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A 56-year-old man presented with rapidly evolving/sub-acute upper and lower motor neuron syndrome in 2015 with significant weakness in the four limbs and the bulbar region. Amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-r) was rated 34/48. On electromyography, there was a diffuse and active denervation in the four limbs and the tongue. A diagnosis of definite ALS according to international criteria was made. Six months later the patient stopped worsening. In the following years he progressively recovered. ALSFRS-r score improved to reach 48/48 in 2021. His neurological examination is normal and electromyography shows no denervation. Inquiry revealed that he presented a few months and, again a few days before onset, a mushroom poisoning. He was used to eating false morels either crude or undercooked and developed muscles cramps, nausea and vertigo. The relationships between this reversible sub-acute motor neuron syndrome and mushroom intoxication are discussed in the light of the recently described cluster in the Alps with a high incidence of ALS cases. Epidemiological investigations showed that all patients, but not their spouses, used to eat crude or undercooked false morels. Such a mushroom contains hydrazines, a known neurotoxic agent. We are not aware of another case of ALS reversal in that cluster area. We propose that a potential mushroom poisoning be thoroughly searched for when facing with a patient with sub-acute or rapidly worsening ALS syndrome.

Objectives: To describe a family with heterozygous P67S and D91A SOD1 mutations. Methods: The ALS profile of the proband was described. SOD1 gene sequencing was performed in the proband and his chi...

Little is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.Sera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single-molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.sNfL levels were higher in ALS patients than in controls at the two time points (p 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale-revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003).In this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.

Objectives: To describe a patient with facial-onset sensory-motor neuronopathy (FOSMN) that later developed Huntington’s disease (HD). Case report: A 62-year-old woman complained of progressive dysphagia 8 years before referral. At initial evaluation, there was excessive salivation, dysphagia, and sensory-motor trigeminal impairment. Denervation was noted on the upper limbs and the tongue. Blink reflexes were abolished. Genetic study of amyotrophic lateral sclerosis (ALS)-related genes was normal. She was diagnosed with FOSMN syndrome. Her clinical state progressively worsened with corneal anesthesia, severe denutrition, right arm and axial weakness. Seven years after referral, she was unable walk and developed generalized chorea. Abnormal huntingtin gene repeat expansion confirmed the diagnosis of HD. She died 16 years after onset of dysphagia. Conclusion: Cases with both HD and ALS have already been reported but not FOSMN and HD, to our knowledge. Some FOSMN cases have been linked to ALS-related gene mutations and HD phenocopies have been associated with C9ORF72 repeat expansions. Recently, huntingtin repeat expansions were described in the ALS population. Although a chance association cannot be excluded, data from the literature are in favor of a pathogenic relationship between FOSMN and HD in this particular case. We suggest that huntingtin gene be more systematically studied in patients with FOSMN.

To assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France.This population-based study (2003-2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill's test, Global Moran's Index, Kulldorf's spatial scan statistic, Local Moran's Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results.The standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31-2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50-2.25).We report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.

International audience

Covid-19-related lockdown (LD) in France precluded in-person follow-up in referral ALS centers. ALS patients' evolution and worsening before and during LD were studied to analyze its impact. A total of 84 patients were identified. The monthly rate of ALSFRS-R decline during LD was 1.06 ± 1.42 and was significantly increased compared to the pre-LD period, 0.58 ± 0.73, corresponding to an 83% increase (p = 0.007). Weight loss was unchanged between pre-LD and LD, gender and site of onset did not influence the rates of change of ALSFRS-R score. Several factors may be implicated in this increased severity of ALS during LD, such as psychological consequences of LD, interruptions of physiotherapy and speech therapy, or in-patient visits both to the tertiary center and the GP. Physicians and health authorities should be aware of that, in order to prevent the consequences of future sanitary restrictions.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3–4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3–4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments., Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.

International audience; Background: In familial amyotrophic lateral sclerosis (ALS) cases, the presence of an abnormal C9ORF72 repeat expansion (C9RE) is the most frequent genetic cause identified. Various clinical phenotypes have been described in relation to the presence of C9RE, including psychiatric disorders or Huntington-like symptoms. In a subset of sporadic ALS, C9RE has also been described. In the present study, all index cases with ALS and C9RE identified in our center and their clinical profile, as well as neurological and psychiatric characteristics of identified family members, were described. Clinical characteristics of ALS patients were compared to 999 patients with sporadic ALS (SALS) from our database.Results: From the 70 index cases with ALS identified, a total of 200 individuals were studied, 118 with ALS, 32 with fronto-temporal lobe degeneration (FTD), 37 with ALS/FTD, and 13 with psychiatric disorders. A familial history was present in 57 of the index cases (81%). In ALS and ALS/FTD cases with C9RE, the age of onset (AoO) was earlier than that in SALS cases, p < 0.0001 and p = 0.008, respectively. Sporadic cases with C9REALS (n = 13) had an earlier AoO compared to familial C9REALS ones, p < 0.0001. Within families, there was an earlier AoO in index cases and their siblings compared to their parental generation (p < 0.01). There was also a significant intrafamilial correlation for bulbar onset of ALS. The parental generation had significant female predominance compared to index cases and their siblings (sex ratio 0.47 vs. 1.4, p = 0.004), and this predominance was also present when considering parent-child pairs. In the group with psychiatric disorders, suicide was prominent (n = 9) and mean age was 54 years.Conclusion: Although our sample size is rather limited, the earlier AoO in index cases and their siblings compared to the parental generation may suggest an anticipation. Reasons for predominance of female transmission are unclear, but the hypothesis that gender influences transmission of the genetic trait or C9RE size variation may be taken into account. Intrafamilial correlation suggests that genetic aspects underlie the occurrence of bulbar onset in ALS patients. Studies on larger samples are warranted to confirm those results.

A 20-year-old man presented with subacute dysarthria, along with bilateral facial and brachial palsy, after a febrile odynophagia. Initially brisk, his upper limb deep tendon reflexes decreased with muscle wasting concerning the C5-T1 myotomes. MRI showed bilateral prefrontal gyri and thalami lesions with anterior cervical spinal cord lesion (figures 1 and 2). Upper limb lower motor neuron involvement was confirmed by EMG. CSF analysis showed lymphocytic pleiocytosis, elevated protein, and normal glucose levels . Epstein-Barr virus (EBV) serology revealed acute infection with the presence of viral capsid antigen (VCA) immunoglobulin M and VCA immunoglobulin G (IgG), in the absence of Epstein-Barr nuclear antigen–1 IgG. EBV DNA load was increased in blood and CSF. Other investigations including HIV screening remained negative. Simultaneous upper and lower motor neuron injury, well-described in HIV, is an unusual finding in EBV infection.1

Introduction L’ataxie de Friedreich (FA), pathologie autosomique recessive rare, est liee a une expansion de triplet GAA du gene de la frataxine. Sa prevalence semble plus importante sur l’Ile de la Reunion. Objectifs Caracteriser la population reunionnaise atteinte de la maladie, comparer les patients ayant debute la maladie avant ou apres 25 ans et aborder les facteurs explicatifs de certaines complications. Methodes Etude transversale de tous les dossiers des patients atteints de maladie de Friedreich confirmee genetiquement et suivis entre 2015–2017 au CHU de la Reunion. Les caracteristiques demographiques de la population et les principaux symptomes et complications de la maladie ont ete relevees. Les donnees ont ete analysees par des tests statistiques adaptes aux donnees non parametriques : Chi2 et Mann–Whitney pour les comparaisons ou en regression lineaire pour etablir des correlations. Resultats Cohorte de 65 patients, âge median de debut de la maladie 22 ans (range : 4–70 ans) : 38,5 % l’ont debute apres 25 ans (LOFA : late onset FA), 21,5 % apres 40 ans (very LOFA). Le nombre de copies GAA1 (plus petit allele) median est de 370 (IQ : 200–470). Perte de la marche en moyenne vers 39,6 ans apres une mediane de 18 ans d’evolution. Au total, 59,4 % sont spastiques, 23 % conservent leurs reflexes, 10,9 % ont des anomalies ETT. Discussion L’insularite et le communautarisme historiques a la Reunion rendent compte de la forte prevalence de certaines maladies recessives sur l’ile. Notre cohorte comprend une forte proportion de Friedreich de revelation tardive, de spasticite et peu de cardiopathie patente. La perte de la marche survient tardivement. La mediane de GAA1 est plus faible qu’habituellement decrite (generalement 600–900 copies). Conclusion La Reunion possede un cluster d’ataxie de Friedreich a faible nombre de repetition GAA, dont les caracteristiques peuvent rappeler les formes acadiennes, qui sont egalement le resultat d’un effet fondateur.

Introduction Pour chaque UNV la reduction des delais est un challenge dont l’impact est majeur, evalue en moyenne a 1,8 journee d’autonomie supplementaire pour chaque minute gagnee sur le delai door-to-needle (DTN) median (Meretoja et al. Neurology 2014). Objectifs Nous rapportons un plan d’action visant a reduire la DTN sur le CH de Perpignan et les resultats intermediaires a 8 mois. Patients et methodes Apres un cycle de formation et ajustement des procedures, monitorage prospectif des delais globaux (DTN) et intermediaires pour les patients consecutifs traites de mars 2015 a novembre 2015. Les resultats rapportes mensuellement aux acteurs de la filiere via une newsletter ou toute perte de temps constatee lors d’une phase intermediaire y est signalee. Cela donne lieu a des plans d’action trimestriels axes sur les points bloquants. L’impact est evalue par le DTN median compare au DTN2012–2014. Resultats Sur les 6 premiers mois, 106 dossiers ont ete analyses dont 95 cas traites par tPA-IV, 11 cas transferes sur le CHU de Montpellier pour thrombectomie (Tm) sans thrombolyse IV. Une IRM initiale etait realisee dans 82 cas (96,5 %). Le DTN median est de 63 minutes (min 26, max 171) soit une reduction de 24 minutes (DTN2012–2014 = 87 min.). L’analyse mois par mois fait apparaitre une reduction des delais intermediaires et du DTN (DTN median 8 e mois = 50 min vs DTN median 5 premiers mois = 64 min. ; p Discussion Notre action a permis de reduire le DTN median de 24 minutes ce qui suggere une reduction de la perte d’autonomie evaluee a 4104 jours pour les 95 patients traites sur l’UNV en 8 mois (hors Tm). Les perspectives sont de consolider la reduction des delais (et atteindre l’objectif d’un DTN median a 45 minutes). Ce plan d’action pilote par un animateur filiere ARS pourrait etre reproduit sur d’autres UNV s’inscrivant dans cette demarche. Conclusion Notre action a permis de reduire la DTN de 24 minutes ce qui suggere une reduction de la perte d’autonomie evaluee a 4104 jours pour les 95 patients traites sur l’UNV (hors Tm).

PC-1 (NPP-1) inhibitors may be useful as therapeutics for the treatment of CDDP (calcium pyrophosphate dehydrate) deposition disease and osteoarthritis. We have identified a series of potent quinazolin-4-piperidin-4-ethyl sulfamide PC-1 inhibitors. The series, however, suffers from high affinity binding to hERG potassium channels, which can cause drug-induced QT prolongation. We used a hERG homology model to identify potential key interactions between our compounds and hERG, and the information gained was used to design and prepare a series of quinazolin-4-piperidin-4-methyl sulfamides that retain PC-1 activity but lack binding affinity for hERG.