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A growing spectrum of neurological manifestations are being recognized in association with IgLON5 autoimmunity, including recent reports of motor-neuron-disease-like phenotype. Here we describe four cases of IgLON5 autoimmunity with motor neuron involvement and evaluate an additional 109 probable or definite amyotrophic lateral sclerosis cases seen in our neuromuscular clinic for IgLON5-IgG seropositivity. The presence of parasomnias, vocal cord dysfunction or hyperkinetic movements in a patient with motor-neuron-disease-like phenotype should prompt evaluation for IgLON5-IgG autoantibodies. Recognition and treatment of this autoimmune disease with immunosuppressive agents may bring about significant neurological improvement in a minority of cases.

Background. Delirium disorder is a frequent neurological complication of SARS-CoV-2 infection and associated with an increased disease severity and mortality. Cognitive impairment is a major risk factor for developing delirium disorder during Covid-19, which, in turn, increases the risk of subsequent neurological complications and cognitive decline. Summary. The bidirectional connection between delirium disorder and dementia likely resides at multiple levels, and its pathophysiological mechanisms during Covid-19 include endothelial damage, blood-brain barrier dysfunction and local inflammation, with activation of microglia and astrocytes. Here, we describe the putative pathogenic pathways underlying delirium disorder during Covid-19 and highlight how they cross with the ones leading to neurodegenerative dementia. Key messages. The analysis of the two-sided link can offer useful insights for confronting with long-term neurological consequences of Covid-19 and framing future prevention and early treatment strategies.

IMPORTANCE: The SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. OBJECTIVE: To determine T-cell responses to the Omicron spike protein in anti-CD20–treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis. INTERVENTIONS: Blood sampling before and 1 month after the third vaccine dose. MAIN OUTCOMES AND MEASURES: Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose. RESULTS: Of 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, 73.6-114.5; Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell–depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

Background and purpose Progressive multifocal leukoencephalopathy (PML) is a severe infection caused by the polyomavirus JC that develops in the central nervous system (CNS) of immunosuppressed patients. The infection frequently starts in the brain hemispheres and can spread into other CNS regions such as the brainstem. Initial isolated PML brainstem lesions are exceptional. We aimed to describe the challenging diagnosis of PML with isolated brainstem lesions at the time of disease onset. Methods We describe a case of PML starting with an isolated brainstem lesion and reviewed clinical, radiological, and biological features of all the reported cases of isolated brainstem PML. Results Isolated brainstem PML at disease onset is extremely rare. In addition to our case, only nine PML cases presenting with strictly isolated radioanatomical brainstem location at the time of disease onset were retrieved through the literature. All patients share similar brain magnetic resonance imaging features, without contrast enhancement. Eight patients presented with initial clinical worsening, but full recovery occurred in three patients, partial recovery in two, and death in three. Even if prognosis is reserved because of the surrounding vital structures in the brainstem, clinical recovery may occur. Conclusions This case report and literature review emphasize that isolated brainstem lesion is an atypical presentation of PML at disease onset.

This study analyzed the cerebrospinal fluid features of 31 coronavirus disease 2019 (COVID-19) patients with neurological complications. We observed neither severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the cerebrospinal fluid, nor intrathecal immunoglobulin G (IgG) synthesis but did observe signs of blood-brain barrier disruption. These results might serve as a basis for a better understanding of SARS-CoV-2 related neuropathogenesis.

BACKGROUND AND PURPOSE: Covid-19, initially described as a respiratory system's infection, is currently more and more recognized as a multiorganic disease, including neurological manifestations. There is growing evidence about a potential neuroinvasive role of SARS-CoV-2. The purpose of this study is to describe new findings, in the form of cerebral microbleeds affecting different brain structures, observed in MRIs of critically ill patients. METHODS: For this purpose, the MR images of 9 patients with a common pattern of abnormal findings (2 women/7 men; 55-79 years of age; mean age: 67.7 years) were depicted. All patients were tested positive for SARS-CoV-2 and presented with delayed recovery of consciousness or important agitation, requiring brain MRI. RESULTS: All patients had suffered from severe (5/9) or moderate (4/9) acute respiratory distress syndrome, requiring prolonged stay in the intensive care unit. Their common MRI finding was the presence of microbleeds in unusual distribution with a specific predilection for the corpus callosum. Other uncommon locations of microbleeds were the internal capsule (5/9), as well as middle cerebellar peduncles (5/9). Subcortical regions were also affected in the majority of patients. CONCLUSIONS: Brain MRI raised evidence that Covid-19 or its related treatment may involve the brain with an unusual pattern of microbleeds, predominantly affecting the corpus callosum. The mechanism of this finding is still unclear but the differential diagnosis should include thrombotic microangiopathy related to direct or indirect-through the cytokine cascade-damage by the SARS-CoV-2 on the endothelium of brain's vessels, as well as mechanisms similar to the hypoxemia brain-blood-barrier injury.

Background CD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8+ T cells by using a MOG35–55 T cell-mediated EAE model. Methods Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55 in complete Freund’s adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay. Results In the present study, we observed that a fraction of murine effector CD8+ T cells expressed c-Met receptor (c-Met+CD8+) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met+CD8+ T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein37–50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met+CD8+ T cells in cell-mediated cytotoxicity reactions Conclusions Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8+ T cell-mediated neuroinflammation.

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p

Lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the 2-fold aim of the present study was to (i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase and (ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnoea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analysed, and statistical intergroup analyses were then performed on behavioural and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed a significant decrease in connectivity, in the anosognosic group as compared with the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4c-Met expression by CD4CD4

ObjectivesInfectious lumbosacral radiculitis and myelitis, a clinical entity called Elsberg syndrome, is classically linked to HSV-2 and VZV. Here, we report a case of an Elsberg syndrome caused by primary cytomegalovirus (CMV) infection in an immunocompetent patient.MethodsHere is a case report at an academic medical center. Cerebral and spinal cord MRI, electroneuromyography, and serum and CSF analysis were performed.ResultsWe investigated a 31-year-old healthy woman presenting with acute paresthesia of both feet ascending to the pelvic region, urinary retention, and constipation. Neurologic examination revealed symmetrical hyperesthesia of both inferior limbs up to the pelvic region, with patellar and Achilles hyporeflexia. Although MRI was normal, a dysfunction of the S1 left nerve root was observed on electroneurography. CSF analysis was inflammatory. Blood CMV PCR was positive, and anti-CMV IgG/IgM values indicated seroconversion. Taken together, these results strongly suggested an Elsberg syndrome caused by CMV primary infection. After a course of ganciclovir, a marked improvement of the symptoms was observed.DiscussionThis case highlights that CMV primary infection can be a cause of Elsberg syndrome in immunocompetent patients. CMV testing should be discussed in these patients to initiate adequate antiviral therapy.

Patients treated with anti-CD20 therapy are particularly at risk of developing severe COVID-19, however little is known regarding COVID-19 vaccine effectiveness in this population. This study assesses humoral and T-cell responses to mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n=37), compared to immunocompetent individuals (n=22). SARS-CoV-2-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4+ T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8+T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). Vaccine-specific CD4+and CD8+T cells were polyfunctional but expressed more IL-2 in patients than in controls. In summary, our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the prevention of severe COVID-19.

Encephalopathy is a neurological complication of COVID-19. The objective of this exploratory study is to investigate the link between systemic inflammation and brain microstructural changes (measured by diffusion-weighted imaging) in patients with COVID-19 encephalopathy. 20 patients with COVID-19 encephalopathy (age: 67.3 $$\pm$$ ± 10.0 years; 90% men) hospitalized in the Geneva University Hospitals for a SARS-CoV-2 infection between March and May 2020 were included in this retrospective cohort study. COVID-19 encephalopathy was diagnosed following a comprehensive neurobiological evaluation, excluding common causes of delirium, such as hypoxemic or metabolic encephalopathy. We investigated the correlation between systemic inflammation (measured by systemic C-reactive protein (CRP)) and brain microstructural changes in radiologically normal white matter (measured by apparent diffusion coefficient (ADC)) in nine spatially widespread regions of the white matter previously associated with delirium. Systemic inflammation (CRP = 60.8 ± 50.0 mg/L) was positively correlated with ADC values in the anterior corona radiata (p = 0.0089), genu of the corpus callosum (p = 0.0064) and external capsule (p = 0.0086) after adjusting for patients’ age. No statistically significant association between CRP and ADC was found in the other six white matter regions. Our findings indicate high risk of white matter abnormalities in COVID-19 encephalopathy patients with high peripheral inflammatory markers, suggesting aggressive imaging monitoring may be warranted in these patients. Future studies should clarify a possible specificity of the spatial patterns of CRP–white matter microstructure association in COVID-19 encephalopathy patients and disentangle the role of individual cytokines on brain inflammatory mechanisms.

Acute encephalopathy is one of the most frequent neurological complication in patients hospitalized for COVID-19. Electrolyte imbalance, drugs, and hypoxemia can all affect brain homeostasis, leading to acute cognitive dysfunction and direct implications of the SARS-CoV-2 are not completely understood. Neurological complications of SARS-CoV-2 infection are poorly understood: an inflammatory insult to the endothelium affecting the blood-brain barrier may explain the clinical presentation, but other hypotheses including direct viral damage or an immune-mediated reaction are also suggested. Among these various potential mechanisms, often combined, the controversy remains.L’encéphalopathie aiguë est l’une des principales complications neurologiques des patients hospitalisés pour un Covid-19. Si les complications électrolytiques, les différents traitements et l’hypoxémie ont un effet sur l’homéostasie cérébrale entraînant une perturbation de la cognition, les conséquences cérébrales directes ou indirectes du SARS-CoV-2 ne sont pas complètement élucidées. L’implication du virus entraînant une atteinte endothéliale des vaisseaux cérébraux pourrait participer à cette encéphalopathie, via une fragilisation de la barrière hémato-encéphalique et un passage facilité des cytokines pro-inflammatoires. L’atteinte virale directe ou la réaction autoimmune secondaire ont également été invoquées. Face aux multiples mécanismes physiopathologiques possibles pouvant expliquer cette encéphalopathie, le débat est ouvert.

BackgroundThere is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can include long-term neuropsychological deficits, even in its mild or moderate respiratory forms.MethodsStandardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 ± 22.54 days post-discharge following SARS-CoV-2 infection.ResultsDeficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed.ConclusionThe data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes.

International audience; Abstract Study Objectives The COVID-19 pandemic has had dramatic effects on society and people’s daily habits. In this observational study, we recorded objective data on sleep macro- and microarchitecture repeatedly over several nights before and during the COVID-19 government-imposed lockdown. The main objective was to evaluate changes in patterns of sleep duration and architecture during home confinement using the pre-confinement period as a control. Methods Participants were regular users of a sleep-monitoring headband that records, stores, and automatically analyzes physiological data in real time, equivalent to polysomnography. We measured sleep onset duration, total sleep time, duration of sleep stages (N2, N3, and rapid eye movement [REM]), and sleep continuity. Via the user’s smartphone application, participants filled in questionnaires on how lockdown changed working hours, eating behavior, and daily life at home. They also filled in the Insomnia Severity Index, reduced Morningness–Eveningness Questionnaire, and Hospital Anxiety and Depression Scale questionnaires, allowing us to create selected subgroups. Results The 599 participants were mainly men (71%) of median age 47 (interquartile range: 36–59). Compared to before lockdown, during lockdown individuals slept more overall (mean +3·83 min; SD: ±1.3), had less deep sleep (N3), more light sleep (N2), and longer REM sleep (mean +3·74 min; SD: ±0.8). They exhibited less weekend-specific changes, suggesting less sleep restriction during the week. Changes were most pronounced in individuals reporting eveningness preferences, suggesting relative sleep deprivation in this population and exacerbated sensitivity to societal changes. Conclusion This unique dataset should help us understand the effects of lockdown on sleep architecture and on our health.

Importance The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Background No studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse. Methods This retrospective cohort study compared the clinical courses of MS patients in the year before and after rabies vaccination. The year before vaccination was defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period. All adult MS patients immunized with RV between 2014 and 2018 and with available medical records in the two-year window were included. The primary outcome was the incidence of symptomatic MS relapse in the exposure-risk period versus the pre-exposure period. Results Fifty-five patients received at least one dose of RV. Most (38/55, 69%) were female; mean age was 38.5 years (SD ±9.2). While 21 (38%) patients experienced 24 relapses in the year before vaccination, only three (5%) experienced one relapse each in the post-vaccination exposure-risk period; three others (5%) experienced a total of four relapses in the subsequent post-risk period. The annualized relapse rates in the pre-exposure, exposure-risk, and post-risk periods were 0.44, 0.22, and 0.10, respectively (rate ratio for exposure-risk to pre-exposure periods, 0.509 [95% CI 0.098-1.677]). Conclusions In this cohort, rabies vaccination was not associated with clinical MS relapse. Larger, prospective studies are needed to confirm these results.

Severe acute respiratory coronavirus 2 (SARS‐CoV‐2) has been associated with neurological complications, including acute encephalopathy. To better understand the neuropathogenesis of this acute encephalopathy, we describe a series of patients with coronavirus disease 2019 (COVID‐19) encephalopathy, highlighting its phenomenology and its neurobiological features. On May 10, 2020, 707 patients infected by SARS‐CoV‐2 were hospitalized at the Geneva University Hospitals; 31 (4.4%) consecutive patients with an acute encephalopathy (64.6 ± 12.1 years; 6.5% female) were included in this series, after exclusion of comorbid neurological conditions, such as stroke or meningitis. The severity of the COVID‐19 encephalopathy was divided into severe and mild based on the Richmond Agitation Sedation Scale (RASS): severe cases (n = 14, 45.2%) were defined on a RASS

We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. By categorical analysis, in patients with IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF < median. Dose-dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging-defined disease activity and sNfL. This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

ObjectiveTo determine whether CSF interleukin 8 (IL-8) concentration can help to distinguish Guillain-Barré syndrome (GBS) from chronic inflammatory demyelinating polyneuropathy (CIDP) at the initial stage of the disease.MethodsWe performed retrospective immunoassay of IL-8 in CSF, collected at the University Hospitals of Geneva between 2010 and 2018, from patients diagnosed with GBS (n = 45) and with CIDP (n = 30) according to the Brighton and European Federation of Neurological Societies/Peripheral Nerve Society criteria by a physician blinded to biological results.ResultsCSF IL-8 was higher in GBS (median: 83.9 pg/mL) than in CIDP (41.0 pg/mL) (p < 0.001). Receiver operating characteristic analyses indicated that the optimal IL-8 cutoff was 70 pg/mL. Above this value, patients were more likely to present GBS than CIDP (specificity 96.7%, sensitivity 64.4%, positive predictive value [PPV] 96.7%, and negative predictive value [NPV] 64.4%). Among GBS subcategories, IL-8 was higher in acute inflammatory demyelinating polyneuropathy (AIDP, median: 101.8 pg/mL) than in other GBS variants (median: 53.7 pg/mL). In addition, with CSF IL-8 above 70 pg/mL, patients were more likely to present AIDP than acute-onset CIDP (p < 0.001; specificity 100%, sensitivity 78.8%, PPV 100%, and NPV 46.2%) or other CIDP with nonacute presentation (p < 0.0001; specificity 95.8%, sensitivity 78.8%, PPV 96.3%, and NPV 76.7%).ConclusionCSF IL-8 levels can help to differentiate AIDP variant of GBS from CIDP, including acute-onset CIDP, with high specificity and PPV. This may improve early and appropriate treatment.Classification of EvidenceThis study provides Class II evidence that CSF IL-8 levels accurately distinguish patients with GBS from those with CIDP.

Background and Purpose Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with several complications of the central nervous system (CNS), including acute encephalopathy. Methods In this pilot study, we report a series of 39 patients (66.5 ± 9.2 years; 10.3% female) with acute encephalopathy, who underwent a standard brain magnetic resonance imaging (MRI) at 1.5 T during the acute symptomatic phase. In addition to diffusion-weighted imaging, MR angiography and susceptibility-weighted images, high-resolution vascular black blood sequences (in 34 cases) were used to investigate the vasculature of the brain. Results In 29 out of 34 patients with COVID-19 encephalopathy (85%) with high-resolution vessel wall imaging, we found a circular enhancement and thickening of the basilar and vertebral arteries, without any correlation with ischemia or microbleeds (reported in 21% and 59%, respectively). Conclusion We report a high prevalence of vascular changes suggestive of endotheliitis as reported in other organs. This could suggest an inflammatory mechanism underlying this encephalopathy.

We consider the safety of live vaccines when used in patients on natalizumab, a long-acting immunosuppressive monoclonal antibody. Based on this drug's specific mode of action we propose a benefit/risk assessment on a case-by-case basis with individual considerations, rather than a generic contra-indication.

The spectrum of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), includes different neurologic manifestations of the central and peripheral nervous system. From March through April 2020, in two university hospitals located in western Switzerland, we examined three patients with Guillain-Barré syndrome (GBS) following SARS-CoV-2. These cases were characterized by a primary demyelinating electrophysiological pattern (Acute inflammatory demyelinating polyneuropathy or AIDP) and a less severe disease course compared to recently published case series. Clinical improvement was observed in all patients at week five. One patient was discharged from hospital after full recovery with persistence of minor neurological signs (areflexia). Two of the three patients remained hospitalized: one was able to walk and the other could stand up with assistance. We report three cases of typical GBS (AIDP) occurring after SARS-CoV-2 infection and presenting with a favourable clinical course. Given the interval between COVID-19-related symptoms and neurological manifestations (mean of 15 days) we postulate a secondary immune-mediated mechanism rather than direct viral damage.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Immunosuppressive treatments are part of the therapeutic armamentarium in MG. Long-term systemic steroid administration carry considerable risks and adverse events. Consequently, steroid-free immunosuppressive therapy is necessary to reduce the dose or discontinue steroids. First immunosuppressive drug trials in MG were performed in the mid-60s using standard and nonspecific immunosuppression. Since then, only few randomized controlled clinical trials were conducted in MG and assesed drug efficacy in terms of its steroid-sparing capacity and the ability to reduce myasthenic signs and symptoms. Treatment strategy in MG is quite challenging, mainly due to the disease heterogeneity in terms of clinical presentation, immunopathogenesis and drug response. To solve this dilemma, emerging treatment are based on biological drugs and use new targets of the immune pathway.

One hundred twenty patients with coronavirus disease 2019 (COVID-19) were hospitalized in our intensive care unit, Geneva, Switzerland, between March 9 and April 16, 2020. We report the clinical evolution of 5 consecutive patients intubated because of COVID-19–related acute respiratory distress syndrome, presenting with a pathologic recovery of consciousness, which was responsive to high-dose glucocorticoids. These patients all presented with angio-MRI signs of inflammation of CNS arteries, consistent with an endothelialitis rather than a vasculitis. The median time between COVID-19 first symptoms and intubation was 10 days (IQR 10–11 days).

Myasthenia gravis (MG) is an autoimmune disease characterised by fluctuating muscle weakness with potentially life-threatening symptoms due to insufficiency of respiratory muscles. Treatment usually includes immunosuppressive drugs and cholinesterase inhibitors. COVID-19 is an infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), defined as a pandemic by the World Health Organisation (WHO). Although guidelines for the management of patients with MG during the COVID-19 pandemic have been published,1 these recommendations are based on theoretical considerations only, as no clinical data are available. We describe four patients with generalised MG affected by COVID-19 (around 10% of patients in our cohort). Clinical data are summarised in table 1. View this table: Table 1 Clinical data of four patients with generalised gravis and SARS-CoV-2 ### Case 1 A 36-year-old female patient, class IIa according to the Myasthenia Gravis Foundation of America (MGFA) score (166 cm, 67 kg), presented to Geneva University Hospital on 15 March 2020 with myalgia, coughing and fever >38°C on the same day. She was taking azathioprine (AZA) 50 mg, reintroduced at the end of January 2020, and pyridostigmine 60 mg five to six times per day. The last deterioration of MG had occurred in January 2020 requiring intravenous immunoglobulin (IVIG) treatment (Myasthenia Muscle Score 65/100). COVID-19 real-time PCR (RT-PCR) revealed a positive result. Chest X-ray showed no pulmonary infiltration and peak flow was at 400 mL (82%). The Myasthenia Muscle …

ObjectiveWe examined the effect of glatiramer acetate (GA) on B-cell maturation, differentiation, and antigen presentation in MS and experimental autoimmune encephalomyelitis (EAE).MethodsA cross-sectional study of blood samples from 20 GA-treated and 18 untreated patients with MS was performed by flow cytometry; 6 GA-treated patients with MS were analyzed longitudinally. GA-mediated effects on B-cell antigen-presenting function were investigated in EAE, or, alternatively, B cells were treated with GA in vitro using vehicle as a control.ResultsIn MS, GA diminished transitional B-cell and plasmablast frequency, downregulated CD69, CD25, and CD95 expression, and decreased TNF-α production, whereas IL-10 secretion and MHC Class II expression were increased. In EAE, we observed an equivalent dampening of proinflammatory B-cell properties and an enhanced expression of MHC Class II. When used as antigen-presenting cells for activation of naive T cells, GA-treated B cells promoted development of regulatory T cells, whereas proinflammatory T-cell differentiation was diminished.ConclusionsGA immune modulates B-cell function in EAE and MS and efficiently interferes with pathogenic B cell–T cell interaction.

Background and purpose In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. Methods This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. Results Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naive prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. Conclusion In this Swiss cohort of naive and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

ObjectiveThis cross-sectional study aims to assess the association between neuroaxonal damage assessed by serum neurofilament light chain (sNfL) and the Timed Up and Go (TUG)—a reliable and rapid measure of global neurologic disability—in patients with MS.MethodsA total of 41 consecutive patients with MS (38.0 ± 10.4 years; 57% women) with low level of disability (Expanded Disability Status Scale [EDSS] score 0–3) (EDSS score 1.0, interquartile range [IQR] 0.0–2.0) were included in this study. The TUG and sNfL were measured in a 6-month interval, together with a comprehensive neuropsychological and quantitative gait evaluation. The association of sNfL (dependant variable) with TUG, and other gait, cognitive, and behavioral measures (independent variables) were evaluated with multiple linear regressions adjusted for age, sex, and EDSS score.ResultsThe sNfL concentration was 23.51 pg/mL (IQR 16.51–32.21 pg/mL), and the mean TUG was 9.27 ± 1.70 seconds. Only the TUG was associated with sNfL (β = 0.021; 95% CI 0.003–0.037; p = 0.022) (after adjusting for age, sex, and EDSS score), whereas this was not the case for gait and neuropsychological measures.ConclusionsThe TUG—an easy and unexpansive measure of disability—is associated with the degree of neuroaxonal damage, as measured by sNfL, in patients with MS with low level of disability. These findings confirm the validity of the TUG as a reliable bedside measure of global neurologic disability as a result of neuroaxonal damage.

ObjectiveTo determine whether live-attenuated yellow fever vaccine (YFV) was associated with MS relapse, we evaluated the clinical courses of 23 patients in the year before and the year after immunization at the university hospital of Geneva, Switzerland.MethodsThis self-controlled retrospective cohort included adult patients with MS receiving YFV between 2014 and 2018 and defined the year before vaccination, the 3 months thereafter, and the 9 months following as the pre-exposure (PEP), exposure-risk (ERP), and postrisk (PRP) periods, respectively. The primary outcome was the relative incidence of relapse in the ERP vs the PEP. Secondary end points included the presence of new T2-weighted (T2) or T1-weighted gadolinium-positive (T1Gd+) MRI lesions.ResultsOf 23 patients with MS receiving YFV (20 relapsing MS and 3 primary progressive MS), 17 (74%) were women; mean age was 34 years (SD ±10); and 10 of 23 (40%) were treated with disease-modifying therapies (DMTs). Although 9 patients experienced 12 relapses in the PEP, only one experienced a relapse in the ERP; 3 other patients experienced one relapse each in the PRP. None of the 8 patients receiving natalizumab at the time of vaccination experienced relapse thereafter. In the PEP, ERP, and PRP, 18, 2, and 9 patients had new brain and/or spinal cord lesions on T2 or T1Gd + MRI, respectively.ConclusionsIn this cohort, YF vaccination was associated with neither an increase in MS relapse nor emergence of brain and/or spinal lesions. Further studies are warranted to confirm these findings.Classification of evidenceThis study provides Class IV evidence that for persons with MS, YFV may not increase relapse risk.

We report the case of a patient affected by systemic sclerosis (SSc) who developed autoimmune limbic encephalitis, which improved under immunosuppressant agents and high-dose intravenous immunoglobulins. In our patient the autoimmune encephalitis occurred during apparently quiescent SSc, though concomitantly with novel arthritis. Moreover, our patient showed auto-antibodies directed against SSA antigen but the panel of auto-antibodies associated with autoimmune encephalitis was negative. We discuss the potential for immunopathogenic inflammatory events affecting the central nervous system in SSc then favoring the occurrence of autoimmune encephalitic disorders. The possibility of a "neuro-scleroderma" may have important consequences in terms of therapeutic approaches.

Recommandations consensuelles en collaboration du Conseil scientifique de la Societe de la sclerose en plaques et de la Societe Suisse de Neurologie.