Asymptomatic deep venous thrombosis identified on routine screening in patients with hospitalized neurological diseases.

PURPOSE: Patients with neurological diseases are potentially at high risk for developing deep venous thrombosis (DVT). We sought the prevalence and clinical background of patients with neurological diseases in whom DVT was detected during hospitalization. METHODS: Consecutive patients admitted due to neurological diseases were prospectively registered. Those who were at risk for DVT were screened using venous duplex ultrasonography of the lower extremities. Predictors for DVT detection were analyzed. RESULTS: During the study period, 192 of 785 patients received duplex ultrasonography. There were 34 patients with DVT identified (18%, age 63 ± 17 years). Three patients had DVT in the popliteal or femoral vein and the others had below the knee; all of the DVT were asymptomatic. DVT was observed most frequently in patients with systemic vasculitis, followed by demyelinating disease. In patients with DVT, the median D-dimer level was 2.1 µg/mL. On multiple logistic regression analysis, female ([odds ratio, 95% confidence interval] 3.2, 1.2-8.4), supine or sitting position for > 48 h (5.3, 1.8-15.0), D-dimer level ≥ 2.0 µg/mL (6.2, 2.3-16.4), and white blood cell count ≥ 7,600 (4.2, 1.6-11.3) were independent predictors of DVT detection at the first screening ultrasonography. DVT was detected in 1, asymptomatic pulmonary embolism was detected in 2, and both in 1 on chest computed tomography. CONCLUSION: DVT is not rare in patients with neurological diseases. Clinicians should be mindful of subclinical DVT in hospitalized neurological disease patients with decreased daily activity and elevated D-dimer levels or blood cell counts, especially in women.

Development of Quality of Life Questionnaire for Patients with Parkinson's Disease Undergoing STN-DBS.

In device-aided therapy (DAT) for Parkinson's disease (PD), factors such as device-related adverse effects, psychological and lifestyle changes, and specific disease progression can affect the quality of life (QoL) of patients with advanced PD. However, there is no existing QoL scale that includes the effects of therapeutic devices. From a semi-structured interview with patients with PD undergoing deep brain stimulation (DBS), we extracted the content of utterances that were thought to affect the QoL and created a draft questionnaire consisting of 113 items. This questionnaire was administered to 54 other patients undergoing DBS, whose data were examined for reliability and validity by factor analysis, and finally, a 24-item PD QoL questionnaire for patients on DAT (PDQ-DAT) was developed. Presently, the PDQ-DAT is the only scale that can assess the QoL of patients on DAT, including the influence treatment devices have on them. In the future, it might be used to help in shared decision-making in medicine by incorporating the patient's sense of burden and values in the selection of treatment methods.

gAChR antibodies in children and adolescents with acquired autoimmune dysautonomia in Japan.

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 (<20 years, 20 cases; ≥20 years, 175 cases) with clinical features of AAD. RESULTS: Upon comparing pediatric and adult patients, we found that antecedent infection and autonomic symptoms at onset with gastrointestinal symptoms occurred more frequently in children with AAD. We confirmed that four children (20.0%) met the diagnostic criteria for postural orthostatic tachycardia syndrome (POTS). A significantly higher number of children than adults had POTS (P = 0.002). In addition, upper GI dysfunction was more prevalent in children than in adults (P = 0.042). In particular, nausea and vomiting occurred in 60.0% of children with AAD and in 21.1% of adults (P < 0.001). The frequency of paralytic ileus was significantly higher in children with AAD (20.0%) relative to adults (6.3%) (P = 0.030). Regarding extra-autonomic manifestations, encephalopathy was more frequent in children (15.0%) than in adults (1.1%) (P < 0.001). INTERPRETATION: Pediatric AAD patients have their own clinical characteristics, and these features may be unique to children and adolescents.

Antibodies to the α3 subunit of the ganglionic-type nicotinic acetylcholine receptors in patients with autoimmune encephalitis.

Since autonomic dysfunction is closely associated with autoimmune encephalitis (AE), the objective of this study was to determine the autonomic symptoms and the prevalence of anti-α3 subunit of the ganglionic-type nicotinic acetylcholine receptor (gAChRα3) antibodies in the patients with AE. We reviewed the clinical features of 19 AE patients, and specifically analyzed sera for anti-gAChRα3 antibodies using the luciferase immunoprecipitation system (LIPS) assay. Cardiovascular autonomic symptoms were found to be common in patients with AE, and hypersalivation was seen only in patients with NMDAR encephalitis. LIPS detected anti-gAChRα3 antibodies in the sera from patients with AE (5/29, 26%). This study is the first to demonstrate that clinical characteristics including autonomic symptoms of AE patients with seropositivity for gAChR autoantibodies. It will be important to verify the role of gAChR antibodies in autonomic dysfunction and brain symptoms to clarify the pathogenesis of AE.

A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy.

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 gAChRß4 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 gAChRß4-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-gAChRß4 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 gAChRß4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

Author Correction: Fingolimod-induced decrease in heart rate may predict subsequent decreasing degree of lymphocytes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CSF TACI and BAFF levels in patients with primary CNS lymphoma as novel diagnostic biomarkers.

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.

Fingolimod-induced decrease in heart rate may predict subsequent decreasing degree of lymphocytes.

Here, we determined whether degree of decreased heart rate due to fingolimod treatment correlates with decreasing degree of lymphocytes in relapse-remitting multiple sclerosis (RRMS). In total, 30 patients with RRMS were treated with 0.5 mg fingolimod and their heart rate recorded every 30 minutes for 24 hours. Time trends of heart rate were characterised as three individual amplitudes and phase angles from three cosine curves using a mixed-effect model. Spearman's correlation coefficient and regression analysis were used to determine the effect of heart rate information on change in lymphocyte count pre- and post-fingolimod treatment. Moreover, the degree of decreased lymphocytes induced by fingolimod treatment on heart rate was compared between low and high influence groups. Positive correlation between amplitude from the second curve and difference in lymphocyte number (p = 0.006) was observed. Regression analysis was also significant (p = 0.002). Moreover, the second curve derived from the high amplitude group exhibited a greater decrease in lymphocyte number after fingolimod treatment than the low amplitude group (p < 0.001). We suggest that the degree of decreased lymphocytes after fingolimod treatment (main effect) may be predicted by estimating the influence of degree in heart rate (side effect).

Autoimmune autonomic ganglionopathy: an update on diagnosis and treatment.

INTRODUCTION: 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. 123I-MIBG myocardial scintigraphy may be a useful tool to monitor the therapeutic effects of immunotherapies.

[Anti-Ganglionic Acetylcholine Receptor Antibodies, Autoimmune Autonomic Ganglionopathy, and Related Disorders].

The clinical associations of the anti-ganglionic acetylcholine receptor (gAChR) have not yet been described fully. It is not known whether central nervous system (CNS) involvement and endocrine disorders are the extra-autonomic features of autoimmune autonomic ganglionopathy (AAG), or whether it is related to circulating anti-gAChR antibodies (Abs). The present study prospectively identified 123 Abs-positive AAG patients in Japan and collated their clinical features, investigations, and immunotherapy responses. Luciferase immunoprecipitation systems were used to detect anti-α3 and -ß4 gAChR Abs. A gradual mode of onset was more common among the 123 seropositive AAG patients examined. Patients with AAG demonstrated widespread autonomic dysfunction. In particular, orthostatic hypotension and lower gastrointestinal tract dysfunction were frequently observed. Approximately 80% of patients with seropositive AAG exhibited extra-autonomic manifestations, including CNS involvement, endocrine disorders, other autoimmune disease, and tumors. Additionally, the majority exhibited a marked improvement in clinical status and the levels of anti-gAChR Abs with immunotherapy. CNS involvement and endocrine disorders were frequent among the seropositive patients with AAG, indicating that seropositivity for AAG may be associated with underlying conditions such as autoimmune diseases or tumors.

Autoimmune postural orthostatic tachycardia syndrome.

The aim of this study was to evaluate the association between postural orthostatic tachycardia syndrome (POTS) and circulating antiganglionic acetylcholine receptor (gAChR) antibodies. We reviewed clinical assessments of Japanese patients with POTS, and determined the presence of gAChR antibodies in serum samples from those patients. Luciferase immunoprecipitation systems detected anti-gAChR α3 and ß4 antibodies in the sera from POTS (29%). Antecedent infections were frequently reported in patients in POTS patients. Moreover, autoimmune markers and comorbid autoimmune diseases were also frequent in seropositive POTS patients. Anti-gAChR antibodies were detectable in significant number of patients with POTS, and POTS entailed the element of autoimmune basis.

Intratumoral hemorrhage in a patient with malignant meningioma under anticoagulant therapy.

We report the case of an elderly woman with malignant meningioma and atrial fibrillation who started taking anticoagulants after an ischemic stroke and subsequently developed intratumoral hemorrhage. Further studies are required to confirm whether a particular anticoagulant agent is suitable for patients with brain tumor and atrial fibrillation.