BACKGROUND AND OBJECTIVES:It is currently difficult to accurately predict who, after the index event of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), will develop relapsing disease (R-MOGAD). Several clinical features have been reported as possibly predictive, but none have been validated in clinical practice. We used a prospectively designed analysis to assess a combined model of reported clinical prognosticators for developing R-MOGAD in 101 patients with MOGAD (86% with onset in adulthood) from 3 UK specialist centers. METHODS:A multivariable binary logistic regression model using variables identified from a scoping literature review was fitted in a retrospective clinical data set of patients with MOGAD (Nottingham MS & Neuroinflammation Centre [NUH]), with validation analysis in 2 independent data sets (Walton NMOSD Specialist Centre [WSC]; Imperial College London [ICL]). Secondary analysis investigated time to first relapse using Cox proportional hazards on the combined cohort. Results from the significant variables from the initial analysis were further examined in a meta-analysis of relevant literature studies. RESULTS:In the Neuroinflammation - Nottingham University Hospitals NHS Trust data set (n = 33), treatment with steroids ≥10 mg for ≥ 3 months after the index event was significantly associated with a lower likelihood of developing R-MOGAD (p = 0.006) with sensitivity 83% (95% CI 59-96) and specificity 73% (95% CI 45-92). A persistently positive MOG-IgG status, age at onset, optic neuritis at onset, and sex were not significant predictors of developing R-MOGAD. To assess generalizability, this predictor was tested in 2 independent data sets. In Walton Centre Liverpool (n = 39), not receiving prednisolone ≥10 mg ≥ 3 months was associated with R-MOGAD (OR = 9.7; 95% CI 2.1-45.4; sensitivity 63%; 95% CI 38-84; specificity 85%; 95% CI 62-97). In ICL (n = 29), the association was directionally consistent but inconclusive, with wide confidence intervals crossing unity (OR = 2.7; 95% CI 0.5-13.4; sensitivity 73%; 95% CI 39-94; specificity 50%; 95% CI 26-74). For the combined cohort (n = 101), not receiving prednisolone ≥ 10 mg for ≥3 months was associated with increased odds of developing R-MOGAD (OR = 6.2; 95% CI 2.6-14.8; p < 0.0001). Conversely, prednisolone ≥10 mg ≥ 3 months was associated with a lower hazard of relapse (HR = 0.47; 95% CI 0.24-0.91; p = 0.024). Median follow-up for monophasic patients was 42 months (IQR: 17.5-64.5). DISCUSSION:Prednisolone ≥10 mg for ≥ 3 months after the index event was associated with a lower likelihood of relapsing MOGAD. This association was supported in first external cohort and directionally consistent but inconclusive in a second, smaller cohort. Further prospective multicenter studies are required to assess the reproducibility and clinical utility of this association.
BACKGROUND AND OBJECTIVES:Although anti-CD20 monoclonal antibodies (anti-CD20s) theoretically represent an ideal treatment option for women with multiple sclerosis (wwMS) planning a pregnancy, the paucity of real-world data still limits their use in this context. Through our Italian registry "CD20-PREGNANCY," we aim to report pregnancy, infant, and maternal outcomes in wwMS treated with anti-CD20s. METHODS:In this observational study, wwMS having received rituximab (RTX), ocrelizumab (OCR), or ofatumumab (OFA) before and/or during pregnancy (≤12 months for RTX/OCR, ≤6 months for OFA) were included. Considering drug pharmacokinetics and timings of immunoglobulin placental transfer, pregnancies were classified as "exposed" (last administration pre-pregnancy ≤2.3 months for RTX, ≤3 for OCR, ≤1.8 for OFA) and "not-exposed" (last administration beyond these intervals) for comparative analysis. RESULTS:A total of 153 pregnancies (85 "not-exposed," 68 "exposed") across 27 Italian MS centers were collected. The median age at conception was 33.9 years (interquartile range 30.0-37.6) with 39.9% of women older than 35 years. Most pregnancies occurred in patients treated with OCR (77.1%). 80.4% of pregnancies ended in livebirth and 13.1% in spontaneous abortions (SA), without stillbirths/neonatal deaths. There was a significantly higher percentage of SA in "exposed" pregnancies than "not-exposed" (20.6% vs 7.1%, p = 0.014), but with values similar to those reported in general population. One serious perinatal infection ("exposed" group) and 2 major congenital anomalies (MCA) (one per group) were reported. Compared with the 12 months pre-pregnancy, annualized relapse rate remained stable during pregnancy but slightly increased postpregnancy (0.00 vs +0.09) in "not-exposed." Conversely, it decreased in both periods (-0.02 vs -0.13) among "exposed". Compared with pre-pregnancy, postpregnancy combined unique active lesions decreased in both groups (-0.15 in "not-exposed", -0.38 in "exposed"), while 2 confirmed disability worsening were observed ("not-exposed"). DISCUSSION:In conclusion, a good control of disease activity was observed without an increased risk of MCA or perinatal infections. Percentages of SA were overall in line with those of general population, although with a higher proportion in the "exposed" group. These findings support the use of anti-CD20 therapies in wwMS planning pregnancy, although further data are needed to better define their safety profile in this setting.
BACKGROUND AND OBJECTIVES:Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), yet its longitudinal trajectories and determinants remain poorly characterized. We aimed to identify trajectories of cognitive and physical fatigue in relapsing-remitting MS (RRMS) and to determine baseline clinical and MRI predictors of worsening fatigue. METHODS:We conducted a prospective, single-center cohort study embedded in the Predicting Optimal INdividualised Treatment response in MS (POINT-MS) program at the Queen Square MS Centre (London, United Kingdom). Adults with RRMS initiating a new disease-modifying therapy within 3 months of baseline were enrolled and underwent clinical and MRI assessments at baseline, 6 months, and 18 months. Key inclusion criteria were a diagnosis of RRMS, availability of baseline brain and cervical spinal cord MRI, and completion of at least 3 Modified Fatigue Impact Scale (MFIS) assessments. The primary outcome was the longitudinal change in MFIS cognitive and physical subscale scores. Fatigue trajectories were identified using growth mixture modeling. Baseline predictors included demographic factors, disability, cognitive performance, depression diagnosis, proportion of disease duration on disease-modifying treatments (DMTs), and MRI-derived measures of cervical spinal cord cross-sectional area (C-CSA) and regional brain volumes standardized to healthy-control norms. Predictor importance was assessed with conditional random forests, followed by multivariable modeling. RESULTS:We enrolled 225 participants. Three distinct fatigue trajectories emerged for both cognitive and physical MFIS subscales, including improving, stable/mild-worsening, and worsening classes. Worsening trajectories showed annualized increases of +3.32 points/year (cognitive) and +3.37 points/year (physical). Smaller baseline C-CSA was the strongest MRI predictor of worsening trajectories. Clinically, the proportion of disease duration spent on DMTs was the most influential predictor. DISCUSSION:Fatigue in RRMS follows heterogeneous trajectories over short-term follow-up. Smaller cervical spinal cord area was the strongest MRI predictor of worsening fatigue. Damage to ascending somatosensory axons within the cervical cord may reduce afferent input to the thalamus and diminish thalamocortical drive, contributing to both the motor and the cognitive-arousal dimensions of fatigue. These findings support incorporating cervical cord MRI into prognostic models and future fatigue research.
BACKGROUND AND OBJECTIVES:CSF inflammatory biomarkers in Huntington disease (HD), a neurodegenerative CAG-triplet expansion disorder, usually increase with disease progression. CSF leukocytes as an inflammatory marker have not been explored in HD. We explored high-precision CSF-leukocyte counts across different HD stages in the multicenter prospective biosample HD study HDClarity and their association with CSF neurofilament light chain (NFL) and cytokine and chemokine patterns. METHODS:A cross-sectional case-control study of the first average CSF leukocyte count of HDClarity study control participants (N = 94) and those carrying a repeat-expanded Huntingtin (HTT) allele (N = 335) categorized as having successive stages of presymptomatic and motor manifest HD as predefined by the HDClarity protocol (early presymptomatic [N = 48]: disease burden score [DBS] <250; late presymptomatic [N = 93]: DBS ≥ 250; early manifest HD [N = 171]: total functional capacity [TFC] 7-11; and late motor manifest HD [N = 23]: TFC < 11) was performed. CSF-NFL was available in 165. Results were juxtaposed with an independent single-center data set of 18 CSF cytokines and chemokines (57 CSFs, 19 control, 6 early and 8 late presymptomatic HD CSFs, and 19 manifest HD CSFs). RESULTS:CSF leukocytes peaked in late premanifest (median, interquartile range: 1.0/µL, 0.33-1.33/µL) when compared with early premanifest (0.0/µL, 0.0-1.0/µL) but also early (0.33/µL, 0.0-1.0/µL) and late manifest HD (0.0/µL, 0.0-0.67/µL). CSF leukocytes in late premanifest HD were higher than in controls (0.0/µL, 0.0-1.0/µL). A CSF-leukocyte peak at a DBS between 256 and 344 closely corresponded to the late premanifest HD peak. Higher CSF leukocytes in late premanifest HD were associated with higher CSF-NFL levels. Exploratory analysis of CSF cytokine and chemokine levels revealed that low interleukin (IL)-7 but high vascular endothelial growth factor (VEGF) and C-C motif chemokine ligand (CCL)22 levels may distinguish HD from control CSF; high VEGF, IL-6, and IL-15 early from late premanifest HD CSF; and low CCL2, CCL17, and IL-8 late premanifest from manifest HD CSF. When consecutively applied, these patterns identified late premanifest HD participants with a 75% sensitivity (95% CI 41%-96%) and 90% specificity (78%-96%). DISCUSSION:CSF leukocytes peaking in late premanifest HD, their association with increased CSF-NFL, and the corresponding stage-specific chemokine/cytokine changes indicate a temporally dynamic, probably neurotoxic inflammatory signaling network in HD.
BACKGROUND AND OBJECTIVES:Fc gamma receptor 3A (FCGR3A) V158F polymorphism has been shown to modify the response to anti-CD20 therapy across several autoimmune diseases. Ocrelizumab (OCR), an anti-CD20 agent, suppresses inflammatory activity in multiple sclerosis (MS), yet whether FCGR3A V158F polymorphism affects its efficacy in MS remains unclear. Here, we tested whether this genetic variant influences B-cell repopulation and disease activity in MS participants treated with OCR and assessed genotype-dependent differences in OCR binding to FcγRIIIa-expressing natural killer (NK) cells. METHODS:In this observational cohort study, we enrolled people with MS treated with OCR consecutively between May 2022 and August 2025. FCGR3A V158F genotyping was performed by pyrosequencing. The primary outcome was preinfusion CD19+ B-cell repopulation, defined as CD19+ B cells ≥1%. Secondary outcomes included clinical and MRI inflammatory activity and composite disease activity/disability-worsening measures. In a parallel mechanistic ex vivo substudy, OCR or rituximab (RTX) binding to NK cells was evaluated in genotype-selected donors by flow cytometry. Cycle-based repeated measures were analyzed using mixed-effects logistic regression. RESULTS:In 101 participants, 500 interinfusion intervals were analyzed. The odds of B-cell repopulation decreased with higher cycle number (odds ratio [OR] per cycle 0.77; 95% CI 0.65-0.91; p = 0.002) and increased with longer infusion intervals (OR per +30 days, 2.02; 95% CI 1.27-3.21; p = 0.0029). FCGR3A F-carrier status significantly modified the effect of interval length (interaction OR, 2.47; 95% CI 1.04-5.89; p = 0.042). Specifically, the odds of B-cell repopulation increased with longer intervals in MS participants carrying the FCGR3A-F allele (OR, 3.67; 95% CI 1.84-7.34; p = 0.00023) but not in FCGR3A-VV individuals (OR, 1.49; 95% CI 0.87-2.54; p = 0.146). FCGR3A genotype was not associated with clinical or MRI activity outcomes. In ex vivo assays, NK cells from FCGR3A-FF donors exhibited significantly lower binding of OCR (p = 4.34 × 10-4) and RTX (p = 0.00172) as compared with VV donors. DISCUSSION:Longer OCR infusion intervals were associated with higher odds of B-cell repopulation. The FCGR3A V158F polymorphism modified this interval-dependent repopulation, possibly by affecting OCR binding to NK cells. Prospective studies are needed to determine whether FCGR3A V158F polymorphism and B-cell repletion kinetics can inform optimized interval-based OCR dosing in MS.
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are inflammatory disorders of the CNS with distinct immunopathologic mechanisms and treatment responses and partially overlapping clinical phenotypes. The identification of aquaporin-4 (AQP4)-IgG and MOG-IgG has transformed disease classification and diagnosis, enabled a classification of antibody-defined subgroups, and facilitated the development of targeted therapies. However, optimal use of these biomarkers in clinical practice requires careful interpretation within the appropriate clinical and radiologic context. This review synthesizes current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility. We review antibody detection using cell-based assays, highlighting differences between live and fixed platforms and the impact of antigen conformation on sensitivity and specificity, particularly for MOG-IgG. Common causes of false-positive and false-negative results are discussed, including low-titer reactivity, testing in low pretest probability populations, treatment-related antibody titer reduction, and assay-specific limitations. The diagnostic challenges posed by indiscriminate testing in adult cohorts with multiple sclerosis, in whom disease prevalence markedly exceeds that of MOGAD, are emphasized. We also discuss the role of repeat testing during acute attacks and paired serum-CSF analysis in improving diagnostic confidence when results are equivocal or discordant. Beyond disease-defining antibodies, we examine biomarkers of tissue injury and immune activation. Serum and CSF neurofilament light chain and glial fibrillary acidic protein provide complementary measures of neuroaxonal and astrocytic damage and show associations with attack severity, disease activity, relapse risk, and long-term disability. Cytokines, chemokines, and complement components reflect inflammatory pathways, including IL-6-driven immune activation in NMOSD and MOGAD and complement-mediated astrocytopathy in NMOSD, and may support mechanistic stratification and treatment monitoring in both conditions. We further review the contribution of CSF analysis, neuropathology, genetics, and antigen discovery platforms to refine disease classification, particularly in seronegative or atypical presentations. Finally, we outline priorities for future research, including assay harmonization, standardized sampling protocols, longitudinal biomarker profiling, and integrative multiomic approaches. Collectively, advances in biomarker science have the potential to improve diagnostic precision, guide individualized therapeutic strategies, and support de-escalation decisions in NMOSD and MOGAD.
OBJECTIVES:Immune checkpoint inhibitor (ICI)-related parkinsonism is an exceedingly rare neurologic immune-related adverse event (irAE). METHODS:We reviewed retrospectively the French Pharmacovigilance Agency and French National Center for Autoimmune Encephalitis and Paraneoplastic Neurologic Syndromes Lyon databases (2015-2025) following identification of index case. RESULTS:We identified 4 male and one female patient, with a median age of 67 years (range 34-75), who developed acute-to-subacute parkinsonism after a median of 4 ICI cycles (range 1-12). The predominant phenotype was bilateral akinetic-rigid syndrome (rigidity n = 5, bradykinesia n = 4, tremor n = 3); the median modified Rankin Scale score at onset was 3. CSF analysis showed pleocytosis in 2/4 tested patients and elevated protein in 4/4 tested patients. Dopamine transporter imaging demonstrated bilateral dopaminergic denervation in both patients tested (n = 2), with documented reversibility in one. ICI discontinuation alone (n = 1/2) or combined with immunomodulatory therapy (n = 3) yielded clinical improvement over a median follow-up of 15 months (range 3-30). Levodopa/carbidopa supplementation was required in 2 patients. DISCUSSION:Post-ICI-related parkinsonism is a rare but potentially reversible irAE. Early recognition and prompt ICI discontinuation may favor significant clinical recovery. Immunosuppressive therapy should be considered for severe cases or those not improving after ICI discontinuation alone.
BACKGROUND AND OBJECTIVES:Reliable biomarkers for autoimmune encephalitis (AE) are limited, and emerging CSF markers are not incorporated into current diagnostic criteria. Prognostic tools remain insufficient, highlighting the need for biomarkers that support both early diagnosis and assessment of disease severity and prognosis. METHODS:In this multicenter prospective cohort study, we analyzed clinical data and paired CSF-serum samples from adults with definite AE enrolled in the German Network for Research on Autoimmune Encephalitis registry and the CSF biobank of Hannover Medical School. Of 2,330 screened individuals, 92 patients with anti-N-methyl-d-aspartate receptor (NMDAR, n = 53), anti-leucine-rich glioma-inactivated 1 (LGI1, n = 20), or anti-contactin-associated protein-like 2 (CASPR2, n = 19) encephalitis were included and followed longitudinally for a median of 38 months. Control groups comprised patients with relapsing multiple sclerosis, varicella-zoster virus encephalitis, and noninflammatory neurologic conditions (each n = 30), as well as antibody-positive patients without AE (n = 15), with the groups frequency-matched for age and sex. Kappa free light chain (KFLC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokines were measured in paired CSF-serum samples obtained at baseline and during follow-up. Disease severity and disability were assessed using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score and the modified Rankin Scale (mRS). RESULTS:Intrathecal synthesis of KFLC was detected in 94% of anti-NMDAR, 50% of anti-LGI1, and 53% of anti-CASPR2 encephalitis cases, demonstrating higher diagnostic sensitivity than CSF-restricted oligoclonal bands or pleocytosis. Diagnostic specificity across pooled control groups was moderate at 44% but reached 90% when compared with noninflammatory neurologic controls. CSF NfL z-score levels were strongly associated with baseline disease severity, with each 1-standard deviation increase corresponding to an approximately 10-point higher CASE score, independent of clinical covariates (β = 0.61). Longitudinal changes in NfL concentrations in CSF and serum were associated with disease severity and neurologic disability at follow-up (CASE score: adjusted R2 = 0.401; mRS score: adjusted R2 = 0.203). GFAP and cytokines showed limited diagnostic or prognostic utility. DISCUSSION:Intrathecal KFLC synthesis represents a highly sensitive CSF marker that supports early suspicion of autoimmune encephalitis and prompts antibody testing. NfL provides robust biochemical information on baseline disease severity and longitudinal changes that may aid prognostic assessment across AE subtypes.
BACKGROUND AND OBJECTIVES:Bispecific antibodies (BisAbs) have transformed the management of relapsed and refractory multiple myeloma (MM), achieving high response rates in heavily pretreated patients. However, these therapies induce profound immune perturbation, including plasma cell aplasia, hypogammaglobulinemia, and T-cell exhaustion, predisposing patients to serious infections. Progressive multifocal leukoencephalopathy (PML) has rarely been reported in this setting. METHODS:We report on 5 patients with MM who developed PML following BisAbs therapy. Clinical presentation, prior treatments, imaging, CSF studies, pathology, and outcomes were reviewed. In addition, T-cell immunophenotyping and antiviral T-cell responses were evaluated. RESULTS:Five patients (median age 63 years; range 60-77; 3 male) developed PML after treatment with elranatamab (1) or teclistamab (4), with (3) or without (1) talquetamab (1). All patients were under BCMA-directed BisAbs treatment at the time of PML diagnosis. Patients had received a median of 5 prior treatment lines (range 2-7) and 4 had undergone autologous stem cell transplantation. All demonstrated significant immune compromise. Median time from BisAbs initiation to PML diagnosis was 12 months (range 6-24; mean 15.4 months). One patient developed PML after only 2 prior therapies. Three of 5 patients had positive PCR for JC virus (JCV) in the CSF, while the other 2 were positive for JCV on brain biopsy. Clinical manifestations included dysarthria, ataxia, cognitive decline, and focal weakness. Although all patients demonstrated significant immune compromise (lymphopenia and hypogammaglobulinemia), 2 of 4 tested, showed specific anti-JCV/BKV T-cell response. DISCUSSION:PML represents a rare but serious, life-threatening complication of BisAbs therapy in MM. Although most patients were heavily pretreated, occurrence after limited prior therapies and the presence of specific anti-JCV T cells in 2 patients suggests BisAbs-related immune modulation may contribute independently to the risk. Duration of exposure may also be relevant. Given emerging therapeutic options such as immune check point inhibitors and anti-JCV-specific T-cell therapies, early recognition is critical. PML should be considered in patients receiving BisAbs therapy who develop new neurologic symptoms, and prompt evaluation is warranted.
BACKGROUND AND OBJECTIVES:Neuromyelitis optica spectrum disorder (NMOSD) is a severe condition usually associated with aquaporin-4 (AQP4) antibodies. A clinical presentation suggestive of NMOSD can also be associated with myelin oligodendrocyte glycoprotein (MOG) antibodies (MOGAD). NMOSD can be diagnosed in the absence of autoantibodies (double-negative NMOSD [DN-NMOSD]), but this subgroup has been poorly investigated. We conducted a systematic review and meta-analysis to define the clinical spectrum, prognosis, and treatment response in DN-NMOSD vs AQP4-NMOSD/MOGAD. METHODS:We searched on PubMed, Scopus, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov databases of studies on patients fulfilling inclusion criteria. Patient characteristics, outcome measures, and treatment regimens were extracted. RESULTS:We included 41 of 1,027 articles screened and analyzed 671 patients with DN-NMOSD (median age 38.6 years [range IQR: 32.5-42.85]; female-to-male ratio 1.5:1; median follow-up 44.4 months [range 1-600]), 73.6% of which relapsed. In the meta-analysis, mean annualized relapse rate (ARR) was higher, albeit not significantly, in DN-NMOSD (1.08; 95% CI 0.73-1.43) vs AQP4-NMOSD (0.84; 95% CI 0.45-1.23) and MOGAD (0.61; 95% CI 0.39-0.83, p = 0.08). Administration of maintenance immunosuppression in DN-NMOSD led to a significant ARR reduction (pooled rate ratio 0.19, 95% CI 0.07-0.49; p = 0.001), with high heterogeneity (I2 = 90%, p < 0.0001). In meta-regression, no covariates were associated with ARR reduction, including the administration of specific drugs (rituximab, p = 0.288; azathioprine, p = 0.291; mycophenolate, p = 0.918). The pooled mean difference in pre‑ and post‑maintenance treatment Expanded Disability Status Scale values indicated a significant change in disability in MOGAD (-0.93, 95% CI -1.67 to -0.19, p = 0.02) but not in AQP4-NMOSD (-0.62, 95% CI -1.85 to 0.61, p = 0.27) or DN-NMOSD (-0.52 (95% CI -1.30 to 0.25, p = 0.16). DISCUSSION:DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction. The administration of maintenance immunotherapy reduces the relapse risk and should be considered early to prevent further disability.
BACKGROUND AND OBJECTIVES:Pediatric-onset opsoclonus-myoclonus-ataxia syndrome (POOMAS) is a rare, neuroinflammatory syndrome that targets the cerebellum and can cause irreversible cerebellar structural changes, namely cerebellar atrophy. We investigated the frequency of cerebellar atrophy, as well as associated risk factors and functional outcome measures, using the largest active POOMAS registry. METHODS:This was a retrospective observational study of participants with POOMAS with disease onset from 1995 to 2025 using data from the multinational, multicenter POOMAS registry. Variables were compared between the cerebellar atrophy subgroups using the Fisher exact test or Wilcoxon rank-sum test. RESULTS:Of participants with follow-up imaging, cerebellar atrophy developed in 9.5% (6/63) of those with an MRI scan obtained at least 6 months after disease onset and 12.5% (3/24) with an MRI scan obtained at least 48 months after disease onset. Half of the participants who developed cerebellar atrophy (3/6) were identified more than 48 months after disease onset. Cerebellar atrophy was associated with older age at diagnosis (p = 0.023), but not with other demographic or clinical characteristics. There were no statistically significant differences in functional outcome measures or educational setting. DISCUSSION:The overall frequency of cerebellar atrophy was likely underestimated in this study because of the lack of standardized MRI timing and the large number of patients without MRI scans beyond 48 months.
BACKGROUND AND OBJECTIVES:CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS. METHODS:Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls. RESULTS:The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature. DISCUSSION:Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.
Over the past decade, therapeutic paradigms in multiple sclerosis have shifted toward a "hit-hard-and-early" approach to suppress inflammatory activity and delay progression. However, adverse events, safety concerns, aging, comorbidities, and life circumstances frequently necessitate treatment transitions during the patient journey. Sequencing decisions generally arise from 3 scenarios: insufficient efficacy, tolerability or safety issues, and conceptual considerations such as family planning or exit strategies for discontinuation. Discontinuation or de-escalation of therapy is associated with a significant risk of disease reactivation, particularly after lymphocyte-trafficking inhibitors, underscoring the importance of proactive transition planning to maintain disease control. Evidence suggests that treatment-specific immunologic effects strongly influence optimal sequencing. This narrative review synthesizes mechanistic insights and real-world clinical evidence to guide sequencing strategies for disease-modifying therapies (DMTs) in multiple sclerosis (MS), an increasingly relevant challenge in the era of early high-efficacy treatment. Following natalizumab, anti-CD20 monoclonal antibodies demonstrate superior control of relapse and MRI activity compared with sphingosine-1-phosphate receptor modulators (S1PRMs). Short transition intervals (<30 days) may minimize risk of rebound activity. After S1PRMs, rapid initiation of anti-CD20 therapies or cladribine seems effective, whereas prolonged washout periods increase relapse risk. Anti-CD20 therapies provide sustained suppression of inflammatory activity but are associated with long-term risks, including hypogammaglobulinemia and infections; cladribine may represent a viable exit strategy by enabling durable immune reconstitution. Platform therapies permit straightforward escalation without major rebound concerns, although lymphopenia must be considered when switching from dimethyl fumarate. Emerging Bruton tyrosine kinase inhibitors may further reshape sequencing paradigms, potentially functioning as maintenance therapies targeting compartmentalized inflammation after initial immune-depleting treatment. Future strategies will likely rely on close clinical and biomarker-based monitoring to individualize transitions and identify therapeutic windows. Overall, pragmatic sequencing that anticipates future switches and balances rebound risk against cumulative immunosuppression is essential for optimizing long-term outcomes in MS.
BACKGROUND AND OBJECTIVES:Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a novel and potentially treatable entity. Therefore, it is important to recognize all clinical symptoms and diagnostic clues. We specifically investigated neuromuscular signs and symptoms and muscle biopsy pathology, providing a link between IgLON5 and clinical features of myopathy. METHODS:All patients diagnosed with anti-IgLON5 disease in the Netherlands between 2016 and 2023 were included. Serum and CSF samples were tested with immunohistochemistry on rat brain and in-house cell-based assay using live cells. Biopsies of the vastus lateralis muscle were performed in patients with neuromuscular signs and symptoms and analyzed in Vienna together with 3 biopsies of non-Dutch patients sent to Vienna for second opinion. RESULTS:Twenty patients with anti-IgLON5 disease were included (10 male, 50%). The median age at onset was 61.5 years (range 45-85), and the median time from onset to diagnosis was 30 months (range 3-280). Neuromuscular symptoms were present in over half of the patients (11/20), including proximal limb weakness (n = 11), axial weakness (n = 1), muscle atrophy (n = 6), and fasciculations (n = 5). All 12 muscle biopsies (9 from the Dutch cohort, 3 external) showed mild myopathic alterations, 2 additionally presented target fibers and fiber type grouping (compatible with neurogenic myopathy), and 3 patients showed immune cell infiltration. We found a strong upregulation of IgLON5 expression in muscle fibers in all patients and also in different muscle disease controls, while immunoreactivity in healthy control muscle was faint/absent. DISCUSSION:Our data support that IgLON5 might play a role in muscle regeneration, which might result in proximal myopathy as a prominent clinical feature in anti-IgLON5 disease. This finding broadens the clinical phenotype of anti-IgLON5 disease and can be an important clue for earlier diagnosis and start of immunotherapy.
BACKGROUND AND OBJECTIVES:Ravulizumab, a complement component 5 inhibitor, was approved for the treatment of adults with anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) based on results of the primary treatment period (PTP) of CHAMPION-NMOSD, a phase 3, open-label, external placebo-controlled trial. Here, we report the final efficacy and safety results of CHAMPION-NMOSD (PTP and the long-term extension [LTE]). METHODS:Adult patients with AQP4-Ab+ NMOSD received an IV, weight-based loading dose of ravulizumab on day 1 and a maintenance dose on day 15 and every 8 weeks thereafter. After completion of the PTP (up to 2.5 years), patients could enter the LTE. The primary endpoint was time to first adjudicated on-trial relapse. The placebo group of the eculizumab phase 3 trial PREVENT was used as an external comparator because eculizumab availability at CHAMPION-NMOSD initiation precluded the use of concurrent placebo control. RESULTS:Of 58 patients enrolled in the trial, 56 entered and 55 completed the LTE. The overall median (range) follow-up was 170.3 (11.0-243.0) weeks, with 100.8 (53-137) weeks during the LTE. No patient receiving ravulizumab had an adjudicated on-trial relapse throughout the PTP (84.0 patient-years) and LTE (105.7 patient-years); relative reduction in risk of relapse vs placebo (n = 47) was 98.9% (95% CI 91.8-100; p < 0.0001). Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 94.8% and 27.6% of patients, respectively, during the PTP and LTE. Most TEAEs were grade 1 and unrelated to ravulizumab. One patient discontinued ravulizumab because of TEAEs. Two cases of meningococcal infection occurred during the PTP; none occurred in the LTE. One death due to hypertensive heart disease (unrelated to ravulizumab) occurred during the LTE. DISCUSSION:Long-term ravulizumab treatment (median follow-up, >3 years) continued to show significant relapse risk reduction in patients with AQP4-Ab+ NMOSD, and the safety profile was consistent with the known safety profile for ravulizumab. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov, NCT04201262; EudraCT: 2019-003352-37. Submitted December 11, 2019. First patient enrolled: December 13, 2019. clinicaltrials.gov/study/NCT04201262. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that long-term ravulizumab treatment, as compared with placebo, decreases the probability of clinical relapse in patients with AQP4-Ab+ NMOSD.
BACKGROUND AND OBJECTIVES:Compartmentalized CNS inflammation involving B cells is implicated in gray matter injury and disease progression in multiple sclerosis (MS). Products secreted by B cells of patients with MS can kill oligodendrocytes and neurons, a cytotoxicity conferred by their exosome-enriched extracellular vesicle (Ex En) fraction. METHODS:To explore the potential molecular mediators of this cytotoxicity, we profiled proteomic and transcriptomic cargo of Ex En isolated from B cells of patients with treatment-naive MS and matched healthy controls. RESULTS:MS B-cell-derived Ex En appeared enriched in cell-death-associated proteins (including fibrinogen, complement C9, APP, and SPARC) and deficient in cell-survival-associated proteins (such as galectin-3). Abnormal enrichment for cell-death proteins was supported by gene set enrichment analysis. Protein pathway analysis revealed densely connected prodeath modules in the MS B-cell-derived Ex En, contrasting with homeostatic signatures in controls. Transcriptomic analysis further revealed that Ex En of MS B cells appeared to carry reduced levels of miRNAs (miR-182, miR-212, and miR-1270) known to inhibit apoptosis. DISCUSSION:Our findings indicate that B-cell-derived Ex En of patients with MS, previously shown to impair neuronal and glial survival, harbor an abnormal cytotoxic molecular profile that may contribute to CNS-compartmentalized injury and progressive MS biology.
