[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.

Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study.

BACKGROUND: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking. AIMS: To compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), and Bell's palsy with a matched control population. METHODS: Swiss multicenter, prospective, observational, matched case-control study over 3 years (September 2019-October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti-HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real-time polymerase chain reaction (RT-PCR). RT-PCR was performed on sera to confirm IgM positivity. RESULTS: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti-HEV IgM-positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = -0.25) was observed only between acute HEV infection and NA. CONCLUSION: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

Emerging biomarkers to predict clinical outcomes in Guillain-Barré syndrome.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an immune-mediated poly(radiculo)neuropathy with a variable clinical outcome. Identifying patients who are at risk of suffering from long-term disabilities is a great challenge. Biomarkers are useful to confirm diagnosis, monitor disease progression, and predict outcome. AREAS COVERED: The authors provide an overview of the diagnostic and prognostic biomarkers for GBS, which are useful for establishing early treatment strategies and follow-up care plans. EXPERT OPINION: Detecting patients at risk of developing a severe outcome may improve management of disease progression and limit potential complications. Several clinical factors are associated with poor prognosis: higher age, presence of diarrhea within 4 weeks of symptom onset, rapid and severe weakness progression, dysautonomia, decreased vital capacity and facial, bulbar, and neck weakness. Biological, neurophysiological and imaging measures of unfavorable outcome include multiple anti-ganglioside antibodies elevation, increased serum and CSF neurofilaments light (NfL) and heavy chain, decreased NfL CSF/serum ratio, hypoalbuminemia, nerve conduction study with early signs of demyelination or axonal loss and enlargement of nerve cross-sectional area on ultrasound. Depicting prognostic biomarkers aims at predicting short-term mortality and need for cardio-pulmonary support, long-term patient functional outcome, guiding treatment decisions and monitoring therapeutic responses in future clinical trials.

Specificity of Quantitative Functional Brain Mapping with Arterial Spin-Labeling for Preoperative Assessment.

BACKGROUND AND PURPOSE: Arterial spin-labeling is a noninvasive MR imaging technique allowing direct and quantitative measurement of brain perfusion. Arterial spin-labeling is well-established in clinics for investigating the overall cerebral perfusion, but it is still occasionally employed during tasks. The typical contrast for functional MR imaging is blood oxygen level-dependent (BOLD) imaging, whose specificity could be biased in neurologic patients due to altered neurovascular coupling. This work aimed to validate the use of functional ASL as a noninvasive tool for presurgical functional brain mapping. This is achieved by comparing the spatial accuracy of functional ASL with transcranial magnetic stimulation as the criterion standard. MATERIALS AND METHODS: Twenty-eight healthy participants executed a motor task and received a somatosensory stimulation, while BOLD imaging and arterial spin-labeling were acquired simultaneously. Transcranial magnetic stimulation was subsequently used to define hand somatotopy. RESULTS: Functional ASL was found more adjacent to transcranial magnetic stimulation than BOLD imaging, with a significant shift along the inferior-to-superior direction. With respect to BOLD imaging, functional ASL was localized significantly more laterally, anteriorly, and inferiorly during motor tasks and pneumatic stimulation. CONCLUSIONS: Our results confirm the specificity of functional ASL in targeting the regional neuronal excitability. Functional ASL could be considered as a valid supplementary technique to BOLD imaging for presurgical mapping when spatial accuracy is crucial for delineating eloquent cortex.

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.

Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study.

In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12-22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not.

Interleukin 8, a Biomarker to Differentiate Guillain-Barré Syndrome From CIDP.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: CSF 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%). CONCLUSION: CSF 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 EVIDENCE: This study provides Class II evidence that CSF IL-8 levels accurately distinguish patients with GBS from those with CIDP.

Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study.

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.

[Small fiber neuropathy in systemic autoimmune diseases]. / Neuropathie des petites fibres dans les maladies autoimmunes systémiques.

Small fiber neuropathy (SFN) causes damage to small-calibre nerve fibers (unmyelinated C fibers and myelinated A-delta fibers). The symptoms of SFN usually are sensitive including paresthesia, dysesthesia or burning pain, and protopathic deficits, sometimes associated with dysautonomia. The causes of SFN can be classified in six main groups: idiopathic, toxic, metabolic, immunological, infectious and hereditary. In this article, we present the diagnostic approach to SFN, the most common autoimmune aetiologies, as well as elements of their therapeutic management.

La neuropathie des petites fibres (NPF) implique une atteinte des fibres nerveuses de petit calibre : les fibres C non myélinisées et les fibres A-delta myélinisées. Elle se manifeste principalement par des troubles sensitifs : paresthésies, dysesthésies ou douleurs neuropathiques (brûlures) et déficits protopathiques, associés à des symptômes dysautonomiques. Les étiologies possibles des NPF sont variées : idiopathiques, toxiques, métaboliques, immunologiques, infectieuses et héréditaires. Nous présentons dans cet article la démarche diagnostique des NPF, les étiologies autoimmunes les plus fréquemment associées aux NPF, ainsi que des éléments de prise en charge thérapeutique.

Update in immunosuppressive therapy of myasthenia gravis.

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.

Impaired conduction of Ia sensory fibers in multifocal motor neuropathy: An electrophysiological demonstration.

OBJECTIVES: To report the clinical and electrophysiological findings in two patients with multifocal motor neuropathy (MMN) and bilateral absent patellar and Achilles tendon reflexes despite normal strength of quadriceps and calf muscles. METHODS: The medical history and clinical evaluation were completed by electrophysiological tests: sensory and motor nerve conduction studies, needle electromyography, motor-evoked potentials (MEPs) after transcranial magnetic stimulation, patellar T (tendon) responses, quadriceps and soleus H (Hoffman) reflex recordings. RESULTS: In the two patients, history, clinical evaluation, nerve conduction studies, favorable response to intravenous immunoglobulins, and positive anti-GM1 antibodies fulfilled the diagnosis of MMN. The lower limbs were asymptomatic, except for a unilateral weakness of foot dorsiflexion. The patellar and Achilles tendon reflexes disappeared during the course of the disease. The sensory nerve conduction studies were normal or minimally modified, M-wave and MEP/M amplitude ratio to the quadriceps were normal, patellar T (tendon) responses were virtually absent, and H-reflex to the quadriceps and soleus muscles were absent. CONCLUSIONS: These observations, which show the interruption of the reflex afferent pathway, raise the question of Ia afferent involvement in the lower limbs of these two patients with MMN. Further investigations should determine the frequency and significance of these findings in this disorder.

Risk of MS relapse after yellow fever vaccination: A self-controlled case series.

OBJECTIVE: To 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. METHODS: This 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. RESULTS: Of 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. CONCLUSIONS: In 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 EVIDENCE: This study provides Class IV evidence that for persons with MS, YFV may not increase relapse risk.

Symptomatic tandem spinal stenosis: a clinical, diagnostic, and surgical challenge.

Tandem spinal stenosis (TSS) is an entity which refers to spinal canal diameter narrowing in at least two distinct regions of the spine. When symptomatic, management of TSS is controversial. In this study, we present a consecutive series of patients with symptomatic TSS and report diagnostic and surgical challenges. We retrospectively reviewed a consecutive series of N = 8 patients with symptomatic TSS who underwent surgical treatment in at least one region of the spine. Patients presented with multiple complaints, including neurogenic claudication, progressive gait disturbances, and signs of radiculopathy and/or myelopathy, among others. Modified Japanese Orthopedic Association (mJOA) and Oswestry Low Back Pain Disability Questionnaire (ODI) were obtained in pre- and postoperative period. Electroneurophysiological examinations were limited to patients whose clinical and radiological signs were not sufficient to determine which region was more affected. From 2015 to 2018, we included N = 8 consecutive patients with TSS who underwent surgery by a staged approach. The stenosis was localized in the cervical and lumbar region in six patients (75%) and in the cervical, dorsal, and lumbar level (triple TSS) in two patients (25%). Four patients (50%) underwent cervical and lumbar surgery, two (25%) underwent cervical surgery alone, and two (25%) were operated in all three involved regions. Surgical treatment allowed an improvement of the mean mJOA score (from 12.5/17 to 15/17) and mean ODI score (from 41 to 28%). TSS represents a clinical, diagnostic, and surgical challenge. We recommend to systematically obtain electrophysiological and radiological examinations and then to perform a staged surgery, beginning at the most symptomatic region.

IL-8 as a potential biomarker in Guillain-Barre Syndrome.

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis.

Limbic encephalitis associated with systemic sclerosis.

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.