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Steven Vernino - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Autonomic Disorders.
CONTINUUM: Lifelong Learning in Neurology, 2020Co-Authors: Steven VerninoAbstract:PURPOSE OF REVIEW Autonomic disorders sometimes occur in the context of systemic Autoimmune disease or as a direct consequence of autoimmunity against the nervous system. This article provides an overview of Autonomic disorders with potential Autoimmune etiology. RECENT FINDINGS Recent evidence highlights a close association between the Autonomic nervous system and inflammation. The Autonomic nervous system regulates immune function, and Autonomic manifestations may occur in a number of systemic Autoimmune diseases. In a few instances, autoimmunity directly influences Autonomic function. Autoimmune Autonomic Ganglionopathy is the prototypic antibody-mediated Autonomic disorder. Over time, a better understanding of the clinical spectrum of Autoimmune Autonomic Ganglionopathy, the significance of ganglionic nicotinic acetylcholine receptor antibodies, other immune-mediated Autonomic neuropathies, and Autonomic manifestations of other systemic or neurologic Autoimmune disorders has emerged. SUMMARY Autoimmune Autonomic disorders may be challenging, but correct identification of these conditions is important. In some cases, potential exists for effective immunomodulatory treatment.
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Autoimmune Autonomic neuropathies and ganglionopathies: epidemiology, pathophysiology, and therapeutic advances
Clinical Autonomic Research, 2019Co-Authors: Elisabeth P. Golden, Steven VerninoAbstract:Autonomic disorders can be the result of autoimmunity. The classic, well-characterized example is Autoimmune Autonomic Ganglionopathy (AAG), in which antibodies against the ganglionic nicotinic acetylcholine receptor impair Autonomic transmission, causing Autonomic failure, which responds to immunotherapy. However, a number of other Autoimmune disorders cause Autonomic failure through a variety of mechanisms. In this article, we review Autoimmune disorders causing impairment of the peripheral Autonomic nervous system (ganglia and nerves), including AAG, other Autoimmune Autonomic neuropathies, paraneoplastic Autonomic neuropathies, and neuromuscular and rheumatologic diseases with Autonomic symptomatology. Awareness of primary Autoimmune Autonomic disorders and the Autonomic manifestations of other Autoimmune diseases promotes timely diagnosis and appropriate management, including supportive care for unpleasant or dangerous Autonomic dysfunction, a search for underlying malignancy when indicated, and the use of immunotherapy when appropriate. A better understanding of the underlying pathophysiology aids in the judicious use and selection of immunotherapy.
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Seronegative Autoimmune Autonomic neuropathy: a distinct clinical entity
Clinical Autonomic Research, 2018Co-Authors: Elisabeth P. Golden, Meredith A. Bryarly, Steven VerninoAbstract:Purpose Autoimmune Autonomic Ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with Autoimmune Autonomic failure lacking this antibody. Methods Retrospective chart review. Results Six patients presented with subacute Autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids. Conclusion In these cases of Autoimmune Autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative Autoimmune Autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.
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Seronegative Autoimmune Autonomic neuropathy: a distinct clinical entity
Clinical Autonomic Research, 2017Co-Authors: Elisabeth P. Golden, Meredith A. Bryarly, Steven VerninoAbstract:Autoimmune Autonomic Ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with Autoimmune Autonomic failure lacking this antibody. Retrospective chart review. Six patients presented with subacute Autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids. In these cases of Autoimmune Autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative Autoimmune Autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.
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Autoimmune Autonomic Ganglionopathy:
2015Co-Authors: Md P. Sandroni, Steven VerninoAbstract:Background—Autoimmune Autonomic Ganglionopathy (AAG) is an acquired immune-mediated form of diffuse Autonomic failure. Many patients have serum antibodies that bind to the ganglionic acetylcholine receptors (AChRs) that mediate fast synaptic transmission in Autonomic ganglia. Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder. Methods—Using whole-cell patch clamp techniques, we recorded ganglionic AChR currents in cultured human IMR-32 cells and examined the effects of bath application of IgG derived from patients with AAG. Results—IgG from seven patients with AAG all produced a progressive decline in whole-cell ganglionic AChR current, whereas IgG from control subjects had no effect. The effect was abolished at low temperature. Fab antibody fragments had no effect unless a secondary antibody was added concurrently. IgG from one patient also produced a more immediate reduction of ganglionic AChR current. Conclusions—The characteristics of antibody-mediated inhibition of ganglionic acetylcholin
Shunya Nakane - One of the best experts on this subject based on the ideXlab platform.
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A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with Autoimmune Autonomic Ganglionopathy
Journal of Autoimmunity, 2020Co-Authors: Shunya Nakane, Osamu Higuchi, Akihiro Mukaino, Mari Watari, Makoto Yamakawa, Keiichi Nakahara, Koutaro Takamatsu, Maeda Yasuhiro, N. Tawara, Atsushi KawakamiAbstract:Abstract 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.
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A case of Autoimmune Autonomic Ganglionopathy with prolonged delirium.
Asian Journal of Psychiatry, 2019Co-Authors: Shinya Uenishi, Shunya Nakane, Shun Takahashi, Yoshiaki Nakayama, Yasuhiro Hiwatani, Tomikimi Tsuji, Satoshi UkaiAbstract: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.
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Autoimmune Autonomic Ganglionopathy: an update on diagnosis and treatment
Expert Review of Neurotherapeutics, 2018Co-Authors: Shunya Nakane, Osamu Higuchi, Akihiro Mukaino, Mari Watari, Yasuhiro Maeda, Makoto Yamakawa, Keiichi Nakahara, Koutaro Takamatsu, Hidenori Matsuo, Yukio AndoAbstract:ABSTRACTIntroduction: Autoimmune Autonomic Ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to Autonomic failure. The disorder is associated with autoantibodies to the gangli...
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Autoimmune Autonomic Ganglionopathy associated with sjogren s syndrome presenting with recurrent abdominal distension
Case Reports, 2018Co-Authors: Takeshi Yoshida, Mitsuyo Kinjo, Shunya NakaneAbstract:A 65-year-old woman with Sjogren’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.
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Anti-Ganglionic Acetylcholine Receptor Antibodies, Autoimmune Autonomic Ganglionopathy, and Related Disorders
Brain and nerve = Shinkei kenkyu no shinpo, 2018Co-Authors: Shunya Nakane, Mari Watari, Yukio AndoAbstract: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 -β4 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.
Phillip A. Low - One of the best experts on this subject based on the ideXlab platform.
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11-year Follow-Up of a Case of Autoimmune Autonomic Ganglionopathy (P03.024)
Neurology, 2013Co-Authors: Tonette L. Gehrking, Robert D. Fealey, Phillip A. Low, David M. Sletten, Wolfgang SingerAbstract:OBJECTIVE: To describe the disease course of a patient with seronegative Autoimmune Autonomic Ganglionopathy (AAG) with serial assessment of Autonomic symptoms and function. BACKGROUND: AAG is an immune-mediated Autonomic disorder usually presenting as acute pandysautonomia. The pathophysiology has been well characterized owing to the discovery of nicotinic ganglionic acetylcholine receptor antibodies in patients with AAG, though at least half of cases presents without detectable autoantibodies. Little is known about the long-term prognosis of AAG in general and seronegative AAG in particular. DESIGN/METHODS: We followed a case of seronegative AAG for 11 years. In addition to routine clinical and laboratory assessments, standardized Autonomic testing and standardized assessment of Autonomic symptoms (composite Autonomic symptom score, COMPASS) were completed. RESULTS: The patient presented with subacute onset of abdominal pain, vomiting, bloating, constipation, orthostatic hypotension, heat intolerance, urinary retention, and erectile dysfunction. Autonomic reflex testing showed pandysautonomia (CASS score=9 out of 10). Immunomodulatory treatment resulted in negligible benefit and was discontinued. Upon re-evaluation one year later, most symptoms had modestly improved. CASS score was 7 related to improvement in cardiovagal function. Thermoregulatory sweat test showed global anhidrosis except for small islands of preserved sweating. By eleven years after symptom onset, most symptoms had improved markedly and the patient had returned to near normal functioning. Remaining symptoms included erectile dysfunction and lack of thermoregulatory abilities. COMPASS had improved from 61.3 (year 1) to 34 (year 11). There was continued severe sudomotor failure, improvement of cardiovascular adrenergic function, and normalization of cardiovagal function (CASS=5). CONCLUSIONS: 11-year follow-up in a patient with seronegative AAG reveals definite but incomplete improvement of Autonomic function and symptoms. Sudomotor and erectile function remained markedly impaired. This confirms prior short-term follow-up reports of an overall favorable prognosis but often incomplete recovery. The long duration of selected deficits would suggest structural impairment beyond functional blockade of ganglionic function. Supported by: NIH (NS32352, U54NS065736, K23NS075141, UL1RR24150), and Mayo Funds. Disclosure: Dr. Gehrking has nothing to disclose. Dr. Sletten has nothing to disclose. Dr. Fealey has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea, Pfizer Inc, and WR Medical Inc. as a consultant. Dr. Low has received personal compensation in an editorial capacity for Autonomic Neuroscience. Dr. Singer has received payments from Jacobus Pharmaceuticals.
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Sudomotor dysfunction in Autoimmune Autonomic Ganglionopathy: a follow-up study
Clinical Autonomic Research, 2012Co-Authors: Kurt Kimpinski, Steven Vernino, Valeria Iodice, Paola Sandroni, Robert D. Fealey, Phillip A. LowAbstract:Objective We have previously shown that sudomotor dysfunction in Autoimmune Autonomic Ganglionopathy is severe, widespread, and predominantly post-ganglionic. However, the long-term changes in sudomotor function have not been studied in detail. Our objective was to characterize the long-term changes in sudomotor dysfunction in patients with Autoimmune Autonomic Ganglionopathy. Methods Changes in sudomotor function were compared in a cohort of nine α3 nAChR antibody positive Autoimmune Autonomic Ganglionopathy patients over an approximate 5-year period. Standard measurements of sudomotor function were used including the thermoregulatory sweat test and quantitative sudomotor axon reflex test. Results Total body anhidrosis on thermoregulatory sweat testing showed improvement in four of nine patients. Quantitative sudomotor axon reflex testing for both forearm and foot sites was variable with four of nine patients showing improvement in total sweat output. Distribution of sudomotor dysfunction at follow-up was post-ganglionic in seven of nine patients at the foot site and three of nine patients at the forearm site. Overall, sudomotor dysfunction was post-ganglionic in seven of nine patients throughout the follow-up period (62.4 ± 19.4 months). Interpretation Sudomotor dysfunction in Autoimmune Autonomic Ganglionopathy was severe and widespread throughout the follow-up period for the majority of patients studied. Sudomotor dysfunction was predominantly post-ganglionic throughout the follow-up period.
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Autoimmune Autonomic Ganglionopathy Associated with Voltage-Gated Potassium Channel Antibodies (P05.209)
Neurology, 2012Co-Authors: Wolfgang Singer, Christopher J. Klein, Andrew Mckeon, Phillip A. LowAbstract:Objective: To report a case of Autoimmune Autonomic Ganglionopathy (AAG) associated with neuronal voltage-gated potassium channel (VGKC) antibodies. Background Ganglionic acetylcholine receptor (AChR) autoantibodies have been described in patients with idiopathic Autonomic neuropathies, and with further characterization of the pathophysiologic role of these antibodies, the terminology of this condition has changed to AAG. The majority of patients fulfilling clinical and laboratory criteria for AAG are, however, seronegative and additional pathogenetic antibodies have been postulated. Recently, an association between N-type calcium channel antibodies and AAG has been described. Design/Methods: A 65 year-old woman with a one year history of orthostatic intolerance, heat intolerance, diarrhea, and sicca complex underwent comprehensive Autonomic and laboratory evaluations and was diagnosed with AAG associated with VGKC antibodies. She underwent serial standardized Autonomic, clinical, and laboratory evaluations for 2 years, before and during treatment with intravenous immunoglobulin (IVIG). Results: During her initial evaluation, the patient was found to have widespread anhidrosis with otherwise essentially normal Autonomic function. A paraneoplastic antibody panel was positive for VGKC antibodies, which did not react to recently recognized specific VGKC-associated antigens (Lgi1, Caspr2). A search for an occult malignancy remained negative. During subsequent evaluations, progressive cardiovascular adrenergic impairment was documented with evidence of orthostatic hypotension, associated with a rise in the antibody titer. At that time, treatment with IVIG was initiated. Six months after initiation of IVIG, Autonomic testing had essentially normalized, associated with a notable decrease in antibody titer. Conclusions: AAG may be associated with Autoimmune antibodies other than the classic ganglionic ACHR and the recently reported calcium-channel antibodies. Whether the VGKC antibodies in our patient have a pathophysiologic role or are nonspecific indicators of an underlying immune process remains subject for further study. This association is, however, important to recognize regardless of the underlying mechanism, considering this patient9s remarkable response to immunomodulatory therapy. Supported by: R.F. Kinney Executive Dean for Research Career Development Award and NIH (BIRCWH 5K12HD065987-02 and NS44233). Disclosure: Dr. Singer has nothing to disclose. Dr. Klein has received personal compensation for activities with Pfizer Inc as a consultant. Dr. McKeon has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea, Pfizer, and WR Medical Inc. as a consultant.Dr. Low has received personal compensation in an editorial capacity for Autonomic Neuroscience.
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Autoimmune Autonomic Ganglionopathy
Primer on the Autonomic Nervous System, 2012Co-Authors: Steven Vernino, Phillip A. LowAbstract:Publisher Summary Subacute Autonomic neuropathies can be further divided into dysautonomia associated with sensory and motor neuropathy, dysautonomia associated with malignancy or idiopathic Autoimmune Autonomic Ganglionopathy (AAG). The most convincing evidence of an Autoimmune pathogenesis for AAG is the demonstration of high titers of ganglionic nicotinic acetylcholine receptor (AChR) antibodies in the serum of about 50% of patients. The diagnosis of idiopathic AAG is suspected in cases of acquired Autonomic failure without somatic neuropathy when toxic or paraneoplastic causes have been excluded. Patients with paraneoplastic Autonomic neuropathy may be clinically indistinguishable from idiopathic AAG until a cancer, usually small-cell carcinoma of the lung, is detected. The original case of acute pandysautonomia was remarkable for highly selective Autonomic involvement and complete recovery. Subsequent case series have documented that most patients have a distinct clinical course with monophasic worsening followed by stabilization or remission without recurrences. Treatment for AAG has largely been symptomatic. The convincing evidence that AAG is an antibody-mediated channelopathy supports the use of immunomodulatory therapy for AAG.
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Sudomotor dysfunction in Autoimmune Autonomic Ganglionopathy: a follow-up study
Clinical Autonomic Research, 2011Co-Authors: Kurt Kimpinski, Steven Vernino, Valeria Iodice, Paola Sandroni, Robert D. Fealey, Phillip A. LowAbstract:Objective We have previously shown that sudomotor dysfunction in Autoimmune Autonomic Ganglionopathy is severe, widespread, and predominantly post-ganglionic. However, the long-term changes in sudomotor function have not been studied in detail. Our objective was to characterize the long-term changes in sudomotor dysfunction in patients with Autoimmune Autonomic Ganglionopathy.
Osamu Higuchi - One of the best experts on this subject based on the ideXlab platform.
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Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.
International Journal of Molecular Sciences, 2020Co-Authors: Michie Imamura, Osamu Higuchi, Akihiro Mukaino, Koutaro Takamatsu, Hidenori Matsuo, Yukio Ando, Hiroto Tsuboi, Hideki Nakamura, Saori Abe, Tadashi NakamuraAbstract:Autonomic neuropathy has been reported in Autoimmune rheumatic diseases (ARD) including Sjogren'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.
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A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with Autoimmune Autonomic Ganglionopathy
Journal of Autoimmunity, 2020Co-Authors: Shunya Nakane, Osamu Higuchi, Akihiro Mukaino, Mari Watari, Makoto Yamakawa, Keiichi Nakahara, Koutaro Takamatsu, Maeda Yasuhiro, N. Tawara, Atsushi KawakamiAbstract:Abstract 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.
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Autoimmune Autonomic Ganglionopathy: an update on diagnosis and treatment
Expert Review of Neurotherapeutics, 2018Co-Authors: Shunya Nakane, Osamu Higuchi, Akihiro Mukaino, Mari Watari, Yasuhiro Maeda, Makoto Yamakawa, Keiichi Nakahara, Koutaro Takamatsu, Hidenori Matsuo, Yukio AndoAbstract:ABSTRACTIntroduction: Autoimmune Autonomic Ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to Autonomic failure. The disorder is associated with autoantibodies to the gangli...
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Anti-ganglionic AChR antibodies in Japanese patients with motility disorders
Journal of Gastroenterology, 2018Co-Authors: Akihiro Mukaino, Osamu Higuchi, Yasuhiro Maeda, Hitomi Minami, Hajime Isomoto, Hitomi Hamamoto, Eikichi Ihara, Tohru Okanishi, Yohei Kokudo, Kazushi DeguchiAbstract:Background 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). Methods 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. Results 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. Conclusions 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.
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Anti-ganglionic AChR antibodies in Japanese patients with motility disorders.
Journal of Gastroenterology, 2018Co-Authors: Akihiro Mukaino, Osamu Higuchi, Yasuhiro Maeda, Hitomi Minami, Hajime Isomoto, Hitomi Hamamoto, Eikichi Ihara, Tohru Okanishi, Yohei Kokudo, Kazushi DeguchiAbstract:Background 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).
Christopher H. Gibbons - One of the best experts on this subject based on the ideXlab platform.
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A novel treatment for Autoimmune Autonomic Ganglionopathy? (4706)
Neurology, 2020Co-Authors: Priyanka Shekhawat, Roy Freeman, Alice Tang, Christopher H. GibbonsAbstract:Objective: To introduce a potential novel treatment for Autoimmune Autonomic Ganglionopathy (AAG). Background: AAG is a rare disorder characterized by subacute, generalized sympathetic and parasympathetic failure. Pathogenesis is attributed to an underlying Autoimmune etiology, evidenced by detection of ganglionic nicotinic acetylcholine receptor serum antibodies (α3-nAChR). Treatment guidelines are not established, and typically include a combination of immunomodulatory therapies. Design/Methods: Case report. Results: We report a case of a 57-year-old man who presented with worsening orthostatic hypotension over 12 months on a background of seronegative polyarthritis for 15 years. At his initial presentation in 2003, he had symptoms of syncope, sicca, chronic constipation, incomplete bladder emptying, decreased sweating, and weight loss. He was found to have generalized Autonomic dysfunction associated with nAChR of 14.3 nmol/L (normal Etanercept, a tumor necrosis factor-alpha inhibitor was started in 2005 at an outside hospital for treatment of his polyarthritis. The patient experienced symptomatic improvement in AAG with etanercept, with subsequent improvement in Autonomic function testing (AFT). He now presents with clinical deterioration in the setting of nAChR of 98.5 nmol/L. Quantitative Autonomic testing revealed abnormal parasympathetic (abnormal heart rate variability to deep breathing and Valsalva maneuver) and sympathetic function (abnormal blood pressure response during a Valsalva maneuver and a >100 mmHg drop in systolic blood pressure). Conclusions: This case highlights the inadvertent treatment of AAG for >10 years using etanercept in a patient being treated for seronegative polyarthritis. These findings suggest etanercept may be a novel treatment option for patients with AAG - a disorder that may require two or more immunomodulatory interventions - although the recent resurgent symptoms and increase in antibody titer suggest a limited durability of treatment. Disclosure: Dr. Shekhawat has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Freeman has nothing to disclose. Dr. Gibbons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck Inc.. Dr. Gibbons has received personal compensation in an editorial capacity for Associate Editor for Autonomic Neuroscience: Basic and Clinical. Dr. Gibbons has received compensation for serving on the Board of Directors of Cutaneous NeuroDiagnostics. Dr. Gibbons holds stock and/or stock options in Cutaneous NeuroDiagnostics. Dr. Gibbons has received research support from Grifols Inc..
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Author response: Effects of orthostatic hypotension on cognition in Parkinson disease.
Neurology, 2017Co-Authors: Justin Centi, Christopher H. Gibbons, Roy Freeman, Sandy Neargarder, Alexander O. Canova, Alice Cronin-golombAbstract:We thank Guaraldi et al. for their comment on our article,1 and for drawing our attention to their work assessing cognitive function in patients with peripheral Autonomic disorders, pure Autonomic failure (PAF), and Autoimmune Autonomic neuropathy.2 The results in their study are similar to our results in Parkinson disease (PD),2 and to data we reported earlier on reversible cognitive impairment in individuals with orthostatic hypotension (OH) due to the peripheral disorder Autoimmune AutonomicGanglionopathy.3 Cognitive changes in all of these studies are most significant in the domains of attention and executive functioning; while disease-specific decrements vary across each participant group regardless of posture, the totality of these data strongly suggest an independent effect of OH that may go unnoticed during standard clinical assessment. This is perhaps most relevant for PD, where the management focus tends to be on motor features and OH may be unrecognized whereas dysAutonomic signs are prioritized in Autoimmune Autonomic Ganglionopathy, Autonomic neuropathies, and PAF. All these studies highlight the need for clinical awareness of cognitive impairment in association with OH, and for additional work to delineate the pathophysiologic mechanisms underlying OH-induced cognitive impairment.1–3
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Autoimmune Autonomic Ganglionopathy - Symptom Antibody Correlations (P1.273)
Neurology, 2015Co-Authors: Christopher H. Gibbons, Roy FreemanAbstract:BACKGROUND: Autoimmune Autonomic Ganglionopathy (AAG) is a disorder defined by antibodies to the nicotinic acetylcholine receptor of the Autonomic ganglia (ganglionic AChR). Patients present with symptoms of Autonomic failure including recurrent syncope, orthostatic hypotension, bowel and bladder hypomotility, pupillary dysfunction, dry mouth and dry eyes. We have reported a strong relationship between the ganglionic AChR antibody titer and disease severity early in the clinical course of the disease. METHODS: We report 3 patients with AAG and severe Autonomic failure on chronic immunosuppression for treatment of AAG (all with AChR titers >2 nnmol/L). The goal of immunomodulatory therapy (mycophenolate mofetil and intermittent plasma exchange) was symptomatic relief (generally achieved with AChR titers
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Autoimmune Autonomic Ganglionopathy symptom antibody correlations p1 273
Neurology, 2015Co-Authors: Christopher H. Gibbons, Roy FreemanAbstract:BACKGROUND: Autoimmune Autonomic Ganglionopathy (AAG) is a disorder defined by antibodies to the nicotinic acetylcholine receptor of the Autonomic ganglia (ganglionic AChR). Patients present with symptoms of Autonomic failure including recurrent syncope, orthostatic hypotension, bowel and bladder hypomotility, pupillary dysfunction, dry mouth and dry eyes. We have reported a strong relationship between the ganglionic AChR antibody titer and disease severity early in the clinical course of the disease. METHODS: We report 3 patients with AAG and severe Autonomic failure on chronic immunosuppression for treatment of AAG (all with AChR titers >2 nnmol/L). The goal of immunomodulatory therapy (mycophenolate mofetil and intermittent plasma exchange) was symptomatic relief (generally achieved with AChR titers <0.2 nmol/L). After 5 years of stable symptoms, immunomodulatory therapy was tapered in order to determine the need for long term therapy. RESULTS: In all 3 cases, immunosuppressive therapy ceased after a period of taper (3-6 months). In 2 of 3 cases the symptoms of Autonomic failure did not recur during 18 months of follow up. During those 18 months, AChR antibodies rose from 2 nmol/L with no evidence of Autonomic failure. No orthostatic hypotension was detected, although symptoms of bowel and bladder dysfunction increased slightly. Pupillary reactivity was diminished. In the 3 rd case, antibody titers rose quickly after cessation of immunomodulatory therapy and severe Autonomic failure was evident within 3 months (with orthostatic hypotension, gastroparesis, urinary retention and fixed dilated pupils), requiring reinstitution of immunomodulatory therapy. CONCLUSIONS: In patients with chronic AAG, the ganglionic AChR antibody titers may not predict clinical outcomes and the need for ongoing immunosuppressive therapy should be based on symptoms and signs of Autonomic failure. The mechanisms that underlie the lack of antibody symptom correlation in the chronic disease are not known. Study Supported by: NIH U54NS065736 Disclosure: Dr. Gibbons has received personal compensation for activities with Pfizer Inc. and Grifols as a scientific advisory board member. Dr. Freeman has received personal compensation for activities with Pfizer, Abbott, Chelsea, and Johnson & Johnson. Dr. Freeman has received personal compensation in an editorial capacity for Autonomic Neuroscience- Basic and Clinical.
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A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy
Archives of Neurology, 2012Co-Authors: Srikanth Muppidi, Christopher H. Gibbons, Maggie Scribner, Beverley Adams-huet, Elaine B. Spaeth, Steven VerninoAbstract:Objective To demonstrate a unique abnormality of the pupillary light reflex in patients with Autoimmune Autonomic Ganglionopathy (AAG). Design Case series. Setting Autonomic clinics at 2 university hospitals (University of Texas Southwestern Medical Center and Beth Israel Deaconess Medical Center). Participants Seven patients with antibody-positive AAG. Interventions All patients with AAG underwent either monocular or binocular infrared pupillometry using a standard 2-second light stimulus at a defined intensity. Findings were compared with those from healthy control subjects and patients with other Autonomic disorders. The light stimulus used in this study was selected to eliminate the normal phenomenon of pupil escape. Main Outcome Measures The time to onset of redilation as well as other indices of pupillary constriction to light stimulus. Results Patients with AAG exhibited premature pupillary redilation (mean [SD], 1.02 [0.20] seconds) compared with healthy control subjects (mean [SD], 2.24 [0.10] seconds) and other patients with Autonomic disorders (mean [SD], 2.30 [0.12] seconds) (P Conclusions Premature redilation of the pupil is a unique physiological feature seen only in patients with AAG. This phenomenon appears to be a manifestation of pupillary fatigue, a clinical correlate of defective synaptic transmission at the level of Autonomic ganglia in antibody-positive AAG.
