[The diagnostic challenge of autoimmune encephalitis]. / Le défi diagnostique des encéphalites auto-immunes.

Autoimmune encephalitis encompasses a spectrum of neurological disorders characterized by an autoimmune response directed against neurons and glia. Around two-thirds of cases exhibit autoantibodies targeting neuronal or glial antigens in the cerebrospinal fluid and/or serum. The diagnosis is based on specific criteria combining a subacute clinical presentation and complementary test results. However, approximately one-quarter of patients do not present any paraclinical abnormalities, making the diagnosis complex. Testing for anti-antibodies is pivotal for diagnosis, and their interpretation should be contextual. Best practices for anti-neural antibody detection involve appropriate sample collection and confirmation of positive results in relation to the clinical picture.

L'encéphalite auto-immune comprend un spectre de troubles neurologiques caractérisés par une réponse auto-immunitaire dirigée contre les neurones et les cellules gliales. Environ deux tiers des cas présentent des autoanticorps dirigés contre des antigènes neuronaux et gliaux dans le liquide céphalorachidien et/ou le sérum. Le diagnostic repose sur des critères spécifiques combinant une présentation clinique subaiguë et des résultats d'examens complémentaires. Environ un quart des patients ne présente pas d'anomalie paraclinique, rendant le diagnostic complexe. La recherche des autoanticorps est cruciale pour le diagnostic de certitude et son interprétation doit être contextuelle. Les bonnes pratiques pour leur dosage impliquent le prélèvement d'échantillons appropriés et la confirmation des résultats positifs par rapport au tableau clinique.

[Discontinuing disease-modifying therapies in multiple sclerosis]. / Traitements de la sclérose en plaques : quand les arrêter ?

Aging in multiple sclerosis (MS) leads to altered clinical manifestations, where the pathophysiology shifts towards compartmentalized inflammation that drives clinical progression independent of relapse activity. Consequently, the effectiveness of disease-modifying therapies (DMTs) diminishes in older patients, coinciding with an elevated risk of adverse events. This raises the question of whether MS therapies should be discontinued after a certain age, which is often proposed for patients over 55 years. Studies on treatment discontinuation have shown a slight increase in disease activity, yet without significant disability progression. This suggests that the decision to stop DMTs should be discussed with older patients, considering existing comorbidities. Following the cessation of therapy, meticulous monitoring is essential.

L'avancée en âge modifie la présentation clinique de la sclérose en plaques (SEP). La physiopathologie évolue progressivement au profit d'une inflammation restreinte au système nerveux central entraînant une progression clinique indépendante des poussées. Cette évolution est associée à une baisse d'efficacité des traitements de la SEP, alors qu'en parallèle le risque de complications augmente. Se pose donc la question d'un arrêt des thérapies de la SEP après un certain âge, souvent proposé à 55 ans. Bien que les premières études suggèrent une légère reprise d'activité à l'arrêt des traitements, celle-ci n'est pas associée à une progression du handicap. L'arrêt du traitement chez les patients les plus âgés devrait donc être envisagé en prenant en compte les comorbidités. Par la suite, une surveillance méticuleuse est indispensable.

[Anti-MOG associated disease]. / Maladie du spectre des anticorps anti-MOG.

Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD) is an autoimmune disease responsible for demyelination of the central nervous system that can occur in adults or children. Overlapping phenotypes between MOGAD, multiple sclerosis (MS) and neuromyelitis optica spectrum disease (NMOSD) have been described. The diagnostic criteria for MOGAD were proposed by a panel of international experts and published in 2023. Defining clinical, biological and imaging characteristics specific to this entity helps to improve diagnostic specificity. In this article, we present the clinical characteristics suggestive of MOGAD and discuss the importance of the antibody detection method and therapeutic management.

La maladie du spectre des anticorps anti-MOG (glycoprotéine de myéline oligodendrocytaire) (myelin oligodendrocyte glycoprotein antibody-associated disease, MOGAD) est une maladie autoimmune responsable d'une démyélinisation du système nerveux central pouvant survenir chez les adultes ou les enfants. Des phénotypes de chevauchement entre MOGAD, sclérose en plaques et maladie du spectre de la neuromyélite optique ont été décrits. Les critères diagnostiques de MOGAD ont été proposés par un panel d'experts internationaux et publiés en 2023. Ils permettent de définir des caractéristiques cliniques, biologiques et d'imagerie propres à cette entité, afin d'améliorer la spécificité diagnostique. Nous présentons dans cet article les caractéristiques cliniques en faveur de MOGAD, discutons de l'importance de la méthode de détection des anticorps et terminons par une mise au point sur la prise en charge thérapeutique.

[Management of chronic inflammatory demyelinating polyradiculoneuropathy]. / Prise en charge de la polyradiculoneuropathie inflammatoire démyélinisante chronique.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic autoimmune neuropathy. Its management has considerably evolved over the last decade. In 2021, the diagnostic guidelines for CIDP were updated and the diagnostic criteria simplified. They enable better characterization of the electro-clinical phenotype of the disease, and emphasize supportive criteria, in particular neuro-muscular imaging. In terms of pathophysiology, the discovery of antibodies directed against antigens in the nodal and paranodal regions has given rise to the concept of autoimmune nodopathy. Finally, the preliminary results of the ADHERE study on efgartigimod have rekindled hopes of a new, effective therapy for CIDP.

La polyradiculoneuropathie inflammatoire démyélinisante chronique (PIDC) est la neuropathie auto-immune chronique la plus fréquente. Sa prise en charge a largement évolué durant la dernière décennie. En 2021, les recommandations diagnostiques de la PIDC ont été mises à jour et les critères diagnostiques simplifiés. Ils permettent une meilleure caractérisation du phénotype électroclinique de la maladie et mettent en avant les critères de support diagnostiques, en particulier l'imagerie neuromusculaire. Sur le plan physiopathologique, la découverte d'anticorps dirigés contre des antigènes des régions nodale et paranodale a fait naître le concept de nodopathie auto-immune. Enfin, les résultats préliminaires de l'étude ADHERE sur l'efgartigimod font émerger l'espoir d'une nouvelle thérapie efficace dans la PIDC.

[Novel immunomodulatory therapies in myasthenia gravis]. / Myasthénie grave : nouvelles thérapies immunosuppressives.

Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating weakness of skeletal muscles. Despite current treatments, a significant percentage of patients remain symptomatic. This review explores new immunosuppressive therapies and ongoing clinical trials in MG, including depletion of B lymphocytes with agents such as rituximab and inebilizumab, as well as the use of eculizumab, efgartigimod, satralizumab, tocilizumab, and CAR-T (Chimeric Antigen Receptor-T) cell therapy. These advancements aim to improve disease control and patients' quality of life.

La myasthénie grave (MG) est une maladie auto-immune caractérisée par une faiblesse fluctuante des muscles squelettiques. Malgré les traitements classiques, un pourcentage significatif de patients reste symptomatique. Cet article explore les nouvelles thérapies immunosuppressives et les essais cliniques en cours pour la MG, notamment la déplétion des lymphocytes B avec des agents tels que le rituximab et l'inébilizumab, ainsi que l'utilisation de l'éculizumab, de l'efgartigimod, du satralizumab, du tocilizumab et de la thérapie par cellules CAR-T (Chimeric Antigen Receptor-T). Ces avancées visent à améliorer le contrôle de la maladie et la qualité de vie des patients.

[Treatments for multiple sclerosis: update]. / Traitements de la sclérose en plaques : mise à jour.

The management of multiple sclerosis (MS) has undergone a veritable revolution in recent years, with the arrival of highly effective treatments. In some cases, therapeutic discussions even precede the first clinical signs of the disease. The aim of this review is to present the therapeutic arsenal of progression-preventing treatments available in 2024 for MS, with anti-CD20 antibodies taking pride of place, also available for certain progressive forms of MS. The use of these immunosuppressants requires in-depth knowledge of their mechanisms of action, in order to understand their risks, such as the occurrence of opportunistic infections.

La prise en charge de la sclérose en plaques (SEP) a subi une véritable révolution ces dernières années avec l'arrivée de traitements à haute efficacité. La discussion thérapeutique précède même, dans certains cas, l'apparition des premiers signes cliniques de la maladie. Cet article a pour but de présenter l'arsenal des traitements de fond de la SEP disponibles en 2024. Parmi eux, les anticorps monoclonaux anti-lymphocytes B (anti-CD20) occupent une grande place. Ces derniers sont validés dans la forme poussée-rémission mais aussi pour les formes progressives de la SEP. L'utilisation de ces traitements nécessite une connaissance approfondie de leurs mécanismes d'actions afin de comprendre leurs risques tels que la survenue d'infections opportunistes.

Persistence and emergence of new neuropsychological deficits following SARS-CoV-2 infection: A follow-up assessment of the Geneva COVID-COG cohort.

Background: Despite numerous observations of neuropsychological deficits immediately following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, little is known about what happens to these deficits over time and whether they are affected by changes in fatigue and any psychiatric symptoms. We aimed to assess the prevalence of neuropsychological deficits at 6-9 months and again at 12-15 months after coronavirus disease 2019 (COVID-19) and to explore whether it was associated with changes in fatigue and psychiatric symptoms. Methods: We administered a series of neuropsychological tests and psychiatric questionnaires to 95 patients (mean age = 57.12 years, standard deviation (SD) = 10.68; 35.79% women) 222 (time point 1 (T1)) and 441 (time point 2 (T2)) days on average after infection. Patients were categorised according to the severity of their respiratory COVID-19 symptoms in the acute phase: mild (no hospitalisation), moderate (conventional hospitalisation), and severe (hospitalisation in intensive care unit (ICU) plus mechanical ventilation). We ran Monte-Carlo simulation methods at each time point to generate a simulated population and then compared the cumulative percentages of cognitive disorders displayed by the three patient subgroups with the estimated normative data. We calculated generalised estimating equations for the whole sample to assess the longitudinal associations between cumulative neuropsychological deficits, fatigue, and psychiatric data (anxiety, depressive symptoms, posttraumatic stress disorder, and apathy). Results: Most participants (>50%) exhibited a decrease in their neuropsychological impairments, while approximately 25% showed an escalation in these cognitive deficits. At T2, patients in the mild subgroup remained free of accumulated neuropsychological impairments. Patients with moderate severity of symptoms displayed a decrease in the magnitude of cumulative deficits in perceptual and attentional functions, a persistence of executive, memory and logical reasoning deficits, and the emergence of language deficits. In patients with severe symptoms, perceptual deficits emerged and executive deficits increased, while attentional and memory deficits remained unchanged. Changes in executive functions were significantly associated with changes in depressive symptoms, but the generalised estimating equations failed to reveal any other significant effect. Conclusion: While most cumulative neuropsychological deficits observed at T1 persisted and even worsened over time in the subgroups of patients with moderate and severe symptoms, a significant proportion of patients, mainly in the mild subgroup, exhibited improved performances. However, we identified heterogeneous neuropsychological profiles both cross-sectionally and over time, suggesting that there may be distinct patient phenotypes. Predictors of these detrimental dynamics have yet to be identified.

High-dose glucocorticoids in COVID-19 patients with acute encephalopathy: clinical and imaging findings in a retrospective cohort study.

OBJECTIVES: Acute encephalopathy (AE) has been described as a severe complication of COVID-19. Inflammation has been suggested as a pathogenic mechanism, with high-dose glucocorticoids (GC) showing a beneficial effect. Here, we retrospectively analyzed the clinical and radiological features in a group of COVID-19 AE patients who received GC treatment (GT) and in a non-treated (NT) group. METHOD: Thirty-six patients with COVID-19 AE (mean age 72.6 ± 11 years; 86.11% men) were evaluated for GC treatment. Twelve patients (mean age 73.6 ± 4.5 years; 66.67% men) received GC, whereas 24 patients who showed signs of spontaneous remission were not treated with GC (mean age 70.1 ± 8.6 years; 95.83% men). Differences in clinical characteristics and correlations with imaging features were explored. RESULTS: The GT group showed signs of vulnerability, with a longer hospitalization (p = 0.009) and AE duration (p = 0.012) and a higher hypertensive arteriopathy (HTNA) score (p = 0.022), when compared to NT group. At hospital discharge, the two groups were comparable in terms of clinical outcome (modified Rankin scale; p = 0.666) or mortality (p = 0.607). In our whole group analyses, AE severity was positively correlated with periventricular white matter hyperintensities (p = 0.011), deep enlarged perivascular spaces (p = 0.039) and HTNA score (p = 0.014). CONCLUSION: This study suggests that, despite signs of radiological vulnerability and AE severity, patients treated by high-dose GC showed similar outcome at discharge, with respect to NT patients. Imaging features of cerebral small vessel disease correlated with AE severity, supporting the hypothesis that brain structural vulnerability can impact AE in COVID-19.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. METHODS: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. RESULTS: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). DISCUSSION: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

c-Met+ Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models.

CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met+ CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell-cell contact on the modulation of inhibitory checkpoint molecules' expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met+) and compared it to c-Met- CTL clones. Our results indicated that, similar to their murine counterparts, c-Met+ human CTL clones exhibited increased cytolytic activity compared to c-Met- CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Exposure: Association between NfL z scores and CDW. Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Obstructive sleep apnea: a major risk factor for COVID-19 encephalopathy?

BACKGROUND: This study evaluates the impact of high risk of obstructive sleep apnea (OSA) on coronavirus disease 2019 (COVID-19) acute encephalopathy (AE). METHODS: Between 3/1/2020 and 11/1/2021, 97 consecutive patients were evaluated at the Geneva University Hospitals with a neurological diagnosis of COVID-19 AE. They were divided in two groups depending on the presence or absence of high risk for OSA based on the modified NOSAS score (mNOSAS, respectively ≥ 8 and < 8). We compared patients' characteristics (clinical, biological, brain MRI, EEG, pulmonary CT). The severity of COVID-19 AE relied on the RASS and CAM scores. RESULTS: Most COVID-19 AE patients presented with a high mNOSAS, suggesting high risk of OSA (> 80%). Patients with a high mNOSAS had a more severe form of COVID-19 AE (84.8% versus 27.8%), longer mean duration of COVID-19 AE (27.9 versus 16.9 days), higher mRS at discharge (≥ 3 in 58.2% versus 16.7%), and increased prevalence of brain vessels enhancement (98.1% versus 20.0%). High risk of OSA was associated with a 14 fold increased risk of developing a severe COVID-19 AE (OR = 14.52). DISCUSSION: These observations suggest an association between high risk of OSA and COVID-19 AE severity. High risk of OSA could be a predisposing factor leading to severe COVID-19 AE and consecutive long-term sequalae.

Markers of limbic system damage following SARS-CoV-2 infection.

Alterations of the limbic system may be present in the chronic phase of SARS-CoV-2 infection. Our aim was to study the long-term impact of this disease on limbic system-related behaviour and its associated brain functional connectivity, according to the severity of respiratory symptoms in the acute phase. To this end, we investigated the multimodal emotion recognition abilities of 105 patients from the Geneva COVID-COG Cohort 223 days on average after SARS-CoV-2 infection (diagnosed between March 2020 and May 2021), dividing them into three groups (severe, moderate or mild) according to respiratory symptom severity in the acute phase. We used multiple regressions and partial least squares correlation analyses to investigate the relationships between emotion recognition, olfaction, cognition, neuropsychiatric symptoms and functional brain networks. Six to 9 months following SARS-CoV-2 infection, moderate patients exhibited poorer recognition abilities than mild patients for expressions of fear (P = 0.03 corrected), as did severe patients for disgust (P = 0.04 corrected) and irritation (P < 0.01 corrected). In the whole cohort, these performances were associated with decreased episodic memory and anosmia, but not with depressive symptoms, anxiety or post-traumatic stress disorder. Neuroimaging revealed a positive contribution of functional connectivity, notably between the cerebellum and the default mode, somatosensory motor and salience/ventral attention networks. These results highlight the long-term consequences of SARS-Cov-2 infection on the limbic system at both the behavioural and neuroimaging levels.

Paroxysmal painful tonic spasms in neuromyelitis optica spectrum disorder.

Background: Recently, an association between painful tonic spasms (PTS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) was established. Objective: To describe the clinical characteristics of PTS in NMOSD based on a video recording and to provide a literature review on the topic. Methods: We report a case of a 38 years-old woman with a diagnosis of NMOSD and positive aquaporin-4 IgG antibody status who developed PTS five weeks after an episode of longitudinal extensive transverse myelitis (LETM). Results: Repetitive, brief, and painful episodes of muscle contraction were observed on the patient's left hand, spreading to the left arm, and then extending to the four limbs. While pregabalin and topiramate had no influence on these episodes, the patient responded to carbamazepine (CBZ), without symptom recurrence after one year. Conclusions: PTS in association with LETM can be considered typical for NMOSD. Although the exact mechanism is unknown, ephaptic transmission after spinal cord damage and excitatory soluble factors released during acute inflammation responses are sought to be involved. Symptomatic treatment with CBZ achieved remission of spams in our case.

Brain functional connectivity alterations associated with neuropsychological performance 6-9 months following SARS-CoV-2 infection.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

Elsberg Syndrome Secondary to Cytomegalovirus Infection in an Immunocompetent Patient: A Case Report.

OBJECTIVES: Infectious 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. METHODS: Here is a case report at an academic medical center. Cerebral and spinal cord MRI, electroneuromyography, and serum and CSF analysis were performed. RESULTS: We 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. DISCUSSION: This 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.

Motor-neuron-disease-like phenotype associated with IgLON5 disease.

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.

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

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.