Search Results (125)

Background: Diagnostic evaluation of suspected neuromyelitis optica spectrum disorder (NMOSD) integrates AQP4-IgG testing, clinical assessment, neuroimaging, and exclusion of alternative inflammatory demyelinating disorders; nevertheless, some patients remain diagnostically unresolved or may be misclassified as multiple sclerosis (MS) or other disorders. Methods: This single-center retrospective exploratory study analyzed quantitative serum proteomics from 20 patients with MS and 20 with NMOSD. Proteins meeting nominal p < 0.05 together with prespecified fold-change criteria were considered exploratory candidates. VWF, PPBP, and SERPINA3 were subsequently assessed by ELISA in a separate, non-overlapping cohort from the same center, together with routine hematological variables. Results: Among 261 protein entries, 34 met the exploratory nominal threshold and fold-change criteria, but none remained significant after Benjamini–Hochberg correction (lowest q = 0.0734). VWF and PPBP showed no significant differences across the four validation groups. SERPINA3 differed across groups (Kruskal–Wallis H = 44.982, p = 9.34 × 10⁻¹⁰) and was higher in NMOSD than in MS, TBI, and HCs after Holm adjustment (adjusted p = 0.036, 1.49 × 10⁻⁹, and 1.13 × 10⁻⁵, respectively). In the full ELISA cohort, the AUC was 0.928 for NMOSD versus HC and 0.800 for NMOSD versus MS. In a post hoc sensitivity analysis excluding participants with preceding infection, the NMOSD–MS separation was attenuated. In smaller complete-case analyses, adding an additional laboratory variable to SERPINA3 did not significantly improve apparent discrimination. Conclusions: SERPINA3 is therefore an exploratory adjunctive serum biomarker candidate rather than a stand-alone diagnostic test; prospective external validation in clinically representative cohorts is required. Full article

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy in which antibodies against the aquaporin-4 (AQP4) water channel produce a stereotyped group of syndromes determined by the anatomical distribution of AQP4 expression. Six core clinical presentations are recognized: optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome, acute brainstem syndrome, diencephalic syndrome, and cerebral syndrome. Because disability in NMOSD almost always accrues at discrete, treatable relapses rather than through insidious progression, early recognition, supported by prompt AQP4-IgG testing and pattern recognition on MRI, is essential to preserving vision, mobility, and independence. This review summarizes the pathophysiology, clinical and radiologic features, diagnostic evaluation, and differential diagnosis of each core syndrome and synthesizes contemporary evidence for relapse prevention. Over the past decade, the therapeutic landscape has been transformed: agents targeting complement (eculizumab, ravulizumab), the interleukin-6 receptor (satralizumab, tocilizumab), and B cells (rituximab, inebilizumab) now have randomized evidence of efficacy in seropositive disease, with complement inhibitors ranking highest across indirect treatment comparisons. Evidence in seronegative disease remains limited, no approved agents have been compared head-to-head, and the optimal role of early plasma exchange is unsettled. Emerging neuroprotective strategies and chimeric antigen receptor T-cell therapy, both of which remain experimental, may further expand options for refractory disease. Once uniformly disabling, AQP4-IgG NMOSD is now a highly treatable condition in which timely diagnosis and sustained immunotherapy can meaningfully alter long-term outcomes. Full article

Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes. Full article

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease with important disability accumulation. Early-onset NMOSD, defined as disease onset before age 50, exhibits distinct clinical characteristics compared to late-onset disease. We present a case series of patients with first symptom onset before age 30. Methods: A retrospective review of 10 patients diagnosed with NMOSD at our center in San Luis Potosí, Mexico, with disease onset before age 30. Clinical presentation, imaging findings, AQP4 antibody status, treatment response, and disability outcomes were analyzed. Results: The mean age at onset was 18.6 years (range 6–30). Area postrema syndrome was the most common presentation (40%), followed by acute myelitis and optic neuritis (30% each). All tested patients were AQP4-positive. The mean EDSS at follow-up was 6.6, indicating severe disability. Most patients received rituximab with variable response rates. Conclusions: Our cohort showed higher disability than reported in other early-onset series, emphasizing the need for prompt diagnosis and aggressive treatment in this population. Full article

Introduction: Neuropathic pain (NP) in neuromyelitis optica spectrum disorder (NMOSD) represents a significant and often under-recognized complication arising from central nervous system (CNS) lesions. Unlike other demyelinating disorders, NMOSD involves a distinct immunopathogenesis primarily driven by aquaporin-4 antibodies (AQP4-IgG), leading to severe inflammatory damage. NP is typically the consequence of inflammatory damage to the spinothalamic tract or dorsal columns, resulting in both acute and chronic pain syndromes. Methods: A systematic review and meta-analysis were conducted following a comprehensive search of Medline and Scopus, identifying nine eligible studies reporting on NP in NMOSD. Results: Pooled prevalence was estimated using a random-effects metaprop meta-analysis with Freeman–Tukey transformation and REML-based heterogeneity estimation. The pooled prevalence of NP among patients with NMOSD was 56.2% (95% CI: 41.7–70.1%; I² = 95.3%, p < 0.001). Sensitivity analysis including only AQP4-IgG⁺ cohorts revealed a prevalence of 63.2% (95% CI: 23.4–94.7%; I² = 98.1%, p < 0.001). No significant difference was found between mixed and AQP4-IgG⁺-only populations (53.05% vs. 63.27%, p = 0.63). Meta-regression showed no significant associations between NP prevalence and age (β = 0.01, p = 0.33) or disability (β = 0.08, p = 0.18). Qualitative synthesis demonstrated an association between thoracic spinal cord lesions and NP, and also indicated that NP was often resistant and refractory to standard pharmacologic therapies. Conclusions: NP affects one in two NMOSD patients, and is associated with thoracic spinal cord lesions. In comparison with multiple sclerosis, NP in NMOSD is primarily structural and immunopathological in origin. Treatment strategies remain inadequate, emphasizing the need for early recognition and a disease-specific therapeutic approach. Full article

C-reactive protein (CRP) has emerged as a crucial link between systemic and neuroinflammatory processes, though its role across neurological autoimmune disorders remains incompletely understood. Pathologies such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), Guillain–Barré syndrome (GBS), and myasthenia gravis (MG) share chronic, dysregulated inflammation resulting from loss of immune tolerance. Their pathogenesis arises from interactions among genetic susceptibility, environmental factors, and gut microbiota alterations that trigger autoreactive immune cascades through molecular mimicry, ectopic antigen expression, or paraneoplastic cross-reactivity. These immune pathways sustain inflammation and promote neuroaxonal injury. CRP, synthesized mainly by hepatocytes in response to interleukin-6 (IL-6), functions as both an effector and reporter of inflammation, linking systemic immune activation to neuroinflammatory damage. Elevated CRP levels correlate with unfavorable outcomes, including accelerated disability in MS, IL-6-mediated astrocyte injury in NMOSD, respiratory failure in GBS, and crisis susceptibility in MG. Composite indices such as the CRP-to-albumin ratio are emerging as refined prognostic markers, though interpretation is limited by non-specificity and biological variability. This review integrates current evidence on CRP’s mechanistic roles, clinical associations, and translational potential in neuroinflammatory disorders, combining molecular, clinical, and imaging perspectives to refine its role within inflammation-driven neurodegeneration. Full article

In this study, blood cell counts and serum C3, C4, and CH50 values at baseline and after more than 6-month drug use were measured to elucidate changes in blood cells and complements during relapse prevention therapies for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD). A total of 70 patients with AQP4+ NMOSD (87% female, median age 56 years) were enrolled. They were divided into the following treatment groups: glucocorticoids and/or immunosuppressants (GC/IS, n = 22), inebilizumab/rituximab (anti-CD19/20, n = 13), satralizumab (anti-IL-6R, n = 22), and eculizumab/ravulizumab (anti-C5, n = 13). At baseline, the blood counts and complement levels did not differ among the groups. At follow-up, the neutrophil and platelet counts in the anti-IL-6R group decreased from those at baseline (p < 0.0001 and p < 0.001, respectively). Compared with the GC/IS, anti-CD19/20, and anti-C5 groups, the anti-IL-6R group had lower levels of C3 (p < 0.0001, p < 0.01, and p < 0.05, respectively) and C4 (p < 0.0001, p < 0.01, p < 0.001, respectively). Furthermore, the anti-C5 group had significantly lower CH50 levels than the GC/IS, anti-CD19/20, and anti-IL-6R groups (p < 0.0001, p < 0.0001, p < 0.05, respectively). In addition, the anti-IL-6R group had lower CH50 levels than the GC/IS and anti-CD19/20 groups (p < 0.001 and p < 0.05, respectively). The present study demonstrated that anti-IL-6R therapy broadly and mildly suppressed the complement system and decreased the neutrophil and platelet counts. It also showed that anti-C5 therapy strongly suppressed total complement activity but did not affect the C3 and C4 levels or blood counts. These findings may have implications for the mode of action of the drugs and the risk of adverse drug reactions, including infections. Full article

Background: Sudden, non-traumatic hearing loss has been associated with vascular or inflammatory disorders. Hearing loss in Neuromyelitis optica spectrum disorder (NMOSD) is a very rare presentation. Methods: In this paper, we describe the case of a 58-year-old female patient with aquaporin-4-positive NMOSD exhibiting bilateral tinnitus and right-sided deafness in the context of a relapse. The auditory brainstem responses pointed to a lesion of the right peripheral auditory pathway (cochlea and/or auditory nerve). The patient’s hearing failed to improve after high-dose intravenous steroids; however, it showed slight improvement after plasmapheresis. We also conducted a systematic literature review in databases MEDLINE and Scopus in English, searching for all reported cases of hearing loss in NMOSD. Results: We included 10 studies reporting 15 cases of NMOSD with hearing loss. The vast majority of patients were female (11 out of 15, 73.3%), with an age range of 26 to 70 years. Hearing loss, ranging from mild to severe, seems more frequent in AQP4-positive cases, and it can even be the presenting symptom. It can present isolated or in combination with tinnitus, ataxia, and/or intractable vomiting. The auditory pathway impairment in NMOSD seems to be localized either centrally, i.e., cochlear nuclei or higher brainstem levels, or peripherally, i.e., in the cochlea or cochlear nerve itself. Intravenous methylprednisolone in high doses, followed by oral tapering, was the most common treatment option, resulting in a gradual improvement. Conclusions: This paper describes a rare case of peripheral auditory pathway affection in NMOSD, which is an inflammatory astrocytopathy mainly affecting the central nervous system. Early recognition of hearing loss in the context of an NMOSD relapse and subsequent treatment have a crucial impact on the hearing outcome of NMOSD patients. This expands our knowledge of NMOSD as an autoimmune aquaporin-4 channelopathy. 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: Neuromyelitis optica spectrum disorder (NMOSD) involves demyelinating astrocytopathy. Most cases have autoantibodies against aquaporin-4 (AQP4 ab), but AQP4 ab-negative patients may also meet NMOSD criteria. Overlapping clinical phenotypes of CNS inflammatory demyelinating diseases (IDDs) complicate understanding NMOSD mechanisms. Objectives: Investigate molecules related to neuroinflammation and astrocyte function as potential biomarkers of NMOSD and other IDDs by using clinical data and in vitro assays. Methods: Subjects (176) with different IDDs (NMOSD (37), MS (125), MOGAD (3), ADEM (3) and eight radiologic isolated syndromes (RIS)) were studied. Plasma concentrations of TGF-β and other cytokines were measured by single molecule array (SIMOA), Luminex and ELISA assays. Functional assays used in vitro cultured human astrocytes exposed to NMOSD subjects’ serum, followed by immunolabeling. Results: TGF-β levels were higher in NMOSD patients during attacks compared to inactive phases. AQP4+ groups in inactive phases had lower TGF-β levels than AQP4− groups. No significant difference was found for IL-1β, IL-8, IL-10, IL-17A and Thrombospondin plasma concentrations, with a minor difference for VEGF in the AQP4+ group. Astrocytes exposed to NMOSD AQP4+ and AQP4− subjects serum, with or without TGF-β1, showed no changes in C3, NFkB and HMGB1. However, the content of GLT-1 decreased in AQP4+ serum-treated astrocytes, reversed by TGF-β1. Conclusions: TGF-β may be a potential NMOSD activity biomarker, indicating different disease mechanisms based on AQP4 ab presence. Full article

Background/Objectives: Neuromyelitis Optica Spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system with a globally heterogeneous prevalence/ To estimate the prescription-based prevalence of NMOSD in Greece and determine the use of long-term immunotherapies and concomitant medications in these patients. Methods: We analyzed anonymized prescription records from the national prescription database, dating from 1 January 2017 to 1 May 2024. The administrative point prevalence of NMOSD in Greece on 1 January 2022 was calculated according to the national census conducted in late 2021. Results: We identified 219 cases of NMOSD and a 1:6.8 male-to-female ratio. The point prevalence on 1 January 2022 was 1.97 per 100,000, with the highest detected in the region of Crete, and the lowest in the regions of Eastern Macedonia and Thrace. The mean age of people with NMOSD on that date was 51.3 years old. Azathioprine was the most frequently prescribed maintenance immunotherapy, while antidepressants were the most common concomitant medications prescribed. Polypharmacy was observed in 28.9% of the identified cases. Conclusions: We hereby present the prescription drug use of people with NMOSD in Greece in the era just before the introduction of NMOSD-specific immunotherapy in Greece. Full article

Background and Clinical Significance: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by acute or subacute bilateral central vision loss, typically in young males. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated demyelinating diseases that may present with optic neuritis and myelitis. Although distinct in etiology, recent evidence suggests that mitochondrial dysfunction and neuroinflammation can overlap, giving rise to combined phenotypes such as LHON-MS (also known as Harding’s disease). Case Presentation: We report a 42-year-old man who initially presented in 2018 with right-eye pain and severe visual loss diagnosed as idiopathic optic neuritis. Despite corticosteroid and plasma-exchange therapy, visual recovery was poor, and he was maintained on azathioprine. One year later, he developed visual flashes and left-eye visual loss with bilateral optic nerve thinning on OCT. Genetic testing revealed a pathogenic MT-ND4 (m.11778G>A) mutation, confirming LHON. In 2021, he presented with ascending lower-limb numbness and bladder urgency. MRI demonstrated a central thoracic cord lesion at T11, consistent with acute transverse myelitis, while serum AQP4 and MOG antibodies were negative. CSF showed five unique oligoclonal bands. The diagnosis of LHON-MS overlap was established, and he was treated with corticosteroids followed by rituximab with clinical stability thereafter. Conclusions: This case highlights the diagnostic challenges of LHON with atypical optic neuritis initially followed by the development of demyelinating disease. Red flags such as poor visual recovery, bilateral or sequential optic neuropathy, and steroid-refractory episodes should prompt genetic testing to rule out LHON. Recognition of the mitochondrial–immune overlap is essential for accurate diagnosis, counseling, and an appropriate therapeutic strategy. Full article

Background: Neuromyelitis optica spectrum disorder (NMOSD) causes severe optic nerve (ON) inflammation and vision loss. Current treatments remain limited, prompting exploration of new therapeutic strategies. This study evaluated the efficacy of ITRI-E-(S)4046 (ITRI-ES), a dual ROCK1/2 and MYLK4 kinase inhibitor, in a rat model of NMOSD optic neuritis. Methods: NMOSD-like optic neuritis was induced in rats by applying NMOSD patient serum-soaked sponges around the ON. Rats received intravitreal injections of either 0.2% ITRI-ES, phosphate-buffered saline (PBS), or intraperitoneal methylprednisolone (MP). Visual function was assessed using flash visual-evoked potentials (fVEP). Retinal ganglion cell (RGC) survival and apoptosis were quantified using FluoroGold retrograde labeling and TUNEL assay. ON inflammation and demyelination were evaluated via immunohistochemistry and Western blot analysis of aquaporin-4 (AQP4), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and inflammatory markers. Results: ITRI-ES significantly preserved visual function, restoring fVEP amplitudes (~36 μV vs. ~21 μV in PBS-treated, p < 0.05) and RGC density (~85% of normal vs. ~37% PBS). RGC apoptosis was reduced (~2.3-fold lower vs. PBS, p < 0.05). PBS-treated rats showed decreased AQP4 and MBP (2.5–2.8-fold vs. sham) and increased GFAP (2.8-fold). ITRI-ES maintained higher AQP4 (~3.5-fold) and MBP (~1.5-fold) levels, suppressed GFAP (~5.5-fold vs. PBS), reduced NF-κB, IL-1β, TNF-α, microglia activation, and macrophage infiltration, and increased anti-inflammatory Arg1 and CD206 markers (~3-fold vs. PBS). Conclusions: ITRI-ES alleviates optic nerve inflammation, preserves retinal integrity, and maintains visual function in NMOSD-associated optic neuritis, underscoring kinase inhibition as a promising therapeutic strategy. Full article

A 70-year-old Japanese woman with longstanding hearing loss and asthma developed floating sensations, left finger numbness, and postural instability one day after influenza vaccination, leading to hospital admission. Neurological examinations showed hearing loss, hyperreflexia, left-predominant ataxia, bilateral mild bathyanesthesia, and inability to tandem gait. Cerebrospinal fluid (CSF) analysis showed no pleocytosis or malignant cells, but revealed positive oligoclonal bands and elevated myelin basic protein. Despite no contrast agent use due to asthma, brain magnetic resonance imaging (MRI) revealed pontine hyperintensities on diffusion-weighted imaging (DWI) and T2-fluid attenuated inversion recovery (T2-FLAIR) sequences, along with hyperperfusion on arterial spin labeling (ASL) imaging. Serum anti-aquaporin-4 antibodies (AQP4-Ab) were negative by ELISA. Given the temporal proximity to vaccination and elevated demyelination markers, brainstem-type acute disseminated encephalomyelitis (ADEM) was initially suspected. Symptoms nearly resolved after two cycles of methylprednisolone pulse therapy. Notably, hyperperfusion gradually improved on ASL imaging. Post-discharge, a cell-based assay confirmed the diagnosis of neuromyelitis optica spectrum disorder (NMOSD) by detecting positive anti-AQP4-Ab. She has been relapse-free for about a year without any immunosuppressants or biologics. Although contrast-enhanced MRI remains the gold standard modality for lesion evaluation due to its high sensitivity, hyperperfusion on ASL may provide a useful alternative in patients for whom contrast agents are contraindicated, such as those with asthma or impaired renal function. Full article