ABSTRACT Background Beyond regulating sleep, the orexin/hypocretin system participates in bidirectional neuro‐immune interactions that may influence neurodegenerative diseases (NDs) and chronic inflammatory conditions. This systematic review aimed to conceptually synthesize evidence on these interactions and their clinical implications. Methods Following PRISMA 2020 guidelines, a comprehensive search was performed in PubMed, Embase, Web of Science, Scopus, and PsycINFO. Studies were included if they reported original empirical data (human, animal, or in vitro) examining orexin signaling in relation to cytokines, microglial activation, or neuroinflammation. Results Of 1248 records screened, 18 studies (three human, 13 animal, two in vitro/ex vivo) were included. Human studies, albeit limited, showed consistent suppression of the immune‐to‐orexin signaling: an 11‐fold increase in CD4 + T cells was observed specifically in the hypocretin region in NT1 brains; peripheral LPS reduced orexin neuron activity, and lower orexin‐A levels correlated with elevated pro‐inflammatory cytokines and worse cognitive/fatigue outcomes in epilepsy, depression, and Sjögren's syndrome. Conversely, preclinical studies showed that orexin‐to‐immune signaling demonstrated consistent anti‐inflammatory effects. Orexin‐A shifted microglia toward an anti‐inflammatory phenotype, inhibited key pathways (NF‐κB, ERK, NEK7/NLRP3), reduced cytokines (IL‐1β, IL‐6, TNF‐α), and attenuated astrogliosis across models of intracerebral hemorrhage, chronic hypoperfusion, sepsis‐associated encephalopathy, experimental autoimmune encephalomyelitis, and gut‐brain inflammation. Sex‐ and region‐specific effects were noted. Conclusion Inflammation generally suppresses orexin signaling, while orexin‐A signaling exerts predominantly anti‐inflammatory effects by modulating microglial phenotype and key inflammatory pathways. These bidirectional interactions highlight the orexin system as a potential bridge between sleep dysregulation and neuroinflammation. However, most evidence on orexin‐to‐immune signaling derives from preclinical models, and significant gaps remain in human mechanistic studies and clinical translation on immune‐to‐orexin signaling. Orexin receptor agonists warrant further investigation as candidate adjunctive therapies in neurodegenerative and chronic inflammatory conditions.
ABSTRACT Objective Performance‐based monitoring in multiple sclerosis (MS) is widely used, yet objective deterioration in routine regional practice is not well quantified. We aimed to estimate 24‐month trajectories of cognitive processing speed and ambulation and to quantify confirmed worsening in these performance measures. Methods We performed a retrospective, single‐center longitudinal study of 59 patients with repeated Symbol Digit Modalities Test (SDMT) and/or Timed 25‐Foot Walk (T25FW) assessments. Linear mixed‐effects models with random intercepts estimated marginal means at 0, 6, 12, 18, and 24 months, adjusting for prespecified covariates. T25FW was modeled on the log scale; unmeasurable T25FW was summarized separately. Confirmed performance worsening was defined as at least a 4‐point SDMT decline or at least a 20% T25FW increase from baseline, confirmed at a reassessment at least 6 months later. Inference was restricted to 0–24 months. Results Mean changes over 24 months were small, but observed paired changes varied widely. Confirmed performance worsening occurred in 7/59 patients (11.9%) for SDMT and 8/56 (14.3%) for T25FW (among those measurable at baseline). Unmeasurable T25FW was present in 3/59 (5.1%) at baseline and occurred during follow‐up in 2/56 (3.6%) of baseline‐measurable patients. Conclusion In routine regional MS care, approximately one in eight patients met criteria for confirmed worsening in SDMT or T25FW during the 24‐month observation period despite modest mean trends. Longitudinal monitoring should also capture transitions to unmeasurable walking status.
ABSTRACT Background Neuromyelitis optica spectrum disorder (NMOSD) is an immune‐mediated disorder of the central nervous system associated with autoantibodies against aquaporin‐4 (AQP4). This is distinct from myelin‐oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), defined by anti‐MOG antibodies. The coexistence of AQP4 and MOG antibodies is rare and remains incompletely understood. Case Presentation We present a rare case of a 53‐year‐old woman with dual AQP4 and MOG antibodies in serum and a clinical presentation of recurrent myelitis. She presented with four discrete episodes of bilateral lower limb sensory deficits and mild weakness. Cerebrospinal fluid analysis demonstrated lymphocytic pleocytosis without oligoclonal bands. An MRI spine demonstrated high T2 signal in the right anterior hemicord; MRI brain demonstrated nodular enhancement within the posterior horn and atrium of the right lateral ventricle. High‐titre anti‐AQP4 and anti‐MOG antibodies were detected in serum and remained positive on serial cell‐based assays. Despite maintenance intravenous immunoglobulin, she relapsed and was commenced on rituximab, achieving subsequent clinical stability. Conclusions Dual anti‐AQP4 and anti‐MOG seropositivity is rare and presents diagnostic and therapeutic challenges. This case highlights overlapping clinical features of NMOSD and MOGAD and the need for further research to guide classification and management.
ABSTRACT Background Hashimoto's encephalopathy (HE) is a rare steroid‐responsive autoimmune syndrome. Although HE is associated with anti‐thyroid antibodies, its concurrence with malignant thyroid tumors has rarely been described and its clinical implications remain poorly understood. Case Presentation A 54‐year‐old euthyroid woman presented with a 5‐month history of progressive cognitive decline and behavioral changes, leading to profound hypolalia and restlessness. Serum anti‐thyroglobulin and anti‐thyroid peroxidase antibodies were markedly elevated. Brain MRI, electroencephalography, and cerebrospinal fluid tests were unremarkable. Corticosteroid therapy resulted in rapid resolution of neuropsychiatric symptoms and cognitive dysfunction. Subsequent thyroid evaluation identified papillary thyroid carcinoma (PTC) on a background of chronic lymphocytic thyroiditis. The patient underwent total thyroidectomy and radioiodine therapy. At 1‐year follow‐up, she remained free of HE relapses and cancer recurrence, with a corresponding decline in anti‐thyroid antibody titers. Conclusions This is the first reported case of HE occurring concurrently with PTC. The findings raise the possibility that a shared autoimmune milieu may predispose to both HE and PTC. This case underscores the importance of comprehensive thyroid evaluation, including oncological screening, in patients with HE.
ABSTRACT Background IgG4‐related disease (IgG4‐RD) is a systemic, immune‐mediated, fibroinflammatory disorder with multiorgan involvement and variable clinical presentation, often creating diagnostic difficulty. Myasthenia gravis (MG) is an antibody‐mediated autoimmune disorder of the neuromuscular junction, most commonly associated with anti‐acetylcholine receptor (AChR) antibodies. Although both conditions involve immune dysregulation and affect the ocular region, their coexistence is extremely rare. We report a rare case of anti‐AChR antibody–positive MG overlapping with IgG4‐RD. Case Presentation A 66‐year‐old man developed bilateral diplopia, ptosis, and mild eyelid swelling over 3 months. Anti‐AChR antibodies were positive, and an edrophonium test improved ptosis. Single‐fiber electromyography showed abnormal jitter, leading to a diagnosis of ocular MG. Chest CT revealed an anterior mediastinal nodule, and thymectomy showed follicular hyperplasia. Despite pyridostigmine, tacrolimus, and surgery, the patient's ocular symptoms progressively worsened and he was admitted for re‐evaluation. Although serum IgG4 was within the normal range, imaging showed bilateral enlargement and enhancement of the lacrimal glands and extraocular muscles. Lacrimal gland biopsy showed dense lymphoplasmacytic infiltration, fibrosis, approximately 20 IgG4‐positive plasma cells per high‐power field, and an IgG4/IgG ratio > 40%. The patient fulfilled the 2019 ACR/EULAR classification criteria for IgG4‐RD. Intravenous methylprednisolone followed by oral prednisolone markedly improved eyelid swelling, although ocular movement limitation persisted at 6 months. Conclusions IgG4‐RD may closely mimic ocular MG and delay diagnosis, particularly in seronegative cases. Unexplained eyelid or lacrimal gland swelling in refractory MG should prompt consideration of IgG4‐RD and early histopathological evaluation.
ABSTRACT Myasthenia gravis (MG) is thought to be primarily caused by autoantibodies targeting proteins at the neuromuscular junction. It has been established that autoantibodies, primarily acetylcholine receptor (AChR) antibodies, act on the neuromuscular junction, impairing neuromuscular transmission or destroying the structure of the neuromuscular junction. However, cellular immunity also plays a significant role, activating various T‐cell subsets and stimulating B cells to produce antibodies, ultimately leading to disease onset. Immune responsiveness changes throughout life. The immune system develops and matures after birth, then declines with age. At each stage, mechanisms protect the body against pathogenic microorganism invasion. It can also lead to conditions where the immune response is insufficient, even against neoplasms formed within the body. This immune response fundamentally operates through the balance between effector T (Teff) cells and regulatory T (Treg) cells. Imbalances in this equilibrium can occur during the course of MG and various other pathologies. Treatment strategies and methods often achieve therapeutic effects by normalizing this balance. In this review, from the perspective of a pediatrician who has long treated patients with not only adult MG but also childhood MG, we would like to discuss the role Treg cells play in regulating this activation of cellular immunity.
ABSTRACT Background Some patients with myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) experience multiple relapses and poor prognoses; however, the factors associated with these outcomes are unclear. This study aimed to identify factors associated with relapse and neurological prognosis in patients with MOGAD. Methods We retrospectively analyzed clinical data from a nationwide epidemiological survey of MOGAD conducted in Japan in 2021 to examine the associations of clinical characteristics with relapse and neurological prognosis. Prognosis was assessed using the Expanded Disability Status Scale (EDSS), comparing patients with EDSS scores ≤ 2 (good prognosis) to those with EDSS scores ≥ 4.5 (poor prognosis). In the multivariate analyses, clinical characteristics, phenotypes, cerebrospinal fluid data, acute‐phase treatments at disease onset, and maintenance treatments were analyzed. Outcomes were also compared between patients with oligoclonal IgG bands (OCB) positivity and negativity. Results Of the 679 patients with relapse information, 371 (54.6%) experienced relapse, whereas 308 (45.4%) did not. In the multivariate analysis, OCB positivity was associated with relapse, whereas plasma exchange (PE) administration at disease onset was associated with a monophasic course. Of the 637 patients with EDSS scores, 541 (84.9%) had a good prognosis, whereas 46 (7.2%) had a poor prognosis. In the multivariate analysis, PE administration at disease onset was associated with poor prognosis. The number of patients experiencing relapse was higher among those with OCB positivity, although no differences were observed in the median interval from onset to the first relapse. Conclusion In MOGAD, OCB positivity may predict relapse, and adequate acute‐phase treatment may reduce relapse risk.
ABSTRACT Multiple sclerosis (MS) was long considered rare in Japan until the 1950s, but epidemiological evidence has since accumulated. This review outlines the development of MS epidemiology in Japan and summarizes nationwide and regional trends in prevalence, clinical and laboratory features, genetic and environmental risk factors, and disease burden. Across five nationwide surveys (1972–2018), the estimated number of patients and crude prevalence have increased substantially, although prevalence remains lower than that in Western countries. Distinct features have been reported in Japanese MS, including relatively mild disability and a low oligoclonal IgG band positivity rate. Although many genetic and environmental risk factors are shared with MS in Western countries, HLA‐DRB1*04:05 , which is most frequent in Japanese patients with MS but rare in Western populations, may partly explain phenotypic differences in a subset of patients. Nationwide surveys and analyses of health insurance claims databases suggest improving disease severity and declining hospitalization rates in recent years, likely reflecting broader availability and increased use of disease‐modifying drugs. Despite mild disability and improving disease severity, the burden of MS remains substantial, with cognitive impairment, reduced quality of life, work productivity loss, and increasing healthcare costs. Further understanding of population‐specific factors and features is needed to translate epidemiologic insights into better symptom control and outcomes. Prospective longitudinal cohort studies that enroll a larger number of patients and distinguish MS, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody‐associated disease are warranted.
ABSTRACT Objectives To evaluate longitudinal changes in cognition, depression, and health‐related quality of life (HRQOL) over a 2‐year follow‐up in Japanese individuals with multiple sclerosis (MS), and also investigate whether cognition, depression, or HRQOL was associated with subsequent changes in Expanded Disability Status Scale (EDSS) scores. Methods The Brief International Cognitive Assessment for MS (BICAMS), Beck Depression Inventory‐Second Edition (BDI‐II), and Functional Assessment of MS (FAMS) were used to assess cognition, depression, and HRQOL, respectively, in 127 Japanese adults with MS (92 women, 35 men; mean age, 41.2 ± 10.7 years). A cross‐lagged panel model analysis was used to examine longitudinal associations between each factor and EDSS scores. Results BICAMS scores at the 2‐year follow‐up were significantly higher than those at baseline. The increase in BICAMS scores from baseline to 2 years was greater in participants with baseline EDSS scores ≤ 3.0 than in those with scores ≥ 3.5. The cross‐lagged panel model analysis showed that lower baseline scores on each of the three BICAMS tests were associated with higher EDSS scores 2 years later. Lower baseline FAMS scores, particularly for mobility and emotional well‐being, also showed time‐lagged associations with higher EDSS scores at the 2‐year follow‐up after accounting for autoregressive paths. Conclusion In Japanese individuals with MS, poorer baseline cognitive performance and some HRQOL measures were associated with worse EDSS outcomes at 2 years.
ABSTRACT Background Tumor necrosis factor‐α (TNF‐α) inhibitors are widely used to treat autoimmune diseases, but accumulating evidence has linked TNF‐α inhibitor therapy to inflammatory central nervous system (CNS) disorders. While an association with demyelinating disease has been established, the relationship between TNF‐α inhibitors and autoimmune cerebellar ataxia (ACA) or autoimmune encephalitis remains poorly defined. Case Presentation We report a 55‐year‐old woman with rheumatoid arthritis who developed progressive gait ataxia and dysarthria 1 month after starting golimumab, a TNF‐α inhibitor. Cerebrospinal fluid analysis showed an elevated IgG index (1.44) with normal cell count, cytokine levels, and negative oligoclonal bands. Brain magnetic resonance imaging (MRI) revealed mild cerebellar atrophy, and single‐photon emission computed tomography demonstrated cerebellar hypoperfusion. A tissue‐based immunofluorescence assay using rat brain sections showed the patient's Cerebrospinal fluid (CSF) IgG binding to the neuropil of the cerebellar molecular layer, suggesting cell‐surface anti‐neuronal antibodies. Intravenous methylprednisolone pulse therapy and discontinuation of golimumab led to clinical improvement, partial normalization of cerebellar perfusion, and a decrease in IgG index. Conclusion This case suggests that TNF‐α inhibitor therapy may trigger ACA through the production of anti‐neuronal antibodies. Clinicians should consider drug‐induced autoimmunity when new‐onset cerebellar ataxia develops during TNF‐α inhibitor treatment and promptly initiate immunologic evaluation and treatment.
ABSTRACT Background Satralizumab is used for the treatment of neuromyelitis optica spectrum disorder (NMOSD). However, there are currently no standardized guidelines regarding the method or speed of steroid tapering after its introduction. In 2023, we proposed a method to commence tapering prednisolone at a rate of 1 mg every 4 weeks, starting 8 weeks after satralizumab introduction (following four subcutaneous administrations of 120 mg each). Here we report the clinical courses of four patients with aquaporin‐4 antibody (AQP4)‐positive NMOSD who discontinued steroids following a similar tapering method, advocating for the utility of this approach. Case Presentation Case 1 (67‐year‐old female) and Case 2 (66‐year‐old female) exhibited optic nerve and spinal cord lesions. Case 3 (43‐year‐old female) involved lesions extending from the medulla to the spinal cord, whereas Case 4 (68‐year‐old female) exhibited only optic neuritis. All patients were diagnosed with AQP4‐antibody‐positive NMOSD based on the 2015 International Diagnostic Criteria. The initial prednisolone doses before reduction in Cases 1–4 were 25, 25, 10, and 7 mg/day, respectively. The durations from steroid discontinuation to September 11, 2025, for Cases 1–4 were 248, 1178, 1120, and 838 days, respectively, with no relapses observed to date. Conclusions Initiating prednisolone tapering at a rate of 1 mg every 4 weeks starting 8 weeks after satralizumab introduction appears to be an effective and safe approach.
Cognitive impairment is a common symptom of multiple sclerosis (MS) and has a substantial impact on quality of life (QoL). In Japan, cognitive assessment has traditionally lagged behind that in Western countries. With the emerging concept of smoldering‐associated worsening, the importance of longitudinal cognitive monitoring is becoming increasingly recognized. In this review, we aimed to systematically integrate existing evidence on cognitive function, neuroimaging features, clinical symptoms, and QoL in Japanese patients with MS to support improved clinical management. A literature review was conducted using PubMed and the Clinical and Experimental Neuroimmunology database, focusing on studies evaluating cognition and QoL in Japanese patients with MS. Validation studies have confirmed the applicability of Western batteries (Brief Repeatable Battery of Neuropsychological Tests and Brief International Cognitive Assessment for Multiple Sclerosis) to Japanese patients; however, copyright restrictions limit their widespread use. The iPad‐based Symbol Digit Modalities Test has been validated using Japanese‐specific normative data, revealing significant differences from US norms. Neuroimaging studies in Japan have demonstrated that cognitive decline correlates with cortical lesions, gray matter atrophy, and regional volume loss. Cognitive dysfunction is also associated with olfactory impairment, driving performance, and Theory of Mind. Notably, cognitive processing speed is a significant predictor of health‐related QoL and employment status, independent of physical disability. Objective cognitive assessment is feasible and essential in Japanese clinical practice. Integrating validated digital tools with an improved understanding of the links between cognition, brain pathology, and daily functioning may improve the management of patients with MS in Japan.
Although a locally published paper clinically characterized Guillain Barre syndrome (GBS) patients admitted in one of the Philippines' largest hospitals, extensive identification of risk factors associated with poor outcomes has yet to be done. The main objective of this study is to determine the possible association between several outcome measures and GBS risk factors using different regression analytic methods of secondary data. Data from 71 GBS patients from our previous study about possible determinants related to dysautonomia were analyzed. To determine the possible factors associated with binary outcomes like status on discharge, ambulation at 1 month, and presence or absence of pneumonia during admission, multiple logistic regression analysis was used while factors associated with continuous outcome like onset of motor recovery, multiple linear regression analysis was utilized. For failure outcomes with survival times, including days to dysautonomia or intubation, a cox proportional hazard model or its variants were utilized. Using dysautonomia as the main independent variable, and age and presence of pneumonia prior to GBS diagnosis as the possible confounders, no association between dysautonomia and different outcome parameters was noted whether unadjusted or adjusted odds ratio (OR) was used. Compared to other GBS variants, the odds of being bed or wheelchair bound on discharge was 10 times (95% CI: 1.7–57.7, p = 0.01) when a patient has the axonal variant of GBS. Moreover, the same cohort was 20 times (95% CI: 3.2–125.0, p < 0.01) more likely to be nonambulatory in 1 month when compared to other GBS variants. In terms of types of treatment, no association between the type of treatment and different outcome variables was noted whether uncontrolled or factors such as sex, days until admission, expanded disability status scale (EDSS) at admission, initial GBS-DS, presence of pneumonia, proportion of patients with Brighton diagnostic level 1, and GBS type were controlled. In the Philippines, the type of GBS is found to be associated with poor prognosis. Nevertheless, when possible confounders were controlled, the type of GBS, dysautonomia, and type of treatment were noted not to affect the outcomes. The insufficient power of the study may explain the negative results of the commonly associated factors of poor prognosis.
Cognitive impairment affects up to two-thirds of patients with multiple sclerosis (MS); however, profound global deficits, defined as a full-scale IQ below 70, are uncommon and rarely constitute the primary symptom. We describe a 27-year-old woman with severe multidomain cognitive impairment due to MS. Neuropsychological testing showed marked slowing of processing speed and perceptual reasoning, while verbal abilities remained relatively preserved. Although such profound dysfunction is atypical, the cognitive profile remained typical of MS: prominent deficits in processing speed and perceptual reasoning with sparing of verbal abilities. This case suggests that atypical MS with unrecognized cognitive dysfunction presents a diagnostic challenge.
