eighteenth meeting of the european neurological society 7 ... · clinical neurophysiology ii/93...

J Neurol (2008) 255 [Suppl 2]:1–235DOI 10.1007/s00415-008-2001-5

Eighteenth Meeting of theEuropean Neurological Society7–11 June 2008, Nice, FranceSymposia and Free Communications

The abstracts have been reviewed by:Z. Argov, O.A. Bajenaru, R. Baringer, C. Bassetti, K. Bhatia, T. Brandt,H. Cock, G. Comi, C. Desnuelle, V. Dietz, A. Ducros, C. Elger, M. Eraksoy,J. Ferro, M. Filippi, O. Hardiman, H-P. Hartung, L. Kappos, J. Kesselring,C. Krarup, P. Landrieu, G.L. Lenzi, R. Lewis, D. Leys, H. Manji, D.H. Miller,I. Milonas, G. Moonen, D. Pareyson, Y. Parman, V. Planté-Bordeneuve,P. Pollak, H. Reichmann, M. Rousseaux, G. Said, E. Scarpini, E. Schmutzhard,A. Sena, V. Silani, R. Soffietti, C. Sommer, A. Steck, J. Valls-Solé,M.J.D. Vidailhet, J. Volkmann

JON_Suppl_Abstract_02_08 06.05.2008 14:18 Uhr Seite 1

2

Contents

Presidential symposiumComa and locked-in syndrome II/3

SymposiaBehavioural disorders and dementia II/4Autoimmune disorders of the nervous system II/5Multiple sclerosis: when to start a treatment and which treatment II/6Transient ischaemic attack (TIA): imaging and management II/7

FREE COMMUNICATIONSOral Sessions

Session 1: Multiple sclerosis 1 II/8Session 2: Cerebrovascular disorders 1 II/11Session 3: Peripheral neuropathy II/12Session 4: Epilepsy 1 II/14Session 5: Neurogenetics II/16Session 6: Neuro-oncology II/18Session 7: Multiple sclerosis 2 II/20Session 8: Infection II/21Session 9: Neurorehabilitation II/23Session 10: Cerebrovascular disorders 2 II/25Session 11: Pain II/26Session 12: Epilepsy 2 II/28Session 13: Clinical neurophysiology II/30Session 14: Extrapyramidal disorders 1 II/31Session 15: Muscle disorders II/33Session 16: General neurology 1 II/34Session 17: Multiple sclerosis 3 II/36Session 18: Higher function disorders II/38Session 19: Cerebrovascular disorders 3 II/39Session 20: Neuro-ophthalmology II/41Session 21: Coma and sleep disorders II/42Session 22: Multiple sclerosis 4 II/38Session 23: Higher function disorders 2 II/39Session 24: Cerebrovascular disorders 4 II/48Session 25: Motor neuron disease II/49Session 26: Extrapyramidal disorders 2 II/51Session 27: New insights into MS disease mechanisms II/52Session 28: General neurology 2 II/53Session 29: Child neurology II/54

POSTER SESSIONS

Poster Session 1Cerebrovascular disorders II/55Clinical neurophysiology II/60Neurogenetics II/65Child neurology II/71Peripheral neuropathy II/74Multiple sclerosis II/78Neuro-imaging II/83

Poster session 2Cerebrovascular disorders II/89Clinical neurophysiology II/93Extrapyramidal disorders II/97Epilepsy II/101Peripheral neuropathy II/104Multiple sclerosis II/109Motor neuron disease II/114Neurorehabilitation II/119

Poster session 3Peripheral neuropathy II/123Dementia II/125Infection II/129Epilepsy II/134General neurology II/137Multiple sclerosis II/141Muscle disorders II/145Neuro-oncology II/151

Poster session 4Cerebrovascular disorders II/156Higher function disorders II/161Extrapyramidial disorders: Parkinson’s disease II/165Epilepsy II/168General neurology II/172Multiple sclerosis II/176Muscle disorders: neuromuscular junction disorders II/182Neuro-opththalmology II/185

Poster session 5Cerebrovascular disorders II/189Dementia II/193Extrapyramidial disorders II/197Preclinical neurology II/199General neurology II/200Multiple sclerosis II/204Pain and headache II/212Sleep disorders II/218

Author index II/221


3

Presidential symposium

Coma and locked-in syndrome

1Coma and locked in syndrome – Disorders of consciousnessG. MoonenUniversity of Liège (Liège, BE)

Physiological and pathological alterations of consciousness can be classifiedon a two axis diagram wakefulness x awareness. We will focus on the defin-ition,diagnosis and prognosis of vegetative (VS) and of minimally consciousstates (MCS) pointing out the frequent misdiagnosis.Currently,clinical eval-uation, electrophysiology and neuroimaging should be combined to charac-terize as precisely as possible “the clinical phenotype” of these patients.

We will point out 1) the urgent need for objective markers available at thebedside, 2) impaired fronto-parietal global workspace and disconnectionsyndrome in VS while 3) preserved pain and emotional perception in MCS.

Finally, self evaluation of quality of life by chronic locked-in syndromepatients gave “unexpected” results when compared with matched controlspointing out their right to die but also and more often to communicate andto receive appropriate care.

2Multimodal neuroimaging studies of recovery of consciousness after severebrain injuryN. SchiffCornell University Medical College (New York, US)

Despite major advances in neuroscience, recovery of consciousness afterbrain injury remains poorly understood.At the origin of this challenge is thesurprising degree of uncertainty of underlying brain function that may bepresent when confronted with patient at the bedside with very limited oreven no overt signs of behavioral responsiveness. Across the range of be-haviorally defined states from vegetative state (no evidence of self or envi-ronmental awareness), minimally conscious state (at least some evidence ofawareness), and up but not including patients in locked-in state (full con-sciousness with no motor control) there are many patients whose level ofconsciousness we cannot at present confidently assess.

This lecture will focus on multi-modal neuroimaging studies that pro-vide emerging insight into possible biological mechanisms at a ‘circuit-level’underlying recovery of consciousness after severe brain injury. Standardclinical imaging modalities and behavioral assessments provide very limitedguides for prognosis.Moreover,current neurological practice relies on prob-ability estimates derived from these standard measures without considera-tion of a variety of possible underlying mechanisms producing impairedbrain function. The discussion will review recent studies of severely brain-injured patients in vegetative state and minimally conscious state. We willexamine multi-modal neuroimaging evidence of residual functional capac-ity and possible changes in brain structural connectivity in some patients re-maining in prolonged minimally conscious state. Rare patients within thissubgroup have demonstrated spontaneous recoveries of consistent commu-nication. Possible common underlying ‘circuit-level’ mechanisms of braindysfunction will be discussed based on measurements obtained from func-tional magnetic resonance imaging, quantitative electroencephalography,positron emission tomography,and diffusion tensor imaging techniques.Wewill also discuss the clinical and neuroscientific foundations underpinninga recent study that demonstrated behavioral improvements with centralthalamic stimulation in a single severely brain-injured human subject whohad remained in the minimally conscious state (MCS) for 6 years.

Collectively, experimental and clinical data support further research todevelop diagnostic and investigational therapeutic approaches at the ‘cir-cuit-level’ to address the problem of recovery of consciousness after severebrain injury. The long-range goal of these studies is to establish methods totrack, predict, and assist recovery across a heterogenous pool of brain-in-jured patients. However, such development will require stringent effort todevelop patient assessment strategies, study designs and ethical frameworksto ensure that this line of enquiry remains aimed at achieveable and desir-able patient-centered goals.

3Detecting awareness in non-communicative patients using fMRIA.M. OwenMRC Cognition and Brain Sciences Unit (Cambridge, UK)

The vegetative state is one of the least understood and most challenging con-ditions in modern medicine. The term describes a condition in which pa-tients who emerge from a coma appear to be awake, but show no signs ofawareness. It is extremely difficult to assess cognitive function in these pa-tients, because their movements may be minimal or inconsistent, or becauseno cognitive output is possible. This factor, coupled with limited experienceof this complex condition and closely related disorders such as the mini-mally conscious state, has been linked to an alarmingly high rate of misdi-agnosis on clinical audits. In a series of recent studies,we have demonstratedthat functional neuroimaging can be used to identify residual cognitivefunction, and even conscious awareness, in some patients who are assumedto vegetative state or minimally conscious state, but still have abilities thatcannot be detected by standard clinical means2-13. I will describe a series ofparadigms that systematically increase in complexity with respect to thecognitive processes required, and therefore allow us to infer how much cog-nition remains based on ‘normal’ patterns of brain activation. At the lowestlevel, we examine responses to various sound and speech stimuli. A signifi-cant minority of vegetative and minimally conscious patients producespeech-related responses in the superior temporal-lobe region that are in-distinguishable from those in a healthy brain. More complex linguistic stim-uli, which produce distinct patterns of activation associated with compre-hension, also elicit normal responses in some, but fewer, patients. However,an appropriate neural response to the meaning of spoken sentences is notunequivocal evidence of awareness. For example, we have recently demon-strated that light sedation in healthy volunteers disrupts the ‘normal’ neuralresponse to speech comprehension and is associated with a marked reduc-tion in performance. We have therefore developed a new approach in whichpatients assumed to be vegetative or minimally conscious are instructed toperform mental imagery tasks at specific points during the fMRI scan. Re-sults from a small group confirm that some patients, diagnosed as vegeta-tive, retain the ability to understand spoken commands and to respond viatheir brain activity rather than speech or movement. Reproducible and ro-bust task-dependent responses to commands without the need for practiceor training could be a novel way for some vegetative, minimally conscious,or locked in patients to use their residual cognitive capacities to communi-cate thoughts by modulating their own neural activity. Our pilot results inhealthy volunteers confirm that this method can be used to communicatereal-time ‘yes’ and ‘no’ responses, without the need for any overt behavior,with 100 % reliability.

4Brain-computer interfaces in the locked-in syndromeA. Kübler, F. Nijboer, A. Furdea, S. Halder, N. BirbaumerUniversity of Tubingen (Tubingen, DE)

Brain-computer interfaces (BCI) provide connections between the brain anda computer. Voluntary regulation of neuro-electrical activity or brain activ-ity as a response to sensory stimulation are used to control cursor move-ments or switches on a computer. BCIs are aiming at restoring communica-tion particularly in locked-in patients.With more than 35 severely paralysedpatients, some of them in the locked-in state, it could be shown that BCI con-trol and communication is possible in all stages of paralysis. BCI on the ba-sis of neurofeedback and those which use evoked potentials (P300) also op-erate in the auditory mode rendering this technology feasible for patientswith impaired vision; time needed for training, however, exceeds by far thatof visual BCI. New applications for the P300-BCI are Internet browser andPainting. Instead of letters, weblinks and graphic icons are presented in amatrix for selection. Healthy volunteers and patients are highly motivated touse a BCI and BCI performance is influenced by motivation, but not by cur-rent mood. Specifically, mastery confidence increases with training whereasfear to fail decreases with training. At the same time fear to fail is positivelyrelated to performance confirming the well-established Yerkes-Dodson lawthat a medium level of arousal promotes optimal performance. Future de-velopment is aiming at merging different EEG and muscular signals, differ-ent sensory presentation modes, and a variety of applications into one sys-tem for the benefit of severely impaired patients.


4

Symposia

Behavioural disorders and dementia

25Pathophysiological basis of behaviour: relevance to dementiaT.W. RobbinsUniversity of Cambridge (Cambridge, UK)

The study of dementia requires careful neuropsychological assessment forthe monitoring of progress of disease and of effects of any putative treat-ments. In this presentation, I will describe the use of the CANTAB automatedtest battery which has been validated in brain damaged patients with dis-crete cortical lesions and by functional neuroimaging where feasible. I willdescribe the design and use of a visuospatial paired associates learning test,which has been shown to have utility in the detection of Alzheimer’s disease,both in patients with questionable dementia and in the normal healthy pop-ulation. This test is sensitive to damage to the hippocampus and to the pre-frontal cortex, and I will present data from functional neuroimaging studiesin the normal population. I will contrast this with a neuropsychological as-sessment of basal ganglia diseases such as Parkinson’s and Huntington’s dis-ease, where the accent is on assessment of fronto-striatal executive function,in tests of planning, working memory, inhibition, decision-making and cog-nitive flexibility. Many of these tests are based on procedures used in exper-imental animals to enable a translational approach and this will also bedemonstrated, using novel data that also indicates possible sensitivity tocandidate pharmacological treatments.The utility with respect to functionalgenomics will also be illustrated in the context of the COMT polymorphismin Parkinson’s disease. The theoretical significance as well as the applicationof this neuropsychological approach will also be described.

26Behavioural disorders in the synucleinopathiesS.F. CappaVita-Salute University and San Raffaele Scientific Institute (Milan, IT)

The careful definition of clinical phenotypes maintains its importance in theera of molecular neurology. In the field of neurodegenerative disorders, animportant aim is the definition of specific profiles of cognitive and behav-ioural dysfunction, and the assessment of their relationship to the topogra-phy of brain pathology and to the underlying molecular mechanisms of dis-ease. The spectrum of behavioural manifestations which can be observed inthe synucleinopathies (SNP) is wide,and presents an important overlap withthe behavioural disorders found in the tauopathy spectrum. This is not un-expected, for a number of reasons. In the first place, many behavioural dis-orders are manifestations of the multiple facets of executive dysfunction,which actually reflects the pathological involvement of fronto- subcorticalmechanisms, rather than the specific mechanism of disease. Second, othersymptoms, such as depression or agitation, may be due to environmental in-teractions, or represent side effects of symptomatic pharmacological treat-ments. However, it is likely that some features of cognitive and behaviouraldysfunction may be relatively specific for the SNP,reflecting underlying neu-robiological differences. In the case of Parkinson’s disease (PD), depressionis an important clinical issue, which may be more prevalent than in the caseof other neurodegenerative disorders, reflecting the complex combinationof neurotransmitter abnormalities, involving dopamine, serotonin and nor-epinephrine.Another clinically relevant aspect in the management of PD arethe impulse control disorders, such as pathological gambling and hypersex-uality, which appear however to be related to dopaminergic medications. Ithas been proposed that a form of parasomnia, i.e. REM sleep behaviour dis-order (RBD), may represent a relatively specific behavioural marker of theSNP. RBD is characterised by the loss of the physiological muscle atonia dur-ing REM sleep, and by prominent dream enactment behaviour. RBD hasbeen found to precede the onset of PD,multiple system atrophy (MSA) or de-mentia with Lewy bodies (DLB) by years or even decades. In particular, theobservation that subclinical neuropsychological impairments are present inpatients with the idiopathic form of RBD has led to the suggestion that thecondition may represent a risk factor for evolution to dementia, an hypoth-esis that needs to be evaluated with longitudinal studies. The high frequencyof RBD in the SNP probably reflects the pathological involvement of specificbrainstem nuclei in these conditions. Similarly, it has been suggested that vi-sual hallucinations, which are one of the diagnostic hallmarks of DLB, maybe attributed to a disease-specific physiopathological mechanism of corticalfunctional imbalance.

27MCI and Alzheimer’s diseaseH. FeldmanClinic for Alzheimer’s Disease and Related Disorders, University of BritishColumbia (Vancouver, CA)

The broad spectrum of neuropsychiatric symptoms (NPS) that occurs inAlzheimer’s disease (AD) can be considered along both the stages of diseaseand its sub-classification into type of symptoms (e.g. psychosis, affect andbehavior). NPS have a complex genesis that includes neurobiological, socialand psychological factors which interplay and which must be taken into con-sideration. Together, NPS represent one of the strongest predictors of the fu-ture need for nursing home placement and are associated with caregiver dis-tress including increased their increased use of psychoactive medications,poorer self-rated health and depression.

Recently proposed AD research criteria require that there be a gradualand progressive impairment in episodic memory with supportive biomark-ers of medial temporal lobe atrophy on MRI, abnormal temporal parietalFDG PET and abnormal A 1-42, total tau and p-tau in CSF. This case defini-tion allows that patients can be diagnosed in the prodromal stage of AD be-fore there is significant multidomain cognitive impairment with significantfunctional disability. It is important in turn to characterize the NPS withinthis prodromal stage. While there is no specification around the presenceand type of NPS symptoms in prodromal AD studies indicate that the mostfrequent symptoms on the Neuropsychiatric Inventory are depression, apa-thy, irritability and anxiety. Their presence is associated with a significantlyincreased risk of progression from defined Mild Cognitive Impairment toAD and they are associated with increased levels of cognitive impairmentand functional disability.

In the mild to moderate stages of AD, agitation and aberrant motor ac-tivity become particularly prevalent as they affect 50-66 % of patients andbegin to negatively impact social function. Current recommendations forcare of NPS in mild to moderate AD include both routine evaluation for NPSas well as a multidimensional plan that includes community programs, non-pharmacological and pharmacological treatments.

The moderate to severe stages of AD include the highest rates of preva-lence of NPS and the time when management is most challenging as se-mantic memory, and language abilities become most impaired. Maintainingcircadian rhythms, addressing psychosis and managing agitation areamongst the challenges clinicians face at a time when pharmacological op-tions with psychoactive medications are used with increasing cautionaround their risks and benefits. The utility of acetylcholinesterase inhibitorsand memantine are a treatment option with potential benefit on NPS andcan represent a useful treatment consideration at these stages.

28Behavioural disturbances in frontotemporal lobar degeneration: recent ad-vances in molecular genetics and neurobiologyE. Scarpini, Daniela GalimbertiUniversity of Milan, Fondazione Ospedale Maggiore Policlinico (Milan, IT)

Behavioural symptoms, including apathy, dishinibition, irritability, are typ-ical features of neurodegenerative dementias. Among these disorders, Fron-totemporal Lobar Degeneration (FTLD) represents the second most com-mon type of early-onset degenerative dementia after Alzheimer’s disease.FTLD is the clinical term used to describe a complex and heterogeneous syn-drome that includes Frontotemporal Dementia (FTD), semantic dementia(SD), and Progressive Aphasia (PA). More recently, Progressive SupranuclearPalsy (PSP) and Corticobasal Degeneration Syndrome (CBDS) have beenconsidered under the same label of FTLD, because they overlap both clini-cally and neuropathologically. The presenting clinical features consist of be-havioral dysfunction and personality changes, often with language impair-ment, loss of social awareness, overeating and impulsiveness, whereasmemory is relatively spared. Concerning FTLD, in 1994 an autosomal dom-inantly inherited form of FTD with parkinsonism was linked to chromo-some 17q21.2. Subsequently, other familial forms of FTD were found to belinked to the same region, resulting in the denomination “frontotemporaldementia and parkinsonism linked to chromosome 17” (FTDP-17) for thisclass of diseases. All cases of FTDP-17 have so far shown a filamentouspathology made of hyperphosphorylated tau protein. Although many FTDfamilies exhibit MAPT mutations, in some cases these mutations did not oc-cur suggesting that other, related genes on chromosome 17 also cause FTDin an autosomal-dominant manner.

Subsequently, the region within the 3.53 centimorgan critical region de-fined by haplotype analysis in reported families was examined.Several path-ogenic mutations were found in progranulin gene (PGRN), harbouring anew causative gene in FTLD pathology. Progranulin is a widely expressedgrowth factor, which plays a role in development, wound repair and inflam-


5

mation by activating signalling cascades that control cell cycle progression.Its role in neurodegeneration is at present under investigation. Neu-ropathology analysis revealed that ubiquitin immunoreactive neuronalcytoplasmatic and intranuclear inclusions were associated with PGRN mu-tations. Additional studies demonstrated that mutations in PGRN are asso-ciated with highly variable clinical phenotypes, including PSP and CBDS,suggesting that other unidentified environmental and genetic factors mightproduce considerable phenotypic variability even in patients carrying thesame mutations.

Autoimmune disorders of the nervous system

29Latest developments in multiple sclerosisG. ComiUniversità Vita Salute San Raffaele (Milan, IT)

Some recent epidemiological studies suggest that the prevalence of multiplesclerosis (MS) in increasing.The modification of the risk has been attributedto the changes in lifestyles or to a more strict control of infections in earlylife because of the ameliorated hygienic conditions. The increase of preva-lence seem to be predominantly present in females, a finding in line with thefirst hypothesis. Last year has been a break through in genetic analysis ofMS: besides the well known role of two other genes codifying for the inter-leukin 7 receptor and the interleukin 2 receptor alpha have been discoveredto ply a significan role in MS. A great contribution to the discovery camefrom whole genome analysis, thank to the contribution of the concerted ac-tion of many centres. Ongoing studies on subgroup of patients may con-tribute to clarify the other genetic factors determining the risk of MS and in-fluencing the disease course.Genomic and proteomic studies are also largelyused to evaluate pathways involved in MS pathogenesis and are expected tocontribute to a more individualised treatment. The role of environmentalfactors has been recognised since a long time, nevertheless the ascertain-ment of toxic or infective factors involved remain questionable at the best.Agreat attention has been arised about the potential role of Epstein Barr virus:a recent study found EBV genome in the majority of a group of MS brain andexceptionally in control brain. These findings have not been replicated yetfrom other laboratories.

There are growing evidences that the immunoloical abnormalities char-acterising MS change along the disease evolution. In the early phases thereis a predominant role of the acute inflammatory lesions, inflammation in MSis dominated by class I MHC restricted CD8+ T-cells, with a potential rolefor CD4+ T cells in initiating the lesions. On the progressive phases of MSthe immunological derangement is compartimentalized with evidence oflymphatic like tissue in subependimal space. Moreover grey matter involve-ment, rare in early MS become relevant. The correlation between early andlate immunological changes remain elusive.

Therapy of MS is substantially improved; availability of different drugswith specific efficacy/safety profile call for the individualisation of treat-ments based on the prognostic factors and the disease phase. Early treat-ment is perhaps the most important strategy to follow,recently supported bythe evidence that the control of inflammation in early MS allow to signifi-cantly modify the short and long term disease evolution.

30Autoimmune diseases of the neuromuscular junctionA. VincentJohn Radcliffe Hospital (Oxford, UK)

Myasthenia gravisMost patient with myasthenia gravis have AChR antibodies (AChR-MG) thatcause morphological damage,by cross-linking the AChR divalently resultingin increased internalization and degradation, and by direct inhibition of theACh binding site causing a pharmacological block of function. Patients withMG can be divided into subgroups based on age at onset, HLA association,thymic involvement, and AChR antibody status. Thymoma occurs in up to10 % of MG patients, mostly presenting between the ages of 30 and 60 years.Ocular MG occurs in about 20 % of patients, and only 50 % have AChR anti-bodies.

About 10 % to 15 % of all patients with MG and generalized symptomsdo not have anti-AChR antibodies detectable by the radioimmunoprecipita-tion test.A proportion of patients without AChR antibodies have antibodiesto MuSK which is a receptor tyrosine kinase restricted to the neuromuscu-lar junction in mature muscle. Interestingly, the prevalence of MuSK anti-

bodies among patients without AChR antibodies is highly variable betweendifferent centres around the world suggesting a possible environmentalstimulus. They are mainly IgG4, and are almost never found in patients withAChR antibodies or with thymoma. The distinctive features of MuSK-MGare often marked ocular, bulbar, neck or respiratory symptoms and, in con-trast to AChR-MG, the patients may have normal electrophysiology in limbmuscles with evidence of neuromuscular defects in facial muscles (eg. Or-bicularis occuli). They respond to immunosuppression with prednisoloneand azathioprine but often alternative immunosuppressive treatments arerequired. It is not yet clear how the antibodies cause the neuromuscularjunction defect.

There remaining patient usually have less severe symptoms and are moreresponsive to standard treatments than the MuSK-antibody positive pa-tients. Recently we proposed that they have AChR antibodies undetectableby current laboratory tests.At least a proportion of these patients have AChRantibodies detectable by an immunofluorescent method using human em-bryonic kidney cells to express AChRs at high density (Leite, Willcox andVincent unpublished observations).

Other neuromuscular junction disordersTwo other autoimmune diseases of the neuromuscular junction, the

Lambert Eaton syndromes and acquired neuromyotonia,are associated withantibodies to voltage-gated calcium and potassium channels respectively. InLEMS the antibodies are found equally in cases with or without small celllung cancer (or rarely other tumours) but those with cancer may also de-velop cerebellar ataxia. The peripheral symptoms tend to improve withtreatment whereas the central symptoms rarely show a good response.About 20 % of cases of acquired neuromyotonia are associated with thy-moma, and/or myasthenia. Most patients can be treated with anti-epilepticdrugs and do not need immunosuppression. However, Morvan’s syndrome(severe neuromyotonia, autonomic and central disturbance) often requiresimmunotherapies, although some cases show spontaneous improvementover time.

31Pathogenesis and treatment of the Guillain-Barré syndromeH-P. HartungHeinrich-Heine-University (Dusseldorf, DE)

Guillain-Barré syndrome (GBS) continues to be a challenge as an emergencycondition associated with significant mortality and disability. Recent yearshave witnessed enormous advances in deciphering the pathogenesis of GBS.It is now widely accepted that GBS represents a spectrum including AIDP,AMAN, AMSAN, Fisher syndrome (FS), and regional variants. Most are pre-ceded by an infective illness and the leading bacterial agent recorded is C. je-juni. The detection in sera of antibodies to gangliosides and related gly-cosphingolipids of protean specificities and to ganglioside complexes hasprompted efforts to establish a link through the process of molecular mim-icry.The case has been proven most convincingly for the AMAN variant ofGBS. Epidemiologically, there is a clear relationship between antecedent C.jejuni infection and the presence of ganglisode IgG antibodies, mostlyagainst GM1, GD1a anfd GalNAc-GD1a. Parenteral administration of gan-glsiodemixtures generated in few patients an anti-GM1 IgG response andAMAN type neuropyhsiology and neuropathology. It has been possible toinduce a replica of AMAN in rabbits by immunizing with GM1 and similarlyby injectinmg an isolated lipoologosaccharide fraction from a C. jejunistrain associated with development of GBS that contained GM1-like epi-topes. In FS, a GT1a-like lipooligosaccharide mimicking GQ1b was purifiedfrom a C. jejuni isolate emphasizing that epitopes shared between the mi-crobial agent and peripheral nerve drive an antibody response that under-lies the neuropathy. The clinical manifestation within the spectrum of GBSmay be largely determined by lipooligosaccharide biosynthesis genes andtheir polymorphisms. Ganglioside antibodies may perturb neuromusculartransmission and in a clearly complement-dependent fashion disrupt themolecular topography of nodal and paranodal proteins, induces motor ax-onal degeneration and perisynaptic Schwann cell injury.

Supportive and intensive care management had already greatly im-proved the guarded prognosis of GBS when in the 1980s plasma exchangeand later IVIG were introduced as equally effective treatments. Some pa-tients however still show a poor recovery, in particular when axonal damageoccurs during the course of the disease.

Given the key impact of complement activation with assembly of themembrane attack complex,complement targeted therapies have successfullybeen studied in animal models.Most recently the monoclonal C5 convertaseantibody eculizumab, approved for paroxysmal nocturnal haemoglobin-uria, was shown to prevent functional and pathological changes in an invitro and an in vivo model of FS.

In view of the pathological heterogeneity of the disease, other im-munointerventions directed at T cells may also be worth assessing.


6

References

Halstead SK et al. (2008) Brain epubaheadKieseier BC et al. (2004) Muscle Nerve 30:1131–156Kiesier BC et al. (2006) Curr Opin Neurol 19:433–436 and 437–445Meyer zu Hörste G et al. (2007) Nat Clin Pract Neurol 3:198–211Meyer zu Hörste G et al. (2008) Muscle Nerve 37:3–13Yuki N (2007) Muscle Nerve 35:691–711

32Immunopathogenesis of inflammatory myopathiesR. HohlfeldLudwig Maximilians University (Munich, DE)

Three types of inflammatory myopathy are traditionally distinguished:polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis(DM). IBM is the most common inflammatory myopathy in adults, whereas“pure” PM is much less common than was previously thought.

In PM and especially IBM, clonally expanded, CD8-positive T cells in-vade muscle non-necrotic fibers expressing MHC class I antigens. Thecausative target antigen(s) have not been defined. Recently it became possi-ble to “revive” putatively pathogenic, autoimmune CD8+ T cells from frozenmuscle biopsy tissue. These “resurrected” T cells can be used to search forthe target antigen(s). Apart from T cells, the inflammatory infiltrates in PMand IBM muscle contain B cells, macrophages, and myeloid dendritic cells.

In DM the mechanisms of muscle fiber injury seem to be different. Theinfiltrates contain plasma cells and plasmacytoid dendritic cells. Accordingto one hypothesis, anti-endothelial antibodies cause capillary injury andsubsequent peri-fascicular atrophy. According to another hypothesis, anti-DNA and/or anti-RNA antibodies play a major role, triggering a cascade ofpathogenic changes amplified by interferon-alpha, as has been proposed forsystemic lupus erythematosus.

References:

Hohlfeld, Engel (1994) Immunol Today 15:269–274Wiendl, Hohlfeld, Kieseier (2005) Trends Immunol 26:373–380Dalakas, Hohlfeld (2003) Lancet 362:971–982Greenberg (2007) Neurology 69:2008–2019Hohlfeld, Engel (2007) Neurology 69:1966–67

Multiple sclerosis: when to start a treatment and whichtreatment

46The rationale for early treatment in multiple sclerosisA. CompstonUniversity of Cambridge (Cambridge, UK)

The arrival of therapies that are considered to modify the course of multiplesclerosis, and the licensing of the first wave of medications, marks the be-ginning of an era that will close with the discovery of fully effective and safemedicines for this complex and potentially disabling disease.Taken together,the results of clinical trials support the hypothesis that inflammation is nec-essary for new lesion formation and conditions axon degeneration. The im-plication is that immunological therapies will best prevent sustained accu-mulation of disability and disease progression if given early in the courseand before the cascade of events leading to axon degeneration is irretriev-ably established. This may explain the present limitations of immunother-apy in patients with secondary progressive multiple sclerosis. But it raisesthe dilemma of exposing individuals who may never develop disabilitiesfrom multiple sclerosis to the unpredictable hazards of prolonged immuno-suppression as the price paid for stabilising the disease process in those whoare destined to do badly. The goals of future therapies in multiple sclerosismust confront the main unmet need of how to limit the neurodegenerativeaspect of disease progression. One analysis of the interplay between inflam-mation and neurodegeneration is that areas of focal damage, constitutingplaques, are driven by inflammation and microglial activation. Regions ofthe central nervous system or the brain and spinal cord as a whole may begenetically susceptible to neurodegeneration but this vulnerability never-theless has to be exposed by inflammation. Early treatment aims to inhibitthe establishment of immunological chronicity manifesting as diffuse mi-croglial activation; protect intact axons from acute injury using anti-excito-toxic and membrane stabilizing agents; provide trophic support for persis-tently demyelinated axons using growth factors and strategies that might

include pharmaceutical strategies for enhancing remyelination; and pro-mote plasticity and axon regeneration by manipulation of extracellular ma-trix molecules and manipulation of inhibitory environments. Together, it ishoped that these interacting processes will effectively and safely limit and re-pair the damage.

47Starting treatment after a CISG. ComiUniversità Vita Salute San Raffaele (Milan, IT)

There are converging evidences that axonal damage starts very early in mul-tiple sclerosis (MS). This early nervous damage occurring inside the de-myelinating lesions is due to inflammation, which is predominant in earlystages of MS. In order to prevent irreversible nervous damage, the underly-ing cause of disability, it is essential to start disease modifying treatment asearly as possible.

Patients with a Clinically Isolated Syndrome (CIS) and exclusion of otherdiseases, have a high risk of developing MS, particularly if they show abnor-malities on the initial magnetic resonance imaging (MRI) scan of the brainand/or evidences of intrathecal synthesis of immunoglobulins. Epidemio-logical studies and clinical trials performed in CIS patients demonstratedthat, whitin 2 years, about 90 % of these patients can be diagnosed as MS ac-cording the McDonald criteria. Moreover patients with a high number of le-sions and/or enhancing lesions in the bran MRI performed at first presenta-tion, have a very high risk of experiencing a second attack shortly after thefirst. Baseline MRI feature in patients with a first event seem not only to de-termine the risk of conversion to clinically definite MS, but also correlatewith later disability.

All the three clinical trials of beta interferons conducted in CIS patients- the BENEFIT study, the Controlled High-risk Avonex multiple sclerosisPrevention study (CHAMPS) and the Early Treatment of MS study (ETOMS)– have shown that treatments can reduce the rate of conversion to clinicallydefinite MS, prolong the time to the second attack and reduce brain MRI ac-tivity. Extension of these studies confirmed that even after 5 years of followup patients who received immediate treatment still maintain a significantbenefit on the prevention of a second attack.Moreover the 3-year data analy-sis of the BENEFIT trial revealed a significant (40 %) reduction of the risk ofconfirmed EDSS progression in those who received immediate treatmentcompared to those who had a delayed interferon beta 1b treatment (after the2 years of the double blind phase), a definite evidence that early treatmentprotects from irreversible nervous damage. More recently the PRECISE clin-ical trial demonstrated that also Glatiramer Acetate significantly reduce inCIS patients the risk of conversion to clinically definite MS by 44 %.

Based on the uniform positive results of all these clinical trials treatmentof CIS with beta interferons is now widely recognized and both EMEA andFDA approved this indication; unfortunately some countries still refuse toreimburse such treatment to CIS patients for economic reasons. Neverthe-less not all CIS patients should receive an immediate treatment. Patientswithout brain/spinal cord lesions have a low risk to develop a second attack.The same reservation against an immediate treatment should be appliedalso to CIS patients without an adequate exclusion of alternative diagnoses.

48Starting treatment when definite MS is diagnosedC. ConfavreuxHôpital Neurologique (Lyon, FR)

The therapeutic armamentarium in multiple sclerosis (MS) have greatly de-veloped over the last years, notably for relapsing forms of MS. Moreover, newtherapies are continuously emerging.Since 1993,several pivotal studies haveshown that beta-interferons and glatiramer acetate, at the stage of clinicallydefinite MS (CDMS), are able to reduce relapse frequency and MRI activityby about 30 % and 50 %, respectively. However, their impact on the accumu-lation of disability in the mid and long run remains uncertain. In the latenineties, several studies suggested that efficacy among interferons could dif-fer depending on the unit dose per intake and the frequency of administra-tion. That said, none of these studies was definitely convincing, especiallywhen blinding was considered. Last months have introduced some clarifica-tion and simplification in the area. Indeed, different studies (BEYOND, RE-GARD, BECOME) have allowed an head-to-head comparison between sev-eral drugs. The conclusion is that the different beta-interferons andglatiramer acetate exhibit a similar level of efficacy in relapsing MS. In themeantime, natalizumab has emerged as a new therapy with a much greaterefficacy as it decreases the relapse rate by 60 % and MRI activity by 80 %. Un-fortunately, it is also likely to induce serious infectious and, possibly, neo-plastic complications requiring the closest monitoring while administrating


7

the drug.Last,but not least, since early 1990’s, several studies have shown themain advantage of intensive immunosuppressive interventions with mitox-antrone and, to a lesser extent, with cyclophosphamide, in aggressive formsof MS.

Considering the different treatments available and current evidence oftheir efficiency, what are the therapeutic choices to the physician in 2008 indefinite MS? Official guidelines for the approved therapies may prove quiteuseful as a first guide. In the relapsing forms of MS with a low relapse rate,the choice to treat can be dismissed according to many criteria including thepatient’s wish. In more active forms with,at least,one or two relapse(s) in theone or two preceding year(s), it is logical to propose interferons or glati-ramer acetate. In some cases, and for various reasons, oral immunosuppres-sants such as mycophenolate mofetil, or even azathioprine, can also be sug-gested. These treatments are the first-line of interventions. In the cases witha more severe clinical activity and those showing resistance to interferons orglatiramer acetate, it is logical to prescribe natalizumab with a close moni-toring. This therapy is proposed in the second place. Last, in the rare formsof aggressive MS right from onset or during a disease breakthrough, oneshould propose third place therapies like mitoxantrone, or even cyclophos-phamide.

This apparently simple therapeutic design hides many uncertaintiesthough.When to start a treatment? Which is the place of MRI in therapeuticdecisions? Which first-line therapy is to be proposed? What are the criteriasto assess the efficacy of a treatment? When to stop a treatment? When to ad-just a treatment or to switch to another one? Should one look for therapeu-tic windows after a given period, let us say 24 months, of continuous treat-ment with natalizumab? Should one propose a treatment to take over frommitoxantrone or cyclophosphamide and which treatment ? This list is notlimitative … Despite these many uncertainties, it is clear that MS has enteredthe therapeutic area and that it is nowadays possible to tailor the immuneintervention for controlling the acute focal recurrent inflammatory processwhich is the first edge of MS.Are we able to control in parallel the diffuse andprogressive neurodegenerative process which is the other edge of the dis-ease? This is another story. We may expect however that concentrating onmolecules which are able to penetrate in the central nervous system beyondthe blood-brain barrier and on early and intensive immune interventioncould represent the next significant steps in the long route of the cure of thisoften devastating disease.

49Immunosuppresents as first choice, followed by immunomodulatory agentsR.P. LisakWayne State University School of Medicine (Detroit, US)

After 140 years of no therapies that successfully modify the course relapsingremitting multiple sclerosis (MS), the past 15 years have seen the approvalof three types of therapy (interferon-beta, glatiramer acetate and natal-izumab) that have been demonstrated to reduce relapses and have a positiveeffect on progression to disability, at least over the periods of time that arefeasible for clinical trials. There are new agents being tested that also holdpromise and studies of combinations of approved agents. Suggestions havebeen made that intensive immunosuppression can be of benefit for patientswho are clearly having frequent relapses despite treatment with one or moreof the approved agents. All of this supports the clinical observation that thecurrent therapeutic approaches are imperfect. This has lead to the sugges-tion of inducing disease control with immunosuppressive agents given si-multaneously or for several months before initiating treatment with an im-munomodulatory agent that is know to have acceptable side effects, limitedtoxicity and tolerability. Most published studies combining immunosup-pression with immunomodulatory agents are, as noted, for treatment fail-ures and there are very few studies of any size or with controls demonstrat-ing the efficacy or even the long-term safety of such an approach.As we haveseen one cannot assume that combinations are safe, even short-term induc-tion therapy. This argues against routine use of induction therapy with im-munosuppressive therapy followed by immunomodulation. Two questionsneed to be considered. One is how would you organize such a study includ-ing patient selection, selection of agents and outcome measures. The relatedquestion is that in the absence of such available data, are there patients inwhom the theoretical benefits and their clinical course at the time of diag-nosis or prior to any treatment with disease modifying agents, should be of-fered such therapy.

Transient ischaemic attack (TIA): imaging and management

50Diagnosis and risk assessment for TIAP.M. RothwellUniversity of Oxford (Oxford, UK)

Approximately 30 % of ischaemic strokes are preceded by a transient is-chaemic attack (TIA). However, due to methodological problems in earlystudies of prognosis, the immediate risk of stroke after a TIA was underes-timated. Recent hospital-based and population-based cohort studies havereported 7-day risks of stroke of up to10 %. Yet, there is considerable inter-national variation in how patients with suspected TIA are managed in theacute phase, with some healthcare systems providing immediate emergencyinpatient care and others providing non-emergency outpatient clinic as-sessment. Clinical guidelines state that all patients in whom a diagnosis ofTIA is suspected should be assessed and investigated quickly, although thetime limit set varies from 24 hours to 14 days. However, the key question isnot, in fact, whether emergency in-patient care or non-emergency outpa-tient care is most appropriate. Rather, it is for which patients is emergencyassessment required and which patients can be appropriately managed in anon-emergency outpatient setting? Only about 50 % of patients referred forspecialist assessment with suspected TIA have the diagnosis confirmed andso even if the 7-day stroke risk after a TIA is as high as 10 %, 95 % of refer-rals will not have a stroke in that time period.

Validated scores are now available to predict the short-term risk of strokeafter TIA. These scores have several uses. Firstly, they allow primary care andother front-line physicians to identify which of the patients in whom theysuspect a diagnosis of TIA should be referred-on for specialist assessmentas an emergency. Secondly, they allow secondary care physicians to deter-mine which patients with probable or definite TIA require emergency in-vestigation and treatment. Thirdly, they allow public education about theneed for medical attention after a TIA to focus on the specific symptoms andcharacteristics that identify high-risk individuals.

The relationships between clinical risk scores and findings on brain andvascular imaging and other investigations are now being determined andcomposite scores are being derived and validated. It is likely that these mod-els will allow very accurate prediction of risk in individual patients, whichwill facilitate decisions about the urgency and intensity of treatment and theneed for hospitalisation, as well as the design of treatment trials in the acutephase after TIA.

Reliable data on prognosis, risk factors, and correlates with findings onbrain and vascular imaging is also leading to a better understanding of themechanisms of early recurrence, which is vital if effective new treatmentsare to be developed. Studies of biomarkers, particularly markers of an in-creased tendency to thrombosis, are also leading to potential new treatmenttargets.

There are, in fact, few other areas of clinical practice in neurology thathave seen such a rapid increase in understanding of prognosis, risk factors,investigation, mechanisms and treatment than TIA and minor stroke.

51Ultrasound and MRI in the diagnosis of transient ischaemic attacks (TIA)M.G. HennericiUniversity Clinic Mannheim (Mannheim, DE)

The most intense neuroimaging stroke research focuses upon expandingneuroimaging to provide information to the treating physican about theacute state of the ischaemic brain, and the risks and benefits that may be as-sociated with reperfusion therapy in a given individual. Clinically useful in-formation is likely to result from rapid, widely accessible and accepted tech-nologies that can distinguish brain tissue likely to die unless reperfused (=true penumbral tissue) from tissue likely to die despite reperfusion (= coretissue). Less developed but equally important are techniques to predictwhich patients are most likely to be at risk from reperfusion treatment e.g.from haemorrhage due to an apparent leakage of the blood-brain barrier.Decisions about returning blood flow to the ischaemic brain will be made onbiologic data regarding the amount and location (topographic aspects) aswell as regeneration/remodelling capacities (functional aspects) of braintissue that will die unless there is reperfusion. This cannot be achieved bymeans of the traditional definition of cerebral ischaemia (“TIA” vs. strokesubtypes based on the time course of relapsing/persistent clinical signs orsymptoms), which disregard the aforementioned instantaneous brain tissuechanges plus their underlying, often overlapping and rapidly changing vas-cular mechanisms (hemodynamic/embolic/collateral blood flow/small ves-sel perfusion/partial reperfusion and distal embolism from thromboticfragmentation etc).Short lasting,relapsing and remitting symptoms (“TIA”)


8

in the acute phase are highly specific predictors of a poor short-term prog-nosis but are still most difficult to assess with presently available neu-roimaging techniques (MRI/US) because of the obscure presentation andheterogeneity of associated oligaemic tissue, that will eventually survivewithout reperfusion (and without clinical deficit), but represents the area ofhighest vulnerability to deteriorate early within hours/days. While such ar-eas can be identified with current PET in highly selected patients recruitedin research studies only, areas of different degrees of abnormal perfusioncannot yet be discriminated by means of MRI/US. This is the most promis-ing area of research to develop algorithms for brain maps presumed to char-acterise core/penumbra/oligaemic areas and display changes during thespontaneous and treatment-related course in real-time. Pilot clinical studiesare on their way and will improve from currently developed hard- and soft-ware technologies. They will replace the already outdated concept of TIA inacute brain ischaemia.

52Feasibility and efficacy of ultra early evaluation and intervention after a TIAP. AmarencoHôpital Bichat-Claude-Bernard (Paris, FR)

Text not yet available

53TIA clinic conceptP. CanhãoHospital de Santa Maria (Lisbon, PT)

Patients with a transient ischemic attack (TIA) need urgent and expert eval-uation soon after their event, as they are at high risk of suffering a stroke. Itis controversial what the optimal setting for their first assessment is.Patientswith a suspected TIA are frequently seen at emergency department or bytheir family doctor as outpatient. Comprehensive testing and diagnosis of-ten cannot be organized at those places,and there is a long delay between theTIA and completeness of the diagnostic evaluation and start of treatment.Because the risk of stroke is higher in the first days after TIA, those types ofcare are currently considered unsatisfactory to prevent stroke. On the otherhand, some patients are directly referred and admitted to hospital, but thisapproach may be not cost-effective and carry unnecessary hospitalizationrisks.

TIA clinic is an alternative setting to evaluate patients with suspectedTIA,providing it can be of easy access,may be able to perform investigationsurgently, and initiate appropriate treatment soon after the TIA.

To be effective, TIA clinic should be immediately available. Long delaysto assessment to TIA clinic are not adequate. Audits usually identify thatlong delays to assessment are associated with high rates of recurrent strokebefore the clinical appointment.

TIA clinic should be organized to: 1) provide a standardized assessmentby vascular neurologists or specialist stroke services, able to distinguish be-tween TIA or minor stroke and other stroke mimics; 2) make available aux-iliary tests to clarify the etiology of the TIA, and exclude other conditions;3) Identify patients at high risk for subsequent stroke, for example accord-ingly to the ABCD2 score and the results of further ancillary tests; 4) makeclinical decisions,deciding whether the patient could be discharged home orbe admitted to a stroke unit; 5) Start immediately secondary prevention.

At the TIA clinic, immediate work-up diagnostic should be organized toprovide: brain imaging (either MRI or a CT scan); electrocardiography to ex-clude a high-risk source of cardiac embolism; carotid duplex ultrasonogra-phy and transcranial Doppler of brain arteries, to exclude a high-gradestenosis; routine blood tests; individual patients may need transthoracic ortransoesophageal echocardiography when a cardiac source for embolism issuspected.

Several reports confirmed the feasibility of urgent investigation andearly treatment of patients seen at TIA clinics. Some reports further suggestthat evaluation at TIA clinics and immediate treatment reduces stroke riskafter TIA. It is also likely to involve lower costs than those of hospitalization,and greater patient satisfaction because most of patients can be dischargedhome.

Improvement of the articulation between TIA clinics and primary carephysicians, emergency departments, and other clinics or hospital depart-ments, may increase the access of patients with suspected TIA, and their po-tential for preventing or treating stroke.

FREE COMMUNICATIONSOral Sessions

Oral session 1

Multiple sclerosis 1

O54Abnormal connectivity inside the motor network in patients with multiplesclerosis: a multicentre fMRI studyM. Rocca, M. Absinta, P. Valsasina, O. Ciccarelli, A.J. Thompson, L. Mancini,S. Marino, N. De Stefano, A. Rovira, X. Montalban, A. Gass, L. Kappos, C. Weg-ner, C. Enzinger, S. Ropele, T. Korteweg, F. Barkhof, P.M. Matthews, M. FilippiScientific Institute San Raffaele (Milan, IT); University College London(London, UK); University of Siena (Siena, IT); Hospital Vall d’Hebron(Barcelona, ES); University Hospital (Basel, CH); University of Oxford (Ox-ford, UK); Medical University Graz (Graz, AT); VU University Medical Cen-tre (Amsterdam, NL); Imperial College and Hammersmith Hospital (Lon-don, UK)

Objectives: In small groups of multiple sclerosis (MS) patients,abnormal ac-tivations of areas of the sensorimotor network and, more recently, abnormalconnectivities between these areas have been shown. The aims of this studywere to characterize abnormalities of functional connectivity within themotor network in a large number of MS patients and their correlation withstructural MRI parameters.We also assessed the feasibility of a multi-centrefMRI studies of brain connectivity.

Methods: Structural and functional MRI scans during right hand move-ment were acquired in 61 right-handed MS patients without hand impair-ment and 74 age-matched controls at eight European sites. T2 lesion load(LL) and corpus callosum area (CCA) were measured. In a subgroup of sub-jects, diffusion tensor (DT) MRI metrics inside the CC and the corticospinaltracts (CST) were also assessed.

Results: CCA was reduced in MS patients compared to controls(p < 0.0001). DT MRI metrics inside the CC and the left CST were signifi-cantly abnormal in MS patients compared to controls. Dynamic causal mod-elling optimisation showed that in both patients and controls a model withthe left primary sensorimotor cortex (SMC) as the seed region to computecorrelation maps was the best predictor of system behaviour. In this model,compared to controls,MS patients had increased functional connectivity be-tween: the left primary SMC and the left prefrontal cortex (PFC), the left PFCand the supplementary motor areas (SMA) and vice versa, the left secondarysensorimotor cortex (SII) and the SMA and vice versa, the right SII and theSMA and vice versa, the left SII and the right SII, and the right SMC and theSMA. They also showed reduced functional connectivity between the leftSMC and the right cerebellum. No interaction was found between diseasegroup and centre. Coefficients of altered connectivity were weekly corre-lated with brain T2 LL and moderately correlated with left CST damage.

Conclusions: Multi-centre fMRI studies of functional connectivitychanges in diseased people are feasible. This large fMRI study shows consis-tent changes of measures of abnormal functional connectivity in MS pa-tients in comparison with controls,which might have an adaptive role in lim-iting the clinical consequences of structural damage. The analysis ofconnectivity shows that short-range connectivities are enhanced as long aslong-distance connectivities might be impaired by progressive pathology.

O55Functional sensory motor connectivity is preserved in patients with paedi-atric multiple sclerosisM. Rocca, M. Absinta, A. Ghezzi, L. Moiola, M. Sormani, G. Comi, M. FilippiScientific Institute San Raffaele (Milan, IT); Department of Neurology (Gal-larate, IT)

Objectives: The occurrence and effectiveness of adaptive cortical mecha-nisms have been considered among the factors contributing to limit the clin-ical manifestations of multiple sclerosis (MS). To further elucidate the roleof brain plasticity in MS, we investigated changes of measures of functionalconnectivity inside the motor network in patients with pediatric MS, whoare usually considered to have a more favourable clinical course, in compar-ison with those with the adult-form of the disease. We also assessed the cor-relation between changes of measures of connectivity and structural dam-age within the corpus callosum (CC) and the corticospinal tract (CST).


9

Methods: Dual-echo, diffusion tensor MRI and functional MRI scansduring right hand movement were acquired in 17 patients with pediatric MS,16 adult patients with clinically isolated syndromes (CIS) suggestive of MS,14 adult patients with relapsing-remitting (RR) MS and no clinical disabil-ity, and 10 healthy controls. Whole brain, CC and CST T2 lesion load (LL) aswell as diffusivity metrics within the CC and the CST were measured.Analy-sis of connectivity was performed using a dynamic causal modelling (DCM).

Results: DCM analysis showed that coefficients of connectivity of thesensorimotor network were similar between healthy controls and pediatricMS patients, while in adult patients with CIS and in those with RRMS therewas a progressive increase of functional connectivity between the left andthe right primary sensorimotor cortex (SMC) and vice versa, the right cere-bellum and the left SMC,the right cerebellum and the right SMC,the left sec-ondary sensorimotor cortex (SII) and the left SMC, and the supplementarymotor area and the left SMC. All these connectivity changes were more pro-nounced in patients with RRMS. Increase of coefficients of connectivity wascorrelated with disease duration and regional damage inside the CC and theCST.

Conclusions: The preservation of brain adaptive properties might con-tribute to explain the more favourable clinical outcome of pediatric MSpatients. The progressive recruitment of cortical networks over time inpatients with the adult forms of the disease, partially related to the accumu-lation of irreversible structural damage in selected white matter regions,might result in a more precocious exhaustion of the their plastic reservoir,thus contributing to the clinical progression of the disease.

The study was supported by a grant from the Fondazione Mariani (contractR-07-62).

O56Detection of EBV antigens in germinal centres in the brain of people withmultiple sclerosisC. Maggiore, G. Trillo-Pazos, R. Reynolds, G. Giovannoni, D. MillerInstitute of Neurology (London, UK); Imperial College (London, UK)

Objectives: Understanding the neuropathology of multiple sclerosis (MS) isessential to understand mechanisms of damage and to develop new thera-pies. MS lesions have distinct histological and immunopathological charac-teristics depending on disease activity. However, the aetiology of the im-mune response in this disease is still unknown.

Importantly, in a significant proportion of people with MS (PwMS) af-fected by a secondary progressive disease ectopic B-cells follicles with ger-minal centers can be detected in the meninges. These data have been alreadyconfirmed by Prineas et al. and Serafini and al. and our preliminary data. Inthis study, we tested for the presence of germinal centres and EBV infectionin MS, as recent studies have involved EBV as a possible trigger agent of dis-ease activity.

Methods: Using snap frozen brain blocks from PwMS provided by MStissue bank UK, we identified by immunohistopathology lesions and lym-phoid infiltrates.

We used different markers for lymphoid tissues and in particular CD79afor the B-lineage, CD68 for macrophages, CD19 for B lymphocytes and CD20for mature B cells and follicular dendritic cells; for lesions we used GFAP,MAP2, PLP and CNPase. We stained for EBV involvement in the lesions andin the tertiary lymphoid organs (TLOs) using antibodies targeting antigensof EBV latent phase such as EBNA-1, LMP-1 and LMP-2a.

Results: We confirmed the presence of germinal centres that are CD20+,CD21+, CD3+ with expression of EBV antigens (EBNA1, LMP-1 LMP-2) inbrains of PwMS. These germinal centres were microdissected using lasercapture microdissection to test for the presence of viral gene expression us-ing The Human Panviral Diagnostic Array.

Conclusion: In contrast with classic germinal centers, TLOs are found in non-lymphoid tissue and are defined by chronic inflammation, the local production of immunoglobulin, and the chronic upregulation ofchemokines normally absent in these tissues. EGCs are a feature of severalchronic infectious and inflammatory diseases, including rheumatoid arthri-tis, ulcerative colitis, Sjögren’s syndrome, and Helicobacter gastritis. Ourpreliminary data suggest that MS can follow the same pathogenic mecha-nism and that EBV could be the trigger agent in EGCs of SPMS. Currently weare testing if other viruses are also present within MS at different stages ofdisease using a microgenomics approach.

O57Structural and functional MRI abnormalities of the language network in pri-mary progressive multiple sclerosis: a combined functional MRI and trac-tography studyM. Rocca, A. Ceccarelli, G. Riccitelli, M. Rodegher, G. Comi, M. FilippiScientific Institute San Raffaele (Milan, IT)

Objectives: Impairment of several cognitive domains, including attention,memory, reasoning and verbal fluency, is frequently encountered in patientswith primary progressive multiple sclerosis (PPMS). In this study, we com-bined functional magnetic resonance imaging (fMRI) and diffusion tensor(DT) MRI tractography to explore functional and structural abnormalitiesof the language network in PPMS patients.

Methods: Using a 3 Tesla scanner, dual-echo, DT MRI and fMRI duringthe performance of a verbal fluency task were acquired from 15 right-handed PPMS patients and 17 sex- and age-matched healthy volunteers.Neuropsychological tests (NPT) exploring memory,attention,verbal fluencyand reasoning were administered. DT MRI tractography was used to calcu-late DT derived metrics inside the left and right arcuate fasciculus. The cor-ticospinal tracts (CST) were studied as “control” white matter fiber bundles.fMRI analysis was performed using statistical parametric mapping.

Results: None of the patients showed abnormal performance in NPT ex-ploring verbal fluency. Compared to controls, PPMS patients had increasedMD values in the arcuate fasciculus and CST, bilaterally. During fMRI, com-pared to controls, PPMS patients had significantly reduced activation of theleft caudate nucleus and the left inferior frontal gyrus (IFG). They alsoshowed increased activation of the left precuneus, and the inferior parietallobule, bilaterally. In PPMS patients, MD increase in the left arcuate fascicu-lus was significantly related to increased activation of the left precuneus(r = 0.87) and decreased activation of the left caudate nucleus (r = –0.83) andthe left IFG (r = –0.86), while no correlations were found with CST damage.

Conclusions: In PPMS patients without verbal fluency deficits, abnormalrecruitment of language-related network occurs. The correlation found be-tween measures of abnormal activation and selective damage of the left ar-cuate fasciculus suggests that functional cortical changes in patients withPPMS might represent an adaptive response driven by damage of specificWM structures.

This study was supported by a grant from FISM (Fondazione Italiana Scle-rosi Multipla) – contract n. 2003/R/48.

O58Magnetic resonance imaging findings of a phase III trial comparingBetaferon® with Copaxone® treatments in relapsing-remitting multiplesclerosisM. Filippi, B.G.W. Arnason, G. Comi, S. Cook, D. Goodin, H-P. Hartung, D.Jeffery, L. Kappos, P. O’Connor, T. Bogumil, B. Stemper, V. Filipov, M. Groth,F. BoatengScientific Institute University Hospital San Raffaele (Milan, IT); SurgeryBrain Research Institutes (Chicago, US); UMD New Jersey Medical School(Newark, US); University of California (San Francisco, US); Heinrich-Heine-Universitat (Dusseldorf, DE); Wake Forest University School of Medicine(Winston-Salem, US); University Hospital (Basel, CH); St Michael’s Hospital(Toronto, CA); Bayer Schering Pharma AG (Montville, US); Bayer ScheringPharma AG (Berlin, DE)

Objective: To directly compare magnetic resonance imaging (MRI) out-comes in relapsing-remitting multiple sclerosis (RRMS) patients treatedwith interferon beta-1b (IFNB-1b; Betaferon®) or glatiramer acetate (GA;Copaxone®).

Methods: This Phase III, randomised,multicentre study was a large-scalehead-to-head comparison of the efficacy, safety and tolerability of IFNB-1b500 mcg, IFNB-1b 250 mcg and GA 20 mg. Treatment-naïve patients withRRMS were randomised to subcutaneous IFNB-1b 500 mcg or 250 mcgevery-other-day, or GA 20 mg daily for ?104 weeks. Changes in MRI para-meters, including T2-weighted, and T1-gadolinium (Gd)-enhancing lesions,volume of T1-weighted hypointense,and total brain volume,were secondaryor exploratory endpoints. MRI scans were performed at screening and an-nually.

Results: The clinical efficacy and tolerability results of this study havebeen presented elsewhere. A total of 2244 patients from 198 centres world-wide were randomised; 899 patients to IFNB-1b 500 mcg,897 to IFNB-1b 250mcg and 448 to GA 20 mg. At the end of the study, there were no significantdifferences between the groups in number or volume of T1 Gd-enhancinglesions. Similarly, there were no significant differences between groups inchange in volume of T1-hypointense lesions (‘black holes’) and brain vol-ume from screening. The cumulative number of T2 lesions at the end ofstudy, however, was lower in the IFNB-1b groups compared with GA


10

(p = 0.001 and 0.017 for 500 mcg and 250 mcg vs GA). T2 lesion volumechange between screening and study end was also lower in the IFNB-1bgroups compared with GA (p = 0.001 and p < 0.001).

Conclusions: This was the first large-scale study to directly compareIFNB-1b with GA and included MRI monitoring of all patients. There wereno differences between treatment groups in terms of T1-hypointense le-sions,T1 Gd-enhancing lesions and brain volume. This may indicate that theeffects of the two treatments on MRI-derived surrogates, potentially reflect-ing neuronal or axonal loss, are similar. IFNB-1b-treated patients however,experienced greater reductions in T2 lesion numbers and volumes thanthose treated with GA, suggesting differences in treatment effects on theoverall burden of disease.

This study was supported by Bayer Schering Pharma AG, Berlin, Germany

O59Treatment with glatiramer acetate delays conversion to clinically definitemultiple sclerosis in patients with clinically isolated syndrome suggestive ofMSG. Comi, M. Filippi on behalf of the PreCISe Study Group

Objective: To evaluate the efficacy of early treatment with glatiramer acetate(GA, COPAXONE®) in delaying progression to clinically definite multiplesclerosis (CDMS) in patients presenting with clinically isolated syndrome(CIS) suggestive of MS.

Background: GA reduced relapse rate and MRI-monitored disease activ-ity in relapsing-remitting MS patients. This is the first prospectivelyplanned, randomized, controlled, multicenter trial, which assessed the effi-cacy of GA therapy initiated shortly after the first clinical event suggestiveof MS.

Design/methods: Patients presenting with a first clinical event and > 2T2-weighted brain lesions > 6 mm were enrolled. Only patients with unifo-cal manifestation were randomized to receive either sc 20 mg/day GA orplacebo. The primary outcome was time to CDMS, based on a second clini-cal attack. MRI metrics served as secondary and exploratory endpoints.Treatment continued for up to 36 months, unless a conversion to CDMS oc-curred. A preplanned interim analysis was performed on data accumulatedfrom approximately 80 % of the three-year study exposure.

Results: A total of 481 patients were randomized to receive GA (n = 243)or placebo (n = 238). Key baseline characteristics were: age (31.1 ± 6.9 years),time from first event to randomization (74.0 ± 14.9 days), corticosteroid usefor first attack (64 % of patients), EDSS (1.0 ± 1.0), number (31.5 ± 30.7) andvolume (6.0 ± 6.2 ml) of T2 weighted lesions, and number (1.5 ± 2.9) and vol-ume (0.3 ± 0.6 ml) of Gd-enhanced lesions; no difference between the studyarms. Results from interim analysis showed that GA reduced the risk of de-veloping CDMS by 45 % compared to placebo. The 25th percentile time toCDMS was prolonged by 115 % for GA (to 722 days from 336 days forplacebo; hazard ratio 0.55, p = 0.0005). The proportion of patients convertedto CDMS was reduced from 43 % in the placebo to 25 % in the GA group(p < 0.0001).GA was well tolerated,with 16 % overall withdrawals to the timeof the interim analysis,and a safety profile similar to that observed in RRMS.Following the results of the interim analysis all subjects were offered openlabel therapy with GA and continued follow-up as planned in the originalprotocol.

Conclusions/relevance: The results establish efficacy of early treatmentwith GA on disease evolution in CIS patients and a positive scan at screen-ing MRI.

Study supported by TEVA Pharmaceutical Industries Ltd

O60The relationship between brain NAWM and GM damage is localised to spe-cific, clinically relevant areas in early primary progressive multiple sclerosisB. Bodini, Z. Khaleeli, M. Cercignani, D.H. Miller, A.J. Thompson, O. Cic-carelliInstitute of Neurology, UCL (London, UK)

Objectives: Magnetic Resonance Imaging (MRI) investigation of the early,most clinically dynamic stages of primary progressive multiple sclerosis(PPMS), allows examination in vivo of the pathological mechanisms under-lying progression. Diffuse MRI abnormalities have been demonstrated inthe normal appearing white matter (NAWM) and grey matter (GM) of pa-tients with PPMS. Aim of this study was to investigate whether and to whatextent the NAWM damage correlates with the connected abnormal GM, andhow their relationship contributes to disability.

Methods: We studied 35 patients with PPMS within five years of clinicalonset. All patients were assessed using the Expanded Disability Status Scale

(EDSS) and the Multiple Sclerosis Functional Composite (MSFC) subtests.The recently developed method of tract-based spatial statistics (TBSS) wasused to localise regions of reduced fractional anisotropy in the NAWM. Anoptimised voxel-based morphometry (VBM) approach was employed toidentify regions of GM atrophy in patients. Anatomical correspondence be-tween abnormalities in the NAWM and atrophy in the GM was identified,and quantitative correlation between the two compartments was then esti-mated using the Spearman’s correlation coefficient. In the quantitativelylinked areas, the relative contribution of NAWM and GM damage to disabil-ity, as measured by the EDSS and MSFC subtests, was assessed using multi-ple regression analyses.

Results: Patients showed widespread NAWM damage and diffuse GM at-rophy.Anatomical correspondence between reduced NAWM FA and reducedGM atrophy was found in 11 regions. Four of these areas showed a quantita-tive correlation, namely the right sensory-motor region with the adjacentcortico-spinal tract, the left and right thalamus with the corresponding thal-amic radiations and the left insula with the immediately adjacent white mat-ter. All four areas were clinically eloquent, showing an independent and dis-tinct contribution of NAWM and GM to disability.

Conclusions: NAWM damage and GM atrophy in early PPMS are inter-dependent in specific, clinically relevant brain regions. This suggests thatthere may be a link between the pathological processes occurring in the twocompartments in these areas. Longitudinal studies are needed to determinewhether GM damage is secondary to damage in connected NAWM tracts or,alternatively, it represents the primary target of the disease process leadingto secondary axonal degeneration and demyelination in WM.

B. Bodini is funded by the European Neurological Society.

O61Therapy-related headache in multiple sclerosis patients under interferon-beta: a prospective studyR. Tanasescu, M. Ticmeanu, E. Moraru, I. Cojocaru, A. Oprisan, E. Constan-tinescu, D. Luca, A. Frasineanu, C. Burcin, A. Gitman, A. Nicolau, C. BaicusColentina Hospital (Bucharest, RO); University of Medicine and PharmacyCarol Davila (Bucharest, RO)

Headache (H) can occur with 58% life-time prevalence in multiple sclerosis(MS) patients. Initially, H frequency during interferon beta (IFNB) therapywas not considered significantly higher vs placebo, but an increase was laterreported. In order to describe H prevalence, characters and changes in MSpatients under IFNB, we performed a prospective study on 71 MS patients.

71 patients with relapsing-remitting MS (mean age 36+/–6,34) treatedwith IFNB (52 IFNB1a, 24 IFNB1b) were followed for a mean time of 20(18–38) months,under a protocol including 3 month-visits,special-designedinterview including McGill pain questionnaires and individual prospectivediary. No H syndrome was considered if part of flu-like syndrome. We de-fined the H therapy-related (TRH) if occurred in the first 24 hours afterIFNB injection. Chi-square and Fisher exact tests were used to observe as-sociation between categorical variables (Graphpad Instat 3).

63,4 % (45) of patients developed TRH,occurring at 1-20 h (mean 6)frominjection and during for 1–24 h (mean 8,5). H was unilateral in 35%, bilateral65 %, throbbing 28 %, pressing 64 %, and was classified as mild in 43 %, mod-erate 45 %, severe 12 %. Nausea and photophobia where encountered in 25 %and 28 %, respectively. TRH generally started later than flu-like syndrome(mean 4 h). 56 % of H fulfilled the ICHD criteria for tension headache, 18 %for common migraine, the remaining unclassified.

We didn’t find any association between H and age, sex, gender, age at MSonset, IFNB type.

In 31 patients (43,7 %), there was a history of H prior to IFNB treatment(primary headache, PH). 27 of them (87 % of PH patients) developed TRH,20 (64,5 %) in the first 6 months of treatment, and 21 of PH patients (67,7 %)noticed changes in H intensity/duration, and 5 (16,1 %) in H type. There wasa significant presence of TRH among MS patients with PH (p = 0,0004), witha relative risk of 1.935 (95 % Confidence Interval 1.339 to 2.798) to developTRH mainly in the first 6 months of therapy.

Concluding, TRH is more frequent in our patients than already reported.Patients with PH have a higher risk to develop TRH. We suggest a thoroughfollow-up of MS patients under IFNB, especially those with PH, to optimizeearly attack and prophylactic therapy of H. Even that H existence is not at alla contraindication for IFNB therapy, it is important to determine the pres-ence and extent of H before the start of IFNB and closely monitor them, inorder to adjust therapy if H increases.


11

Oral session 2

Cerebrovascular disorders 1

O62The effect of antiplatelets during or after endovascular coiling for aneurys-mal subarachnoid haemorrhageW.M. van den Bergh, R.S.C. Kerr, A. Algra, G.J.E. Rinkel, A.J. Molyneux onbehalf of the International Subarachnoid Aneurysm Trial (ISAT) Collabora-tive Group

Objective: Antiplatelets (APTs) are often used during or after endovascularcoiling of aneurysms in patients with subarachnoid haemorrhage (SAH).There is, however, no evidence that APTs improve outcome in these patients.

Methods: All 43 centres in the International Subarachnoid AneurysmTrial (ISAT), comparing endovascular coiling with neurosurgical clipping inpatients with ruptured intracranial aneurysms, were sent a questionnairewhether they never, sometimes or always used APTs during or after coiling.Risk ratios (RR) for coiling compared with clipping for poor outcome after2 months and 1 year were calculated. These RRs were calculated separatelyfor patients treated in hospitals that always used APTs during or after coil-ing and in patients treated in hospitals that used APTs never or sometimes.

Results: Nineteen centres responded, representing 1422 (66 %) of the2143 patients randomised in ISAT. Standard prescription of APTs duringcoiling was done in two responding centres (8 % of coiled patients), whereasit was done after coiling in 6 centres (24 %). The overall RR for poor outcomeof coiling versus clipping was 0.67 (95 % CI 0.57–0.79) after two months and0.74 (0.62–0.89) after one year. For two months’ outcome RR was 0.82(0.45–1.49) in hospitals that always used APTs during coiling versus 0.66(0.55–0.78) in those that never or sometimes used APTs (ratio of RR’s 1.24,p =0.56). Similar observations were made for APT use after coiling. The ra-tio of RRs for one-year outcome was 1.01 (p = 0.89) for APT use during coil-ing and 1.00 (p = 0.77) for use after coiling.

Conclusion: The results of this study do not support the assumption thatAPTs during or after endovascular coiling improve outcome in patients withaneurysmal SAH.

O63Polymorphisms and mutational analysis of the NOTCH3 gene in a large co-hort of patients affected by leukoencephalopathyC. Ungaro, F.L. Conforti, T. Sprovieri, P. Servillo, M. Liguori, L. Citrigno, A.L.Gabriele, A. Magariello, A. Patitucci, M. Muglia, R. MazzeiISN National Research Council (Mangone, IT)

Objective: The aim of the present study was to analyse the coding region andintron-exon boundaries of the NOTCH3 gene in a large cohort of patients af-fected by leukoencephalopathy to investigate the presence of genetic vari-ants.

Patients and methods: We analyzed the exons 2–23, exons 3–4, exons 3-4-6-8 respectively in 157, 684 and 542 patients affected by leukoen-cephalopathy. Genomic DNA was extracted from peripheral-blood leuco-cytes using the salting out method. Twenty-two exons (2–23) out of 33 of theNOTCH3 gene and their intronic flanking sequences were amplified by PCRwith sets of oligonucleotide primers specific for NOTCH3. The ampliconswere then analyzed by Denaturing High Performance Liquid Chromatogra-phy; patients’ chromatograms for each exon were compared with corre-sponding normal controls and the exons showing an abnormal DHPLCeluition profile were directly sequenced in both forward and reverse direc-tions on an ABI Prism 3130XL genetic analyzer.

Results: The molecular analysis revealed several nucleotide alterations incomparison to the wild type sequence. In particular we identified 20 differ-ent mutations in 45 subjects from 30 families, 23 polymorphisms, 11 of themwere novel, and seven genetic variants of unknown pathological meaningnever been reported previously.

Discussion and conclusion: Cerebral Autosomal Dominant Arteriopathywith Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a cere-brovascular disease caused by mutations in the NOTCH3 gene. MostCADASIL associated mutations result in a gain or loss of a cysteine residuein one of the 34 EGF-like repeats in the extracellular domain of the Notch3protein, thus sparing the number of cysteine residues within a domain. Todate, more than 130 different mutations in the NOTCH3 gene have been re-ported in CADASIL patients, the 95 % being missense point mutations.Manypolymorphisms have also been identified in the NOTCH3 coding sequencesome of them leading to amino acids substitutions.

Here, we report a summary of 20 mutations, 23 polymorphisms and

7 new nucleotide variations in a cohort of 684 patients affected by leukoen-cephalopathy and we hope this NOTCH3 gene mutational analysis in a sosignificant number of unrelated and related patients may help in molecularscreening for NOTCH3 gene and it may contribute to enlarge the NOTCH3gene variations database.

The work was in part supported by the Italian Ministero dell’Istruzione, del-l’Università e della Ricerca Grants MIUR-FIRB2006-RBIP06PMF2_006.

O64Prothrombotic gene variation and new vascular events after cerebral is-chaemia of arterial originD.M.O. Pruissen, F.R. Rosendaal, C.J.M. Frijns, L.J. Kappelle, H.L. Vos, A. Al-gra on behalf of the SMART Study Group

Objectives: Several genetic variants involved in haemostasis have been asso-ciated with ischaemic stroke or myocardial infarction. Stroke patients whocarry a prothrombotic genotype may also be at increased risk for new vas-cular events.

Methods: We included 887 patients with nondisabling cerebral ischaemiaof arterial origin, who were referred to a university medical center in TheNetherlands between 1995 and 2005 and followed them for the occurrenceof ischaemic stroke, myocardial infarction or death. The primary outcomewas a composite of death from all vascular causes,nonfatal ischaemic stroke,nonfatal myocardial infarction, whichever happened first. Through a sys-tematic literature search we identified 22 prothrombotic variants in 14 genesthat were previously associated with ischaemic stroke or myocardial infarc-tion.

Results: During a 4.6-year follow-up period new vascular events oc-curred in 135 patients (annual event rate 3.3 %). None of the 22 variants wasassociated with the occurrence of new vascular events. Eight additionalanalyses with secondary outcomes or among subgroups revealed four asso-ciations that were likely to be false positive after accounting for multiple test-ing.

Conclusion: In this cohort, prothrombotic genetic variants do not affectthe risk of new vascular events after cerebral ischaemia of arterial origin.This study does not support the use of prothrombotic genetic variants toidentify stroke patients at increased risk for new vascular events or to guideantithrombotic treatment.

This study was funded by a grant from the Medical and Health Research Pro-gramme of the Netherlands Organisation for Scientific Research (NWO),grant No. 904-61-190.

O65Prothrombotic genetic variants and atherosclerosis in patients with cerebralischaemia of arterial originD.M.O. Pruissen, L.J. Kappelle, F.R. Rosendaal, A. Algra on behalf of theSMART Study Group

Objectives: Several prothrombotic genetic variants have been associatedwith an increased risk of arterial disease. These variants probably affect ar-terial thrombus formation but may also promote atherosclerosis. We hy-pothesized that specific prothrombotic variants lead to advanced athero-sclerosis in patients with cerebral ischaemia of arterial origin.

Methods: We included 689 patients with nondisabling cerebral ischaemiaof arterial origin. Twenty-two variants in 14 genes that were previously as-sociated with ischaemic stroke or myocardial infarction, were genotyped.Carotid intima-media thickness, the presence of symptomatic carotid steno-sis and age at the occurrence of cerebral ischaemia were documented.

Results: None of the variants was associated with carotid intima-mediathickness or younger age at the occurrence of cerebral ischaemia. Factor VLeiden (mean prevalence difference 25 %; 95 % CI 11–40) and the glycopro-tein 1b-alpha Thr145Met variant (mean prevalence difference 12 %; 95 % CI2.3–22) were associated with symptomatic carotid stenosis. The factor XIIIsubunit B His95Arg variant was marginally associated with older age at theoccurrence of cerebral ischaemia (mean age difference 2.3 years; 95 % CI0.03–4.5).After accounting for multiple testing by determination of the falsediscovery rate, only the association between factor V Leiden and sympto-matic carotid stenosis remained present.

Conclusion: Prothrombotic genetic variants showed no consistent asso-ciation with three markers of advanced atherosclerosis in patients with cere-bral ischaemia of arterial origin. This study does not support the hypothe-sis that prothrombotic genetic variants have a direct role in the pathogenesisof atherosclerosis.

This study was supported by a grant from the Medical and Health Research


12

Programme of the Netherlands Organisation for Scientific Research (NWO),grant No. 904-61-190.

O66Contribution of obesity and abdominal fat mass to risk of stroke: theMannheim-Heidelberg Stroke StudyY. Winter, S. Rohrmann, J. Linseisen, O. Lanczik, A. Ringleb, J. Hebebrand,T. BackCenter for Mental Health (Stuttgart, DE); German Cancer Research Center(Heidelberg, DE); Klinikum Mannheim (Mannheim, DE); University Hei-delberg (Heidelberg, DE); University Duisburg-Essen (Essen, DE); SaxonHospital (Arnsdorf, DE)

Objectives: Obesity has become one of the most prevalent conditions thatpose a large impact on public health worldwide. We investigated markers ofobesity and abdominal fat mass in a case-control study in cerebrovascularpatients to evaluate the risk contribution to stroke and transient ischemic at-tacks (TIA) in central Western Europe.

Methods: 1137 participants were included in the study, 379 cases and 758regional controls matched for age and sex. Consecutive cases of ischemicstroke (n = 301, 79 %), intracerebral hemorrhage (ICH) (n = 37, 10 %) orTIAs (n = 41, 11 %) were recruited at the University Depts. of Neurology inMannheim and Heidelberg between February 1, 2005 and January 31, 2006.Associations were assessed between different markers of obesity (body massindex [BMI], waist-to-hip ratio [WHR], waist circumference and waist-to-stature ratio [WSR]) and risk of stroke or TIA by using conditional logisticregression adjusted for other risk factors.

Results: BMI showed a moderate association with cerebrovascular riskwhich was non-significant after adjustment for physical inactivity, smoking,hypertension, and diabetes (odds ratio [OR] 1.37, 95 % confidence interval[CI] 0.87–2.17, top quartile vs. bottom quartile). Markers of abdominal fatmass were strongly associated with risk of stroke and TIA. For the waist-to-hip ratio, adjusted OR for every successive quartile were greater than that ofthe previous one (2nd quartile: OR 1.34, CI 0.68–2.64; 3rd quartile: OR 3.22,CI 1.75–5.91; 4th quartile: OR 8.44, CI 4.73–15.08). Significant associationswith risk of stroke/TIA were also found for waist circumference and WSR(OR 4.53, CI 2.77–7.39 and OR 3.99, CI 2.42–6.58, top vs. bottom quartile af-ter risk adjustment, respectively).

Conclusion: Markers of abdominal adiposity (waist circumference,WHR) showed a graded and significant association with the risk of strokeand TIA that is independent of other vascular risk factors. Waist circumfer-ence and related ratios can better predict stroke than BMI.

The study was supported by the German M

eighteenth meeting of the european neurological society 7 ... · clinical neurophysiology ii/93...

Documents