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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.

The purpose of this study was to compare the costs and organizational benefits of diagnostic workup without and with MRI dedicated to the ED.We conducted a prospective observational uncontrolled before-after study in one ED of a university hospital in France from July 1, 2018, and January 3, 2020. We included all consecutive patients presenting with dizziness or diplopia. The main outcomes were the clinical decision time of ED physicians and the total costs for each strategy. Outcomes were compared using propensity score with inverse probability weighting in the 2 arms and an incremental cost-effectiveness ratio (ICER) was calculated.Among the 199 patients during the "before" period (average age: 60.4 years ± 17.6): 112 men (57%), and 181 during the "after" period (average age, 54.8 years ± 18.5): 107 men (59%), the average costs were €2701 (95% CI 1918; 3704) and €2389 (95% CI: €1627; 3280) per patient, respectively. The average time to clinical decision was 9.8 h (95% CI: 8.9 10.7) in the group "before" and 7.7 h (95% CI: 7.1; 8.4) in the group "after" (ICER: €151 saved for a reduction of 1 h in clinical decision time). The probabilistic sensitivity analysis estimated a 71% chance that the MRI dedicated to ED was dominant (less costly and more effective).Easy access to MRI in the ED for posterior circulation stroke-like symptoms must be considered a relevant approach to help physicians for an appropriate and rapid diagnostic with reduction of costs.NCT03660852 KEY POINTS: • A dedicated MRI in the ED for diplopia or dizziness may be considered an efficient strategy improving diagnostic performance, reducing physicians' decision time, and decreasing hospital costs. • This strategy supports clinical decision-making with early treatment and management of patients with posterior circulation-like symptoms in the ED. • There is 71% chance that the MRI dedicated to ED was dominant (less costly and more effective) compared with a strategy without dedicated MRI.

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.

Introduction L’ETP dans la SEP se developpe, elle ne se limite plus qu’aux traitements injectables. Son interet et ses repercussions sur la prise d’un traitement par voie orale sont peu etudies. Objectifs Mesurer l’impact de l’ETP pour les traitements par voie orale au sein du reseau alSacEP sur la persistance et le risque d’arret du DMF dans une cohorte de vraie vie. Patients et methodes Tous les patients alsaciens debutant le DMF entre 2013 et juin 2019 ont ete inclus dans cette etude retrospective. Certains patients ont eu des seances d’ETP et d’autre non (par choix ou non propose par leur neurologue) et ont ete apparies par score de propension 1 :1. L’ETP consistait en une visite a domicile par une infirmiere specialisee puis 4 entretiens telephoniques. Le critere de jugement principal etait la persistance au traitement au cours du suivi. Resultats Le temps moyen de suivi sous DMF etait similaire : ETP : 2,31 (± 1,76) ; controles : 2,32 (± 2,0) annees. Au total, 291 patients sous ETP et 133 controles ont ete analyses par appariement. Le delai avant arret du DMF etait plus long dans le bras ETP (p = 0,03). L’ETP etait un facteur protecteur d’arret du DMF (OR = 0,505, IC95 % : 0,317–0,805, p = 0,004). Les facteurs de risque d’arret (p Discussion Dans notre etude, l’ETP dispensee par le reseau alSacEP etait un facteur protecteur d’arret du DMF. Une analyse de sensitivite avec IPTW a demontre des resultats similaires, soulignant la robustesse des resultats. Issue de donnees de registre, les principales limites de l’etude sont l’absence de randomisation et le caractere retrospectif du recueil des donnees. Conclusion L’ETP a demontre son efficacite dans le maintien du DMF chez les patients avec une SEP. Ces resultats doivent etre confirmes par des etudes prospectives et portant sur d’autres traitements.

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 Une reactivation de la sclerose en plaques remittente-recurrente (SEP-RR) a ete decrite apres arret du natalizumab (NTZ). Cependant, des donnees avec des traitements recents comme l’ocrelizumab sont manquantes. Objectifs L’objectif etait de comparer l’efficacite du fingolimod et de l’ocrelizumab en relais du NTZ dans la SEP-RR. Patients et methodes Dans cette etude observationnelle, tous les patients SEP-RR traites par fingolimod ou ocrelizumab en relais du NTZ (relais Resultats Nous avons inclus 35 patients sous ocrelizumab et 89 sous fingolimod. Les groupes etaient homogenes sauf pour la duree du NTZ qui etait plus longue dans le groupe ocrelizumab que le groupe fingolimod (76 mois contre 39 mois, p Discussion Dans notre etude, les patients sous ocrelizumab avait moins de poussees precoces que sous fingolimod. Ceci peut s’expliquer par une meilleure efficacite ou un delai d’action plus rapide de l’ocrelizumab par rapport au fingolimod. Ces resultats doivent etre confirmes dans de plus longues cohortes. Conclusion En relais du NTZ, les patients sous ocrelizumab ont moins de poussees que ceux sous fingolimod a un an.

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.

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.

Introduction Les ataxies avec apraxie oculomotrice comprenant les ataxies telangiectasies (AT), les ataxies avec apraxie oculo-motrice de type 1 (AOA1) et 2 (AOA2) n’ont jamais ete directement comparees. Objectifs Effectuer une comparaison multimodale des ataxies telangiectasies (AT), ataxies avec apraxie oculo-motrice de type 1 (AOA1) et 2 (AOA2) dont une video-oculographie. Patients et methodes Entre 2008 et 2015, 40 patients presentant une AT, AOA1 et AOA2, suivis dans deux centres de reference francais (Paris, Strasbourg) de mouvements anormaux de l’adulte ont ete compares a 17 sujets sains controles. Presentation clinique, scores fonctionnels, video-oculographie, ENMG, IRM cerebrale et biomarqueurs seriques ont ete evalues. Resultats Les patients presentent a l’enregistrement video-oculographique des troubles oculomoteurs complexes par rapport aux sujets controles. Des signes cerebelleux, une fixation alteree, une poursuite alteree, des saccades hypometriques et des antisaccades anormales etaient constants. Les latences des saccades horizontales pouvaient etre tres augmentees, refletant une apraxie oculomotrice chez 27 a 40 % des patients. Une plus grande variabilite des latences des saccades etait observee chez les patients. Des taux discriminants d’AFP ont ete determines : 7–15 μg/L pour AOA1, 15 − 65 μg/L pour AOA2, >65 μg/L pour AT. Les autres points communs etaient : debut precoce, handicap severe, mouvements anormaux, neuropathie sensitivo-motrice, atrophie cerebelleuse. Discussion/conclusion Les AOA1, AOA2 et AT ont un tableau oculomoteur proche et complexe. Elles devraient etre considerees comme un groupe particulier caracterise par une ataxie avec oculomotricite complexe et AFP elevee. Elles peuvent etre discriminees grâce a des seuils specifiques d’AFP. Ces elements phenotypiques clinicobiologiques aident a interpreter la pathogenicite des differents variants retrouves par sequencage haut debit.

Introduction L’ataxie de Friedreich (AF) est une maladie neurogenetique liee a l’accumulation de triplets GAA sur le gene de la frataxine (FXN). Nous rapportons le cas d’une patiente presentant une AF avec des depots de fer a l’IRM. Observation Une patiente de 64 ans, sans antecedent familial de syndrome cerebelleux, se presenta pour des troubles de la marche a type d’instabilite, d’aggravation lentement progressive depuis 2 ans, plus recemment associe a une dysarthrie et a une maladresse des membres superieurs. L’examen clinique retrouvait un syndrome cerebelleux axial et segmentaire aux 4 membres, une dysarthrie cerebelleuse ainsi qu’un syndrome pyramidal. Les reflexes osteotendineux etaient conserves. Le bilan biologique etait sans particularites. L’IRM cerebrale notait une atrophie cerebelleuse globale associe a des hyposignaux en sequence T2 echo de gradient au niveau putaminal de facon bilateral et symetrique ainsi qu’au niveau des noyaux denteles du cervelet. Ces hyposignaux etaient egalement retrouves sur les sequences Flair. En T1, ces anomalies apparaissaient egalement en hyposignal. L’analyse genetique du gene FXN a objective une accumulation de triplet GAA dans les deux alleles (expansion de 90 triplets pour la plus petite) permettant de poser avec certitude le diagnostic d’AF. Discussion L’AF est l’ataxie genetique autosomique recessive la plus frequente. La maladie debute souvent avant 25 ans mais des formes tres tardives ont ete decrites. Les hyposignaux T2 sont inconstants et seraient lies a une modification de la repartition du fer. L’atrophie cerebelleuse et du cordon medullaire est plus frequemment retrouvee a l’IRM. Le diagnostic precoce d’AF permet de depister la cardiopathie associee. Conclusion L’AF devrait systematiquement etre envisagee devant un syndrome cerebelleux lentement progressif meme chez les sujets âges et meme en l’absence d’antecedent familial en cas de depot de fer au niveau du cervelet ou des noyaux gris centraux a l’IRM.

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.