). S. Strasser-Fuchs, F. Fazekas, F. Deisenhammer, G. Nahler, B. Mamoli, for the AIMS Study Group, Austria Relapse rate and disability constitute well accepted measures for determining the efficacy of drugs in the treatment of multiple sclerosis (MS). To the patient a variety of other factors may also seem important. Some of these variables have been documented in the Austrian Immunoglobulin in MS Study (AIMS). In short, AIMS was a 2-year randomised, placebo-controlled, double blind, multicenter trial of monthly intravenous immunoglobulin (IVIG) at a dosage of 0.2 g/kg bodyweight in patients with relapsing-remitting MS (Lancet 1997, 349 : 589–593). In addition to conventional outcome measures we also used the IFMSS self rating scale to record changes of the patients’ general functions including social elements and documented the need for hospitalisation. These variables were compared between IVIG (n = 75/64) and placebo (n = 73/56) treated patients (intent-to-treat/completers). Uniformly, all variables in regard to every

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day living, mood and fatigue were rated better by IVIG treated patients. This was also true in regard to social activities while the capacity for working deteriorated to a similar extent in both groups. The number of hospitalisations was 32 in the IVIG treated group and 54 in the placebo group with fewer days per hospitalisation (13.3 ± 9.8 vs. 20.2 ± 16.7) and a lower mean total time per patient (3.4 ± 7.6 vs. 7.8 ± 14.2; p = 0.06). These results suggest a beneficial effect of monthly IVIG also in regard to more general aspects of MS patients’ living and the reduced need for hospitalisation with all its consequences.

P393 MAGNETIZATION TRANSFER CHANGES IN THE NORMALAPPEARING WHITE MATTER PRECEDE THE APPEARANCE OF ENHANCING LESIONS IN PATIENTS WITH MULTIPLE SCLEROSIS. M. Filippi, M. A. Rocca, M. A. Horsfield*, G. Martino, G. Comi. MS Biosignal Analysis Center, IRCCS Hosp. S. Raffaele, University of Milan, Milan, Italy; *Division of Medical Physics, University of Leicester, Leicester, UK This longitudinal magnetization transfer imaging (MTI) study was designed to evaluate whether a change of the normal-appearing white matter (NAWM) is seen in patients with multiple sclerosis (MS) before enhancing lesion appearance. Every four weeks for three months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, after 0.3 mmol/Kg gadolinium (Gd) injection. During each session, MT and dual echo scans were also performed before Gd injection. On co-registred images, the MT ratio (MTR) was measured in NAWM subsequently involved by enhancing lesions, in NAWM on the same slices but outside any present or future MR abnormality and in enhancing lesions at the time of their appearance. Forty-eight new enhancing lesions with no evidence of any previous MRI abnormalities were identified. The average MTR of all the areas of NAWM studied outside visible MS lesions was 50.0 (SD = 1.6) % and that of new enhancing lesions at the time of their appearance was 33.1 (8.4) %. At each time point the mean MTR for NAWM in areas of future enhancement was significantly lower than the mean MTR in the other NAWM. There was a progressive and significant reduction in MTR in areas of NAWM which subsequently enhanced (F = 51.7; p < 0.000001). During the follow-up period, there was no significant change of the MTR in NAWM outside areas of subsequent enhancement in the ROIs studied. These results suggest that changes in the NAWM of patients with MS occur before lesions become evident on conventional MRI scans.

P394 HYPOINTENSE LESION LOAD ON FAST-FLAIR MRI SCANS FROM MULTIPLE SCLEROSIS PATIENTS: A NEW MARKER OF DISEASE SEVERITY? M. Rovaris, M. A. Rocca, G. Mastronardo, B. Colombo, G. Comi, M. Filippi. MS Biosignal Analysis Center, IRCCS H. San Raffaele, University of Milan, Milan, Italy On fast-fluid attenuated inversion recovery (fast-FLAIR) brain magnetic resonance imaging (MRI) scans, areas of hypointense signal are sometimes visible in the context of hyperintense multiple sclerosis (MS) lesions. These areas might represent severely damaged tissue and in this study we assessed their correlations with clinical findings and other MRI measures. Fifty patients (32 with relapsing-remitting – RR – and 18 with secondary progressive – SP – MS) were studied; their median expanded disability status scale (EDSS) score was 4.0. On the same 1.5 Tesla scanner and in the same session, dual echo rapid acquisition relaxation-enhanced (RARE), fast-FLAIR and T1-weighted conventional spin echo (CSE) MRI scans with 24 axial 5-mm thick contiguous interleaved slices were obtained. Median total lesion loads (LL) were 17.4 ml (range: 0.4– 76.5 ml) on PD-weighted, 2.9 ml (range: 0.0–47.2 ml) on T1-weighted and 20.0 ml (range: 1.1–75.7 ml) on fast-FLAIR MRI scans. The median number of hypointense lesions visible on fast-FLAIR images was 0.0 (range 0–22); their median LL was 0.0 ml (range: 0.0–12.6 ml). Median LL were significantly higher in SPMS than in RRMS patients for PDweighted ( p = 0.02), for T1-weighted (p = 0.005) and for fast-FLAIR (p = 0.03) scans. Both the number ( p = 0.003) and the load ( p = 0.002) of hypointense fast-FLAIR lesions were significantly higher in SPMS patients. Significant correlations were found between patient EDSS scores and MRI LL; “r” values were 0.53 for PD-weighted, 0.65 for T1-weighted, 0.52 for fast-FLAIR and 0.51 for hypointense fast-FLAIR LL. Our data confirm that hypointense LL on T1-weighted MRI is the best predictor of MS clinical disability; they also suggest that fast-FLAIR imaging may provide informations about different MS pathological substrates with a single acquisition.

P395 AN MRI STUDY TO ASSESS THE RELATIONSHIP BETWEEN DURATION OF INFLAMMATORY ACTIVITY AND DEMYELINATION IN MULTIPLE SCLEROSIS LESIONS. N. C. Silver, M. R. Symms, M. Lai, G. J. Barker, A. J. Thompson, W. I. McDonald, D. H. Miller. NMR Research Unit, Institute of Neurology, London, UK Magnetization transfer (MT) imaging provides a useful measure of myelin integrity. We have studied 3 patients with clinically definite multiple sclerosis (MS) (1 relapsing-remitting, 2 secondary progressive) using serial weekly gadolinium-enhanced MRI and MT imaging to evaluate whether persistent inflammation (indicated by enhancement) results in more significant demyelination (lower MT ratios) within MS lesions. At each session MT, T2, proton density and gadolinium contrast-enhanced T1-weighted images were obtained at 1.5 Tesla. Overall, 25 lesions were analysed that were unaffected by partial volume and showed new gadolinium enhancement that ceased prior to the final study. For each lesion, we measured the duration of enhancement (mean = 3.7 weeks), the largest area of proton density signal change (mean = 26.3 mm2) and the MT ratio (MTR) nadir (i.e. the greatest decrease in MT ratio; mean = 11% reduction) compared with pre-enhancement values. A significant relationship was seen between duration of enhancement and MTR nadir (r = 0.52, p < 0.01). The relationship between lesion area and MTR nadir was less apparent (r = 0.41, p < 0.05). No significant association was seen between duration of enhancement and maximal lesion area (r = 0.28, p > 0.05), suggesting that the effect of enhancement duration on MTR reduction is relatively independent of partial volume effects. Whilst very small changes in MTR may result from oedema associated with inflammation, more persistent inflammation appears to result in greater decreases that suggest predominant demyelination. These results suggest that therapies aimed at reducing the duration of inflammation in new MS lesions might also be useful to reduce any associated demyelination. P396 A PATHOLOGICAL AND MRI STUDY OF CORTICAL LESIONS IN MULTIPLE SCLEROSIS. D. Kidd, F. Barkhof, I. V. Allen, T. Revesz. London, Amsterdam and Belfast Although it is known that MS lesions may involve the cerebral cortex, little published research is available on the distribution of such lesions. We used neuropathological techniques and MRI in order to attempt this. Material and methods: 1 cm thick coronal slices of a formalin fixed brain were scanned using a T2-weighted sequence and for comparison sections stained with LFB/H & E were subsequently evaluated. In a further 12 cases, using large sections, cortical lesions were characterised and their relationship to cortical veins was analysed (Duvernoy et al. Brain Res Bull 1981; 7 : 519–579). Results: MRI identified 134 lesions; 58 were in the subcortical white matter and two were purely cortical. In contrast subsequent neuropathological examination revealed 328 lesions; 108 were cortical involving the subjacent white matter. In the 12 cases 478 cortical lesions were detected, 372 (76%) also involved the subcortical white matter. Seven different lesion types were determined, the majority arose within the territory of the principle cortical veins while a minority in the territories of several neighbouring cortical principal veins or of small branch or superficial veins. Conclusions: The common cerebral cortical lesions are underreported by MRI. Investigation of the cortical venous supply shows how such lesions may arise and why the majority also extends into the subjacent white matter. P397 THE SEASONAL INFLUENCE ON THE ONSET OF RELAPSINGREMITTING MULTIPLE SCLEROSIS IN A POPULATION-BASED GROUP OF MULTIPLE SCLEROSIS PATIENTS. K. Lauer. Institute of Neuroepidemiology, affil. with the Clinic of Neurology, Academic Teaching Hospital Darmstadt, Germany In a population-based long-term field investigation on multiple sclerosis in Southern Hesse, Germany including totally 950 period-prevalent cases, data on the season of the first attack could be assessed retrospectively in 415 patients with a relapsing-remitting course of a definite or probable MS. The distribution over the 4 seasons was compared with the expected value using a goodness of fit chi 2-test assuming an equal distribution over the year. For the total group of 415 patients, MS onset showed a unequal distribution with a clear peak in spring (March – June) and a lower occurrence than expected during autumn and winter (September – February) (chi 2 = 20.16. d.f. 3; P < 0.001). The clustering of onset during spring was more evident among female patients (chi 2 = 13.79; d.f. 3; P < 0.005) than

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among males (chi 2 = 6.41; d.f. 3; P < 0.1) and found only among relapsing-remitting cases, but not in cases being secondary chronic progressive at entry into the study. Both gender and type of time course were independent associated with season. Whereas the socio-economic status was unrelated to the seasonal pattern, significant spring peak was observed only among patients originating from large cities with > 5000 inhabitants (chi 2 = 14.74; d.f. 3; P < 0.01), but not among those from small towns (5 000– 50 000 inhabitants (chi 2 = 4.11; d.f. 3; n.s.) and rural places with less than 5 000 inhabitants (chi 2 = 2.58, n.s.), thus indicating effect modification by type of residence. A secondary chronic progressive course in comparison with relapsing-remitting course, when assessed in a cross sectional way at study entry, was associated in univariate analysis with an age at onset > 29 (chi 2 = 30.98; P < 0.0001), male gender (chi 2 = 3.53; P < 0.06 and with a manual occupation or a lower SES, respectively (chi 2 = 7.11; P < 0.008), but not with the type c residence (urban vs. rural). Supported by the Hertie-Foundation, Frankfurt /Main, Germany. P400 COMPARATIVE ASSESSMENT OF DISABILITY IN PATIENTS WITH MULTIPLE SCLEROSIS. DATA FROM A POPULATIONBASED SURVEY. M. A. Pina, P. J. Modrego, J. R. Ara, F. Morales. Teruel and Zaragoza, Spain There are a few reports about disability in MS patients from populationbased surveys. The aim of our study is to evaluate the degree of disability in MS patients from the sanitary district of Calatayud (northern Spain) and to compare the results with patients from other parts of the world. Thirty four patients with clinically definite MS collected from a prospective survey (from October 1990 to July 1996) underwent the Incapacity Status Scale (ISS). This scale consists of 16 items that range from 0 to 4 points. The scores were compared with those obtained in 1043 patients from 6 international series. The mean score for the full scale was 13.4 (sd: 14.8, range: 0–55), for the items was as follows: 1.3 (sd: 1.5) for the item “ambulation”, 1.4 (sd: 1.6) for “stair climbing”, 1.2 (sd: 1.5) for “transfers”, 0.6 (sd: 0.8) for “bowel function”, 0.8 (sd: 1.2) for “bladder function”, 1.4 (sd: 1.7) for “bathing”, 1 (sd: 1.5) for “dressing”, 0.7 (sd: 1.2) for “grooming”, 0.4 (sd: 0.7) for “vision”, 0.4 (sd: 0.8) for “speech and hearing, 0.3 (sd: 0.7) for “medical problems”, 0.9 (sd: 0.7) for “mood and thought”, 0.5 (sd: 0.8) for “mentation”, 0.9 (sd: 1) for “fatigability” and 1.6 (sd: 1.6) for “sexual function”. In conclusion, the patients of our study are better than those from international series in all items but “sexual function” where no differences were seen. We think that it is essential to evaluate the incapacity of MS patients from data based on long-term population-based surveys and not on hospital series in order to calculate the nurse requirements. P401 THE ROLE OF GRIP FORCE DEFICITS IN THE DEVELOPMENT OF HANDWRITING DISORDERS IN PATIENTS WITH MULTIPLE SCLEROSIS. T. Schenk, E. Walther, N. Mai. Munich, Germany It has been suggested that deficient control of grip force in the dominant limb is responsible for the disturbed handwriting performance of patients with writer’s cramp. Disturbed handwriting movements are also commonly found in patients with multiple sclerosis (MS). The handwriting disorder in MS is often accompanied by motor or sensitivity deficits of the upper limb which may affect grip force control. We tested the hypothesis that disturbed grip force control is responsible for the handwriting disorder in MS. Grip force and handwriting performance were assessed in 20 MS patients and 20 healthy subjects. An encased force and acceleration transducer was used to measure grip force under static and dynamic conditions. Handwriting movements were recorded with a digitizer. Abnormally elevated grip forces were found in 13 patients. Ten patients showed disturbed handwriting movements. Grip force deficits were found with similar frequency in patients with and without a handwriting deficit. Thus, deficits in grip force control are neither a necessary nor a sufficient condition for the occurrence of handwriting deficits. In addition 9 of 10 patients with a handwriting deficit were able to produce perfectly normal movements when the task was to make scribbles. This finding shows that “cognitive” factors (i.e., relevance of the written output) affect handwriting performance in MS patients. Such cognitive effects could be employed in the treatment of handwriting disorders in MS patients. P402 MULTIPLE SCLEROSIS: INTEREST OF VISUAL EVOKED POTENTIALS BY LOCALIZED STIMULATIONS USING A SCANNING LASER OPHTHALMOSCOPE. J. de Seze, C. F. Arndt, T. Lebrun, Ph. Debruyne, J. C. Hache, P. Vermersch. Lille, France

Visual evoked potentials (VEP) are a thorough tool in diagnosis multiple sclerosis (MS). Nevertheless, VEP are normal in about 25% of clinical or laboratory definite MS. Aim of the study: To detect visual pathway involvement using localized checkerboard reversal stimulation generated by a scanning laser ophthalmoscope (SLO) in normal subjects and MS patients. Patients and methods: 30 definite relapsing remitting MS with normal full field VEP and 30 age matched controls were studied. Two different checkerboard reversal stimuli (15 and 60 minutes of arc) were used with 3 different spatial distributions: central 8° × 8° square, central 8° × 8° exclusion square and full field. Results: All controls had responses at 4 of the 6 different procedures. In the 15’ peripheral stimulation a response was obtained in 28/30 controls (93%) and in the 60’ central stimulation in 29/30 (97%). In MS, localized stimulation allowed to detect a dysfunction of the visual system in 47% of cases ( p < 0.0001). Conclusion: This work confirms the interest of VEP induced by a SLO, especially for localized stimulations, in MS. Further studies are needed necessary to assess the interest of this new method in the early diagnosis of MS. P403 SERIAL STANDARD- AND TRIPLE-DOSE MRI TO MONITOR THE EFFECT OF INTERFERON ?-1A ON MULTIPLE SCLEROSIS ACTIVITY. M. Filippi, M. Rovaris, R. Capra, C. Gasperini, M. A. Rocca, R. Garavaglia*, G. Comi. MS Biosignal Analysis Center, IRCCS H. San Raffaele, University of Milan, Milan; *Serono Pharma, Rome, Italy Several studies report that the use of a triple dose (TD) of Gd markedly increases the sensitivity of enhanced magnetic resonance imaging (MRI) in detecting multiple sclerosis (MS) active lesions. Since the lesions detected by either standard (SD) or TD Gd doses probably have different degrees of blood-brain barrier (BBB) disruption and previous studies demonstrated that interferon (IFN) ? reduces MRI activity in MS patients, aim of this study was to compare the sensitivities of SD and TD MRI for detecting the early effects of this treatment. Eighteen patients with relapsing-remitting MS were studied. Brain MRI were obtained every four weeks for 3 months before and 4 months after starting treatment with recombinant (rh) IFN ?-1a (Rebif, 12 MIU weekly IM). At each time point, T1-weighted scans were obtained after injection of SD (0.1 mmol/kg of Gd) in one session and TD (0.3 mmol/kg of Gd) in another one, separated by a 24-36 hour interval. The mean numbers of total and new enhancing lesions/patient/ month in the pre-treatment period were 1.74 and 1.44 on SD scans, 3.37 and 2.44 on TD scans. During the treatment period, mean numbers of total and new enhancing lesions/patient/month dropped to 1.61 (–7.5%) and 1.10 (–24%) on SD and to 2.40 (–29%) and 1.33 (–45%) on TD scans. The median percentage differences between TD and SD scans in the numbers of total and new enhancing lesions were 75% and 45% in the pre-treatment period and 23% (p = 0.04) and 0% (p = 0.01) in the treatment period. Similar results were found when enhancing lesion volumes were analyzed. This study suggests that the magnitude of the effect of rhIFN ?-1a on Gd enhancememt is inversely related to the degree of lesion BBB disruption. It also indicates that the use of more sensitive MRI techniques have higher chances to reveal a treatment effect in its earliest phases. P404 CARDIOVASCULAR AUTONOMIC DYSFUNCTION IN MULTIPLE SCLEROSIS. Flachenecker P, Wolf A, Krauser M, Hartung H-P*, Reiners K. Departments of Neurology, Universities of Würzburg, Germany, and *Graz, Austria Autonomic dysfunction is frequently observed in multiple sclerosis (MS) and may lead to bladder, bowel and sweating disturbances. Cardiovascular abnormalities were less commonly reported, with a great variation between clinical studies. – Methods: In 49 patients (35 females, 14 males, aged 35.9 ± 9.4 years) with relapsing-remitting (n = 35) and secondaryprogressive (n = 14) MS (median EDSS 3.0, range 1.0–6.5) parasympathetic (heart rate responses to Valsalva maneuver [VR], deep breathing [DB] and active change of posture [HRACP]), and sympathetic function tests (blood pressure responses to active change of posture [BPACP] and sustained handgrip [BPHG]) were compared to those obtained in 24 healthy volunteers (13 females, 11 males, aged 29.4 ± 7.2 years). A 10-point composite autonomic score (CAS), and subscores for parasympathetic (pCAS) and sympathetic dysfunction (sCAS) were performed, with higher scores indicating more severe dysfunction. – Results: Autonomic tests were abnormal in 2.0% (VR and HRACP), 12.2% (DB), 6.1% (BPACP) and 24.5% (BPHG) of patients. CAS was ≥ 2 in 21 patients and 5 controls, but ≥ 4 in only 3 patients and 1 control. Median CAS and sCAS were significantly higher in patients than in controls, with no difference in pCAS. Out of 15 patients with abnormalities in at least one sympathetic function test,

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12 (80%) reported symptoms of orthostatic dizziness. – Conclusions: Cardiovascular abnormalities, usually of mild degree, were mainly attributed to sympathetic vasomotor dysfunction, and were closely related to orthostatic dizziness. P405 AN INVESTIGATION OF MAGNETIZATION TRANSFER HISTOGRAM ANALYSIS TECHNIQUES TO QUANTIFY THE DISEASE BURDEN IN MULTIPLE SCLEROSIS. N. C. Silver, A. Gass, A. Reginald, G. J. Barker, P. S. Tofts, D. H. Miller. NMR Research Unit, Institute of Neurology, London, UK The weak relationships seen between T2-weighted MRI and disability in multiple sclerosis(MS) may result from both poor pathological specificity and difficulty in detecting microscopic abnormalities in “normal-appearing” white matter. We have investigated the role of histogram analysis for assessing the distribution of structural changes occuring within the brain, as determined by magnetization transfer (MT) imaging. Calculated MT ratio (MTR) brain images were obtained for 42 patients with MS (10 benign, 11 relapsing-remitting (RR), 11 secondary progressive(SP), 10 primary progressive (PP)) and 11 healthy controls using an interleaved spin-echo sequence at 1.5Tesla. For each subject, a composite MTR histogram was produced from 3 standardised periventricular slices. Pixels with MTR values < 5 percent units(pu) were discarded before normalising the distribution to the remaining volume. Significant reductions in MTR peak height were seen for RR, SP and PP subgroups (p < 0.02). A significant reduction in MTR mode was also seen for those patients with benign or SP MS ( p < 0.001). No significant correlations were seen between peak height/mode and disability (as measured with the expanded disability status scale, EDSS). For histogram areas (bin width = 5 pu), significant correlations were seen with EDSS for all regions between 5 and 20 pu (highest for 10 + 2.5 pu; r = 0.55, p < 0.001). In conclusion, certain approaches to MTR histogram analysis may be useful to assess the global burden of disease in MS. As such, these techniques appear promising for monitoring the efficacy of putative therapies in this disease. P406 VISUAL PSYCHOPHYSICAL DEFICIT AND MRI IN ACUTE OPTIC NEURITIS: A CONTRAST WITH MULTIPLE SCLEROSIS. KEELE MULTIPLE SCLEROSIS RESEARCH GROUP. M. B. Davies, P. A. Caruana, R. Williams, N. Haq, D. Foster, C. P. Hawkins. Department of Neurology, Royal Infirmary, North Staffordshire Hospital and MRI Unit, Cornwall House, Stoke-on-Trent, England Unenhanced MRI correlates poorly with visual acuity in acute optic neuritis. Visual psychophysics is a more sensitive measure of visual function than visual acuity. We studied 10 patients serially using MRI and visual psychophysics. A Phillips (0.5 T) scanner was used. We measured optic nerve and postchiasmal MRI lesion number and area on optic nerve STIR images (IR 1400/140/25, 4 mm slices) and T1, T2 and proton density weighted axial brain images (NH, MBD). Visual psychophysics was performed during the acute and later phase of unilateral optic neuritis to obtain threshold responses (PEST routine, sinusoidal gratings, 0.25, 1.0, and 4 cycles/degree) for the parvocellular (P) and magnocellular (M) visual pathways. Results were combined to obtain a weighted mean for each eye. In general there was a strong correlation between weighted mean psychophysical threshold and optic nerve lesion number1 and area2 in the symptomatic eye for the P pathway (r 1, 2 = 0.6, 1 month; r 1, 2 = 0.7, 3 months) and M pathway (r 1 = 0.57, acute; r 1 = 0.69 & r 2 = 0.6, 1 month; r 1 = 0.82 & r 2 = 0.87, 3 months) respectively ( p < 0.05 except for P acute phase). There was no relationship between psychophysical deficit and MRI lesion number and area in the asymptomatic eye and postchiasmal pathway. In contrast to established multiple sclerosis, the extent of unenhanced abnormality on optic nerve MRI correlates with visual psychophysical deficit in acute optic neuritis. P407 DOWNREGULATION OF TNF-α PRODUCTION? DURING TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS) WITH COPAXONE®. Volker Hoffmann, Nurtac Ari, Maike Rieks, Sebastian Schimrigk, Horst Przuntek, Dieter Poehlau*. Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, D-44791 Bochum, Germany; *Sauerlandklinik Hachen, Sundern-Hachen, Germany Treatment of RRMS patients with Copaxone® (Copolymer-1, Glatiramer Acetate) has been shown to be clinically effective. Tumor necrosis factor

alpha (TNF-α) is a proinflammatory TH-1 type cytokine exerting a deleterious effect on myelin and myelin-forming cells. In the present study we analysed the effect of Copaxone® treatment on TNF-α-production. Patients: In a longitudinal study we analysed 15 patients with stable relapsingremitting MS. Within the last 6 weeks before the initiation of treatment with Copaxone® patients had no acute relapses, no signs of acute or chronic infections and received no immunomodulating therapy. Patients were treated by subcutaneous daily administration of 20 mg Cop-1. Blood samples were obtained prior to and 6, 12 and 18 weeks during treatment. Methods: Peripheral blood mononuclear cells (PBMC) were stimulated with Cop-1 (1 µg/ml), myelin-basic protein (MBP) (2 µg/ml) or bovine serum albumin (BSA) (2 µg/ml) or medium alone. After 48 hours incubation the cells were restimulated for 5 hours with PMA and ionomycin and with monensin for secretion inhibition and cytokine accumulation. After fixation and permeabilization staining of cytokines and surface markers was done using a FITC-conjugated mouse-anti-human TNF-α-MAB and a PECy5-conjugated anti CD4-MAB. The percentage of TNF-α producing lymphocytes were compared with baseline values using the Wilcoxon test. Results and Discussion: Copaxone® treatment was found to be associated with a significant lower percentage of TNF-α producing CD4-positive and CD4-negative lymphocytes after 6, 12 and 18 weeks of treatment. The lower percentage of TNF-α-producing lymphocytes may partially explain the beneficial effects of Copaxone® on the clinical course of RRMS. P408 IMMUNOLOGICAL EFFECTS OF IN VIVO βIFN-1B TREATMENT IN 10 MS PATIENTS: A ONE-YEAR FOLLOW-UP. M. Gelati, E. Corsini, A. Dufour, G. Massa, L. La Mantia, C. Milanese, A. Nespolo, A. Salmaggi. Istituto Nazionale Neurologico “C. Besta”, Milan, Italy The clinical efficacy of βIFN-1b in reducing relapse rate in relapsingremitting multiple sclerosis (MS) has been documented and has led to a widespread prescription of this drug. Radiological evidence supports reduction in the frequency of new lesions at MRI. βIFN is able to induce in vivo and in vitro changes in immunological parameters possibly involved in MS, such as cytokines production (i.e., IL-10 and TNF-α) and cell surface molecules expression involved in (auto)antigen presentation (such as HLA-DR). Recent studies investigated the in vitro effects of βIFN treatment on adhesion and transmigration phenomena (Dhib-Jalbut 1996; Stuve 1996), and in vivo effects on soluble adhesion molecules concentration in serum (Calabresi 1997). We evaluated the long term effects of treatment with βIFN-1b (1 year) in 10 MS patients, in respect of adhesion molecules and HLA-DR expression on PBMNCs, adhesion phenomena between PBMNCs and endothelial monolayers, and sVCAM-1 and sICAM-1 concentration in sera. At one year, a marked decrease in the number of mononuclear cells adhering to HUVECs monolayers was observed. sVCAM-1 levels increased during βIFN treatment, suggesting that sVCAM-1, released upon endothelial activation in in vivo βIFN-treated patients, may contribute to buffer the adhesion phenomena. This latter finding adds information to available evidence of the mechanisms of action of βIFN-1b in MS. A significant increase in HLA-DR on peripheral blood monocytes was detected; this late increase in DR molecules on PB monocytes was unrelated to clinical course in our cohort of patients, since we did observe – in agreement with literature data – a sharp reduction in relapse frequency during the year of βIFN-1b treatment.

Neuro-Oncology P409 A SINGLE ADENOVIRAL VECTOR ABLE TO TRANSFER p53 AND p16 FOR TREATMENT OF p53-RESISTANT GLIOMAS. J. Fueyo, C. Gomez-Manzano, R. Alemany*, P. S. Y. Lee, V. A. Levin, and W. K. A. Yung and A. P. Kyritsis. The University of Texas M. D. Anderson Cancer Center, Houston, TX and *Unit of Gene Therapy, Baxter, Chicago, IL Our objective was the design of a new treatment approach for p53-resistant gliomas by using a vector able to express both p53 and p16 tumor suppressor genes. The Adp53 + p16 was constructed using the shuttle p?E1sp1A and the adenoviral plasmid pJM17. Three cell lines, EFC-2, U-87 MG and D54 MG resistant to the apoptotic effect of p53 were selected. Cells were treated with either p53, or p16 or p53 + p16 using adenoviral vectors. Western blots were utilized to confirm the expression of the proteins. Growth arrest and apoptosis was assessed by morphological changes. Viability was assessed by trypan blue exclusion. The percentage of cells in apoptosis was quantitated by flow-cytometry. The Adp53 + p16 induced the expression of both exogenous proteins. p16 transfer resulted in reduction of the

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expression of Rb protein. Co-expression of p16 and p53 proteins induced apoptosis in two of the three cell lines resistant to p53. Due to the heterogeneity of genetic abnormalities of gliomas, combination of genes may be necessary to achieve cancer cell-death. The use of a single vector to express a combination of genes potentiates the anti-cancer effect with low toxicity. P410 ADENOVIRALLY-MEDIATED TRANSFER OF ANTISENSE-VEGF cDNA INHIBITS GLIOMA GROWTH IN VIVO. S. A. Im, C. GomezManzano, J. Fueyo, T. J. Liu, L. D. Ke, P. S. Y. Lee, H.-Y. Lee, J. S. Kim, A. P. Kyritsis, and W. K. A. Yung. The University of Texas M. D. Anderson Cancer Center, Houston, TX Glioblastoma multiforme is one of the most highly vascularized human tumors. Consistent with this the vascular endothelial factor (VEGF) is frequently overexpressed. In this study, we have constructed an adenoviral vector able to express a full length VEGF cDNA in antisense orientation, and tested its anti-cancer properties in vitro and in vivo. In virus-control infected U-87 MG glioma cells, VEGF expression increased with the progressive growth of cells in vitro. However, the level of expression of the secretory VEGF decreased 30–40% as assessed by ELISA after treatment of the U-87 MG glioma cells with the adenovirus-VEGF (20–100 multiplicity of infection units). As expected, the down- regulation of VEGF did not correlate with reduction in growth rate in vitro. Treatment of human glioma xenografts implanted subcutaneously in nude mice with the adenovirus-VEGF resulted in a statistically significant inhibition of tumor growth. Our results indicate that it is possible to inhibit the growth of gliomas in vivo by using an adenoviral construct expressing antisense VEGF. Combination of anti-sense VEGF with other genes involved in control of invasiveness, like p16 or Rb, or vasogenicity, like p53, may greatly enhance its anti-cancer effect. P411 A NOVEL TUMOR SPECIFIC REPLICATION RESTRICTED ADENOVIRAL VECTOR FOR GLIOMA THERAPY. J. Fueyo, C. Gomez-Manzano, P. S. Y. Lee, R. Alemany*, W. K. A. Yung, V. A. Levin and A. P. Kyritsis. The University of Texas M. D. Anderson Cancer Center, Houston, TX and *Unit of Gene Therapy, Baxter, Chicago, IL The majority of normal brain cells are non-dividing cells. Gliomas are formed by the neoplasic accumulation of both dividing and nondividing cells. Adenoviruses replicate in non-dividing cells by inactivating Rb to promote forced entry of cells into S phase. In this study we constructed an adenovirus unable to bind Rb to target and lyse dividing cells and Rb-null resting cells. The mutant adenovirus was constructed by deletion of 24 nucleotides in the E1A region which are indispensable for Rb binding. The deletion was tested by PCR sequencing and restriction enzyme digestion. U-87 MG, EFC-2, U-251 MG, D-54 MG, U-373 MG glioma cells, Saos-2 sarcoma cells, retinoblastoma cells, fibroblasts and fetal brain cells were used to test the bioactivity of the mutant adenovirus. The mutant adenovirus grew with very low efficiency in replicating cells that expressed wild-type Rb protein or nonreplicating cells. However, the adenoviral construct grew with high efficiency in replicating cells with absent Rb expression. Adenovirus able to replicate more efficiently in cells having mutations of the Rb gene may be useful for treatment of Rb-mutant tumors. P412 CYCLIN D1 OVEREXPRESSION IN GLIOMAS CONFERS A GROWTH ADVANTAGE WHICH CAN BE NEGATED BY AN ADENOVIRUS RIBOZYME CONSTRUCT. V. K. Puduvalli, J. Fueyo, C. Gomez-Manzano, J. M. Bruner, W. K. A. Yung and A. P Kyritsis Cyclin D1 governs the orderly passage of the cells through the G1 phase of the cell cycle. Alterations in cyclin D1 expression have been associated with a variety of cancers but their role in glioma proliferation is uncertain. We studied cyclinD1 expression by immunohistochemical analysis in primary glioma samples (from 22 patients) and in glioma cell lines. Also, the effect of a adenovirus-ribozyme construct against cyclin D1 mRNA (Ad5cycRz) on proliferation by BrdU assay, and cell cycle kinetics by flowcytometry, was studied in a human glioma cell line, D54MG which overexpresses cyclin D1. The phosphorylation status of the retinoblastoma protein (Rb) was determined in untreated and ribozyme treated cells. Overexpression of cyclin D1 was seen in subpopulations of cells in all glioma samples as well as several glioma cell lines. The introduction of Ad5cycRz induced a G1 cell cycle arrest and decreased the rate of proliferation in the cell lines. The Rb-negative glioma cell line, EFC-2, did not demonstrate

such changes, confirming that Rb was the downstream effector of these effects. A kinase assay using GST-Rb as a substrate, confirmed the reduced activity of cyclin D1-cdk4 complex, on treatment with Ad5cycRz. Our results suggest that cyclin D1 overexpression can confer a growth advantage to glioma cells and is a potential mechanism for the formation and progression of gliomas. Further, we demonstrate the ability of an adenovirusribozyme construct in abrogating this growth advantage in vitro, suggesting a therapeutic potential for such agents against human gliomas. P413 VEGF FAMILY GENE IN MALIGNANT GLIOMAS. Chatel M*, Gollmer JC**, Dubreuil A*, Paquis P*, Frelin C**. *Groupe de Neurooncologie CHRU Nice, **IMPC Université Nice Sophia Antipolis Growth of solid tumors is stringently dependent on an angiogenic process and it has been proposed that vascular endothelial growth factor (VEGF) plays an important role in vascular proliferation and oedema formation in human malignant gliomas. Expressions of mRNAs coding for VEGF, Placental growth factor (PlGF), VEGF-B and VEGF-C were analyzed in surgical specimens from human astrocytomas. Low levels of expression of PlGF and VEGF-C mRNAs were observed. VEGF mRNAs were found in grade III and grade IV astrocytomas. VEGF-B mRNAs were observed in all tissue samples analyzed, irrespective of the tumor grade. Expression of VEGF mRNAs in cultured glioblastoma cells was upregulated by hypoxia and depressed by dexamethasone. Expression of VEGF-B mRNAs was not affected by the two treatments. A new splice variant of VEGF-B (VEGFB155) is described. It lacks exons 5 and 6 and has the same COOH terminal sequence as VEGF-B167. Glioblastoma cells express HIF-1a mRNAs but not EPAS mRNAs. Hypoxia did not increase HIF-1a message levels. The results suggest that the different genes of the VEGF family are probably not all involved in the pathogenesis of malignant gliomas. P414 MULTIFOCAL CEREBELLAR AND SUPRATENTORIAL MEDULLOBLASTOMA IN AN ADULT. Gliemroth J1, Nowak G1, Kehler U1, Knopp U1, Reusche E2, Arnold H1. 1Department of Neurosurgery, 2Institute of Pathology, Medical University of Lübeck, Germany Cerebellar medulloblastoma most frequently occurs during childhood, but is uncommon in adults. We report on a case of an adult onset multilocular cerebellar medulloblastoma in a 54-year-old male. The computed tomography (CT) and magnetic resonance imaging (MRI) findings in adults with cerebellar medulloblastoma in comparison with findings in children were discussed. Case report: This 54-year-old previously healthy male was admitted to hospital because of headache, nausea, and dizziness. Clinical examination revealed a bilateral cerebellar syndrom. MR imaging showed a multilocular tumor in both cerebellar hemispheres and occipital on the left side with perifocal oedema and marked enhancement after injection of contrast medium. Metastases of an unknown tumor were suspected, but a stereotactic-guided biopsy confirmed the diagnosis of a proliferative medulloblastoma with perivascular growth. Therefore the patient received adjuvant radiation therapy and chemotherapy. Control CT scans showed a marked tumor reduction. Conclusion: A multilocular medulloblastoma is a unique event. Due to the literature we could not find any other description of a multifocal supra- and infratentorial medulloblastoma. Metastases usually occur in the spine, rarely in the subarachnoid space. Except from the frequent cases of diffuse dissemination to the leptomeninges, only two cases of multifocal medulloblastoma have been reported, both were located infratentorial. Generally this unusual mode of tumor spread indicates a unique case of medulloblastoma. P415 LOCO-REGIONAL CHEMOTHERAPY AND REPEATED SURGERY CAN IMPROVE OUT-COME OF GLIOBLASTOMA (Gbm) PATIENTS. PRELIMINARY FINDINGS. Boiardi A, Pozzi A, Salmaggi A, Broggi G, Silvani A. Istituto Nazionale Neurologico “C. Besta”, Milano 54 newly diagnosed GBM pts were treated with systemic BCNU 100 mg/ sqm + cisplatinum 90 mg/sqm iv. for 5 times before, during, and after radiotherapy. 25 out of them were treated also trough an Ommaya reservoir (bleomycin 0.75 mg days 1,2,3 and mitoxantrone 3 mg day 4 every 20 days). At recurrence 15 underwent a repeated surgery. Data were analyzed: a) by considering the whole group, b) by comparing all primary systemically treated patients with those having in addition loco-regional chemotherapy c) by comparing patients undergoing repeated surgery in addition to locoregional chemotherapy as well, with patients not undergoing repeated

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surgery. The TTP and ST of the 54 patients was 10.8 and 23.1 months respectively. The TTP did not differ significantly from the 12.2 months disease-free which was detected in the 10 patients treated with locoregional chemotherapy before recurrence ( p = 0.09 ). The ST of these 10 patients reached 18 months, which did not differ significantly from the ST of 16.3 in the patients neither treated by locoregional chemotherapy nor by repeat surgery. The ST of the 15 patients reoperated and treated locally was 27.6 months; this was statistically significant in comparison with patients not reoperated and not treated locally (log-rank p = 0.04). P416 GLIOMATOSIS CEREBRI – A DIFFICULT INTRA VITAM DIAGNOSIS. K. Eger, A. Lindner, S. Zierz. Klinik und Poliklinik für Neurologie der Martin-Luther-Universität Halle-Wittenberg, Germany Gliomatosis cerebri is rarely encountered and its intra vitam diagnosis is still difficult. We report a case, in which we had difficulties in making intra vitam diagnosis. A 19-year-old man developed brain stem signs. Initial CT scans revealed a slight bilateral hypodense periventricular lesion without contrast enhancement. MRI showed hyperintense periventricular confluent lesions of the cerebral hemispheres and a lesion of the left cerebellum in the T2-weighted images. These findings required differentiation from inflammatory, demyelinating and degenerative disorders. A brain biopsy was performed and revealed a low grade astrocytoma (grade II). MRI and histopathological findings correlated with the diagnosis of Gliomatosis cerebri. We conclude that Gliomatosis cerebri is best detected with MRI. Stereotactic biopsy remains necessary to confirm the diagnosis of gliomatosis cerebri pathohistologically intra vitam. P417 UNUSUAL MANIFESTATIONS OF SPINAL CANCER: THREE CASE REPORTS. M. von Ekesparre, A. Thie. Department of Neurology, Krankenhaus Itzehoe/Germany Spinal manifestations of malignant disease still pose a diagnostic challenge. We report three patients with unusual clinical and diagnostic features. A 87-year-old otherwise healthy woman presented with progressive paraparesis over three months. Magnetic resonance imaging suggested an intramedullary tumour, but surgery revealed extramedullary myelon compression from a large tumour mass extending from the vertebrae, later identified as isolated non-Hodgkin’s lymphoma. A 49-year-old woman developed rapidly progressive paraparesis and mild encephalopathy nine months after chemotherapy for small-cell lung cancer. An isolated intramedullary metastasis in the conus area accounted for the spinal syndrome, but was associated with meningeal and vertebral metastases. Ten years after successful treatment of breast cancer, a 58-year-old woman developed slowly progressive spinal ataxia and paraparesis. Isolated meningeal carcinomatosis was identified without evidence of local recurrence or a second cancer. This patient slightly improved after 17 weeks of intrathecal methotrexate. These cases are analysed with regard to differential diagnostic problems and therapeutic options.

Neuro-Ophthalmology P418 PERCEPTUAL AND OCULOMOTOR EFFECTS OF NECK MUSCLE VIBRATION IN VESTIBULAR NEURITIS: IPSILATERAL SOMATOSENSORY SUBSTITUTION OF VESTIBULAR FUNCTION. M. Strupp, V. Arbusow, M. Dieterich, and T. Brandt. Dept. of Neurology, Munich, Germany Afferent cervical somatosensory input may substitute for absent vestibular information as part of central compensation after unilateral peripheral vestibular deficit. In order to determine the particular contribution of neck muscle spindles to the perception of body orientation and to the oculomotor system, we measured (a) the subjective visual straight ahead (SVA) and (b) the changes in eye position during unilateral vibration of the posterior neck muscles. Twenty-five patients with vestibular neuritis and 25 controls participated in the study. Vibration elicited a horizontal displacement of SVA toward the side of stimulation in controls (ca. 3° on each side). Muscle stimulation on the patients’ lesion side induced a significantly higher displacement (11.5° ± 6.6°, x ± SD) than contralateral stimulation (3.0° ± 2.9°; p < 0.01). Videonystagmography revealed that ipsilateral stimulation in patients induced large horizontal eye deviations toward the side of the lesion (9.1° ± 7.6°). Contralateral stimulation elicited

only small shifts. The correlation coefficient between displacement of the SVA and changes in eye position was high (0.94), indicating that the shift of SVA is the perceptual correlate of the change of gaze. This interpretation was supported by 2 experiments: (a) vibration caused almost no displacement of the subjective straight ahead when it was indicated by pointing with the eyes closed, and (b) SVA reversed its direction if the subject wore reversing prisms. Our data showed: (1) an ipsilateral increase of cervical somatosensory input following unilateral vestibular lesion, which substitutes for missing vestibular input; (2) the perceived effects are secondary to changes in eye position rather than changes in cortical representation of body orientation. P419 THE INFLUENCE OF CALORIC STIMULATION ON FLASH EVOKED VISUAL POTENTIALS. S. Noachtar, H. von Lindeiner, K. J. Werhahn, U. Büttner. Dept. of Neurology, University of Munich, Germany Caloric stimulation (CS) leads to reduction of glucose metabolism in the visual cortex as documented by positron-emission-tomography (Wenzel et al., Brain 1996; 199 : 101–110). This observation has been attributed to suppression of visual input caused by nystagmus. We wished to investigate the influence of CS on flash evoked visual potentials (FEVP). Our hypothesis was that the suppression of visual cortex is not related to the luminance sensitive visual system. We recorded FEVP to 1 Hz and 10 Hz stimulation in 12 normal subjects at baseline, during nystagmus due to CS with cold water, and after cessation of nystagmus and compared the amplitudes of the FEVP. The transient FEVP (1 Hz stimulation) was not influenced by CS. The amplitude of the staedy state FEVP (10 Hz stimulation), however, was significantly reduced by CS as compared to baseline (3.9 µV vs. 3.5 µV, Wilcoxon-Test, p < 0.05). We conclude from our findings that the inhibition of visual cortex by CS seems not to be related to transient FEVP. The influence of CS on staedy state FEVP may be due to activation of magnocellular neurons by rapid flash stimuli which may be involved in the inhibition of the occipital cortex. P420 NEW INSIGHTS INTO POSITIONAL ALCOHOL NYSTAGMUS USING 3-D EYE MOVEMENT ANALYSIS. M. Fetter, T. Haslwanter, M. Bork, J. Dichgans. Department of Neurology, Tübingen, Germany Normally, the semicircular canals selectively transduce angular velocity and are insensitive to gravitational orientation and linear acceleration. In acute alcohol intoxication, a specific gravity differential occurs between the cupulae and the endolymph, rendering the cupulae sensitive to gravity (buoyance mechanism). This results in positional alcohol nystagmus (PAN). We reevaluated PAN in 8 normal subjects by means of 3-D eye movement analysis (dual search-coils). Forty minutes after intake of 0.8 g alcohol/kg bodyweight the subjects were positioned such that the lateral canals were earth vertical. From this position they were rotated about an earth-horizontal axis in the plane of the lateral canals to either 45° or 90° right ear or left ear down and eye movements were recorded in each position for a minimum of 40 sec. While the torsional and horizontal components of the response could be explained by the buoyancy mechanism, the vertical component was in most cases and head positions opposite to the predicted direction. This problem could be solved by assuming an additional vertical bias velocity (all cases slow phase down) induced by the alcohol intoxication. After correction for this bias, the modulation of the eye movement direction was as expected from a buoyancy mechanism that applies to all six cupulae. The bias may represent a toxic effect in central vestibular pathways producing a tone imbalance of the vertical VOR in pitch. P421 DISTURBED VISUAL REFLEX INHIBITION IN PARKINSON’S PATIENTS IS NOT CORRECTED BY A DOPAMINE AGONIST. Luc Crevits, Jan Versijpt, Monique Hanse, Katrien De Ridder. University and University Hospital Ghent, Belgium In contradistinction to data in early Parkinson’s disease, we have reported disturbed visual reflex inhibition in moderate to severe parkinsonian patients. In this stage, almost all patients are being treated by a combination therapy. For the present study, we selected a subgroup of advanced Parkinson’s patients not yet taking a dopamine agonist. When the treating neurologist decided to add pergolide to the usual medication, the patient was included. As a criterion for visual reflex inhibition, the antisaccade test was used. In this paradigm, the reflexive saccade towards the target has to be suppressed. Eye movements were recorded by infrared-oculography.

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Of twenty patients included, 14 could be studied before addition of pergolide and, for the second time, at the moment the treating neurologist evaluated the over-all clinical status as sufficiently improved. The mean antisaccade error ratio, a measure for disturbed visual reflex inhibition, before and after addition of pergolide was 0.41 and 0.38 respectively (Wilcoxon test not significant). Also the latency time of the correct antisaccades was not significantly changed (T-test): 434.36 msec (standard deviation 124.62) before pergolide, 416.29 msec (107.45) after impregnation. We suggest that disturbed visual reflex inhibition in Parkinson’s disease could be mediated, at least in part, by non-dopaminergic dysfunctions. P422 EFFECTS OF GALVANIC VESTIBULAR STIMULATION ON OTOLITHIC AND SEMICIRCULAR CANAL EYE MOVEMENTS. Reto Zink, Alexander Weiss, Thomas Brandt, Marianne Dieterich. Department of Neurology, Ludwig-Maximilians-University, Munich, Germany The aim of this study was to determine the otolithic and semicircular canal contributions to eye movements elicited by galvanic vestibular stimulation with increasing current strengths (1.0 to 7.0 mA). Eye movements were measured with a three-dimensional video-oculography technique (sampling frequency of 60 Hz) in 13 healthy volunteers (9 males, 4 females; mean age 30.8 years; range 23–46) during stimulation with a rectangular, unipolar binaural electric current applied to the subject’s mastoid. Anodal stimulation of the right mastoid led to an ipsiversive tonic ocular torsion of up to 5.4°, which increased in amplitude with the applied increasing current strengths. This reflects otolith stimulation. In most subjects current strengths of 3 mA or more elicited a slight (horizontal-) torsional nystagmus (amplitude 1–2°) that was superimposed on static torsion. This reflects horizontal and vertical semicircular canal stimulation. The absence of vertical deviation and nystagmus can be explained by the counterdirected vertical components of the anterior and posterior semicircular canals. There was a correlation between the amount of torsional eye movement and the applied current strength. Thus, galvanic vestibular stimulation at low current intensities (1–3 mA) tends to excite otolith responses that increase with increasing current intensity. Current intensity above 3 mA elicits additional semicircular canal responses in the form of horizontal-rotatory nystagmus superimposed on static torsional deviations. P423 SMOOTH PURSUIT EYE MOVEMENTS IN SCHIZOPHRENIA: DEFECT OF THE PREDICTIVE OR THE VISUALLY-GUIDED COMPONENT ? Kompf D, Trillenberg P, Heide W. Dept. of Neurology, Medical University, Lübeck, Germany A reduced gain of smooth pursuit (SP) eye velocity has frequently been reported in schizophrenic patients, but the mechanism of this disorder has not yet been understood. To investigate if it is a deficit of the predictive component of SP or of the visually-guided component, we recorded horizontal SP eye movements of 15 subacute schizophrenic patients and of 16 healthy controls, in response to 2 different kinds of foveal visual stimuli: a horizontal step-ramp stimulus, consisting of an unpredictable target jump and subsequent motion of constant velocity, and a predictive sinusoidally moving stimulus, which was suddenly stopped after 4 cycles. SP gain was significantly reduced in schizophrenics, more with the step-ramp than with the predictive stimulus, Patients’ latency of SP initiation was within normal limits, but their saccades to the moving target were dysmetric, implying impaired perception of target velocity. After the sudden stop of predictable target motion, the eye accelerated away from the target for 180 ms, and the resulting velocity error was higher in schizophrenics than in normals. We conclude that schizophrenics have an impaired visuallyguided component of SP, including visual motion perception, whereas their predictive component is rather enhanced thus being compensatory for the deficit. P424 GAZE STRATEGY AND OCULOMOTOR DISTURBANCE IN PROGRESSIVE MOTOR AND VISUAL APRAXIA. J. de Seze, S. DefoortDhellemmes, P. Vermersch, C. Buquet, F. Pasquier, J. C. Hache, Lille France The photo-oculograph is a method that allows study of gaze strategy in reading and current scene observation, saccade and pursuit. We evaluated gaze strategy and oculomotor disturbance in patients with visual and motor apraxia by the mean of a photo-oculograph. We studied 2 patients, with a photo-oculograph, who presented a progressive left motor and visual apraxia without hemianopia or hemineglect. Magnetic resonance imaging

(MRI) showed a right parietal atrophy in the 2 cases. Different scene of the life and easy texts were presented. Saccades and pursuit were also tested with and without pictures in front of the patient. Results: Patients were unable to explore the left hemifield but could report the scene or the text showed. They had a left ophthalmoplegia and a left pursuit impairment only when pictures or peoples were on the front of them. Pursuit without other visual stimulus were normal. Conclusion: This troubles, occurring only with a visual stimulus in the front of the patient, are probably due to the posterior parietal atrophy and to parieto-collicular disconnection. The photo-oculograph allows to differenciate these patients to others with hemineglect or hemianopia. P425 MRI APROACH TO THE PROBLEM OF VISUAL LOSS. I. Vukadinovic, D. Kozic, V. Ivanovic, R. Semnic, B. Petrovic, M. Prvulovic, M. Eric, Z. Babic. Magnetic Resonance Center, Sremska Kamenica, Serbia The aim of this study was to determine the value of MRI with and without contrast medium (Gd-DTPA ), and also different sequences like STIR and FAT SAT, in the evaluation of the various orbital lesions with accentuation of extraconal and intraconal orbital compartements. CT and MRI sensitivity for the detection of mentioned lesions and also the specificity of special magnetic resonance sequences was compared as well. One hundred fifty-nine patients with ophtalmological complaints (unilateral visual loss, diplopia, amblyopia, hemianopsia, ophtalmoplegia, amaurosis) underwent head and orbital MRI for evaluation of different orbital lesions. Images were obtained on a 1.5 T imager (Magnetom SP 63) with all 3 planes performed before and after the application of gadolinium. In majority of patients MR images were analzyed after aplication STIR and FAT SAT sequences. Different lesions in intraorbital segments were revealed in 72 (45.2%) patients. Optic nerve glioma was revealed in 2 (2.7%) patients, meningeoma in 11 (15.2%) nonspecific lesion in 7 (9.7%), metastatic lesions in 4 (lymphoma 3), rabdomyosarcoma in 3 (4.1%), sellar macroadenoma with involvement of optic chiasm in 3 (4.1%), hemangioma in 1 (1.4%), orbital pseudotumor in 1 (1.4%), palpebral carcinoma in 1 (1.4%), hematoma in 1 (1.4%), trauma in 6 (8.3%) and atrophy of the optic nerve in 2 (2.7%) patients. Gadolinium application enabled clear demarcation between the tumor and surrounding tissue in majority of cases, as well as between cystic and solid component of the neoplasm. STIR sequence was positive in almost 75% of patients with optic neuritis. Computerized tomography detected less then 50% of orbital lesions in cases when it was performed before MRI (on which the finding was positive). Conclusion: MRI with Gd-DTPA enhancement provided very high sensitivity for detection of orbital intraconal and extraconal lesions, while STIR and FAT SAT sequences were significantly helpful in increasing specificity of lesion origin. P426 ALTERNATING EPISODES OF VESTIBULAR NERVE EXCITATION AND FAILURE. V. Arbusow, M. Strupp, M. Dieterich, L. Jäger, P. Schulz, T. Brandt. Ludwig-Maximilians University Munich, Germany Recurrent episodes of oscillopsia, rotational vertigo, and postural imbalance were elicited and modulated by changing horizontal head positions of a patient with an arachnoid cyst of the right cerebellopontine angle which displaced and stretched the vestibulo-cochlear nerve. Oculomotor analysis revealed a unique combination of two different types of attacks depending on the particular head position: (1) episodes of vestibular hypofunction (minutes to several hours) with normal head position and (2) paroxysmal vestibular excitation (seconds) with head rotation to the left. The most likely pathomechanism is a transition from conduction block to ectopic discharges. This commonly occurs during compression of various peripheral nerves. One week after surgical resection of the cerebellopontine cyst and decompression of the eighth cranial nerve oscillopsia, rotational vertigo, and postural imbalance promptly disappeared.

Pain and Headache P427 A CROSS-OVER, DOUBLE BLIND, RANDOMISED, MULTICENTER STUDY TO COMPARE THE EFFICACY AND TOLERABILITY OF LEVOSULPIRIDE VERSUS PLACEBO IN THE TREATMENT OF SOMATOFORM DISORDERS. Altamura AC1, Ermentini A2, Guaraldi GP3, Invernizzi G1, Meduri M 4. Department of Psychiatry, University of Milano1, Brescia2, Modena3, Messina4, Italy

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Few studies have been performed to investigate possible therapeutic strategies for Somatoform Disorders (S.D.), a disease with high social costs and unknown pathogenesis. Aim of the present research was to assess the efficacy and tolerability of levosulpiride, a substituted benzamide, in the treatment of S.D. Materials and Methods 74 patients affected by S.D. were treated either with levosulpiride (50 mg b.i.d.) or placebo for 4 weeks. At the end of the first phase patients were switched to the alternative treatment without wash-out and were treated for 4 more weeks. Clinical evaluation was performed before and after treatments using the Somatoform Disorder Schedule (SDS-CISSD), developed by World Health Organisation. Results: We observed that levosulpiride significantly reduced the number of somatoform symptoms compared to placebo (p < 0.007). We also found that 80% of symptoms improved during the treatment sequence placebo-levosulpiride; on the contrary only 44% of symptoms ameliorated during the treatment sequence levosulpiride-placebo (treatment sequence placebo-levosulpiride vs levosulpiride-placebo p < 0.002). No statistically significant differences were observed between levosulpiride and placebo regarding extrapiramidal, anticholinergic and endocrine side effects. Conclusion: Levosulpiride seems to be effective in the treatment for S.D. and it is also safe and well tolerated. These data are very promising also in order to understand the unknown pathogenesis of S.D. P428 PIRACETAM IN THE PREVENTION AND TREATMENT OF POST CONCUSSIONAL. J. Jolles1, T. de Barsy2, A. Mazzucchi3, J. L. Truelle4, B. Van Vleymen5 for the piracetam in PCS study group. 1Maastricht, NL, 2 Louvain, B, 3 Parma, I, 4 Paris, F, 5 Brussels, Belgium PCS is a frequent problem after mild head injury (MHI). We report the protocols of two ongoing trials with piracetam in mild head injury. Two double blind, parallel group design, randomized, placebo controlled multi centre trials evaluate patients after mild head injury. The prevention study evaluates 250 adults who are treated within 12 hours with oral piracetam 12 g/day in 2 divided doses for 1 week followed by 4.8 g/day for 7 weeks. Post concussional symptoms, the Stroop Test and Letter Digit Modality Test are assessed and APO E4 is determined. The primary aim is to show a 20% decrease of incidence of PCS in the piracetam group at 4 weeks after the head injury. Secondary objectives are to evaluate the safety of piracetam and its effect on each symptom of the PCS, cognitive impairment and absenteeism. The influence of APO E4 on the drug effect and on the development and recovery of PCS will also be analysed. In the treatment study (n = 250) the same dosage schedule is started 3 to 14 days after the MHI. Conclusion: Is piracetam efficacious in the prevention or treatment of PCS after MHI? Which is the best approach: early treatment of MHI or treatment of the PCS? Is there a genetic predisposition (APO E4) for the development of PCS or a different drug effect? P429 THERAPY OF CHRONIC MUSCULO-SKELETAL PAIN WITH THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI) FLUVOXAMINE. H. Schreiber1, C. Zeitler1, H. Riesner2, R. Halla3, K. P. Günther2, H. H. Kornhuber1. 1University of Ulm, RKU Hospital, 1Neurological and 2Orthopedic Departments, D-89081 ULM; 3Solvay Arzneimittel, D-30173 Hannover, Germany The therapeutic effects of the SSRI fluvoxamine were investigated in patients suffering from chronic pain due to advanced coxarthrosis or gonarthrosis Design: Monocentric, randomized, double-blind, placebo-controlled study. A flexible add-on dosage of fluvoxamine (50–150 mg/day) was administered for a period of 8 weeks. The non-steroidal antiphlogistics diclophenac, piroxicam or ibuprofen were allowed as concomitant medication. The data profile included a baseline examination, weekly standardized interviews by phone (N = 7) and a final examination. N = 60 probands were randomly assigned to a treatment group (M1) with N = 30 (9 male, 21 female) and a placebo group (M2) with N = 30 (11 male, 19 female). Pain, stiffness and mobility were measured by visual analogue scale (VAS), WOMAC- and GRISS-Scales, psychological functions by Hamilton-Depression Scale and BfS-Scale, and global clinical impression by the CGIScale. Results: In the VAS, no statistical evidence for a major therapeutic effect of fluvoxamine was shown either after two weeks of medication (interval V1–V3) either at the end (V1–V9). For the GRISS-Scale, however, 70% of fluvoxamine-treated patients reported pain improvement at V9 as compared to only 44.8% of patients in the placebo group (p < 0.06). Also for the different items pain, stiffness and mobility of the WOMAC-Scale a greater improvement was consistently found in the M1 group than in M2. Concerning theCGI-Scale, 56.6% of patients of M1, but only 37.9% of M2 groups reported that their general health status had “very much improved”

( p < 0.1). The tolerability of fluvoxamine was good. Conclusions: (1) This study failed to demonstrate a significant therapeutic effect of the SSRI fluvoxamine on isolated pain measurement as assessed by VAS (2) Consistent trends for improvement, however, were found in more complex scales involving mobility and stiffness (3) There is a favorable benefit-risk ratio for therapeutic trials of fluvoxamine in chronic musculo-sketal pain syndromes. P430 IPRAZOCHROME IN THE PROPHYLACTIC TREATMENT OF MIGRAINE – DOUBLE BLIND, PLACEBO CONTROLLED STUDY. Wojciech Kozubski, Dept. Neurol., Univ. Med. Sci., Poznañ, Poland Iprazochrome is believed to inhibit the type 2 serotonin receptors and the process of sterile inflammation of cranial vasculature. Since both of these phenomena are involved in pathophysiology of migraine attack we tried to estimate the efficacy of the drug on the characteristics of migraine episodes. 50 migraine patients were recruited according to the criteria of IHS. The study was designed as double blind, placebo controlled. After 4-week wash out period one group (25 patients) was treated with 15 mg of iprazochrome daily in three equal doses for eight weeks, the rest – with equal amount of placebo tablets. The effectiveness was calculated with the use of Migraine Score (MS) by Couch et al. At least 60% decrease of MS after treatment was regarded as positive effect. 44 patients completed the study. In 21 the therapy was positive: 16 out of them were treated with iprazochrome, 5-with placebo. In 23 patients the treatment was negative: 19 out of them took placebo, 4-iprazochrome. Statistical analysis showed significant influence on the MS (chi-sqare test: p < 0.01; Youle coeff. = 0.88). In iprazochrome group mean decrease of MS was significant after treatment ( p < 0.01), but not significantly changed in the placebo group. According to our results iprazochrome was found as an effective drug in the prophylaxis of migraine. P431 T CELL SUBSETS AND EXPRESSION OF INTEGRINS IN PERIPHERAL BLOOD OF PATIENTS WITH MIGRAINE AND CHRONIC TENSION TYPE HEADACHE. Empl M, Sostak P, Breckner M*, Riedel M*, Müller N*, Gruber R°, Förderreuther S, Straube A. Department of Neurology, Department of Psychiatry*, Department of immunology°, Ludwig-Maximilians-University, Munich, Germany Interactions between the nervous and the immune system – well known in the mediation of inflammatory pain – have been hypothesised to be an essential part of the pathophysiology of migraine, following the animal model of neurogenic inflammation. In humans, it remains to be determined, whether a neurogenic inflammation can be sustained by an enhanced interaction between T cells and the cerebral vascular endothelium or, since the efficacy of anti-inflammatory analgesics is remarkable, even be transferred as a model to other primary headaches. Therefore T cell subsets (CD3+, CD4+, CD8+, and CD45RO+) and the expression of integrins (CD11a and CD49) on lymphocytes were analysed in the peripheral blood of 20 patients with primary headache (migraine with and without aura, chronic tension type headache) by trichromic flow cytometry, and compared with 16 headache-free controls. Patients with chronic headache showed higher proportions of CD4+ T-helper cells (46.9 ± 10%, vs. 40.6 ± 4.9%, p ≤ 0.006), a higher proportion of CD4+45RO+ memory cells (23.5 ± 5.3% vs. 16.7 ± 5.8%, p ≤ 0.001), and a significantly higher expression of CD11a on CD4+ cells (30.1 ± 6.8% vs. 23.0 ± 4.5%, p ≤ 0.002) and on CD8+ cells (49.6 ± 13.6% vs. 29.8 ± 5.0%, p ≤ 0.005). In conclusion, these preliminary results indicate a possible immunological contribution to primary headache syndromes such as migraine and chronic tension type headache. P432 PROPHYLACTICS AND TREATMENT OF PAIN SYNDROME IN LONG-TERM USING OF ACRYLIC DENTURE. Chulak LD, Klaopick LE, Kilimnik OI, Ryaboshapko AA. Odessa State Medical University The actuality of the problem is brought about by specificity of the oral mucous affection under the influence of monomer, protoplasmic toxins, free radicals, dye stuff and other toxic substances excreted by acrylic dentures. The patients often complain of pain, burning sensation, parestesia on the mucous membrane of the palate, tongue cheeks. The aim of our investigation is to work out technology of making inert dentures with fluoroplast covering. Methods and Results: We have used physics-mechanical, biochemical, chromatographic, microbiology, clinic-laboratory and other

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methods of investigation in our work. To carry out effective prophylactic and medical measures we’ve worked out the technology of making dentures with protective covering. Last and liquid investigations showed that the number of residual monomer in water extracts of dentures with the covering is 40 times less in comparison with the control group. The secretors function of the salivary glands is restored, it is 0.62 ± 0.03 before the treatment and 1.23 ± 0.11 after the treatment. The color of the mucous membrane becomes pale pink in 3–4 months. The pain syndrome disappear in 55% of patients, the improvement of the condition is observed in 35% of patients and 10% have no significant improvement. Conclusion: Thus, the conducted investigations proved the high efficacy of protective fluoroplast covering of dentures allowing to reduce considerably the number of complications and relieve the patients from tormenting pain symptoms. P433 COMBINATION OF ETODOLAK AND CARBAMAZEPINE AS A NEW NON-NARCOTIC ANALGESIC. D. Dragana, J. Aco, B. Bogdan*, N. Zivorad*, R. Ranko, L. Toplica, D. Evica, J. Olivera. Department. of Pharmacy*, Department of Neurology, Military Medical Academy, Belgrade, Yugoslavia Combination of two well-known medications Etodolak and carbamazepine were used in order to develop new powerful, less harmful non narcotic analgesic. A new analgesic consists equal concentration – 100 mg/ml of both drugs and is prepared as injection solution. It was our aim to evaluate its analgesic effect. In 60 patients of both sex, aged 18–81 years, with different pain syndrome (low back pain, trigeminal neuralgia, migraine, headache, myocardial infarction postsurgical pain a new drug was used intravenously. The level of pain was marked as severe and moderate (68% severe, 32% moderate), and in majority of patients (84%) complete relief was obtained within 20 minutes of intravenous injection, while the rest had significant pain reduction. During 300 minutes follow-up period free of pain were 90% of patients and in 10% injection was repeated with similar analgesic effect and without side-effects. Except in migraine patients, where certain ataxia and drowsiness were noted, other side-effects has not been registered. In conclusion, newly synthesised drug – Etodolak + Carbamazepine, applied intravenously, is safe effective analgesic in treatment of various pain syndrome.

Peripheral Neuropathy P434 NEUROMUSCULAR BLOCKADE BY IMMUNOGLOBULIN G (IGG) FROM PATIENTS WITH GUILLAIN-BARRÉ SYNDROME (GBS). B. Buchwald, J. Zielasek, A. Weishaupt, J. Dudel, K. V. Toyka. Würzburg, Munich, Germany Background: Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with GBS, but their functional role is not yet elucidated. Materials and Method: We have investigated the effect of serum, purified IgG and IgM from patients (n = 10) with typical GBS on motor nerve terminals in the mouse hemidiaphragm. Endplate currents were recorded by means of a perfused macro-patch-clamp electrode. Antibodies to GM1 and GQ1b were determined by ELISA and dot blot assays. Results: Plasmafiltrate of all ten patients depressed evoked quantal release 5 to 10 fold. Blockade was complete within 7 to 15 minutes and could be overcome by stronger depolarization of the nerve terminal. In addition, five of ten GBSsera reduced the amplitude of postsynaptic currents. In most cases blockade could be reversed by wash-out. Purified GBS-IgG blocked as effective as native GBS-serum, whereas a purified GBS-IgM fraction did not. IgG and sera from healthy subjects were without effect. The observed blockade was independent of complement ond of the presence (8 patients) or absence (2 patients) of detectable antiganglioside antibodies. Conclusion: In GBS, IgG-antibodies to an indetermined antigen blocked presynaptic transmitter release and in some cases the activation of postsynaptic channels. Muscle weakness in the acute stage of GBS may be caused in part by circulating antibodies. P435 DEVELOPMENT OF PERIPHERAL NERVE ABNORMALITES IN PMP22 MUTANT MICE. A. M. Robertson, P. K. Thomas, C. Huxley*, R. H. M. King. Royal Free Hospital School of Medicine and *Imperial College School of Medicine at St. Mary’s, London

Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated with peripheral neuropathy in mice and humans. PMP22 is strongly expressed in peripheral nerves and localises largely to the myelin sheath. In this study we compared the initial stages of postnatal development the sciatic nerve during early postnatal development in a transgenic mouse model with 7 copies of the human PMP22 gene and both homozygous and heterozygous Trembler-J mice which have a point mutation in the PMP22 gene. Affected mice could be distinguished morphologically from normal litter mates at postnatal day (P)4. All the mutant mice had fewer myelinated and more promyelin fibres than control animals. The number of axons that were singly ensheathed by Schwann cells was the same in all groups indicating that PMP22 does not function in the initial separation and ensheathment of axons. Myelin that is formed in the mutant strains is unstable at P4. The proportion of promyelin fibres that were incompletely surrounded by Schwann cell cytoplasm was increased in both Tr J/TrJ and Tr J/+ but not in C22 transgenic animals. This feature was more common in larger fibres suggesting that the mutant protein affects the ability of the Schwann cell to accommodate the increase in axon size that occurs with development. P436 A PROSPECTIVE STUDY OF CRITICAL ILLNESS POLYNEUROMYOPATHY: INCIDENCE AND PATHOPHYSIOLOGY. M. A. C. J. Megens-de Letter1, 2, P. A. van Doorn2, H. F. J. Savelkoul3, L. H. Visser1, A. A. W. Op de Coul1, P. I. M. Schmitz2, F. G. A. van der Meché2. 1Dept. Neurology, St. Elisabeth Hospital Tilburg, The Netherlands. 2 Dept. Neurology and 3 Immunology, University Hospital and Erasmus University Rotterdam, The Netherlands In a longitudinal prospective study we included 98 patients, who needed artificial respiration and followed them for the development of Critical Illness Polyneuromyopathy (CIPNM). We analysed clinical factors, lightmicroscopical and immunohistochemical findings in muscle biopsies of all 30 patients (31%) who developed CIPNM. Standard lightmicroscopical evaluation showed neuropathic, myopathic and both neuropathic and myopathic changes in 32%, 35% and 26% respectively. Immunohistochemical studies showed that the presence of CD68 (macrophages) was correlated with IL-1β ( p-value 0.099), CD68 with IL-12 ( p-value 0.095), TNFαR75 with IL-12 ( p-value 0.013) and IL-12 with VCAM ( p-value 0.095). IFN-γ was present in 43% (12/28) staining on the surface of Thcells. Expression of adhesion molecules ICAM-1 and VCAM was present in 54% (14/26) and 57% (17/30) of the patients respectively. In severe sepsis significantly more myopathic changes were seen, while the group with less severe sepsis correlated with neuropathic changes (p-value 0.047). The severity of sepsis didn’t correlate with the immunohistochemical parameters. Additionally patients who had used neuromuscular blocking agents (NBA) were clinically worse with regard to their muscle strength ( p-value 0.075). Conclusion: In CIPNM the hypothesis is supported that the triggering of macrophages is associated with the release of proinflammatory cytokines and results in temporary Th1-cell activation. Expression of adhesion molecules ICAM-1 and VCAM suggests the possibility of increased vascular permeability. This could allow entry of toxins such as NBA, making NBA a possible injurious agent in CIPNM. P437 CLINICOPATHOLOGICAL AND GENETIC STUDY OF PATIENTS WITH THE DÉJERINE-SOTTAS PHENOTYPE. Yesim Parman*, Violaine Planté-Bordeneuve°, Anne Mantel #, Feza Deymeer*, Piraye Serdaroglu*, Mefkure Eraksoy*, Françoise Goutieres §, Gérard Said°. *Department of Neurology, Medical Faculty, Istanbul-Turkey. °Department of Neurology, # Department of Molecular Biology, Bicêtre Hospital, § Department of Pediatry, Necker Hospital, Paris, France Déjerine-Sottas disease (DSD), originally described as a familial demyelinating neuropathy in children born to clinically unaffected parents, has remained a confusing and controversial entity. Recent studies found mutations in the PMP22 and in the P0 genes. To further explore the spectrum of DSD, we studied the clinicopathological and genetics aspects of 16 DSD patients. Autosomal recessive inheritance was probable in 5 cases. Parental consanguinity and/or affected sibs were found in 5 cases. First manifestations varied from hypotonia at birth to gait ataxia at the age of 3.5 years with delayed motor milestones in 13 cases. Two patients had a relapsing course, one of them responded to corticosteroid. Ultrastructural analysis of the nerves showed de/hypomyelination of nerve fibres and classical onions bulbs. Six patients had excessive folding and irregular thickness of the myelin sheath. We found a molecular defect in the PMP22 gene in 5 patients including a duplication of the 17p11.2–12 region in 2 unrelated

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cases; a heterozygous missense mutation (Ser72Leu) in one case; and a homozygous missense point mutation (Arg157Trp) in 2 sibs. Finally, one patient had a heterozygous double mutation of the P0 gene (delVal 42, Ala 221 Thr). In conclusion the DSD phenotype can be associated with homozygous or heterozygous defects of the PMP 22 or of the P0 genes, or to an early onset chronic inflammatory demyelinating polyneuropathy, which may respond to corticosteroids. P438 INCREASING TRANSMIGRATION CAPACITIES OF CIRCULATING LYMPHOCYTES DURING THE COURSE OF GUILLAINBARRÉ SYNDROME (GBS). Créange A, Sharshar T, Poron F, Raphaël J-C, Gherardi RK. Créteil and Garches, France In order to investigate lymphocyte transmigration through extracellular matrix macromolecules in patients with GBS. GBS is associated with intraneural inflammation, that reflects emigration of immune cells from blood to nerve tissue. We evaluated ex vivo transmigration capacities of circulating lymphocytes in 7 patients with GBS at day 1, 7, 14 and 28 of hospitalization, and in 5 healthy subjects using a modified Boyden Chamber precoated with Matrigel® (a model of basement membrane) or fibronectin. Lymphocytes were deposited in the upper chamber without addition of active molecules. The number of migratory cells in the lower chamber was determined after 24 hours. At day 1, all patients were in the progression phase, at day 28, 6/7 were recovering. Lymphocytes (patients and controls) had poor transmigratory capacities across Matrigel®. Transmigration across fibronectin was decreased at time of progression as compared with controls ( p < 0.01), and increased above control levels at time of recovery ( p < 0.02). The lowest transmigration rate was observed in the most disabled patients. Conclusion: The low transmigration capacities of circulating lymphocytes at time of progression is consistent with an early emigration of lymphocytes into nerve prior to admission. The subsequent increase of transmigration rate at time of recovery, is compatible with a blockade of lymphocyte entry into nerve, or may even suggest a recirculation of lymphocytes. P439 RECESSIVE HEREDITARY MOTOR AND SENSORY NEUROPATHY OF NEURONAL TYPE WITH VOCAL CORD PARESIS. Teresa Sevilla, Maria J. Chumillas, Francisco Palau, Fernando Mayordomo, Ignacio Dobón and Juan J. Vilchez Dysphonia and vocal cord paresis has been described in hereditary motor and sensory neuropaties (HMSN) and distal spinal muscular atrophy. The inheritance in the pedigrees affected was autosomal dominant. We describe five cases belonging to two families with a severe motor and sensory neuropathy. The disorder commences in early childhood and is characterised by a severe degree of muscle weakness and wasting of limbs, vocal cord paresis and sensory loss. The patients became wheelchair-bound around puberty. Peripheral nerves were inexcitable distally with proximal latencies in normal range. Pathological changes in sural nerve biopsy showed an extensive loss of large diameter fibers and nearly absent of regeneratives features. Parents were clinically and electrophysiologically normal and no consanguinity was reported. Severe cases of HMSN of neuronal type (HMSN II) were described by Ouvrier et al. (1981) but none of them had vocal cord paresis. Two families with HMSN II with diaphragm and vocal cord paresis were reported by Dyck et al. (1994) but inheritance was autosomal dominant. Because all affected patients were male, the condition may be transmitted by autosomal recessive or X-linked gene. Molecular studies excluded 17p11.2 (CMT1A) duplication. We think that this families represent a new clinico-genetical entity among HMSN disorders.

considerably (9 months – 6,3 years). Five patients were not seriously incapacitated by their disease (Rankin 1 or 2), four of them being in remission now and one showing a very slow progression. Two patients were moderately disabled (Rankin 3): one with severe persistent sensory ataxia and only weakness during relapses and one with stepwise progression and moderate weakness. We conclude that CIDP and only sensory symptoms is a transient clinical stage that precedes the appearance of weakness in about 70% of patients. P441 LONG-TERM FOLLOW-UP OF A CASE WITH ADULT REFSUM DISEASE UNDER DIETARY TREATMENT AND REPEATED PLASMA EXCHANGE (CASCADE FILTRATION). R. Blattner, W. Köhler, D. H. Hunneman, G. Hertel. Moabit Hospital, Berlin; University of Göttingen, Germany Heredopathia atactica polyneuritiformis (Refsum disease) is a rare inborn error of lipid metabolism due to deficiency of alpha-hydroxylase, resulting in accumulation of phytanic acid in plasma and body tissues. Patients become symptomatic during the first and third decade. Retinitis pigmentosa, deafness, peripheral nerve dysfunction, cardiac and skin involvement as well as sceletal abnormalities are common features. Clinical diagnosis is confirmed by high levels of phytanic acid and low enzyme activity in fibroblasts. Standard therapy consists of dietary treatment, intermittent plasma exchange is applied in severe forms. We present a 61-year-old female patient who was followed up by the authors for seven years under treatment. Onset of symptoms began at the age of 35. Our patient developed visual loss due to retinitis pigmentosa, bilateral cataract and glaucoma, bilateral deafness, polyneuropathic symptoms, mixed ataxia, ichthyotic plaques, but no cardiac involvement. At the age of 54 diagnosis was made and diet commenced. One year later we started repeated cascade filtration that was well tolerated and lowered levels of phytanic acid. Visual impairment and complete deafness could not be influenced, but peripheral nerve dysfunction stabilised and ichthyosis disappeared with cascade filtration. Our results support that diet and cascade filtration can reduce the rate of progression in Refsum disease and that combining treatment is superior to diet alone. Sequential filtration of plasma (cascade filtration) is superior to plasmapheresis because fewer antibodies and clotting factors are lost.

P442 LABIAL SALIVARY GLAND BIOPSY IN ETIOLOGIC INVESTIGATION OF NEUROPATHIES. F. J. Authier, E. Lechapt, A. Creange, M. C. Voisin, R. K. Gherardi. Créteil, France

P440 LONG TERM FOLLOW UP OF PATIENTS WITH CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY AND ONLY SENSORY SYMPTOMS. G. W. van Dijk, N. C. Notermans, H. Franssen, J. H. J. Wokke. University Hospital Utrecht, The Netherlands

Labial salivary gland (LSG) biopsy is a poorly invasive ambulatory test, widely used in patients with predominantly sensory polyneuropathy of unknown origin to search inflammatory changes consistent with Sjögren’s syndrome. LSG biopsy is also a reliable test (sensitivity: 86%) for the diagnosis of primary AL and secondary amyloidosis (Hachulla et al., Arthritis Rheum 1993; 5 : 691–697). We investigated the usefulness of LSG biopsy for the etiologic diagnosis of peripheral neuropathy in 40 consecutive patients. The diagnosis of peripheral neuropathy was established on the grounds of clinical and electrophysiological data. Thirty-one patients had nerve and muscle biopsies. LSG inflammatory infiltrates were observed in 26/40 cases (65%): Chisolm III or IV 2/26, Chisolm II 9/26, Chisolm I 15/26. Amyloid deposition was found in 6/40 cases (15 %), that was of transthyretin (TTR)-type in 4/6 and of AL-type in 2/6. A nerve biopsy was performed in these 6 patients and confirmed the diagnosis of amyloid neuropathy in 5/6, in the 4 patients with TTR-amyloidosis and in one of the 2 with AL-amyloidosis. In 2/40 cases (5 %) LSG biopsy showed nonspecific degenerative changes and in 2/40 cases (5%) LSG biopsy was normal. Briefly, LSG biopsy in patients with peripheral neuropathy (1) showed frequently mild to moderate inflammatory infiltrates; (2) was rarely consistent with the diagnosis of Sjögren’s syndrome; and (3) may allow to evidence TTR-amyloidosis. We conclude that LSG biopsy may be used as a first-line diagnostic tool in peripheral neuropathy of unknown origin.

Although weakness is one of the clinical hallmarks of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), in some patients only sensory symptoms are present despite electrophysiological evidence of demyelination in motor nerve fibres. We describe the long term follow up of seven patients with CIDP and only sensory symptoms with emphasis on the development of motor symptoms and long term disability. At follow up, weakness developed in five patients and persisted in three of them. The mean duration of disease until weakness developed was 3,1 yr., but varied

P443 POPULATION BASED STUDY OF THE PREVALENCE AND THE RISK FACTORS OF POLYNEUROPATHY IN THE ELDERLY. Scarpini E, Candelise L, Siglienti I (Milano); Baldereschi M, Di Carlo A, Maggi S, Amaducci L (Firenze); Grigoletto F, Volonnino G, Minicucci N (Padova); Bonaiuto S (Fermo); Inzitari D (Firenze); Loeb C (Genova); Canal N (Milano); Rengo F (Napoli); Enzi G (Padova); Scarlato G (Milano)

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Distal symmetric neuropathy of lower limbs (DSNLL) is a common complication of several clinical conditions, and the elderly is a subpopulation at higher risk of them. In order to assess the prevalence and risk factors of DSNLL we analyzed, in a descriptive epidemiological survey, the data collected from 8 Italian municipalities taking part in the Italian Longitudinal Study on Aging (ILSA), a multicenter project designed to study age-associated diseases. The definition of peripheral neuropathy by P.J. Dyck (1982) was employed, but only peripheral neuropathies with distal and symmetrical involvement of lower limbs were considered. Diagnosis was articulated in two phases: – phase 1, or screening, administered to all partecipants; – phase 2, or clinical confirmation by a neurologist, administered to the positive screened. Three diagnostic categories were identified: possible, probable and definite DSNLL. The neuropathy was classified as defined only when confirmation by a positive EMG was available. A random sample of 5632 subjects aged 65–84 years was evaluated. A total number of 337 DSNLL was identified (possible, probable or defined). The prevalence is 6.5% (95% C.I. 5.8–7.2) in women and in men; its rates by age, geographic area, and clinical severity are described, and the prevalence of DSNLL in the different groups of diabetic patients and non-diabetic subjects is analyzed. This prevalence is slight lower than that obtained in a similar Italian multicentric study (IGPSG 1995), but in the latter the diagnostic criteria employed were different. Diabetes is the commonest associated disorder with the 20.8% of association, followed by toxic/drug exposure (5% of association). P444 LUMBOSACRAL ROOTS AND FACIAL NERVE ENHANCEMENT IN MILLER FISHER SYNDROME. Pedotti R, Carpo M, Lucchi S, Righini A, Scarlato G, and Nobile-Orazio E. Milan, Italy Miller Fisher syndrome (MFS), the most common variant of Guillain-Barrè syndrome (GBS), is characterised by acute onset of ophthalmoplegia, cerebellar-like ataxia and areflexia. Controversy still exists on the localisation of the causative lesions. We report the brain and spine MRI studies of a 52 y.o. woman who developed MFS after an upper respiratory infection. She also had, not excluding the diagnosis, mild bilateral facial nerve impairment, mild proximal weakness, reduction of vibratory and position senses in the lower limbs and moderate back pain. Anti-GQ1b IgG antibody titers by ELISA were increased in patient’s serum (1 : 400; normal < 1 : 200). MRI of brain and lumbosacral spine performed at 1.5 Tesla, before and after administration of Gadodiamide, in the acute phase of the illness showed a marked diffuse contrast enhancement of nerve roots of the cauda equina and a definite contrast enhancement of the first and intrapetrous segment of both facial nerves, without signal alteration within brain parenchyma. The same MRI protocol repeated after 7 months revealed no contrast enhancement of cauda equina nerve roots and greatly reduced enhancement of both facial nerves, compatible with normal range. Gadolinium-enhancement of nerves has been frequently associated with disymmune neuropathies including GBS and chronic inflammatory demyelinating polyneuropathy, where it is thought to reflect a disruption of the bloodnerve barrier. The finding of a similar nerve enhancement in MFS patients may therefore represent a direct in vivo evidence of a peripheral origin of MFS, and further highlights its similarity with GBS. P445 SUBACUTE POSTOPERATIVE FUNICULAR MYELOSIS MIMICKING SENSORY NEURONOPATHY. Lahrmann H, Hitzenberger P, Sellner Y, Grisold W. Ludwig Boltzmann Institut für Neuroonokologie, Zentralroentgen-Institut, Kaiser Franz Josef Spital, A-1100 Wien, Austria Subacute loss of proprioception with onset in the upper limbs and severe gait ataxia after general surgery is a rare feature. Case: A 69-year-old caucasian male presented with loss of proprioception accompanied by paresthesias and numbness in upper extremities and gait ataxia developing within 14 days. He had had a cholecystectomy with nitrous oxide anesthesia (1.5 hours) 7 weeks prior to onset of symptoms. Macrocytic anemia was detected preoperatively. Results: Clinical examination revealed normal findings of cranial nerves; deep tendon reflexes were normal in the upper and brisk in the lower extremities; plantar responses were extensor bilaterally; gait was atactic. He had severe loss of position and vibration sense resulting in inability to identify objects with his hands and pseudoathetotic movements of fingers. Motor and sensory nerve studies including H-reflex and F-wave were normal in upper and lower limbs. Electromyography and visually evoked potentials were uncontributory. Cerebrospinal fluid protein and cell count were normal. Somato-sensory evoked potentials were not recordable. T2-weighted MRI scans demonstrated hyperintense signal alterations in the cervical posterior column. Laboratory tests revealed macro-

cytic anemia, markedly lowered Vit B12 level (47 pg/ml) and positive Schilling test. Clinical symptoms improved with hydroxycobalamin treatment, confirming the etiology of the disorder. Conclusions: Funicular myelosis due to Vit B12 deficiency should be considered in patients with symptoms mimicking subacute sensory neuronopathy shortly after an anesthesia with nitrous oxide. P446 STRUCTURAL ABNORMALITIES OF ENDONEURIAL VESSELS IN CHRONIC IDIOPATHIC AXONAL POLYNEUROPATHY. Teunissen LL, Notermans NC, Jansen GH, Banga JD, Veldman H, Wokke JHJ. University Hospital Utrecht, The Netherlands Increased basement membrane thickness of endoneurial vessels can be demonstrated in different neuropathies. In some of these neuropathies, as diabetic neuropathy or neuropathy in chronic obstructive pulmonary disease, ischemia is thought to be an important factor. We hypothesized that chronic ischemia might play a role in the developement of chronic idiopathic axonal neuropathy (CIAP). We therefore searched for basement membrane abnormalities of endoneurial vessels in sural nerve biopsies of 18 patients with chronic idiopathic axonal polyneuropathy (CIAP), 4 patients with diabetes mellitus (DM), 6 patients with hereditary motor and sensory neuropathy type II (HMSN II) and 11 autopsy controls. Electron micrographs (2000 ×) were made of endoneurial vessels. The basement membrane thickness (BMT) was measured and the number of lamellae of the basement membrane, number of endothelial cell nuclei and pericyte nuclei were counted. The mean BMT was 4.3 µm in CIAP, 4.5 µm in DM, 3.4 µm in HMSN II and 3.8 µm in controls. Compared to controls, BMT was enlarged in CIAP and DM ( p < 0.01). In DM, the number of endothelial cell nuclei and lamellae was larger compared to the other groups. No differences were found in the number of pericyte nuclei. BMT was enlarged both in CIAP and in DM. In CIAP, the enlargement is not attended by duplication of lamellae, as is found in DM. This suggests a different pathogenesis of the basal membrane abnormalities. P447 SERUM IGG ANTIBODIES AGAINST GQ1b AND GM1 GANGLIOSOSIDES IN PATIENTS WITH MILLER-FISHER SYNDROME AND GUILLAIN-BARRÉ WITH OPHTHALMOPLEGIA. C. Lebrun*, J. Boucraut**, J. Brunetto*, C. Desnuelle***, M. Chatel*. Services de Neurologie*, de réeducation fonctionnelle***, NICE; Hôpital la Timone**, Marseille, France Objective: To investigate the significance of serum anti-GQ1b and antiGM1 IgG antibodies in acute inflammatory demyelinating polyneuropathy (AIDP) with ophthalmoplegia. Background: The presence of serum IgG antibodies to GQ1b ganglioside have been reported in the acute phase of Guillain-Barré syndrome (GBS) with ophthalmoplegia, in Miller-Fisher syndrome (MFS) as in other acute ophthalmoparesis. Design/Methods: Anti-GQ1b and anti-GM1 antibodies titers were analysed in the serum of 9 patients with ophthalmoparesis and GBS (5 patients) or MFS (4 patients), and in 9 patients with GBS without ophthalmoparesis. The ELISA for the detection of IgG and IgM against anti-GQ1b and anti-GM1 antibodies (Sigma) was performed as previously described (Azoulay). Results: Anti-GQ1b antibodies were detected only in the serum of the 4 MFS patients and levels of anti-GM1 antibodies were found not significant. Serum anti-GQ1b antibodies were not detected in patients with GBS with or without ophthalmoplegia. Titer of serum anti-GM1 antibodies was significantly high in respectively 3/5 and 2/9 of the patients with typical GBS with and without ophthalmoparesis. Conclusions: We confirm that MFS is associated with high titer of anti-GQ1b IgG antibodies, anti-GM1 antibodies being not detected in this form. In our series the absence of anti-GQ1b antibodies in patients in the acute phase of GBS with ophthalmoplegia may suggest that different mechanisms could occur in the pathogenesis of ocular muscle involvement in AIDP. P448 RELATIONSHIPS BETWEEN DYNAMIC FOOT PRESSURE PATTERNS, AUTONOMIC CARDIOVASCULAR FUNCTION TESTING (AFT), QUANTITATIVE SENSORY TESTING (QST) AND METABOLISM IN TYPE 1 DIABETES MELLITUS (IDDM). Haslbeck KM1, Mehnert H 2. Neurological Department of the University Erlangen-Nürnberg Germany1; Diabetes Research Institut Munich, Germany2 Up to now relationships between AFT, QST, dynamic foot pressure patterns (early detection of diabetic foot syndrome) and metabolism are still un-

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clear. In our crossectional study we performed AFT (4 tests), QST (vibration and thermal perception thresholds) and dynamic foot pressure measurements (Emed SF) in 72 IDDM patients (age 15–50, diabetes duration 1–30 years). Metabolic situation was characterized by measuring blood glucose, HbA1c, fructosamine and blood lipids immediately before AFT, QST and dynamic gait analysis. Results ( p < 0.05): Patients with pathological AFT/QST had elevated peak pressures (33.8 + 13 vs 45.2 + 14 N/ cm2) and impulses (95.2 + 31.1 vs 114 + 21 Ns) under the forefoot. Patients with pathological AFT had elevated triglyceride levels (160 + 80 vs 117 + 41 mg/dl). Correlations ( p < 0.05) were found between: – warm sensitivity thresholds and the impulses under the whole foot (r = 0.44), – heart rate variability, toe peak pressures (r = 0.34) and triglyceride levels (r = 0.31), – triglyceride levels and warm and cold sensitivity thresholds (r = 0.40 and 0.39). Conclusions: Our results give evidence that somatosensory and autonomic small fibre function is influenced by elevated triglyceride levels and is involved in the pathogenesis of impaired gait dynamics in IDDM. P449 AUTOSOMAL RECESSIVE TYPE II HEREDITARY MOTOR AND SENSORY NEUROPATHY (HMSN II) WITH ACRODYSTROPHY. P. K. Thomas, R. H. M. King and D. Claus. London, UK and Darmstadt, Germany In type II HMSN the underlying pathology is an axonopathy, in contradistinction to the demyelination in type I HMSN. In both, autosomal dominant and autosomal recessive pedigrees occur. Considerable advances have been made in the molecular genetics of HMSN I which has been shown to be highly heterogeneous genetically. Linkage studies have also established that autosomal dominant HMSN II is heterogeneous. Autosomal recessive HMSN II is still poorly delineated. We have investigated a family with 3 affected siblings born to consanguinous (first cousins) unaffected Turkish parents. All 3 siblings (2 female, 1 male) presented in childhood with a distal motor and sensory neuropathy affecting both the lower and upper limbs. We examined a male aged 22 years and a female aged 20 years. Prominent mutilation of the feet was present related to severe sensory loss which affected all modalities. Electrophysiological investigations indicated an axonopathy. Sural nerve biopsy from both showed a virtually total loss of myelinated fibres and severe depletion of unmyelinated axons. No specific pathological features were demonstrable. An elder sister died in her third decade from secondary renal amyloidosis. The severity of the distal motor involvement that accompanied the sensory loss indicated that the diagnosis was one of HMSN and not autosomal recessive hereditary sensory neuropathy. Sensory loss of this severity in autosomal recessive HMSN II has not hitherto been described. This family therefore represents a new variant. P450 POLYNEUROPATHY DUE TO ALCOHOLISM AND NUTRITIONAL DEFICIENCY: STUDY OF 116 BRAZILIAN CASES. Marcos R. G. De Freitas, Osvaldo J. M. Nascimento, Pedro F. M. Filho, Edmar Araújo, Gabriel R. De Freitas. Niterói, Rio de Janeiro, Brazil In Brazil, chronic alcoholism with nutritional deficiency is the second most frequent cause of polyneuropathy (PN). It is difficult to separate alcohol direct toxic action on the nerve from the effects of undernourishment. We studied 116 cases of this PN to determine the following parameters: age, sex, race, type of alcoholic beverages, clinical presentation of PN, EMG findings, presence of other associated neurological or systemic disorders, treatment and prognosis. There were 104 men and 12 women. The majority used to drink “cachaça” (the most common Brazilian alcoholic beverage). In 46 patients there was a mixed PN, in 38 the PN was sensory and in 32 it was ataxic. The evolution was acute in 8 cases, subacute in 14 and chronic in 94. The most frequent associated disturbances of the nervous system were: convulsions (9 cases), Wernicke-Korsakoff syndrome (9) and reduction of vision (7). The commonest systemic findings were: liver disease (14 cases), tuberculosis (11), pancreas disease (7) and cardiomyopathy (6). EMG was compatible with axonal degeneration. The treatment was alcohol withdrawal, balanced nutrition, thiamine, multiple-vitamine and physical therapy. At follow-up in 2 years (51 cases), 48 were completely symptom-free, 2 had severe disability and 1 died. We observed that the prognosis of alcohol-nutritional deficiency PN is better if the treatment is prescribed early. P451 A CLINICAL METHOD ASSESSING SENSITIVITY TO ISCHEMIA IN NORMAL AND DISEASED PERIPHERAL HUMAN NERVE. S. Horn, J. Groskeutz, U. Hoffmann, S. Quasthoff. Dpt. of Neurology, TU, Munich, Germany

Standard electrophysiological methods require long periods of ischemia to show significant changes of nerve excitability and provide little information about underlying pathology in peripheral neuropathy. We used threshold tracking in combination with defined polarizing currents to gain information about differential effects of ischaemia on axonal excitability in normal and diseased peripheral human nerve. Thresholds of a 40% of maximal response in median motor and sensory axons were measured at the wrist. Responses to 1 ms test pulses without prior polarization as an indicator of nodal excitability were compared to alterations induced by preceding (100 ms) hyperpolarizing currents as measure of internodal excitability before, during and after 5 min of ischaemia. Results from 45 normal controls served as reference to those of 54 diabetic patients, 47 ALS patients, 17 patients with taxol-cisplatin induced neuropathy and 24 patients with various other neuropathies. Sensitivity to ischemia was shown to be dependent on the age of the probands. Between above types of neuropathy, five minutes of ischaemia were sufficient to show highly significant differences in nodal and internodal sensitivity to ischaemia in both motor and sensory axons. As a general finding, responses to test pulses preceded by hyperpolarization were more sensitive in demonstrating ischemia induced differences in axonal excitability among different neuropathies than responses to a test-pulse alone. Therefore, testing excitability of the para- and internodal membrane seems to be a more sensitive method to demonstrate sensitivity to ischemia than testing the nodal membrane with a simple test pulse alone. Supported by the W. Sander Stiftung. P452 ELECTROPHYSIOLOGICAL TESTINGS SUGGESTS A LENGTH DEPENDENT AXONOPATHY IN X LINKED CHARCOT-MARIETOOTH DISEASE (CMT X). J. M. Guglielmi1, 2, V. Planté1, J. N. Tillier 2, G. Said1. 1C.H.U. Bicêtre and 2 CH Argenteuil, France CMT X is a form of hereditary motor and sensory neuropathy with progressive weakness, distal atrophy and sensory loss. Connexin 32 gene mutations have been linked to CMT X. Four male patients defined as CMT X on the basis of DNA testing have had an extensive electrophysiological evaluation. Near nerve sensory action potentials (SNAPs) amplitude and conduction velocities were studied in sural, median, ulnar, superficial radial sensory branch and lateral or medial antebrachial cutaneous nerves. Motor conduction velocities of median, ulnar, peroneal and tibial nerves were recorded. Nerve biopsies had been performed in three patients before the availability of DNA testing. Sensory nerve conduction studies showed evidence of a decrease of SNAP amplitude in a length dependent pattern: sural, median, ulnar are decreased in amplitude (0 µV–3 µV) with conduction at 34 ± 3 m/s; superficial radial sensory branch (3 µV–11 µV) with conduction at 41 ± 3 m/s; lateral or medial antebrachial cutaneous nerves (7 µV–14 µV) with conduction at 55 ± 4 m/s. Median and ulnar conduction velocities were 34 ± 2 m/s with decrease compound muscle action potential amplitudes. On nerve biopsy specimens, the density of myelinated fibers was slightly reduced in patients 2 and 3 (4165 and 5960 MF/mm2 respectively), normal in patient 1 (7330 MF/mm2), with reduction of the density of larger, a high proportion of hypomyelinated fibers and of clustered regenerating fibers. Active degeneration was rarely seen. Electrophysiological and pathological findings are compatible with a distal axonopathy associated with hypomyelination predominating on larger myelinated axons in CMT X patients. These observations underline the role of connexin 32 in axon-Schwann cell interactions.

Clinical Neurophysiology P453 MEDIAN NERVE MONONEUROPATHY IN SPONDYLOTIC CERVICAL MYELOPATHY: DOUBLE CRUSH SYNDROME? Bednaøík Z. Kadaòka and S. Voháòka. Brno, Czech Republic One hundred consecutive patients with advanced cervical spondylosis (CS) leading to either clinically overt spondylotic cervical myelopathy (SCM) – 60 patients – or subclinical compression of the spinal cord – 40 patients – were evaluated electrophysiologically with respect to the presence of distal entrapment mononeuropathies at the upper extremities. Electromyographic (EMG) signs of focal median nerve mononeuropathy (MNM) at the carpal tunnel were found in 27 patients: in 20 myelopathic patients (33.3%) and in 17 non-myelopathic patients (17.5%); in the other five cervical spondylosis patients there were EMG signs of ulnar nerve neuropathy at the elbow. The prevalence of EMG signs of MNM was higher ( p < 0.01) in comparison with 11% prevalence in sex and age matched control group. While the EMG abnormalities of the anterior horn cells lesion did

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not match the segmental level (C8-Th1) in those patients with the evidence of MNM, the abnormality of the medullar segmental N13 component of the median nerve somatosensory evoked potentials (SEP MED) was associated significantly ( p < 0.01) with MNM. The N 13 component of the SEP MED is, however, believed to be generated postsynaptically in the interneurons at dorsal horns at C6–7 level. Though the proximal lesion of the peripheral sensory neuron could increase the susceptibility of the neuron to the compression at the distal site or to the manifestation of a subclinical pre-existing distal lesion through the DC mechanism, current electrophysiological data offer no direct support for such a hypothesis. The high prevalence of MNM in CS does not inevitably mean an etiologic linkage between these two conditions. The association between these two common conditions could also be explained by the influence of common extrinsic causal factors, especially long-lasting physical stress overload of the cervical spine and the upper extremities, leading to both accelerated spondylosis and MNM. P454 EEG, MRI AND NEUROPSYCHOLOGICAL FINDINGS IN PATIENTS WITH DNA-PROVEN JUVENILE FORM OF HUNTINGTON DISEASE. K. Niedzielska, W. Kuran, N. Habib, M. Rzeski, R. Poniatowska, D. Hoffman, T. Jakubowska. Warsaw, Poland Juvenile form of Huntington disease (HD) is usually associated with rapid degenerative process and progress of the disease. We examined 20 patients (aged 13–30) with early onset of HD (range 11 to 21) with disease duration 1–9 years. Diagnosis was DNA-confirmed with CAG repeats number ranging from 50 to 77. In 17 cases HD-affected person in the family was father and in 3-mother. In all patients EEG, MRI, psychological examination were performed. We analysed correlations between the EEG changes, cognitive disfunction, brain atrophy and CAG repeat number. The EEG revealed no abnormalities in 11 cases (low-amplitude EEG in 6) and background slowing in 9 (low-amplitude in 7). In patients with diffuse EEG slowing higher CAG repeat number than in patients with no EEG changes were observed; similarly lower MiniMental State Examination (MMSE) scores in group with EEG abnormalities were found. The differences were statistically significant (Mann-Whitney U Test). We didn’t find evident relationship between EEG and MRI results but there was high correlation between MMSE scores and brain atrophy. Our observation confirmed that the high CAG repeat number is a good predictor of the severe juvenile HD progression manifesting with EEG changes, brain atrophy and cognitive disfunction. P455 THE SYMPATHETIC SKIN RESPONSES IN MONORADICULAR SYNDROMES DUE TO LUMBAR DISK HERNIATION. Osio M, Comi C, Mangoni A. Department of Neurology, Sacco Hospital, Milan, Italy Vasogenic changes and pain outside the dermatome corresponding to the radicular impairment are common findings in lumbar disc herniation. These symptoms may be related to changes in autonomic reflex activity. Therefore we studied the sympathetic skin responses (SSR) in 21 patients affected by lumbar monoradicular syndrome. Patients were divided into two groups, based on pain localization. In the first group patients complaining symptoms both in the dermatomeric region and outside the dermatome were included; the second group contained patients with typical radicular pain. SSR were obtained by stimulating the tibial nerve at the ankle, ipsi- and contralaterally to the affected side and recording from the skin surface of the studied dermatome. Patients of the first group showed significantly enhanced SSR values in the painful limb (1379 ± 205 vs 758 ± 146 µVsec) with no correlation to the dermatomeric distribution and sometimes the absence of SSR in the non-painful leg, both for ipsi- and contralateral stimulation. Patients of the second group showed reduced SSR values in the painful area (693 ± 53 vs 810 ± 39 µVsec); moreover 25% of the stimuli applied on the painful area did not evoke SSR. Present data confirm the presence of two different sympathetic skin reflex activities in patients with lumbar monoradicular syndrome. The two observed patterns correlate with the presence or absence of sensitive symptoms outside the dermatomeric region of the involved spinal root. P456 NEUROPHYSIOLOGICAL ABNORMALITIES IN OSTEOPETROSIS ASSOCIATED WITH CARBONIC ANHYDRASE 11 DEFICIENCY. M. Fred*, S. Helioui**, R. Gouider*, M. Bejaoui**, A. Mrabet*. *Neurological Department, EPS Charles Nicolle, Tunis; **Tunisia Centre de Greffe de Moelle Osseuse, Tunis, Tunisia

Osteopetrosis is an inherited metabolic bone disease characterized by diffuse, symmetrical osteosclerosis. Neurological disturbances may be due to direct compression of different nervous structures by osteosclerosis. The present study was undertaken to determine whether auditory (AEP), visual (VEP) somatosensory (SEP) evoked potentials, nerve conduction studies (NCS) and EEG are valuable methods for identifying asymptomatic neurological disturbances in osteopetrosis. We investigated 12 patients with osteopetrosis, SEP were performed in 12 patients, VEP in 10 cases, AEP in 12 cases. EEG was performed in 10 and NCS in 10 patients. All investigated patients had neurological examination, mean age at onset was 7.66 years (range P 16 years). VEP were impaired in 7 cases with delayed latencies of P 100 and normal in 3 cases. AEP were abnormal in 7 cases with peripheral abnormalities in 5 cases, bilateral in 1 case and unilateral in 4 cases. In 2 cases latencies were delayed for waves 111 and V and interwaves between waves 111-V and I-V which suggested central auditory pathways lesions. EEG was normal in 8 cases and showed spike-waves discharges in 2 asymptomatic cases. SEP and NCS are normal in all cases. We conclude that neurophysiological investigations are reliable methods for detection of asymptomatic neurological disturbances in osteopetrosis. P457 CEREBROVASCULAR MECHANISMS OF ORTHOSTATIC SYNCOPES. Rolf R. Diehl, Dieter Linden, Anke Diehl, Peter Berlit. Autonomic Laboratory, Dept. of Neurology, Krupp Hospital, Essen, Germany Theoretically, secondary types of syncope (cerebral ischemia due to systemic circulatory depression) may be differentiated from primary syncopes (cerebral ischemia due to cerebrovascular mechanisms of dysregulation). We assessed systemic and cerebral circulation in 40 patients with different forms of orthostatic syncopes/presyncopes during head-up tilt (HUT). A continuous monitoring of cerebral blood flow velocity (CBFV) from both middle cerebral arteries by transcranial Doppler and of arterial blood pressure (ABP) and heart rate (HR) by Finapres was carried out in supine position and during HUT. Parameters of relative cerebral blood flow, cerebrovascular resistance (CVR) and cerebral autoregulation were calculated. ABP and HR responses to HUT enabled the following diagnoses: hypoadrenergic orthostatic hypotension in 15 patients (immediate systolic ABP drop of > 30 mm Hg), postural tachycardia syndrome in 10 patients (rise in HR of > 35 beats/min), and neurocardiogenic syncope in 15 patients (sudden systolic ABP drop of > 30 mm Hg and bradycardia). In each patient group, syncope/presyncope was accompanied by a drop in CBFV, increased CVR, and undisturbed autoregulation. Normal autoregulation in different types of orthostatic syncopes indicates that cerebral ischemia cannot be attributed only to systemic ABP changes (secondary syncope). Increases in CVR and drops in CBFV are probably the result of an active vasoconstricting process (primary syncope). We conclude that orthostatic syncopes are evoked by a cerebrovascular reflex which aims at a supine body position in order to enable a normalization of the systemic circulation. P458 LATERALIZING VALUE OF SCALP ICTAL EEG IN EXTRATEMPORAL LOBE EPILEPSY (ETLE). K. Garganis, E. Veliou, T. Bourboulas, T. Konstantinidis*, I. Milonas. B’ University Dept. of Neurology, AHEPA Hospital, Thessaloniki, Greece. *Dept. of Epidemiology, Aristotle University, Thessaloniki Greece Objective: To determine lateralizing value of scalp-ictal EEG features in Partial Onset ETLE. Methods: Among patients undergoing prolonged Video-EEG monitoring, eight (8) were identified with intractable extratemporal onset seizures lateralized to a single hemisphere. Extratemporal localization was suggested by interictal spike activity on extratemporal electrodes with or without an MRI lesion congruent with seizure semiology and interictal EEG. Seizure onsets were thought lateralized to the same hemisphere when at least two of the following three were present pointing to the same side: a) Lateralized interictal spiking, b) An MRI epileptogenic lesion, c) seizure semiology sonsistent with onsets from that side. A total of thirty two (32) seizures were analyzed and the presence and lateralizing value of certain ictal EEG features determined for activity at seizure onset (ASO) and late ictal phase (LIP). Results: Repetitive epileptiform potentials (REPs) were detected during either ASO or LIP in 70% of seizures. When lateralized (87.5% of seizures) were always congruent with ictal onset side. Alpha/theta rythms present during LIP in 68% of seizures were 80% lateralized and 100% congruent, while beta rythms present during ASO or LIP in 66% of seizures were 70% lateralized and 80% congruent. Conclusions: REPs and alpha/theta rhythms when present and lateralized were always congruent with presumed ictal onset hemisphere. These ictal EEG features appear of high lateralizing significance.

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P459 MAJOR MISTAKE IN THE RE-PROGRAMMING OF FAST MOVEMENTS FOLLOWING A CEREBELLAR INFARCTION. M. Manto1, J. Hildebrand1, J. Jacquy 2. 1Neurologie, Hôpital Erasme, Bruxelles; 2Neurologie, CHU-Charleroi, Charleroi, Belgium Understanding of the mechanisms underlying inadequate or absent recovery following a stroke is a crucial step to establish strategies of rehabilitation. We describe a patient presenting a cerebellar infarction who developed an aberrant recovery demonstrated by motion analysis. This 85-yearold woman was admitted for clumsiness of left upper limb. Neurological examination showed a scanning speech, intention tremor and dysdiadokokinesia in left upper limb. Gait was ataxic. Brain CT scan showed an infarction in the territory of the left superior cerebellar artery. Fast wrist movements (aimed target = 15 deg) were recorded repeatedly in 9 sessions during recovery, and were also analysed in 9 healthy subjects (HS; mean age: 76, range: 68–89; 9 women). Initially, our patient exhibited hypermetria with a mean amplitude of movements of 23.5 deg (HS: 15.8 ± 1.1 deg), antagonist EMG activity was depressed at 43.1 a.u. (HS: 79.4 ± 10.7) and onset latency of antagonist EMG activity was increased at 135 msec (HS: 46 ± 10). The hypermetria turned into a hypometria during recovery. The return to normal of the intensity of antagonist EMG activity followed the return to a normal onset latency of antagonist activity, contrasting with classical recovery pattern of cerebellar hypermetria (Ann. Neurol. 1995; 38 : 437–445). We suggest that in our patient CNS was unable to overstep this major mistake, leading to an aberrant recovery characterized by a shift from hypermetria to hypometria.

Cerebrovascular Disorders (2) P460 OPEN, BLIND CLINIC TRIAL OF TREATMENT OF SPASTICITY IN MULTIPLE SCLEROSIS AND POST-STROKE USING LOCAL INJECTIONS OF BOTULINUM TOXIN TYPE A. C. Marrero, E. Díez Tejedor, C. Sánchez, F. Vivancos, P. Barreiro. Neurology Department, University Hospital “La Paz”, Autónoma University, Madrid, Spain Background: Our goal is to provide the therapeutic efficacy and safety of botilinum toxin type A (BTX-A) in multiple sclerosis (MS) and post-stroke spasticity. Patients/Methods: We studied during three months patients with spasticity in MS and stroke. We shut out patients with muscular atrophy, drugs or preexisting disorders affecting neuromuscular junction function. One neurologist injected BTX-A in the involved muscles and another one evaluated the patients using Ashworth scale (AS) (severity of spasticity), spams frequency score, pain and functional scales and, possible adverse effects. Stadistic method: Student’s t test. Results: 21 patients (8 MS, 13 stroke). Age: 56 + 14.69 years (MS: 46.3; stroke: 61.5). Mean evolution time: 57.18 + 41.8 months (MS: 93; stroke: 36.7). At follow-up a significant improvement was observed on the AS (MS, p: 0,000001; stroke, p: 0.000001) and a decrease in spams frequency (MS, p: 0.000004; stroke, p: 0.00008) and pain (MS, p: 0.007; stroke, p: 0.0367) scales. No significant adverse effects were noted. Conclusions: This study demonstrates that BTX-A is effective in reducing spasticity in SM and post-stroke and decrease spams frequency and pain asociated. No significant adverse effects were noted. P461 UPPER LIMB PROXIMAL PALSY IN 3 PATIENTS WITH HOMOLATERAL EXTRA-CRANIAL VERTEBRAL ARTERY DISSECTION. C. Guiraud Chaumeil, P. Labouret, E. Leroux, J. L. Dietemann, C. Tranchant, J. M. Warter. Service des Maladies du Système Nerveux et du Muscle, Services de Radiologie B et II, Hôpitaux Universitaires, Strasbourg, France Extracranial vertebral artery dissection (ECVAD) can occur spontaneously, or often after neck injury. It usually presents with occipital or neck pain preceding basilar ischemic symptoms. Isolated infarction of the cervical spinal cord has been exceptionally described, in spite of vertebral artery involvement in spinal cord vascularisation. We report 3 patients with an upper limb proximal peripheral deficit, indicative of an ipsilateral vertebral artery dissection. Case reports: Three patients (2 men and 1 woman) between 22 and 49 years old, developped a few days after a severe latero cervical pain, ipsilateral acute proximal unilateral palsy of the upper limb. Muscular testing demonstrated deltoid, infraspinatus and, only in 2 patients, biceps brachii palsy. Ipsilateral C5 and C6 reflexs were absent. There was no sensitive clinical signs. Electrophysiological examination

showed unilateral neurogenic signs in C5 and C6 muscles. Angiography demonstrated ECVAD which was bilateral in 2 patients and unilateral in the third one. Anticoagulant were prescribed, and evolution was good in a few weeks. Discussion: In ECVAD, angiography reveals irregular stenosis with or without pseudoanevrysm, double lumen or occlusion of the artery. So, the most frequent complication of ECVAD is stroke. Upper cervical spinal cord vascularisation is dependent on vertebral arteries which give some radiculomedullar arteries participating in formation of anterior and posterior spinal axis. However spinal cord infarction is not reported as a current complication of ECVAD. In these 3 cases, the proximal motor deficit was explained by a probable upper cervical cord ischemia, located in the anterior horn of the spinal cord, and due to segment V2 extracranial vertebral artery dissection. Conclusion: ECVAD should be discussed in front of any unexplained upper cervical cord ischemia. P462 DIAGNOSTIC INFORMATION OF MRI IN HYPERACUTE STROKE. A. Gass1, J. Gaa2, A. Sommer1, S. Behrens1, A. Schwartz1, M. Georgi2, M. G. Hennerici1. Dept. of Neurology1 and Radiology2, Klinikum Mannheim, University of Heidelberg, FR Germany With diffusion weighted (DW) magnetic resonance imaging (MRI) it is possible to detect structural abnormality in cerebral ischaemia before CT and conventional MRI show definite abnormality. In conjunction with MR angiography (MRA) and perfusion weighted (PW) imaging studies may provide information on the presence and location of ischaemia, the area at risk for stroke and the site of occlusion. We investigated 22 patients with suspected hyperacute middle cerebral artery stroke who were potential candidates for thrombolytic treatment. A MRI stroke protocol (PD-, T2-, T1-weighted, DW, PW, MRA) with integrated ADC map and Time-toPeak map calculation without further post-processing providing immediate results was used. The lesion conspicuity was much higher on DW compared to conventional MRI. DW MRI demonstrated the acute pathology in 17 patients unequivocally, in 3 patients presenting within 90 minutes DW MRI failed to demonstrate definite abnormality despite severe hemiparesis, in 2 patients haemorrhages were demonstrated. Perfusion studies provided an estimate of the haemodynamically compromised tissue. MRA in conjunction with DW MRI helped to demonstrate the site of the occlusion (peripheral vs. main stem mca) in 17 patients. The positive diagnostic information provided by MRI should have high priority in hyperacute stroke patients that are potential candidates for systemic thrombolytic treatment. Larger natural history studies are needed to acertain the exact prognostic significance of different patterns of imaging abnormality (DW-PW-MRA) particularly in order to minimise the risk of bleeding complications in aggressively treated patients. P463 RESISTANCE TO ACTIVATED PROTEIN C IS ASSOCIATED WITH DURAL ARTERIOVENOUS FISTULAS. Jürgen A. Kraus, Bettina K. Stüper, Peter Berlit. Department of Neurology, Alfried-Krupp Hospital, D-45117 Essen, Germany Resistance to activated protein C (APC) (APCR) has been shown to be the most common genetic risk factor for venous thrombosis. Mostly, APCR is caused by a single point mutation at nucleotide position 1691 (guanine-toadenine substitution) in exon 10 of the gene for factor V (FV) leading to substitution of arginine at position 506 with glutamine in the FV protein (FV Leiden). As dural arteriovenous fistulas (DAVFs) have been shown to be associated with cerebral venous thrombosis we looked for the FV Leiden mutation in seven patients with DAVFs. The APCR ratio is expressed by the anticoagulant response of APC in a modified activated partial thrombin time (APTT) reaction as ratio of APTT in the presence of APC to APTT in the absence of APC. For APCR ratios considered pathological (less than 2.0) analysis for FV mutation was done by a reverse hybridisation assay. Three of the seven patients showed pathological APCR ratios and heterozygosity for FV Leiden mutation. We conclude that FV Leiden might be involved in the pathogenesis of DAVFs. P464 AUTOREGULATION MONITORING IN THE STROKE UNIT. A. Diehl, R. R. Diehl, D. Linden, P. Berlit. Dept. of Neurology, Krupp Hospital, Essen, Germany The autoregulatory capacity of cerebral circulation can be determined by simultaneous continuous arterial blood pressure (ABP) and transcranial Doppler measurements of cerebral blood flow velocity (CBFV). Usually,

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a modification of ABP is introduced (leg-cuff method, deep breathing) and the temporal changes of CBFV are evaluated. We developed a new standardized autoregulation test based on spontaneous ABP oscillations that can be used for continuous autoregulation monitoring. ABP shows spontaneous oscillations around 12 cycles per minute (cpm) and around 6 cpm (respiratory and Mayer waves, respectively). These fluctuations are transmitted to CBFV. According to the highpass-filter properties of cerebral autoregulation, CBFV oscillations are shifted to the left relatively to the corresponding blood pressure waves. A phase shift angle of 90° demonstrates perfect autoregulation, while 0° indicates exhausted autoregulation. Using computerized cross spectral analysis, phase shifts between CBFV and ABP can be calculated continuously and displayed as a monitoring parameter in the stroke unit. We present our first experience with this method in 50 normal subjects and in 30 patients with different cerebral or cerebrovascular diseases. Normal subjects show consistent phase angle shifts around 60° at least for Mayer waves with a lower pathological limit of 20°. Patients with hemodynamically relevant carotid artery diseases, space-occupying cerebral infarctions or increases in intracranial pressure often show strongly reduced phase angle shifts. Conclusions: Continuous autoregulation monitoring by CBFV and ABP cross spectral analysis reveals significant information about cerebral hemodynamics. It may be of particular interest in patients with space-occupying infarctions or increases in intracranial pressure who are assumed to benefit from pressure-relieving procedures.

P465 DEPRESSION IN ACUTE STROKE PATIENTS. A. Santomé, E. DíezTejedor; A. Frank, B. Yagüe, M. A. Santana, P. Barreiro. Department Neurology, Hospital Universitario “La Paz” Universidad Autónoma de Madrid, Spain Introduction/Objectives: The role of stroke in development of depression is a matter of controversy. The aim of this study was to test influence of depression in hospitalized patients with acute stroke (AS) and controls without neurological damage. We studied its relation with cognitive output, hospitalization days and with the etiology and localization of the brain damage. Patients/Methods: 39 patients with AS and 39 control subjects (CS) were investigated. The evaluation [Neurological score, Neuroimaging techniques, Geriatric Depression Scale (GDS), Mental State Examination (MSE)] was made in the first 3 ± 1 days on the in-patient area. Statistical analysis: Student’s t, χ2 and ANOVA. Results: Depression frequency was similar in AS (41%) than in CS (36%). No relation was found between depression and hospitalization period. Patients with high score in GDS had lower MSE (24.77 ± 7.13) than patients with low GDS (27.95 ± 5.67) ( p < 0.05). The presence of depression in AS patients was more frequent in cerebral haemorrhage (66.6%) than in ischaemia (36.4%) (NS), in established stroke (50%) than in transient ischaemic attack (18.18%) (p = 0.06) and in vertebro-basilar (60%) than in +carotid artery territory (32%) (NS). Conclusions: Presence of depression is similar in hospitalized patients either with AS or without neurological damage and it exerts an important influence on the cognitive output. Depression could be related with the type and vascular territory of stroke, but more studies with larger series should be done.

P466 EPIDEMIOLOGY OF STROKE AND ROLE OF SICKLE CELL TRAIT IN THE FRENCH WEST INDIES. A. Lannuzel, V. Salmon, D. CaparrosLefebvre. CHU de Pointe à Pitre, France Objective: To assess the epidemiology of stroke and the influence of sickle cell trait in a population of African-American and Indian people living in the French West Indies. Background: Sickle cell disease (homozygotes SS) is known as a risk factor for both ischemic and hemorrhagic stroke, but heterozygotes (AS) seem to be spared. Patients and Methods: We carried out a study including 300 patients native from Guadeloupe, who referred from October 1995 to January 1997 to our neurological department for a focal and acute deficit. They had undergone biological exams, haemoglobin electrophoresis, CT scan, EKG, cervical and cardiac echodoppler. Percentages of AS, AC, and AA were compared to a control population of 70000. Results: Ischemic, hemorrhagic stroke and stroke complications represented respectively 83%, 11% and 6% of the whole group. The prevalence of risk factors for stroke showed high prevalence of hypertension (71%) and association of hypertension and diabetes (19%). The percentage of heterozygotes AS was lower in the group with ischemic stroke (4%) in comparison with controls (8.4%), while AS was more frequent in hemorrhagic stroke (16%). With the same other risk factors, the risk for hemor-

rhage was 10 fold higher in AS patients, while the risk for ischemic stroke was reduced by 15 fold. Discussion: These data suggest that sickle cell trait could be a risk factor for hemorrhagic stroke and could prevent for ischemic stroke. This is in accordance with the low frequency of stroke in homozygote SS children in Guadeloupe and could suggest a genotypic specifity or an association with another hemoglobinopathy.

P467 ISOLATED OCULOMOTOR SYNDROMES DUE TO AN ACUTE MIDBRAIN INFARCTION. Roquer J, Pou A, Rodríguez Campello A, Perich X*. Servei de Neurologia i CRC-Mar*. Hospital Universitari del Mar. Barcelona. Spain Objective: To describe the etiology, clinical characteristics, MRI correlation, and outcome in patients with isolated oculomotor syndromes as the only manifestation of an acute midbrain infarction. Methods and results: We prospectively evaluated a consecutive series of 18 patients with acute midbrain infarct (that accounted for 11.8% of vertebrobasilar strokes and 2.1% of all strokes). Of these 18 patients, 12 had oculomotor symptoms and 4 of them (3 men and 1 woman, mean age 62 years) had an isolated oculomotor syndrome. Three patients developed a unilateral oculomotor palsy (nuclear in 1 and fascicular in 2) while one experienced a bilateral vertical-gaze palsy. In a diabetic patients the isolated oculomotor palsy simulated a diabetic peripheral nerve lesion. With regard to the etiology, lacunar infarct due to atherosclerosis was found in 2 patients, lacunar infarct due to hypertension in 1 and unknown in 1. Outcome was good and a complete recovery of oculomotor dysfunction occurred in 3 of the 4 patients, whereas only 2 of 8 with oculomotor signs associated to other midbrain symptoms showed a complete recovery. Conclusions: Isolated oculomotor syndromes were the single manifestation in the 22.2% of acute ischemic midbrain strokes. In diabetics, isolated oculomotor palsy may simulate a diabetic peripheral nerve lesion. Full recovery was common in patients with isolated oculomotor syndromes (75%) but was unusual in patients with other associated signs of midbrain infarct (25%). P468 PURE DYSARTHRIA CLUMSY HAND SYNDROME AS FIRST EVER STROKE IS AN INDICATOR OF EMBOLIC ETIOLOGY. J. C. Bier, S. Blecic, M. Martinez, J. G. Hildebrand. Service de Neurologie. ULB. Hôpital Erasme. Bruxelles, Belgium Dysarthria Clumsy Hand Syndrome (DCHS) is found in stroke located in several different area including brainstem, cerebellum and in the territory of the deep perforators of MCA. Few patients can have DCHS after cortical lesion. According to CM Fisher, crural paresis can also be found.The aim of this work was to reevaluate locations and etiologies of DCHS. Patients and methods. 43 (1.9%) out of 2293 patients (pts) admitted in the stroke unit between 1991 and 1997 had DCHS. Mean age was 63.3 ± 9 YO. There were 54.6% males. All pt had clinical work up including MRI and trans oesophageal echocardiography. Results. The lesion was unique in all pts. 30 pts had deep lesion (DL): 16 were located in the anterior part of the pons and14 in the internal capsulae. Crural paresis was found in all pts with DL. All of them had a probable thrombotic stroke, since all had two or more concommitant risk factors for thrombosis. 13 pts had superficial lesions (SL) involving the cortex: 8 in the corona radiata and 5 in the centrum ovale. In pts with SL crural paresis was never found suggesting that these patients had pure DCHS (PDCHS). An embolic source was seen exclusively and in all patients with SL: 10 had definite cardioembolism and 3 had ipsilateral carotid stenosis. Conclusion. DCHS can result from different stroke mechanisms but in PDCHS an embolic etiology, mainly cardioembolism should first be rulled out. P469 KORO-LIKE SYNDROME IN A PATIENT WITH HEMORRHAGIC THALAMIC STROKE. S. Lorenzl, M. Schneider, and F. v. Rosen. Neurolgische Klinik Bad Aibling, Germany We report on a 54-year-old patient with right-sided intracerebral hemorrhage in the thalamus, the crus posterior of the capsula interna and in the lentiform nucelus who had two months after infarction the obsession that his penis is shrinking. This symptom is comparable to “Koro”, a disease that occurs mainly in southern China and is described as an anxiety reaction in which a man has the body illusion that his penis is shrinking. The patient who had a long lasting history of arterial hypertension presented

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initial with left-sided hemiparesis and loss of consciousness. Nearly two months after the intracerebral bleeding the patient started to report of a feeling that his penis is shrinking and retracting into the abdomen which was making him frightened. At this time he was wheel-chair-bound and not able to walk because of a left-sided hemiparesis. Despite he made remarkable progress during rehabilitation his mood decreased over the obsession of his shrinking penis. In our opinion this symptom represents a thalamic body illusion. Treatment with Paroxetine failed to resolve the obsession, also did Venlafaxine. We started to treat with Amitriptyline, which improved the central pain of the hemiplegic left arm, but had no effect on the body illusion. This case demonstrates, that body illusions which often do not respond to drug treatment can be a reason for mood depression after stroke.

P470 MIGRAINE WITH AURA PATIENTS ARE AT INCREASED RISK OF PARADOXICAL CEREBRAL EMBOLISM – A TRANSCRANIAL DOPPLER STUDY. Anzola GP, Magoni M, Guindani M, Pezzini A, Dalla Volta G. Clinica Neurologica, Brescia, Italy The recently found association between patent foramen ovale (PFO) and transient global amnesia (TGA) prompted the suggestion that paradoxical microembolization in the terminal vertebrobasilar territory might underlie at least some TGA cases. Migraine with visual aura is another paroxysmal disturbance in which a sudden dysfunction of cortical areas fed by the terminal branches of the basilar artery is believed to trigger the attack. Therefore we investigated the prevalence of PFO in a consecutive unselected cohort of migraine patients. Eighty-two patients, consecutively referred by the Headache Outpatient Clinic for migraine with aura (MA+, mean age 33 + 12), were compared to 35 patients suffering from migraine without aura (MA–, mean age 38 + 15) and to 22 age-matched non migraine patients (C, mean age 31 + 10) selected among the inpatient population. PFO was assessed by means of transcranial Doppler sonography with intravenous injection of agitated saline, a technique which has proven 95% sensitive and 100% specific. The prevalence of PFO was 60% (49/82) in MA+ patients, 23% (8/35) in MA- patients and 27% (6/22) in control subjects.The difference between MA+ and MA– was statistically highly significant (OR 5.1, 95% CI 1.88–13.75, χ2 = 11.93, p = .0005), as well as between MA+ patients and controls (OR 3.96, 95% CI 1.28–12.77, χ2 = 6.10, p = .01), whereas MA- patients did not differ from controls (OR 0.79, 95% CI 0.20–3.18, χ2 = 0, p = .9).These findings suggest that patency of foramen ovale is statistically associated to migraine with aura but not to migraine without aura. The increased risk of stroke which has been found in epidemiological studies in MA+ patients could thus be explained by an increased propensity to paradoxical cerebral embolism.

P471 QUALITY CONTROL ASSESSMENT FOR STROKE MANAGEMENT: DO CLINICAL CENTERS ROUTINELY ADHERE TO STANDARD GUIDELINES OF CARE? Christiansen W, Kunze K, Förster M, Berger J, Leffmann C, Hamburg, for the members of the HSMP, Germany The Hamburg Stroke Management Project (HSMP) was established to evaluate epidemiological variables of stroke patients and quality control indicators of stroke management. One goal of this ongoing analysis is to assess whether standard guidelines for stroke treatment are routinely applied in clinical practice. Methods: Based on epidemiologic data of 1114 acute stroke patients enrolled in the HSMP pilot study from January 1994 to September 1995, a quality control questionnaire was developed for routine use. By June 1996 this practical, one page inquiry was completed by physicians of 1064 patients in 16 centers. Quality control indicators of patient management were analyzed. Results: High variation occurred between individual centers; the proportion of patients undergoing brain imaging ranged from 38% in the center reporting the lowest proportion to 100% in the center with the highest. After a first stroke, patients < 75 years old underwent brain imaging 86 to 100% of the time. Extra- or transcranial ultrasound was performed on 20 to 100% of patients. Zero to 50% of patients developed preventable complications. The proportion receiving secondary prophylaxis ranged from 52 to 100%. 39 to 94% had physiotherapy while 0 to 72% received speech therapy. Conclusions: Our multicenter HSMP allows long-term comparison of participating centers and provides important feedback to treating institutions. Reasons for differences between centers and potential for improvement of acute stroke management will be discussed. Long-term follow-up of patients will determine whether adherence to standard clinical guidelines results in improved patient outcomes.

Poster Session 5 Cerebrovascular Disorders P472 ACUTE AUTONOMIC DYSFUNCTION IN STROKE PATIENTS. B. Riedl, T. Beckmann, F. Birklein, B. Neundoerfer. Neurologische Universitätsklinik, Schwabachanlage 6, 91054 Erlangen, Germany After cerebral ischaemia, about 70% of patients show an acute swelling of the paretic limb. Aim of this study was, to measure autonomic function and to compare results with complex regional pain syndrome patients (CRPS), where central origin of sympathetic dysfunction is discussed. Fourteen patients (6 female and 8 male) were investigated within one week after stroke. Skin temperature of the paretic and healthy limb was assessed by infrared thermography. To measure local sweating, evaporation hygrometry was used. Sweating was stimulated peripherally via carbachol iontophoresis (quantitative sudomotor axon reflex test = QSART) and centrally by drinking hot tea (thermoregulatory sweat test = TST). Skin temperature was significantly lower on the paretic limb ( p < 0.01, Wilcoxon, mean 33.51 ± 1.7° C) than on the healthy (34.28 ± 1.58° C), resulting in a mean difference of 0.76° C. TST responses were significantly higher on the paretic limb ( p < 0.05, Wilcoxon), whereas QSART responses failed to show a side to side difference ( p = 0.95, n.s.). Skin temperature and TST responses showed a significant postive correlation on the paretic limb (R = 0.66, p < 0.05), in contrast to the healthy limb (R = 0.21, n.s.). Previous studies have shown that CRPS-patients show raised ipsilateral skin temperature and enhanced TST and QSART responses (Birklein et al., Pain 1996). We conclude that cerebral ischaemia leads to enhanced central sweating (TST), whereas the response to peripheral stimulation (QSART) remains unchanged. Vasal tone of the paretic limb is raised, indicated by a reduced skin temperature. CRPS and stroke differ in their autonomic dysfunction patterns, indicating different sites of pathology. Supported by Deutsche Forschungsgemeinschaft, SFB 353, Projekt C3. P473 PERFUSION IMAGING IN ACUTE PHASE OF STROKE: AUTOMATIC ANALYSIS OF EARLY 99MTC-ECD BRAIN SPECT. O. David, Mh. Mahagne, O. Migneco, J. Darcourt, F. Bertand, M. Chatel, F, Bussière. Centre Hospitalier Universitaire, Nice, France Brain SPECT could help in identifying sub-groups of patients in acute phase of stroke, providing informations on brain perfusion and with more recent tracers, on cell metabolism. Most of time, SPECT patterns are visually analysed. In order to evaluate the reliability of such an analysis, we have compared visual and automatic analysis of 99mTc-ECD brain SPECT images. Methods: 17 patients with a first-ever middle cerebral artery stroke (MCA) were prospectively studied with ECD-SPECT within 12 hours after stroke onset. Neurological evaluation was performed using Orgogozo’s scale at admission and 3 months later in order to calculate evolution indices EI%. 1000 Mbq of ECD were injected 60 minutes after reconstitution. 120 projections of 55 seconds were obtained with a triple-head camera equipped with low-energy ultra-high resolution fan beam collimators. Visual analysis was performed in 7 regions relevant for MCA territory using a color scale. Extent and degree of hypoperfusion were calculated. 3 degrees of perfusion were considered: normal, ischaemic, irreversibly damaged. Scores I (ischemic) and IDT (irreversible damaged tissue) were obtained. For automatic analysis, after selection of healthy hemisphere and cortical segmentation, mapping of ischemic and IDT voxels was obtained. Results: Extent of IDT is strongly correlated with EI% and represents a good predictor of outcome. Values obtained with automatic analysis have higher predictive value ( p = 0.0002) than visual IDT scores ( p = 0.002).

P474 METEOROLOGICAL CONDITIONS AND STROKE IN SOUTHERN ISRAEL. R. Masalha, E. Zaady*, Z. Y. Offer*, R. Gulman, and Y. O. Herishanu. Department of Neurology, Soroka Medical Center and Jacob Blanstein. Institute for Desert Research. Ben-Gurion University of the Negev-Beer-Sheva*. Beer-Sheva, Israel We investigated the effect of weather on the incidence of stroke in the Negev area. Our study included all stroke patients admitted to the Department of Neurology at Soroka Medical Center in the three years period (Jan. 1994 – Dec. 1996). They were stratified according to gender and age; less than 45 years, 45–65, and over 65 years. Data on average monthly temperature and humidity in these three years were obtained from the Me-

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teorological Survey of Israel. Correlation of stroke incidence and meteorological conditions was analyzed by one-way and two-way ANOVA. The incidence of ischemic stroke was found to be higher during the winter months ( p < 0.05). The highest incidence was in December and January, which are the coldest months of the year in this area with atmospheric temperature often dropping below the freezing point. The highest winter incidence is among women over 65 years. Also the incidence of hemorrhagic stroke was higher in winter, among all ages. No correlation was found between humidity and stroke incidence. Conclusion: These data suggest an increase in stroke incidence during the coldest period of the yearly cycle. Low environmental temperature is associated with elevated platelet and red cell count, increased blood viscosity, and elevated arterial blood pressure as well as other factors which may increase the risk for thromboembolic events. P475 EX VIVO STUDY OF CYTOKINE RELEASE FROM BLOOD CELLS OF STROKE PATIENTS. C. Ferrarese1, P. Mascarucci2, M. Frigo1, C. Zoia1, B. Begni1, R. Cavarretta1, L. Frattola1, and M. G. De Simoni2. Dept. of Neurology, Univ. of Milan, Monza1, and M. Negri Institute, Milan, Italy2 Cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-a (TNF-α) play a role in tissue damage after acute stroke; they are increased in brain after experimental ischemia and in cerebrospinal fluid of patients with stroke. However, data on their serum levels are controversial. To determine the source and time course of cytokines in peripheral blood, we investigated the release of Il-6 and TNF-α from blood cells of patients after acute stroke. Blood was obtained from 50 stroke patients on days 1-2, 4, 10, 30 and 90; cytokine release was stimulated with 100 ng/ml LPS at 37° C for 4 hours and was analyzed by bioassays. 20 normal age-related volunteers were used as controls. Both IL-6 and TNF-α release from stimulated blood cells was elevated in stroke patients, respect to controls subjects, starting from the first day up to three months after stroke. A peak response (+ 270%, p < 0.01 vs controls) was at 4 days for IL-6, while TNF-α was largely and significantly increased (+ 290%, p < 0.01 vs controls) from day 1–2 until 30 days after stroke. These data indicate increased and long lasting peripheral production of cytokines after stroke; peripheral blood cells, likely activated by the ischemic processes in the CNS, are a major source of serum cytokines. Peripheral cytokine release could then be involved in inflammatory reaction within the ischemic brain area and possibly in the mechanisms of repair. P476 THE SIGNIFICANCE OF COBALT-55 POSITRON EMISSION TOMOGRAPHY IN ISCHAEMIC STROKE. J. De Reuck, H. Stevens, H. Jansen, J. Keppens, K. Strijckmans, P. Goethals, I. Lemahieu, P. Santens, J. Korf. PET Centre UZ/RUG, Gent, Belgium Cobalt-55 (55Co) has been shown to be an interesting positron emission tomography (PET) tracer that may reflect calcium (Ca) influx in damaged cerebral tissue. Since Ca load is important in the ischaemic cascade, the exact meaning of 55Co PET in stroke patients has to be demonstrated. The present study compares the degree of 55Co uptake to regional cerebral blood flow (rCBF) and regional cerebral metabolic rate for oxygen (rCMRO2) values in brains of patients with ischaemic stroke. Eighteen patients with an ischaemic event in the middle cerebral artery territory were examined with PET using in a same session 55Co and the 15O steady state technique. The 55Co ratio was assessed in ischaemic and infarcted regions and compared to the rCBF and rCMRO2 values. The average 55Co ratio is inversely correlated to the rCBF and rCMRO2 values. Also 55Co accumulation tends to increase during the weeks following the onset of stroke and decreases down to normal levels after months. The degree of 55Co uptake corresponds to the severity of the ischaemic damage within the first month after stroke. As it increases with time it probably reflects the Ca accumulation due to the progression of the inflammatory response within and around the infarct core. P477 IMPROVEMENT OF SONOGRAPHIC DIAGNOSIS OF INTRACRANIAL OCCLUSIVE LESIONS BY BR1, A NEW ECHOCONTRAST AGENT. S. Gass, C. Kornblum, D. Röhrig, F. Ries. Department of Neurology, University of Bonn, Germany TCCS is an established method in evaluation of intracranial vascular pathology, but is frequently limited by an insufficient signal-to-noise ratio.

Echocontrast agents may overcome this problem. We report first results of BR1, a new phospholipid stabilized microbubble preparation, in patients with suspected intracranial occlusive lesions and insufficient signal for unenhanced TCCD. 10 Patients with insufficient unenhanced signal intensity were investigated with four doses of BR1, a suspension of phospholipid stabilized gaseous microbubbles containing sulphurhexafluoride, using a 2–2.5 MHz ATL duplex system. The time to color contrast appearance ranged from 16–24 seconds, clinically useful dose-dependent contrast enhancement lasted 235 to 361 seconds, artefactual contrast lasted dose-dependently 61 to 175 seconds. All efficacy parameters showed an obvious increase from baseline to even the smallest dose of BR1, but only smaller differences between doses. In all 6 patients investigated with transtemporal approach a strong contrast enhancing effect allowing diagnosis of stenosis of the middle cerebral artery (MCA) was seen even after the lowest dose. In the vertebrobasilar examinations a conclusive diagnosis was possible only in 2 patients and required in 1 patient the highest dose. BR1, a longlasting contrast agent, improves TCCS signal intensity considerably allowing the noninvasive diagnosis of intracranial occlusive lesions in the majority of patients. Assessment of the anterior circulation is especially improved even after small doses, whereas the diagnosis of vertebrobasilar disease is more difficult, may be achieved in a smaller proportion of patients and require higher doses, but still has major diagnostic and therapeutic consequences.

P478 MORTALITY, DISABILITY AND OUTCOME IN PATIENTS WITH ACUTE STROKE AND ATRIAL FIBRILLATION. Palomeras E, Roquer J, Munteis E, Pou A. Servei de Neurologia. Hospital Universitari del Mar. Barcelona. Spain Objective: To analyse the mortality, disability and outcome in patients with and without atrial fibrillation (AF) who suffered an acute stroke. Methods: We studied, in 747 consecutive patients with an acute stroke, the relationship between the presence of AF and mortality rate, functional disability (Barthel scale), clinical severity (Canadian scale), presence of complications, length of hospital stay and discharge rate to own home. Results: Among the 747 patients, 205 (27.4%) had AF on admission. Mortality rate during the hospital stay was 22.4% in AF patients and 10.9% in non-AF patients ( p < 0.001). Patients with AF had also a higher initial disability, length of hospital stay (18.9 days in AF patients and 9.2 in non-AF patients) and a lower discharge to own home (45.9% and 55.4%). The Barthel Index score at discharge was higher in patients with AF (p < 0.001). Conclusions: Acute stroke in patients with AF is more severe than in non-AF patients. It is characterised by a higher disability, higher morbidity and higher mortality. This emphasises the importance of the prevention of stroke in AF patients.

P479 CEREBRAL VENOUS THROMBOSIS PRESENTING AS TRANSIENT ISCHEMIC ATTACKS. Huerta M, Baiges JJ. Dept. of Neurology, Hospital Verge de la Cinta, Tortosa, Spain Cerebral venous thrombosis (CVT) presents with a remarkably wide clinical spectrum. Symptoms and signs of intracranial hypertension, mental changes, drowsiness, confusion or coma, focal signs and seizures are characteristic. Focal signs, like motor or sensory deficits are frequently present, but presentation as transient ischemic attacks is very unusual. We report the case of a 73-year-old man admitted to our hospital because of headache and repeated transient episodes of left hemiparesis and paresthesias lasting from 5 to 45 minutes. Three years earlier a deepvein thrombosis in his right leg had been diagnosed. During the attacks neurological examination confirmed mild left hemiparesis, but between two episodes was normal. A cranial computed tomography scan showed a right parietal small cortical linear hyperdensity suggestive of hemorrhage. No other direct or indirect radiological signs of CVT were found. Magnetic resonance imaging (MRI) showed absence of flow void and changes in T1 and T2-wheighted images suggestive of superior sagittal sinus thrombosis and a right frontoparietal subacute cortical infarct. Venous MR angiography confirmed the diagnosis. A positive lupus anticoagulant was detected. Conclusion: CVT rarely can mimic arterial transient ischemic attacks as Bousser stated. Our aim was to report our case in view of the small number of cases reported in the literature. We should be aware of this potential misleading clinical presentation of the condition. Physiopathological mechanisms will be discussed.

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P480 ECHO CONTRAST AGENTS IN THE EVALUATION OF CEREBROVASCULAR DISEASE WITH COLOR-CODED SONOGRAPHY. Eva Bartels, K. A. Flügel. Department of Neurology and Clinical Neurophysiology, Hospital Bogenhausen, München, Germany Background: The aim of this study is to present the diagnostic utility of Levovist in the evaluation of cerebrovascular disease based on two years clinical experience with this agent. Methods: The examinations were performed with a color Doppler imaging system ACUSON 128 XP 10 by using a 2 MHz sector transducer for transcranial duplex ultrasonography or by using a 7 MHz linear transducer for extracranial imaging. For the contrast enhanced study 8.5 ml Levovist (300 mg/ml) was administered intravenously. Results: 1) In the examination of carotid arteries, contrast enhancement facilitates the differentiation between stenosis and occlusion. 2) In vertebral sonographic examination, echo contrast agents enable the detection of low blood flow velocities in hypoplastic vertebral arteries, or in the case of a dissection. 3) In transcranial examination, in patients with an insufficient temporal bone window a flow signal in the middle cerebral artery was detectable in 93%. This proved useful in patients with acute stroke, since an occlusion of the middle cerebral artery could be ruled out easier. Conclusion: Echo contrast agents facilitate routine clinical investigation in difficult examining conditions. Confirmation is needed in larger clinical studies. P481 SPONTANEOUS ECHO CONTRAST (SEC) AND FIBRINOGEN LEVELS IN AF PATIENTS WITH OR WITHOUT CEREBRAL EMBOLIC EVENTS. Stathis P1, Tolis B2, Smigadis N2, Maltezou M1, Habibi K1, Papageorgiou H1, Frigas N1, Trontzas P3, Georgaras A1. 1Dept. of Neurology, 2 Dept. of Cardiology 1st Hospital, 3 Dept. of Rheumatology 6th Hospital of Social Security Services-Athens, Greece It has been suggested that Spontaneous Echo Contrast (SEC) a “smokelike” swirling echo seen on Transesophageal Echocardiography, in the left atrium (LA) is more frequent associated with Atrial Fibrillation (AF) and since there is a strong link between grade of SEC and elevated plasma fibrinogen, fibrinogen may be a risk factor for cardioembolism. The goal of this study is to investigate the possible contribution of elevated fibrinogen levels to cardiogenic embolic stroke. Methods: We selected 14 patients with non-valvular AF and SEC, presumed to suffer from stroke subtype of cardiogenic embolism. We also enroled 12 patients with non-valvular AF, without stroke or TIA’s. Demographic and hemorheologic parameters were both taken under consideration. SEC graded mild or marked. Fasting morning blood samples were obtained and diluted 9 : 1 by volume in a solution of 3,8% sodium citrate for fibrinogen determination. Significance of SEC between groups was assessed by χ2. Groups were compared by means of ANOVA with Bonferroni corection. Mann Whitney U test was used for comparirisons of grade of SEC and fibrinigen levels in each group. Results: SEC appearence and LA enlargment were more prominent in stroke than in no-stroke group: Chi-test = 7.2, p = 0.007 for SEC and 45.92 ± 7.36 and 41 ± 4.29, p = 0.04 for LA diameter respectively. Only in the stroke group, fibrinogen levels were high assosiated with the grade of SEC, median values: 342 (ir 384.5–281) for mild and 420 (ir 485– 391.5) marked SEC respectively ( p = 0.01). Conclusion: We suggest that SEC is associated with cardiac findings that promote thrombus formation in the LA, like LA enlargment. Fibrinogen with its important role in the genesis of SEC, could be a risk factor for recurrent cardioembolic stroke. P482 ETIOPATHOGENETIC IMPLICATIONS IN 89 PATIENTS WITH JUVENILE ISCHEMIC STROKE. P. Cerrato, M. Torchio, L. Priano, S. Leombruni, L. Calvi, E. Verdun, D. Imperiale, M. Bergui, D. Daniele, M. F. Ferrio, G. B. Bradac, B. Bergamasco. Department of NeurosciencesUniversity of Turin, Italy To analyze etiopathogenetic features of juvenile cerebrovascular disease. Methods. We have studied 89 patients (39 females and 50 males) less than 50 years old (range 17–50 years, mean age 42.6) with acute ischemic stroke. Patients were evaluated by cranial CT (100%), brain MRI (33.7%), cervicocephalic vessels ultrasonography (100%), cerebral angiography (29.2%), transthoracic (70%) and transesophageal ecocardiography (50%), coagulative (PT, aPTT, fibrinogenemia, D-Dimer, ATIII, emocoagulative C and S proteins, APC resistance, antiphospholipid antibodies, LAC) and immunologic studies (antinuclear factor, anti-ENA antibodies, p-ANCA, c-ANCA). Results. Ischemic events were: stroke (70.8%), RIND (8.9%),

TIA < 1 h (8.9%), TIA > 1 h (10.1%). Patients were divided into 5 groups based on the putative etiopathogenesis: (1) cardioembolism (24.7%);. (2) large vessels disease (14.6%); (3) small vessels disease (19%); (4) others (15.7%); (5) criptogenetic stroke (24.7%). The fourth group comprised 10 patients with arterial dissection (6 carotide and vertebro-basilar), 3 patients with primary antiphospholipid syndrome and 1 patient with panarteritis nodosa. Coagulative inhibitors deficits were never found. Therefore we have evaluated infarct topography based on neuroimaging and vascular risk factors frequencies (diabetes, arterial hypertension, tabagism, dyslipidemias, alcohol consumption, obesity). Conclusions. In a relevant part of young patients with ischemic stroke it is not possible to identify precise etiopathogenetic mechanism. Particular attention should be paid to arterial dissection and low-risk embolic cardiopathies.

P483 EVALUATION OF SYSTEMIC AND CEREBROVASCULAR AUTOREGULATION. S. Ries, A. Valikovics, D. Spiegel, G. Panczel, M. Daffertshofer, M. Hennerici. Depz. of Neurology, University of Heidelberg, Mannheim, Germany To understand the interdependence of cardiovascular and cerebrovascular changes under postural stress, we investigated 50 controls and 203 patients with diseases linked to orthostatic intolerance (Parkinson disease, n = 16; polyneuropathy, n = 43; combination of both, n = 10; migraine, n = 28; epilepsy, n = 38; cerebral ischemia, n = 68). The examination consisted of a passive tilt to an 80% upright-position for 15 minutes. Heart rate, blood pressure, pO2, pCO2 and cerebral blood flow velocities (CBFV) were assessed. PD-patients showed a diminished increase in heart-rate ( p < 0.01) and an impaired blood pressure control. A disturbance of peripheral autoregulation was seen in patients with PNP. Consecutively a significant decline of CBFV occurred ( p < 0.01). Migraine sufferers showed a pronounced increase in heart rate with an impaired blood pressure control. Patients with epilepsy showed a remarkable drop in CBFV ( p < 0.01), occurring despite a normal peripheral autoregulation. Patients with cerebral ischemia had a significant drop in peripheral blood pressure and in cerebral blood flow velocities. With respect to the interdependence of blood pressure and CBFV-changes peripheral orthostatic dysregulation was highest in patients with PNP (25.58%). Migraine sufferers revealed a comparable distribution of dysregulation. In patients with epilepsy the incidence of isolated cerebrovascular dysregulation was highest (13.16%). For patients with cerebrovascular disease we found isolated peripheral autoregulation disturbance and isolated cerebrovascular autodysregulation to be frequent (13.24% and 10.3% respectively). A paradigm combining peripheral and CBFV measurements increases the understanding of individual autoregulatory capacities.

P484 DIFFUSION-WEIGHTED MR IMAGING OF CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY (CADASIL). C. Berchtenbreiter, R. Bruening, R. H. Wu, T. Yousry, M. Dichgans #, M. Mayer #, U. Porn, M. Reiser. Munich, Germany. Dept. of Diagnostic Radiology University Hospital Großhadern, # Dept. of Neurology University Hospital Großhadern Purpose: To describe the MR features in patients with CADASIL using conventional MRI and diffusion weighted sequence. Materials/Methods: We reviewed the 42 MR examinations with of T1, T2-w (TR/TE = 600; 2500/15; 90 msec) and diffusion-weighted gradient echo (PSIF) sequence (TR/TE = 23/2, 3, 5 msec; b-values 165, 288, 598 s/mm2). The patients ranged from 32 to 64 years and had positive family history of CADASIL. Results: Two young patients (aged 32 and 34 years) with family history and headache had normal MR images. Fourty of the fourtytwo patients had lesions, as multiple small deep infarcts scattered in subcortical parietal (85%), frontal, occipital and temporal white matter and basal ganglia (25%), external capsule (55%), internal capsule, thalamus, brainstem, and cerebellum (15%). More or less extensive and relative symmetric leucodystrophy was observed in 34 patients. Leucodystrophy of external capsule was identified in 16 patients. All lesions were readily identificable by diffusion weighted MRI, whereas T2-weighted imaging was less sensitive in especially characterisation of lesion size (68%) and number (93%). Atrophy was only found in two older patients (aged 64 and 60 years). None of lesions was enhanced on enhanced T1-weighted images. Conclusion: The MR features of CADASIL are characteristic, and well observed with diffusion weighted imaging. There are multiple lacunar infarcts and leucodystrophie without contrast enhancement.

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P485 SINUS VEIN THROMBOSIS DUE TO TAMOXIFEN THERAPY. W. Schmaus, T. Stelzl, W. Hupfer, and K. A. Fluegel. Abteilung für Neurologie und Klinische Neurophysiologie, Staedtisches Krankenhaus München-Bogenhausen, Germany Here we report for the first time the case of a 32-year-old male with a sinus vein thrombosis due to tamoxifen therapy. He was treated with this anti-oestrogen for seven weeks because of oligospermia and was delivered to our hospital with a two-weeks-history of right occipital headache. Neurologic examination showed a slightly somnolent patient with a homonymous Hemianopia to the left, a mild left hemiparesis, hemi-apraxia, and stereoagnosia. The initial CT scanning was normal. Soon after admission he had a generalized epileptic seizure. Cerebral angiography and magnetic resonance imaging revealed an almost complete sinus sagittalis superior and right sinus transversus thrombosis as well as right hemispheric ischemic lesions (considered as venous infactions) that obviously caused the neurologic symptoms. Besides termination of tamoxifen the treatment consisted of anticoagulation with heparin and later warfarin and resulted in a complete recovery of the patient (and by the way in the production of a healthy daughter afterwards). As other causes could be excluded and there were no other prothrombotic risk factors, the association with the tamoxifen therapy seems likely. This is the first report of tamoxifen therapy causing a sinus vein thrombosis (so far only peripheral venous and arterial thromboembolism was known) and it shows the importance of a detailed drug history and the closely monitoring for the development of thromboembolism during tamoxifen treatment. P486 THE IMPORTANCE OF STIMULATION FREQUENCY IN THE TREATMENT OF VASCULAR HEADACHE WITH TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (TENS). Mokrusch T. Hedon-Klinik, Lingen, Germany The value of TENS in the treatment of vascular headache is discussed controversially. The question was, whether different stimulation patterns lead to different results in the treatment of vascular headache. Methods: 19 Patients with vascular headache were investigated following an A-B-A design. The therapy was performed seven days a week, twice daily with a duration of 20 minutes each, with an intensity slightly above the sensory threshold. Six patients (group I) received a stimulation pattern with continuous impulses of 80 Hz, six patients (group II) a burst-stimulation and seven patients (group III) a variable impulse pattern. The therapeutical effect was estimated using a 100 mm visual analogue scale. Results: A significant improvement was seen with each of the three therapy forms: + 32.1 mm (group I), + 18.8 mm (group II) and + 28.7 mm (group III). The difference between group I and II was significant with p: 50.011, the difference between group III and II with p ≤ 0.040. Discussion and Conclusion: According to the present results, TENS-therapy is clinically effective in reducing vascular headache. When using TENS, the continuous stimulation pattern can be recommended just like the stimulation regime with variable impulse patterns. Electrotherapy with bursts in the low frequency range is effective, too, but significantly less. P487 SYMPTOMATIC AND ASYMPTOMATIC CAROTID ARTERY OCCLUSION (CAO): ETIOLOGIES, CLINICAL AND VASCULAR FINDINGS IN 174 PATIENTS. Th. Baumann, Ph. Lyrer, A.-J. Steck. Departement of Neurology, University Hospital Basel, Switzerland Detailed descriptions of clinical aspects in CAO in the past were usually based on findings in patients who had undergone conventional angiography. With widespread use of advanced ultrasound technology, more asymptomatic forms are detected. This study aimed at identifying factors associated with symptomatic or asymptomatic CAO. We looked retrospectively at 174 consecutive patients with ultrasound diagnosis of common or internal CAO regarding clinical manifestations at time of carotid occlusion, previous cerebrovascular events, ultrasound specific findings, etiology and outcome. 69% of the patients were male, 31% were female. Mean age was 66 years. 69% had symptomatic occlusion, in 31% occlusion was asymptomatic. 78% of the symptomatic patients had infarction, 22% had transient ischemic attack (TIA). 82% of the symptomatic patients had hemispheric manifestations, 17% had retinal symptoms. 69% were left with no or slight disability, 30% with moderate or severe disability. The etiology was in 78% atheromatosis, in 5% dissection, in 2% thromboembolism and in 14% not determinable. In symptomatic CAO, TIA of the homolateral hemisphere prior to manifestation of occlusion was more common than in

asymptomatic cases (18% vs. 43%, p = 0.004). Atherosclerosis was related to asymptomatic occlusion (98% vs. 85% in symptomatic occlusion, p = 0.034). The occurrence of asymptomatic CAO is a common finding in patients sent for neurovascular ultrasound investigation. Patients with asymptomatic CAO usually have atherosclerosis, while in those with symptomatic CAO further etiologies like dissection and embolism are observed.

Extrapyramidal Disorders P488 PERMANENT CEREBELLAR ATAXIA DUE TO BORDETELLA PERTUSSIS. F. Setta1, M. Baecke2, J. Jacquy3, J. Hildebrand4, G. Monseu5, M. Manto4. 1Universita La Sapienza, Roma (I); 2 Faculté de Médecine, ULB (B); 3 CHU-Charleroi, Charleroi (B); 4 Hôpital Erasme, ULB (B); 5 Hôpital de Braine-L’Alleud (B) Bordetella pertussis is a highly contagious gram-negative cocco-bacillus causing whooping cough. Bordetella pertussis has not been recognized so far as a cause of permanent cerebellar ataxia in human. We describe 3 men (age: 50, 27 and 30) who developed a cerebellar syndrome beginning after whooping cough. The infection occurred at the age of 15 (patient 1), 14 (patient 2) and 13 years (patient 3). The delay between whooping cough and first neurological symptoms was 3 months for patient 1, 1 month for patient 2 and 3 weeeks for patient 3. In the 3 patients, the cerebellar syndrome was characterized by dysmetria of saccades, scanning speech and ataxic gait. Brain MRI demonstrated a pancerebellar atrophy in all. Experimental studies have demonstrated that lymphocytosis-promoting factor (LPF), a purified toxin from Bordetella pertussis, is deleterious for cerebellum. The mechanism of this toxicity might be a marked increase in the levels of 3´,5´ guanosine monophosphate (cGMP). The same toxic effect might be the cause of cerebellar ataxia in our 3 patients. LPF is also considered as a source of the febrile response, which might play a role in the genesis of ataxia. We suggest to add Bordetella pertussis to the list of infectious agents causing permanent cerebellar syndrome. P489 DETAILED GENOTYPING OF THE N-ACETYLTRANSFERASE 2 (NAT2) GENE CONFIRMS ASSOCIATION BETWEEN THE SLOW ACETYLATOR PHENOTYPE AND FAMILIAL PARKINSON’S DISEASE. O. Bandmann, J. Vaughan, P. Holmans. C. D. Marsden, N. W. Wood. University Department of Clinical Neurology, Institute of Neurology, Queen Square, London, UK Recent epidemiological studies have established both a positive family history as well as exposure to environmental toxins as risk factors for the development of Parkinson’s disease. Thus, it has been postulated that an inherited defect might make certain individuals more susceptible to substances toxic for the dopaminergic cells of the substantia nigra. We have previously analyzed functionally relevant genetic polymorphisms in six detoxification enzymes and found a strong association between the slow acetylator phenotype of N-Acetyltransferase 2 (NAT2) and familial Parkinson’s disease (FPD) (Lancet 1997, 350 : 1136–1139), slow acetylators being defined by the presence of two mutant alleles. However, the previously chosen “screening” method for the detection of the slow acetylator phenotype only detects the four most common alleles (the wild type allele and the mutant alleles M1, M2 and M3), but not less common mutant alleles. This leads to an overall underestimation of the slow acetylator frequency. To validate our initial findings, we have now undertaken more detailed genotyping of all previously studied patients and controls. This more accurate, but considerably more laborious method detects all NAT2 alleles which occur at a frequency of more than 1% in Caucasians. Four groups were analyzed: 100 pathologically normal controls (PNC), 100 patients with Huntington’s disease (HD) as a disease control group, 100 apparently sporadic patients with pathologically proven Parkinson’s disease (SPD) and 100 cases of FPD, in whom at least one further living member of the family also suffered from this disorder. As expected, the frequency of slow acetylators rose in all four groups: PNC: 43/100 slow acetylators (previously 39/100); HD: 52/100 (48/100); SPD: 60/100 (59/100); FPD: 73/100 (69/100). Comparison of the slow acetylator phenotype between FPD and PNC gave an odds ratio of 3.58 (95% confidence intervalls (CI): 1.96–6.56; p = 0.00003), and an odds ratio of 2.50 (95% CI: 1.37–4.56) for the comparison of the slow acetylator phenotype frequency between the FPD group and the HD group ( p = 0.003). These data confirm the validity of our initial findings. Furthermore, they establish the usefulness of the initial, comparatively quick “screening method” for the detection of relevant differences in the NAT2 slow acetylator frequency between pa-

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tient and control groups, facilitating the investigation of additional patients and controls in our own or other populations. P490 CONTRIBUTION OF MICRORECORDING GUIDANCE IN PALLIDOTOMY. Molinuevo JL, Valldeoriola F, Nobbe FA, Rumià J, Tolosa E. Barcelona, Spain The usefulness of microrecording to adequately place pallidotomy is not thoroughly accepted. We have analysed the deviation of the initial stereotactic target from the definite centre of the lesion, corrected by intraoperative microrecording techniques, in 23 consecutive parkinsonian patients (mean age 58.7, mean disease duration 14.4 years). Stereotaxic co-ordinates were calculated applying a digitised brain atlas adapted to neuroimaging techniques. Two to five recording tracks were used to locate the sensorimotor area of the internal pallidum. Three lesions were made in all cases. At 3 months follow-up, pallidotomy improved contralateral bradykinesia by 44%, rigidity by 35%, tremor by 59% and dyskinesias by 92%. No major side effects were noted. The first recording track was located out of the sensorimotor area of the pallidum in 10 cases and out of the limits of the internal pallidum in 6 cases. Lesion centre was displaced from the initial target in all cases (9 posterior, 11 anterior, 9 medial, 11 lateral). The lesion was located more than 6 mm from the initial target in 5 patients and more than 3 mm in 10 other cases. The mean distance between the initial target and the centre of the lesion was 1.4 (± 1.1) mm in the mediolateral and 2.6 (± 1.3) mm in the anteroposterior plane. Microrecording guidance is a useful tool to avoid lesioning of adjacent structures and to precisely localise the sensorimotor area of the internal pallidum. P491 ADDUCTOR LARYNGEAL BREATHING DYSTONIA (ALBD): CLINICAL FEATURES AND RESPONSE TO BOTULINUM TOXIN (BTX) TREATMENT. G. Salazar, M. J. Marti, F. Aguilar, A. Cardozo, E. Muhoz, M. Frances, E. Tolosa. Neurology Service, Hospital Clinic, Barcelona, Spain ALBD is a rare form of laryngeal dystonia, characterized by paradoxical vocal cord closure during inspiration, causing stridor and breathing difficulty. We describe here the clinical findings and the response to BTX therapy on a further five patients with ALDB. Patients and Methods. Five patients with ALBD symptoms underwent neurological and otolaryngological (ORL) evaluation. All patients received BTX, at doses between 2.5 and 10 U in each thyroarytenoid muscle. Symptoms severity was scored before and after treatment using a subjective rating scale (100% = normal function; 0% = severe dysfunction). Results. All the patients but one developed laryngeal stridor 4 to 48 months after Meige syndrome had been diagnosed. Various degrees of respiratory difficulty, without voice changes, were present. Etiology was idiopathic in four and tardive in one. ORL examination showed adductor spasms of vocal cords during inspiration. Response to BTX injections was initially effective in four patients, but two required eventually urgent tracheotomy for acute obstructive dyspnea. The remaining two patients have been receiving repeated injections with good results (average improvement 50% of function), for 18 and 12 months respectively. One patient showed not response to treatment with BTX. Conclusion. ALBD is a disabling and life-threatening dystonia, which can be seen alone or with other dystonic features. Although BTX treatment relieves ALBD, the intensity of symptoms can lead to severe upper airway obstruction and intubation or tracheotomy may be required. P492 IBZM-SPECT IN IDIOPATHIC PARKINSON’S DISEASE AND DEMENTIA WITH LEWY BODIES. Luginger E*, Donnemiller E, Bösch S, Wenning GK, Riccabona G, Poewe W, Ransmayr G. *Department of Neurology, University Hospital, 6020 Innsbruck, Austria [123I]-Iodobenzamide (IBZM) single photon emission tomography (SPECT) has been suggested as an aid in the differential diagnosis of Parkinson’s disease (PD) and atypical parkinsonism with reduced binding in the latter and normal binding in the former. To our knowledge, comparative IBZM SPECT studies have not been performed in patients with PD versus dementia with Lewy bodies (DLB), latter being increasingly recognized among the atypical parkinsonian syndromes. Methods: Seven patients with probable DLB and 5 patients with probable PD diagnosed according to established clinical criteria were subjected to IBZM SPECT. Mean age at disease onset and mean disease duration were comparable in the two patients groups. Striato-cerebellar (s/c) and striato-frontal (s/f) ratios were determined using a local protocol (Donnemiller et al., Eur J Nucl Med 1997;

24 : 320–325). Results: Average s/c and s/f ratios were similar in DLB and PD patients (s/c ratios 1.44 versus 1.37, p > 0.05; s/f ratios 1.24 versus 1.16, p > 0.05). Conclusion: Postsynaptic dopamine receptors are spared in PD as shown in a number of SPECT studies. Our data revealed striatal IBZM binding in DLB patients similar to that in PD patients suggesting that postsynaptic dopamine receptors are relatively preserved in DLB. Measurements of postsynaptic dopamine receptor binding using IBZM SPECT therefore fails to contribute to the differential diagnosis of DLB and PD. P493 DYSTONIA IN MULTIPLE SYSTEM ATROPHY. Bösch S, Wenning GK, Ransmayr G, Poewe W. Department of Neurology, University Hospital, 6020 Innsbruck, Austria Antecollis has been established as a characteristic clinical feature in multiple system atrophy (MSA). Other types of dystonia have not been systemically studied in this disorder. We therefore performed a prospective study of dystonia in a cohort of patients with probable MSA. Methods: Thirty patients with probable MSA diagnosed according to Quinn (1989) were recruited at our Movement Disorders Unit and followed up until 1995. The following features of dystonia in MSA were recorded: age and disease duration at onset of dystonia, type and distribution of dystonia, and ist relationship to L-Dopa therapy. Results: At first visit 10 (33%) out of 30 MSA patients presented with dystonia including antecollis in 7, and limb dystonia in 4 patients. Levodopa induced dyskinesias developed in 14 (61%) of 23 patients with striatonigral degeneration (SND) type MSA, but in none of the 7 olivopontocerebellar atrophy type (OPCA) MSA patients. Peak-dose dyskinesias were dominated by dystonia of axial musculature (neck, n = 9; orofacial, n = 7) in contrast to predominantly choreatic limb dyskinesias (n = 5). Off-period leg dystonia and end-of-dose leg or cervical dystonia were less common. Conclusion: The present study demonstrates that dystonia is frequently observed in SND type MSA, affecting both levodopa naive and levodopa treated patients. Most of the patterns of levodopa-induced dyskinesias observed in Parkinson’s disease (PD), particularly peak-dose dyskinesias, were also present in our MSASND patients. In contrast to PD patients dystonic symptoms in MSA-SND predominantly affected axial musculature (face, neck). P494 REPLACEMENT OF DOPAMINE AGONISTS WITH TOLCAPONE AS ADD-ON THERAPY IN PARKINSON’S DISEASE PATIENTS: A COMPARISON OF TWO STRATEGIES. Tobias Eichhorn ‡, Roland Selzer* and the Switch-Study group. ‡ Neurologische Klinik der PhilippsUniversität Marburg; Marburg, Germany; *Hoffmann-La Roche, GrenzachWyhlen, Germany The catechol-O-methyltransferase (COMT) inhibitor tolcapone is a new adjunct to levodopa therapy for Parkinson’s disease (PD). This open-label, randomized study investigated means of completely replacing dopamine agonists, (pergolide, lisuride or bromocriptine) with tolcapone (100 mg or 200 mg tid) as adjunct in PD patients with predictable end-of-dose ‘wearing-off’. On entry, patients were being treated with Madopar® (levodopa plus benserazide) or Nacom® (levodopa plus carbidopa) plus a dopamine agonist (DA). Two approaches (mid-term; short-term) to replacement of DA’s were evaluated using patient diaries (‘off’ time). Mid-term adjustment involved reducing levodopa dose in 50 mg steps, up to six times before day 21 of the study, unless parkinsonism worsened, and tapering out DA’s by day 23. In the short-term adjustment, DA’s were replaced within 6 days of initiation of tolcapone treatment and levodopa was subsequently down-titrated. Both time frames of replacement refer to the maximum recommended doses of DA’s. 150 patients completed the study; 71 were evaluated in this interim analysis (mid-term 36; short-term 35). A substantial reduction in mean percentage ‘off’ time from baseline to week 10 was observed in both arms after complete replacement of DA’s with tolcapone (mid-term: 44.0% to 25.2%; short-term: 41.7% to 25.7%) indicating an improvement for the whole sample from baseline under DA’s to endpoint assessment under tolcapone. In conclusion, both adjustment strategies were shown to be equivalent for daily ‘off’ time. Thus they appear equally applicable and easy to handle in a clinical context. P495 CHRONIC ELECTRICAL STIMULATION OF THE SUBTHALAMIC NUCLEUS IMPROVES HANDWRITING IN PATIENTS WITH ADVANCED PARKINSON’S DISEASE. H. R. Siebner, A. Ceballos-Baumann, H. Standhardt*, C. Auer, B. Conrad, F. Alesch*. Department of Neurology, Technical University, Munich, Germany and * Department of Neurosurgery, Allgemeines Krankenhaus, Vienna, Austria

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We studied the effect of high-frequency electrical stimulation of the subthalamic nucleus (STN) on handwriting in 11 patients with advanced Parkinson’s disease (Hoehn & Jahr score 4–5). All antiparkinsonian medication was discontinued the evening prior to testing. Handwriting was evaluated with the stimulators switched on or off. The patients were asked to write repetitively the sentence “Die Wellen schlagen hoch” (The waves are surging high). The movements of the tip of the pencil were recorded using a pressure-sensitive digitizing tablet and a PC-based writing analysing program of single up and down strokes (CS, MedCom,Germany). In all patients, bilateral STN stimulation induced a marked improvement of the motor performance during handwriting. Normalized maximum writing velocity, stroke frequency, as well as the mean stroke length increased indicating a stimulation-related improvement of bradykinesia and micrographia ( p < 0.01, Paired t-test). Our data show that bilateral STN stimulation has a clear beneficial effect on skilled hand movements. Recording handwriting movements seems to be a useful tool to monitor the effect of STN stimulation on manual motor performance and may be helpful to adjust the electrical stimulation parameters.

P496 SPHINCTER ELECTROMYOGRAPHY IN PROGRESSIVE SUPRANUCLEAR PALSY PATIENTS. Capone L, Pramstaller PP, Schönhuber R, Pentore R. Department of Neurology, Regional General Hospital, Bolzano, Italy Both urethral and anal sphincter are innervated by anterior horn cells in Onuf’s nucleus. These cells are affected in multiple system atrophy (MSA), explaining occurrence of bladder dysfunction in these patients. Resulting pathological electromyographic (EMG) findings in the sphincter muscle were previously reported in MSA patients. Aim of the study: to assess sphincter muscle EMG abnormalities in progressive supranuclear palsy (PSP) patients. Methods: Needle examination of the external anal sphincter muscle was performed in eight PSP patients (seven males, mean age 68.4, range 60–75), diagnosed according to published criteria. A sample of EMG activity was recorded by changing the position of the needle from deep to superficial muscle layer. In the same patients nerve conduction studies of the peroneus nerve and needle examination of the tibialis anterior muscle were performed to investigate occurrence of peripheral neuropathy. Results: Two patients showed fibrillation potentials and reduced recruitment in the sphincter muscle. Recruitment was pathological in four patients. Nerve conduction studies were pathological in three patients. Needle examination of the tibialis anterior muscle was pathological in two patients. Conclusions: In PSP patients pathological EMG findings are found. Occurrence of fibrillation potentials and reduced recruitment in the sphincter muscle suggests acute denervation associated with neuronal loss. Increased MUPs amplitude is suggestive of chronic reinnervation. These data show Onuf’s nucleus involvement in PSP.

P497 VENTRICULAR ENLARGEMENT AND BASAL GANGLIA LESIONS IN HUNTINGTON´S DISEASE VISUALIZED BY TRANSCRANIAL SONOGRAPHY. Th. Postert, B. Lack, W. Kuhn, J. Andrich, B. Braun*, M. Jergas*, H. Przuntek, Th. Büttner. Departments of Neurology and Radiology*, Ruhr-University Bochum, Germany Transcranial real-time sonography (TS) was applied to 49 patients with Huntington’s Disease (HD) and 39 control subjects. For comparison we performed in 12 HD patients with and in 9 patients without alterations of the basal ganglia echotexture as detected by MRI. Furthermore, the width of the ventricles was depicted in TS examinations and correlated with corresponding CT slices.18 out of 45 (40%) of the HD patients with adequate insonation conditions showed hyperechogenic lesions (HL) of at least one basal ganglia region. In 12 patients TS depicted HL of the substantia nigra (SN), in 6 patients the head of the caudate nucleus (CN) was affected. The lenticular nucleus (LN) (n = 2) and the thalamus (TH) (n = 0) were less often affected or spared. HL were significantly more frequent in HD than in 39 control persons. Severily affected patients had more frequently HL of the SN than mildly impaired patients (p < 0.01). HL of the SN correlated with the number of CAG repeats (p < 0.01). HL of the CN were associated with an increased signal intensity in T2-weighted MR images (p < 0.05). All TS parameters indicating brain atrophy correlated with CT findings ( p < 0.0001). In conclusion, our study demonstrates that TS detects primarily CN and SN abnormalities in HD. These changes in the echotexture most likely represent degenerative changes in the basal ganglia matrix and are partially associated with CAG repeat expansion and the severity of clinical findings.

P498 DIFFERENCES IN STRIATAL 18F-DOPA UPTAKE IN CORTICOBASAL DEGENERATION AND PARKINSON’S DISEASE. S. Laureys, E. Salmon, G. Garraux, C. Lemaire, G. Franck. Department of Neurology and Cyclotron Research Centre, University of Liège, B30 Sart Tilman, 4000 Liège, Belgium 18F-Dopa

uptake was studied with positron emission tomography (PET) in six patients with the clinical diagnosis of corticobasal degeneration (CBD), fourteen patients with idiopathic Parkinson’s disease (PD), and eight agematched controls. Decreased 18F-Dopa uptake was observed in putamen of patients with CBD as compared to controls (0.61 ± 0.14 vs. 0.91 ± 0.08, p < 0.005). The 18F-Dopa uptake in caudate was not significantly lower in patients with CBD than in controls. However, it was found significantly higher in CBD than in PD patients (0.83 ± 0.08 vs. 0.69 ± 0.13, p < 0.01). The index of asymmetry of 18F-Dopa uptake in both putamen and caudate was significantly higher in patients with PD as compared to controls. This asymmetrical uptake pattern was not always observed in our patients with CBD as compared to controls (1.31 ± 0.46 vs. 1.07 ± 0.09 for putamen, and 1.07 ± 0.21 vs. 0.98 ± 0.12 for caudate). The variations in 18F-Dopa uptake pattern in patients with CBD as compared to PD confirm the differences in the underlying pathophysiological mechanisms of both diseases. Contrary to clinical and metabolic (18FDG-PET) findings, 18FDopa uptake was not always asymmetrical in the our six patients with CBD.

P499 THE POSSIBLE ROLE OF APOPTOSIS IN THE PATHOGENESIS OF PARKINSON’S DISEASE. Shengdi Chen, Ming Guo, Zhenguo Liu, Hongzhuan Chen. Department of Neurology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai 200025, P. R. China The possible role of apoptosis in the pathogenesis of Parkinson’s disease was studied. C57-BL mice were treated with different dosages of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and pretreated with Eldepryl or Riluzole prior to MPTP (301 kg) injection. Then TUNEL and FACS analysis of apoptosis in the neurons of substantia, nigra were performed on the different group mice. The same methods were used to test PC 12 cells treated with MPP´´– or MP1T. This result showed that consecutive treatment of 30 mg/kg MPIT for seven days could induce apoptosis in the neurons of substantia nigra. Whereas lower dosage of MPTP (10 mg/kg) could not induce apoptosis. MPTP induced neuronal apoptosis in substantia nigra can be completely prevented by pre-treatment of Eldepryl. Riluzole can also reduce the MPTP-induced apoptotic process in the nigral neurons. MPP+ concentration of 20 µm could induce apoptosis of PC 12 cells, while the same concentration of MPTP had no such effect on PC 12 cells. It is concluded that the nigral neurons apoptosis may be involved in the pathogenesis of Parkinson’s disease and that MPP, intermediate metabolite of MPTP is specific for the nigral neurons apoptosis.

P500 ESSENTIAL TREMOR PATIENTS WITH SYNCHRONOUS ACTIVITY OF ANTAGONIST MUSCLES ARE MORE DISABLED THAN THE ONES WITH ALTERNATING ACTIVITY. Sedat Ulkatan, M. Cenk Akbostanci, Aytaç Yig˘ it, Nursel Aydin, Nermin Mutluer. Ankara University, Medical Faculty, Neurology Department, Ankara, Turkey According to some studies, patients with essential tremor (ET) could be subdivided into two electrophysiological groups, one with alternating, and the other with synchronous contractions of antagonist muscles. Forty-eight patients with ET were evaluated to further delineate the characteristics of the subgroups mentioned above. We performed electromyographical (EMG) recordings by superficial electrodes from forearm flexors and extensors. The two groups identified were 25 patients with synchronous contractions (EMG bursts) of antagonist muscles and 23 patients with alternating activity. We compared the two groups in terms of sex, age at onset, duration of illness, family history of tremor, symmetry and frequency of tremor, and by a disability scale. The only difference reaching statistical significance was the disability scale score which is 49 in the group with synchronous contractions, and 40 in the group with alternating contractions. This means that ET patients with synchronous contractions are more disabled than the patients with alternating contractions. We think this result is also another evidence that distinct electrophysiological subgroups of ET exists with distinct clinical properties.

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P501 PARKINSON DISEASE FOLLOW-UP STUDY BY P-VEP. Paladini D, Cinti A, Guidoni P, Cocci Grifoni S, Di Marzio F, Angeleri F. Clinica Neurologica, Ospedale Generale Regionale, 60020 Torrette di Ancona, Italy We examined 10 early Parkinson’s disease (PD) subjects (less than 6 months from onset of symptomatology), with pattern visual evoked potentials (P-VEP) and clinical state by means of the Unified Rating Scale for Parkinsonism (UPDRS) in drug wash out condition and 100 minutes after oral administration of 125 mg L-DOPA (plus 28.4 mg benserazide). After 1 year follow-up new control was carried out using the same techniques. P-VEP were recording using an active electrode in Oz and reference electrode in Fz. Signals were filtered between 1 and 150 Hz and averaged 100 times. Four spatial frequencies were employed 0.57, 1.17, 2.33, 4.66 cycles/ degree). The examination was performed monocularly. The P100 mean latency at the highest spatial frequency in drug wash out condition was 125.5 msec and after administration of L-DOPA 112.3 msec, at the baseline. After 1 year the P100 mean latency in drug wash out was 127 and after administration of L-DOPA 115.2 msec. We will discuss correlation between the Parkinson’s disease (PD) clinical course by means UPDRS and the P-VEP changes. P502 CHILDHOOD INFECTION IN ADULT DYSTONIA. G. Galardi, M. A. Volonté, S. Amadio, R. Fazio, G. Comi. Movement Disorders Unit, Scientific Institute San Raffaele, Milano, Italy We describe two patients with infantile onset of mild movements disorders followed by severe worsening during adult life. Both of them had in their medical history a brain damage likely due to an infection during childhood. The first patient is a 41-year-old woman who developed left arm dystonia one week after febrile illness when she was 9. This focal dystonia, that remained unchanged until she was 35, turned in a generalized form within two years. The second patient, a man aged 58, had a febrile tonsillitis when he was 8 followed by blepharoclonus and multiple motor jerks affecting his shoulders. These features remained unchanged for forty-five years up to three years ago, when he began to show progressive dystonic symptoms in his right arm leading to a complete functional impairment. The persistence of mild movement disorders following a febrile illness are supposed to be the expression of an unrecognized encephalitis. The retrospective analysis of these two cases share a two-steps pattern of evolution suggesting that an adult form of dsytonia may follow an encephalitis experienced during childhood. While more severe encephalitis are followed by a rapidly developing monophasic dystonia, the milder ones might lead to dystonia after an interval of many years. Therefore adult dystonic syndromes, diagnosed as idiopatic forms, could actually be secondary forms related to infantile brain damages, that must be considered in epidemiological studies. P503 PHARMACODYNAMIC EQUIVALENCE OF 1.25 mg ZYDIS SELEGILINE (ZELAPAR™) AND 10 mg SELEGILINE TABLETS. A. Clarke and E. S. Johnson. Scherer DDS, Blagrove, Swindon SN5 8RU, UK To avoid first-pass metabolism of selegiline, a fast-dissolving dosage form (Zydis selegiline) has been developed, from which the drug is absorbed pregastrically. This permits a reduction in the administered dose. We report a meta-analysis of bioavailability and pharmacodynamic results of studies with 1.25 mg Zydis selegiline (ZELAPAR™; Zel) and 10 mg selegiline tablets (Tabs). The frequency plot of AUCs for Tabs (n = 93) was skewed, with 10% of subjects having high bioavailabilities, possibly reflecting slow hepatic metabolism by some subjects. The frequency plot from subjects given Zel (n = 47) was symmetrical about the mode. Thus, the bioavailability of Zel was more predictable. Establishing formal pharmacokinetic bioequivalence was difficult because of high variability of AUCs in the tablet group. Urinary excretion of β-phenylethylamine (PEA) is a marker for inhibition of brain monoamine oxidase (MAO) type-B. Zel and Tabs were pharmacodynamically equivalent (mean bioequivalence ratio for PEA excretion = 0.99; 90% CI: 78% to 127%). Selegiline’s efficacy is thought to derive from inhibition of brain MAO type-B. Reduction in the selegiline dose from 10 mg to 1.25 mg in Zel, led to a marked reduction in plasma concentrations of selegiline metabolites. Since Zel and Tabs are pharmacodynamically equivalent, and since both formulations give similar plasma concentrations of selegiline, this suggests that selegiline and not its metabolites inhibits brain MAO type-B and is responsible for therapeutic efficacy. Thus, the need for conventional formulations, resulting

in high concentrations of therapeutically-inactive l-amphetamine metabolites, should be questioned. P504 IMAGE ASSISTED STEREOTACTIC DEEP BRAIN STIMULATION FOR THE TREATMENT OF PARKINSON’S DISEASE. Servello D, Broggi G, Franzini A, Dones I, Caraceni T*, Fetoni V*, Girotti F*. Dept. Neurosurgery and *Dept. Neurology, Istituto Nazionale Neurologico “C. Besta”, Milano, Italy The effectiveness of chronic deep brain stimulation in the treatment of movement disorders led to renewed interest in surgical therapy of Parkinson’s disease. The research of new targets for chronic stimulation and the advances in image assisted neuronavigation technology contributed to extend the indications for this stereotactic procedure. After the preliminary cases, in 1991, at the Istituto Nazionale Neurologico “C. Besta”, deep brain electrodes (Medtronic Inc., USA) have been stereotactically implanted, since January 1996, in 35 patients affected by Parkinson’s disease. In 28 patients (age 35–75, mean 62) affected by disabling lateralized and drug resistant tremor the thalamic Vim nucleus was chosen as a target for the electrode implant. One patient with bilateral tremor underwent bilateral Vim neurostimulation. In 7 patients (age 33–62, mean 51 years) affected by DOPA induced on-off phenomenon and diskinesias the target was the ventro-postero-lateral part of the pallidum internum (GPi): bilateral pallidal stimulation was performed in 2 cases. The target was set on CT stereotactic images fused with MRI and coupled with a stereotactic atlas (Stereoplan, Radionics, USA). The whole procedure for the calculation of the target lasted about 45 minutes while the intraoperative session electrode implant, stimulation with different parameters and clinical tests lasted about 60 minutes. In all cases a postoperative MRI (1–2 days after surgery) was performed together with a clinical evaluation. When uncorrect electrode positioning was detected a second procedure was performed few days later. This was the major complication of this method (6 cases, 17%). All patients showed a marked decrease or even disappearance of their tremor and a relevant improvement in their UPDRS scoring could be estimated after surgery. 57% of patients submitted to pallidal implant had a marked decrease or disappearance of diskinesias and rigidity. Although the short term follow-up of this series, the postoperative good results seem to validate not only the indication to deep brain stimulation but also the use of this imageassisted stereotactic method to perform surgery for Perkinson’s disease. P505 THE ROLE OF GRIP FORCE DEFICITS IN WRITER’S CRAMP. T. Schenk, N. Mai. Munich, Germany The aim of the present study was to assess the role of grip force deficits in the pathogenesis of writer’s cramp. Grip force and handwriting performance were analyzed in a group of 22 patients with writer’s cramp. Although about half of the patients showed abnormal grip force performance, the extent of the grip force deficit and the handwriting impairment did not correlate. Moreover, the grip force abnormality could be eliminated in all patients by a simple training procedure. In addition, the performance of a stroke patient who suffered from a pronounced sensitivity deficit without accompanying paresis is reported. While this patient’s grip force performance was massively impaired, his handwriting was normal. All in all, these results refute the hypothesis that a sensorimotor deficit, indicated by abnormal grip force performance, is responsible for the handwriting disorder in writer’s cramp (Odergren et al. 1996, Brain 119 : 569–583). Instead the grip force abnormalities could be the consequence of the handwriting disorder. The implications of these results for the pathogenesis of writer’s cramp are discussed. P506 COMBINED THALAMIC STIMULATION AND PALLIDOTOMY FOR PARKINSON’S DISEASE – A CASE REPORT. F. A. Nobbe, E. Tolosa, F. Valldeoriola, J. Rumià, E. Ferrer, J. L. Molinuevo, M. Alegret. Hospital Clínic, Universitat de Barcelona, Spain We report a patient with advanced of Parkinson’s disease who underwent bilateral surgical treatment by chronic thalamic stimulation and contralateral pallidotomy. Thalamic stimulation resulted in marked improvement of contralateral tremor, however, significant functional improvement could not be achieved because of the persistence of contralateral and axial symptoms, and severe levodopa-induced dyskinesias. After pallidotomy, the patient experienced abolition of severe bilateral tremor and dyskinesias and

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marked improvement of bradykinesia, rigidity, and gait. Excellent symptomatic and functional outcome and improvement of motor fluctuation profile are demonstrated by clinical rating scales, objective timed tests, self-assessed disability scales and patient diaries. Postoperative neuropsychological tests revealed no clinically significant alterations. Bilateral ablative surgery of homologous area seems to have an increased risk of neurological and neuropsychological side effects. Stimulation techniques might have an advantage regarding the side effects in bilateral procedures but its precise mechanism is still unknown and there are several shortcomings due to added expense and time-consuming clinical management, which accumulate when it is applied bilaterally. Thus, we propose this combined bilateral approach as a valuable option in the surgical treatment of advanced tremorogenic Parkinson’s disease with severe dyskinesias. (Videopresentation.) P507 HEMIPARKINSON AND IPSILATERAL CEREBELLAR HYPOPLASIA: A CASE REPORT. R. Denays, M. Rubinstein, M. Stegen, M. Manto*, S. Dethy*, M. Guerchaft, A. Collier. Centre Hospitalier Etterbeek-Ixelles, *Hôpital Erasme, Bruxelles, Belgium Hemiparkinsonism (HP) with body hemiatrophy (HA) and/or contralateral brain HA is a rare form of parkinsonism. Its clinical features include early age of onset, slowly progressive course, premedication dystonia and relatively poor response to levodopa treatment. Abnormal neuroradiological findings, when present, usually consist of contralateral cerebral cortical atrophy and/or contralateral enlarged lateral ventricle. Ipsilateral cerebellar atrophy has been recorded in only one case, to our knowledge. We report the case of a 64-year-old patient who had a history of right hemiparkinsonism for 7 years. Neurological examination showed mild right face hemiatrophy, bilateral highly asymmetric parkinsonism with the most prominent signs on the right side, and right pyramidal signs. There was no cerebellar ataxia. MRI showed left cerebral cortical atrophy and right cerebellar hypoplasia. At the Tc-99m bicisate SPECT study, the semi-quantitative analysis performed in comparing activity of symmetrical regions of interest, showed marked left cerebral cortical and basal ganglia hypoperfusion, and symmetrical cerebellar perfusion. The finding of cerebellar hypoplasia at the MRI and the absence of cerebellar blood flow asymmetry at the SPECT study suggest a static rather than progressive cerebellar injury. This supports the generally accepted view that HP-HA is the result of natural or pathological dopaminergic system degeneration exacerbated by a prior insult. P508 TECHNETIUM HMPAO SPECT STUDY IN DEMENTIA WITH LEWY BODIES, ALZHEIMER’S DISEASE AND IDIOPATHIC PARKINSON’S DISEASE. L. Defebvre1, V. Leduc1, A. Duhamel2, P. Lecouffe3, F. Pasquier 4, Ch. Lamy-Lhullier3, M. Steinling3, A. Destée1. Departments of Neurology A1, Medical Informatics2, Nuclear Medecine3 and Memory Center 4, Lille, France The aim of the present study was to compare the regional cerebral blood flow measurements studied by SPECT with 99m-Technetium HMPAO in Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), to determine the contribution of SPECT to the differential diagnosis of these two diseases. Twenty patients with probable DLB, 20 patients with probable AD and 20 patients with idiopathic Parkinson’s disease (IPD) were studied. Compared with IPD there was, in the DLB group, a global decrease of HMPAO uptake in cortical regions of interest except in the posterior frontal and occipital regions; in the AD group there was a limited left temporal and parietal hypoperfusion. In the DLB group frontal HMPAO uptake was significantly lower than in AD group. Two predictive scores were established by a factorial discriminant analysis from cortical indexes and minimental state, which correctly classified 53/60 patients (83%) (DLB: 18/20, AD: 16/20, IPD: 19/20). These findings indicate presence of diffuse cortical abnormalities in DLB and suggest that SPECT may be useful in discriminating in vivo DLB from AD. We estimate that SPECT study increases the possibility of separating DLB and AD, because both disorders share different patterns of CBF abnormality.

General Neurology P509 SOMATOFORM DISORDERS IN NEUROLOGY: A PILOT EPIDEMIOLOGICAL TRIAL IN ITALY. Rossini Paolo Maria, Martino Gennaro. A.Fa.R. Divisione Di Neurologia, Ospedale San Giovanni Calibita Fatebenefratelli, Roma, Italy

In the last years great attention has been paid by the medical community, and particularly by Word Health Organization (WHO), on Somatoform Disorders (S.D.) because of the high costs of the disease. Only few studies have been conducted to evaluate the frequence of S.D. in neurology. Aim of this study is to investigate the incidence of S.D. in comorbidity with neurological diseases at the Division of Neurology of Ospedale San Giovanni Calibita Fatebenefratelli – Roma, Italy. Materials and Methods: 177 patients admitted to the Hospital because of neurological disorders (mainly cerebrovascular, demyelinating, and traumatic) were evaluated using a diagnostic system for S.D. developed by WHO, the Somatoform Disorder Schedule (SDS). Results: 38% of patients interviewed was affected by S.D. in comorbidity with neurological diseases. The most frequent somatoform disorders, diagnosed according DSM-IV criteria, were S.D. Not Otherwise Specified (NOS) (38%), undifferentiated S.D. (10%), somatoform pain disorder (5%), and Hypocondriasis (5%). The association undifferentiated and pain S.D. was very frequent (23%). Patients affected by cerebrovascular diseases, demyelinating disorders, epilepsy, spinal cord pathologies showed a high incidence of co-morbidity with specific S.D. (39–69%). Conclusions: S.D. are frequently observed in neurology. An evaluation of the possible association between S.D. and specific neurological disorders should be mandatory before planning therapeutic strategy.

P510 A NEW CLINICAL MANOEUVRE FOR UPPER LIMBS TO EVALUATE PATIENTS WITH CEREBELLAR ATAXIA. M. Manto1, J. Jacquy2, J. Hildebrand1. 1Neurologie, Hôpital Erasme-ULB, Bruxelles, Belgium; 2 Neurologie, CHU-Charleroi, Charleroi, Belgium In every day practice, the most frequently used clinical tests in upper limb for patients with cerebellar disease are: finger-to-nose test, alternate movements of hands, fine finger movements, to maintain arms against gravity, handwriting, evaluation of muscle tone by moving passively the joints, Stewart-Holmes test and Barany’s test. None of these conventional tests combines a voluntary limb movement and a concomitant ocular saccade. We describe a new clinical manoeuvre combining limb movement and ocular saccade, consisting of a fast horizontal pointing movement of one upper limb towards an area delineated by the index and the thumb of the other hand, which is kept motionless. We have prospectively compared this manoeuvre and conventional tests for upper limb in 79 patients (mean age: 52, range: 38 to 70, 46 males) with a cerebellar disease confirmed by brain MRI and in 44 control subjects (mean age: 54, range: 29–68, 24 males). The sensitivity of our test is 72%, that of the finger-to-nose test is 70%. The other tests have a sensitivity lower than 55%. The specificity of our test is 85 %, which is lower than the specificity of finger-to-nose test (94%), but similar to specificity of alternate movements of hands (84%). We conclude that our manoeuvre is a sensitive clinical tool for testing of patients with cerebellar disease.

P511 CEREBROSPINAL FLUID HIV-1-SPECIFIC IGG PROFILES IN AIDS. Fainardi E, Balboni P*, Benassi N°, Bedetti A^, Vaghi L, Paolino E. Section of Neurological Clinic, *Section of Microbiology, °Department of Serology, ^ Department of Infectious Diseases, Ferrara, Italy In this study, we evaluated intrathecal production of IgG directed to Human Immunodeficiency Virus type 1 (HIV-1) antigens in 72 patients belonging to Group IV of the Centers for Disease Control classification of Atlanta and divided in different groups according to clinical picture, CD4+ cell count and antiretroviral treatment. HIV-1 specific intrathecal IgG synthesis was detected by Antibody Index in 72.2% and by Affinity-Mediated Immunoblot in 26.4% of the patients. Cerebrospinal fluid (CSF) anti-ENV, anti-POL and anti-GAG reactivity was found in 100%, 51.4% and 44.4% of the cases, respectively. A significantly higher frequency was documented for HIV-1-specific oligoclonal IgG local synthesis patterns (mainly “mixed” profile), in patients with primary neurological manifestations and without Zidovudine therapy, for CSF anti-POL p65 response in primary and secondary neurological complications, for CSF IgG anti-POL p65 and antiGAG in patients with CD4+ count between 50 and 299/mm3 compared to those with CD4+ < 50/mm3. Therefore, HIV-1-specific intrathecal humoral immune response, mainly polyclonal and directed to ENV products, could be common in AIDS, while oligoclonal IgG profiles with anti-POL and anti-GAG reactivity in CSF may help to identify the different HIV-1-related clinical pictures, as well as the progression of the disease. Moreover, antiretroviral treatment would seem to decrease IgG anti-HIV-1 oligoclonal response.

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P512 HIGH RESOLUTION MAGNETIC RESONANCE ANGIOGRAPHY IN HEMIFACIAL SPASM. Ho SL*, Cheng PW, Wong WC, Chan FL, Khoo J, Chan J, Tsang KL*, Leong L. *Dept of Medicine, University of Hong Kong, and Dept of Diagnostic Radiology, Queen Mary Hospital; Hong Kong Hemifacial spasm is characterised by disabling involuntary facial muscles spasms. It usually presents unilaterally and has been described as idiopathic in origin. Recent magnetic resonance angiography (MRA) techniques have improved the visualisation of the root entry zone (REZ) of the facial nerve. We used a modifed MRA technique to assess neurovascular contact and identify the blood vessels involved. We conducted a two-year prospective study on 44 patients with hemifacial spasm and 20 controls. 128 facial nerves were assessed using conventional MR study and high resolution three-dimensional (3D) time-of-flight MRA (1mm slice thickness with no interslice spacing) under blinded (to diagnosis and the side of symptom) conditions. The course and relationship of the facial nerve to surrounding blood vessels was clearly defined. Neurovascular contact was highly correlated to the side of the spasm (p < 0.001) and occurred most frequently at the REZ. The commonest blood vessel involved was anterior inferior cerebellar artery, followed by posterior inferior cerebellar and vertebral arteries. Overall number of true positive, true negative, false positive and false negative results were 37, 73, 11 and 8 respectively. The sensitivity was 83% and specificity was 87%. Our modified MRA protocol is a highly accurate, non-invasive diagnostic tool in evaluating hemifacial spasm. We confirmed earlier MRA findings that hemifacial spasm is correlated to neurovascular contact of the facial nerve, and clearly defined the blood vessels involved, the degree and site of the neurovascular contact. P513 DOUBLE-BLIND STUDY OF BOTULINUM-A-TOXIN IN AXILLARY HYPERHIDROSIS. P. Schnider, M. Binder*, H. Kittler*, P. Birner, E. Auff. Division of Neurological Rehabilitation, *Division of General Dermatology, University of Vienna, Austria Excessive axillary hyperhidrosis is a socially embarrassing condition resulting in psychological disturbance. Hitherto applied treatment strategies do not resolve the problem in all cases. Subcutaneous injections of botulinumtoxin have been reported as effective in focal hyperhidrosis. We performed a randomized double-blind study within-group comparison in 13 patients to study the effect of subcutaneous injections of botulinum-A-toxin in axillary hyperhidrosis. A total dose of 200 mU (mouse units) of botulinum-A-toxin (Dysport®) was injected into six different sites at one axilla, whereas the other was injected with sterile saline. Objective quantification of sweat production was performed using digitized Ninhydrin-stained sheets. Three weeks after treatment, the mean difference of Ninhydrin staining between botulinum and placebo treated axillae was – 34.5% ( p < 0.001), after 8 weeks – 36.9% ( p < 0.001) and after 13 weeks – 28.4% ( p < 0.001). Subjective rating of sweat production was evaluated on a visual analogue scale (0: no sweating, 100: maximum sweating). Three weeks after treatment the difference between the botulinum and the placebo treated axilla was – 56.5 points ( p < 0.001), after 8 weeks – 67.4 points ( p < 0.001) and after 13 weeks – 62.5 points (p < 0.001). No serious sideeffects were reported. In summary, subcutaneous injections of botulinumtoxin are a highly effective treatment in patients with severe axillary hyperhidrosis resistant to conventional treatment. P514 NEUROLOGICAL COMPLICATIONS OF BEHÇET’S DISEASE. D. Kidd, A. Steur, M. Denman, P. Rudge. London, U.K. Neurological complications of Behçet’s disease are well known but poorly characterised, with only small series having been published outside of Turkey. In order to attempt clearly to characterise the various clinical syndromes which may occur we have undertaken a review of all patients seen with such disorders at the National Hospital over the past 15 years. This is therefore the largest series from a European centre. Thirty eight patients were seen, mean age 28 years (17–52). The median latency to onset of neurological complications from disease onset was 2 years (0–32). 30 patients were born of UK stock, the remaining from Middle Eastern countries or the Indian Subcontinent. 17 patients presented with brainstem syndromes, 8 with meningitis, 5 with raised intracranial pressure, 3 with cord syndromes, 2 with hemisphere disease leading to hemiparesis. One had optic neuropathy, 2 had involvement of the vestibulocochlear nerve alone. CSF abnormalities arose in 24 of 30 patients assessed, of which 21 showed high CSF protein, 24 a leucocytosis. Polymorphs were present in 12 cases.

Oligoclonal bands were absent, but matched serum/CSF bands were seen in 5 cases. Incomplete recovery occurred in most cases, with a complete recovery in 5. Those followed up showed a tendency to relapse if the presenting syndrome indicated parenchymal involvement, but relapse of meningitis or raised intracranial pressure was rare. Three cases showed a progressive decline leading to severe disability. These data further characterise this disorder and help to plan future formal treatment trials. P515 CAUSES OF DEATH IN MITOCHONDRIAL DISEASES. Thomas Klopstock. Munich, Germany Little is known about the causes of death in mitochondrial diseases. We report eight patients who died suffering from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), CPEO (chronic progressive external ophthalmoplegia), or an unclassified mitochondrial multisystem disorder. The diagnosis was confirmed by the presence of ragged red fibers in muscle biopsy, the finding of a specific mutation of the mitochondrial genome, or both. In four MELAS cases, mean age at death was 35.5 years. The causes of death were (1) epileptic status, (2) pulmonary embolism, (3) renal insufficiency, and (4) cardiopulmonary insufficiency. In three CPEO cases, mean age at death was 56.3 years. The causes of death were (1) aspiration pneumonia, (2) cardiopulmonary insufficiency, and (3) pulmonary embolism. The patient with an unclassified mitochondrial disease had depression and seizures from age 20, followed by external ophthalmoplegia, deafness, ataxia, and dementia. Dysphagia led to recurrent aspiration pneumonia, and she died at age 45. Thus, only one of eight patients died from a specific neurological cause (grand mal status). Two patients died from medical complications of neurological symptoms (aspiration pneumonia caused by dysphagia). Two patients died from pulmonary embolism, and three from cardiopulmonary or renal insufficiency. We conclude, that most patients with mitochondrial diseases die from complications that may be prevented. Therapy should include effective antiepileptic medication in the presence of seizures, and early anticoagulation if there is a risk of pulmonary embolism. Surgical therapy of dysphagia should be considered. P516 CENTRAL NERVOUS SYSTEM INVOLVEMENT IN CASES WITH FAMILIAL MEDITERRANEAN FEVER: AN ASSOCIATION WITH INFLAMMATORY DEMYELINATING DISEASE? Akman-Demir G*, Gürol E*, Gül A**, Öge AE*, Bahar S*, Gürvit H*, Saruhan-Direskeneli G***, Koniçe M**, and Eraksoy M*. Istanbul Faculty of Medicine Departments of *Neurology, **Rheumatology, and ***Physiology, Istanbul, Turkey Familial Mediterranean Fever (FMF) is an inherited recurrent inflammatory disease of unknown cause. Central nervous system (CNS) involvement in FMF is uncommon. Aseptic meningitis, optic neuritis, pseudotumor cerebri, and neurologic syndromes due to complications are known to occur occasionally in FMF. Recently, cases with multiple sclerosis (MS) and FMF have been reported. Here we present 10 cases (3 males, 7 females) seen in our department between 1986–1997, with long lasting FMF, who developed various forms of CNS involvement and multifocal lesions compatible with inflammatory- demyelinating disease. Mean age at admittance was 31 (range: 17–55) and mean follow-up period was 32 months (range: 0–81 months). Seven cases (including a pair of sisters) showed MS-like clinical features and MRI findings; another case had an acute spastic quadriparesis and bulbar palsy with widespread white matter lesions. On the other hand, the remaining two cases had cognitive changes and hemiparesis with large enhancing subcortical lesions. Five of six cases showed oligoclonal IgG bands in CSF. Corticosteroids were added to colchicine in seven of the patients which resulted in various degrees of improvement. Although coincidence remains a possibility, the concurrent presence of two such recurrent inflammatory conditions, is noteworthy, and might be a clue of a common etiopathogenetic mechanism. P517 DENSITY OF FRONTAL AND HIPPOCAMPAL NMDA RECEPTORS IN PATIENTS WITH CHRONIC ALCOHOL INTAKE. E. Villegas, R. Estruch, E. Antúnez, E.Tobías and A. Urbano-Márquez. Barcelona, Spain Chronic alcoholic consumption causes brain damage and a great variety of behavioural and cognitive disorders. Although the underlying pathogenic mechanisms are poorly understood, some studies have suggested that brain lesions associated to alcohol intake could be produced by selective inhibitory

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effects on glutamate transmission. We have performed a post-mortem study to analyse the density of the glutamatergic receptor N-methyl-D-aspartate (NMDA) in the brain of 10 patients with daily alcohol intake more than 100 g in the five years previous to death, and 10 control subjects. The density of NMDA receptors was determined by autoradiographic techniques in the frontal cortex and hippocampus (CA1 and gyrus dentatus), two cerebral areas frequently involved in alcoholic brain damage. Mean density of NMDA receptors in alcohol consumers was 2 fmol/mg tissue in the frontal cortex, 5.39 fmol/mg in the CA1 and 3.71 fmol/mg in the gyrus dentatus. In control subjects mean NMDA receptors density was 1.87 fmol/mg tissue in the frontal cortex, 4.49 fmol/mg in the CA1 and, 3.76 fmol/mg in the gyrus dentatus. No statistically significant differences were found among the two groups of patients. Chronic alcohol consumption does not result in quantitative alterations of NMDA receptors in the frontal cortex and hippocampus. In consequence, there is no evidence from this study of a possible relationship between chronic alcohol consumption and altered NMDA transmission. P518 CEREBRAL INVOLVEMENT IN SJOGREN SYNDROME: CLINICAL AND RADIOLOGICAL FINDINGS. S. Bohlega, J. Alwatban, Z. Patay, M. Z. Al-Kawi, A. Al-Semari, P. Chavis, S. Omer. Riyadh, Saudi Arabia Various forms of focal central nervous system (CNS) lesion occur in 10%– 30% of patients with primary Sjogren syndrome (SS). We evaluated nine females and one male (aged 26–56 years) whose neurological presentation led to the diagnosis of primary SS. Optic neuritis occurred in two with focal neurological deficit first resembling multiple sclerosis in five, transverse myelopathy in two and dementia with psychiatric symptoms in one. Anti-nuclear antibodies were positive in four, buccal serology positive in seven, anti-SSA(Ro) and SSB positive in 70% and 20% respectively. Cranial MRI revealed disseminated periventricular and/or subcortical white matter lesions in all. Two types of lesion were identified: (I) indistinct, faintly hypo-intense or invisible on T1- and hyper-intense on T2-weighted images, simulating focal demyelination; (II) well defined, markedly hypointense on T1 and hyper-intense on T2-weighted images, simulating lacunar infarcts. Spinal cord involvement was followed by atrophy and hyperintense T2-weighted lesions were seen in three patients. Anti-SSA(Ro) antibodies were associated with a more severe neurological presentation. Disease control and reversal of symptoms occurred in more than 50% of patients. We conclude that CNS-SS is under-diagnosed and may be the clue for diagnosing systemic SS. MRI is highly sensitive although not specific for detecting brain lesion. Based on differential MRI lesions we speculate that the parenchymal lesions are related to autoimmune small vessel angiopathy, focal autoimmune leucoencephalitis, or both. P519 INFLUENCE OF CHRONIC ALCOHOL ABUSE ON THE LEVEL OF 8-OHDG IN THE MTDNA OF HUMAN THROMBOCYTES. A. Gottschalk, B. Janetzky, S. Pohli*, M. E. Götz*, J. Böning*, P. Riederer*, H. Reichmann. Institute of Neurology, Dresden and *Institute of Psychiatry, Würzburg, Germany In the last few years the influence of alcohol on the level of oxidative stress has been extensively discussed. In this study we examined the influence of chronic abuse on oxidative stress. Because of potential long-term effects caused by oxidative DNA damage our interest was especially on the oxidative damage in the mitochondrial DNA (mtDNA) of human thrombocytes. Thereby we used the oxidized DNA-base 8-hydroxy-2´-deoxyguanosine (8-OHdG), which is the most frequent oxidative DNA-adduct and a very strong mutant, as a marker. The idea supposes that the 8-OHdG-level should be increased in alcoholics compared to non-drinking age-matched controls. Besides it is possible that the oxidative damage is reversible and decreases after a while of non-drinking. Therefore alcoholics were examined on the first day and 40 days after they stopped drinking. The results of this study support the theory of a continuing increased oxidative damage caused by chronic alcohol abuse: the level of 8-OHdG in the mtDNA was about 58% higher in the patients on day 1 than in controls. Even on day 40 the average level of 8-OHdG remained increased compared to controls. P520 MRI FINDINGS IN PIRIFORMIS MUSCLE SYNDROME: A CASE REPORT. Serrao M, Cardinali P, Rossi P, Di Cesaria V, Valente G, Parisi L, Bianco F. Istituto di Clinica delle Malattie Nervose e Mentali, Università degli Studi di Roma “La Sapienza”

The piriformis syndrome is a disputed and rarely recognised condition. The syndrome is characterised by pain in the buttock with or without irradiation to the leg and to the coccygeal region. The pain is made worse by hip abduction, internal rotation and sitting position and the symptoms present almost identically to lumbar disk syndrome. The cause of this condition is still unclear. The diagnosis is primarily clinical as no investigation has proved to be decisive. However, with the contribute of imaging techniques, the piriformis syndrome appears to be on firmer ground. We present a case report of piriformis syndrome documented by MRI. A 30-yearold woman developed persistent pain in the buttock irradiated to the posterior region of the left thigh and associated to intermittent paresthesias down the posterior aspect of the knee and calf one year prior to admission. She had no history of direct trauma of the buttock but she was affected by severe scoliosis since adolescence. Neurological examination showed an hypoestesia in the posterior-lateral region of the left leg; Friberg’s and Pace’s manoeuvres were positive. MR scan of lumbosacral tract was unremarkable. MR imaging of piriformis muscle showed an enlargement of left muscle with a clear dislocation of ischiatic nerve. We suggest to include MR imaging of the piriformis muscle in diagnostic evaluation of patients with sciatic painful syndromes without radiological evidences of lumbo-sacral disk abnormalities. P521 SUPERFICIAL SIDEROSIS OF THE CENTRAL NERVOUS SYSTEM. Flachenecker P, *Brechtelsbauer D, *Bendszus M, Gold R. Departments of Neurology and *Neuroradiology, University of Würzburg, Germany Superficial siderosis of the central nervous system is a rare disorder characterized by sensorineural deafness, cerebellar ataxia and pyramidal signs due to chronic subarachnoid hemorrhage. However, the source of the bleeding was found in only half of the cases. We report one patient in whom superficial siderosis could be attributed to cerebral vasculitis. – Case report: This 56-year-old man experienced sudden-onset numbness of the left side and an unsteady gait one day before admission. Neurological examination disclosed left-sided hemihypesthesia, mild right-sided spastic hemiparesis with bilateral pyramidal signs and ataxia of gait and limbs. Magnetic resonance imaging (MRI) showed multiple lacunar infarctions in the right thalamus and the left cerebellar hemispheres, and marginal hypointensities around the brainstem, cerebellum and spinal cord on T2-weighted images. The CSF was xanthochromic, with elevated erythrocytes, leucocytes, erythrophages and siderophages. Cerebral angiography was suggestive of vasculitis. On control lumbar punctures two and 11 weeks after the initiation of corticosteroids CSF findings improved. Sensory disturbances also improved, but ataxia and pyramidal signs remained essentially unchanged. Serum iron levels, and particularly ferritin levels, were elevated. The diagnosis of hemochromatosis was supported by MRI and histopathological changes of the liver. – Conclusions: This is the first report providing evidence that superficial siderosis may also be caused by cerebral vasculitis. More intriguing, systemic hemochromatosis was found simultaneously with chronic subarachnoid hemorrhage. At present it is not clear whether this is an accidental correlation. P522 PRIMARY SJOGREN’S SYNDROME REVELATED BY MYELITIS. C. Daems-Monpeurt, F. de Oliveira, A. Mackowiack, T. Stojkovic, E. Hachulla, J. P. Pruvo, P. Vermersch. Departments of Neurology, Internal medicine and Neuroradiology, CH&U of Lille, France Although disorders of the peripheral nervous system are not unusual in primary Sjogren’s syndrome (PSS), central nervous system (CNS) involvement has been described only rarely. The lesions can be distributed throughout the nevraxis, but isolated spinal cord involvement is rare. We described 3 cases of PSS revealed by an acute transverse myelitis. Neurologic symptoms were isolated in 2 women aged 44 and 69 years. A man aged 62 years had also multiple systemic localizations. All cases presented with acute or subacute severe weakness of the lower limbs and sensitive signs suggestive of a dorsal level. Magnetic resonnance imaging (MRI) demonstrated in 2 women cases T1 hypointensities and T2 hyperintensities. MRI dont show abnormal intensity in the man case. Cerebrospinal fluid analysis showed in all cases hyperlymphocytosis. Laboratory results suggested an inflammation in all cases. In the 3 cases, minor salivory gland biopsies showed the characteristic changes of PSS, scoring 3 for one case and 4 for the other, according to Chisholm classification. In any case, the serologic profile indicated other connective tissue disease or autoimmune disease. Precipitating antibodies against Ro(SSA) and La(SSB) were not detected in any case. The pathogenesis of CNS complications in PSS are clearly unknown. Probably 2 distinct pathologic processes are effective: direct mono-

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nuclear cell infiltration of CNS tissue or vasculitis. A vasculitis process is know to be associated with the presence of anti Ro(SSA) antibodies. The absence of anti Ro(SSA) in our cases doesn’t argue for a vasculitis process. P523 REGIONAL METABOLIC IMPAIRMENT IN VEGETATIVE STATE. A POSITRON EMISSION TOMOGRAPHY STUDY WITH CONJUNCTION ANALYSIS. S. Laureys1, 2, B. Sadzot1, 2, S. Goldman3, P. Van Bogaert 3, C. Phillips2, P. Maquet1, 2, G. Franck1, 2. 1Department of Neurology, CHU Sart Tilman, Liège, Belgium; 2 Cyclotron Research Centre, ULG, Liège, Belgium; 3 PET/Biomedical Cyclotron Unit and Department of Neurology, ULB Erasme, Brussels, Belgium In the present study, regional brain glucose metabolism distribution (rCMRGlu) was assessed by means of statistical parametric mapping (SPM96) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in four cases of vegetative state (VS) of various aetiologies. The patients were scanned in two different PET-centres and compared to their respective centre-defined age-matched control population, using SPM96. A conjunction analysis provided the common pattern in rCMRGlu decreases characterising VS patients. Results were significant at the cluster and voxel level ( p < 0.05). Significant rCMRGlu decreases were observed in the left and right middle and superior frontal gyri, the left inferior frontal gyrus, the left inferior parietal lobule, the left middle temporal gyrus, the right superior temporal gyrus, the precuneus/posterior cingulate cortex, and the left pre- and post-central gyri. Our results show the functional importance of the prefrontal and parieto-temporal association areas as the critical neuroanatomic substrate for VS. These cortical regions are known to be involved in several higher cognitive functions such as attention, working memory, episodic memory retrieval or mental imagery. Impairment of these functions likely participates in the dissociation between external awareness and arousal observed in VS.

P524 HEREDITARY SPASTIC PARAPLEGIA: A HISTORICAL REVIEW. Polo JM, Combarros O, Berciano J. Santander, Spain Traditionally, the eponym “Strümpell-Lorrain disease” has been used to designate hereditary spastic paraplegia (HSP). However HSP is not a single disease but rather a group of clinically and genetically different disorders. The aim of this study was to revisit the papers by Strümpell and Lorrain in order to analyze their respective contribution to the knowledge of the disease. In 1880 and 1893, Adolf Strümpell published clinical and familial features of the Gaum and Polster families, in which affected members suffered only from progressive spastic paraparesis. In 1886 and 1904, he reported the results of the autopsies done in one patient in each family, in which findings were similar: symmetric degeneration of the pyramidal pathways, the Goll and spinocerebellar tracts being affected in lesser degree. In 1898, Maurice Lorrain revised in this doctoral thesis familial spasmodic paraplegia. But the familial nature of his personal observations is questionable, since 4 cases were sporadic. Furthermore, the remaining 2 families and Lorrain’s literature review, 23 families from 20 publications since Strümpell, included a hotchpotch of clinical and genetical cases. Lorrain did not describe any personal neuropathological study of familial disease either. In conclusion, if an eponym is to be used in reference to “pure” HSP, credit should be given to Adolf Strümpell who certainly described a clinico-pathological entity; but this eponym should not be used to designate other complicated forms of the disease. P525 IS EVIDENCE-BASED TREATMENT OF PARKINSON’S DISEASE (P.D.) POSSIBLE? Nunes S*, Macedo A*, Ferreira J*, Castro-Caldas A**, Durão V*, Sampaio C*. *Base Unit of the Cochrane Review Group for Movement Disorders, Instituto de Farmacologia e Terapêutica Geral; **Centro de Estudos Egas Moniz, Faculdade de Medicina de Lisboa, Portugal Evidence based Medicine (EBM) is a process to inform medical decisions. The effectiveness of the EBM process depends on the existence of evidence when it is needed and on its quality. The objective of this study is to survey the controlled trials assessing different therapeutic options for the treatment of Parkinson’s disease in order to evaluate the practical feasibility of a evidence based treatment of Parkinson’s disease. A systematic search of the databases MEDLINE and EMBASE allowed the retrieval of

780 controlled or randomised controlled trials. Descriptors utilized to classify the retrievals: country of origin of the 1st author; drug studied; type of design; type of comparator; sample size and duration of follow-up. These descriptors were applied to the all database (n = 780). A random, stratified sample of all database was evaluated. Quality assessment tools: two rating scales Chalmers’ (JAMA 1990; 263 : 1401–1405) and Jadad’s (Cont. Clin. Trials 1996; 17 : 1–12) were used. Our analysis showed that most of randomised trials published did not report the method of randomisation making the assessment of the concealment of randomisation impossible. In spite of the great development of the methodological theoretical background in last years the „Quality“ did not change with time. There is a clear trend for the available trials to provide just short-term, efficacy data making generality difficult. Conclusions: It is urgent to define a strategy for future trials in P.D. in order to make evidence based treatment of P.D. a reality.

P526 STRICT VERSUS LIBERAL BEDREST FOR SCIATICA. Ernest J. Wouda, Jan A. L. Vanneste. Department of Neurology, Sint Lucas Andreas Ziekenhuis, Postbus 9243, 1006 AE Amsterdam, NL Background. Bedrest and the type of bedrest for sciatica due to lumbar disc disease remain controversial. Aims of this pilot study. To compare the effectiveness of 2 types of bedrest: (1) strict bedrest (SB) consisting of 24 hour in bed restriction; (2) “liberal” bedrest (LB) during which mobilisation for meals, sanitary stops, and short walkings was allowed. Methods. A prospective, randomised, single-blind study in patients with sciatica presumably due to lumbar disc disease was carried out. Baseline assessment included lumbar spine CT scan, scoring pain intensity with a 10-point visual analogue pain scale (VAS), and functional impairment by calculating the Oswestry-index. Randomisation blocks contained 20 patients. A neurologist who was blinded to the type of bedrest assessed the final outcome 2 months after the bedrest had been started. These measures included the VAS score, the Oswestry index and the need of lumbar surgery. Results and conclusions. Fourty-nine patients were randomised (SB, N = 29; LB, N = 20); 41 terminated the study (SB, N = 23; LB, N = 18). Analysis of outcome after 2 months in the 41 patients who completed the study showed no significant difference in baseline clinical characteristics, decrease of pain intensity (SB: 2.8; LB: 2.9), amelioration of the Oswestry index (SB: 15.7; LB: 12.5) and the need of surgery (22% in both groups). The low number of included patients precludes firm conclusions, but our results suggest that the effectiveness of strict bedrest might be modest.

P527 AMIODARONE-INDUCED VESTIBULAR POSITIONING VERTIGO AND VOMITING. V. Arbusow, M. Strupp, P. Schulz, J. H. Planck, T. Brandt. Ludwig-Maximilians University, Munich, Germany Common neurological side effects of amiodarone, an effective antiarrhythmic drug, are reversible tremor, ataxia, and peripheral neuropathy. We describe a unique case with amiodarone-induced, prolonged severe positioning vertigo/vomiting due to central vestibular dysfunction. Repetitive vomiting was elicited even by single head movements which made the patient immobile and parenteral alimentation necessary for four weeks. Associated symptoms were downbeat nystagmus and mild limb ataxia. Intravenous application of ondansetrone (24 mg/d), dimenhydrinate (200 mg/d), and triflupromazine (up to 75 mg/d) and clonazepam (2 mg/d) had only little effect on positioning vertigo/vomiting and downbeat nystagmus. Aetiologies other than amiodarone intoxication could be excluded by repeated highresolution MRI during the course of the disorder and extensive laboratory investigations. Six weeks after discontinuation of amiodarone therapy a gradual resolution of positioning vertigo/vomiting and downbeat nystagmus occurred. Vestibular positioning vertigo/vomiting so far has been described only for structural lesions of the dorsal vermis and the caudal cerebellar peduncles or in diffuse cerebellar pathologies such as paraneoplastic syndromes. Amiodarone was causative in the described syndrome for three reasons: (1) The course of the symptoms parallels to the known delayed neurotoxic side effects and the exceptionally long half-life of the drug, which passes the blood-brain barrier and accumulates in neuronal tissue. (2) Other possible aetiologies of reversible positioning vertigo/vomiting and downbeat nystagmus were largely ruled out by diagnostics. (3) The syndrome resolved six weeks after discontinuing of therapy. This is the first case of reversible positioning vertigo/vomiting after drug intake without structural pathology in the brainstem or cerebellum.

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P528 PERGOLIDE AS ADJUNCT THERAPY IN PARKINSON’S DISEASE EVALUATED USING SPES. Klein C1, Melamed E2, Korczyn A3, Gilad C, Peretz A5, Rabey LM. Departs. of Neurology, 1Assaf Harofeh Med. Ctr., Zerifin, 2 Rabin Med Ctr., Petach Tikvah, 3 Sourasky Med, Ctr., affiliated to Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, 4 HaCarmel, Faculty of Medicine, affiliated to Rapaport Technion University, Halfa, and 5 Rambam Medical Center, Haifa, Israel

and cerebellar atrophy, with bilateral focal lesions at the dentate nuclei and adjacent cerebellar white matter. Tc-99m bicisate SPECT revealed marked cerebellar hypoperfusion and, in the supratentorial areas, decreased activity in frontal areas, mainly in the premotor cortex. These results suggest that Tc-99m bicisate SPECT can be of value in CTX to localize the most impaired cerebral areas. This may be helpful for a better understanding of the pathogeny of central nervous system injury in CTX.

Thirty-two patients suffering from idiopathic Parkinson’s disease (mean age 65.3; mean disease duration 7.4 years) with fluctuations were enrolled in different out-patient clinics throughout Israel. After a basic clinical evaluation the patients were treated with pergolide in increasing doses as add-on therapy. It was an open trial, lasting 3 months. The clinical evaluation was performed applying the Short Parkinson’s Evaluation Scale (SPES), a new friendly score, recently created by a joint European team (Rabey et al., Clinical Neuropharmacology, 1997). During the trial 13 patients withdrew: 9 due to side effects (persistent hypotension 3; nausea and dizziness 3; constipation 1; chest pains 1 and headaches 1); protocol violations 1, and lost to follow up 3. Of the 19 patients who completed the study, there was improvement in the motor scoring (according to SPES) p = 0.0 1, and also in activities of daily living ( p = 0.001) 1). In summary, we have confirmed the benefit of pergolide as add-on therapy for PD patients and advise that in view of possible side-effects the dose be carefully and gradually increased. In addition, SPES seemed to be a useful tool in the clinical evaluation of PD patients.

P531 IDIOPATHIC MONOCULAR PARESIS: CLINICAL, LABORATORY AND PROGNOSTIC FEATURES. E. Linetsky, I. Steiner and A. Karni. Department of Neurology, Hadassah University Hospital, Jerusalem, Israel

P529 THE EVALUATION OF MITOCHONDRIAL DYSFUNCTION USING A MULTIDISCIPLINARY APPROACH. Hardiman O, Brett F, Droogan O, Gallagher P, Harmey M, King M, Murphy J, Perryman R, Sukumaran S, Walsh J, Farrell MA. Irish Institute of Neurology and Neurosurgery; School of Biological Sciences, University College Dublin; Dublin Institute of Technology, Dublin, Ireland We have established a national multidisciplinary research unit to analyse mitochondrial dysfunction in patients with suspected metabolic disease. We have evaluated a total of 60 patients in 12 months. Following clinical, haematologic and biochemical evaluation, all patients undergo muscle biopsy. Each muscle is divided into 3 portions, for biochemical analysis, histopathology and tissue culture. Fresh mitochondria are extracted for oxidative phosphorylation studies. Mitochondria are then harvested, and studies of in organello protein synthesis, and the activity of all five complexes of the respiratory chain are performed. Histopathologic evaluation includes combined staining with succinic dehydrogenase and cytochrome oxidase and electron microscopy. Mitochondrial DNA is extracted from harvested mitochondria, and subjected to mutational and deletional analysis. Using these techniques, we have identified 8 patients whose phenotype and genotype were consistent with the common deletion. In addition, we have identified 6 patients with novel phenotypes, 2 of whom have the common deletion, 1 of whom has the MELAS mutation, and 3 of whom have a disorder of in organello protein synthesis. Our multidisciplinary approach facilitates the generation of an extensive database that correlates clinical, biochemical, histopathologic and genetic features of patients with mitochondrial disease. P530 BRAIN SPECT IN CEREBROTENDINOUS XANTHOMATOSIS. R. Denays, F. Foureau, M. Manto*, M. Stegen, A. Verrips**, M. Guerchaft, J. Alexiou, M. Rubinstein. Hôpital New Paul Brien, *Hôpital Erasme, Bruxelles, Belgium; **University Hospital of Nijmegen, The Netherlands Cerebrotendinous xanthomatosis (CTX), a rare autosomal-recessive lipid storage disease, has been well characterised clinically and radiologically, using CT and MRI. However, functional imaging studies using SPECT or PET are lacking. A 42-year-old woman who had a history of progressive deterioration of walking for ten years and surgery for bilateral cataracts at the age of sixteen, was diagnosed as having CTX based on an elevated serum cholestanol level and molecular genetic analysis. She is compound heterozygote for 2 known mutations in the gene encoding sterol 27-hydroxylase: a C-insertion in exon 1 leading to a frameshift and a premature termination codon, with on the other allele a C→T transition in exon 6 resulting in an amino acid substitution. Neurological examination showed distal muscle atrophy, kyphoscoliosis, pes cavus and hammer toes, spastic paraparesis with mild cerebellar ataxia and mild intellectual impairment Tendon xanthomas were absent. Electrophysiological study was consistent with an axonal sensori-motor neuropathy. CT and MRI showed cerebral

Acquired monocular paresis (AMP) is a common neurological disorder due to a wide range of etiologies. However, the distribution of the various causes, and the clinical features of patients with idiopathic monocular paresis are yet undelineated. We analyzed the medical records of 101 consecutive patients, who presented with recent onset of non-traumatic AMP. Epidemiological data, medical history and clinical manifestations, blood tests, auxiliary studies and the outcome through the follow up for at least 6 months, were evaluated. Patients mean age was 56.6 years, male : female ratio was 1.4. A cause was identified in 55 patients: diabetes mellitus (DM) – 23, DM with hypertension (HTN) – 8, HTN – 7, lymphoproliferative disease – 4, myasthenia gravis – 4, pseudotumour cerebri – 4, Tolosa-Hunt syndrome – 3, meningioma – 1 and DM combined with thiamine deficiency – 1. The distribution of the weakness in the 46 undiagnosed (idiopathic) patients was: 23 oculomotor nerve, 21 abducens nerve, 1 trochlear nerve, 1 oculomotor with trochlear nerves and 1 oculomotor with abducens nerves. The undiagnosed and the DM patients had similar age distribution, male : female ratio and rate of recovery within 6 months. The recovery of the undiagnosed patients was not affected by oral prednisone treatment. The recommended laboratory test for evaluation of acquired non-traumatic monocular paresis are: plasma glucose level and GTT, αAChR Ab and tensilon test, thiamine level, CSF analysis and brain imaging. Idiopathic monocular paresis is usually a benign and a self limiting disorder which does not require steroid treatment. P532 PALATAL MYOCLONUS – A TWIN STUDY. Shanahan P, Doherty C, Toland J, Connolly S, Hardiman O. Dept of Neurology, Beaumont Hospital, Dublin. Dept of Neurology, St. Vincent’s Hospital, Dublin Palatal Myoclonus is a form of segmental myoclonus characterised by involuntary rhythmic movements of the palate and pharynx, which are present during sleep as well as waking. It has been attributed to disruption of the brainstem circuitry. Pathological studies of patients with secondary palatal myoclonus have demonstrated abnormalities of the dentato-rubroolivary pathways, with olivary pseudohypertrophy. It may occur following a variety of brainstem insults, or as an isolated condition where the mechanism is unknown. We present the case of a 35-year-old man with a 10year history of idiopathic palatal myoclonus in the absence of any other neurological findings. We have evaluated the patient and his asymptomatic monozygotic twin using clinical, neurophysiological, and radiological techniques. An MRI of the patient revealed enlargement of the olives. MRI scans of the patient and his brother were then performed using volumetric analysis of the inferior olivary nuclei. Palatal EMGs were then performed on both siblings to determine whether the unaffected sibling had any subclinical evidence of abnormal discharges. This is the first reported case of monozygotic twins that are discordant with respect to a segmental myoclonus. P533 NON HODGKIN’S LYMPHOMA WITH SPINAL EPIDURAL INVOLVEMENT AS INITIAL MANIFESTATION. Grabli D, Lecoeuvre N, Ameri A, Allard C, Chedru F. Neurology Department, Centre Hospitalier De Meaux, France Spinal cord compression by epidural involvement as a first symptom of malignant lymphoma is infrequent. Case report: A 49-year-old man was admitted with dorsal pain, impairment of the sphincter function, paresthesia and weakness of lower limbs. Examination disclosed hypoesthesia with a T10 sensitive level. MRI showed a spinal cord compression by an epidural tumoral process at three levels: T5, T7 and T8–T10. There was no associated vertebral involvement. No evidence of any systemic lymphomatous lesion was found by the staging evaluation. The patient underwent initial decompressive laminectomy. Histological analysis showed an

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aggressive peripheral T-cell lymphoma. Treatment was completed by radiotherapy, together with systemic and intrathecal chemotherapy. At five years follow up, functional outcome was good and there was no relapse. Discussion: A review of the literature shows that among malignant epidural spinal tumors, non Hodgkinís lymphoma are uncommon. Spinal cord compression is a rare presentation of this pathology. Most of the cases are aggressive lymphomas with intermediate or high grade of malignancy, occurring at an advanced stage of the illness. Treatment should always include surgery associated with radiotherapy, chemotherapy or radiochemotherapy. Prognosis depends on the extent of the disease rather than on the histological type. Conclusion: As demonstrated in our case, lymphomas revealed by isolated epidural involvment, has a favourable outcome if treated early and aggressivly. However, data concerning pathogenesis, prognosis and treatment of such a pathology are subject to debate. P534 THE UPPER ESOPHAGEAL SPHINCTER DYSTONIA RESPONDING TO NITRATES. Jamrozik Z, Czyzewski K, Kwieciñski H. Warsaw, Poland We described a 47-year-old man with ischemic stroke of unknown etiology who developed a brainstem syndrome with persistent dysphagia. Elective feeding via percutaneous endoscopic gastrostomy (PEG) was not accepted by the patient. Subsequently, he had to intermittently place the nasogastric tube by himself before each meal for more than 6 months. All treatment attempts with benzodiazepines, antidepressants and various spasmolytic agents were unsuccessful. Endoscopic investigation of the pharynx, larynx, and the esophagus did not show any structural abnormalities. MRI examination revealed small infarcts in the right occipital lobe and in the lower brainstem. Videofluoroscopic investigation revealed excessive, repetitive and long-lasting spasms of the upper esophageal sphincter which were triggered by the bolus, and were associated with the massive aspiration and nasal regurgitation of the contrast. Patient rapidly responded to the oral treatment with nitroglycerin and isosorbide dinitrate with complete recovery of the normal swallowing. Such beneficial effect of nitrates seems to be rather unusual in a case of the upper esophageal sphincter dystonia, contrary to the hypertensive lower esophageal sphincter or achalasia where nitrates were found to be sometimes effective. P535 SPINAL VASCULAR MALFORMATIONS. D. Kozic, V. Ivanovic, Z. Babic, M. Eric, I. Vukadinovic, R. Semnic, B. Petrovic, D. Bogdanovic, D. Djilas. Magnetic Resonance Center, Sremska Kamenica, Serbia

A 33-year-old non-immunocompromised woman was admitted to the hospital for pain in the inferior limbs. Examination revealed a febrile meningeal syndrome, a spastic tetraparesis with a right-sided Babinski sign, a D12 sensory level and bladder distension. The lumbar puncture yielded clear cerebrospinal fluid (CSF) with 154 white blood cells/mm3 (58% lymphocytes) and elevated protein content (1.28 g/l). Spinal cord MRI showed a T2 weighted hypersignal extending between C5 and T5. With the exception of cytomegalovirus (CMV) serology, viral work-up (including HIV serology) was negative, as were bacterial and immunologic investigations. A primary infection by CMV was evidenced by 1) the presence of CMV-specific IgM associated with a low avidity index (AI) of CMV-specific IgG on the first serum sample. 2) the decrease of IgM associated with a significant increase of AI during the following two months. CMV DNA was detected by PCR on 3 CSF samples obtained during the first month of the disease, but only in the first serum sample of the patient, therefore eliminating any contamination from blood. This data support a direct mecanism of infection of the spinal cord by the virus. A treatment with corticosteroïds was given. The patient improved and MRI performed after one month was normal. Six months later, only bladder dysfunction remained. This case indicates that a CMV acute myelitis can occur in immunocompetent patients. P537 A SHORT ESTIMATION OF THE NEUROPSYCHOLOGICAL STATUS: THE “LINGENER NEUROPSYCHOLOGIC INCLEX” (LNI). Mokrusch T, Wallat M. Hedon-Khnik, Lingen, Germany Usually, several tests are necessary to evaluate the neuropsychological status of patients with neurological disorders. The Lingener Neuropsychologie Index (LNI) was designed as an easy, fast and reliable tool for estimatiner the actual status at the time of admission and for the follow-up. Methods: The index is composed of ten items, each scoring from 0–4 points, and includes five rating scales and five tests. The maximum score is 40 points. Items and scores: Consciousness, Orientation, Drive/motivation, Emotion, Social interaction, Concentration, Memory, Visuo-construction, Visuo-motor capacity, Calculation. Results: The reliability was evaluated with parametric and non-parametric statistical tests in a three week interval (N = 30). The Spearman rank correlation was calculated by r = 0.933, Pearson 0.964. Significant changes of mean values were found from the first to the second investigation with z = –3.36 (Wilcoxon test) and p = 0.00029 (Student’s t-test). Discussion and Conclusion: According to the present data, the LNI provides discriminating and reliable results as an unspecific measure for global cognitive changes in patients with CNS lesions. In a prospective study it is now planned to evaluate the reliability of the LNI in estimating the course of the disease during therapy.

The purpose of the study was to evaluate clinical characteristics of the spinal vascular malformations which were divided into spinal dural arteriovenous fistulae, intramedullar arteriovenous malformation and spinal cord cavernous angioma. Medical records of 11 patients with radiographic diagnosis of spinal vascular malformations were retrospectively reviewed for clinical symptoms. Spastic weakness of the lower extremities was evidenced in 80% of patients with spinal dural arteriovenous fistulae. In all of them, MR examination revealed distended intradural veins that presented like tortuous “flow voids” identified at the cord margin, along the dorsal medullar surface in midthoracic and thoracolumbal region. Patients with diffuse hyperintense zone on T2W sequences within the spinal cord demonstrated severe paraparesis. This zone reflected nonspecific cord edema and swelling due to venous hypertension and passive congestion. Spinal MR angiography was not useful in more detailed visualisation of abnormal vessels. In one patient with successfully accomplished interventional radiology by selective embolization, obvious clinical improvement and disappearance of severe venous hypertension and spinal cord swelling by MRI were documented. All four young patients with cavernous angioma within the cervical spinal cord have been for several years misdiagnosed as multiple sclerosis due to their symptoms. In one older patient who has been mistreated for cervical spondylosis, MR examination was performed after sudden-onset paraplegia. Arteriovenous malformation with large hematoma was identified and fatal outcome appeared couple of days later. Our results suggest that MRI should be performed in all patients with progressive upper or lower extremity weakness since other diagnostic modalities demonstrate low sensitivity and very poor specificity.

This study was undertaken to evaluate the role of methyl prednisolone in the management of acute transverse myelitis. Method. methyl prednisolone 500 mg IV was administered to 9 consecutive patients with ATM who were treated by us during 1995–1997. Twelve consecutive patients managed during 1992–1994 served as controls. All the patients underwent neurological examination. spinal MRI, Somatosensory and motor evoked potentials of both upper and lower limbs and concentric needle EMG on admission. The clinical and neurophysiological studies were repeated 3 months later. The outcome was defined on the basis of Barthel index (BI) score at the end of 3 months into good (BI > 12) and poor (BI < 12). Results: The age of study group was 25.5 y (range 12–42) and 3 were females. The age of control group was 33.5 y (range 16–70) years and 2 were females. In the study group 33% had poor outcome compared to 67% in the control group. The patients with complete paraplegia, evidences of denervative on EMG and unrecordable CMCT-TA and tibial SEP were associated with poor outcome irrespective of treatment. Global test statistics did not suggest beneficial role of methyl prednisolone in the outcome of ATM. Conclusion: our results do not suggest beneficial role of methyl prednisolone on 3 month outcome of ATM as assessed by BI score.

P536 CYTOMEGALOVIRUS-ASSOCIATED MYELITIS IN AN IMMUNOCOMPETENT PATIENT. A. Ferreira, F. Rozenberg, S. Levy, A. Améri, C. Barbanel, F. Chédru. Neurology Department, Centre Hospitalier de Meaux, France

P539 NEURO BEHÇET: A REPORT OF 13 CASES. M. Fredj*, R. Gouider*, C. Kooli*, E. El Bahri-Ben Mrad*, A. Gargouri*, A. Haddad**, A. Mrabet*. *Neurological Department, EPS Charles Nicolle, Tunis, Tunisia; **Service de Médecine Interne B, EPS Charles Nicolle, Tunis, Tunisia

P538 IS METHYL PREDNISOLONE USEFUL IN ACUTE TRANSVERSE MYELITIS? J. Kalita, U. X. Misra, Dept. of Neurology, Sanjay Gandhi PGIMS, Lucknow, India

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The central nervous system (CNS) involvement in Behçet’s disease (BD) occurs in 4% to 29% of patients, usually appearing within 5 years of disease onset. There is a wide range of clinical manifestations according to the type and localisation of the lesion. We report clinical, neurophysiological and radiological study of 13 cases of neuro Behcet’s disease 5NBD) with a mean age of onset of 37.9 years (range 18–35). There was no male predominance (sex ratio 0.85). The upper motor neuron signs were found in 76% cases, followed by headache (66%), isolated or multiple cranial nerve involvement in 30%, pseudo bulbar paresis in 7.6% of cases, sphincter disturbances in 46%, deep sensory loss in 53.8% and superficial sensory disturbances in 15.2%. The neurological signs antedated the systemic signs (uveitis genital ulceration and skin lesions) in 33% of the patients. The cerebral CT Scan showed abnormalities in 46% and MRI in 75%, sensory visual and brainstem evoked potentials were impaired in 66%. The association of neurophysiological assessment to the clinical examination can be a reliable index to evaluate the response of NBD to treatment.

P540 NEUROMUSCULAR COMPLICATIONS OF ORTHOTOPIC LIVER TRANSPLANTATION. Stefano Jann1, Ignazio Santilli1, Antonella Gatti1, Roberto Sterzi1, Elio Scarpini 2, Domenico Forti 3, Carlo Alberto Defanti1. Department of Neurology1 and Surgery 3, Niguarda Hospital, Milan, Italy. Neurological Clinic 2, Policlinico Hospital, University of Milan, Italy Among the post operative complications of orthotopic liver transplantation (OLT), neurological symptoms are very common, being reported in 18– 33% of patients, and are associated with bad prognosis. Furthermore a high incidence of neuromuscular diseases, such as AIDP, can complicate the post operative course (7% of cases in previous studies). To assess the incidence and clinic characteristics of neurological complications following OLT, with particular attention to neuromuscular syndromes and their prognosis, we reviewed 280 consecutive cases of OLT at Niguarda Hospital in Milan, Italy. Patients with neuromuscular complications underwent clinical and neurophysiological examination. In some cases with progressive worsening of strength and diagnosis of peripheral neuropathy, sural nerve biopsy was performed. The incidence of neurological complications was 41% with significant association with mortality. Neuromuscular complications were 17% of all neurological complications and acute polyneuropathy represented the 50% of all neuromuscular complications. Part of these patients were spontaneously reversible. In others with a steadily progressive course, sural nerve biopsy showed severe axonal damage. Our study confirm that neurological complications are one of the most troublesome sequelae of OLT. Neuromuscular syndromes are frequent, often acute, and in some cases associated with bad prognosis.

P541 DYSAUTONOMIC HEADACHES: A NEW/OLD SYNDROME OF MIGRAINE, MITRAL VALVE PROLAPSE (MVP) AND PSYCHIATRIC DISTURBANCES. Peter Herman, MD. New York, USA Goals: Follow up of a group of patients with migraine, MVP and psychiatric disturbances and assessment of long term evolution. Design/Methods: 35 patients with headaches and MVP were followed clinically at appropriate intervals over an 11-year period. The incidence of this combination was about 7% in the migraineur population. Results: All patients had migraines with or without aura; 34 were female, 1 was male; age range was 26–27, median 39. MVP by ECHO was present in all patients with concomitant cardiac symptoms of tachycardia, heat pain, low blood pressure and fluctuating pulse. Measurable dysautonomic dysfunctions showed large pupils in more than 50% of patients, 61% displayed skin blotching. Psychiatric symptoms were present in 85% of patients and included anxiety, manic depressive personality, frank depression, panic attacks and borderline personality. Three patients had reversible neurologic deficits, EEG was abnormal in 5 of 29 patients and 3 showed small infarcts on CT scans. Doppler studies in 7 patients showed increased intracranial flow velocity in 3 patients. Propranolol was the best overall drug. Alternate therapies included calcium channel blockers, tricyclic agents, antidepressants and corticosteroids with various results. Headaches persisted in most patients. Conclusions: Dysautonomic headaches are a common disorder that present in teens and continue often unchanged into adult life. Because of common psychiatric symptoms, they are often misdiagnosed as a psychiatric disorder. Correct diagnosis results in effective B-blocker therapy and cessation of inappropriate polytherapy.

P542 BENIGN PAROXYSMAL POSITIONAL VERTIGO AS A COMPLICATION OF VENTRICULO-PERITONEAL SHUNT-OP FOR NORMAL PRESSURE HYDROCEPHALUS. S. Reinbott, B. Strebel. Rheinische Kliniken Düsseldorf, Kliniken der Heinrich-Heine-Universität, Dept. Psychiatry/ Neurology A 84-year-old lady presented with a half year history of gait disorder, progressive cognitive dysfunction and urinary incontinence. After confirming clinical diagnosis of a normal pressure hydrocephalus by cCT and lumbar puncture a ventriculo-peritoneal shunt-system was implanted. The operation was otherwise uneventful but shortly afterwards she developed slight positional related dysequilibrium. Neurological examination revealed a rotatory nystagmus with the fast component beating to the undermost ear on left as well as on right ear down position without habituation provoked by head rotation in supine position. CCT-control showed correct positioning of the shunt system. After serially application of positioning manoeuvres for one week Hallpike positional testing elicited a rotatory nystagmus to the undermost ear on the left side with short latency and habituation. After continuing serial positional manoeuvres vertigo diminished over two weeks. BPPV is the most common cause of vertigo in the elderly. 1994 Steddin and Brandt presented evidence that typical features of BPPV can be explained by canalolithiasis showing typical differences according to the semicircular canal which is affected. In this unusual case BPPV of the horizontal semicircular cabal changed into BPPV of the posterior semicircular canal. According to Baloh the most common causes were idiopathic, head trauma and viral labyrinthitis: BPPV as a complication of ventriculo-peritoneal shunt has not yet been reported. P543 MANAGEMENT OF WILSON DISEASE – KUWAITI EXPERIENCE. A. Khan, J. M. Hussein Fifteen patients with Wilson’s Disease (WD) between 11–25 years were studied at the Neurology Center Ibn Sina Hospital. Three of them had no CNS manifestations. D-Penecillarnine treatment was very effective in them. The clinical CNS manifestations in YX corresponded to neuroradiological and neurophysiological data. However, treatment of CNS Wilson’s disease with D-Pencillamine did not adequately improve the clinical state in five patients while one died. Zinc sulfate was added to the treatment. This resulted in the remarkable improvement in their clinical CNS manifestations. Cases of WD with poor response to D-Pencillamine reqdire an adjuvant (Zinc sulfate) agent in their therapeutic management. P544 SEVERE NEURONAL MIGRATION DISORDER AS OCCASIONAL DISCOVERY IN AN ADULT. R. Bella, G. Fava, M. Ferlito, G. Alagona, M. Vincenzino, G. Rapisarda. Institute of Neurological Sciences, University of Catania, Italy A male patient, 38 years old, came to our observation because of headache occurred after cranial trauma. Until that day he had normal life and worked as lorry-driver; he had not history of epileptic seizures. He had not neurological deficits. His EEG was normal. Neuropsychological investigations showed slight right hemisphere function disorders. TC scan demonstrated hemispheric asymmetry and right lateral ventricle larger than contralateral one with irregular internal profile, but didn’t allow a correct diagnosis. MRI evidenced, in addition to the abnormalities showed by TC scan, the presence of neuronal heterotopia and 2 abnormal sulci surrounded by pathological cortex extended almost until the right lateral ventricle; such disorders have been interpreted as hemimegalencephaly, polymicrogyria and neuronal heterotopia. Neuronal migration disorders are generally associated with neurological disorders as focal neurological deficits, severe mental retardation and almost invariably epileptic seizures. Conclusion: this case report demonstrates that a complex neuronal migration disorder can be an occasional discovery in an adult with normal life and no history of epilepsia. MRI is the most useful tool for a correct diagnosis. P545 LEUKOENCEPHALOPATHY WITH SWELLING AND DISCREPANTLY MILD CLINICAL COURSE IN A BOY WITH PSEUDODEFICIENCY OF ARYLSULFATASE A. P. Richard1, C. Clerc1, L. Rumbach2, M. Bataillard1. 1Department of Neurology, Montbéliard; 2 Besançon, France We report the case of a young boy who presented generalized tonicoclonic seizures from the age of 18 months. Initial psychomotor develop-

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ment was normal. When he was 8 years old, a moderate intellectual decline and a pyramidal syndrome of the lower legs were noted. At 16, he presented spastic paraparesia. MRI revealed diffuse leukoencephalopathy with temporal and frontal cysts. Von der Knaap et al. reported the same characteristics in 8 children, calling this state “Leukoencephalopathy with Swelling and Discrepantly Mild Clinical Course”. In these 8 children and in our patient there was a discordancy between the moderate clinical evolution and the abnormalities revealed by MRI. However, our case differs from the others in that both megalencephalia and ataxia were absent. Complementary exams revealed a dramatic decrease in leukocyte and fibroblast arylsulfatase A levels. Urinary sulfatides excretion was normal. DNA analysis revealed that the patient was homozygote for arylsulfatase A pseudodeficit. The relationship between this particular leukoencephalopathy and the pseudo deficit of arylsulfastase A will be discussed. P546 BILATERAL LOSS OF DEEP SENSITIVITY AND PSEUDOCHOREOATHETOSIS BY CENTRAL PONTINE MYELINOLYSIS. Jens Federlein, Thomas Postert, Horst Przuntek and Thomas Müller. Department of Neurology, Ruhr-University Bochum, Bochum, Germany We present a case of central pontine myelinolysis due to compensation of hyponatremia, resulting in acute onset of pseudochoreoathetosis and sensory disturbances. Complete loss of touching, vibration and position sense in all limbs appeared in this female patient, but pain and thermal sensation maintained. MRI showed no signs of extrapontine myelinolysis. We speculate, that myelinolysis caused an alteration of the medial lemniscus of the pons but spared the spinothalamic tract.

Higher Functions Disorders P547 GENDER DIFFERENCES IN COGNITIVE IMPAIRMENT: NEUROPHYSIOLOGIC FEATURES: Gandolfo C, Saggese J, Povedano G, Gabrielli H. Hospital Churruca Centro Gallego, Buenos Aires, Argentina Obsectives: Scientific evidence for consistent differences in cognitive functions between men and women has been accumulated for over 50 years. It has been suggested that male’s and female’s brains are to a significant extent wired differently since prenatal period. It has been reported that women have more diffuse lateralization and localization of cognitive functions, so males are cognitively more vulnerable to unilateral damage than females. Subjects and Methods: We studied a sample of 233 patients (146 women and 87 men; mean age 71.51 ± 10.22 years) with memory complaints, by means of Brain Mapping, Minimental State Examination (MMSE) and CT brain scan. Dominant frequencies and relative power for alpha, theta and delta bands in four leads. Oz, FzJ3, T4 according to 10– 20 IS were analysed in brain mapping. In all cases, 15 epochs of 2 seconds, artifact free, were averaged and processed. We considered significant a cognitive impairment when MMSE score was 25 or less. Then, the sample was divided in a group without (n = 128) and another with (n = 109) cognitive deterioration. Data were analyzed according to Mantel Haenzsel, Yates corrected, chi square value. Results: We detected significative increase of men’s delta band relative power in T3 exclusively in deteriorated group ( p < 0.004). This was not found in theta and alpha frequencies. In normal group, there were no differences in frequence behaviour. This couldn’t be explained by age or history data’s references. Conclusions: Our results suggest that pathological aging process may be different for men and women with regard to this neurophysiological approach. P548 A NEW SYNDROME OF HEMIPLEGIC MIGRAINE WITH PAROXYSMAL COMA AND PROGRESSIVE PERSISTENT PSYCHOSIS: A MITOCHONDRIAL ENCEPHALOMYOPATHY? C. Kornblum, R. R. Mundegar, D. Röhrig, F. Ries. Department of Neurology, University of Bonn (D). Germany Familial hemiplegic migraine may present with neurological symptoms including paresis, psychosis or seizures. Case History: We report on a 41year-old female patient with migraine attacks accompanied by brainstem dysfunction and sensorimotor hemisyndrome, progressing to a total of eight severe episodes with grand mal seizures, coma for up to three days, extrapyramidal syndrome, myoclonus and paranoid-schizophrenic psychosis. The course of the disease resulted over a period of two years in a loss of

verbal, mnestic and psychomotor functions. Technical examinations: ϑ/δdysrhythmia and spike-/sharp wave-complexes in serial EEG, blood flow velocity abnormalities in transcranial Doppler sonography following one migraine attack, high protein level in cerebrospinal fluid without pleocytosis, normal CT-scan and MRI of the brain including diffusion- and perfusion-MRI and a depressed perfusion in HMPAO-SPECT in the left hemisphere and basal ganglia. PET (18-Fluordeoxyglucose) showed an increased glucose metabolism in the left hemisphere parieto-occipital and in the right cerebellar cortex. Blood tests showed an intermittently decreased potassium level and signs of a precocious menopause. Muscle biopsy showed discrete unspecific alterations without ragged red fibres and biochemical analysis of the respiratory enzymes showed an equivocal succinate dehydrogenase level, indicating a possible mitochondrial encephalopathy. A molecular genetic analysis for familial hemiplegic migraine was not feasible, since no material from other family members was available. One brother apparently suffered from a schizophrenic psychosis. Drug therapy including β-blockers, calcium antagonists, valproic acid and carbamazepine as well as neuroleptics were without persistent effect. Conclusion: This case represents a rare coincidence of a migraine with aura, epileptic seizures, extrapyramidal syndrome, psychosis and dementia, most probably to be considered as a non-familial hemiplegic migraine. A potentially underlying mitochondrial disease with encephalopathy should be considered. P549 FIRST THERAPEUTIC EXPERIENCE WITH FLUPIRTINE IN PATIENTS WITH CREUTZFELDT-JAKOB DISEASE. Markus Otto1*, Immo Boekhoff1, Peter Ratzka1, Jens Wiltfang2, Christian Riedemann1, Stefan Kropp1, Inga Zerr1, Eva Irle2, Gabriela Pergande3, Sigrid Poser1, Hilmar Prange1. 1Department of Neurology, 2 Department of Psychiatry, Göttingen, Germany, 3ASTA Medica AG, Frankfurt, Germany Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. No therapy is currently known to stop it. In vitro experiments have shown that flupirtine, a clinically well-established analgesic agent, is able to protect rat neuronal cells from apoptosis induced by toxic prion protein fragment. We assessed this drug in patients with CJD. Nine patients diagnosed as possible CJD patients according to standard criteria were treated. All patients were still able to communicate when treatment with flupirtine was started. A battery of mental status tests and a performance rating were used to assess the further course of dementia under flupirtine therapy in regular intervals. Death occurred in three patients at a median of 44 days after treatment start. Six patients are alive with a median follow up of 194.5 days. One of these patients initially recovered remarkably well, is able to talk and walk and shows only gradually declining mental performance 1.5 years after treatment start. The small patient number, the different degree of deterioration at the time of treatment start and the natural variation of disease progression make definite conclusions difficult. We suggest that a a double blind, placebo controlled trial be conducted, in order to clarify the effect of flupirtine. P550 APOLIPOPROTEIN E GENOTYPES AND SERUM LIPOPROTEIN PROFILE IN PATIENTS WITH DEMENTIA. K. Czyzewski, M. Lalowski, A. Pfeffer, H. Kwieciñski, M. Barcikowska, Warsaw, Poland The ε4 allele of apolipoprotein (APOE) has been identified as a major risk factor for late- onset Alzheimer’s disease (AD). An association between ε4 allele and premature ischemic heart with dyslipidemia has been also shown. ApoE4 exhibits high affinity binding to very- low density lipoprotein receptors which results in elevated total and low density lipoprotein cholesterol levels. There is however, a paucity regarding the lipid metabolism in AD patients. The aim of this study focused on correlation between serum lipoprotein profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol(HDL-C) and APOE genotype polymorphism in patients with dementia. APOE genotypes were determined according to the protocol by Chapman et al., (Neurology 1996, 46 : 1484). We included 55 mild to moderate AD and 19 MIX patients according to DSM-III-R and NINCDS-ADRDA criteria, 37 nondemented first degree relatives of AD (NDR) and 20 nondemented control cases (NC). Our data indicate that there are no statistical differences in lipid parameters among demented and control subjects within the same APOE genotype subgroup. Secondly, no statistical differences in serum lipid parameters between selected APOE genotypes (ε3/3, ε3/4, ε4/4) in AD, MIX, NDR and NC were found, however in our NC and NDR group lower HDL-C and TG levels in cases with ε2/4 versus ε3/3 and ε3/4 genotype were observed. These results do not support the

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hypothesis relating certain ApoE genotypes with abnormal serum lipid levels in demented patients. P551 COGNITIVE DEFICITS IN MULTIPLE SCLEROSIS: PREVALENCE, PATTERN AND CORRELATION WITH MAGNETIC RESONANCE IMAGING. C. Simon1, M. S. Damian2, G. Schilling3, G. Bachmann4, W. Dorndorf1. 1Department of Neurology, Gießen. 2 Department of Neurology, Dresden. 3 Department of Psychosomatic, Bonn. 4 Department of Radiology, Gießen, Germany 45 patients with Multiple Sclerosis (MS) and mild functional impairment were examined with a battery of psychometric tests. Prevalence and pattern of cognitive deficits were identified and dependence on findings in magnetic resonance imaging (MRI) was studied. Cognitive impairment was found in 15.5% of our patients. Cognitive deterioration did not result in a global impairment but in a typical pattern of cognitive dysfunction including psychomotor speed, visual perception and attention, concentration, sustained attention and accuracy while other abilities like language skills remained unimpaired. This pattern of cognitive deficits is compatible with subcortical dementia. MRI was analysed concerning size of white matter lesions (WML) as well as lesion pattern. The extend of WML alone did not correlate with cognitive deficits. But significant cognitive decline was observed in patients with WML immediately underlying cortex. Subcortical plaques may cause cognitive deficits by affecting intrahemispheric associative fibres resulting in a disturbance of information processing and transfer from primary to associative cortical areas. Frontal subcortical WML may also cause a deactivation of frontal lobes which is discussed to be a pathogenetic factor of subcortical dementia. P552 EPIDEMIOLOGY OF DEMENTIA IN DOWN’S SYNDROME (DS) AND EEG CORRELATIONS. E. Strijks1, H. Schoonderwaldt1; A. F. J. de Haan2. Department of Neurology1 and Medical Statistics2, University Hospital Nijmegen, The Netherlands Age related cognitive decline is seen earlier and more often in DS then in general population. Histopathologic changes as seen in Alzheimer’s dementia are consistently seen in aged DS. We studied epidemiology of dementia in DS in a cross-sectional design. The study included DS living in an institute for mentally retarded who were 40 years or older and DS that had died there aged 40 or older (n = 99). Assessment was done by retrospective and actual observations and with a dementia-checklist for mentally retarded. For DS with serial EEG’s (n = 44; 5-years intervals), α reduction (> 0.5 Hz) was assessed blindly. Results: In DS ≥ 40 years, 35% was demented (≥ 50 years: 81%, ≥ 60 years 100%). Median age at onset: 52 years (95% CI[50; 56]). Median duration of symptoms in the deceased (n = 13): 84 months (range: 3–120). Dementia in women was increased when compared with men: Hazard Ratio = 2.52 (95% CI[1.01; 6.32], p = 0.042). Epilepsy of late onset (generalized and partial seizures, myoclonus) occurred in 54 % in demented and in 5 % in non-demented (p < 0.001) and increased with the aging of the demented. However, there was no significant relation between epileptic activity on EEG and clinical seizures. Reduction in α frequency occurred more in demented (p = 0.005; sensitivity 79%, specificity 69%); photic driving occurred less in demented DS ( p = 0.041). Conclusion: Dementia is more prevalent and has a different epidemiology in DS then in general population. Female DS are more affected. Serial EEG’s may be helpful in diagnosis. P553 ECONOMIC ANALYSIS OF ALZHEIMER’S DISEASE IN OUTPATIENTS IN GREECE. CORRELATION WITH THE SEVERITY OF THE DISEASE. M. Tsolaki, V. Iakovidou, Ch. Anastasopoulou, M. Aminta, A. Kazis. 3rd Department of Neurology, Aristotle University of Thessaloniki, Greece The financial consequences of the Alzheimer’s Disease (AD), have not been studied in Greece until now. Sixty two probably AD outpatients according the NINCDS-ADRDA criteria were studied, aged from 60 years and over with mean disease duration 4.3 ± 1.9 years and MMSE 13.08 ± 7.5. A questionnaire consisted of 17 questions was used, referred to financial data, related exclusively with the disease, that relatives mentioned. The SPSS statistical program was used for the analysis. The mean cost which the family mentioned was 33.641 ± 88.186 drh. The cost of the other care (medication, medical care, neuropsychological assessment and rehabilitation program) was 135.000 drh per month The total cost was

168.000 drh per month approximately, that is $ 560 versus $ 4 000 in other countries. A positive and significant correlation between disease severity and cost was also found. Three amounts were correlated significantly with MMSE or FRSSD: cost for medication ( p = 0.007), cost for transportation ( p = 0.008) and cost for incontinence problems (p = 0.001). Conclusively the cost in Greece for AD patient is lower than in other countries and the severity of the disease increases the cost. P554 NEUROPSYCHOLOGICAL FEATURES AFTER BACTERIAL MENINGOENCEPHALITIS. Merkelbach S, Sittinger HA1, Schweitzer I, Müller M. Departments of Neurology and 1Psychiatry, Homburg-Saar, Germany The clinical courses of patients suffering from bacterial meningitis vary from death to severe or mild sequelae and complete recovery. The purpose of this study was to investigate common neuropsychological features in unselected, nonbiased patients in the long-term period after bacterial meningitis. Patients and methods: 19 patients (13 men, 6 women, mean age 53 ± 18 years) were neuropsychologically reexamined 33 ± 12 months after the acute stage of the bacterial meningoencephalitis applying the Multiple-choice-vocabulary-test (MWT-B), Number-Connection-test (ZVT), Benton-test (BT), Wechsler-Memory-scale (WMS), d2-test (d2), and the short form of Wechsler-Intelligence-test (WIP). Results: As compared to normatives, pathological findings were observed with decreasing frequency in the ZVT, number of impaired patients, n = 11), BT (n = 9), visual subtests of the WMS (e.g. WMS-6; n = 4), d2 (n = 3), and visual subtests of the WIP (e.g. WIP-4; n = 3). Minor deficits were observed in verbal subtests of the WIP and the WMS. No abnormalities were found in the MWT-B. Conclusion: MWT-B values indicated unimpaired premorbide intelligence. The principal neuropsychological findings at the follow-up examination were decreased psychomotor speed and attention, impaired nonverbal memory, reduced visual reproductive abilities and visuoconstructive capacity. Verbal memory and functions including semantic abstraction or associative learning were involved to a minor degree only. The neuropsychological features indicate a subcortical type of cognitive decline after bacterial meningitis.

Neuro-Oncology P555 TRANSCRIPTIONAL ACTIVATION IS NOT NECESSARY FOR E2F1-MEDIATED SUPPRESSION OF GLIOMA GROWTH. C. GomezManzano, J. Fueyo, W. K. A. Yung, S. Majumder, V. A. Levin and A. P. Kyritsis. The University of Texas M. D. Anderson Cancer Center, Houston, TX The transfer of the tumor suppressor E2F-1 correlates with suppression of glioma growth in vitro and in vivo. As E2F-1 is a strong inducer of transcription, it has been proposed that E2F-1 may activate apoptosis-mediator genes. In this study we evaluated whether or not the transcription ability of E2F-1 is necessary for the induction of apoptosis. E2F-1 cDNA was transferred using adenoviral vectors. Cell cycle analyses and apoptosis were performed by flow-cytometry techniques including DNA content and TdT. The transcription function in glioma cells was blocked by using αamanitin. The target genes of E2F-1 were studied by western blot analyses. After E2F-1 transfer to U-373 MG glioma cells, there was activation of the caspases cascade (CPP32 and PARP), and induction of apoptosis within 96 h. The cell death was preceded by a massive entry of cells into S phase. Pretreatment of glioma cells with α-amantin did not prevent E2F1 exposed cells to undergo apoptosis. These results indicate that E2F-1 either represses genes necessary for cell survival or is a component of the enzymatic machinery for apoptotic cleavage. Activation of E2F-1 may be a powerful tool for glioma treatment. P556 HEADACHE IN PATIENTS WITH CANCER. M. H. Christiaans, F. A. Timmer, C. C. Tijssen. Department of neurology, St. Elisabeth Hospital, Tilburg, The Netherlands There is only one prospective study looking at headache as the presenting symptom in patients with cancer: 30% had intracranial metastases. No characteristic brain tumor headache was found. Aims of the study: What is the incidence of intracranial metastases in patients presenting with headache and known with cancer? Are there characteristic headache symp-

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toms? What is the value of neurological evaluation and MRI. Methods: 22 patients with new or changed headache and a history of cancer underwent a structured interview and neurological examination. After the interview and after the examination we predicted the probability of cerebral metastases. Subsequently an MRI was performed. Results: 7 out of 22 patients had cerebral metastases. In 11 patients with the clinical prediction ‘metastasis absent’ 2 patients had cerebral metastases. In 6 patients with the prediction ‘metastasis present’ 1 had no metastase. In 5 patients with uncertain outcome none had a metastasis. Vomiting was a associated symptom in 6 of the 7 patients with metastases and only in 2 of the 15 patients without metastases. The cumulated score of nausea, vomiting, awakening from headache, worsening after exercise and Valsalva-maneuver with a cut off score 3 or more predicted 5 out of 7 metastases. In the group of patients without metastases 13 out of 15 had a score less than 3. Conclusions: 32% of the group of patients had cerebral metastases. Vomiting is a predictive symptom in our patients as is a cumulated score of 3 or more. However, both are still not sufficiently reliable to select patients for MRI. A larger population will be studied to confirm these data.

P557 BURKITT’S LYMPHOMA PRESENTING AS OPHTHALMOPARESIS IN A PREVIOUSLY HEALTHY ADULT. A. Ashkenazi, G. Amir, O. Abramsky, Ph.D1 and D. Ben-Yehuda. Departments of Neurology1, Pathology2 and Hematology3, Hadassah University Hospital, Jerusalem, Israel Objective: To describe an elderly patient with Burkitt’s lymphoma presenting with ophthalmoparesis. Background: Burkitt’s lymphoma is a lymphoproliferative tumor usually affecting children or young adults. Presentation of the disease in late adulthood was described in immunosuppressed patients, e.g. after organ transplantation, but not in previously healthy individuals. Nervous system involvement in the disease is well documented but rare as a presenting symptom. Case presentation: A 71-year-old previously healthy woman presented with ptosis of the right eye and diplopia of three days duration. On examination she had ptosis and weakness of the lateral rectus muscle on the right, as well as hyporeflexia and ataxic gait. There was a high protein level in the cerebrospinal fluid but cytology was negative. MRI showed a diffuse dural enhancement and a lesion in the right cavernous sinus. Examination of the oral cavity, which was performed due to severe pain in the jaw, revealed a right maxillary mass, which was biopsied. Histologic diagnosis was Burkitt’s lymphoma. Further investigation revealed involvement of the disease in the kidneys, abdominal lymph nodes, blood and bone marrow. She was treated with steroids and allopurinol but deteriorated rapidly and died 13 days after admission. Conclusions: Burkitt’s lymphoma should be considered in adult patients presenting with ophthalmoparesis, even without immunosuppression.

P558 FOTEMUSTINE (F) / CISPLATINE (CDDP) / ETOPOSIDE (VP16) COMBINATION WITH OR WITHOUT BRAIN IRRADIATION IN THE TREATMENT OF NON SMALL CELL LUNG CANCER (NSCLC) BRAIN METASTASES. F. Peyrade*, C. Lebrun**, M. Lonjon***, P. Paquis***, J. Lagrange*, P. Marcy*, M. Chatel**, P. Grellier***, M. Frenay*. Centre Antoine Lacassagne*, Services De Neurologie**, De Neurochirurgie**, Nice, France Although efficiency of chemotherapy (CT) on brain metastases has been proven in several studies, neo-adjuvant brain irradiation is still considered as the standard treatment. Patients/Methods: This retrospective study aimed to assess feasibility and efficiency of F (100mg/m2, day1)/CDDP (100 mg/ m2d1)/VP16 (100 mg/m2d1–3) q21–28d regimen on brain metastases of NSCLC either alone or immediately following brain irradiation (BRT). Since both treatments (BRT and CT) are efficient, we aim to define if their combination is synergistic. This study included 27 patients with symptomatic brain metastases of NSCLC. 17 of them had initial brain irradiation. None of them had chemotherapy before. Objective response was evaluated with CT scan after chemotherapy. Results: Objective response rates were 9/17 (CR = 3, PR = 6) in pre-irradiated group and 6/10 (CR = 2, PR = 4) in the non-irradiated group. Mean duration of the response seems to be longer in the former group (27 versus 15.5 weeks). Median survival was 30.5 weeks in the whole group, 22 weeks in non-pre-irradiated and 37 in pre-irradiated patients. Toxicity was moderate and mainly hematological (grade III–IV thrombopenia: 29/101 cycles; leucopenia: 30/101 cycles). Conclusion: These results confirm the efficiency of chemotherapy on NSCLC brain metastases mostly if associated with brain irradiation.

P559 METASTATIC MERKEL CELL CARCINOMA IN CEREBROSPINAL FLUID. Lehrieder G, Molitor H. Juliusspital Würzburg, Department of Neurology; Juliuspromenade 19, 97070 Würzburg, Germany Merkel cell carcinoma is a very rare, highly aggressive cutaneous tumor of neuroendocrine origin. We report a case of metastatic Merkel cell carcinoma in a 68-year-old man, who was referred for evaluation of unspecific vertigo and gait disorder. Seven months before admission he had resection and lymphadenektomy of tumor mass in the left axilla, where several lymph nodes histopathologically revealed metastatic disease of Merkel cell carcinoma. Clinical examination showed no signs of cerebellar or spinal ataxia, no brainstem disorder or any kind of peripheral neuropathy. All neurophysiological tests were done without abnormal findings. Computed tomography (CT) revealed a diffuse contrast-enhancement in the meninges, control CT showed rapid progressive disease with few diffuse hypodense lesions. Magnet Resonance Imaging showed similarly marked Gadolinium-enhancement in the meninges and a focal, nodular mass in the right Sylvian fissure. In cerebrospinal fluid (CSF) there were found 1600/3 cells, which cytologically and immunohistochemically proved to be cells of Merkel cell carcinoma. There was never found a primary cutaneous tumor or a further locoregional metastastic disease. In spite of immediate intrathecal chemotherapy with methotrexate and cytosine-arabinoside the patient died five weeks later due to progressive disease. We present, to our knowledge for the first time, MRI-findings of metastatic Merkel cell Carcinoma involving the central nervous system. Diagnosis however is confirmed by cytological and immunohistochemical evaluation of CSF. P560 SERUM sICAM-1 AND sVCAM LEVELS IN MALIGNANT GLIOMA PATIENTS. A. Salmaggi, M. Eoli, E. Ciusani, S. Frigerio, A. Silvani, A. Boiardi. Neurological Institute “C. Besta”, Milan, Italy Evidence indicates that adhesion molecules play a role in tumor progression and may promote tumor growth and dissemination. The recently discovered expression of those molecules on glioma cells, tumor infiltranting lymphocytes and endothelial cells within the tumor underline their relevance also in the CNS malignancies. To evaluate whether serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecules (sVCAM) were elevated also in gliomas as in other human malignancies, we measured by enzyme linked immunoassorbent assay sICAM -1 and sVCAM levels in 19 glioblastomas, 5 anaplastic astrocytomas and 19 healthy controls. No statistically significant differences were detected: sICAM 298.7 ± 66 in patients and 271 ± 80 in controls, sVCAM 671 ± 120 in patients and 656 ± 185 in controls; suggesting that the alteration in the adhesion molecules is probably confined in the central nervous system and does not reflect in circulating blood. P561 INTRAMEDULLARY GLIOBLASTOMA MULTIFORME WITH SPINAL AND INTRACRANIAL SEEDING. S. Cursiefen1, C. Sommer1, R. Behr 2, M. Warmuth-Metz 3, R. Klein 4, K. V. Toyka1. Department of 1Neurology, 2 Neurosurgery, 3 Neuroradiology and 4 Neuropathology, University of Würzburg, Germany Intramedullary glioblastomas are uncommon (about 1.5% of spinal cord tumours). While seeding of intracranial glioblastomas to the spinal subarachnoidal space occurs in about 25% of cases, seeding of an intramedullary glioblastoma to the brain is very rare. We report on a 16-yearold boy with paralysis of his left hand and mild paresis of both upper limbs with areflexia. The reflexes were brisk in both legs and Babinski sign was positive on the left. Touch, temperature and pain sensation was impaired on the left arm and from Th1 downwards. Spinal MRI revealed an intramedullary tumour at C5-Th1, cranial MRI was unremarkable. The tumour was only partially removed, the histological diagnosis was glioblastoma multiforme (WHO IV). Local radiotherapy was administered (46 Gy) followed by intrathecal and systemic chemotherapy. There was no recurrence of the primary tumour in MRI. Five months later the patient developed symptoms of increased intracranial pressure. Cranial MRI revealed large bilateral tumours with oedema and spinal MRI disclosed extensive leptomeningeal and intramedullary dissemination. The patient died 2 month later. Although pathology of the intracranial tumours was not confirmed, dissemination from the spinal tumour was strongly suggested because of the simultaneous intraspinal and intramedullary seeding. This case illustrates the rare occurrence of intracranial seeding of a primary intramedullary glioblastoma during chemotherapy.

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P562 INTRACEREBRAL LARGE-CELL LYMPHOMA IN A PATIENT WITH WALDENSTRÖM’S MACROGLOBULINEMIA. T. Rotermund, H. Menger, J. Jörg. Department of neurology and clinical neurophysiology, University of Witten/Herdecke, Klinikum Wuppertal, Germany

P565 THE MAGNETIC STIMULATION OF THE LONG THORACIC NERVE IS SUPERIOR TO THE ELECTRICAL STIMULATION IN DETECTING PROXIMAL NERVE LESIONS. Pelliccioni G, Scarpino O. Unit di Neurologia, INRCA, Ancona, Italy

We report a patient with the diagnosis of a Waldenström’s macroglobulinemia in which a high-grade intracerebral centroblastic Non-Hodgkinlymphoma of the B-cell-type was found. The occurance of different kind of lymphoma in different sites is known as a discordant lymphoma. The combination we found occurred in very rare cases only, and authors then classified it as a variant of the wellknown Richter-syndrom. In those cases the large-cell lymphoma was never found intracerebral, so that this case seems to be the first description of this kind of discordant lymphoma. The 70-year-old patient was admitted with her first epileptic seizure and a 6 month history of an increasing tiredness and weakness. We treated her like a primary intracerebral lymphoma, and after a 60 Gy cerebral radiation a clear regression of the tumor was found and the patient was without any symptoms.

Different methods are described to measuring motor nerve conduction in the long thoracic nerve by electrical stimulation. At present the procedure of magnetic stimulation of the same nerve is not standardized. To this purpose we compared the magnetic stimulation of the long thoracic nerve with the electrical stimulation in a group of 10 healthy subjects and in a patient with a long thoracic neuropathy causing scapular winging. The nerve was electrically stimulated at the supraclavicular fossa, just above the midpoint of the clavicle. The magnetic stimulation was obtained by placing the centre of the coil 2 cm lateral to the spine at the C5 level. The motor responses were recorded by surface electrodes. The active electrode was placed on the serratus anterior muscle along the midaxillary line on the 5th rib, the reference electrode was located 2 cm anteriorly. The mean latency of electrical and magnetic stimulation in the normal group was 4.6 ± 0.5 msec and 6.5 ± 0.6 msec respectively. The subject with long thoracic neuropathy showed normal latency values in both sides by using electrical stimulation. A lack of motor response following magnetic stimulation resulted in the affected side. The magnetic stimulation of the long thoracic nerve at C5 level, allows to evaluate the nerve conduction along its whole lenght and to detect proximal plexual lesions.

Peripheral Neuropathy P563 PROXIMAL DIABETIC NEUROPATHY – CLINICAL SIGNS AND NEUROPHYSIOLOGICAL PARAMETERS. A. Barada, M. Reljanovic, Z. Milièevic, N. Car, S. Ljubic, V. Profozic, Z. Metelko. Vuk Vrhovac Institute, Zagreb, Yugoslavia The aim of the study was to define the characteristic neurophysiological parameters and clinical signs of proximal diabetic neuropathy (PDN). Twelve patients with PDN (Group 1) and 30 patients with diabetic polyneuropathy (DPN), but without signs and symptoms of proximal diabetic neuropathy (Group 2) were examined. The groups were comparable with regard to age, gender and diabetes duration. In Group 1 all patients had type 2 diabetes, mean PDN symptoms duration 4.3 ± 1.8 months, whereas duration of distal polyneuropathy symptoms in the same patients was 3.2 ± 2.3 yrs. Bilaterally affected upper legs were recorded in 9 patients and unilateral in 3. Clinical picture in all Group 1 patients was characterised by pronounced pain in the upper legs (mean visual analogue scale value = 7.4 cm), atrophy of upper leg muscles, loss of predominantly pelvifemoral muscle strength and significant weight loss. Among neurophysiological parameters significant difference between Group 1 and Group 2 was found in motor conduction velocity of femoral nerve (37.3 m/s vs. 61.4 m/s, respectively, p < 0.0001), while no significant difference was found for peroneal and sural nerves. PDN is present in type 2 diabetics older then 50 years of age and is characterised by pain, muscle atrophy in the upper legs, weight loss and reduced motor conduction velocity of femoral nerve. P564 IgM ANTIBODY REACTIVITY WITH A HUMAN NEUROBLASTOMA CELL LINE IN PATIENTS WITH PERIPHERAL NEUROLOGICAL DISORDERS. Cavanna B, Carpo M, Scarpini E, Pedotti R, Scarlato G, Nobile-Orazio E. Milan, Italy Autoantibodies directed against different neural antigens have been detected in the sera of patients affected by dysimmune neuropathies, and less frequently, motor neuron diseases. Since neural antigens recognized by patients’ antibodies may be also expressed on the surface of human neuroblastoma cells, these cells have been frequently used as target in studies of autoimmune diseases of the nervous system. To determine whether we could use this model to test the mechanism of action in vitro of different anti-neural antibodies found in our patients, or to detect new antibody reactivities, we tested by indirect immunofluorescence the sera of 107 patients affected by different peripheral neurological disorders (53) and motor neuron diseases (54) and with different antibody reactivities, using the human SK-N-SH neuroblastoma cell line as a model of differentiated neurons. As controls we used other neurological diseases (8) and normal controls (18). We found antibody reactivities in four patients with GuillainBarré syndrome and in one with motor neuropathy associated with IgM M-protein. All positive sera contained high titers of anti-GM2 IgM antibodies, while none of the negative patients by IIF had anti-GM2 antibodies. In conclusion, even if we did not find a clear correlation between the pattern of immunostaining of positive patients’ IgM and specific clinical features, the strong association of this reactivity with the presence of antiGM2 antibodies seems to indicate that SK-N-SH can be a suitable model to investigate the in vitro functional effects of anti-GM2 antibodies.

P566 A SURVEY OF THE GUILLAIN-BARRÉ SYNDROME IN THE SOUTH-WEST OF THE NETHERLANDS. Van Koningsveld R1, van Doorn PA1, Schmitz PIM 2, van der Meché FGA1. 1Department of Neurology, University Hospital Rotterdam, Rotterdam, The Netherlands. 2 Department of Trials and Statistics, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands Purpose Inventory of clinical, epidemiological and treatment characteristics of patients with the Guillain-Barré Syndrome (GBS) in the Netherlands. Patients and methods: Records were reviewed of all patients discharged according to the International Classification of Diseases code for GBS from 1987 to 1996 in the south-west region of the Netherlands (4.2 million inhabitants). All patients were discussed within our group in order to confirm the diagnosis GBS using the criteria according to Asbury. Results: Until now 60% of the study population has been reviewed and 256 cases were identified. The crude annual incidence rate was1.02 per 100.000/ year (95% CI 0.90–1.16). Based on regression analysis of incidence rates on age and sex, a significant increase with age was found. The overall incidence rate for males was 1.23 (95% CI 1.04–1.44) and for females 0.83 (95% CI 0.68–1.00) while the rates for man were higher at older age. Incidence rates appear to increase slightly during the period 1988–1996. Conclusions: The incidence rate, male/female rate ratio and the increase in incidence with age are within the range and results of other studies suggesting this survey being representative and therefore suitable as a source to study further clinical and epidemiological research questions. It appears that the incidence slightly increased during the past 10 years. P567 MULTIFOCAL MOTOR NEUROPATHY WITH CONDUCTION BLOCK: ARE THE FORMS STARTING WITH THE LOWER LIMBS DIFFERENT? C. Dupel-Pottier, N. Le Forestier, B. Chassande, J.-M. Léger, P. Bouche Multifocal motor neuropathy with conduction block (MMNCB) usually starts in the upper limbs asymmetrically. We report the clinical, biological, and electrophysiological features of 7 cases with MMNCB in whom onset occured in the lower limbs. There was no difference from the usual picture with a male predominance (5/2), an average age of 48 years and, at the time of the study, a mean duration of the symptoms of 7 years. Fasciculations and cramps were frequent (5/7) and a lower limb muscle atrophy was present in 6 patients. Tendon reflexes were decreased or absent in 6 patients. Weakness in distal muscles was severe (score 0 at MRC scale) in 4 patients. The neuropathy involved later the upper limbs in 5 cases. Biological study showed an increase of total protein count in CSF (3/5) and anti-GM1 antibodies (= 1/1600) (5/6). At the time of the study, only one patient had two conduction blocks (CB) in both peroneal nerves, and the 6 others had severe denervation in peroneal nerves, of whom 5 had CB in the upper limbs. An initial good response to IVIg treatment occured in 4 of 6 patients. Four patients additionally needed immunosuppressors. In conclusion, patients with MMNCB starting with the lower limbs do not seem

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to have a specific profile, although some cases may have a more severe evolution. P568 IDIOPATHIC POLYNEUROPATHY IN ELDERLY: A PROSPECTIVE STUDY. D. Baudoin, H. Franck, E. Laborde, F. Viallet, C. Creisson. Aix en Provence, France The clinical features of polyneuropathy were prospectively studied in 103 elderly (over 75) patients (25 men, 78 women) in a geriatric center during one year. Three examiners included the same neurologist assessed each patient for sensory complaints, muscle strength and gait capacity, tendon reflexes, tactile and vibration senses, in limbs and for signs of dysautonomia. Two abnormalities were necessary to reach the criteria of polyneuropathy. Patients with known aetiology of neuropathy were excluded. All the patients (mean age 86 ± 4) gave their informed consent for the study. The population without neuropathy was used as control group. In this prospective study, 24 patients reached the polyneuropathy criteria and were identified as neuropathic group. Four reasons plead for the existence of an idiopathic polyneuropathy growing in elderly: The neuropathic group is significantly older than the control group. The frequency of the idiopathic neuropathy is progressively increasing with the age. The sex ratio was the same in the control and neuropathic group. The clinical pattern was a progressively ascending sensory loss evoking an axonal polyneuropathy according to the histologic study on the ageing nerve (Vital et al., Clin. Neuropathol 1990; 9 : 10–15). As additional remark, this rather painful neuropathy (63% painful against 37% in the control group) did not retain the patient from walking. But associated with visual loss and vertigo, this sensory neuropathy could lead to falls, a frequent reason of severe morbidity in elders.

Clinical Neurophysiology P569 ADVANTAGES OF A NEW 1-MHZ-PROBE FOR TRANSCRANIAL DOPPLER SONOGRAPHY IN INTRACRANIAL STENOSES OR OCCLUSIONS. Christof Klotzsch, Maria Mosso, Rebecca Bertelmann, Johannes Noth. Department of Neurology, RWTH Aachen, Germany The diagnostic value of a new 1-MHz probe for TCD was compared with a standard 2-MHz probe in patients with intracranial vessel disease. Patients/Methods: During a period of 3 months 110 consecutive patients (46 women, 64 men; mean age 59 ± 16 (± SD) were investigated with a standard 2-MHz probe and subsequently with a new 1-MHz probe. The first group consisted of 68 intracranial stenoses (20 low-grade, 22 moderate, 26 severe) and 12 patients with vasospasm (8 subarachnoidal hemorrhage, 4 meningitis). The second group consisted of 30 patients with extracranial occlusion of the internal carotid artery (ICA) and corresponding intracranial low-flow signals in the ipsilateral middle cerebral artery (MCA). Results: In group 1. the 1-MHz probe showed a better visualization of high frequency signals in all 26 (100%) severe stenoses, where flow velocity exceeds 350 cm/s. Especially in greater depth (> 60 mm) Doppler spectra of the 1-MHz probe showed no aliasing up to flow velocities of 600 cm/s. While the Doppler signals of the 1-MHz probe sounds duller in all cases, no differences of the Doppler spectra were observed. In all 30 (100%) patients of group 2. the 1-MHz probe was able to demonstrate low flow signals in the MCA distal to a ICA occlusion. Conclusions: The 1-MHz probe provides the opportunity to perform a better visualization of deep severe stenoses with high velocities exceeding 350 cm/s. No disadvantages of the 1-MHz probe compared to the 2-MHz probe were observed in patients with intracranial stenoses or low flow signals distal to extracranial ICAocclusions. P570 DISTURBED CONDUCTION ACROSS THE CARPAL TUNNEL IN DIABETICS. O. Hasegawa, S. Matsumoto, M. Iino, I. Mori, R. Kurita. Yokohama, Japan Under the existence of polyneuropathy peripheral nerves become fragile and the incidence of entrapment neuropathies will increase. Subclinical conduction disturbances across the carpal tunnel in patients with diabetes mellitus were studied. Distal latency ratio (DLR) was determined by comparison of distal motor latency of the median nerve with that of the ulnar nerve. In normal subjects DLR was 1.290 ± 10 (SD). In 11% of 412 diabetics DLR exceeded 2, nevertheless, only 18% of them complained of

symptoms of carpal tunnel syndrome (CTS). In 30% of diabetics DLR exceeded 1.5, the upper limit of normal. Then, 40 diabetic patients, without findings of CTS by clinical and electrophysiological criteria, were examined their median nerves. A microelectrode was inserted into the nerve trunk at the elbow and supramaximal electrical stimulations were given at 20 mm proximal and 40 mm distal to the wrist. Forty age-matched normal controls were also selected. Amplitude reduction ratio of compound nerve action potentials across the carpal tunnel was larger ( p < 0.001) in diabetics (38 ± 11%) than in controls (24 ± 11%). These results suggest that the incidence of disturbed conduction across the carpal tunnel increases in diabetics. This phenomenon might also be called a sort of “double crush syndrome”. P571 SUBTHALAMIC NUCLEUS (STN) AND TREMOR IN PARKINSON’S DISEASE (PD). M. C. Rodriguez, J. Guridi, A. Gorospe, E. Ramos, A. Mozo, G. Linazasoro, J. A. Obeso. Neurologia, Clinica Quiron, San Sebastian, Spain Objectives: To know the implication of the STN in the pathophysiology of tremor in PD. Background: Microrecording studies of the STN in MPTP monkeys have shown periodic oscillatory activity correlated with tremor. Methods: Neuronal action potentials in the STN have been recording during surgical treatment in 5 patients with PD and tremor. Tremor was recorded with surface electrodes (EMG). Data were collected and stored for off-line analysis. Labview program and autopower spectrum were used to analyse the neuronal action potentials and to correlate the neuronal activity with the EMG. Results: 32 units showed an oscillatory pattern of discharge with a mean firing frequency of 24.8 Hz (9.6–66.6). Thirty units had bursting discharges that correlate with the rhythmical activity recorded simultaneously in the EMG. The auto power spectrum for the EMG activity had a peak frequency of 5.23 Hz (4.25–9.25). The auto power spike for the oscillatory neuronal activity had a peak frequency of 12.55 Hz (4.25– 60.5). The peak frequency for the auto power spectrum of X-correlation was 5.44 (4.13–11.75). Conclusions: Neuronal activity of the STN in patients with PD and tremor has an oscilatory pattern with a frequency highly correlated with tremor. The STN is involved in the mechanisms underlying parkinsonian tremor. P572 QUADRICEPS SPARING IN PATIENTS WITH MULTIPLE SCLEROSIS AND PROGRESSED DISABILITY. Avi Askenazi, Arnon Karni, Oded Abramsky, and Dimitrios Karussis. Department of Neurology, Hadassah University Hospital, Jerusalem, Israel Objective: To evaluate the involvement of lower extremity muscles in paraparetic patients with Multiple sclerosis (MS). Background: Differential involvement of lower extremity muscles was observed in certain myopathies e.g. Hereditary inclusion body myopathy (HIBM). A similar pattern has not been described in neurogenic diseases. Design/Methods: 20 patients with clinically definite MS (according to Poser’s criteria) and EDSS of 3.5–7.5 were included in this study. The muscle power in the lower extremities was evaluated according to the 0–5 muscle power scale. Results: A striking difference was observed between the muscle power of the quadriceps, (mean: 4.7 ± 0.34) and the iliopsoas (mean: 1.07 ± 0.76), ( p < 0.0001, t-test). A similar, but less significant, differential involvement was observed between the foot extensors (more severely affected) and foot flexors. In contrast, no significant differences in the muscle power of the quadriceps and iliopsoas, were found in patients with acute paraplegia/ hemiplegia following stroke or trauma. Discussion/Conclusions: The disproportional involvement of iliopsoas in MS patients and the relative sparing of quadriceps may be explained by physiological mechanisms associated with the involvement of the pyramidal tract in the innervation of antigravity muscles (imbalance between the pontine and medullary reticulospinal tracts). This data may be of importance in the investigation of neurophysiological mechanisms involved in chronic pyramidal syndromes and spasticity, and in the design of suitable neuro-rehabilitation programs for these patients. P573 FACILITATION OF PICTURE NAMING BY RAPID-RATE TRANSCRANIAL MAGNETIC STIMULATION (Rtms) OVER WERNICKE’S AREA. F. M. Mottaghy, M. Hungs, R. Töpper, J. Noth. Neurology Department, RWTH Aachen, Germany Naming of an visually presented object is accompanied by a sequential activation of visual cortex, language areas and motor cortex. In previous ex-

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periments we showed facilitation of naming latencies with focal TMS over Wernicke’s area preceding object presentation. Significant effects of TMS on higher cortical functions have been reported when using rTMS. The effect of rTMS over Wernicke’s and Broca’s area was investigated. Eight healthy male right-handed subjects were presented with ten pictures of different black and white line-drawings which were randomly presented twice during each condition. In order to minimize naming latency variability’s pictures were presented to the subjects four times prior to the actual experiment. A train of 20 stimuli (20 Hz) with 55% of maximum output was applied for one second over CP5 and F5. Immediately and two minutes after the end of the train subjects were presented with the pictures. Only directly after the end of train a significant shortening of naming latency could be achieved with Wernicke’s area stimulation (p < 0.05). Two minutes later as well as following Broca’s area stimulation no significant effects on reaction time were observed. We postulate (1) that rTMS of Wernicke’s area leads to an facilitation effect by shortening the processing time and (2) this facilitation outlasts the stimulation less than two minutes. P574 GALVANIC STIMULATION AT MASTOID LEVEL ACTIVATES CORTICAL VESTIBULAR, AUDITORY, AND NOCICEPTIVE AREAS (AN fMRI STUDY). M. Dieterich, S. F. Bucher, M. Wiesmann, A. Weiss*, R. Zink, T. A. Yousry, Th. Brandt*. Departments of Neurology and Neuroradiology*, Ludwig-Maximilians-University, Munich, Germany Experimental vestibular stimulation is obtained by using caloric irrigation or galvanic stimulation at mastoid level. Caloric irrigation involves only semicircular canal function, while galvanic stimulation involves semicircular canal and otolith function. Our interest in experimental activation of the vestibular cortex prompted the following investigation of cerebral activation with functional MRI during galvanic stimulation of the mastoid in six right-handed healthy volunteers. Since galvanic stimulation also elicits moderate pain, cutaneous stimulation at neck C4/C5 level served as a control to differentiate between brain activation patterns caused by pain and those mediating vestibular function. During mastoid stimulation bilateral vestibular activation occurred in the posterior insula – the human homologue of the monkey parieto-insular vestibular cortex (PIVC) – and the thalamic pulvinar. Furthermore, auditory activation was observed in the transverse temporal (Heschl’s) gyrus without accompanying acoustic sensations. The cutaneous pain simultaneously elicited by galvanic stimulation caused bilateral activity of separate areas in the medial part of the insula and the anterior median thalamus. Thus, galvanic stimulation at the mastoid level activates three different sensory systems with distinct locations in the insula-thalamic region: the vestibular, auditory and nociceptive system. P575 HORIZONTAL AND VERTICAL OPTOKINETIC STIMULATION ACTIVATE VISUAL AND VESTIBULAR CORTEX AREAS WITH RIGHT HEMISPHERIC DOMINANCE: AN fMRI STUDY. M. Dieterich, S. F. Bucher, K. C. Seelos*, Th. Brandt. Departments of Neurology and Neuroradiology*, Ludwig-Maximilians-University, Munich, Germany The differential effects of optokinetic stimulation with and without fixation suppression were analyzed in an functional MRI (fMRI) study in ten right-handed healthy subjects. Horizontal or vertical optokinetic stimulation activated the same multiple visual, ocular motor, and vestibular cortical and subcortical areas independent of the stimulus direction. Several new aspects were discovered: All activated areas representing cortical (occipitotemporal cortex, parietal eye field, frontal eye field, prefrontal cortex, supplementary eye field) and subcortical (caudate nucleus, putamen, globus pallidus) ocular motor structures were activated under both experimental conditions, but the activation was significantly stronger with optokinetic nystagmus (OKN) than with fixation of a stationary target during optokinetic stimulation. The anterior and posterior parts of the insula (human homologue of the parieto-insular vestibular cortex) were activated during OKN but not during fixation of a stationary target. The only relatively increased activity during fixation suppres-sion was seen in the superior frontal gyrus (supplementary eye field) and the anterior cingulate gyrus. A significant right hemispheric dominance was found under both conditions in the ocular motor centers; this was most prominent in the occipitotemporal cortex, but did not occur in the primary visual cortex and in subcortical ocular motor structures (putamen, globus pallidus). There is evidence that activation of the vesti-bular cortex by optokinetic stimulation is related to ocular motor function rather than self-motion perception.

P576 MUSCULOCUTANEOUS NERVE LESION AFTER STRENUOUS PHYSICAL ACTIVITY: A CLINICAL AND NEUROPHYSIOLOGICAL STUDY. Simonetti S. Division of Neurology, E. O. Ospedali Galliera, Genoa, Italy Musculocutaneous nerve lesions are uncommon and are usually due to external trauma that results in direct or indirect nerve injury. The indirect lesions are usually consequent to fracture or dislocation of the clavicle or humerus, or to malpositioning of the upper extremity in abduction, during general anaesthesia. Musculocutaneous lesions that are not associated to external trauma are rare and have been reported as a consequence of violent extension of the forearm (Trojaborg 1976; Kim 1984) or vigorous upper extremity activity (Braddom 1978; Mastaglia 1986; Pecina 1993). In these cases an entrapment of the nerve where it passes through the coracobrachialis muscle has been postulated but a direct electrophysiological evidence of a nerve conduction block has never been reported. We describe a 26-year-old right-handed man who developed weakness of right elbow flexion and sensory loss on the lateral aspect of the right forearm, two days after a strenuous physical activity of the upper limbs. In this patient, electromyographical studies showed neurogenic signs in the right biceps brachii and brachialis muscles, and normal findings in the right coracobrachialis and the other upper limb muscles. A sensorimotor conduction block between axilla and Erb’s point was found in the musculocutaneous nerve by a near-nerve needle technique. The conduction block resolved progressively together with the clinical signs, in about five months. P577 FACILITATION OF DIFFERENT H-REFLEXES OF THE UPPER EXTREMITY BY SIMULTANEOUS APPLICATION OF SUBTHRESHOLD TRANSCRANIAL MAGNETIC STIMULI. Jahnke U*, Straschill M, Stendel R+. Department of Clinical Neurophysiology, + Department of Neurosurgery, Benjamin Franklin Hospital, Free University, D-12200 Berlin, Germany Introduction: The H-Reflex is a useful tool to test electrically the transmission of segmental spinal reflexes. In normal subjects only in flexor carpi radial and soleus muscle a reliable H-response can be obtained. Since subthreshold transcranial cortical stimulation can increase spinal exitability we used this technique in order to facilitate various H-reflexes of the upper extremity. Methods and Results: 30 healthy subjects (17 female, mean age 38 (26–62) years) were studied. H-reflexes were recorded using the standard technique with surface electrodes over the right biceps, brachioradial m., flexor carpi radial (fl.c.r.) and ulnar (fl.c.u.) muscle. As other authors we saw a reliable answer in biceps muscle in 57%, brachiioradial m. 50%, fl.c.r. 73% and fl.c.u. 43% of the normal subjects. In a second trial contralateral subthreshold transcortical magnetic stimuli were applied simultaneously in order to facilitate the reflex response. For the fl.c.r. and brachioradial m. in 100% and for biceps muscle and fl.c.u. in 97% a reliable H-reflex could be obtained. Amplitudes of the faciliated H-response increased on the average by about 300%. Latencies were not significantly changed. Conclusion: Since it was possible to obtain reliable reflex answers even in the biceps and brachioradial muscle in almost all normal subjects, this technique could be very useful in the early diagnosis of acute radiculopathies in the upper extremities. P578 INFLUENCE OF ELECTRICAL STIMULATION OF THE THALAMIC VENTRAL INTERMEDIATE NUCLEUS (VIM) ON LONG LATENCY REFLEXES IN INTRINSIC HAND MUSCLES IN TREMOR PATIENTS. Jahnke U*, Straschill M, Funk Th+, Kern Chr+, Vesper J+. *Department of Clinical Neurophysiology, + Department of Neurosurgery, Benjamin Franklin Hospital, Free University, D-12200 Berlin, Germany Introduction: The pathways involved in the generation of long latency (LL-)reflexes of intrinsic hand muscles are still a matter of controversy. In case of trancortical transmission LL-reflexes should depend on transthalamic afference. Deep brain stimulation offers the unique possibility to study the effect of a reversible neuroinhibition in the VIM and/or in neighbouring structures on electrically evoked LL-reflexes. Methods: 7 patients with a unilateral VIM stimulator implanted for tremor treatment were investigated using different stimulation parameters. Contralateral LL-reflexes (median nerve stimulation, surface electrodes on the thenar muscles, 100 trials averaged) were recorded at least twice under each condition and correlated to the amount of tremor suppression. Results: In 5 patients a > 40% amplidude reduction of contralateral LL-reflexes was observed.

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But values of stimulation parameters such as contact selection, stimulus amplitude and frequency, which were optimal for tremor reduction, differed from those, which yielted a maximal LL-response suppression. Conclusion: Our results suggest, that LL-reflexes and tremor activity are transmitted by neighbouring, but spatially separated thalamic neuronal elements. Tremor reduction is probably based on the modification of cerebellar outflow rather than on suppression of reafferent proprioceptive lemniscal input. P579 KINEMATICS OF FAST WRIST MOVEMENTS IN PATIENTS WITH CEREBELLAR ANTERIOR LOBE DISEASE AND NORMAL EXAMINATION IN UPPER LIMBS. F. Setta1, H. Topka2, M. Baecke3, J. Jacquy 4, E. Godaux 5, J. Hildebrand 6, A. Booze 2, M. Manto6. “La Sapienza”, Roma1; 2 University of Tübingen (G); 3 Facultd de Medecine ULB (B); 4 CHUCharleroi (B); 5 Universitd de Mons-Hainaut (B); 6 Hôpital Erasme (B) We analysed kinematics of fast wrist movements in 5 patients exhibiting a syndrome of cerebellar anterior lobe dysfunction (mean age: 50 ± 8.5 years; 5 men) and in 9 healthy subjects (HS; mean age: 52.1 ± 7.9 years; 9 men). The 5 patients exhibited a postural lower limb tremor of 3 Hz. Neurological examination was normal in upper limbs. Brain CT demonstrated atrophy in anterior lobe. Mean movement amplitudes were similar in both groups ( p = 0.83) but variability of movements was increased in patients ( p < 0.001). Peak velocities were 441 ± 68 deg/sec and 445 ± 73 deg/sec respectively in patients and HS ( p = 0.92). Mean ratio of maximal to averaged velocity Vmax/Vave, was 2.7 ± 0.16 in patients and 2.28 ± 0.13 in HS ( p < 0.001). Mean ratio of acceleration peak divided by deceleration peak was 0.98 ± 0.02 in HS and 1.17 ± 0.08 in patients (p = 0.003). Kinematics of fast wrist movements are impaired in patients with a normal clinical examination in upper limbs despite a cerebellar anterior lobe disease. These kinematic profiles can be considered as a marker of subclinical cerebellar dysfunction in these patients. P580 MOTION ANALYSIS IN A PATIENT WITH HIGH VULNERABILITY TO ALCOHOL. F. Setta1, J. Jacquy2, J. Hildebrand 3, M. Manto 3. 1Neurologia, La Sapienza, Roma (I); 2 Neurologie, CHU-Charleroi, Charleroi and 3 Neurologie, Erasme, Bruxelles (B) Alcohol is a well known cause of cerebellar ataxia, affecting mainly anterior lobe. It has been suggested, but not demonstrated, that cerebellar toxicity was due to idiosyncratic sensitivity. We describe a 46-year-old man with a high vulnerability to small doses of alcohol. Since the age of 15, he had observed that small doses of alcohol induced clumsiness. There was no family history of sensitivity to alcohol. Neurological examination was normal. EEG, evoked potentials and conduction velocities, brain CT were normal. We recorded fast wrist movements towards a fixed target (15 deg) before and 30 minutes after ingestion of 5 gr of alcohol. Before alcohol, mean movement amplitude was 14.5 deg (control group of 5 subjects with a mean age of 42 ± 5 years: 15.3 ± 0.9 deg) and the ratio of the rate of rise (RR) of agonist activity divided by the RR of antagonist activity agoQ30/ antagoQ30 was 1.09 (controls: 0.97 ± 0.09). After alcohol, he exhibited a nystagmus, scanning speech and postural leg tremor. Mean movement amplitude was 24.3 deg (controls: 14.9 ± 1.0) and the ratio agoQ/antagoQ30 was 2.51 (controls: 0.97 ± 0.09). We demonstrate that low doses of alcohol can induce a severe increase in the ratio agoQ30/antagoQ30, a defect previously described in cerebellar degeneration involving medial parts (Ann. Neurol. 1996; 39 : 271–274). P581 AUTONOMIC FAILURE CHANGES WITH TIME COURSE OF COMPLEX REGIONAL PAIN SYNDROME. F. Birklein, B. Riedl, B. Neundörfer. Neurologische Klinik, Friedrich-Alexander-Universität Erlangen, Germany The present investigation was conducted to describe autonomic dysfunction in acute and more chronic stages of complex regional pain syndrome (CRPS). Patients were investigated twice: First investigation as soon as possible after diagnosis was established during the acute stage of CRPS and the second investigation about two years later. 21 patients finished the follow-up. The median duration of CRPS was 5 (2–21) weeks at first investigation and 94 weeks (22–148) at follow-up. Skin temperature was recorded by thermography, the thermoregulatory sweat test (TST) and the quantitative sudomotor axon reflex test (QSART) were performed. Skin temperature was warmer on the affected side at first investigation (p <

0.001) and colder at follow-up ( p < 0.02). Sudomotor output was enhanced both after TST ( p < 0.005) and QSART ( p < 0.05) at time of first investigation on the affected side. At follow-up, however, sweating after TST was still increased ( p < 0.04) while QSART responses were not different between affected and unaffected limb. In conclusion, the present investigation proved that vasomotor and sudomotor control are substantially altered in CRPS. In the acute stage vasomotor control is obviously decreased in the affected limb whereas sudomotor function was enhanced. This may be probably the result of disturbances of thermoregulation. Different secondary peripheral mechanisms, concerning vasomotor and sudomotor function, contribute to clinical presentation of CRPS and affect autonomic function at all stages of CRPS. This work was supported by the DFG, SFB 353, C3. P582 FOCAL NEGATIVE MYOCLONUS OF CORTICAL ORIGIN. F. Cassim, P. Derambure, J. L. Bourriez, L. Defebvre, A. Destée, J. D. Guieu. Clinical Neurophysiology and Neurology, CHU Lille, France A 49-year-old patient presented with abnormal involuntary movements (AIM) of the left upper limb. He had a partial cryptogenic epilepsy of the right central region insensitive to antiepileptic drugs. The AIM, considerably worsened by vigabatrin, consisted of rare jerks at rest and, with outstretched hand, a fine irreguliar tremor with arrhythmic brisk flexionextension wrist movements, suggesting an asterixis. Polymyography revealed positive myoclonus and EMG silences (negative myoclonus) often preceded by a brief EMG burst (type II), synchronous over wrist flexors and extensors. Left median nerve stimulation evoked normal frontal responses but poorly defined parietal potentials with no N20. EEG-EMG polygraphy showed no abnormality related to myoclonus. Back averaging EEG prior to positive myoclonus demonstrated a positive-negative potential, maximal over C4, preceding the myoclonus by 20 ms. Back averaging EEG prior to negative type II myoclonus showed the same potential, but followed by a slow negative wave. Negative myoclonus may be of cortical origin, with a distinctive pattern of back averaged EEG which may shed light on the mechanisms. Interictal AIM should be extensively assessed for, when a cortical origin is demonstrated, that means that it is part of the epileptic syndrome. P583 CARDIOVASCULAR AND CEREBROVASCULAR RESPONSES TO ORTHOSTASIS IN PARKINSON’S DISEASE. G. Böckeler, L. Niehaus. Dept. of Neurology, Virchow-Klinikum, Charité, Humboldt-University, Berlin, Germany Orthostatic hypotension is a well recognised feature of impaired autonomic function in Idiopathic Parkinson’s Disease (IPD). Visual blurring, dizziness and nausea may result from reduced cerebral blood flow (CBF) which is associated with hypotension. It remains controversial whether these symptoms are primarily caused by inadequate cardiovascular adaptation in orthostasis, or whether impairment of cerebral autoregulation itself contributes to a fall of CBF. 15 patients with IPD and 15 healthy age- and sexmatched subjects were studied during tilt-testing. Heart rate (HR), mean arterial blood pressure (MAP) and mean blood flow velocity (MBFV) in the middle cerebral artery, measured by transcranial Doppler sonography, were obtained simultaneously at rest and during 70° head-up tilt. Changes in both MAP and MBFV, and the relationship between the two were assessed. In the first minute of orthostasis the reduction of MAP was larger in patients (–4.0%) than in controls (–0.6%). MAP rose to the pre-tilt values within two minutes in controls and after five minutes in patients. Twelve minutes after tilting patients had a smaller increase in HR than controls (16.3% vs. 24.2%). After 12 minutes of tilt MBFV fell similarly in patients (–15.4%) and controls (–17.9%). Changes of MAP correlated poorly with changes of MBFV. Our findings suggest that both vagal and sympathetic function is impaired in IPD. However the regulation of cerebral blood flow in orthostasis is unaffected in IPD. P584 CORTICAL MOTOR REORGANIZATION IN 6 PATIENTS WITH HEMISPHERECTOMY FOR INTRACTABLE EPILEPSY DEMONSTRATED BY TRANSCRANIAL MAGNETIC STIMULATION. Kastrup O, Leonhard G, Kurthen M, Hufnagel A. University Clinic Essen, Germany, Department of Neurology Objectives of the study: 6 patients who had previously undergone hemispherectomy for the treatment of intractable seizures were examined using

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ipsi- and contralateral transcranial magnetic stimulation to study reorganization of motor tracts by the remaining hemisphere. Methods: Motor evoked potentials (MEP) to the biceps, abductor pollicis brevis and anterior tibial muscles were evoked bilaterally without facilitation using a conventional 1.2 tesla Magstim stimulator connected to a 12 and 7 cm diameter round coil. We analyzed latency, amplitude, threshold, CMCT (central motor conduction time) and point of maximal cortical response of the MEP. The points where maximal compound MEP (magnetically evoked potentials) could be elicited over the cortex was determined by repetitive stimulation. Results: 1) In 2 patients with moderate hemiparesis no MEP could be induced ipsilaterally. 2) Completely normal MEP could be recorded on either side in 2 patients. 3) 2 patients demonstrated increased latencies of ipsilateral MEP 4) No MEP could be recorded using the small coil at all. Conclusions: Cortical reorganization of ipsilateral motor control following hemispherectomy can be extremely diverse.Whereas ipsi- and contralateral induction of MEP was identical in 2 patients, latencies to ipsilateral muscles can be largely increased in others. In contrast two patients in whom no ipsilateral MEP could be demonstrated, recovery of moderate motor function occured in the absence of reproducible ipsilateral MEP.

P585 FUNCTIONAL EVIDENCE FOR IPSILATERAL SHORT-LATENCY CORTICOSPINAL CONNECTIONS IN PATIENTS WITH VERY EARLY LESIONS TO THE MOTOR CORTEX. A. Schulze-Bonhage, C. E. Elger. Clinic of Epileptology, University of Bonn, Germany Projections from the ipsilateral motor cortex have been discussed to be crucial for the regeneration of motor deficits e.g. after stroke. Ipsilateral projections to proximal muscles of the extremities have been supposed to be crucial for their better functional recovery. As plasticity of the cerebral cortex is thought to be age-dependent, we have investigated the occurrence of ipsilateral motor evoked potentials (MEP) in patients with very early unilateral damage to the motor cortex using focal transcranial magnetic stimulation. Compound motor potentials of the first dorsal interosseus muscle were evoked in 15 patients suffering from spastic hemiparesis due to pre- or perinatal damage to one motor cortex using a 1,5 T Magstim 200 stimulator. Stimuli were applied over both motor cortices via a figure-ofeight shaped coil or a circular coil placed tangential to the skull during rest and pre-innervation. In 13 of 15 patients ipsilateral MEP could be recorded on the paretic side with stimulation of the intact motor cortex. Responses were of short corticomuscular latency (maximal 25.1 ms), yet motor thresholds were higher and amplitudes of motor evoked potentials were lower for ipsilateral potentials. In contrast, there were no ipsilateral responses when recording from the non-paretic side. The study gives evidence for plastic changes of corticospinal connections with functional direct influcence also to a distal arm muscle on the paretic side in the majority of patients with early unilateral damage to the motor cortex.

P587 THE ORIGIN OF THE R3 COMPONENT OF THE BLINK REFLEX. Jovicic A, llic T, Raicevic R, Djordjevic D, Petkovic S. Military Medical Academy, Belgrade, FR Yugoslavia The component R3 of the blink reflex might be elicited by electrical stimulation of the supraorbital nerve. The latency of the R3 component is more than twice that of R2 component. This fact was thought to be due activation of slow afferents. R3 component could be evoked by electrical stimulus at intensities near to the pain threshold and therefore it was concluded that R3 is a result of activation of the nociceptive afferents. If it is true, R3 component should be abnormal M the lesions of the upper half of the cervical spinal cord. The aim of this study was to examine R3 component in patients with upper cervical spinal cord lesions. The investigation was carried out in 20 healthy volunteers and 5 patients with cervical spinal stenosis at the C2–C5 level. In all patient the pathology of the brain-stern was excluded by evoked potential and magnetic resonance examinations. Electrical stimuli applied to the supraorbital nerve to elicit R3 component were with mean intensity of about 20 mA and were delivered at intervals of 25 s. The results of this study showed that mean latency of R3 in healthy subjects was 88 ms, and mean duration of 29 ms. Among the patients R3 component was abnormal (prolonged latency, extended duration, or absent) in 3 patients, and normal in 2 patients. These inconsistent findings in patients with the same pathological changes of the cervical spinal cord might suggest that the R3 component results from the activation of nociceptive trigeminal afferents, or that R3 component of the blink reflex has a different origin. P588 EVOKED BRAIN POTENTIALS DURING DEPLUMBISATION IN LEAD POISONED PATIENTS. Andelko Vrca. Zagreb, Croatia Evoked brain potentials were determined in four groups of subjects exposed to different levels of lead: lead battery production, lead crystal production, lead paint production, and five subjects accidentally poisoned by lead during treatment with so-called Ajurvedic tonic. Deplumbisation with ethylenediaminetetraacetic acid (EDTA) was performed and evoked brain potentials recorded on three occasions: before, during and three days after deplumbisation. The concentration of lead, coproporphyrin and erythroporphyrin in peripheral blood was determined immediately before recording evoked brain potentials. Visual evoked potentials, “pattern shift reversal” type (VEP) and evoked brain stem potentials (BEAP) with different frequencies of “click stimulus”; 8, 15 and 30 Hz, were determined and results compared with laboratory standards and during deplumbisation in each group. Conclusions: 1. Both types of evoked brain potentials differentiated lead poisoned subjects from the so-called standard, control population. 2. BEAPs showed relatively greater sensitivity in the lead poisoned subjects. 3. Parameters of evoked potentials were relatively stable in the chronically exposed subjects, regardless of deplumbisation, and 4. In the acutely -sub-acutely poisoned subjects parameters of evoked brain potentials changed during deplumbisation.

P586 IS QUANTITATIVE GAIT ANALYSIS USEFUL FOR DIFFERENTIATE BETWEEN PARKINSONIAN AND SENILE ALTERATION OF WALKING? L. Priano, S. Vighetti, G. Asteggiano, P. Cerrato, M. Rizzone, L. Lopiano, P. Barbero and B. Bergamasco. Dpt of Neurosciences, University of Turin

P589 INVOLVEMENT OF IA RECIPROCAL INHIBITION IN PATHOPHYSIOLOGY OF MOVEMENT DISORDER IN PARKINSON’S DISEASE. Vidailhet M, Meunier S, Katz R, Gallouedec G, Houeto JL. Paris, France

Aim of this study was to evaluate if computerized gait analysisis may differentiate between senile gait and parkinsonian gait in the early stage of the disease. 12 patients affected from parkinson disease (PD) and 10 healthy elderly controls (EC) were submitted to a computerized gait analysis. Inclusion criteria of PD included UPDRS items regarding posture and gait less than 2 (mild alteration of gait at clinical evaluation). The results showed alterations in parkinsonian gait, statistically different from elderly controls: a) reduction of swing phase duration (24% of gait cycle duration in PD, 37% in EC; p = 0.0019); b) increase of double support phase duration (49% of gait cycle in PD, 28% in EC; p = 0.002); c) reduction range of stride frequencies (67 ± 5 stride/min in PD, 80 ± 18 stride/min in EC, p = 0,02 d) alteration in EMG activity (linear envelopes) in the weightaccepting muscles; d) alteration in the vector profiles of weight forces. In conclusion this preliminary study shows that computerized gait analysis is a sensitive tool to differentiate parkinsonian gait from senile gait. References: 1) D. Winter and HJ Yack. EMG profiles during normal human walking: stride to stride and inter-subject variability. Electroenceph Clin Neurophis 97 (1995) 408–415; 2) JCM Zijlmans et al. Quantitative gait analysis in patients with vascular parkinsonism. Movement disorders. Vol. 11, No 5, 1996, pp 501–508.

Activity in some spinal pathways (Ib inhibition, propriospinal excitation) has been shown to be abnormal in Parkinson’s disease (PD). Abnormality of Ia reciprocal inhibition in PD is still debated although antagonist cocontraction could be observed in severe patients. As all the studies concerning the Ia reciprocal inhibition, in the upper limb, have been done at rest, the rationale behind our experiments was that abnormalities should be revealed better during phasic movements than at rest. We compared 12 control subjects and 12 Parkinsonian patients. They were treated and had mild clinical severity (I–II on Hoehn and Yahr scale). Electrical stimulation of the radial nerve evoked a clear inhibition of the wrist flexor H reflex. Amount of the first 1 ms part of this inhibition can be used to assess the Ia reciprocal inhibitory level. Amount of this inhibition was compared at rest and at the onset of a phasic voluntary contraction of the wrist. In normal subjects a strong descending modulation of the Ia reciprocal inhibitory level was observed: inhibition decreased at the onset of the flexion. At rest, the amount of the inhibition was not modified in patients but, at the onset of movement, descending modulation was significantly less than in controls. Loss of a descending discriminating control of the reciprocal innervation could play a role in disturbances of precise voluntary movements in Parkinson’s disease.

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P590 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, PIGMENTARY RETINOPATHY, DIABETES MELLITUS AND STROKE LIKE EPISODE WITH MITOCHONDRIAL DELETION. H. Przibylia1, H. Porschke1, Chr. Lange2, H. Goebel 3, H. Reichmann4, G. Deuschl1. 1Dept. of Neurology, University of Kiel, 2 Dep. of Medicine, Rendsburg Hospital, 3 Dept. of Neuropathology, 4 University of Mainz, Dept. of Neurology, University of Dresden, Germany We report the case of a 42-year-old woman with a mitochondrial cytopathy. She presented with chronic progressive external ophthalmoplegia (CPEO) and mild pigmentary retinopathy. CPEO began with ptosis two years before her first admittance. Additional symptoms were mild palsy of shoulder girdle type, short stature, hearing impairment since childhood, alopecia since her 23 rd. year of age, diabetes mellitus, excessive hypertriglyceridemia and polyneuropathy. Her admittance in July 97 was due to a first stroke like episode with motor aphasia and right-sided central facial weakness. Aphasia remitted within three hours. By ECG and ultrasound no abnormalities of cardiac function or extra- and intracranial arteries were detected. Electromyography showed a mild myopathic pattern in proximal muscles and more neurogenic alterations in distal muscles due to a generalized axonal neuropathy, which was confirmed by electroneurography. The muscle specimen (deltoid muscle) showed ragged red fibers and cytochrome-oxidase-negative fibers and a mitochondrial deletion was seen in southern blot analysis. Clinical, electrophysiological, laboratory and magnetic resonance imaging results will be discussed.

P591 A CASE OF CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA (CPEO) AND WHITE MATTER LESIONS IN MRI SHOWING A DE NOVO MITOCHONDRIAL DELETION AND A MATERNALLY INHERITED 3250-POINT-MUTATION OF THE MITOCHONDRIAL GENOME. H. Porschke1, T. Gronewald 2, H. Przibylla1, H. H. Goebelo, P. Seibel 4, H. Reichmarin3. 1Dept. of Neurology, University of Kiel, 2 Dept. of Neurology, University of Dresden, 3Dept. of Neuropathology, University of Mairiz, 4 Theodor Boveri Institute, University of Würzburg, Germany A case of a mitochondrial myopathy in a 27-year-old woman is reported presenting predominantly as CIDE0 and weakness of the shoulder more than the pelvic girdle. The symptoms, being slowly progressive, started at an age of 13 years with a bilateral ptosis. Later a difficulty in swallowing and a bilateral ataxia developed. The cranial magnetic resonance tomography showed diffuse white matter lesions and a pleocytosis and mildly elevated protein concentration in spinal fluid. No cardiac or retinal affection and no mental impairment were found. Signs of a generalized axonal lesion were confirmed neurographically and the latencies of visually and somatosensory evoked potentials were delayed. The muscle biopsy showed ragged red fibers and by southern blot analysis a deletion (of about 2.5 kbp) of the mitochondrial genome was detected. In addition, a 3250point-mutation was found in the patient and in some of her clinically unaffected family members (mother, brother and sister, but not in father and a second sister), while the deletion was found in the patient only.