The Japanese Society of Neurological Therapeutics is pleased to announce the launch of an electronic version of the Society's journal. Beginning in 2016, the Society's journal will be open access and all manuscripts will be accessible in both PDF and HTML (XML) format on J–STAGE (Japan Science and Technology Information Aggregator, Electronic). Each manuscript will have a unique digital object identifier (doi) that provides a permanent link to the manuscript and facilitates citation by researchers anywhere in the world. Members of the Japanese Society of Neurological Therapeutics will receive regular emails that include the table of contents of new issues as well as other important information about the journal.
Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Over time, many different types of autoimmune encephalopathy have been discovered. In such clinical situations, we often recognize that patients with autoimmune encephalopathy are often misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. We clinically analyzed 63 patients (14 males and 49 females; age range, 15–79 years) diagnosed with autoimmune encephalopathy in our hospital from 2013 to 2015. Throughout this period we diagnosed almost no conversion disorders in our department. These patients were diagnosed using the diagnostic criteria for each disease, following clinical features showing neurological symptoms of brain origin, responsiveness to immunosuppressive therapy, the existence of known pathological antibodies, and/or history of human papilloma virus (HPV) vaccination. Fourty–two patients showed motor disturbance (weakness, paresis of extremities, or slower pinching) and 35/42 (83.3％) patients showed give–way weakness, indicating disruption of continuous muscle contraction. Fourty–four patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or fast neurologic pain. Surprisingly, most pain was distributed in manner that was not explainable anatomically, while some patients also showed patchy, stocking–glove, or localized pain. Seventeen patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. In most patients, such motor, sensory, or involuntary movements were markedly improved with immunosuppressive therapies such as prednisolone, azathioprine, or immune adsorption therapy. We observed memory loss, PNES (psychogenic non–epileptic seizure), dissociative amnesia, hyperventilation, opsoclonus, epilepsy, or autonomic symptoms amongst our patients. Although give–way weakness, anatomically unexplainable pain/abnormal sensation, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders (DSM–IV, ICD–10) or functional movement disorders. Without first excluding autoimmune encephalopathy, we propose that physicians should not diagnose somatoform disorders. Since autoimmune encephalopathy patients often possess so–called psychogenic signs, it is possible that such signs might be generated by autoimmune encephalopathy instead of somatoform disorders. In conclusion, we propose that give–way weakness and anatomically unexplainable pain/abnormal sensation are key symptoms of autoimmune encephalopathy. We hope that many patients with autoimmune encephalopathy will now be identifiable using our new neurological examination and that each patient can be given an exact diagnosis and therefore be administered with the appropriate treatments.
A. Non–herpetic acute limbic encephalitis & anti–NMDAR encephalitis Non–herpetic acute limbic encephalitis is diagnosed with the characteristic onset symptom of limbic system and absence of herpes simplexes virus in CSF. Anti–NMDAR encephalitis is diagnosed with presence of antibodies to complex of NMDA–type GluR subunits by cell–based assay. Non–herpetic acute limbic encephalitis & anti–NMDAR encephalitis are causally related with antibodies to NMDA–type GluR, which internalize complex of NMDA–type GluR subunits on neural cell surface. Internalization may lead to protection from apoptosis by excitotoxicity related with increased glutamate and cytokines, and less phosphorylation of Akt in these encephalitides. Passive transfer of rabbit antibodies to n–terminal of human GluN2B into hippocampi of mice caused probable excited behavior and impairment of memory in behavioral analysis, and decreased expression of pam gene in microarray analyses and quantitative analyses of gene expression. In non–herpetic acute limbic encephalitis, factors including granzyme B, glutamate, etc., other than antibodies are causally related with neuronal cell death. B. Encephalitis mediated by antibodies to voltage–gated potassium channel (VGKC) In encephalitides mediated by antibodies to VGKC, patients with antibodies to leucine–rich glioma–inactivated 1 (LGI1) show characteristics of limbic encephalitis, and patients with antibodies to contactin–associate protein (Caspr) 2 show Morvan's syndrome with thymoma. C. Acute disseminated encephalomyelitis (ADEM) ADEM is the most common immune–mediated encephalitis, and its immune–mediated pathophysiology was not revealed. Recently, antibodies to myelin–oligodendrocyte glycoprotein were found in a few pediatric patients.
Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease that is distinct from myxedema encephalopathy, based on an autoimmune mechanism associated with Hashimoto's thyroiditis, and steroid treatment was successfully administrated. Recently, we discovered the serum autoantibodies (Abs) against the NH2–terminal of α–enolase (NAE) as a highly specific diagnostic biomarker for HE. We analyzed the serum anti–NAE Abs and the clinical features in 80 cases of HE from institutions over Japan and other countries. About a half of HE patients carried anti–NAE Abs. Most of HE patients were in euthyroid states, and all patients had anti–thyroid (TG) Abs and/or anti–thyroid peroxidase (TPO) Abs. HE consists of various clinical phenotypes such as acute encephalopathy form, chronic psychiatric form and other particular clinical forms including limbic encephalitis, progressive cerebellar ataxia and Creutzfeldt–Jakob disease (CJD)–like form. Such a wide clinical spectrum in HE easily leads to mis– or under–diagnosis of the disease. The differential diagnosis varied among viral myxedema, encephalitis, non–herpetic limbic encephalitis, spinocerebellar degeneration, schizophrenia, front–temporal lobe dementia, Alzheimer's disease, CJD and other toxic/metabolic conditions. The common neuropsychiatry features are consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures and ataxia. Abnormalities on EEG and decreased cerebral blood flow on the brain single photon emission computed tomography (SPECT) are common findings whereas abnormalities on brain MRI are rare. Cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD), and is characterized by absence of nystagmus, absent or mild cerebellar atrophy. The serum from a HE patient with anti–NAE Abs immunologically reacted with cultured human brain vascular endothelial cells, and merged with α–enolase in the cytoplasm. In contract, a patch–clump study using a patient's CSF containing anti–NAE Abs in rat cerebellar slices demonstrated defective glutamate release, which suggests that the Abs' target is neurons in HE. Taken together, we should provide an attention to the possibility of Hashimoto's encephalopathy, and should search for the pathogenesis.
A relatively high incidence of chronic limb pain, frequently complicated by violent, tremulous involuntary movements, has been noted in Japanese girls following human papillomavirus (HPV) vaccination. The average incubation period after the first dose of the vaccine was 5.47±5.00 months. Frequent manifestations included headaches, general fatigue, coldness of the legs, limb pain and weakness. The skin temperature examined in the girls with limb symptoms exhibited a slight decrease in the fingers and a moderate decrease in the toes. Digital plethysmograms revealed a reduced height of the waves, especially in the toes. The limb symptoms of the affected girls were compatible with the diagnostic criteria for complex regional pain syndrome (CRPS). The Schellong test identified a significant number of patients with orthostatic hypotension and a few patients with postural orthostatic tachycardia syndrome. Electron–microscopic examinations of the intradermal nerves showed an abnormal pathology in the unmyelinated fibers in two of the three girls examined. The symptoms observed in this study can be explained by abnormal peripheral sympathetic responses. The most common previous diagnosis in the studied girls was psychosomatic disease. Additionally delayed manifestation of cognitive dysfunction in the post–vaccinated girls has been paid much attention: memory loss, difficulty in reading textbooks and/or calculation.
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that inflammation in the CNS is involved in the pathophysiology of CFS/ME, there were no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia and/or astrocytes is related to neuroinflammation. Our recent PET study successfully demonstrated that neuroinflammation (activation of microglia and astrocytes) is present in widespread brain regions in patients with CFS/ME, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with CFS/ME may be essential for understanding the core pathophysiology, as well as for developing the objective diagnostic criteria and effective medical treatments for CFS/ME. We here describe related pathophysiological findings and topics, and mention the diagnostic and therapeutic attempts through these findings in Japan.