Search Results (142)

mGlu5 metabotropic glutamate receptors are highly expressed and functional in early postnatal life, but their role in brain development remains to be elucidated. We now report that mGlu5^−/− mice showed a large reduction in mRNA and protein levels of myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and myelin basic protein (MBP) in the cerebral cortex and cerebellum at postnatal day (PND) 14. Expression of these proteins reflects oligodendrocyte differentiation and myelin formation in the CNS, a process that is prominent in the second week of postnatal life in mice. Expression of myelin markers recovered at later developmental stages, with the exception of MAG and MBP levels in the cerebellum, which were still reduced in mGlu5^−/− mice. We also observed a large reduction in myelin protein markers in the cerebral cortex and cerebellum of mice treated with the mGlu5 receptor negative allosteric modulator MTEP (3 mg/kg, i.p.) from PND 7 to PND 14. MTEP-treated mice also showed reduced motor coordination and sensorimotor function at PND 14. Treatment with MTEP reduced oligodendrocyte maturation without affecting proliferation of oligodendrocyte progenitor cells in primary cultures prepared from the rat cerebral cortex. These findings suggest that endogenous activation of mGlu5 receptors contributes to myelin formation during postnatal development in mice. Full article

Background: Therapeutic plasma exchange (TPE) is increasingly used in pediatric neuroimmunological disorders; however, evidence remains limited, particularly for rare neuroinflammatory and infection-triggered encephalopathy syndromes. We aimed to describe the clinical characteristics, treatment patterns, and outcomes of critically ill children who underwent TPE for neuroimmunological disorders in a tertiary pediatric intensive care unit. Methods: This retrospective observational study included consecutive patients younger than 18 years who received TPE for neuroimmunological disorders between September 2020 and December 2025. Demographic characteristics, disease spectrum, TPE indications, treatment details, neuroimaging findings, cerebrospinal fluid (CSF) characteristics, and clinical outcomes were reviewed. Neurological outcome at hospital discharge was assessed using the Pediatric Cerebral Performance Category (PCPC) score. Results: Twenty-two patients were included. The median age was 104 months (IQR, 62.3–151.8), and 50% were female. Guillain–Barré syndrome (GBS) was the most common diagnosis (n = 6), followed by autoimmune encephalitis (n = 6), infection-triggered encephalopathy syndrome (ITES)/acute necrotizing encephalopathy (ANE) spectrum disorders (n = 4), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (n = 3), acute disseminated encephalomyelitis (ADEM) (n = 2), and mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) (n = 1). The median interval from symptom onset to TPE initiation was 9 days (IQR, 6–13), and patients underwent a median of 7 TPE sessions (IQR, 5–10.5). Nine patients (40.9%) required invasive mechanical ventilation and four (18.1%) required vasoactive support. Favorable neurological outcomes at hospital discharge were observed in 63.6% of patients, whereas 36.4% had unfavorable neurological outcomes. Mortality occurred in 13.6% of patients and was confined to severe encephalopathic syndromes. No major TPE-related complications were observed. Conclusions: TPE was used across a heterogeneous spectrum of pediatric neuroimmunological disorders, including both guideline-supported and non-standard indications. Approximately one-quarter of patients had conditions not specifically addressed in current ASFA recommendations, highlighting the gap between real-world clinical practice and the available evidence base. Multicenter studies are needed to better define the optimal role, timing, and patient selection criteria for TPE in pediatric neuroimmunology. Full article

Background: The diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) relies on sensitive serological detection of MOG-IgG. Fixed cell-based assays (CBAs) may yield low-positive or borderline results that complicate early clinical decision-making, whereas live CBAs—recommended as the reference method—preserve native antigen conformation and offer higher analytical sensitivity. Importantly, low-positive titres should not be confused with true seronegativity, as they may nevertheless be clinically meaningful. Case Presentation: A 14-year-old previously healthy male presented with left optic neuritis and perineuritis following an upper respiratory infection. Initial MOG-IgG testing on a fixed CBA was low-positive (1:10). He partially responded to intravenous methylprednisolone and required intravenous immunoglobulin (IVIG) for complete resolution. Over three years, he experienced sequential, steroid-dependent bilateral optic neuritis with perineuritis, relapsing on every steroid taper. Rituximab and subsequently mycophenolate mofetil failed to induce remission. Repeat testing with a live CBA at a reference laboratory yielded a high-positive MOG-IgG titre of 1:1000, confirming MOGAD. Tocilizumab (8 mg/kg every 4 weeks) was initiated and allowed complete corticosteroid withdrawal. At age 18, the patient remained asymptomatic, with an Expanded Disability Status Scale score of 0, best-corrected visual acuity of 20/20 in both eyes, and stable peripapillary retinal nerve fibre layer thickness on spectral-domain optical coherence tomography. Conclusions: In paediatric patients with recurrent optic neuritis with perineural involvement and borderline fixed-CBA results, confirmatory testing with a live CBA at a reference laboratory should be considered to avoid diagnostic delay and therapeutic misdirection. In refractory, steroid-dependent cases, IL-6 receptor blockade may represent a reasonable therapeutic option, in line with emerging evidence. Full article

Background and objectives: Movement disorders are an underrecognized phenomenon in Myelin Oligodendrocyte Glycoprotein-Associated Disease (MOGAD). The aim of this paper was to summarize all movement disorders previously described in MOGAD. Materials and Methods: We conducted a systematic literature search in PubMed, Web of Science, and Scopus in English, focusing on patients with MOGAD exhibiting a movement disorder, i.e., ataxia, tremor, dystonia, parkinsonism, chorea, athetosis, myoclonus, ballism, tics, stereotypies, dyskinesia. Results: We included 58 studies, with a total of 91 patients with MOGAD and a movement disorder (45.6% male, 54.4% female). Movement disorders had a mean latency of 2.1 years (±6.9, 0–42) after MOGAD onset; however, they could be the presenting feature (in approximately 70% of cases), especially in pediatric patients. Cerebellar ataxia was the most common movement disorder, occurring in 77 patients (84.6%). Tremor, postural and/or kinetic, was the second most common movement disorder (15%). Dystonia was reported in 8.8%, presenting as cervical, or limb dystonia or stereotyped dystonic episodes. Myoclonus and hypokinetic movement disorders were rare. Subcortical (in 60%), brainstem and cerebellar lesions (in 50% respectively) were the most common imaging findings. The most common accompanying symptoms were encephalopathy, fever and headache. Approximately half of the patients made a full recovery, and the other half showed a significant improvement in the movement disorder after immunomodulatory treatment, most commonly steroids. Conclusions: The new onset of a movement disorder, especially ataxia, in a young patient should prompt the search for MOGAD or can indicate a relapse in patients with an established diagnosis. Full article

Myelination is essential for rapid axonal conduction and neuronal integrity, and its loss in demyelinating diseases such as multiple sclerosis (MS) leads to progressive neurological impairment. Despite advances in immunomodulatory therapies, effective strategies that promote remyelination remain limited. Here, we identify Morusin, a prenylated flavonoid natural compound, as a potent enhancer of oligodendrocyte (OL) differentiation and myelination-associated outcomes. Using a fluorescence-based screen of diverse flavonoids in primary rat oligodendrocyte progenitor cells (OPCs), it was found that Morusin markedly increased myelin basic protein (MBP) expression. To enable cross-species validation, we established a SOX10-inducible human OPC differentiation system, which shortened differentiation time and allowed functional screening in human cells. In this platform, Morusin enhanced OL maturation and induced a transcriptional profile enriched for myelination- and axon ensheathment-related genes, including MBP, PLP1, MAG, and SIRT2. Furthermore, in myelin oligodendrocyte glycoprotein (MOG)₃₅–₅₅-induced experimental autoimmune encephalomyelitis (EAE) mice, Morusin improved myelination-associated histological features and functional recovery, comparable to the benchmark compound Benztropine. Collectively, these findings identify Morusin as a promising natural compound with pro-myelinating activity across multiple experimental systems and highlight the potential of rationally guided natural compound screening for regenerative therapy in demyelinating diseases. Full article

A 78-year-old woman with a history of rheumatoid arthritis (treated with methotrexate) developed disturbed consciousness, emesis, and intestinal perforation. Initial labs revealed hyperammonemia (189 μg/dL) and hypertonic dehydration. Despite ammonia normalization, her neurological status improved only slightly, necessitating additional tests. Cerebrospinal fluid analysis showed no pleocytosis but positive oligoclonal bands and markedly elevated myelin basic protein (>500 pg/mL). Serum autoimmune markers were negative, including anti-aquaporin-4 (AQP4), anti-myelin oligodendrocyte glycoprotein (MOG), and anti-glial fibrillary acidic protein (GFAP) antibodies. MRI revealed T2/DWI-hyperintense lesions in the left parietal lobe and cerebellum. Crucially, extensive T2/DWI-hyperintense lesions with diffusion restriction spanned the white matter from the medulla oblongata to the lumbar spinal cord. Axial spinal DWI demonstrated diffuse hyperintensity throughout the entire white matter, accompanied by gray matter atrophy. Subsequent metabolic screening revealed low folate and hypocupremia (34 μg/dL) as well as urinary orotic acid and low serum citrulline, suggesting late-onset ornithine transcarbamylase (OTC) deficiency. Given the clinical context, this was interpreted as a metabolic breakdown rather than an established genetic diagnosis. This case is characterized by a long, diffusion-restricted lesion from the brainstem to the spinal cord that does not correspond to vascular territories. She experienced sudden death. We hypothesize that an underlying metabolic disorder, nutritional deficiencies and drug-induced neurotoxicity contributed to lesion formation. Full article

Optic neuritis (ON) has been recognized since antiquity, but its modern clinical identity emerged only in the late 19th century and was definitively shaped by the Optic Neuritis Treatment Trial (ONTT). The ONTT established the natural history, visual prognosis, association with multiple sclerosis (MS), and therapeutic response to corticosteroids, building the foundation for contemporary ON management. Subsequent discoveries—most notably aquaporin-4 IgG-associated ON (AQP4-ON), myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON), and double-negative ON—have fundamentally transformed this paradigm, shifting ON from a seemingly uniform demyelinating syndrome to a group of biologically distinct disorders. These subtypes differ in immunopathology, clinical course, MRI features, retinal injury patterns, CSF profiles, and long-term outcomes, making early and accurate differentiation essential. MRI provides key distinctions in lesion length, orbital tissue inflammation, bilateral involvement, and chiasmal or optic tract extension. Optical coherence tomography (OCT) offers complementary structural biomarkers, including severe early ganglion cell loss in AQP4-ON, relative preservation in MOG-ON, and variable patterns in double-negative ON. CSF analysis further refines diagnosis, with oligoclonal bands strongly supporting MS-ON. Together, these modalities enable precise early stratification and timely initiation of targeted immunotherapy, which is critical for preventing irreversible visual disability. Despite major advances, significant unmet needs persist. Access to high-resolution MRI, OCT, cell-based antibody assays, and evidence-based treatments remains limited in many regions, contributing to global disparities in outcomes. The understanding of the pathogenesis of double-negative optic neuritis, the identification of reliable biomarkers of relapse and visual recovery, and the determination of standardized cut-off values for multimodal diagnostic tools—including MRI, OCT, CSF analysis, and serological assays—remain unresolved challenges. Future research must expand biomarker discovery, refine imaging criteria, and ensure equitable global access to cutting-edge diagnostic platforms and therapeutic innovations. Four decades after the ONTT, ON remains a dynamic field of investigation, with ongoing advances holding the potential to transform care for patients worldwide. Together, these advances expose a fundamental tension between historically MS-centered diagnostic frameworks and the emerging biological heterogeneity of ON, a tension that underpins the structure and critical perspective of the present review. Full article

Background/Objectives: White matter degeneration is a significant and early mediator of cognitive impairment in Alzheimer’s disease (AD), yet the critical pathologic features remain poorly understood, under-detected, and therapeutically untargeted. Herein, we characterize molecular features of white matter glial cells in AD brains and assess the utility of non-invasive approaches for detecting related abnormalities in extracellular vesicles (EVs) isolated from serum (SEV). In addition, results from unfractionated (SEV-T) and O4 sulfatide-selected SEVs were compared to determine whether white matter abnormalities were detected with greater sensitivity in oligodendrocyte-specific SEVs (SEV-O4). Methods: Oligodendrocyte glycoprotein and astrocyte mRNA levels were measured in postmortem human AD and control frontal lobe white matter by RT-PCR. Immunoreactivity to oligodendrocyte glycoproteins, astrocyte structural proteins, neurofilament light chain (NfL), and aspartyl-asparaginyl-β-hydroxylase (ASPH) was measured by ELISA in SEV-T and SEV-O4 from patients with moderate AD or normal aging. Results: AD brain pathology was associated with significantly reduced mRNA expression of multiple oligodendrocyte glycoproteins and increased mRNA expression of astrocytic structural genes. SEV analyses demonstrated significantly increased immunoreactivity to 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), myelin-associated glycoprotein 1 (MAG1), astrocyte proteins, and ASPH, a potent activator of Notch and myelin-regulated homeostatic functions. There were no significant benefits of measuring SEV-O4 compared with SEV-T immunoreactivity. Conclusions: AD is associated with significant molecular abnormalities in oligodendrocyte and astrocyte function in brain tissue. The abnormalities detected in SEVs likely reflect oligodendrocyte injury and degeneration, as well as astrocytic activation. The findings suggest that low-invasive SEV approaches, including the novel analysis of ASPH upregulation, can be used to detect and monitor AD white matter degeneration. Full article

Background and Objective: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a significant component of demyelinating diseases in pediatric populations. Recently, diagnostic criteria for MOGAD were established. This study aims to evaluate and compare the diagnostic efficacy of the fixed-cell-based assay (Fixed-CBA) and the live cell-based assay (Live-CBA) in patients who meet the 2023 clinical diagnostic criteria for MOGAD. Methods: This retrospective study included patients suspected of having MOGAD who were enrolled between June 2023 and June 2024. Patients were selected based on the “core clinical demyelinating events” outlined in the 2023 proposed criteria of the International MOGAD Panel. Patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 antibody-positive (AQP4-Abs-positive), and non-central nervous system (non-CNS) inflammatory diseases were chosen as controls. Serum samples were simultaneously tested for MOG-Abs using Fixed-CBA and Live-CBA. Results: A total of 86 patients were enrolled in the study: 52 in the suspected MOGAD group and 34 in the control group. Out of these patients studied, 16 presented with optic neuritis (ON), 5 with myelitis, 8 with acute disseminated encephalomyelitis (ADEM), and 7 with cortical encephalitis. Sixteen patients could not be classified by clinical phenotype. The highest MOG-Ab positivity rate was among patients with cortical encephalitis [85.7% (Live-CBA)/71.4% (Fixed-CBA)]. Both assays identified 22 positive samples, with Fixed-CBA and Live-CBA sensitivities at 44.2% and 55.8%, respectively, and a specificity of 97%. Of the patients suspected of having MOGAD, 19 cases were confirmed using the Fixed-CBA, while 28 cases were confirmed using the Live-CBA. This resulted in an upgrade in diagnostic classification for nine cases. This led to a diagnostic reclassification in nine cases. Conclusions: Both the Fixed-CBA and Live-CBA were associated with higher sensitivity for patients selected based on the 2023 MOGAD clinical diagnostic criteria. The Live-CBA exhibited an 11.6% increase in sensitivity, contributing to a 17.3% (9/52) enhancement in clinical diagnostic accuracy. Full article

This narrative review explores the impact of diet and physical exercise both as a risk factor of central nervous system inflammatory diseases, but more importantly as potential adjunctive disease modifiers in Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorders (NMOSD), and Myelin Oligodendrocyte Glycoprotein (MOG) antibody-associated disease (MOGAD). The majority of evidence relies on MS preclinical and clinical studies, but preclinical studies also support the benefit of lifestyle intervention in NMOSD and MOGAD. In MS, adherence to healthy diets (particularly Mediterranean and MIND diets) could lead to a milder disease course with reduced relapse rates, while structured exercise from early disease stages promotes neuroprotection by upregulating neurotrophic factors and preserving brain volume, possibly impacting disease progression. The ketogenic diet and intermittent caloric restriction also showed promising results. Physical activity, including both aerobic training and resistance training, emerges as a potential disease-modifying strategy by promoting neuroprotection, reducing inflammation, and supporting functional and cognitive outcomes, particularly when implemented early in the disease course. A synergistic approach alongside disease-modifying treatments (DMTs) would further positively modulate core pathological processes. Evidence for NMOSD and MOGAD warrants further investigation. We highlight that integrating personalized lifestyle strategies would be beneficial from the early stages. However, future large-scale, standardized trials are required to fully confirm the neuroprotective potential of diet and exercise across the entire spectrum of CNS disorders. Full article

Background and Objectives: Neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) are distinct autoimmune demyelinating disorders of the central nervous system, characterized by different pathological and clinical features. Reliable biomarkers are essential for accurate diagnosis and monitoring of disease activity. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are promising candidates, reflecting astrocytic and axonal damage, respectively. Materials and Methods: To investigate the relationship between astroglial (GFAP) and neuronal (NfL) protein levels in the peripheral blood, 89 plasma samples were analyzed using Simoa immunoassays. The concentrations of pNfL and pGFAP were measured in three groups: AQP4-IgG-positive NMOSD patients (n = 18), MOGAD patients (n = 12), and healthy controls (HCs, n = 19). Statistical analyses assessed group differences, correlations, and the predictive value of biomarkers for disease activity. Results: Both NMOSD and MOGAD patients exhibited elevated pNfL compared with controls, indicating neuroaxonal injury. No significant differences in pNfL, pGFAP, or pGFAP/pNfL ratios were observed between patient groups. The pGFAP levels and the pGFAP/pNfL ratio were significantly higher in NMOSD patients, particularly during attacks, indicating prominent astrocyte damage. Correlations revealed associations between biomarker levels, disability, and disease duration. pNfL demonstrated high accuracy in predicting recent relapses (AUC = 0.906), whereas pGFAP showed moderate predictive capacity (AUC = 0.638). Elevated pNfL and pGFAP levels were associated with an increased likelihood of relapse within six months. Conclusions: Plasma NfL and GFAP are promising biomarkers for assessing tissue injury and disease activity in NMOSD and MOGAD. NfL predicts relapses, while GFAP primarily reflects astrocytic damage in NMOSD. Longitudinal studies are warranted to validate these biomarkers and establish clinical thresholds for disease management. Full article

Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is an inflammatory demyelinating disorder of the central nervous system characterised by heterogeneous clinical and radiological presentations. Accurate interpretation of serum anti–myelin oligodendrocyte glycoprotein (anti-MOG) antibody titres is critical to improve diagnostic precision and prognostic assessment. This single-centre retrospective study evaluated 19 patients diagnosed with MOGAD in 2023, all of whom were seropositive for anti-MOG IgG, as confirmed by live cell-based assays (CBAs) using full-length human MOG and IgG1-specific secondary antibodies. Antibody quantification combined a ratiometric semi-quantitative fluorescence index with classical endpoint dilution titres, enabling classification into low, medium, and high titre groups. Stratification revealed titre-dependent phenotypic heterogeneity: high-titre patients were older at onset and predominantly presented with optic neuritis, often bilateral, and encephalic involvement, whereas low-titre patients more frequently exhibited spinal cord syndromes, cerebellar or brainstem symptoms, and a higher prevalence of cerebrospinal fluid-restricted oligoclonal bands. Semi-quantitative fluorescence ratios correlated consistently with endpoint titres, and exponential decay analysis demonstrated slower signal loss in high-titre sera, confirming assay reliability. No significant association emerged between titre level and monophasic versus relapsing disease course. Anti-MOG antibody titres could serve not only as a diagnostic biomarker but also to capture clinically relevant immunopathological diversity, supporting a titre-stratified approach to diagnosis and early prognostication. Incorporating semi-quantitative metrics alongside clinical and imaging features may refine the diagnostic algorithm and prevent misclassification of atypical presentations. Full article

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has emerged as a distinct autoimmune demyelinating disorder, characterised by clinical, radiological, and immunopathological features that differentiate it from Multiple Sclerosis (MS) and AQP4+ neuromyelitis optica spectrum disorder (AQP4+NMOSD). This review provides a comprehensive synthesis of the evolving landscape of MOGAD, from its immunopathogenesis and diagnostic criteria to treatment strategies and global epidemiological insights. We explore the role of MOG-IgG antibodies in disease mechanisms, the utility of emerging biomarkers, and the prognostic value of tools like clinical scores or longitudinal MOG-IgG assessment. Special attention is given to regional disparities, with a focus on Latin America, highlighting diagnostic delays, access inequities, and unique clinical phenotypes. We also examine the limitations of current evidence, including gaps in long-term longitudinal follow-up and variability in diagnostic testing. Finally, we discuss global collaborative efforts and clinical trials that are shaping the future of personalised care in MOGAD. As the field advances, integrating biomarker-driven monitoring, equitable access to therapies, and regionally adapted guidelines will be essential to improving outcomes for patients worldwide. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by sustained neuroinflammation and demyelination within the central nervous system (CNS). Vesatolimod (VES), a selective Toll-like receptor 7 (TLR7) agonist, has demonstrated both antiviral and immunomodulatory properties; however, its potential therapeutic value in neuroinflammatory contexts remains poorly understood. In this study, we evaluated the efficacy of VES in the experimental autoimmune encephalomyelitis (EAE) model of MS and elucidated its mechanisms of action. EAE was induced in mice by immunization with myelin oligodendrocyte glycoprotein (MOG_35–55). The therapeutic effects of VES were assessed through clinical scoring, body weight monitoring, histopathology, flow cytometry, quantitative proteomics, and Western blot analysis. Additionally, an in vitro model of lipopolysaccharide (LPS)-induced microglial activation was employed to investigate cell-autonomous mechanisms. Results showed that VES administration significantly ameliorated disease severity, reduced weight loss, and enhanced neurological function in EAE mice. Treatment with VES inhibited the differentiation of pro-inflammatory Th1 and Th17 cells while expanding regulatory T cell (Treg) populations. It also preserved blood–brain barrier (BBB) integrity, attenuated demyelination, and modulated microglial activation phenotypes within the CNS. At the molecular level, VES activated the Nrf2/HO-1 antioxidant pathway, thereby enhancing the expression of cytoprotective proteins. Proteomic profiling further revealed the downregulation of inflammation-related proteins, specifically those associated with TNF, IL-17, and NOD-like receptor signaling pathways. Collectively, these findings demonstrate that VES alleviates neuroinflammation in EAE through multimodal mechanisms—including peripheral and central immune regulation, BBB protection, and activation of endogenous antioxidant defenses—supporting its further development as a promising therapeutic candidate for MS. Full article