Amyotrophic lateral sclerosis (ALS) shows marked clinical heterogeneity, while standard clinical assessments may fail to capture its multidimensional burden. Integrating quantitative muscle strength, functional tests and patient-reported outcomes (PROs) may improve disease characterization. Ten ambulant adults with ALS were enrolled in a cross-sectional pilot study. Functional performance was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R), Six-Minute Walk Test (6MWT), Ten-Meter Walk Test, Timed Up and Go, Berg Balance Scale and a fatigability index, lower-limb strength with dynamometry, and PROs with ALS Assessment Questionnaire-40 (ALSAQ-40), Hospital Anxiety and Depression Scale, Fatigue Severity Scale and Modified Fatigue Impact Scale (MFIS). Despite relatively preserved ALSFRS-R scores (40.6 ± 2.8), participants showed reduced 6MWT (61.3 ± 21.7% predicted), marked fatigability (- 47.3 ± 112.3%) and a lower-limb strength index of 58.2 ± 13.8% predicted. The ALSAQ-40 score averaged 183.1 ± 59.5. Fatigue was prominent, while anxiety and depression remained mild. Muscle strength correlated positively with ALSFRS-R gross motor score and inversely with anxiety. ALSAQ-40 and MFIS components showed significant associations with both functional and walking performance. Even at ambulant stages, measurable muscle weakness and fatigability co-occur with functional and PROs changes in ALS, supporting the use of multidomain, sensitive clinical assessment. The trial was registered at ClinicalTrials.gov (NCT06199284) on 29/12/2023.

BACKGROUND:Spinal muscular atrophy (SMA) types III and IV are the most common late-onset forms, and they progress slowly, making the identification of sensitive biomarkers critical. The Motor Unit Number Index (MUNIX) estimates motor unit loss and may complement traditional electrophysiological measurements such as Compound Muscle Action Potential amplitudes (CMAP). However, their respective performances have never been directly compared in adult SMA. METHODS:In a French multicenter study (NCT04690998), 71 adult patients with SMA and 24 healthy controls underwent clinical and electrophysiological evaluation. MUNIX, CMAP, and Motor Unit Size Index (MUSIX) were recorded in four muscles, and sum scores (SumMUNIX, SumCMAP, SumMUSIX) were calculated. Reliability was assessed using intraclass correlation coefficients (ICCs), and associations with functional outcomes were explored. RESULTS:MUNIX and CMAP effectively distinguished SMA patients from controls, showing strong test - retest reliability. MUNIX showed the highest discriminative performance (AUC = 0.92), while CMAP demonstrated the strongest and most consistent associations with clinical severity. In multivariate analyses, only CMAP remained independently associated with all functional and strength measures, whereas MUNIX and MUSIX lost significance. CONCLUSION:MUNIX demonstrated the highest discriminative performance among biomarkers for differentiating SMA from controls, indicating early motor unit loss even when CMAP values were within normal limits. However, disease burden and functional impairment were better reflected by CMAP, probably due to it integrating both motor unit loss and reinnervation. The complementary nature of these profiles supports their combined use (concurrent application), and longitudinal studies are warranted to assess their responsiveness in adult SMA as well as their appropriateness for clinical trial settings.

OBJECTIVES:Radiation-induced (radiculo)plexopathy [RI(R)P] is a debilitating delayed neurological adverse event occurring in cancer survivors years after the irradiation of the brachial or lumbar plexuses. No effective treatments have been identified to date. The objective of this work was to evaluate the effectiveness of the anti-VEGF bevacizumab in the treatment of RI(R)P. METHODS:We retrospectively identified patients diagnosed with contrast-enhancing RI(R)P and treated with bevacizumab in the setting of an institutionally sponsored expanded access program over the last 10 years. Clinical, radiological, and neurophysiological records were reviewed. RESULTS:We identified nine patients manifesting with neurophysiological-confirmed RI(R)P (brachial plexopathy, 4; lumbosacral radiculoplexopathy, 5) after a median of 13 years from radiotherapy for their cancer. Symptoms included focal weakness, paresthesia, cramps, hypoesthesia, amyotrophy, and pain. Patients received bevacizumab at 7.5 mg/kg/q2 weeks for a median of six cycles (range, three to nine cycles). Clinical improvement was noted in three cases and clinical stabilization in two. Patients treated within 2 years since symptom onset appeared as most likely to benefit. Enhancement reduction on follow-up MRI was associated with the clinical benefit. DISCUSSION:Bevacizumab could be effective in the treatment of RI(R)P, particularly when patients are managed early in their disease. Further prospective clinical trials are warranted to validate these results.

INTRODUCTION:Robotic rehabilitation on locomotion is a new approach in amyotrophic lateral sclerosis (ALS) and previous studies showed its feasibility. In this study, we aim to evaluate safety, patient's experience and efficacy of a gait training programme with the Atalante exoskeleton, compared with usual care, on walking ability, functional capacity and other symptoms associated with ALS. METHODS AND ANALYSIS:EXALS is a monocentric, prospective, interventional, open trial. 20 slowly progressing patients with gait deficits will be recruited. The study is conducted in three phases, each lasting 6 weeks, following the ABA procedure. Phase B represents the intervention phase, during which patients practise their gait training at a rhythm of three sessions/week, as an add-on to usual care. In the two phases A, patients receive usual care with no additional treatment. An evaluation is planned before, in the middle and at the end of each phase. The primary outcome of the study is safety and tolerability of the Atalante exoskeleton. Secondary outcomes include: participants' subjective impact and experience, attitude and motivation, efficacy and interactivity of the exoskeleton, walking ability, functional capacity, spasticity, balance, postural stability, lower limb muscle strength, quality of life, pain, fatigue, anxiety and depression. Statistical analyses will include descriptive methods for all variables and adverse events. Quantitative outcomes are analysed using repeated-measures ANOVA (analysis of variance) across the seven visits, with post hoc tests applied when appropriate. Nominal outcomes are evaluated using Cochran's Q test with McNemar pairwise comparisons when significant. Associations between variables are examined using Spearman correlation coefficients. Missing data will be replaced using linear interpolation, and sensitivity analyses will be planned. Qualitative interview data are analysed using thematic analysis. ETHICS AND DISSEMINATION:This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.

BACKGROUND:Parvovirus B19 (B19V) infection has been associated with neurological complications. Rarely, patients present with multiple mononeuropathy (MM). The present study aimed to better characterize the clinical, electrophysiological, and prognostic features of patients with B19V-related MM. METHODS:This retrospective, observational, multicenter study included patients with B19V-related MM diagnosed between January 2015 and January 2025 in seven university hospitals in France and Switzerland. RESULTS:Twenty-one patients were included. Twelve were female (57%). All were immunocompetent. The median age at symptom onset was 40 years [IQR: 31-44]. All patients experienced sensory symptoms, 19 (90%) reported neuropathic pain, nine (43%) developed motor weakness, and seven (33%) had cranial nerve involvement. The most frequently involved nerves were the median (14 patients, 67%), fibular (n = 13; 62%), and ulnar (n = 10; 48%) nerves. B19V IgM antibodies were present in 12/20 patients (60%), and all 21 patients were positive for IgG. B19V DNA was detected in blood by PCR in 20 patients (95%). Nerve biopsy showed necrotizing small-vessel vasculitis in one patient (17%), perivascular lymphocytic and macrophagic infiltrates in five (83%), and B19V DNA was detected by PCR in all four tested nerves. Most patients received immunomodulatory treatment (n = 19; 90%). MM relapse occurred in four patients (19%). A partial recovery was observed in 17/20 patients (85%), two remained stable (10%), and one achieved complete recovery (5%). CONCLUSIONS:B19V infection should be systematically investigated in patients presenting with MM, especially in young individuals (including children) with predominantly sensory symptoms, predominant upper limb nerve involvement, and/or cranial nerve involvement.

In amyotrophic lateral sclerosis (ALS), progressive weakness makes walking practice increasingly unsafe and difficult, accelerating loss of mobility and autonomy. Lower-limb exoskeletons could preserve task-specific stepping in a controlled setting, but evidence in ALS remains scarce. This study evaluated the safety of an intensive Atalante exoskeleton gait-training program and explored its effects on walking and related clinical outcomes. In this prospective, monocentric ABA pilot study, 10 ambulatory persons with ALS underwent three consecutive 6-week phases over 18 weeks: A1 (baseline, usual care), B (intervention: Atalante exoskeleton gait training added to usual care; 18 sessions, 3 times/week), and A2 (withdrawal, usual care), with repeated assessments every 3 weeks. The primary endpoint was safety, assessed by adverse events (AE). Secondary endpoints included ALS Functional Rating Scale-Revised, forced vital capacity, standardized walking tests (6-minute walk test, 10-meter walk test, Timed Up and Go test), Berg Balance Scale, postural control on a force platform, lower-limb strength with dynamometry, spasticity with isokinetic dynamometer, Fatigue Severity Scale, Modified Fatigue Impact Scale, ALS Assessment Questionnaire-40, and Hospital Anxiety and Depression Scale. Exoskeleton-specific patient-reported outcomes (PROs) included intrinsic motivation, participants’ attitudes toward the intervention, perceived subjective impact of the training, perceived efficacy and interactivity of the exoskeleton. The results were analyzed with linear mixed-effects models. No serious AE occurred, and one mild AE was certainly related to the intervention. No outcome showed significant phase-specific slopes or slope contrasts, although several measures displayed directionally consistent trends compatible with attenuated decline during phase B and a return toward a less favorable trajectory after withdrawal. Exoskeleton-specific PROs indicated high intrinsic motivation and acceptability (usefulness for standing, perceived safety, ease of participation, and ease of installation/uninstallation rated very highly), with perceived gait-training efficacy generally positive. Participants frequently reported reduced immobility and increased accomplishment (80

OBJECTIVES:To explore patients' expectations and lived experience of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis (ALS). METHODS:In the EXALS study (NCT06199284), 10 ambulatory ALS participants completed 18 sessions of Atalante exoskeleton-assisted gait training. After completion of the intervention phase, post-training semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis approach. Structured interview items were summarized descriptively. RESULTS:Ten participants reported positive expectations and experiences. Initial expectations most often included contributing to research (5/10), maintaining walking ability (4/10), and improving gait quality/balance (3/10). Expectation fulfillment was high (very satisfied: 7/10). The rehabilitative aspect was most frequently ranked as most reflective of the experience (rank 1: 4/10), followed by motivational/recreational (rank 2: 4/10), psychological/emotional was most often ranked last (rank 5: 5/10). Participants described perceived benefits including improved upright posture, stability, reduced stiffness, smoother gait, and reduced fear of falling, though some effects were described as short-lived. Three-word summaries were predominantly positive (8/10), commonly "interesting" and "motivating," with occasional negatives (tiring/heavy/repetitive/disappointing; 2/10). Compared with conventional physiotherapy, sessions were perceived as more dynamic and walking-focused, with a structured, innovative, closely supervised set-up. Suggested improvements centered on increasing access/dose, expanding walking space and training content, and enhancing safety/user control. Most participants would continue training if available (8/10), most commonly preferring two sessions per week (4/8). CONCLUSIONS:Exoskeleton-assisted gait training was experienced as acceptable and meaningful. Translating this into practice will require aligning future protocols with patient priorities, autonomy/safety, access and delivery logistics, and broader functional content alongside quantitative evaluation.

Introduction La SMA types III-IV chez l’adulte est lentement évolutive. Le suivi nécessite des biomarqueurs sensibles. Le MUNIX estime la perte unitaire motrice et pourrait compléter le CMAP, mais leurs performances respectives restent peu étudiées dans la SMA adulte. Objectifs Comparer la performance du MUNIX, du CMAP et du MUSIX pour distinguer les patients SMA des témoins ; évaluer leurs corrélations avec la sévérité clinique, et leur reproductibilité. Méthodes Dans l’étude multicentrique nationale SMOB (NCT04690998), 71 patients SMA adultes et 24 témoins ont bénéficié d’une évaluation clinique et électrophysiologique sur quatre muscles. Les scores sommatifs MUNIX, CMAP et MUSIX ont été calculés. La reproductibilité a été estimée par le coefficient de corrélation intraclasse (ICC), et les corrélations électrocliniques par analyses uni- et multivariées. Les courbes ROC ont évalué le pouvoir discriminant des biomarqueurs. Résultats Le MUNIX et le CMAP étaient significativement réduits chez les patients SMA. Le MUNIX présentait la meilleure capacité discriminante (AUC=0,92), tandis que le CMAP montrait les corrélations les plus fortes et indépendantes avec les scores moteurs et fonctionnels. En analyse multivariée, seul le CMAP restait indépendamment corrélé aux scores cliniques. Le MUSIX était augmenté, suggérant une réinnervation compensatrice. La reproductibilité était excellente pour MUNIX (ICC=0,86) et CMAP (ICC=0,90) (Fig. 1) (Fig. 2). Discussion Le MUNIX semble le biomarqueur le plus sensible pour différencier les patients SMA des témoins, traduisant une perte motoneuronale précoce, même lorsque les valeurs de CMAP restaient dans la normale. En revanche, le CMAP rendait mieux compte de la sévérité clinique et fonctionnelle, possiblement par son caractère intégratif reflétant à la fois la perte unitaire et la réinnervation collatérale. Conclusion MUNIX et CMAP apparaissent comme deux biomarqueurs robustes, reproductibles et complémentaires dans la SMA adulte. Les études longitudinales préciseront leur sensibilité au changement respectif.

Diagnostic certainty criteria for ICI-myocarditis

Methods concerning Immune-checkpoint proteins profiling on peripheral blood mononuclear cells and Circulating immune checkpoint agents drug monitoring

Delay between presentation for ICI myocarditis, appearance of life-threatening myotoxicity criteria (severity grade 4, Supplementary Table 5 for details concerning grading) and start of the immunosuppressive treatments (with dose) in severe ICI-myocarditis patients requiring abatacept.

Treatment modalities and reported adverse events by quartile of period of inclusion.

Effect of plasmapheresis on ICI circulating levels in the 10 patients receiving plasmapheresis in our cohort.

Example of the first severe ICI-myocarditis case treated with abatacept guided by real-time immune-monitoring assessment of CD86RO (CD86 receptor occupancy) on circulating monocytes.

BACKGROUND AND PURPOSE:This systematic review evaluated the effectiveness and safety of immune and symptomatic treatments in patients with stiff-person syndrome (SPS). METHODS:A systematic search of PubMed, Embase, and the Cochrane Library was conducted up to September 30, 2024 in accordance with the PRISMA guidelines. All studies that involve SPS patients treated with symptomatic pharmacotherapy or immunotherapy and where the outcome is reported were included in the initial screening. Case reports were excluded. Two independent reviewers carried out study selection, bias assessment with the Murad et al. tool for case series, ROBINS-I for observational studies or RoB-2 for randomised trials, and data extraction into a predefined template. All available efficacy and safety data were recorded. A narrative synthesis was conducted to address the heterogeneity of the studies. RESULTS:Thirty-six studies were included. Most of the included studies consisted of small-scale studies, with 21 case series, 10 cohort studies and only five randomised controlled trials. Outcome assessments varied across the reviewed studies. Most studies assessed measures with subjective self-report and/or through clinical observations. Spasms and stiffness were assessed in around 60% of studies. Walking ability and pain were evaluated in less than half of studies. Only 10 (28%) studies assessed functional improvement using a valid and reliable tool. The present review highlights the paucity of data and the heterogeneity in SPS treatment responses and underscores the need for individualised therapeutic strategies. CONCLUSIONS:Standardised assessment methods in clinical practice are necessary to benefit understanding and approval of future therapy strategies.

Proposed management algorithm for ICI-myotoxicities as a function of severity criteria grading

INTRODUCTION/AIMS:Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients. METHODS:We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients. RESULTS:These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles. DISCUSSION:The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidaemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analysed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from 13 ALS patients and 10 asymptomatic ALS-mutation gene carriers compared to 16 control subjects. Using human control primary myotubes, we investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disorder characterized by motor neuron loss leading to extensive paralysis. There is emerging evidence that the disease involves a prolonged presymptomatic period during which motor function is preserved. Understanding the molecular mechanisms involved is key as the presymptomatic phase represents a critical window of opportunity for early intervention. Using RNA sequencing, we investigated changes in gene expression patterns in the skeletal muscle of ten asymptomatic carriers of ALS mutations (8 C9ORF72 expansion carriers and 2 SOD1 mutation carriers). We found that specific modifications of gene expression profiles are present in skeletal muscle before asymptomatic ALS gene carriers exhibit biomarker changes predictive of phenoconversion. We identified insulin signaling, AMPK signaling, and thermogenesis pathways, together with the TCA cycle as the main contributors to the dysregulated muscle transcriptome. Our data suggest that this metabolic reprogramming of skeletal muscle develops progressively during the transition to phenoconversion, characterized by a gradual increase in the expression of SREBF1 which encodes SREPB1, the key transcriptional regulator of lipid synthesis, in parallel with the progressive activation of AMPK and insulin signaling pathways. Our findings are consistent with a progressive enhancement in fatty acid metabolism and oxidative capacity in skeletal muscle, followed by a decline in oxidative phosphorylation efficiency as phenoconversion approaches. Evidence of muscle metabolic reprogramming in ALS long before motor onset identifies the dysregulation of muscle energy homeostasis as a critical early event in ALS pathogenesis. ### Competing Interest Statement Dr. Soham Saha is the CEO and co-founder of Medinsights SAS in Paris, France. Dr. Dimitrije Milunov is an employee of Medinsights SAS in Paris, France. Other authors report no competing interests. ARSLA