Human stem cell-derived neurons and astrocytes to detect novel auto-reactive IgG response in immune-mediated neurological diseases.

Background and objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.

Increased central obesity correlates with physical activity and food processing in recently diagnosed multiple sclerosis.

BACKGROUND: Environmental and lifestyle factors are associated with an increased risk of Multiple Sclerosis (MS). Metabolic syndrome (MetS) contributes to systemic inflammation, which is associated with poorer MS disease evolution. We compared persons with MS (PwMS) and controls to assess metabolic and lifestyle parameters associated with MS. METHODS: We pooled data from two prospective observational studies with the same eligibility criteria, matching PwMS and controls (1:2 ratio) by sex, age, and body mass index (BMI). We compared anthropometric, biological and lifestyle parameters, including sleep and physical activity. RESULTS: We included 53 PwMS and 106 controls with a median age of 35 years and 79% of women. PwMS had low Expanded Disability Status Scale (median 1.5). Compared to controls, PwMS had increased waist-to-hip (p<0.001) and waist-to-height (p=0.007) ratios, and practiced less physical activity (p=0.03). In regression models, lifestyle factors with the strongest factor loadings to predict central obesity were processed food consumption, and vigorous physical activity. DISCUSSION: Although both groups were matched by age, sex, and BMI, we found increased central obesity in PwMS. Even with minimal neurological impairment, PwMS practiced less physical activity. This suggests that improvement of lifestyle and metabolic parameters should be targeted in MS.

Clinical, paraclinical and outcome features of 166 patients with acute anti-GQ1b antibody syndrome.

BACKGROUND & PURPOSE: In this retrospective study, we aimed at defining the clinical, paraclinical and outcome features of acute neurological syndromes associated with anti-GQ1b antibodies. RESULTS: We identified 166 patients with neurological symptoms appearing in less than 1 month and anti-GQ1b antibodies in serum between 2012 and 2022. Half were female (51%), mean age was 50 years (4-90), and the most frequent clinical features were areflexia (80% of patients), distal upper and lower limbs sensory symptoms (78%), ophthalmoplegia (68%), sensory ataxia (67%), limb muscle weakness (45%) and bulbar weakness (45%). Fifty-three patients (32%) presented with complete (21%) and incomplete (11%) Miller Fisher syndrome (MFS), thirty-six (22%) with Guillain-Barre syndrome (GBS), one (0.6%) with Bickerstaff encephalitis (BE), and seventy-three (44%) with mixed MFS, GBS & BE clinical features. Nerve conduction studies were normal in 46% of cases, showed demyelination in 28%, and axonal loss in 23%. Anti-GT1a antibodies were found in 56% of cases, increased cerebrospinal fluid protein content in 24%, and Campylobacter jejuni infection in 7%. Most patients (83%) were treated with intravenous immunoglobulins, and neurological recovery was complete in 69% of cases at 1 year follow-up. One patient died, and 15% of patients relapsed. Age > 70 years, initial Intensive Care Unit (ICU) admission, and absent anti-GQ1b IgG antibodies were predictors of incomplete recovery at 12 months. No predictors of relapse were identified. CONCLUSION: This study from Western Europe shows acute anti-GQ1b antibody syndrome presents with a large clinical phenotype, a good outcome in 2/3 of cases, and frequent relapses.

[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.

[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.

Patisiran exposure in early pregnancy: a case report.

We describe here the first case of exposure to patisiran treatment, a small interfering RNA molecule, during early pregnancy of a 36-year-old woman with symptomatic hereditary transthyretin-related amyloidosis. There were no major complications during pregnancy and delivery, except for a postpartum hemorrhage due to uterine atony. Vitamin A levels had to be closely monitored during pregnancy, and vitamin A substitution adapted accordingly. There was no sign of minor or major congenital abnormalities of the baby. One month after delivery, the patient showed slight clinical and electrophysiological signs of neuropathy progression due to patisiran treatment withdrawal. Patisiran infusions were resumed 3 months after delivery. Due to the unknown teratogenic potential of patisiran, the risk of neuropathy worsening associated with withholding treatment must of course be weighed against a potential teratogenic risk of treatment during pregnancy. Vitamin A levels need to be closely assessed, and substitution must be adapted accordingly, to avoid embryofetal adverse outcome due to vitamin A deficiency or toxicity.

COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022.

BACKGROUND: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. OBJECTIVES: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. METHODS: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. RESULTS: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave (p < 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25-1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51-2.67]), obesity (OR = 2.36, 95% CI = [1.52-3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46-3.83]), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43-3.06] for EDSS 3-5.5 and OR = 4.53, 95% CI = [3.04-6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85-3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60-0.69]) or off (RR = 0.32, 95% CI = [0.30-0.33]) anti-CD20. DISCUSSION: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.

[Neurology: what's new in 2023]. / Neurologie: ce qui a changé en 2023.

The year 2023 is marked by the arrival on the market of lecanemab for the treatment of Alzheimer's disease. New biomarkers have demonstrated their usefulness in monitoring peripheral neuropathies and diagnosing synucleinopathies. A genetic study has highlighted the role of nervous system cells in the risk of progression of multiple sclerosis (MS). The adverse effects of anticonvulsant treatments after prenatal exposure and on lipid metabolism have been clarified. New anti-CGRP treatments have demonstrated their efficacy in migraine attacks and chronic migraines. The criteria for thrombectomy have been further broadened. And finally, rehabilitation is refining the management of cerebrovascular patients and those with secondary progressive MS.

L'année 2023 est marquée par l'arrivée sur le marché du lécanémab pour le traitement de la maladie d'Alzheimer. De nouveaux biomarqueurs ont démontré leur utilité dans le suivi des neuropathies périphériques ou dans le diagnostic des synucléinopathies. Une étude génétique a mis en évidence le rôle des cellules du système nerveux dans le risque de progression de la sclérose en plaques (SEP). Les effets indésirables des traitements anticonvulsivants lors d'exposition prénatale ou sur le métabolisme des lipides ont été précisés. De nouveaux traitements anti-CGRP ont démontré leur efficacité dans les crises migraineuses et les migraines chroniques. Les critères de thrombectomie se sont encore élargis. Et enfin, la réhabilitation affine la prise en charge des patients cérébrovasculaires et de ceux atteints d'une SEP secondaire progressive.

Immune checkpoint inhibitor-related myositis and myocarditis: diagnostic pitfalls and imaging contribution in a real-world, institutional case series.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are reshaping the prognosis of many cancers, but often cause immune-related adverse events (irAEs). Among neurological irAEs, myositis is the most frequently reported. Our aim is to describe clinical and non-clinical characteristics, treatment and outcome of all irMyositis (skeletal limb-girdle and/or ocular myositis) and irMyocarditis cases in our reference center. METHODS: We retrospectively enrolled all irMyositis/irMyocarditis patients seen between 2018 and 2022. We reviewed demographics, clinical characteristics, biological, neurophysiological, imaging workup, treatment and outcome. RESULTS: We included 14 consecutive patients. The most frequent treatments were pembrolizumab (35%) or ipilimumab-nivolumab combination (35%). Limb-girdle, ocular (non-fluctuating palpebral ptosis and/or diplopia with or without ophthalmoparesis) and cardiac phenotypes were equally distributed, overlapping in 40% of cases. Ocular involvement was frequently misdiagnosed; review of brain MRIs disclosed initially missed signs of skeletal myositis in one patient and ocular myositis in 3. Seven patients had other co-existing irAEs. When performed, myography showed a myogenic pattern. CK was elevated in 8/15 patients, troponin-T in 12/12 and troponin-I in 7/9 tested patients. ICI were discontinued in all cases, with further immunosuppressive treatment in nine patients. In most cases, neurological and cardiological outcome was good at last follow-up. CONCLUSION: Myositis is a potentially severe irAE. Despite its heterogeneous presentation, some highly suggestive clinical symptoms, such as ocular involvement, or radiological signs should raise physicians' attention to avoid misdiagnosis. We thus recommend a multidisciplinary assessment (including complete neuromuscular evaluation) even in case of isolated myocarditis. Our series underlines the importance of an early diagnosis, since suspension of ICI and adequate treatment are usually associated with good functional outcome.

Successful autologous hematopoietic stem cell transplantation in a refractory anti-Caspr1 antibody nodopathy.

AIM: Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin-associated protein 1 (Caspr1)), and usually have a poor response to first-line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti-Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported. METHODS: We report the first case of an anti-Caspr1 antibody-positive nodopathy refractory to high-intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT. RESULTS: A 53-year-old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti-Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post-onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post-AHSCT. At 3 months post-AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected. CONCLUSION: We report a particularly severe anti-Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment-refractory cases.

A severe case of neuroleukemiosis caused by B cell chronic lymphocytic leukemia, presenting as mononeuritis multiplex.

AIMS: To report an exceptional case of nerve infiltration by an otherwise benign chronic B cell leukemia, inducing severe mononeuritis multiplex. METHODS: The patient underwent extensive evaluation, including nerve conduction study and myography, brain and plexus MRI, and nerve biopsy. RESULTS: The clinical and electrophysiological diagnosis was a mononeuritis multiplex with severe motor and sensory involvement; only the nerve biopsy allowed definite diagnosis and introduction of chemotherapy, leading to resolution of sensory deficit and progressive motor improvement. DISCUSSION: Neuroleukemiosis caused by chronic lymphoid leukemia is an exceptional diagnosis. The presence of other possible causes like cryoglobulinemia could induce avoidance of nerve biopsy thus undertreating patient, since steroid treatment is not expected to be efficient on lymphocytic proliferation. Our case stretches the importance of nerve biopsy and raises neuromuscular specialist's awareness of this rare entity.

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages.

BACKGROUND AND PURPOSE: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. METHODS: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. RESULTS: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. CONCLUSIONS: This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.

[Neurology: what's new in 2022]. / Neurologie : ce qui a changé en 2022.

The year 2022 was marked by the development of numerous new treatments for refractory myasthenia gravis. The link between epilepsy and cerebrovascular disorder was studied and lamotrigine discovered to be the optimal treatment choice for epilepsy secondary to stroke to prevent mortality on patient of 45 years and older. New randomized study finally demonstrated the utility of thrombectomy in selected patients with basilar artery occlusion. The causal relationship between Epstein-Barr infection and multiple sclerosis has been proved thanks to a large cohort study. A new possibility of subcutaneous continuous levodopa administration gave promising result. Finally, numerous studies confirmed the efficacy and excellent tolerability of anti-CGRP antibodies.

L'année 2022 a été marquée par l'arrivée de nombreux traitements pour la myasthénie réfractaire. Le lien entre l'épilepsie et le risque cérébro-vasculaire a été bien étudié, démontrant que la lamotrigine semble être le meilleur traitement pour prévenir la mortalité chez les patients de 45 ans et plus. De nouvelles études ont enfin pu établir l'utilité de la thrombectomie dans les occlusions basilaires. Le lien entre le virus d'Epstein-Barr et la sclérose en plaques a pu être prouvé à la suite d'une importante étude de cohorte. Une nouvelle technique d'administration sous-cutanée de la lévodopa semble prometteuse. Enfin, de nombreuses études confirment l'efficacité et l'excellente tolérance des anticorps anti-CGRP (Calcitonine Gene Related Protein).

Ocrelizumab Impairs the Phenotype and Function of Memory CD8+ T Cells: A 1-Year Longitudinal Study in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: Depleting CD20+ B cells is the primary mechanism by which ocrelizumab (OCRE) is efficient in persons with multiple sclerosis (pwMS). However, the exact role of OCRE on other immune cell subsets directly or indirectly remains elusive. The purpose of this study is to characterize the dynamics of peripheral immune cells of pwMS on OCRE. METHODS: We collected blood samples from 38 pwMS before OCRE onset (T0) and at 6 and 12 months (T6, T12) after initiation. To cover the immune cell diversity, using mass cytometry time of flight, we designed a 38-parameter panel to analyze B, T, and innate immune cell markers and CNS migratory markers. In parallel, viral-specific CD8+ T-cell responses were assessed by the quantification of interferon-γ secretion using the enzyme-linked immunospot assay on cytomegalovirus, Epstein-Barr virus, and influenza stimulations. RESULTS: Beside B-cell depletion, we observed a loss in memory CD8+CD20+ and central memory CD8+ T cells but not in CD4+CD20+ T cells already at T6 and T12 (p < 0.001). The loss of memory CD8+ T cells correlated with a lower CXCR3 expression (p < 0.001) and CNS-related LFA-1 integrin expression (p < 0.001) as well as a reduced antiviral cellular immune response observed at both time points (p < 0.001). Of note, we did not observe major changes in the phenotype of the other cell types studied. Seven of 38 (18.4%) patients in our cohort presented with infections while on OCRE; 4 of which were switched from dimethyl fumarate. Finally, using a mixed linear model on mass cytometry data, we demonstrated that the immunomodulation induced by previous disease-modifying therapies (DMTs) was prolonged over the period of the study. DISCUSSION: In addition to its well-known role on B cells, our data suggest that OCRE also acts on CD8+ T cells by depleting the memory compartment. These changes in CD8+ T cells may be an asset in the action of OCRE on MS course but might also contribute to explain the increased occurrence of infections in these patients. Finally, although more data are needed to confirm this observation, it suggests that clinicians should pay a special attention to an increased infection risk in pwMS switched from other DMTs to OCRE.

Serum neurofilament light chain as a reliable biomarker of hereditary transthyretin-related amyloidosis-A Swiss reference center experience.

Hereditary transthyretin-related (hATTR) amyloidosis is a rare disease, causing a disabling and life-threatening axonal length-dependent polyneuropathy. Monitoring of disease progression and treatment response is difficult. We aimed to determine if serum neurofilament light chain (sNfL) is a reliable and early biomarker of peripheral neuropathy in hATTR amyloidosis. We prospectively included 20 hATTR patients, 14 symptomatic and 6 asymptomatic. Patients were assessed at baseline and 1 year, including a full clinical examination with disease severity and functional scores, electrochemical skin conductance measurement with Sudoscan and nerve conduction studies, and sNfL level. hATTR patient sNfL were also compared with sNfL of 4532 healthy controls of a reference database by calculating age and BMI-adjusted Z scores. At baseline, median sNfL concentration was 3.6-fold higher in symptomatic than asymptomatic hATTR patients (P = .003), and this difference was also found in our under 60-years-old patients (P = .003). There was no significant difference of sNfL concentration between asymptomatic patients and healthy controls (Z-score of -0.29), but a significant difference between symptomatic patients and healthy controls (Z-score of 2.52). We found a significant correlation between sNfL levels and most clinical and electrophysiological disease severity scores, the strongest correlation being with the NIS score. sNfL seems to be a reliable biomarker of peripheral neuropathy severity in hATTR amyloidosis and can distinguish between asymptomatic and symptomatic patients. sNfL could also become a reliable biomarker to establish disease onset and treatment response.

Clinical Reasoning: A 39-Year-Old Man With Asymmetric Distal Weakness and Loss of Sensitivity.

A 39-year-old man presented with an asymmetric distal weakness and loss of sensitivity sequentially affecting both lower extremities and the left upper limb. Nerve conduction studies showed a multifocal sensory and motor axonal neuropathy, and a pseudo-conduction block of the right fibular nerve, the whole being consistent with a mononeuropathy multiplex. An uncommon etiology was found after an extensive workup. Axonal loss was severe, with only partial response to treatment with corticosteroids and IV immunoglobulins.