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ObjectiveTo describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG.MethodsThe CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.ResultsAmong 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.ConclusionsThis registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4–2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.

BACKGROUND AND PURPOSE Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. METHODS Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. RESULTS Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. CONCLUSIONS To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.

We performed an exome sequence association study on extreme MRI-markers of cerebral small vessel disease (extensive-CSVD versus minimal-CSVD) in participants from the 3C-Dijon French population-based cohort study, focusing on genes harbouring causal mutations for Mendelian forms of CSVD ( NOTCH3 , HTRA1 , COL4A1 , COL4A2 , TREX1 and CTSA ). The study population comprised 514 participants aged 73.30±4.24 years (59.24% women). The extensive-CSVD group comprised 261 persons in the upper extreme distribution of WMHV residuals adjusted for age, gender, and intracranial volume, prioritizing participants with lacunar brain infarcts within the top quartile of WMHV residuals. The minimal-CSVD group comprised 253 participants without MRI-defined brain infarct who were in the lower extreme distribution of WMHV residuals. These participants were whole-exome sequenced with average depth coverage of 100X. We screened for the presence of known pathogenic genotypes in our cohort, and performed single variant association tests and gene-based burden tests. We identified one individual with extensive-CSVD carrying a heterozygote genotype in HTRA1 previously described as a CARASIL causing mutation in Asians, and not previously reported in European families with the dominant HTRA1 phenotype. We also identified significant association of a common intronic variant, rs2293871, in HTRA1 with extensive-CSVD (p=8.209 х 10 -5 ) that remained significant after correction for multiple testing and accounting for regional linkage disequilibrium. Furthermore, the burden of rare and low frequency protein-modifying alleles in NOTCH3 was significantly associated with increased risk of extensive-CSVD (p=9.990 х 10 -3 ). In conclusion, we describe a novel strategy to identify genetic determinants of CSVD using population cohorts of elderly based on an extreme composite phenotype. We report one clinically important case carrying a heterozygote genotype at the CARASIL causing mutation. We show significant association of an intronic common variant in HTRA1 gene and the burden of rare and low frequency protein damaging variants in NOTCH3 gene with extensive-CSVD. These associations suggest some shared mechanisms between monogenic and multifactorial CSVD.

Topographical disorientation is frequent among patients after a stroke and can be well explored with virtual environments (VEs). VEs also allow for the addition of stimuli. A previous study did not find any effect of non-contextual auditory stimuli on navigational performance in the virtual action planning-supermarket (VAP-S) simulating a medium-sized 3D supermarket. However, the perceptual or cognitive load of the sounds used was not high.We investigated how non-contextual auditory stimuli with high load affect navigational performance in the VAP-S for patients who have had a stroke and any correlation between this performance and dysexecutive disorders.Four kinds of stimuli were considered: sounds from living beings, sounds from supermarket objects, beeping sounds and names of other products that were not available in the VAP-S. The condition without auditory stimuli was the control. The Groupe de réflexion pour l'évaluation des fonctions exécutives (GREFEX) battery was used to evaluate executive functions of patients.The study included 40 patients who have had a stroke (n=22 right-hemisphere and n=18 left-hemisphere stroke). Patients' navigational performance was decreased under the 4 conditions with non-contextual auditory stimuli (P0.05), especially for those with dysexecutive disorders. For the 5 conditions, the lower the performance, the more GREFEX tests were failed. Patients felt significantly disadvantaged by the non-contextual sounds sounds from living beings, sounds from supermarket objects and names of other products as compared with beeping sounds (P0.01). Patients' verbal recall of the collected objects was significantly lower under the condition with names of other products (P0.001). Left and right brain-damaged patients did not differ in navigational performance in the VAP-S under the 5 auditory conditions.These non-contextual auditory stimuli could be used in neurorehabilitation paradigms to train patients with dysexecutive disorders to inhibit disruptive stimuli.

Objective Many patients suffer from a topographical disorientation after having a stroke. Virtual reality tools allow us to evaluate topographical orientation and spatial navigation of several populations of patients, notably after a stroke. Furthermore, they allow us to add stimuli to the software. Contextual stimuli have been already shown to improve spatial navigation in patients with a stroke. We noticed in a previous study that non-contextual stimuli not linked with the navigational task did not impact the performance of patients with a focal hemispheric lesion. But the impact of non-contextual stimuli with higher perceptual or cognitive salience is not known yet. Objective: to determine if non-contextual stimuli with a high perceptual or cognitive salience decrease the navigation performance of patients who have had a stroke, especially those with dysexecutive disorders. Material/patients and methods Forty patients who have had a stroke and 26 healthy control subjects age- and gender-matched were included in this randomized trial. The participants were first familiarized with the virtual environment, the Virtual Action Planning-Supermarket (VAP-S). Then, the participants had to do a searching task of 7 objects in the VAP-S during 5 consecutive days. The navigational tasks were doing in a randomized order with: sounds providing from living beings, from supermarket's objects, beeping sounds, names of products which were not into the supermarket and without auditory stimuli. The main judgment criterion was a composite score made with the navigation time and the number of collected objects into the VAP-S. Results Patients’ performances were significantly decreased in presence of sounds from living beings, sounds from supermarket's objects, and name of products which were not into the supermarket, especially in patients with dysexecutive disorders. The performances of patients into the VAP-S were correlated with the evaluation of dysexecutive disorders using the GREFEX battery. Discussion – conclusion Non-contextual auditory stimuli with a high perceptual or cognitive salience could be useful in neurorehabilitation paradigms, in order to train patients with dysexecutive disorders to inhibit non-contextual information.