Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and T cell-mediated autoimmune processes are assumed to be involved in its pathogenesis. Recently, accumulating evidence has indicated that commensal bacteria interact with the host immune system and that the alteration of commensal bacteria composition, termed dysbiosis, is associated with various autoimmune diseases including CNS autoimmune diseases. The effect of gut microbiota on disease has been initially shown in experimental autoimmune encephalomyelitis (EAE), animal model of MS. Recent analysis of microbiota revealed dysbiosis in patients with MS including the reduction of short chain fatty acid (SCFA). Administration of SCFA ameliorates disease severity of EAE in association with the induction of regulatory T cells. Moreover metabolites of microbiota such as SCFA and tryptophan have been shown to influence glial functions in CNS. In this review, we introduce recent findings regarding the interaction between gut microbiota and MS both in EAE and MS.
Recent progress in genetic analysis can provide a precision diagnosis for many hereditary neuromuscular diseases in daily practice. Moreover, disease-modifying therapies such as nucleic acid medicine for patients with several neuromuscular diseases (i.e., hereditary ATTR amyloidosis, spinal muscular atrophy, and Duchenne muscular dystrophy) have been approved in Japan. For all neurologists, knowledge and practical skills of genetic counseling, especially predictive testing, will increase in importance. To promote personalized medicine for patients with neuromuscular diseases and their families, it is necessary to develop of genetic counseling systems, including nurturing genetic professionals.
Vaccines are important in managing the COVID-19 pandemic caused by SARS-CoV-2. Despite the very low incidence, severe cases of thrombosis with thrombocytopenia after COVID-19 vaccination termed as Thrombosis with Thrombocytopenia Syndrome (TTS) have been reported. TTS clinically resembles autoimmune heparin-induced thrombocytopenia. TTS can cause disability and even death. It usually presents 4-28 days after vaccination characterized by thrombocytopenia and progressive thrombosis, often causing cerebral vein/venous thrombosis (CVT) and splanchnic venous thrombosis. We should avoid all forms of heparin and platelet transfusion. While awaiting further information on the pathophysiological mechanism and treatment of TTS, clinicians should be aware of TTS with CVT in patients receiving COVID-19 vaccinations. This new syndrome of TTS is an active area of investigation globally. Here, we review the available literature.
We conducted nationwide questionnaire surveys of medical genetics for patients with myotonic dystrophy type 1 to certified medical geneticists. Explanations about the patient's problems were influenced by geneticist’s specialties and central nervous system disorders. Many geneticists answered that male patients are also eligible for prenatal/preimplantation genetic diagnosis, and they perform prenatal genetic diagnosis for men if asked. About 40% of respondents answered that criteria for preimplantation genetic diagnosis should be relaxed. Thus, we investigated the implementation status of prenatal/preimplantation genetic diagnosis at the participating facilities of the national liaison council for clinical sections of medical genetics. No facility had an experience of prenatal/preimplantation genetic diagnosis for male patients. Still, one facility was applying for preimplantation genetic diagnosis. The social consensus of reproductive medicine is influenced by technological progress and historical background. It is essential to eliminate the eugenic’s idea and form a social consensus through sufficient discussions with participants from many areas, including the patients and their families.
A 74-year-old woman with a history of asthma and allergic rhinitis rapidly developed multiple mononeuropathy. Although anti-neutrophil cytoplasmic antibodies were negative, the presence of eosinophilia and eosinophilic infiltrations in the sural nerve led to a diagnosis of eosinophilic granulomatosis with polyangiitis. A motor nerve conduction study on admission revealed conduction block, which promptly disappeared after initiating immunotherapy without findings suggestive for remyelination or axonal degeneration. This electrophysiological change distinct from that of Wallerian degeneration. A biopsy of the sural nerve showed many eosinophil infiltrations and degranulation of eosinophilic cationic protein within nerve fascicles, whereas findings of necrotizing vasculitis were absent. These findings suggest that a direct effect of eosinophilic cationic protein, rather than ischemic damage due to vasculitis, was the main mechanism of transient nerve conduction failure in this patient.
A 71-year-old man was hospitalized because of low back pain and weakness in both lower limbs. He presented with fever and stiff neck, and his cerebrospinal fluid sample contained blood. MRI revealed intramedullary and epidural hemorrhages in the spinal cord. Microhemorrhages occurred frequently in the central nervous system over a short period. A brain biopsy was performed. The diagnosis was primary lymphomatoid granulomatosis (LYG) of the central nervous system (grade 2). As a result of lymphocytic infiltration to the vascular walls in LYG, hemorrhages occurred in multiple sites in the central nervous system. The biopsy of samples from the sites of microhemorrhages proved useful for diagnosis even in the absence of mass lesions.
A 57-years-old man with a history of bronchial asthma and pansinusitis developed acute progressive muscle weakness and sensory disturbance of the distal limbs after upper respiratory infection. On day 15 after onset of sensory disturbance and muscle weakness, the patient admitted to our hospital. A neurological examination revealed asymmetry weakness of both proximal and distal muscles, “glove and stocking type” hypoesthesia, and paresthesia without obvious pain. Blood tests and a nerve conduction study demonstrated eosinophilia and elevation of MPO-ANCA, axonal multiple mononeuropathy, respectively. The cerebrospinal fluid was normal. Eosinophilic granulomatosis with polyangiitis (EGPA) or Guillain-Barré syndrome (GBS) were suspected. So intravenous immunoglobulin therapy (IVIg) and high dose methylprednisolone pulse therapy (HDMP) followed by oral prednisolone were started. However, neurological symptoms did not improve. Sural nerve biopsy on day 31 revealed varying myelinating fiber loss at every nerve bundle and perivascular lymphocytic infiltration. The results did not fulfill the pathologic criteria for EGPA, but supported the changes of vasculitis. Cyclophosphamide (CPA) pulse therapy was administered for the additional therapy. Neurological symptoms did not improve and worsened again after decreasing oral prednisolone; therefore, combined therapy with IVIg, HDMP, and CPA was administered. Neurological symptoms then diminished gradually and the MPO-ANCA level and number of eosinophils normalized. This case suggests the importance of early nerve biopsy to obtain pathological findings supportive of EGPA diagnosis to allow introduction of aggressive immunosuppressive therapy such as CPA in a case with acute progressive motor-sensory neuropathy due to EGPA mimicking GBS.
A 78-year-old man was treated with ipilimumab and nivolumab for advanced renal cell carcinoma with liver and lymph node metastasis. He developed diplopia, ptosis, dysphagia, and weakness of the limbs and neck, 1 month after treatment. Serum creatine kinase (CK) levels were elevated, and neck MRI revealed inflammation of the deep trunk muscles. Although anti-acetylcholine receptor antibody was negative, the edrophonium test was positive. Anti-striational antibodies such as the anti-titin and the anti-muscular voltage-gated potassium channel (Kv 1.4) antibodies (which serve as biomarkers of immune checkpoint inhibitors associated with myasthenia gravis and myositis) were positive (anti-titin antibody titer 11.51, normal <1 index; anti-Kv 1.4 antibody titer 15.13, normal <1 index). Intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days), plasmapheresis, and oral prednisolone (PSL) (20 mg/day) administration improved the patient’s neurological function and normalized the serum CK levels. The PSL dosage was tapered without any worsening of clinical signs. The antibody titers decreased but remained positive (anti-titin antibody 5.00, anti-Kv 1.4 antibody 3.83) one year after the initial evaluation. Therefore, low-dose PSL (5 mg/day) administration was continued, and the patient was in remission.
A 62-year-old woman suffering from pulmonary Mycobacterium avium complex (MAC) disease was admitted to our hospital with fever, visual impairment, and lower limb weakness. MRI detected lesions in the optic chiasm and spinal cord extending the length of 6 vertebrae. The anti-aquaporin 4 (AQP4) antibody titer determined by ELISA was elevated to 8.3 IU/l. On the basis of these findings, the patient was diagnosed as having neuromyelitis optica (NMO), when chest CT also demonstrated exacerbation of pulmonary lesions. Methylprednisolone pulse therapy and double-filtered plasma exchange ameliorated the symptoms, and the EDSS score improved from 8.5 to 6.5. Six months later, visual impairment recurred, although ELISA showed that the anti-AQP4 antibody titer had become undetectable. Also, the CSF interleukin-6 (IL-6) level was elevated to 34.8 pg/ml. There have been few reports of NMO associated with pulmonary MAC disease. An increase of IL-6 is considered to exacerbate the clinical picture of NMO, whereas it may suppress progression of the pulmonary MAC disease. Exacerbation of the pulmonary MAC disease and the following internal counteraction with IL-6 may have resulted in a NMO relapse. The present patient was therefore administered eculizumab but not satralizumab, a humanized anti-IL-6 receptor antibody, for prevention of NMO recurrence.
A 69-year-old man was admitted for persistent fever, arthralgia, and visual impairment. Physical examination demonstrated bilateral uveitis and recurrent aphthous stomatitis. The PCR analysis of the aqueous humor of the anterior chamber was positive for the Varicella-zoster virus (VZV). Although no neurological defect was evident, the cerebrospinal fluid contained elevated monocytes but was negative for VZV-PCR. Brain MRI revealed Gd-enhanced lesions in the subcortical white matter, basal ganglia, and cerebellum. With his positive HLAB51, he was diagnosed with neuro-Behcet’s disease (NBD) and was successfully treated with high-dose prednisolone. Although the pathogenesis of Behcet’s disease is still unknown, the involvement of viral infection is reported. The present case implies that NBD could be triggered by herpes zoster virus associate-uveitis; the accumulation of such cases would help clarify the pathogenesis of Behcet’s disease.