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Introduction The spinal cord is one of the two main targets of neuromyelitis optica (NMO). The aim of this study was to highlight cervical spinal cord atrophy in NMO patients as compared to controls and to assess correlations between atrophy and clinical characteristics and cervical spinal cord MRI data. Methods This prospective study investigated 15 patients with a diagnosis of NMOSD and 15 healthy controls. The whole cervical spinal cord was explored by MRI. The cross-sectional area (CSA) was estimate at every level of cup. This measurement was then averaged on the whole cervical spinal cord, providing a single measurement for every subject, denoted as mean CSA. Results Mean CSA was 68.5 mm2 in the population of NMO patients and 72.8 mm2 in the population of healthy subjects. NMO patients had significantly smaller cervical spinal cord area than healthy controls (T test = 0.009). Cervical spinal cord atrophy was associated with clinical signs of medullary involvement (T test = 0.0006). There was a tendency toward a relation between cervical spinal cord atrophy and the Expanded Disability Status Scale (EDSS) (T test = 0.07). This correlation seems statistically significant (T test Conclusion This study provides the first evidence of cervical spinal cord atrophy in NMOSD by studying the entire cervical spinal cord. Upper cervical spinal cord atrophy was substantially correlated to clinical disability and seems more involved in the development of clinical disability in NMOSD patients in comparison to the lower cervical spinal cord.

OBJECTIVE: To analyze the humoral response after COVID-19 vaccination in patients with multiple sclerosis (MS) according to disease-modifying treatments (DMTs) and in comparison with the humoral response after SARS-CoV-2 infection. METHODS: We included 28 MS patients with serological results after COVID-19 vaccination (Pfizer-BioNTech or Moderna ARNm) and 61 MS patients with serological results after COVID-19 (COVID-19 group) among patients followed up at the MS Center of Strasbourg, France, between January and April 2021. The primary endpoint was the IgG index according to DMTs (anti-CD20 mAb, sphingosine 1-phosphate receptor [S1PR] modulator and other treatments) and COVID-19 vaccine or COVID-19 groups. RESULTS: In the vaccinated MS patients, the median IgG index was lower in patients treated with anti-CD20 mAb and in patients treated with S1PR modulator compared to patients receiving other or no DMTs (4.80 [1.58-28.6], 16.5 [16.3-48.5], 1116 [434-1747] and 1272 [658-1886], respectively, P

ObjectivesTo determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.MethodsWe conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.ResultsRegarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.ConclusionOur results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

ObjectiveThe aim of this study was to evaluate whether mutations in ERLIN2, known to cause SPG18, a recessive hereditary spastic paraplegia (SP) responsible for the degeneration of the upper motor neurons leading to weakness and spasticity restricted to the lower limbs, could contribute to amyotrophic lateral sclerosis (ALS), a distinct and more severe motor neuron disease (MND), in which the lower motor neurons also profusely degenerates, leading to tetraplegia, bulbar palsy, respiratory insufficiency, and ultimately the death of the patients.MethodsWhole-exome sequencing was performed in a large cohort of 200 familial ALS and 60 sporadic ALS after a systematic screening for C9orf72 hexanucleotide repeat expansion. ERLIN2 variants identified by exome analysis were validated using Sanger analysis. Segregation of the identified variant with the disease was checked for all family members with available DNA.ResultsHere, we report the identification of ERLIN2 mutations in patients with a primarily SP evolving to rapid progressive ALS, leading to the death of the patients. These mutations segregated with the disease in a dominant (V168M) or recessive (D300V) manner in these families or were found in apparently sporadic cases (N125S).ConclusionsInheritance of ERLIN2 mutations appears to be, within the MND spectrum, more complex that previously reported. These results expand the clinical phenotype of ERLIN2 mutations to a severe outcome of MND and should be considered before delivering a genetic counseling to ERLIN2-linked families.

Introduction Le FOSMN (Facial onset sensory and motor neuronopathy) est un syndrome rare, lentement progressif, caracterise par une atteinte sensitive et motrice predominante dans le territoire du trijumeau et des membres superieurs. Observation Nous presentons le cas d’une patiente de 60 ans, sans antecedents, qui presente depuis 2007 un deficit sensitif de l’hemiface gauche et des membres superieurs puis l’installation progressive d’un deficit moteur proximal d’allure peripherique des membres superieurs et des muscles cervicaux, avec amyotrophie, crampes et tremblement postural. Le bilan biologique (CPK, anticorps antinucleaires, anti-gangliosides, anti-MAG, Lyme, VIH, VHB, VHC) est normal tout comme l’IRM cervicale et l’analyse du liquide cephalorachidien. L’EMG met en evidence des anomalies severes de conduction sensitive et motrice de type axonale, predominant sur le versant sensitif. L’etude a l’aiguille revele une activite spontanee de denervation dans les territoires C6 et C8 bilateral avec une atteinte neurogene chronique diffuse, le blink reflexe etait pathologique a gauche. On ne retrouvait pas d’atteinte myogene. Devant cette double mononeuropathie sensitive et motrice de la partie superieure du corps et l’elimination de diagnostic differentiel (inflammatoire, maladie de Kennedy), le diagnostic de FOSMN syndrome est retenue. Des cas de FOSMN avec des mutations de genes de sclerose laterale amyotrophique hereditaires ont ete rapportes dans la litterature, un panel de gene est en cours. Discussion Le FOSMN est un syndrome rare associant une double mononeuropathie sensitive et motrice dont les etiologies sont probablement multiples. Peu de patients sont decrits dans la litterature. En 2018, un cas familial est publie pour la premiere fois. Sa physiopathologie est mal comprise, les tentatives therapeutiques (immunoglobulines, corticoides…) ont toutes ete inefficaces. Des criteres diagnostiques sont proposes pour la premiere fois en 2016. Conclusion Le FOSMN est un syndrome rare et mal connu, probablement sous diagnostique, necessitant la description de nouveaux cas afin de mieux l’apprehender et ameliorer notre comprehension de cette pathologie.

International audience; Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7-15 \textmug/L), AOA2 (15-65 \textmug/L) and AT (\textgreater65 \textmug/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

International audience; The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40~years of age were included in the prospective, observational study. 80 patients were included over a 2~year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n~=~29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n~=~9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p~\textless~0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p~=~0.001) and more frequently parkinsonism (p~\textless~0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Aim: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. Methods: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known ( n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. Results: Among the patients with Gen2 JCV serology ( n=303) that had been JCV-seronegative one year before ( n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. Conclusion: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

Resume Introduction Les meningiomes sont des tumeurs meningees primitives benignes. Leur decouverte peut etre fortuite ou secondaire a l’exploration de symptomes neurologiques, voire ophtalmologiques. Patients et methodes Nous rapportons les histoires cliniques et paracliniques de cinq patientes ayant presente des symptomes ophtalmologiques qui ont conduit au diagnostic de meningiomes. Resultats Il s’agissait de cinq femmes, âgees de 52 ans en moyenne au moment du debut des symptomes. Elles presentaient toutes une baisse de l’acuite visuelle unilaterale progressive avec un fond d’œil initialement normal, associee a une alteration du champ visuel ipsilateral. Les differents examens complementaires et notamment radiologiques ont du etre repetes pour mener au diagnostic de meningiome dans un delai allant de 18 mois a quatre ans. Discussion Le tableau clinique de ces cinq cas est celui d’une neuropathie optique retrobulbaire ayant oriente le bilan vers la recherche d’une maladie inflammatoire du systeme nerveux central. Mais le caractere atypique de la neuropathie a fait reconsiderer le diagnostic et repeter les examens d’imagerie. Le caractere iso-intense des meningiomes en T1 et peu hyperintense en T2 en imagerie par resonance magnetique (IRM) peut conduire a un retard diagnostique et therapeutique si l’examen n’est pas fait et interprete par un professionnel experimente. L’injection de Gadolinium, les sequences avec suppression de graisse et le centrage sur les voies optiques anterieures sont des elements indispensables lors de l’IRM. Conclusion Devant une neuropathie optique indolore, d’evolution progressive, et resistante a la corticotherapie, le diagnostic de meningiome des voies optiques anterieures doit etre envisage. Celui-ci est facilite par une IRM adaptee aux voies optiques.

International audience; Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

Background Neuromyelitis optica (NMO) is an inflammatory disease involving predominantly the spinal cord and optic nerves. Whether patients with NMO have a loss in white or grey matter (GM) volumes remains to be determined. Methods Thirty patients with NMO, 30 healthy subjects matched for age and gender, 21 patients with multiple sclerosis (MS) and 20 patients with a clinically isolated syndrome (CIS) were studied. We applied a SIENAX post-treatment software. We compared white matter (WM) and GM volumes between groups and explored correlations of changes in NMO patients with age, gender, duration, disease severity, visual acuity and T2 hyperintensities. We also performed a voxel-based morphometry (VBM) analysis to identify the regions affected by loss of volume. Results White matter volume was significantly reduced in patients with NMO (764.4 ± 58.3 cm3) compared to healthy subjects (843.1 ± 49.3 cm3) (P

To measure the prevalence of JCV-specific antibodies in a French cohort of MS patients treated with natalizumab and to identify risk factor(s) of JCV seropositivity. Progressive multifocal leukoencephalopathy (PML) risk may be stratified by anti-JCV antibody status, duration of natalizumab therapy (≥24 months) and prior exposure to immunosuppressive (IS) drugs. No data are available in France on the prevalence of anti-JCV antibodies and distribution of PML risk factors in patients treated with natalizumab. Sera of 361 patients under natalizumab therapy in two MS centers were analyzed using a previously validated ELISA test. We studied different characteristics: demographic, ethnic, radiological, clinical, prior use of immunomodulatory (IM) or IS drugs and natalizumab exposure duration. The JCV seropositivity rate was 51 % for the whole cohort. Mean natalizumab exposure duration was 27.27 months ± 15.57 (mean ± SD), and prior use of IS drugs was observed in 15.24 % of patients. Twenty-three patients (6.4 %) presented the three PML risk factors. By multivariate analysis, presence of anti-JCV antibodies was significantly linked to age, North African origin and natalizumab exposure duration. Anti-JCV antibody prevalence was similar to previously published data. Anti-JCV antibody status was linked to age. We also suggested that anti-JCV antibody status could be linked to natalizumab exposure duration and ethnic characteristics.

Background: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies. Objective: To describe HRS patients and compare them with NMO patients. Methods: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database. Results: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4–70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup. Conclusion: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.

Background: The burden of multiple sclerosis (MS) includes fatigue, depression and worsening of health-related quality of life (HRQOL). These changes have not been yet measured in neuromyelitis optica (NMO). Our aim was to assess the HRQOL, fatigue and depression in NMO. Methods: We administered French validated self-questionnaires on HRQOL (SEP-59), fatigue (EMIF-SEP) and depression (EHD) to 40 patients followed up in two centres. We assessed the relationship of these parameters with gender, age, disability, disease duration, visual acuity and NMO-antibody status and also compared our results with equivalent data in MS and normal subjects derived from previous studies. Results: Health-related quality of life scores were lower (P

Resume Introduction L’existence de troubles psychotiques dans la sclerose en plaques (SEP), en particulier, revelatrice de la maladie, est mal connue. Methode Nous rapportons les caracteristiques neurologiques, psychiatriques, les donnees IRM, l’evolution et le traitement de quatre patients ayant presente des troubles psychotiques ayant conduit au diagnostic de SEP. Observations Parmi les quatre patients, deux ont developpe un delire de persecution, une manie et une patiente une melancolie avec catatonie. Leur âge moyen etait de 39 ans (± 13). Deux patientes avaient un antecedent personnel psychiatrique. Aucun d’entre eux n’avait d’antecedents familiaux psychiatriques. Dans deux cas, les symptomes psychiatriques ont dure trois mois et, dans deux autres, plusieurs rechutes ont emaille l’evolution. Les quatre patients avaient une IRM qui remplissait les criteres de dissemination spatiale de Barkhof et avaient des bandes oligoclonales en IgG dans le liquide cephalorachidien. Pour trois patients, une IRM cerebrale avec injection fut realisee lors du trouble psychotique. Chez trois patients, il existait au moins une nouvelle lesion frontale. Chez la patiente ayant presente une catatonie, il existait aussi une nouvelle lesion cerebelleuse et du tronc. Les quatre patients ont necessite un traitement a visee psychiatrique, en particulier des antipsychotiques. Conclusion Cette etude montre qu’un trouble psychotique peut accompagner une SEP en debut de pathologie. Une localisation frontale est suggeree Nous proposons qu’un episode psychotique puisse etre considere comme un evenement de SEP.

Natalizumab is the first selective adhesion molecule inhibitor indicated for treatment of active relapsing-remitting multiple sclerosis (RRMS). Natalizumab has been available in France since April 2007. The aims of this study are to analyze demographic, clinical, and tolerance data from French patients with RRMS treated with natalizumab in actual clinical practice and to draw comparisons with patients in the pivotal AFFIRM study. All patients with RRMS in the Nord-Pas de Calais and Alsace regions of France treated with natalizumab at any time since April 2007 were included. Variables analyzed included previous treatments; disability status [Expanded Disability Status Scale (EDSS) score]; annualized relapse rate (ARR) at baseline and after 12 months of treatment; and adverse events. Data from 384 patients (72% female) were evaluated. Mean baseline EDSS score was 3.53 and mean baseline ARR was 2.19, both significantly greater than in AFFIRM. One hundred twenty-seven patients completed 12 months of treatment; mean EDSS score in this group was 3.02 (14% reduction) and mean ARR was 0.59 (73% reduction). Although these patients had significantly different baseline characteristics and greater disability compared with patients receiving natalizumab in AFFIRM, average disability remained stable and ARR declined by 73%. Tolerability was similar to that observed in AFFIRM.

The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a cerebellar ataxia autosomal recessively inherited characterized by an ataxic and pyramidal syndrome usually occurring near two years of age. The spastic paraparesis progressively worsens and becomes the prominent sign. Sensorial and motor axonal peripheral neuropathy is frequently reported as well as prominent retinal myelinated fibers on fundus examination. Brain magnetic resonance imaging reveals a predominantly vermian cerebellar atrophy. Mutations in SACS gene on 13q11 are responsible for ARSACS. We report two patients from a non-consanguineous French family, affected with ARSACS, due to the compound heterozygous mutations p.Ala2558Val and p.Pro536Leu. The clinical presentation is in accordance with the previously described ARSACS cases, despite the presence of mental retardation, the predominantly demyelinating peripheral neuropathy, and the evidence of asymptomatic generalized spikes and waves on electroencephalography. We described the clinical heterogeneity in this family including the age at onset of the disease and the first signs as well as the rapidity of the disease progression. We present a review of the litterature on this rare disease mostly described in Quebec.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Resume Introduction Le syndrome de Vogt-Koyanagi-Harada est une maladie inflammatoire rare, associant des manifestations oculaires, neurologiques, audio-vestibulaires et cutanees. Bien que plus frequent en Asie, il n’est pas exceptionnel en Europe. Nous rapportons trois nouveaux cas diagnostiques chez des patients europeens ou originaires d’Afrique du Nord. Observations Ces trois patients presentaient une panuveite bilaterale avec hypoacousie, associee a une paralysie faciale peripherique dans deux cas, a un syndrome vestibulaire dans deux cas et a une meningite lymphocytaire dans un cas. Dans chacun des cas, le typage HLA de classe II etait caracteristique de la maladie et chez un des trois patients existait la presence simultanee d’anticorps anti-retine (de type anti-arrestine), anti-choroide et anti-cochlee. Un traitement par corticoides a ete initialement instaure, mais s’est revele peu efficace, conduisant a la realisation de cures de cyclophosphamide (0,8 g/m 2 ). L’evolution fut dans les trois cas favorable, au prix cependant de sequelles visuelles dans deux cas, et auditive dans un cas. Conclusion Ces cas illustrent les principales caracteristiques cliniques et evolutives du syndrome de Vogt-Koyanagi-Harada. Les resultats des examens immunologiques et en particulier la presence dans un des cas d’anticorps anti-arrestine, anti-choroide et anti-cochlee, ainsi que l’evolution sous cyclophosphamide, confortent les donnees recentes de la litterature et plaident en faveur de l’origine auto-immune de ce syndrome.

Resume Introduction L’histoire naturelle d’une maladie de Charcot-Marie-Tooth (CMT) peut etre marquee par une accentuation des deficits moteurs et sensitifs qui fait evoquer une polyradiculonevrite aigue ou, plus souvent, une polyneuropathie chronique inflammatoire demyelinisante. Observation Une femme de 41 ans, atteinte d’une maladie de Charcot-Marie-Tooth de type 1B (CMT-1B), liee a une mutation de P0, presenta plusieurs episodes d’ataxie proprioceptive des 4 membres reversibles sous immunomodulateurs. Conclusion Cette observation conduit a evoquer 2 hypotheses : une association fortuite entre neuropathie hereditaire et acquise, ou une reaction inflammatoire dysimmunitaire, la proteine mutee se comportant comme un autoantigene. Ces 2 hypotheses sont discutees.

Background : Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine involved in certain inflammatory diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), and Crohn’s disease. The anti-TNF-α treatments used for RA may be associated with inflammatory demyelinating events affecting the central nervous system and may possibly aggravate known MS. Objective : We report here three new cases of inflammatory demyelinating events of the central nervous system following treatment with anti-TNF-α. Results : The neurological symptoms appeared on average 5 months after initiation of the treatment. For all patients, the inflammatory process was confirmed by brain magnetic resonance imaging. The symptoms totally or partially regressed as soon as anti-TNF-α treatment was stopped except for one patient who developed clinically defined MS. Conclusions : Inflammatory demyelination of the central nervous system may be associated with the use of anti-TNF-α. Patients with rheumatoid arthritis treated with these treatments should benefit from a follow-up which includes brain MRI.

Niemann-Pick type C disease (NPC) is a recessive neurolipidosis. We report five adolescent and adult NPC cases to underscore the frequency and heterogeneity of movement disorders in NPC. Clinical, morphologic, biochemical and genetic study was performed in the five patients. Disease onset was between 8 and 50 years. Movement disorders were present in all cases, were heterogeneous and often combined [cerebellar ataxia (5/5), myoclonus (3/5), dystonia (2/5), chorea (1/5) and tremor (1/5)] and were the first sign in 4/5. Two patients were reported to have no vertical supranuclear gaze palsy (VSGP) at the first examination. Two patients experienced acute neuropsychiatric signs leading to death in one case due to myoclonic storm. Filipin staining was always positive. Two NPC1 mutations were identified in three patients, only one in two siblings. NPC should be considered in case of unexplained movement disorders, even when VSGP or cataplexy are not reported. Filipin staining remains a strong support for the diagnosis. Treatment with miglustat should be considered which is currently the only approved disease-specific treatment of NPC in children and adults.

Background: Neuromyelitis optica (NMO) is an inflammatory disease associated with optic neuritis and myelitis. Recently, several studies showed that optical coherence tomography (OCT) could be an interesting method for the evaluation of disease severity; however, to date there are no studies with a longitudinal follow-up of visual function in NMO. The aim of this study was to assess the ability of OCT to evaluate the progression of visual dysfunction in NMO. Patients and methods: A group of 30 NMO patients (thus, 60 eyes), comprised of 20 women and 10 men with a mean age of 43.7 +/− 12.3 years, were prospectively evaluated clinically and by a whole neuro-ophthalmological work-up, including: visual acuity (VA), fundoscopy, visual evoked potential (VEP), visual field (VF) and optical coherence tomography (OCT). All patients were tested at baseline (after a mean disease duration of 6.1 years) and after a mean time of follow-up of 18 months (range: 12–36 months). Results: Mean VA was similar at the two evaluation times (0.77 +/− 0.36 versus 0.77 +/− 0.35). The mean VF defect decreased slightly, but the difference was not significant (−5.9 +/− 1.3 dB versus −5.3 +/− 1.3 dB). In contrast, the mean retinal thickness seen on OCT decreased from 87.4 +/− 23.3 µm to 79.7 +/- 22.4 µm ( p = 0.006). These modifications were only observed in eyes with a past or a recent history of optic neuritis (−15.1 µm; p < 0.001) and not in eyes without any history of optic neuritis (−2.4 µm; not significant). Also, they occurred independently of the occurrence of relapses ( n = 13) and especially optic neuritis episodes; however, the number of optic neuritis episodes was low ( n = 5). Conclusion: OCT seems to be a more sensitive test than VA or VF for monitoring ophthalmological function in NMO and it seems to be helpful for the detection of infra-clinical episodes in patients with a past history of optic neuritis. Our results suggest that this easily performed technique should be used in the follow-up of NMO, but complementary studies are warranted to confirm its interest at an individual level.

The clinical and genetic features of three non-Portuguese and non-Japanese patients with aprataxin gene mutations are reported. Patient 1 came from Italy and presented with typical ataxia with ocular motor apraxia (OMA). She was homozygous for the W279X nonsense mutation, which is associated with the Portuguese founding haplotype. Patients 2 and 3 were French siblings and did not present with either OMA or hypoalbuminemia. They were compound heterozygous for the nonsense W279X mutation and a missense K197Q mutation.

The role of thymectomy in myasthenia gravis remains controversial. The remission rate 5years after surgery varies from 13 to 51% in the literature. Sternotomy is the standard technique, though unacceptable by patients because of significant esthetic sequelae. Our objective was to demonstrate that the robot-assisted technique using the Da Vinci Surgical Robot II is at least as efficient and leaves fewer scars than the standard surgical technique.We retrospectively reviewed the data of 31 consecutive patients suffering from myasthenia gravis who underwent surgery in our center from January 1998 to March 2010. Ten patients with thymoma were excluded from this study. Two groups were formed: group 1 corresponding to patients treated with sternotomy, group 2 patients with robot-assisted technique. The duration of the hospital stay, the pain on D1, the degree of improvement at 1year according to Myasthenia Gravis Foundation of America (MGFA) classification, the frequency of relapses, and perioperative treatment were studied.Our sample consisted of 14 women and seven men. The mean age was 31.3years. The mean delay before surgery was 24months. Group 1 included 15 patients and group 2 had six patients. The complete remission rate at 1year was 9.5% (n=2). Surgery decreased the frequency of relapses after surgery (P=0.08) equally in the two groups. The duration of hospital stay and the pain level on D1 in group 2 were significantly lower than those in group 1 (P=0.02 and P0.001). The degree of postoperative improvement was not significantly different between the two groups (P=0.31).The results at 1year are fully comparable for sternotomy and the robot-assisted technique. The robot provides additional benefits of minimally invasive techniques: minimal esthetic sequelae in often young patients, less parietal morbidity (including pain), shorter hospital stays. Our complete remission rate, lower than those in the literature, must be considered taking into account the early nature of these results. The surgical robot, because of its many advantages, appears to be a promising technique and should facilitate the early management of these patients.

“Disease activity free” in relapsing-remitting multiple sclerosis (RRMS) is a new concept introduced by the results of the AFFIRM study. Our objective was to analyze the clinical and radiological efficacy of natalizumab treatment in actual clinical practice and compare it with the post hoc analysis of the AFFIRM study. All patients with RRMS who began treatment with natalizumab at our two French MS centres between April 2007 and May 2008 were included and followed-up for at least 2 years. No measurable disease activity (“disease activity free”) was defined as no activity on clinical measures (no relapses and no sustained disability progression) and radiological measures (no gadolinium-enhancing lesions and no new T2-hyperintense lesions on cerebral MRI). A total of 193 patients were included. Natalizumab was discontinued in 25.9% of cases before the completion of 2 years of treatment. In our cohort, we observed patients with more severe disease than in the AFFIRM study. The proportion of patients remaining free of clinical activity during 2 years of treatment was lower than in the AFFIRM study (37.8% vs. 64.3%). The proportion of patients remaining free of radiological activity during 2 years of treatment was higher than in the AFFIRM study (68.9% vs. 57.7%), while the proportion of patients remaining free of disease activity during 2 years of treatment was comparable to the AFFIRM study (33.3% vs. 36.7%). Natalizumab seems to be as effective in a real-life setting as in pivotal and post hoc studies. The confirmation of such benefits is important because of the progressive multifocal leukoencephalopathy risk.

Summary Objectives Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe attacks of optic neuritis and myelitis. Brain was classically, unlike in multiple sclerosis (MS), spared. Nevertheless recent studies showed that brain lesions can be seen with MRI. We studied the diffusion characteristics of normal-appearing white matter (NAWM) and abnormal white matter in NMO patients compared with NAWM in healthy subjects. Patients and methods Diffusion tensor imaging (DTI) scans of the brain and spinal cord were obtained from 25 patients with NMO and 20 age- and gender-matched healthy subjects. Region of interest (ROI) analysis of the apparent diffusivity coefficient (ADC) and fractional anisotropy (FA) was performed in brain NAWM (optic radiations, corpus callosum [CC] and anterior and posterior limbs of the internal capsule [IC]) and in spinal cord NAWM and in lesions. Results ADC was increased and FA decreased in NMO patients in the posterior limb of the IC in the optic radiations and in spinal cord NAWM. FA was lower in spinal cord lesions. In contrast, there was no difference between the two groups in the anterior limb of the IC nor in the CC. Conclusion These results suggest that DTI abnormalities are very severe in NMO spinal cord lesions. In our study, DTI abnormalities in NAWM were restricted to optic radiations and cortico-spinal tracts, suggesting secondary Wallerian degeneration. In contrast, NAWM outside these tracts (CC and anterior IC) remained normal suggesting that, unlike what is observed in MS, there is no infra-lesional abnormality in NMO.

Background: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. Methods: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. Results: Mean age at onset was 34.5 years (range 4–66) with a mean disease duration of 10 ± 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score ≥4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity ≤1/10. Conclusions: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

International audience; Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Background To establish whether or not multiple sclerosis (MS) and neuromyelitis optica (NMO) are different pathological entities, we wondered whether MS patients and NMO patients share the same pattern of human leukocyte antigen (HLA) predisposition. Objective To study a putative association between susceptibility to NMO and HLA class I or class II loci in Caucasians. Methods A total of 39 unrelated Caucasian patients with NMO and six patients at a high risk of converting to NMO were studied. DNA genotyping of HLA class I and class II loci was assessed and allelic frequencies were reported at a high-resolution level. A case-control study by comparing the allelic distribution in the NMO patients with that of a French Caucasian MS group and a French Caucasian healthy group was carried out. Results The frequencies of HLA-DQA1, DQB1, and HLA-DRB1 DR2 alleles in the NMO group were intermediate between the healthy control group and the MS group. The DPB1*0501 allele was not increased in the NMO group compared with the healthy control group. The distribution of HLA-DRB1 allele enabled to distinguish between NMO-IgG-positive patients and healthy controls ( P = 0.01). NMO-IgG-negative patients presented an HLA II pattern closer to that of the MS group ( P = 0.01). Conclusion In contrast to the reported results in Asian opticospinal MS, we found no association between the DPB1*0501 allele and NMO in our Caucasian patients. Moreover, we suggest that NMO-IgG-positive patients could represent a distinct NMO group in terms of their genetic susceptibility.

Background and purpose: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined. Methods: Information was obtained from neurologists at ALS centres, patients’ files, and, when deaths occurred outside a medical facility, attending physicians. Results: Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy. Conclusion: The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.

International audience; BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease caused by SETX mutations in 9q34 resulting in cerebellar ataxia in association with peripheral neuropathy, cerebellar atrophy on imaging, an elevated alpha-fetoprotein (AFP) serum level, and occasional oculomotor apraxia. OBJECTIVE: To describe the clinical and molecular findings of 7 patients with a clinical presentation of AOA2 and their relatives. DESIGN: Case report. SETTING: Projet Hospitalier de Recherche Clinique. PATIENTS: Seven patients with AOA2 and their family members. INTERVENTION: Linkage analysis and direct sequencing of all exons of SETX were performed in all patients. Magnetic resonance imaging and electroneuromyography were performed and the patients' AFP serum levels were tested. RESULTS: We identified 7 patients with AOA2 from 4 unrelated families. Three novel SETX mutations were found. The clinical picture of the patients reported is fairly homogeneous and in accordance with the classic AOA2 presentation: onset from 13 to 18 years of progressive cerebellar ataxia and areflexia. Oculomotor apraxia was detected in 1 patient. Predominant axonal neuropathy and a diffuse cerebellar atrophy were found in the 4 patients tested. All patients had elevated AFP serum levels and 5 of 8 nonsymptomatic heterozygous relatives had moderately increased AFP serum levels as well. CONCLUSIONS: Ataxia with oculomotor apraxia type 2 is a homogeneous form of cerebellar ataxia with occasional oculomotor apraxia. Most nonsymptomatic heterozygous carriers present with increased AFP serum levels.

Background: No consensual criteria exist to diagnose neuroborreliosis. The intrathecal anti- Borrelia antibody index (AI) is a necessary criterion to diagnose neuroborreliosis in Europe, but not in the United States. Previous studies to determine the diagnostic value of the AI found a sensitivity ranging from 55% to 80%. However, these studies included only typical clinical cases of meningitis or meningoradiculitis, and none had a control group with CSF anti- Borrelia antibodies. Methods: We studied a sample of 123 consecutive patients with clinical signs of neurologic involvement and CSF anti- Borrelia antibodies. We determined the AI for all patients and a final diagnosis was made. Patients were then divided into three groups (neuroborreliosis, possible neuroborreliosis, control). Results: Thirty of the 40 patients with neuroborreliosis had a positive AI (AI sensitivity = 75%). Two of the 74 patients with another neurologic diagnosis had a positive AI (AI specificity = 97%). Conclusion: The antibody index has a very good specificity but only moderate sensitivity. Given the lack of consensual criteria for neuroborreliosis and the absence of a “gold standard” diagnostic test, we propose pragmatic diagnostic criteria for neuroborreliosis, namely the presence of four of the following five items: no past history of neuroborreliosis, positive CSF ELISA serology, positive anti- Borrelia antibody index, favorable outcome after specific antibiotic treatment, and no differential diagnosis. These new criteria will need to be tested in a larger, prospective cohort.

We assessed the different sets of diagnostic criteria for primary progressive multiple sclerosis (PPMS), in order to determine their sensitivity when applied to a cohort of 261 PPMS patients. According to the Thompson criteria, 168 patients (64.4%) had definite PPMS, 84 patients (32.2%) had probable PPMS, and nine patients (3.4%) had possible PPMS; according to the McDonald criteria, 180 patients (69%) had PPMS; according to the revised McDonald criteria, 194 patients (74.3%) had PPMS. Our findings indicate that the revised McDonald criteria are more sensitive than the original McDonald criteria, but less sensitive than the Thompson criteria. Multiple Sclerosis 2007; 13: 622-625. http://msj.sagepub.com

Gyrate atrophy (GA) of the choroid and retina with hyperornithinaemia is a rare inherited autosomal recessive metabolic disease. It is due to a mitochondrial enzymatic deficiency in ornithine-amino-transferase (OAT), leading to hyperornithinaemia. Most frequently, ocular findings are clinically isolated and spread to blindness. Associated muscular weakness is rare. The present case is that of a patient, from a consanguineous Turkish marriage and the third of seven brothers and sisters, who developed, at age 15 years, loss of night vision with bilateral retinopathy, myopia and cataract. Ophthalmological symptoms progressively worsened. At the age of 18 years, mild proximal weakness appeared in the right arm and slowly spread to the four limbs. At the age of 33 years, he had proximal muscular atrophy of the lower limbs without pain. Clinical examination showed marked bilateral atrophy and mild weakness of the gluteus maximus, and detachment of the shoulder blades. There was no sensitive symptom, reflexes were normal, and there was no sign of central nervous system involvement. Visual acuity was estimated to be 6/30 (right eye) and 6/15 (left eye). Fundoscopy revealed …

Subacute loss of vision accompanied by pain is most commonly due to some form of inflammatory optic neuropathy (ON), and may be the first symptom of multiple sclerosis (MS). ON may also be due to viral or bacterial infection or systemic diseases. Although ON is frequently limited to a single episode, some patients experience recurrent episodes. The name recently given to these recurrent episodes of inflammatory ON with a negative workup for MS or other causes of ON is relapsing inflammatory ON (RION).1 MRI scans are normal and oligoclonal bands are rarely found in the CSF. Some patients with an initial diagnosis of RION are, after several years of follow-up, diagnosed with neuromyelitis optica (NMO), due to the occurrence of one or more episodes of myelitis.2 Recently, a specific marker of NMO, named NMO antibody, was found.3 There is now evidence to suggest that patients who experience recurrent episodes of myelitis and are positive for NMO antibodies are at a high risk of developing NMO.4 A similar hypothesis could be applied to RION. In the first study on NMO antibodies, a positive result was found in 2 of 8 patients with RION.3 However, the …

A 31-year-old man with progressive right hemianopsia and Ollier disease (multiple enchondromatosis) underwent head CT and MRI (figure). Figure Intracranial enchondroma Large extra-axial tumor (arrow) from left clinoid demonstrates calcifications on CT (A), sagittal T1W (B), and transverse GRE (D) …