Background Excessive daytime sleepiness and sleep disturbances are common in Parkinson's disease (PD), considerably affecting the quality of life of patients and caregivers. Antiparkinsonian medications further complicate sleep-wake management. Advanced PD with motor fluctuations often requires continuous dopaminergic stimulation via apomorphine subcutaneous infusion or levodopa/carbidopa intestinal gel infusion (LCIGI). Evidence on LCIGI's effects on sleep and sleepiness remains limited, relying mainly on subjective bias-prone measures. Objective This pilot study used overnight in-laboratory polysomnography (PSG) and the multiple sleep latency test (MSLT), the gold standards for objective measurements, to evaluate effects of LCIGI initiation on sleep and sleepiness. Methods In this prospective, monocentric observational study, 34 patients with motor fluctuations underwent PSG and MSLT before (M0) and three months after (M3) LCIGI initiation. Clinical characteristics included body mass index (BMI), L-Dopa equivalent daily dose (LEDD), and Epworth Sleepiness Scale (ESS) scores to examine correlations between subjective questionnaire-based and objective MSLT-based measures. Results Twenty-three patients completed both assessments. MSLT values remained stable (M0: 12.5 [10.9; 15.8] min; M3: 15.3 [12.2; 16.6] min; P=0.401) as did PSG parameters. As expected, BMI decreased, LEDD increased, dopamine agonist use declined, and clozapine/quetiapine use increased. ESS scores did not correlate with MSLT results at baseline or follow-up. Conclusions LCIGI had no significant impact on objectively measured daytime sleepiness (MSLT) or PSG sleep parameters.
Effective management of multiple sclerosis requires precise monitoring to detect disease progression, yet conventional episodic assessments often fail to capture subtle functional decline. This systematic review aimed to synthesize current evidence on passive digital phenotyping via smartphones and wearable sensors as a tool for continuous and ecological evaluation. Following PRISMA guidelines, fourteen studies meeting strict eligibility criteria were included. These investigations analyzed raw data collected unobtrusively from smartphone touchscreens, inertial sensors, and photoplethysmography. The signals were processed to extract digital features, including keystroke dynamics, gait metrics, physiological markers, and behavioral patterns, to test their associations with standard clinical scales. The results demonstrated robust, significant correlations between these objective digital biomarkers and established clinical scores across motor, cognitive, and symptomatic domains. Specifically, processed typing kinematics and gait parameters significantly aligned with upper limb dexterity and walking ability respectively, while specific keystroke latency metrics proved sensitive to cognitive processing speed. Furthermore, multimodal physiological and behavioral markers successfully tracked complex symptoms such as fatigue, depression, and sleep quality. Overall, the findings highlighted that the integration of these multimodal biomarkers into clinical practice offers a scalable, non-invasive solution for personalized management. This approach could facilitate the early detection of “silent” symptoms and optimize therapeutic strategies, effectively bridging the critical gap between sporadic clinical visits and real-world functioning in multiple sclerosis.
This study comprehensively analyzes and categorizes the etiopathogenesis and pathophysiological mechanisms behind the Kernohan-Woltman notch phenomenon (KWNP), the major cause of ipsilateral hemiparesis (IH), a false clinical localization sign that remains a diagnostic challenge in the era of modern imaging (CT/MRI). For this purpose, a systematic, multilanguage search of articles containing the keywords "ipsilateral hemiparesis", "Kernohan's notch" and "Kernohan-Woltman notch phenomenon" was carried out in the Pubmed database, in quest of well-described IH/KWNP cases studied with modern radiologic and neurophysiologic techniques (time span from 1977 to 2023). A thorough review of the reference lists from all consulted articles yielded a final cohort of 121 cases for analysis, including two own original patients. The triggering intracranial lesions, mechanisms of ipsilateral hemiparesis, types of motor deficits, midbrain injury patterns and neurological outcomes were all categorized and integrated into a novel etiopathogenic classification scheme, which includes six main IH/KWNP etiopathogenic models grouped under the acronym "CHESTnUt": "C" for contusive brain peduncle injury (5%); "H" for acute intracranial hematoma, either of traumatic (34.7%) or spontaneous (21.5%) origin; "E" or Ectors model for fronto-temporal masses, mainly extra-axial tumors (8.3%); "S" for chronic or subacute subdural hematoma (19%); "Tn" for tentorial notch/infratentorial mass lesions (6.6%), and "Ut" for uncrossed corticospinal tracts (2.5%), the main alternative mechanism to KWNP for IH proved in the current cohort. Subsequently, multivariate and logistic regression models were employed to identify the clinical-neuroradiological characteristics associated with each model integrating the scheme and the critical factors associated with a favorable motor outcome. Improvement or full recovery from IH after treatment occurred in 70% of KWNP patients, and this was significantly associated with the E, S and Tn models (P=0.009). A favorable outcome was also associated with unilateral motor deficits (P=0.004), and with absence of a structural lesion involving the contralateral cerebral peduncle (SLCP) on MRI (P=0.014). Hierarchical logistic regression analysis selected the combination of three variables: unilaterality/bilaterality of motor symptoms, patient age and SLCP pattern, allowing accurate prediction of IH outcome in 74% of patients. Consequently, the CHESTnUt scheme represents a novel, helpful clinical tool for IH/KWNP classification which allows for a more accurate discrimination of motor outcome in patients presenting paradoxical ipsilateral hemiparesis.
BACKGROUND AND OBJECTIVE:Morvan syndrome is a rare neurological disorder characterized by peripheral nerve hyperexcitability, autonomic instability, and encephalopathy. Autonomic dysfunction in these patients may have important cardiovascular implications. We characterized cardiovascular autonomic function in Morvan syndrome and compared it with that of healthy controls. METHODS:In this comparative cross-sectional study, 19 patients with Morvan syndrome and 24 healthy controls broadly comparable in age at the group level were evaluated. Heart rate variability (HRV) was assessed using non-invasive electrocardiography, including time-domain and frequency-domain measures. Autonomic function was evaluated using Ewing's battery, including heart-rate response to deep breathing, Valsalva maneuver, orthostatic testing, and isometric handgrip. RESULTS:Morvan syndrome patients showed significant autonomic impairment compared with healthy controls. HRV parameters, including standard deviation of NN intervals (SDNN), root mean square of successive differences (RMSSD), total power, low-frequency power, and high-frequency power, were significantly reduced in patients. Ewing's battery also demonstrated marked abnormalities, including reduced deep-breathing difference, lower Valsalva ratio, impaired orthostatic blood pressure response, and diminished isometric handgrip response. Effect sizes ranged from moderate to large (0.504-0.934), indicating substantial clinical relevance. Disease duration showed significant negative correlations with several HRV indices, including RMSSD (r=-0.68, P=0.001), suggesting progressive autonomic impairment. CONCLUSION:Morvan syndrome patients demonstrated significant cardiovascular autonomic dysfunction compared with healthy controls, reflected by impaired HRV and abnormal autonomic reflex testing. These findings support the value of routine HRV and Ewing's battery assessment in Morvan syndrome for early detection of cardiovascular autonomic involvement and improved clinical monitoring.
BACKGROUND:The impact of stroke etiology on recanalization and clinical outcome following intravenous thrombolysis with tenecteplase (t-IVT) and endovascular therapy (EVT) has not been investigated. We aimed to compare stroke subtypes in a dataset of acute ischemic stroke (AIS) patients treated with t-IVT+EVT. METHODS:Our population was selected from the TETRIS registry, which retrospectively compiled clinical and imaging data on AIS patients treated with t-IVT, with or without EVT, from several French stroke centres. For this study, we only considered patients with anterior circulation large vessel occlusion (acLVO) intended for EVT. Cardioembolic (CE), large artery Atherosclerotic (LAA) and undetermined (UD) subtypes were included and compared; other stroke etiologies and dual causes were excluded. Primary outcome was the 3-month modified Rankin scale (mRS) ordinal distribution. Secondary outcomes were the rates of early recanalization, final successful recanalization, and symptomatic intracranial haemorrhage (sICH). Adjustments on relevant confounding variables were made within multivariate regression models. RESULTS:Among 1,421 patients included in TETRIS, 789 patients (CE=454, LAA=113, UD=222) met our inclusion criteria. LAA etiology was associated with non-significant trends towards worse 3-month mRS distribution than CE (adjusted common odds ratio [acOR] per 1 mRS level improvement=0.69; 95% confidence interval [CI]=0.46-1.02; P=0.063) and UD (acOR=0.67; 95% CI=0.43-1.03; P=0.067) subtypes, while no difference was found between UD and CE cases (acOR=1.03; 95% CI=0.76-1.40; P=0.84). Compared with CE subtype, LAA etiology was associated with a non-significant trend towards less frequent early recanalization (adjusted OR=0.51; 95% CI=0.26-1.01; P=0.052) and significantly lower chances of final successful recanalization (adjusted OR=0.43; 95% CI=0.23-0.78; P=0.005). No significant difference was found regarding sICH. CONCLUSIONS:In the context of bridging therapy with tenecteplase for acLVO AIS, LAA etiology might be associated with less favourable clinical and angiographic outcomes than CE subtype. Whether tenecteplase efficacy varies according to thrombi's composition and origin can only be conjectured and should be further investigated.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system, characterized by severe attacks. Optic neuritis is the most common clinical manifestation, leading to a rapid and often severe loss of vision, which is sometimes bilateral, with frequent sequelae and a risk of very low visual acuity in the long-term. Magnetic resonance imaging (MRI) reveals extensive lesions of the optic nerve, mostly involving the posterior part of the nerve and sometimes extending to the optic chiasm. Myelitis manifests as longitudinally extensive and centrally located spinal cord lesions, which may lead to tetraplegia, sensory disturbances, neuropathic pain and sphincter dysfunction. Area postrema syndrome presents with nausea, vomiting, and severe hiccups, which are often resistant to conventional treatments and may require hospitalization. Diagnosis is confirmed by the detection of anti-aquaporine 4 (AQP4) antibodies in the serum. Attacks should be treated as an emergency, with intravenous (IV) corticosteroids and plasma exchange, without waiting for antibody confirmation. Maintenance therapy includes monoclonal antibodies targeting B lymphocytes, interleukin-6 receptor, complement C5 and non-selective immunosuppressive treatments, according to profile of tolerance. Conventional treatments such as azathioprine or mycophenolate are less commonly used as first-line therapies but remain possible depending on the clinical context. Follow-up is multidisciplinary, with neurological, and according to the symptoms ophthalmological, neuropsychological, urodynamic or sequellar disability consultations. Therapeutic patient education and support from patient organizations are essential for improving quality of life and treatment adherence. Pregnancy is considered high-risk, requiring regular neurological and obstetric monitoring, as the risk of attack increases in the postpartum period. Finally, the rapid and individualized management of attacks as well as the prevention of relapses is crucial to limit functional sequelae and disability.
Multiple sclerosis (MS) is marked by heterogeneous disease activity, progression, and therapeutic response. Here, we developed a prognostic score based on machine learning using randomized clinical trials (RCTs) and observational datasets. The score's ability to predict short-term prognosis, expressed as absolute risk, was assessed on the French population in the context of all common MS therapeutic scenarios. Nine industrial RCTs and one prospective cohort from the French MS registry were used to develop several types of multilabel binary classifiers designed to predict the two-year risk of relapse, advent of new brain T2 lesions, and sustained disability worsening, as well as the respective yearly risks. Model evaluation prioritized calibration of probabilistic predictions over discriminatory capacity. Virtual cohorts simulated from the model predictions were analyzed to determine how the predictive score captured clinically meaningful information, such as the efficacy of different therapeutic classes. The model with the best calibration was evaluated externally on the population-based cohort of the French MS registry. Random forest modeling optimally captured the time-course of MS risks. In the evaluation dataset, calibration shifted with underconfident predictions of relapse and overconfident predictions of new brain T2 lesions. Nevertheless, unadjusted average therapeutic class efficacy on MRI activity generalized well. At external validation, discriminatory capacities were modest: AUC=0.67, 0.75, and 0.58 for relapse, new brain T2 lesions, and sustained disability worsening, respectively. Based on a panel of variables currently available during routine care for MS patients, we propose a score predictive of short-term therapeutic response to commonly prescribed therapeutic classes. Predictions of MRI activity generalized well across the common therapeutic scenarios. The model's probabilistic approach, emphasizing prediction certainty rather than the prediction itself, captured clinically useful information for the selection of disease-modifying treatments.
AIM:Mononeuropathy multiplex is a specific syndromic presentation among peripheral nerve disorders. It is usually associated with rare etiologies with potentially severe complications and thus must be promptly recognized both by general neurologists and neuromuscular specialists. Despite recent descriptions discussing specific etiologies, reviews focusing on the syndromic presentation as starting point are lacking. We provide here a review of mononeuropathy multiplex, focusing on its clinical presentation, electrophysiological and radiological evaluation, diagnostic workup and etiologies.
BACKGROUND:Candesartan is recommended for migraine prevention, but real-world data on effectiveness, persistence of response, and titration tolerability across episodic migraine (EM) and chronic migraine (CM) and treatment lines are limited. METHODS:We analyzed consecutive adults starting candesartan for migraine prevention in the prospective French FHU InovPain registry. Visits occurred at month 3 (M3), month 9 (M9), and month 15 (M15). The primary endpoint was the M3≥50% responder rate, defined as≥50% reduction from baseline in monthly migraine days (MMD). The main analysis used a modified intention-to-treat/last-observation-carried-forward approach (modified ITT/LOCF; n=183), including patients who discontinued candesartan before M3 because of treatment-emergent adverse events as non-responders. Observed-case analyses were supportive. Exploratory analyses assessed EM versus CM, CM-to-EM conversion, and outcomes according to prior preventive exposure. RESULTS:In the modified ITT/LOCF analysis, 77/183 patients achieved a≥50% MMD reduction at M3 (42.1 [95% CI 35.2;49.3]%). In a fully conservative analysis including all candesartan initiators, the M3≥50% responder rate was 77/207 (37.2 [30.9;44.0]%). In the observed-case analysis, 77/163 patients achieved≥50% response (47.2 [39.7;54.9]%). Mean MMD decreased from 14.1 to 9.7 and MHD from 17.3 to 11.2 at M3 (both P<0.001). Among patients remaining on treatment and under follow-up, observed-case≥50% responder rates were 75.6% at M9 and 78.9% at M15; these estimates reflect persistence of response among treatment continuers rather than population-level response rates. Corresponding modified ITT/LOCF≥50% responder rates were 44.8% and 43.2%. At M3, ≥50% responder rates were higher in EM than CM (66.2% vs. 31.5%), while 43.8% of baseline CM patients no longer met CM criteria. Outcomes were similar in prophylaxis-naive and previously treated patients. Treatment-attributed adverse events occurred in 29.0% and led to discontinuation in 15.8%, mainly during early titration. Systolic blood pressure decreased modestly, whereas diastolic blood pressure remained stable. CONCLUSIONS:In this real-world observational cohort, candesartan was associated with clinically meaningful reductions in migraine burden by M3, including in conservative modified ITT/LOCF analyses. Longer-term observed-case data suggested persistence of response among treatment continuers, but should not be interpreted as population-level effectiveness. These findings support candesartan as a pragmatic oral preventive option across migraine phenotypes, while highlighting the need for cautious interpretation of observational data and for prospective comparative studies.
INTRODUCTION:Photophobia is a frequent and often disabling symptom encountered in a wide range of neurological and ophthalmological conditions. Particularly prevalent in migraine, but also observed in common eye diseases, photophobia reflects complex interactions between visual and nociceptive pathways. This review provides a comprehensive overview of the clinical features, pathophysiological mechanisms, diagnostic challenges, and therapeutic strategies of photophobia from both neurological and ophthalmological perspectives. MATERIAL AND METHODS:A narrative literature review was conducted using PubMed up to December 2025, focusing on studies addressing photophobia in neurological and ocular disorders, as well as experimental and translational research exploring its underlying mechanisms. RESULTS:Photophobia is frequently reported in migraine and traumatic brain injury, as well as in common ocular conditions such as dry eye disease and corneal pathology. Current evidence suggests that it involves altered interactions within visual-trigeminal pathways. Photophobia is also associated with impaired daily functioning and psychological distress, highlighting its clinical impact. Management primarily focuses on the underlying condition, while optical filtering strategies may provide additional relief in selected patients. DISCUSSION:Photophobia is a multifactorial symptom reflecting the convergence of ocular and central nervous system mechanisms. Improved understanding of the neural pathways involved may enhance diagnosis and support more targeted and individualized management strategies.
Background Intrathecal antisense oligonucleotides (ASOs) have revolutionized the management of genetic motor neuron diseases. Nusinersen is approved for spinal muscular atrophy (SMA) caused by SMN1 mutations, and tofersen for amyotrophic lateral sclerosis (ALS) linked to SOD1 mutations. Since their approval, some studies reported the presence of macrophagic inclusions in cerebrospinal fluid (CSF) of patients treated with ASOs, first in nusinersen-treated patients and more recently in those receiving tofersen. These findings remain poorly characterized, and their clinical significance is unclear. Methods We first conducted a retrospective study in 21 patients (132 CSF samples): six treated with tofersen (every 4 weeks) and 15 with nusinersen (every 4 months). CSF samples were analyzed for macrophagic inclusions, their time of onset, and persistence over time. To assess clinical and inflammatory correlates of macrophagic inclusions, we then performed an analysis of CSF inflammatory biomarkers and serum ferritin and neurofilament light chain tests in 18 of these patients still under treatment. Results In tofersen-treated patients, macrophagic inclusions were consistently observed and persisted over time, except in one case. In nusinersen-treated patients, inclusions were rare and transient. An inflammatory CSF profile was associated with the presence of inclusions, but their cellular nature remained undetermined. Notably, tofersen-treated patients with “tofersenophages” exhibited favorable clinical responses. Discussion Macrophagic inclusions appear more frequent in the CSF of tofersen-treated patients than previously reported. While their origin remains unclear, they seem linked to CSF inflammation without precluding a beneficial therapeutic response.
BACKGROUND:Stroke disproportionately affects French Guiana, which has the highest incidence and premature stroke mortality among French territories. Beyond traditional vascular risks, cerebral small vessel disease (CSVD) may explain these disparities. This study compared MRI characteristics of acute ischemic stroke and CSVD burden in Cayenne with two mainland French centers (Besançon and Tours). METHODS:In line with the multicenter observational BECATOUR study, we analyzed ischemic stroke subtype, vascular occlusion, T2-FLAIR intravascular hyperintensities, and hemorrhagic markers. CSVD features (white matter hyperintensities, lacunes, microbleeds, enlarged perivascular spaces) were scored using validated scales. Global cardiovascular risk was estimated using a Framingham-based score. FINDINGS:Intravascular T2-FLAIR hyperintensities, reflecting collateral arterial circulation, were less frequent in Cayenne than in mainland France. Patients in Cayenne had a markedly higher CSVD burden (CSVD score >2 according to Lau et al.: 42.4%, 19.8% and 17.2% respectively in Cayenne, Besançon, and Tours, P=0.01), driven by more severe white matter hyperintensities and increased microbleeds. Among 257 patients, a cardiovascular risk >20% was associated with severe white matter hyperintensities and higher overall CSVD burden. In Cayenne, 20% of patients would have met criteria for mechanical thrombectomy, a procedure that is not locally available. INTERPRETATION:Stroke patients in French Guiana carry a substantially higher burden of CSVD, closely linked to modifiable cardiovascular risk. Combined with limited access to advanced acute stroke interventions, these findings highlight major structural health inequities. Strengthening prevention, early risk-factor management, and access to reperfusion therapies is essential to reduce the disproportionate stroke burden in French Guiana.
The genetics of multiple sclerosis (MS) has advanced dramatically through the combined impact of high-throughput genotyping, large biobank resources, worldwide collaborations, and powerful computational analyses. Over the past two decades, genome-wide association studies (GWAS) have significantly reshaped our understanding of the genetic architecture of complex multifactorial diseases such as MS. The number of MS susceptibility-associated genomic regions is now more than 200, underscoring its highly polygenic nature. Within the major histocompatibility complex (MHC), the HLA-DRB1*15:01 allele and its extended haplotypes remain the most robust and reproducible risk factors. This historical association reflects a long-standing link between antigen presentation, immune regulation, and central nervous system autoimmunity. Beyond the MHC, common non-HLA loci implicate a wide network of immune pathways involving T-cell and B-cell activation, cytokine signaling, and antigen presentation. Moreover, rare variant analyses and family-based designs, although limited in power, have uncovered additional susceptibility genes, such as PRF1, CYP27B1, and NLRP1, shedding light on distinct mechanisms of immune modulation and metabolic regulation. The step forward will be now to explore diverse genetic ancestry populations, bearing differences in risk allele frequencies; multi-ethnic and family-based designs are needed to disentangle true genetic effects from environmental confounders. In parallel, progress has been made toward MS progression, as variants potentially influencing disability accumulation and neurodegeneration were identified. These findings have deepened our understanding of MS pathophysiology. They now provide a foundation for future integrative models that combine genetics, environment, and multi-omics data to elucidate disease heterogeneity and guide personalized therapeutic strategies. (c) 2026 The Author(s). Published by Elsevier Masson SAS. This is an open access article under
The 2024 update to the McDonald criteria for multiple sclerosis aims to be more inclusive, covering paediatric and elderly patients, as well as those with atypical symptoms or comorbidities. These criteria emphasise objective evidence of central nervous system involvement through clinical signs and biomarkers from fluid analysis or imaging. Several new biomarkers have been added, although some are not yet widely accessible but are expected to be implemented soon: kappa-free light chains in cerebrospinal fluid, which are more reproducible and cost-effective than oligoclonal bands, along with advanced imaging techniques such as the central vein sign and paramagnetic rim lesions on susceptibilityweighted imaging. Cases with incidental magnetic resonance imaging hyperintensities, identified as radiologically isolated syndrome (RIS), may also be classified as preclinical MS if they show T2 lesions in at least two typical locations and meet other specific biomarker criteria. Careful, step-by-step evaluation is essential to prevent misdiagnosis, especially in paediatric and late-onset MS, and in cases with comorbidities. The inclusion of RIS individuals or those with atypical presentations marks a crucial shift in the MS spectrum, requiring expertise and the use of specific biomarkers. (c) 2026 Elsevier Masson SAS. All rights are reserved, including those for text and data
Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults, characterized by autoimmune demyelination and neurodegeneration. While high-efficacy therapies have transformed relapsing MS management, disability progression remains an unmet need. Emerging evidence implicates compartmentalized central nervous system (CNS) inflammation, including microglial activation, in disease pathogenesis, necessitating novel immunotherapeutic strategies that target both peripheral and CNS-resident immune cells. This review synthesizes recent preclinical and clinical data on emerging MS immunotherapies offering promise for halting disability progression in MS. Their clinical integration will depend on balancing efficacy with safety, particularly in progressive phenotypes where therapeutic options remain limited. (c) 2026 Elsevier Masson SAS. All rights are reserved, including those for text and data
The development of remyelinating therapies is becoming an increasingly important strategy in the treatment of diseases such as multiple sclerosis. In this context, reliable measurement of myelin content is essential for the objective assessment of therapeutic efficacy. Over the past two decades, quantitative MRI has emerged as a method of choice for this purpose, supported by several postmortem validation studies that combine MRI with histology, the latter serving as the reference standard. In this review, we summarize the most relevant quantitative MRI contrasts sensitive to myelin changes and describe the mechanisms by which each contrast provides an estimate of myelin content. In addition, we outline the key steps involved in histological myelin quantification, highlighting the different methodological approaches as well as their limitations and potential pitfalls. (c) 2026 The Author(s). Published by Elsevier Masson SAS. This is an open access article under
Most clinical questions in neurology are inherently causal, yet observational studies have long been interpreted in terms of associations rather than causal effects of well-defined interventions. This limitation has contributed to persistent biases in neurology research, including inappropriate covariate adjustment, temporal misalignment, immortal-time bias, and susceptible depletion. Recent developments in causal inference offer a formal framework to overcome these issues through counterfactual reasoning, causal diagrams, and gmethods. The target trial emulation approach translates these concepts into a practical strategy: investigators first specify the protocol of the randomized trial that would ideally address their question, and then emulate this protocol using observational data. This requires explicit definition of eligibility, treatment strategies, assignment procedures, time zero, follow-up, outcomes, causal contrasts, and handling of intercurrent events, together with prespecified causal assumptions and an appropriate analysis plan. By aligning the design of observational studies with the structure of randomized trials, target trial emulation reduces design-related bias, clarifies the causal question, and provides a transparent foundation for real-world evidence generation. Validation studies, including recent work in multiple sclerosis, have demonstrated good concordance between emulated trials using observational data and randomized controlled trials. Target trial emulation therefore represents an essential complement to randomized evidence, particularly for questions
Multiple sclerosis (MS) is characterized by substantial clinical heterogeneity, yet the factors governing long-term outcomes remain poorly understood. Over the past two decades, genome-wide association studies have identified an increasing number of genetic variants influencing MS susceptibility, predominantly implicating immune pathways. Whether these same variants also shape disease course after onset is a question with direct implications for risk prediction, causal inference, and drug development in patients with established disease. This review examines the relationship between MS susceptibility genetics and disease outcomes, synthesizes emerging efforts to identify genetic determinants of severity, neuroimaging phenotypes, and treatment response, and considers how these findings inform our understanding of the mechanisms driving disease heterogeneity. (c) 2026 The Authors. Published by Elsevier Masson SAS. This is an open access article under
