The motto of Prof. Yoshigoro Kuroiwa, who established the first independent neurology department in Japan at Kyushu University, is “Keep Pioneering”. His students have followed this motto in all fields. I hereby present my efforts to keep pioneering in the following fields: (1) multiple sclerosis (MS); (2) central nervous system (CNS) involvement associated with peripheral atopic inflammation; and (3) care network for patients with intractable neurological disease. In MS, I propose that Th1/Th17 cell-mediated connexin astrocytopathy may play a critical role in producing huge demyelinating lesions in MS, neuromyelitis optica (NMO), and Baló’s concentric sclerosis. I discovered a peculiar myelitis that occurred in patients with atopic disorders, and designated it atopic myelitis. In this condition, allodynia and neuropathic pain are cardinal features, regardless of the presence or absence of spinal cord MRI lesions. We found that peripheral atopic inflammation in mice produces allodynia as well as activation of microglia and astroglia in the spinal cord. It is important to involve a variety of medical specialists and care coordinators for collaborative work on medical and social care issues for people with intractable disease. The motto of “Keep Pioneering” in neurology covers not only advanced research for the creation of new therapies for intractable neurological disease, but also caring for actual people with intractable disease, which I believe is the corporate social responsibility of our neurological society. I think that “Keep Pioneering” is a challenging process that never ends throughout one’s life.

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Myasthenia gravis (MG) was first described in 17^th century. It was after 1960s, when it became clear that MG was an autoimmune disease targeting AChR. Recently, anti-MuSK and anti-Lrp4 antibodies were found as novel antibodies in MG. In 1980s, in addition to cholinesterase inhibitors, high-dose corticosteroid treatment was introduced. This dramatically reduced the mortality rate of MG, but now we recognized that side effects of steroid have influenced patients significantly, and that high dose of steroid correlate with poor QOL. Since we have more means to treat MG at present, and also in the future, we should shift to the strategy in which steroid dose is kept low.

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Charcot-Marie-Tooth disease (CMT) is the most common form of inherited peripheral neuropathy and the prevalence rate is about 10/100,000 population in Japan. Next-generation sequencing techniques discovered more than 50 genes for CMT. Genetic diagnosis of CMT with genetic counseling is critical to speculate the prognosis, complications and therapeutic research development. Surgical therapy, rehabilitation, casting therapy, and weight control are useful to keep health-related quality of life for CMT. Although the disease-modifying therapy for CMT is not available now, new clinical trials to improve QOL are now on going. CMT research groups, which consist of researchers and CMT patient association, are organized in Japan with support of Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan. It is the most important to listen to what afflicted patients may want to share with medical doctors.

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Hereditary amyloid neuropathy includes hereditary ATTR, hereditary AGel, hereditary AApoAI, and hereditary Aβ2M amyloidosis. Among these diseases, hereditary ATTR is the most common type of amyloidosis caused by mutation in the transthyretin (TTR) gene. Hereditary ATTR amyloidosis is a life-threatening, multi-symptom, gain-of-toxic-function disease that may present with peripheral neuropathy, autonomic neuropathy, cardiomyopathy, ophthalmopathy, and/or leptomeningeal amyloidosis. In addition to the clinical symptoms described above, proven amyloid deposition in biopsy specimens and identification of disease-causing mutations in the TTR gene are necessary to establish the diagnosis. Deposition of amyloid in tissue can be demonstrated by Congo red staining of biopsy materials. Liver transplantation has been shown to be an effective therapeutic strategy for ameliorating hereditary ATTR amyloidosis, however, large numbers of patients are not suitable transplant candidates because of their age and/or advanced disease status. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomised clinical trials, and tafamidis has been approved for the treatment of hereditary ATTR amyloidosis in European countries and in Japan. With the availability of disease-modifying therapies, early diagnosis and therapy become increasingly important in ATTR amyloidosis.

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Inherited neuropathy is a genetically and clinically heterogeneous group of neuropathies, the main category becomes Charcot-Marie-Tooth neuropathy (CMT), also known as hereditary motor and sensory neuropathy (HMSN), distal hereditary motor neuropathy (dHMN), and hereditary sensory autonomic neuropathy (HSAN). At least 80 genes have been associated with CMT, HMN or HSAN, a precise molecular diagnosis is often needed to make a clinical diagnosis accurately, enable genetic counseling of the patient and understanding of their molecular mechanisms. To identify the mutation in each patient, using a high-throughput NGS, we established a diagnostic procedure involving screening of disease causing genes in CMT, HMN or HSAN.

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Recently, neural oscillations, especially gamma oscillation (>30 Hz) has been paid attention in the Systems Neuroscience. In monkey, neural oscillations are involved in either intrahemispheric or interhemispheric integrative brain function. Magnetoencephalography (MEG) provides information on human brain functions with the excellent temporal (ms) and spatial (mm) resolution. This technique allows us to identify when, where and how bran works. Here, I present the recent findings in our laboratory on the disruption of the neural network in human.

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In 2013, European MSA Study Group demonstrated the prospective natural history of MSA. This study was greately useful for better patients’ management and future development of disease-modifying therapy. Although the diagnosis of early symptomatic stage is also an important factor for successful outcome of disease-modifying theraphy, current diagnostic criteria for MSA, which has focused on the combination of motor and autonomic manifestations cannot diagnose MSA patients showing isolated autonomic failure in the early course of illness. We presented four premotor MSA patients who had sudden death prior to fulfilling the diagnostic criteria. 4 cases had very mild OPC and SN pathology, but significant autonomic system involvement including the intermediolateral nucleus, Onuf’s nucleus, and medullary autonomic nucleus. Contrary, Petrovic et al reported four pathologically proven MSA patients with disease duration of 15 years or more. All patients presented isolated parkinsonism for a long time and mean duration from onset to dysautonomia was 9 years. Novel diagnostic biomarkers, which have a potential for evaluation of the component of glial cytoplasmic inclusion such as alpha-synuclein radiotracer and serum and CSF alpha-synuclein levels may be a key way to support the diagnosis of patients at the stage of “mono system atrophy”.

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Macroautophagy is a dynamic process whereby cytoplasmic molecules are sequestered within autophagosomes. There exist two groups of mammalian autophagy-related gene (Atg) 8 homologues (LC3 and GABARAPs), which play essential role in autophagosomal formation. We determined whether Atg8 homologues are affected in Lewy body disease (LBD) and multiple system atrophy (MSA). The level of LC3 was increased in an insoluble fraction from the brain of patients with LBD, whereas the level of GABARAPs was decreased in LBD. The level of matured GABARAPs was significantly decreased in the cerebellum of MSA, and that the higher levels of matured and lipidated LC3 were detected in detergent-insoluble fraction of MSA. Furthermore, immunohistochemical staining revealed that both LC3 and GABARAPs were localized in Lewy bodies and glial cytoplasmic inclusions in MSA were positive for LC3. These findings suggest that autophagic function is impaired through alteration of Atg8 homologues in LBD and MSA. Autophagy-enhancing strategies can therefore have therapeutic efficacy for various neurodegenerative diseases including LBD and MSA.

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To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress.

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Approximately one-third of patients with multiple sclerosis (MS) exhibit markedly high-level-expression of Sema4A. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is critical for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. We investigated whether recombinant Sema4A abrogates the efficacy of IFN-β in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-β abrogated the efficacy of IFN-β. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-β.Thus unresponsiveness to IFN-β treatment of MS patients with high Sema4A was also confirmed by model mice EAE. We recommend assaying Sema4A first, and then selecting DMD other than IFN-β for patients with high Sema4A.

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High mobility group box 1 (HMGB1) is a nuclear protein, and released from necrotic cells. Recently, It has been known that HMGB1 is released from monocyte/macrophage, neurons, and endothelial cells, and that HMGB1 is involved in sepsis, brain infarction, etc. We have reported that HMGB1 concentrations were elevated in cerebrospinal fluid (CSF) from patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) and that the elevation was significant in CSF from NMO patients. Moreover, we have also reported that experimental autoimmune encephalitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide (35-55) showed decrease of clinical and pathological severity by treatment with monoclonal anti-HMGB1 antibody. Thus, we think that HMGB1 is associated with pathophysiology in central nervous system in NMO and MS (especially in NMO), and that HMGB1 can be a target molecule for NMO and MS.

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Combined central and peripheral demyelination (CCPD) is a rare clinical entity characterized by inflammatory demyelination in both the central and peripheral nervous system. A recently conducted nation-wide survey revealed that clinical features of CCPD are atypical for multiple sclerosis, including an absence of oligoclonal immunoglobulin G bands in most CCPD cases. We found that autoantibody responses of CCPD target the nodes and paranodes of Ranvier in the brain and peripheral nerve tissues. We identified anti-neurofascin antibody in the serum from these CCPD patients. CCPD patients showed a significantly higher positive rate of anti-neurofascin antibody than the other limited form of inflammatory demyelinating diseases. Autoantibody responses targeting neurofascins, which are common proteins to the central and peripheral nervous system may play a pivotal role in combined demyelination in CCPD.

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In the lesion of experimental autoimmune encephalomyelitis (EAE), two different kinds of macrophages are activated: microglia derived macrophages (MiDM) and monocytes derived macrophages (MDM). These macrophages elicit different functions in the development of demyelination lesions in EAE. MDMs are infiltrated in the acute phase of EAE, and initiate demyelination at the nodes of Ranvier. On the other hands, MiDM always activated at the peak and the chronic stage of the disease. These macrophages express totally different cytokines at different time course of the disease: MDM are activated in the early stage of the disease and express genes that are mainly related to inflammation, while MiDM are activated at the peak and recovery stage and express genes that are related to homeostasis. Our findings provide the idea to develop new therapeutic strategy not only for demyelinating disease but also other neurological diseases with neuro-inflammation.

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In neuromuscular diseases, respiratory disorder is related to sleep disorder. In Duchenne muscular dystrophy, respiratory muscle disorder progresses and induces alveolar hypoventilation. Hypoxemia and hypercapnia develop, requiring appropriate management. Hypoxemia first appears during sleep, initially occurring during the REM period, and it progresses and becomes persistent. Not only a decrease in the respiratory muscle strength but also upper respiratory tract obstruction due to soft palatal hypertrophy or a decrease in the muscle tension during sleep causes noctural ventilatory impairment. Hypoxemia is severe at dawn, and reduces the quality of life, inducing poor arousal in the morning, headache, and decreased appetite. Sleep fragmentation causes hypersomnia during the day. When ventilation is maintained using a respirator, almost all problems are overcome. In myotonic dystrophy type 1, there are respiratory control and sleep disorders due to central nerve abnormalities in addition to respiratory muscle lesions. Even in the stage of mild respiratory muscle lesions, hypoxemia during sleep sometimes appears. Hypersomnia during the day is also an important symptom. Hypersomnia does not disappear even after the correction of hypoxemia using a respirator.

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Many patients with Parkinson’s disease (PD) complain about sleep disturbances. These symptoms originate from motor symptoms, nocturnal problems, psychiatric symptoms, and other sleep disorders including Excessive daytime sleepiness (EDS), REM sleep behavior disorder (RBD), Restless legs syndrome (RLS), and Sleep apnea syndrome (SAS). Especially, RBD is paid attention to prodromal symptoms of PD. Also, one third of patients with PD have RBD symptoms. Moreover, RBD is one of aggravating factors of motor symptoms, autonomic dysfunctions, and dementia. Now, the evidence based medicine for sleep disturbances is lack in patients with PD. We need to evaluate various causes of sleep disturbances in detail and deal with individuals.

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Headache and sleep problems are both some of the most commonly reported symptoms in clinical practice. There is a clear association between chronic headache and sleep disorders, especially headaches occurring during the night or early morning. Identification of sleep problems in chronic headache patients is worthwhile because treatment of sleep disorders among chronic headache patients may be followed by improve of the headache. Morning headache has been recognised as an obstructive sleep apnoea related symptom. Treatment with continuous positive airway pressure usually reduced headache, however, we often encounter obstructive sleep apnoea patients who present various characteristics of morning headache that often do not fulfil the criteria for “sleep apnoea headache” according to the International Classification of Headache Disorders: 2nd edition (ICHD-2) criteria. The pathophysiologic background for a relation between obstructive sleep apnoea and morning headache is multifactorial. We should also be noted that tension-type headache and migraine might be coexisted in obstructive sleep apnoea patients. In addition, we review the relationship between migraine and sleep disorders such as restless legs syndrome, narcolepsy and parasomnia (dream enacting behaviour) including our studies.

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Sleep disturbance is common in patients with dementia. Circadian rhythm sleep disorders are caused by the disturbance of sleep-wake regulation in the central nervous system, disturbed input into the sensory organs, and decreased social activities. Diurnal change of serum melatonin level in Alzheimer’s disease showed decreased amplitude and shifted peak secretion. Age related sleep disturbances and sleep disorders due to the neurodegeneration including REM sleep behavior disorder also increase in dementia. Identifying and treating underlying sleep disorders along with therapeutic approach to circadian mechanism is effective. Treatment of circadian abnormality in dementia require light therapy and increased daytime activity. Use of oral melatonin is also effective for the improvement of nocturnal sleep. Treatment of sleep problems in dementia also contribute to the better management of dementia.

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Migraine is, essentially, an episodic disease. However, characteristis of headache of some episodic migraine change like as tension-type headache and number of headache days also increased, as a result, develop into chronic migraine.However, it is difficult to distinguish chronic migraine and medication oversuse headache. For this reason, and because of the general rule, The international Classification of Headache Disorders, 3rd edition, beta version (ICHD- 3beta) defined the patients meeting criteria for chronic migraine and for medication overuse headache should be given both diagnoses. The pathophysiology of transfomation from episodic to chronic migraine is still unknown. Epidemiological study revealed several risk factors such as medication overusue, frequency of headache, obesity, low education, low income, snoring, depression, neck/head trauma and so on. It is important to contol these risk factors for migraine chronification.

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We reviewed the literature concerning the relationship between migraine and ischemic stroke, and compared our data with reported findings. The incidence of migrainous stroke, strictly defined according to the International Classification of Headache 3 beta version, is quite low. A European MRI study indicated that the relative risk of ischemic stroke is increased two-fold in migraine patients with aura, and white matter lesions are located predominantly in the posterior circulation region. The risk of ischemic stroke in patients with migraine aura under 45 years old was reduced to the control level in the group that avoided oral contraceptives and quit smoking. Migraine is a relatively low risk factor for ischemic stroke, in contrast to classic risk factors for stroke, such as hypertension, diabetes mellitus, and atrial fibrillation. Our data concerning the location of white matter lesions showed predominance in the anterior circulation region, in marked contrast to the European study. The reason for this difference remains unknown. It is possible that the white matter lesions in some migraine patients could be caused by reversible vasoconstriction syndrome.

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Migraine and epilepsy are both common episodic disorders that share many clinical features and underlying pathophysiological mechanisms. The comorbidity of these two conditions is well known. However, the temporal association between migraine and epilepsy is a controversial issue, since these two conditions may occur in numerous ways. Four types of association between headache and epileptic seizure are recognized: pre-ictal headache, headache as the expression of an epileptic manifestation, post-ictal headache, and inter-ictal headache. The classification of epilepsy by the International League Against Epilepsy did not refer to the epileptic headache. On the other hand, the International Classification of Headache Disorders, 3rd edition (ICHD-3) defines three entities: migraine aura-triggered seizure which sometimes referred to as migralepsy, hemicrania epileptica, and post-ictal headache. However, ICHD-3 mentions that there is a complex and bidirectional association between migraine and epilepsy. Most of the previous reports of migralepsy corresponded to occipital seizures that mimic migraine with aura. The term migralepsy has recently been criticized. Migraine and epilepsy share several pathophysiological mechanisms which involve neurotransmitters and iron channel dysfunctions. There is the hypothesis of a shared genetic susceptibility to migraine and epilepsy. Strong support of a shared genetic basis comes from familial hemiplegic migraine.

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It is generally believed that cortical spreading depression (CSD) demonstrated by Leao underlie migraine aura and migraine headache depends on the activation of the trigeminovascular pain pathway proposed by Moskowitz. The onset of migraine attack and the association between CSD and the trigeminovascular pain pathway have remained largely unknown. Recent animal studies indicate that CSD can activate trigeminal nociception and thus trigger headache mechanism. Meanwhile, the nature and mechanism of migraine without aura is still an open question. It is considered that the pain in migraineur is affected by hereditary factors, internal factors such as female sex hormone, and external factors as medication, meal, weather, stress, etc. We review here the current understanding of the migraine pathophysiology, focusing on recent advance regarding cortical spreading depression and pain.

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Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterized by progressive spasticity and weakness of the lower limbs. HSP genetic loci are designated SPG1-72 in order of their discovery. In 206 Japanese families with autosomal dominant HSP, SPG4 was the most common form, accounting for 38%, followed by SPG3A (5%), SPG31 (5%), SPG10 (2%), and SPG8 (1%). We have identified novel mutations in the C12orf65 gene and the LYST gene in several Japanese families with autosomal recessive HSP. JASPAC will facilitate gene discovery and mechanistic understanding of HSP. The future challenge will be the establishment of treatment of HSP.

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Hereditary spastic paraplegias (HSPs) were characterized by progressive leg spasticity with various additional symptoms as follows: peripheral neuropathy, cerebellar ataxia, extrapyramidal symptoms, mental impairment, optic atrophy, pigmental retinopathy, and so on. Many genetic loci (SPG1-72) and more than 50 genes were identified so far. Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55). We also identified the mutation of the LYST gene, that is causative gene for Chediak-Higashi syndrome, for the autosomal recessive complicated spastic paraplegia with cerebellar ataxia and neuropathy. In this review, we introduced clinical symptoms about our cases suffered from SPG4, SPG11, SPG55 and complicated spastic paraplegia due to adult Chediak-Higashi syndrome. SPG4, that is usually exhibits pure spastic paraplegia, but our case shows mental impairment and variable age of onset. HSPs are clinically and genetically heterogeneous syndromes, i. e., same gene mutations with different clinical manifestations or same clinical presentations with different gene mutations. We should perform board range differential diagnosis and analysis of numerous causative genes to the patients with spastic paraplegia, especially autosomal recessive trait.

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Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder which is characterized by spasticity of the leg. HSP is a clinically and genetically heterogeneous disorder. Mutations were detected in about 60% of autosomal dominant HSP patients. SPG4 is the most common form of autosomal dominant HSP worldwide. In autosomal recessive HSP patients, we detected mutations in about 40% using exome sequencing. Causes of autosomal recessive HSP are more heterogeneous than those of autosomal dominant HSP. We have to consider leukodystrophies/leukoencephalopathies, motor neuron diseases, spinocerebellar degenerations, or various metabolic diseases as differential diagnosis of complicated HSP. X-linked HSP or HSP with mitochondorial inheritance are rare. Further work on familial patients would lead to identify novel causative genes, which helps to understand pathophysiology of HSP and the nature of corticospinal tract and establish disease modifying therapy. Mutation detection rate for sporadic HSP is low at the moment, and molecular delineation of sporadic HSP is expected in the future.

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Intrathecal baclofen therapy (ITB) is an established treatment for intractable spasticity. More than 1,100 patients have undergone ITB in Japan, and there are about 50 hereditary spastic paraplegia (HSP) The features of ITB in HSP are 1. small doses of baclofen may often be enough, 2. small changes of doses later the symptoms remarkably, 3. doses can be decreased after long term ITB.

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Improvement of outcomes represents the most important problem in the treatment of bacterial meningitis. To achieve such improvement, revision of the guidelines for the clinical management of bacterial meningitis in Japan has been carried out, and these revised Japanese guidelines will soon be published. The choice of specific antimicrobial agents for initial treatment in bacterial meningitis is influenced by a number of factors, including patient age, systemic symptoms, and local patterns of bacterial resistance. In the revised Japanese guidelines, antimicrobial agents based on current knowledge of the epidemiology in Japan are recommended. Bacterial meningitis is a medical emergency, and patients with this disease require immediate medical assessment and appropriate treatment. Rapid diagnosis and treatment of bacterial meningitis reduces mortality and neurological sequelae. We describe the revised Japanese guidelines for the clinical management of bacterial meningitis 2014, with a focus on adults.

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Acyclovir (ACV), which inhibits the replication of herpes simplex virus, is the standard drug for the treatment of herpes simplex encephalitis. Thanks to the introduction of ACV, the morbidity and mortality of HSE patients have significantly improved. However, the disease is still the severe infection, because it makes some patients with HSE suffer from severe consequences. The sensitivity test of the etiological HSV to ACV is very difficult due to the inability of isolation of the virus from cerebrospinal fluid (CSF). The cases of the ACV treatment-resistant HSE patients have been reported. However, these cases were not virologically confirmed. The first case of encephalitis in newborn baby with HSE caused by an ACV-resistant HSV-1, which was virologically confirmed, was reported by our group. According to the sensitivity profile of the causative viruses to antiviral drugs, the drugs of choice for HSE should be properly considered. Strategy for diagnoses of HSE including antiviral sensitivity assessment and selection of drugs in HSE is reviewed.

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Progressive multifocal leukoencephalopathy (PML) is a rare but fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV). The current diagnostic standard for PML is real-time PCR testing of extracted DNA for assessing the presence of JCV DNA in cerebrospinal fluid (CSF). However, because of its sensitivity, real-time PCR assay for JCV testing has a risk of false-positive results due to DNA contamination. JCV isolates recovered from the brain or CSF of PML patients contain hypervariable mutations within the non-coding control region (NCCR) of the viral genome. In our laboratory, the high-resolution melting (HRM) assay was developed to distinguish the patient-dependent NCCR patterns of JCV DNA variants in clinical specimens. The HRM-based scanning of NCCR serves as a quick and convenient technique for comparing the mutational patterns of JCV variants in clinical samples and for the confirmation of PML diagnosis when combined with routine real-time PCR testing.

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To clarify the pathogenesis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients without ovarian teratoma, we investigate normal human ovary, normal bovine ovary and bovine ova. On the basis of immunohistochemical studies, normal human ovary expressed NR2B epitope in primordial oocytes. The results of SDS-PAGE and immunoblotting using bovine ovarian tissues and ova, we identified two bands of NR1 and NR2B. Moreover, reverse phase liquid chromatography coupled to tandem mass spectrometry showed peptides fractions of NR1, NR2A, NR2B and NR2C. Immunocytochemical study disclosed that normal bovine oocyte has a strong affinity for a patient’s disease-specific IgG. Anti-NMDAR encephalitis involves mainly young women who are in their reproductive age. Ovarian teratoma is important as simultaneous tumor, the percentage of patients with ovarian teratoma is less than 40%. It is obvious that the origin of ovarian teratoma is oocyte. So the existence of NMDAR in normal oocytes is very important to assert that ovary itself is the antigen presenting tissue. And also it is helpful to explain why young women are mainly affected from this disease. It seems to conclude that anti-NMDAR encephalitis is one form of autoimmune synaptic encephalitis and that the antigen presenting tissue is ovary itself.

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The autonomic nervous functional tests assessing baroreceptor reflex (BR) were described. I. Head-up tilt test: Sympathetic nervous function is activated and alginine-vasopressin is secreted through the BR. Orthostatic hypotension is induced by BR dysfunction. II. Spectral analysis of heart and blood pressure: High-frequency power in R-R interval variability indicates parasympathetic function and low-frequency power may reflect BR function. Low-frequency power in blood pressure may indicate sympathetic nervous function. However, spectral analysis of them can not detect a sympathetic nervous hyperfunction. III. Baroreceptor sensitivity during the Valsalva maneuver: Baroreceptor sensitivity is obtained from the correlation of systolic blood pressure and RR interval. It decreases in early stage of Parkinson’s disease. IV. Correlation of heart rate and blood pressure: The correlation of them may reflect qualitative differences in the central autonomic dysfunction.

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From the aspect of physiological roles, sweating on the hairy skin is an important for thermoregulation of body, and that on glabrous skin (the palm or sole) works as an anti-skid material when gripping something or performing a delicate task using the fingertips (emotional sweating). Abnormal sweating, which can be global or localized, is classified into hyperhidrosis and hypohidrosis, and detection of abnormal sweating, such as Horner’s syndrome and Harlequin syndrome, is clinically useful for regional diagnosis of neurological lesions. In addition, sudomotor function tests, where sweat secretion is induced by physiological or pharmacological stimuli, are useful for diagnosis of neurological disorders. In this manuscript, clinical evaluation of abnormal sweating from the aspect of neurological diagnosis is reviewed.

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In patients with multiple system atrophy (MSA), sleep related breathing disorders (SRBD), including obstructive and central sleep apnea, vocal cord abductor paralysis and dysrhythmic breathing pattern, are frequently observed. SRBD may have a considerable impact on variation of autonomic nervous activity during sleep. The previous studies correlated upper airway muscle dysfunction related parkinsonism with increased prevalence of SRBD in patients with Parkinson’s disease (PD). However, recently, the clinical significance of SRBD and its impact on sleepiness and disease severity have been debated. In this review, we discuss sleep and autonomic function, especially, SRBD in PD and related disorders, including the previous studies from our department.

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It is well known that transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) and diabetic peripheral neuropathy are characterized by early selective involvement of small nerve fibers. However, early diagnosis of these diseases is not easy because prominent early diagnostic markers for small fiber neuropathies have not established. Thus, we adopted several methods to evaluate autonomic function accurately for detecting the onset of small-fiber neuropathy, such as laser-Doppler flowmetry, sweating tests using capsule type sweating ratemeter, morphological check of sweat gland, electrogastrography, density check of small-fiber and gastrointestinal interstitial cells of Cajal, R-R interval study, ¹²³I-MIBG myocardial scintigraphy, and head-up tilt test to check the overshoot phenomenon. These tests may indicate very early stage of small-fiber neuropathies in asymptomatic mutated TTR carriers or impaired glucose tolerance patients. Moreover, assessment of the pain thresholds by preferential stimulation of C and Aδ fibers are particularly useful tools for diagnosing the onset of small-fiber neuropathies in addition to the autonomic testing.

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The newly recognized entity IgG4-related disease (IgG4-RD) is characterized by an elevated IgG4 serum concentration, swelling of organ, and tissue infiltration by IgG4-positive plasma cells with fibrosis. IgG4-RD has been reported in various organs. In the field of neurology, hypophysitis and hypertrophic pachymeningitis have been known to be related to IgG4-RD, while reported patients with neuropathy manifesting features compatible to IgG4-RD. The features of IgG4-related neuropathy are characterized by sensory-motor neuropathy, mononeuritis multiplex pattern, and predominant involvement of distal portions of the lower extremities. In the sural nerve biopsy specimens, fibrosis and IgG4-positive plasma cell infiltration in the epineurium and decreased myelinated fiber density due to axonal degeneration were observed. IgG4-RD should be considered as the differential diagnosis of neuropathy.

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The international standard of nomenclature and classification in vasculitis, CHCC 1994,was revised as CHCC 2012. In the first part of this review article I briefly summarized the CHCC 2012 and pointed out the changes in this revision, especially on the disorders related to vasculitic neuropathy. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. In the second part, I mentioned the tips for the diagnosis and treatment of vasculitic neuropathy. Because most of the vasculitic neuropathy patients require rigorous, long-standing immunosuppressive therapy, the accurate diagnosis based on the pathological detection of vasculitic changes is mandatory. In this regard, the value of sural nerve biopsy is still not ignorable. In the treatment of vascultic neuropathy, there are no controlled treatment trials and clinical practice is guided by experience from case series and indirectly by analogy with systemic vasculitis. Although combined therapy using prednisolone and cyclophosphamide is usually recommended by experts, tailor-made treatment regimen based on the conditions of each patient would produce the best outcome in vasculitic neuropathy.

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Neuralgic amyotrophy (NA) is a distinct peripheral nervous system (PNS) disorder characterised by sudden attacks of neuropathic pain, usually in a unilateral upper extremity, and patchy paresis with amyotrophy. Under-recognition of NA patients may be frequent because symptoms of NA can be similar to those of common orthopedic disorders. The lesion sites of NA are commonly considered to be brachial plexus (BP) and/or individual branches of the BP. The cause of NA remains unknown. Some evidence support the concept of a complex pathogenesis in NA that includes underlying predisposition and susceptible PNS structures, and it can be triggered by infection, trauma, and strenuous exercise. Typical presentation of NA is characterized by patchy paresis of the periscapular and periglenohumeral muscles. In such cases, STIR-MRI often shows hyperintense signal abnormalities on the affected side of the proximal upper BP. NA is considered to be broad and encompasses a spectrum of atypical presentations, including involvement of lower part of BP, isolated nerves (anterior interosseous nerve or posterior interosseous nerve), or lumbosacral plexuses. Functional prognosis of NA is less favorable than previously assumed. Administration of corticosteroids and intravenous immunoglobulin was described as potential therapeutics for NA, although their efficacy remains unestablished.

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This review described current status and perspectives of treatment for immune-mediated neuropathies, such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, and demyelinating neuropathy with anti-MAG neuropathy. corticosteroids, immunoglobulin therapy, and plasmapheresis are conventional treatments for these neuropathies, but the responsiveness to the treatments significantly differ among the disorders. Promising new treatment options include anti-complement monoclonal antibody (Eculizumab, anti-C5) for Guillain-Barre syndrome, and rituximab (anti-CD20) for anti-MAG neuropathy. For CIDP, different treatments would be required according to the clinical subtypes; typical CIDP and asymmetric variabt). For multifocal neuropathy, maintainance treatment with immunoglobulin is necessary.

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The various lesions affecting the central nervous system in multiple sclerosis (MS) lead to a wide range of symptoms. Until now, physical disabilities have been the main focus of studies on the symptoms of MS; however, cognitive impairment that prominently affects sustained attention and information processing speed has been found by neuropsychological studies to affect over half of all MS patients. Because this cognitive impairment typically involves domain-specific deficits rather than global cognitive decline, it is usually difficult to detect. Cognitive dysfunction in MS patients could influence social activities, such as employment status. Therefore, we must pay greater attention to cognitive function in the milieu of clinical neurology.

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Multiple sclerosis (MS) has long been considered to be the autoimmune disease that primarily affects oligodendrocyte and myelin in the white matter (WM) of the CNS. However, renewed interest in the gray matter (GM) pathology including cortical and deep GM of MS is emerging. Radiological and pathological assessments demonstrate that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present in even normal-appearing GM in MS. Patients with MS have cognitive impairment as represented by the latent start of impairment from the very early stage of the disease course, and not only WM lesions but also GM lesions might be good predictors for cognitive impairment in MS. Although the cause of the GM lesions in MS has not been fully determined, an increase in knowledge of the structure of GM lesions in MS brains will result in more targeted therapeutic approaches to the disease.

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Around a half of multiple sclerosis (MS) patients suffer from cognitive impairment such as attention deficit. A similar impairment is already observable in one third of patients with clinical isolated syndrome, suggesting that the symptom cannot be solely explained by the accumulation of demyelinated lesions. Recently, several studies indicated that demyelination and atrophy in specific regions of the brain are related to the cognitive impairment, although those patients with brain and cognitive reserves are resistant to the development of such symptom. Aging, male sex and smoking increases whereas certain disease-modifying therapy decreases the risk of cognitive impairment in MS. Together, the development of cognitive impairment in MS appears to be determined by the balance between specific aggravating and protective factors.

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The precise mechanisms of cortical damage in multiple sclerosis (MS) remain unknown. Microglia, the resident immune cells in the central nervous system (CNS), are involved in the chronic neuroinflammation in MS cortical lesions. Microglia produce various inflammatory cytokines such as IFN-γ and IL-β, reactive oxygen species, and glutamate. IL-β secretion is induced by NLRP3. ROS is induced by GM-CSF-producing Th17 cells. Glutamate is released via gap junctions. These molecules exert neurotoxicity. Meanwhile, damaged neurons produce fractalkine and FGF-2, which suppress microglial activation and enhance microglial neuroprotection through anti-inflammatory and anti-oxidant effect. Fractalkine accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. FGF-2 induces microglial migration through the FGFR3–Wnt–ERK signaling pathway. These molecules suppress microglial neuroinflammation, and enhance neuroprotection, which may give us clues for future therapeutic strategy cortical damage in MS.

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Remudy, operated by the NCNP, runs two national registries for Dystrophinopathy and GNE myopathy in Japan under the collaboration with the TREAT-NMD alliance. The aim is to construct the clinical research infrastructure and accelerate the clinical development research for these rare diseases. We successfully provide the data sets for the feasibility studies, send out the appropriate information of the clinical trials for the candidates to speed up the recruitment for trials, collaboration with the Muscular Dystrophy Clinical Trial Network: MDCTN, as well as present the natural history and epidemiological data of the rare diseases with a new ‘registry based’ research style. Remudy provides a prototype of the clinical research infrastructure to over come the rare and incurable diseases.

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Exon skipping therapy by antisense oligonucleotide is a promising approach to Duchenne muscular dystrophy (DMD). We have reported the proof-of-concept studies using morpholino on mice or dog DMD model and on patient derived cells. Based on these results, we had promoted collaborative research with a Japanese pharmaceutical company and encouraged development of DMD gene exon 53 skipping drug, then finally started an investigator-initiated clinical trial from 2013. Furthermore, we are addressing exploratory researches to expand the possibility of AON; such as, an application of AON to Fukuyama congenital muscular dystrophy, and an elucidation of AON uptake mechanism.

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Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease and is characterized by progressive muscle wasting ultimately resulting in death of the patients in their twenties. DMD is characterized by a deficiency of the muscle dystrophin as a result of mutations in the dystrophin gene. Currently, no effective treatment for DMD is available. Promising molecular therapies which are mutation specific have been developed. Induction of the readthrough of nonsense mutations is expected to produce dystrophin in DMD patients with nonsense mutations, which are detected in 19% of DMD cases. Clinical effectiveness of gentamicin and PTC124 have been suggested. We have demonstrated that arbekacin-mediated readthrough can substantially ameliorate muscular dystrophy. We already have begun the clinical trial of the nonsense mutation readthrough therapy using arbekacin. We hope that this molecular therapy will contribute towards the treatment for DMD.

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Myotonic dystrophy (DM), the commonest form of muscular dystrophy in adults, is a multisystem disease caused by repeat expansions located in untranslated regions of the affected genes. Its pathogenesis results from expression of RNAs with these expanded repeats, which causes sequestration of splicing factors and thus series of splicing misregulation. An increased understanding of the disease mechanism has accelerated the development of therapeutic strategies, including correction of individual missplicing by antisense oligonucleotides (ASOs), ASO- or small molecule-mediated neutralization of the RNA toxicity by preventing sequestration of splicing factors, degradation of the toxic RNA by ASOs, and stabilization of the expanded repeats. ASOs targeting the toxic RNA have exhibited promising results in animal models, and a clinical trial has recently been launched. With the advent of clinical trials, we are confronting several challenges. As with other rare diseases, we must identify eligible patients. It may be more important in Japan to establish a standardized best practice management of currently available approaches (e.g., pacemaker use) followed by nationwide dissemination. The national DM registry, about to be launched shortly, might be a promising tool to overcome these issues and lead to improved management of DM.

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Fasciculations and fasciculation potentials (FPs) have been long known as a characteristic feature of amyotrophic lateral sclerosis (ALS). In this article, the history of the researches on fasciculation and FPs is first reviewed. The word and concept of fasciculation was first properly defined by Denny-Brown and Pennybacker (1938). It is noteworthy that they already stressed the necessity of strict discrimination of FPs from the “contraction fasciculation”, a remnant of large voluntary motor unit potentials (MUPs), in this early milestone paper. FPs are rarely observed in neurogenic diseases other than ALS or disorders presenting with conduction block, i. e. they retain a high specificity in ALS diagnosis. Despite such usefulness, FPs were devaluated in the revised El-Escorial criteria. It is welcome that their value has been restored in the newer Awaji criteria. In the actual practice, correct identification of FPs would be a critical point. Remnant of voluntary MUPs is the greatest FP mimic to be differentiated. The key point for differentiation is the firing rhythm. FPs are characterized by a low-frequency and quite irregular firing, showing clustering of discharges. In contrast, voluntary MUPs are characterized by a semiregular firing.

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The Awaji criteria proposed in 2008 re-evaluated electrophysiological findings and emphasized the diagnostic significance of fasciculation potentials (FPs) in amyotrophic lateral sclerosis (ALS). FPs were regarded to be equivalent to denervation potentials (fib-psw) in terms of clinical significance. The implication is that FPs are closely related to the progressive denervation process of muscles in ALS. The characteristic features of FP in ALS are complexity and instability. Complex FPs (CFPs) are thought to originate in distal axonal sprouts, associated with the reinnervation process. These differ from FPs observed in other pathological states, which are thought to originate from anterior horn or nerve root. CFPs may be useful for early diagnosis of ALS patients and should be evaluated in the EMG examination.

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Wide-spread fasciculations are prominent clinical features in patients with amyotrophic lateral sclerosis (ALS), specifically seen in ALS among disorders with neurogenic muscle atrophy. Fasciculations frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of the disease. Neurophysiologic investigations of the upper and lower motor neurons/axons have shown increased excitability. The altered excitability is supposed to relate to motor neuron death. Based on these findings, a clinical trial of mexiletine (non-selective sodium channel blocker) is ongoing.

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In this paper, at first I noted the way how to pick up the neuropsychological signs and symptoms during routine neurological examination, and their diagnostic power. Second, I presented the clinical approach for dementia. Medical history should be obtained from both patients themselves and their caregivers. Examination of daily living activities and behavioral and psychological symptoms are necessary as well as neuropsychological examination.

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Although aphasia is a common neurological condition, and its diagnostic procedure is mostly established, it is not easy to fully evaluate the communicative ability of each patient, as there are huge interindividual differences among patients, and their abilities may vary depending on their circumstances. Even with the advancement of neuroimaging technique, the relationship between lesion localizations and symptoms remains elusive. To evaluate their residual abilities which helps daily communication, it is valuable to observe their abilities in a setting which reflects real social contexts. In this presentation a patient with total aphasia who showed rich communicative abilities in a group therapy setting is presented, which was discrepant from his results of standardized language evaluation. We found that his residual communicative abilities have things much in common with linguistic abilities shown to reside in the right hemisphere. The observation also revealed that the group treatment of patients with chronic aphasia provides a unique occasion to participate in social activities which helps to fulfill their psychosocial needs.

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