Although immune checkpoint inhibitor (ICI) has provided a revolutionary treatment option for many types of cancers, it can induce immune–mediated adverse events (irAEs) due to excessive autoimmune responses. ICI–induced myasthenia gravis (MG), myositis, and myocarditis can also occur concurrently as an overlap syndrome, which is called Triple M syndrome, and known as rare but one of the most severe and life–threatening irAEs. Thymoma can also be associated triple M syndrome, and ICI–induced and thymoma–associated Triple M syndrome may share a common immunopathogenesis. Some patients with Triple M syndrome are refractory to a comprehensive treatment including corticosteroids, intravenous immunoglobulin, plasmapheresis. When the conventional immunotherapies are insufficient to control severe irAE, biologics represent potential therapeutic options. However, the molecular targeted therapies haven't been established. The establishment of treatment based on the molecular mechanism is highly desirable.

Multiple sclerosis (MS) is increasingly recognized not merely as a disorder of acute inflammation but as a condition driven by underlying neurodegeneration and chronic inflammation, known as progression independent of relapse activity (PIRA). PIRA occurs from the early stages of the disease and is a major driver of long–term disability. This review discusses the evolving therapeutic landscape and diagnostic criteria in the context of these pathophysiological insights.

While current disease–modifying therapies (DMTs) primarily target acute inflammation, real–world evidence and clinical trials demonstrate that the early introduction of high–efficacy DMTs (HE–DMTs), such as anti–CD20 monoclonal antibodies, is superior to escalation therapy. Early intensive treatment significantly delays the conversion to secondary progressive MS and suppresses PIRA more effectively than traditional approaches. Furthermore, emerging Bruton's tyrosine kinase (BTK) inhibitors show promise in targeting the innate immune mechanisms associated with smoldering inflammation.

Reflecting accumulating evidence supporting the superiority of early induction therapy, the 2024 revisions to the McDonald diagnostic criteria aim to facilitate earlier diagnosis. Key updates include the incorporation of radiologically isolated syndrome (RIS) into the diagnostic framework, the addition of the optic nerve as a site for dissemination in space, and the utilization of novel biomarkers such as kappa free light chains, the central vein sign, and paramagnetic rim lesions to increase specificity and sensitivity. Ultimately, while early intervention with HE–DMTs is essential to mitigate disability accumulation, developing therapies that effectively target the neurodegenerative component of MS remains a critical unmet need.

Myasthenia gravis (MG) is an autoimmune disease in which neuromuscular transmission is impaired by the action of autoantibodies against target antigens on the postsynaptic membrane. The clinical subtypes of adult–onset MG are broadly divided into ocular and generalized types, Treatment strategies differ between ocular (oMG) and generalized MG (gMG). The Japanese clinical guidelines recommend setting treatment strategies to achieve “MM-5mg” as an earlier, more achievable treatment goal that prioritizes patient quality of life. In gMG, early fast–acting treatment strategy recommended to improve MG symptoms as soon as possible and minimize the use of oral steroids. Furthermore, the administration of molecular target drugs centered on monoclonal antibody agents is considered in cases where current immunotherapy combinations fail to achieve treatment goals. This article focuses on the latest molecular target drugs including anti–complement drugs and neonatal Fc receptor (FcRn) inhibitors for gMG. Regarding anti–complement drugs, while issues remain a fatal adverse event and insufficient investigation into the proportion of non–responders, these agents hold the potential to be highly effective even for the most severe gMG cases. The anti–FcRn inhibitors, which are covered by insurance for MuSK antibody–positive MG and double seronegative MG in Japan, are easy to monitor due to their low incidence of serious adverse events. The introduction of subcutaneous formulations has reduced treatment time in outpatient settings and enabled home self–injection. In clinical practice, molecular target drugs are being introduced for gMG cases where patients wish to minimize impact on lifestyle factors such as employment, or to reduce oral steroids that had previously been difficult to sufficiently taper. There may be a tendency for the introduction of molecular target drugs to be accelerated because of healthcare constraints like immunoglobulin shortages and difficulties in performing plasma exchange.

Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN) are representative immune–mediated neuropathies in which both humoral and cellular immunity contribute to peripheral nerve injury. Although intravenous immunoglobulin (IVIg) and plasma exchange (PE) remain the established standard therapies for GBS, novel disease–specific treatments such as complement inhibitors are now being developed. In CIDP, the identification of antibodies against paranodal proteins―neurofascin 155, contactin 1, and Caspr1―has led to the recognition of autoimmune nodopathy (AN) as a distinct entity with unique clinical and therapeutic profiles. The approval of the FcRn inhibitor efgartigimod for CIDP marks a paradigm shift toward targeted molecular therapy. In MMN, complement–mediated pathology triggered by anti–GM1 IgM antibodies underlies selective motor conduction block, and IVIg remains the only established treatment, though complement inhibitors are under clinical investigation.

Recent progress in understanding disease mechanisms has clarified the roles of antibody–mediated complement activation, FcRn–dependent IgG recycling, and B–cell immunity in these disorders. For CIDP and AN, B–cell–depleting therapy with rituximab has shown benefit, particularly in IgG4 antibody–positive subtypes, while phase 3 trials of FcRn and complement inhibitors are expanding treatment options. Moreover, advanced immunomodulatory strategies such as autologous hematopoietic stem cell transplantation and CD19–directed CAR–T cell therapy are being explored for refractory cases.

Collectively, these advances highlight a transition in the management of inflammatory neuropathies―from nonspecific immunosuppression to precise, pathophysiology–based interventions. Future research should focus on biomarker–driven stratification and individualized treatment approaches to achieve durable remission and functional recovery.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease of the central nervous system characterized by the presence of anti–aquaporin 4 (AQP4) antibodies targeting astrocytes. Recurrent attacks often lead to irreversible disability, making relapse prevention a central goal of treatment. Traditionally, glucocorticoid and oral immunosuppressants have been used, yet they are limited by insufficient efficacy and possible cumulative toxicity. In recent years, advances in understanding NMOSD pathophysiology have led to the development of biologics targeting key immune pathways. Complement C5 inhibitors (eculizumab, ravulizumab) effectively block antibody–mediated complement activation, demonstrating near–complete prevention of relapses. B–cell–depleting agents (rituximab, inebilizumab) suppress multiple pathogenic aspects of B cells, such as antibody production, antigen presentation, and proinflammatory cytokine release, substantially reducing relapse risk. Interleukin–6 receptor blockade with satralizumab inhibits broad spectrum of pathology including plasmablast survival, Th17 cell differentiation, and blood–brain barrier disruption, achieving significant relapse reduction with the advantage of subcutaneous self–administration. Each agent carries unique safety considerations : severe meningococcal infection requiring emergency medical care with complement inhibitors, hypogammaglobulinemia and possible long–term increase in serious infection rate with B–cell depletion, and risk of masking severe infections due to suppressed fever with IL–6 receptor blockade. The choice of therapy requires individualized assessment of disease severity, comorbidities, infection risk, and patient lifestyle. Biologics now allow clinicians to realistically aim for “zero relapses,” but challenges remain, including identification of predictive biomarkers, long–term safety, and cost–effectiveness. Future registry studies and real–world evidence will be essential to optimize treatment strategies.

Human T–cell leukemia virus–1 (HTLV–1)–associated myelopathy (HAM) is chronic progressive myelopathy induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord, caused under the status of high HTLV–1 proviral load in the peripheral blood. The main neurological symptoms, which is motor dysfunction of the lower extremities by spastic paraparesis with urinary disturbance, are progressive and lead to a deterioration in the quality of life (QOL) of patients once the myelopathy develops. Therefore, novel and safe therapeutic regimens are needed for HAM patients to be able to commence the treatments as soon as possible after the development. Although the ideal treatment against HAM is the elimination of HTLV–I–infected cells from the peripheral blood, various treatments were performed for HAM patients until now. Indeed, these treatments have produced some good results. However, there are still many of problems, such as insufficient effects, side effects. In addition, most of these treatments are the open trial in the short term, and it is unclear whether or not these treatments are available in the long–term treatment. Therefore, an ideal therapeutic strategy against HAM is still not established yet. We now need the therapeutic regimens to safely available in long–term course or lifelong course of treatment. Considering the treatment against HAM, its strategies are composed of three parts such as the treatment focusing to, 1) anti–viral effects, 2) anti–inflammatory effects by immunomodulation, and 3) symptomatic treatments for both spastic paraparesis and neurogenic bladder. In this review, we will discuss about the therapeutic strategies by the representative regimens against HAM up to now with introducing the recent reports about the efficacy of new regimens. In addition, we will introduce new regimens having the potential as the candidate of new therapeutic strategies.

Idiopathic inflammatory myopathies are a group of muscle diseases in which muscle fibers are damaged by immunological mechanisms. Advances in muscle pathology and the discovery of numerous myositis–specific autoantibodies have led to their classification into many distinct clinical subtypes : polymyositis, dermatomyositis, immune–mediated necrotizing myopathy, anti–synthetase syndrome, inclusion body myositis. Treatment strategies require careful assessment of muscle strength, systemic inflammatory findings, muscle pathology, muscle imaging, and complications. Glucocorticoids are administered as first–line therapy, while immunosuppressants and intravenous immunoglobulin play a crucial role as second–line treatments. Furthermore, numerous molecularly targeted drugs are currently under development. Presently, treatment strategies for refractory cases remain unestablished, necessitating further development of therapeutic approaches.

Since 2007, a variety of neuronal surface (NS) antibodies have been identified, and a new category of disease named “autoimmune encephalitis (AE)” is established. AE is now defined as a form of encephalitis that occurs as a result of a brain–specific immune response, and usually associates with antibodies against cell surface antigen (Dalmau and Graus definition 2022). It doesn't encompass all of the immune– or neuroinflammation–mediated diseases of the central nervous system (CNS). Multiple sclerosis, neuromyelitis optica spectrum disorder, CNS lupus, neuro–Behçet's disease, or cryptogenic new–onset refractory status epilepticus (C–NORSE) is not, but encephalitis with myelin oligodendrocyte glycoprotein antibodies can be included in AE. AE develops with or without a cancer association, but paraneoplastic neurologic syndromes (PNS) with classical paraneoplastic antibodies against intracellular onconeuronal antigens are considered separately from those with NS antibodies because of different mechanisms.

In 2016, a clinical approach to diagnosis of AE was proposed to start prompt immunotherapy at 3 levels of evidence for AE (possible, probable, and definite) along with a new algorithm for the diagnosis of AE. Diagnostic criteria for PNS was also updated in 2021. However, we should always be aware of a potential risk of misdiagnosis and overtreatment due to misinterpretation of the clinical and laboratory test results. Physicians may also face difficulties in making a diagnosis of C–NORSE in an emergency situation because comprehensive antibody test may not be easily accessible. Therefore, we developed clinically–based C–NORSE score to help physicians to make a diagnosis of C–NORSE and initiate appropriate immunotherapy at the early stage.

In this article, we discuss how to make the diagnosis and treat patients with suspected AE, and briefly review currently developing treatments including ongoing randomized controlled clinical trials (inebilizumab [anti–CD19], rozanolixizumab [FcRn inhibitor], satralizumab [IL–6R inhibitor], and bortezomib [proteasome inhibitor]), GluN1/GluN2 subunit–Fc–fusion construct that neutralizes NMDA receptor antibodies, chimeric antigen receptor T–cell therapy, and monovalent antibody (ART5803) blocking therapy.

【目的】腰椎穿刺後頭痛（post lumbar puncture headache：PLPH）は診断的腰椎穿刺（diagnostic lumbar puncture：dLP）の重要な合併症である．従来型穿刺針（Quincke型）でなく非外傷性針（Sprotte型）を用いるとPLPHの発症率を下げるとされるが，使用頻度は極めて少ない．非外傷性針を用いたdLPの有用性と課題を検討する．

【方法】2016年以降のdLP（連続87例）を後方視的に検討し，患者背景・PLPHの頻度と期間・処置について，針の種類により群分けし，比較検討した．

【結果】非外傷性針でのdLPは21回，従来型穿刺針でのdLPは31回であった．年齢・性別・BMI・基礎疾患には差がなかった．PLPHは非外傷性針群で0回，従来型穿刺針群で7回（22.6%）と非外傷性針群で有意に少なかった（p＜0.03）．従来型穿刺針群の6例で補液を要し，平均期間は5.5日だった．非外傷性針群での穿刺困難例は高齢で腰椎病変が強い例・皮膚抵抗が強く貫けない例の2通りがあったが，後者は穿刺時の工夫で回避可能だった．

【結語】非外傷性針を用いたdLPはPLPHを減らすための有用な選択肢と考えられた．

当院は神経難病医療の提供を政策医療の1つに掲げているが，周囲に神経難病患者のリハビリテーション入院を行う施設がないため，急性期病院である当院がParkinson病（Parkinson disease：PD）や脊髄小脳変性症（spinocerebellar degeneration：SCD）の患者に対するリハビリテーション入院を行ってきた．自力歩行が可能なPD患者81例とSCD患者25例を対象とし，平日に理学療法，作業療法を各40分間行い，一部の患者には言語聴覚療法を追加した．PD患者には週1回の音楽療法を行い，SCD患者25例中20例にはprotirelinの点滴も併用した．入院時と退院時に，PD患者ではUPDRSや歩容を評価し，SCD患者ではSARAとICARSでバランス機能を評価した．退院時の評価項目は両疾患とも有意に改善し有効性が示された．急性期病院ではリハビリテーションスタッフが少なく，機能維持に必要な定期的リハビリテーション入院が難しい点が課題であったが，障害者病棟の設立により問題点が解消されたので併せて報告する．

Hybrid Assistive Limb医療用下肢タイプ（HAL）による歩行運動療法を長期的に継続した球脊髄性筋萎縮症（spinal and bulbar muscular atrophy：SBMA）の長期的な効果について検討した．症例は40歳代男性．HALによる歩行運動療法を集中的に20分/日×5日間実施し，歩行機能が改善した．その後，20分/日×1回/月の低頻度に介入頻度を下げると歩行機能が緩徐に低下したため，再び20分/日×5日間の集中的なHALによる歩行運動療法を実施したところ再び歩行機能が改善した．その後も，集中的なHALによる歩行運動療法を継続した結果，長期的に歩行機能の維持に寄与する可能性が示唆された．

Parkinson病（Parkinson disease：PD）の視覚誘発すくみ現象は，部屋を歩いて狭いドアにさしかかった途端，突然，ときに心の不安焦燥を伴い，足が床に張り付いたように感じスムーズに歩行ができなくなる状態（すくみ）を言う．運動障害は，視覚と情動の影響を受けることが想定されているものの，その機序は十分に明らかにされていない．一方，精神科領域で，視覚誘発すくみ現象に関わる病態として，閉所恐怖が注目され，研究が進められている．PDの視覚誘発すくみ現象の病態機序は十分に明らかでないが，PD患者にとって困る症状であることから，積極的なケアが必要と思われる．