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Autonomic disorders are common in patients with systemic lupus erythematosus (SLE), but the therapeutic strategy and methods for evaluating the effects of therapy have not been established. We describe the three cases of SLE patients who developed severe autonomic disorders as demonstrated by the head-up tilt table test (HUT). All three patients were treated by intensive immunosuppressive treatments including intravenous cyclophosphamide (IVCY); their HUT results all became negative. Our cases suggest that IVCY treatment can be a good therapeutic option for severe autonomic disorders in SLE patients. The HUT is a useful objective method for the diagnosis of and the evaluation of longitudinal therapeutic effects on autonomic disorders in SLE patients with orthostatic intolerance., Modern Rheumatology Case Reports, 6 (1), pp. 47-51; 2022

This report describes a 59-year-old woman who presented with progressive encephalomyelitis with rigidity and myoclonus (PERM)-like symptoms and severe dysautonomia, including orthostatic hypotension, sinus bradycardia, dysuria, and prolonged constipation. Her neurological symptoms improved after immunotherapy, but the dysautonomia persisted. Anti-ganglionic acetylcholine receptor (gAChR) α3 subunit antibodies, which are frequently identified in patients with autoimmune autonomic ganglionopathy, were detected in the pre-treatment serum. The central distribution of the nicotinic acetylcholine receptors, a target of anti-gAChR antibodies, and immunotherapeutic efficacy observed in this case indicate that anti-gAChR α3 subunit antibodies are associated with the PERM-like features accompanied by autonomic manifestations.

The importance of autonomic neurology has grown exponentially since the development of neuroscience, genetics, and immunology. Advances in this field have made it possible to elucidate the pathomechanism of dysautonomia and autonomic nervous system interactions in both health and disease. In the special issue ?Recent Advances in Autonomic Neurology,? four articles covering a wide range of topics in clinical neuroscience, including degenerative diseases, genetic disorders, immune-mediated neuropathy, and autoimmune encephalitis, were published. This review focused on presenting the recent progress in the clinical approaches for dysautonomia in autoimmune diseases, Ehlers-Danlos syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, and coronavirus disease 2019 (COVID-19). Of particular current concern, is Long COVID, defined as the persistence of symptoms after 3 weeks from being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may involve autonomic dysfunction. The research and clinical practice for autonomic dysfunction in neurology is constantly evolving, which is exemplified by the current clinical research on Long COVID.

Objective To determine whether autonomic dysfunction in neurosarcoidosis is associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, which are detected in autoimmune autonomic ganglionopathy. Methods We retrospectively extracted cases of sarcoidosis from 1787 serum samples of 1,381 patients between 2012 and 2018. Anti-gAChR antibodies against the α3 and β4 subunit were measured by luciferase immunoprecipitation to confirm the clinical features of each case. We summarized literature reviews of neurosarcoidosis with severe dysautonomia to identify relevant clinical features and outcomes. Results We extracted three new cases of neurosarcoidosis with severe dysautonomia, among which two were positive for anti-gAChR antibodies: Case 1 was positive for antibodies against the β4 subunit, and Case 2 was positive for antibodies against both the α3 and β4 subunits. We reviewed the cases of 15 patients with neurosarcoidosis and severe dysautonomia, including the three cases presented herein. Orthostatic hypotension and orthostatic intolerance were the most common symptoms. Among the various types of neuropathy, small fiber neuropathy (SFN) was the most prevalent, with seven of nine cases exhibiting definite SFN. Six of eight cases had impaired postganglionic fibers, of which the present three cases revealed abnormality of 123I-MIBG myocardial scintigraphy. Of the 11 cases, 10 were responsive to immunotherapy, except one seropositive case (Case 2). Conclusions The presence of gAChR antibodies may constitute one of the mechanisms by which dysautonomia arises in neurosarcoidosis.

Objective Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction. Methods This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance characterized by symptoms such as lightheadedness, fainting, and brain fog that occur with a rapid elevation in heart rate when standing up from a reclining position. The etiology of POTS has yet to be established. However, a growing body of evidence suggests that POTS may be an autoimmune disorder such as autoimmune autonomic ganglionopathy, an acquired, immune-mediated form of diffuse autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (gAChRs) in the autonomic ganglia. Herein, we describe a 39-year-old female patient with an eight-year history of orthostatic intolerance. POTS was diagnosed based on the findings of a head-up tilt test, in which a rapid increase in the patient's heart rate from 58 bpm in the lying position to 117 bpm in the upright position without orthostatic hypotension was observed. The POTS symptoms were refractory to various medications except for pyridostigmine bromide, which resulted in a partial resolution of her symptoms. Her serum was found to be strongly positive for anti-gAChR (β4 subunit) autoantibody (2.162 A.I., normal range: below 1.0). Based on these findings, a limited form of autoimmune POTS was diagnosed. After obtaining written informed consent, she was treated with intravenous immunoglobulin (IVIg) 400 mg/kg/day for five days, which led to clinical improvement by reducing her heart rate increase in the upright position. She was able to return to work with IVIg treatment at regular intervals. Our case provides further evidence of a potential autoimmune pathogenesis for POTS. Aggressive immunotherapy may be effective for POTS even in chronic cases.

In Kyudo (Japanese archery), there are four disorders that hinder an archer's performance: Hayake (releasing the bow too early), Motare (unable to release the bow when intended), Biku (jerking when aiming), and Yusuri (shaking when drawing the bow, or aiming). These disorders are similar to Yips, a psycho-neuromuscular movement disorder, recognized in various sports, but few studies have examined yips in Kyudo. This study examined the frequency, classification, and risk factors of yips in Kyudo among medical students. The results showed that 41 of 65 students (63.1%) experienced at least one disorder. The frequency of Hayake was the highest (35 patients; 85.3%). An experience of playing was associated with the increased risk of yips in Kyudo. Motare was the only disorder that appeared on its own, and without complications from other disorders. Based on its characteristics, it was suspected that task-specific focal dystonia involved in Motare.

Disaster countermeasures have been implemented by the Japanese Society of Neurology based on the experience of support to the areas affected by the Great East Japan Earthquake on March 11, 2011. The countermeasures activity began at the end of 2011. We, the Committee for Measures Against Disaster, officially started work in 2014. We developed a support network to urgently deal with patients with intractable neurological disease at the time of disaster and strengthen disaster measures, including effective disaster countermeasure training. During the 2016 Kumamoto earthquake, we realized the need to prepare for natural disasters, leading to a state of emergency, at normal times. A list of vulnerable people should be prepared and the individual support plan for disaster should be confirmed during normal times. Furthermore, during disaster, livelihood support is required for patients with intractable neurological disease living in evacuation centers in affected areas. Therefore, we compiled and published the book, titled "The manual of disaster countermeasures," in 2017. The Committee for Measures Against Disaster in the Japanese Society of Neurology has appointed a liaison officer for patients with intractable neurological disease in each prefecture. The liaison's role of is gathering and disseminating information on the disaster-hit areas, arranging medical support, and coordinating health activities, when natural disasters occur. It is hoped that the liaison officer will play an active role both at normal times and during disaster, even unforeseen ones. Although we hope for the best, we aim to be prepared for the worst.

Highlights • We describe the first case of binasal hemianopia due to bilateral optic perineuritis. • Bilateral optic perineuritis should be considered as a causative disease of binasal hemianopia. • Early diagnosis of optic perineuritis is crucial to avoid irreversible visual impairment.

Objective To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). Methods We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. Results In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. Conclusions Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

In April of 2016, major earthquakes occurred in Kumamoto, Japan. There is limited information on how major earthquakes affect patients with Parkinson's disease (PD). This study investigates the effect of major earthquakes on patients with PD. The participants were outpatients with PD from hospitals located in areas heavily damaged by the earthquakes. We performed an anonymous survey at nine medical institutions to investigate the condition of these patients during the month following the earthquakes. We collected questionnaires from 335 patients with PD. The mean age was 72.6, and the mean disease duration was 7.4 years. Regarding physical conditions, 29.3% of the patients worsened, 1.5% improved, and 68.1% had no change. The mental health of 35.2% of the patients worsened, 2.4% improved, and 57.9% had no change. The most frequently exacerbated neurologic symptoms included bradykinesia (56.1%), gait disturbance (51.0%), freezing of gait (40.8%), extension of "off" time (38.8%), and constipation (38.8%). The worsening mental conditions included fear of an aftershock (77.1%), anxiety (49.2%), insomnia (47.5%), melancholy feelings (45.8%), and fatigability (38.1%). Patients forced to evacuate reported significantly more physical and mental health symptoms (p 0.01). The influences of major earthquakes on patients with PD were identified. After major earthquakes, we should consider the care required for patients' physical and mental health especially for those who experienced evacuation.

The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

BACKGROUND AND PURPOSE Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD. METHODS According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. RESULTS Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). CONCLUSIONS Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

The glial cells in the central nervous system express diverse inward rectifying potassium channels (Kir). They express multiple Kir channel subtypes that are likely to have distinct functional roles related to their differences in conductance, and sensitivity to intracellular and extracellular factors. Dysfunction in a major astrocyte potassium channel, Kir4.1, appears as an early pathological event underlying neuronal phenotypes in several neurological diseases. The autoimmune effects on the potassium channel have not yet been fully described in the literature. However, several research groups have reported that the potassium channels are an immune target in patients with various neurological disorders. In 2012, Srivastava et al. reported about Kir4.1, a new immune target for autoantibodies in patients with multiple sclerosis (MS). Follow-up studies have been conducted by several research groups, but no clear conclusion has been reached. Most follow-up studies, including ours, have reported that the prevalence of Kir4.1-seropositive patients with MS was lower than that in the initial study. Therefore, we extensively review studies on the method of antibody testing, seroprevalence of MS, and other neurological diseases in patients with MS. Finally, based on the role of Kir4.1 in MS, we consider whether it could be an immune target in this disease.

Autoimmune gastrointestinal dysmotility (AGID), an idiopathic or paraneoplastic phenomenon, is a clinical form of limited autoimmune dysautonomia. The symptoms of AGID and gastrointestinal manifestations in patients with autoimmune rheumatic diseases are overlapping. Antineuronal autoantibodies are often detected in patients with AGID. Autoantibodies play a key role in GI dysmotility; however, whether they cause neuronal destruction is unknown. Hence, the connection between the presence of these autoantibodies and the specific interference in synaptic transmission in the plexus ganglia of the enteric nervous system has to be determined. The treatment options for AGID are not well-defined. However, theoretically, immunomodulatory therapies have been shown to be effective and are therefore used as the first line of treatment. Nonetheless, diverse combined immunomodulatory therapies should be considered for intractable cases of AGID. We recommend comprehensive autoimmune evaluation and cancer screening for clinical diagnosis of AGID. Univocal diagnostic criteria, treatment protocols, and outcome definitions for AGID are required for prompt diagnosis and treatment and appropriate management of immunotherapy, which will circumvent the need for surgeries and improve patient outcome. In conclusion, AGID, a disease at the interface of clinical immunology and neurogastroenterology, requires further investigations and warrants cooperation among specialists, especially clinical immunologists, gastroenterologists, and neurologists.

A 58-year-old Japanese woman with herpes zoster developed Behcet's disease (BD) with symptoms including orthostatic intolerance as an autonomic disorder. Multiple immune-suppressive therapies and a β-blocker successfully controlled both the disease activity of BD and the autonomic disorders. A cytokine multiplex analysis of her serum revealed the elevation of proinflammatory cytokines [interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor alfa (TNFα), and interferon gamma (IFN-γ)] and a low IL-10 concentration. IL-10 production is reported to be important for defense against herpes zoster virus (VZV). Insufficient IL-10 production is reported in BD. The reactivation of VZV with this cytokine profile suggests that BD will develop with various symptoms, including severe autonomic disorders., Internal Medicine, 59(8), pp.1099-1104; 2020

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

We used an enzyme‐linked immunosorbent assay to measure pretreatment B cell‐activating factor belonging to the tumour necrosis factor family (BAFF) and transmembrane activator and CAML‐interactor (TACI) levels in CSF and serum collected from patients with primary central nervous system lymphoma (PCNSL) and control groups. The decision tree analysis of CSF TACI and BAFF levels for patients with a PCNSL diagnosis showed 100% sensitivity and 100% specificity when we attempted to differentiate PCNSL from glioblastoma and CNS inflammatory diseases. The combination of CSF TACI and BAFF levels may thus be a novel and useful diagnostic biomarker of PCNSL.

Immune checkpoint inhibitors sometimes cause neuromuscular adverse events. Although a few cases of myasthenia gravis with hyperCKemia triggered by immune checkpoint inhibitors have been described, conclusive evidence remains limited. We conducted a systematic review of published cases of myasthenia gravis with hyperCKemia related to immune checkpoint inhibitors. Moreover, we tested anti‐striational antibodies in the case of myasthenia gravis with myositis after nivolumab administration. We located 17 published case reports. Anti‐striational antibodies were tested in six cases and five cases were positive. Our systematic analyses revealed poor prognosis in myasthenia gravis combined hyperCKemia with immune checkpoint inhibitors.

PD-1 blockade therapy activates T cells by blocking the interaction between PD-1 and PD-L1 and promotes IFN-γ and Th1 cytokine production. In turn, IFN-γ and Th1 cytokines produced by activated T cells promote TF synthesis in monocytes/macrophages, which results in hypercoagulability leading to thrombosis.

The hanger reflex (HR) is an involuntary head rotation that occurs in response to a clothes hanger encircling the head and compressing the unilateral fronto-temporal area. Here, we developed an elliptical device to induce the HR and examined its utility for the treatment of cervical dystonia (CD). The study included 19 patients with rotational-type CD. The device was applied to each subject’s head for at least 30 min/day for 3 months. Severity scores on part 1 of the Toronto Western Spasmodic Torticollis Rating Scale were evaluated at baseline and after the 3-month trial. Mean scores without and with the device were significantly different both at baseline (16.6 vs. 14.7, respectively; P < 0.05) and after the trial (14.9 vs. 13.6, respectively; P < 0.05). This preliminary trial suggests that our device can improve abnormal head rotation in patients with CD.

Background : Marburg type multiple sclerosis (MS) is diagnosed with its “acute and fulminant” clinical course. Case reports of “Marburg MS” include variety of patients with radiological findings and heterogeneous clinical courses. Case description : We present a case diagnosed with Marburg MS with frequent relapses of tumefactive lesions successfully treated with mitoxantrone. The patient was followed up for 8 years, and is almost independent in daily life. Conclusions : Mitoxantrone is one of the treatment options for Marburg MS. Here we review the previous reports of Marburg MS and propose a treatment strategy.

Autoimmune autonomic ganglionopathy (AAG), clinically characterized by gastrointestinal dysmotility, orthostatic hypotension and tonic pupils, is an idiopathic acquired disorder of the autonomic nervous system elicited by antibodies against ganglionic acetylcholine receptor (gAChR). We encountered a 60-year-old man who presented with severe anhidrosis, difficulty in thermoregulation, orthostatic hypotension, gastrointestinal dysmotility, tonic pupils and ptosis. Histologically, an anhidrotic skin sample was normal. Routine laboratory examinations of blood, urine and cerebrospinal fluid returned no abnormal findings. Serological examination revealed antibodies against α3 and β4 subunits of gAChR. The diagnosis was AAG. As sudomotor dysfunction reflects ganglionic neuropathy in AAG, we concluded that his anhidrosis was attributable to AAG. Anhidrosis is an important clue for the diagnosis of AAG, a rare neurological disorder.

Background We report a case of a 64-year-old Japanese man who was diagnosed with definite multifocal motor neuropathy and successfully treated with administration of intravenous immunoglobulin (IVIg) spread over two separate weeks. Case presentation After IVIg administration (30 g/day, five consecutive days), motor function was improved, but it was not possible to maintain the muscle strength just a few months after treatment. Although plasma exchange and cyclosporine were combined, the patient developed muscle weakness just 2 weeks after initial IVIg treatment. His grip strength decreased to 0 kg, proximal upper-limb muscle strength reduced to 2/5 according to manual muscle testing, and muscle weakness developed in the proximal lower limb muscle. We modified IVIg administration protocol from five consecutive days to two separate weeks: 3 days in the first week and 2 days in the third week without changing the total dose per month. After initiation of divided IVIg protocol, muscle weakness dramatically improved, and muscle power could be kept normal. Corrected optical density value of immunoglobulin M antibodies against GM1 elevated in the all clinical course did not correlate with muscle strength improvement. Serum immunoglobulin G levels became stable in ≥2000 mg/dL, and were associated with muscle strength improvement. Conclusion Administration of IVIg over two separate weeks might be a treatment option in intractable patients with multifocal motor neuropathy.

Objective Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5′-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis. Methods We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies. Results Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A–positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A–positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A–positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration. Interpretation Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512–525

To clarify the efficacy of thymectomy among myasthenia gravis (MG) patients with and without thymoma. We classified MG patients who underwent thymectomy into 3 groups, such as thymic atrophy group, thymic follicular hyperplasia (TFH) group and thymoma group. We compared the data of clinical features and postoperative prognosis at very short-term, short-term, and medium-term. The clinical course of MG patients with atrophic thymus after thymectomy was even better than those of TFH or thymoma, in this retrospective study. However, we found no significant differences in the comparison of mean dose of prednisolone between the 3 groups at each time point.

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRβ4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRβ4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRβ4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRβ4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

An 84-year-old woman developed spontaneous recurring mutism. During the periods in which she was able to speak, she described that she had a peculiar delusion where her body was melting away. She did not obey orders although she was able to move her limbs spontaneously. Severe fluctuations in blood pressure measurements were observed; they were unaffected by postural changes. She also had urinary retention and constipation. Her psychiatric and autonomic symptoms showed marked daily and diurnal fluctuations. The brain MRI showed no abnormality in the limbic system or temporal lobes. The cerebrospinal fluid showed slightly elevated protein with normal cells counts. This case was initially thought to be an encephalopathy of unknown etiology. On subsequent testings she was shown to have positive anti-ganglionic acetylcholine receptor (gAChR) antibodies. Although the initial steroid pulse and intravenous immunoglobulin therapies markedly improved both psychiatric and autonomic symptoms, they turned ineffective in subsequent recurrences. We were not able to treat her with plasmapheresis or with other immunisuppressive drugs because of her poor general status, thus their effectiveness could not be determined. Judging from her clinical course, in which immunotherapy was effective although somewhat limited, a possible involvement of an autoimmune mechanism was suspected; however, the exact pathogenesis remains undetermined. It is possible that in this case there may have been an involvement of the immune system and that the patient might have had an encephalopathy with anti-gAChR antibodies.

To determine the usefulness of MRI measurements in patients with pure akinesia with gait freezing (PAGF), Richardson’s syndrome, and Parkinson’s disease for diagnosis. We obtained MRI measurements for patients with PAGF, Richardson’s syndrome, or Parkinson’s disease: 9 patients with PAGF, 26 with Richardson’s syndrome, and 93 with Parkinson’s disease. We measured the area of the pons and midbrain on midsagittal MRIs and the midbrain width on axial MRIs. We also calculated the mean values of the superior cerebellar peduncle, middle cerebellar peduncle, and cerebral crus width; the pons area-to-midbrain area ratio; the middle cerebellar peduncle width-to-superior cerebellar peduncle width ratio; and the magnetic resonance (MR) Parkinsonism index. The Richardson’s syndrome group had the highest pons area-to-midbrain area ratio and MR Parkinsonism index; the Parkinson’s disease group had the lowest values. The Parkinson’s disease group also had the highest midbrain width and cerebral crus width, with the lowest values being seen in the Richardson’s syndrome group. The PAGF group had the intermediate values of the pons area-to-midbrain area ratio and MR Parkinsonism index between the Richardson’s syndrome group and the Parkinson’s disease group, whereas significant differences were found only in the pons area-to-midbrain area ratio. Results from receiver operating characteristic curve analyses showed that the pons area-to-midbrain area ratio has a higher sensitivity, specificity, and accuracy than the MR Parkinsonism index. The pons area-to-midbrain area ratio is more useful to distinguish PAGF from Richardson’s syndrome and Parkinson’s disease than the MR Parkinsonism index.

Intracellular aberrant protein aggregation is linked to the mechanism of Parkinson’s disease (PD). Autonomic dysfunction is commonly found because α-synuclein aggregate in autonomic nerves in patie...

Background Magnetic resonance imaging is widely used in the evaluation of multiple sclerosis (MS). Diffusion tensor imaging can provide information about structural changes in MS that is inaccessible with other magnetic resonance imaging techniques. Case presentation We describe the case of a 13-year-old girl presenting with muscle weakness in the right lower limb related to a relapse of MS. The patient underwent full tensor imaging with a high-field magnetic resonance imaging unit and motor evoked potential recording at the phases of relapse and remission. In the diffusion tensor tractography, tracing the left pyramidal tract fiber bundles was improved at relapse compared with at remission. Central motor conduction times and latency were normal at both relapse and remission, but amplitude levels for cortical motor stimulation were higher during remission than relapse. The findings of diffusion tensor imaging reflected the motor evoked potentials results and clinical course. Conclusions We tested a new technique that provides visualization of the pyramidal tracts in a patient with MS. Tractography was shown to be a clinically feasible technique that correlates well with clinical symptoms and motor evoked potentials.

Autonomic dysfunction is closely associated with autoimmune diseases (AID) including primary biliary cirrhosis (PBC). The objective of this study was to determine the prevalence of anti-ganglionic (nicotinic) acetylcholine receptor (gAChR) antibodies in patients with AID.We determined the presence of gAChR antibodies in serum samples from 146 patients (systemic lupus erythematosus [SLE] = 32; rheumatoid arthritis [RA] = 43; systemic sclerosis [SSc] = 38; PBC= 33) without information regarding autonomic symptoms, as well as 34 patients with other neurological diseases [OND], and 73 healthy controls [HC]. We specifically analyzed sera for anti-gAChRα3 and -β4 antibodies using the luciferase immunoprecipitation system (LIPS) assay.LIPS assay detected anti-gAChRα3 and -β4 antibodies in the sera from patients with SLE (12.5%, 4/32), RA (18.6%, 8/43), SSc (13.2%, 5/38), PBC (9.1%, 3/33), OND (2.9%, 1/34), and HC (0.0%, 1/73). There were no significant correlations between the levels of anti-gAChRα3 and -β4 antibodies, and the total titers of autoantibodies in AID.The results demonstrated a significant prevalence of anti-gAChR antibodies in patients with AID, which is independent of the production of other autoantibodies in patients with autoimmune diseases. These anti-gAChR antibodies could mediate the autonomic dysfunction involved in the autoimmune mechanisms of AID.

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to systemic autonomic failure. Autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR) are detected in 50% of AAG patients. We report the first pediatric case of AAG presenting with acute encephalitis. The patient was a 13-year-old boy who presented with orthostatic hypotension, followed by rapidly progressing disturbance of consciousness. Cerebrospinal fluid analysis revealed significant pleocytosis and increased neopterin concentration. Head MRI showed hyperintensities in bilateral caudate nuclei, putamen, hippocampus, and insula cortex. Severe autonomic dysfunctions such as severe orthostatic hypotension, bradycardia, dysuria, prolonged constipation and vomiting appeared. These symptoms were successfully controlled by repeated immunomodulating therapy with intravenous methylprednisolone pulse therapy and intravenous immunoglobulin. Autoantibodies to the α3 subunit of gAChR were detected at neurological onset, but were undetectable five months later. This observation indicates that AAG should be suspected in patients manifesting acute encephalitis characterized by preceding and prolonged autonomic symptoms, and immunomodulating therapy from an early stage can be effective.

Objective Many myasthenia gravis (MG) patients with anti-muscle-specific tyrosine kinase (MuSK) antibodies have prominent oculobulbar symptoms or weaknesses of the neck and respiratory muscles. An ocular form of MG having anti-MuSK antibodies (MuSK-OMG) is very rare. We review the clinical features of two such cases. Methods We reviewed cases of patients with an ocular form of MG having anti-MuSK antibodies, including two new cases. Results We found seven published cases, plus two cases described in this report. The mean age at onset of these nine patients was 37.0 ± 17.7 years, and the mean disease duration (from ocular MG onset to report) was 47.0 ± 43.1 months. The clinical courses appeared benign, but heterogeneous. Five of the patients responded to pyridstigmine. Four patients received immunotherapy, which resulted in improvement. Our two patients had mild ocular symptoms. One patient was stable with no immunosuppressive treatment, and the other patient was treated with prednisolone and tacrolimus. Conclusions Cases of an ocular form of MG having anti-MuSK antibodies do exist. The benign clinical courses and pharmacological responses to cholinesterase inhibitors imply that the antibodies might have different pathogenicities and specificities from those of MuSK-generalized MG. The presence of anti-MuSK antibodies should therefore be determined in ocular MG patients negative for anti-acetylcholine receptor antibodies.

Objective Bullous pemphigoid in amyotrophic lateral sclerosis (BP-ALS) is rare and poorly understood. We herein assessed the association between ALS and BP using clinical and biological findings. Methods The clinical features of six new BP-ALS cases were described and collated with cases from a systematic literature review. Results Our six cases were combined with three other published cases. The mean disease duration (from ALS onset to the occurrence of BP) was 5.6±3.1 years. All patients had limb-onset ALS. Four of the 9 patients received riluzole, with the use of riluzole ranging from a few days to 3 years. When BP occurred, the status of the ALS patients was paretic and/or bedridden in all cases. BP occurred throughout the body, and we confirmed that the bullous lesions were located not only at the compression site, but also at the anterior part of the chest, abdomen, and limbs. Treatment for BP was successful, as oral prednisone and/or local corticosteroids were effective in 8 cases. Conclusion These six new cases, in combination with previous cases, expand our knowledge of the relationship between dermatological lesions and ALS. The pathogenesis of BP-ALS is poorly understood, however, some immunological aberrance is likely.

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. The disorder is associated with autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR). We subsequently reported that AAG is associated with an overrepresentation of psychiatric symptoms, sensory disturbance, autoimmune diseases, and endocrine disorders. Area covered: The aim of this review was to describe AAG and highlight its pivotal pathophysiological aspects, clinical features, laboratory examinations, and therapeutic options. Expert commentary: AAG is a complex neuroimmunological disease, these days considered as an autonomic failure with extra-autonomic manifestations (and various limited forms). Further comprehension of the pathophysiology of this disease is required, especially the mechanisms of the extra-autonomic manifestations should be elucidated. There is the possibility that the co-presence of antibodies that were directed against the other subunits in both the central and peripheral nAChRs in the serum of the AAG patients. Some patients improve with immunotherapies such as IVIg and/or corticosteroid and/or plasma exchange.

A 65-year-old woman with Sjögren’s syndrome presented with recurrent abdominal distension, constipation, weight loss, orthostatic dizziness, loss of sweating and incomplete emptying of the bladder. Gastrointestinal dilatation but no evidence of malignancy or obstruction was found on CT of the abdomen, oesophagogastroduodenoscopy or colonoscopy. Postvoiding residual urine volume was increased. Antiganglionic acetylcholine receptor antibody was positive. We diagnosed as autoimmune autonomic ganglionopathy. The patient responded to corticosteroid treatment. One year after treatment, she continued to have mild gastrointestinal symptoms, but overall condition was stable without further intervention.

The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated disorder that leads to autonomic failure. It is sometimes complicated by mental and behavioral symptoms. We report a case of 72-year-old male with AAG who was admitted to the psychiatric department for prolonged severe delirium. Repeated loss of consciousness attributed to severe orthostatic hypotension disturbed recovery from delirium. In addition, intracerebral hemorrhage occurred during hospitalization, and this cerebrovascular event may have been substantially affected by unstable blood pressure due to AAG. This case suggests importance of differential diagnosis of AAG in patients with mental and behavioral symptoms accompanying severe autonomic failure.

The nervous system and the immune system are two major systems in human body. Although it was revealed these two systems correlated, the control of immune cell dynamics by the nervous system has come to draw a lot of attention at the present time. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in several animal models. One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex", is dependent upon vagus nerve stimulation that inhibits cytokine production and attenuates the inflammation. And the mechanism for controlling lymphocyte trafficking becomes clear, and molecular basis of immune regulation by the nervous system was reported. On the other hand, the nervous system is protected from the invasion of harmful agents by the barrier. However, there are neuroimmunological disorders, which is associated with autoimmunity, tumor immunity, and infection immunity. Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to widespread autonomic manifestations, in which autoantibodies to ganglionic nicotinic acetylcholine receptors play a central role. Previously, we elucidated the prevalence of extra-autonomic manifestations in patients with AAG. It is necessary to establish the new systems for the detection of autoantibodies to other subunits of acetylcholine receptor.

Purpose The goal of the present study was to clarify the clinical characteristics and laboratory results of parkinsonian symptoms among patients with and without camptocormia. Methods Seventy-eight Parkinson's disease (PD) patients with camptocormia and 78 PD patients without camptocormia underwent a neurological examination, a blood test, and spinal magnetic resonance imaging (MRI). PD with camptocormia group and PD with non-camptocormia group were matched on age, age at PD onset, and sex. Principal results Camptocormia group had significantly higher prevalence of compression fractures, more severe parkinsonian symptoms, and a greater incidence of dementia than those without camptocormia. Serum creatine kinase levels in camptocormia group significantly elevated compared with non-camptocormia group. There were higher prevalence of abnormal findings in spine MRI including compression fractures and paravertebral muscle changes in camptocormia group compared with non-camptocormia group. Major conclusions Camptocormia is associated with a greater prevalence of compression fractures and associated with greater UPDRS part II, part III score, axial score, and lower MMSE in this cross-sectional study. Thus, it can be concluded that camptocormia in PD is predominantly myopathic.

Introduction: The aim of this study was to elucidate the effectiveness of oral prednisolone (PSL) according to dosing regimen in 472 patients with myasthenia gravis (MG). Methods: We compared the clinical characteristics and PSL treatment between 226 patients who achieved minimal manifestations (MM) or better and 246 patients who remained improved (I) or worsened, according to the MG Foundation of America postintervention status. Results: Achievement of MM or better at peak PSL dose (odds ratio 12.25, P