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

doi:10.1016/j.jaut.2020.102403

Journal of Autoimmunity

Volume 108, March 2020, 102403

https://doi.org/10.1016/j.jaut.2020.102403 Get rights and content

Highlights

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We screened 1787 sera in Japan using the LIPS for anti-gAChR Abs. (66 characters).
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Anti-gAChR Abs were detected in 179 AAG patients. (49 characters).
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Seropositive AAG included 116 α3-positive, 13 β4-positive, and 50 double positive. (82 characters).
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AAG patients with gAChRβ4 autoantibodies exhibit unique clinical characteristics. (81 characters).
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¹²³I- MIBG myocardial scintigraphy may be useful for monitoring AAG. (68 characters).

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.

Graphical abstract

Introduction

Autoimmune autonomic ganglionopathy (AAG) is a rare disease that presents with various autonomic symptoms. The ganglionic neuronal nicotinic acetylcholine receptor (gAChR) mediates fast synaptic transmission in all peripheral autonomic ganglia in the autonomic nervous system, comprising two α3 subunits and three β4 subunits [1,2]. However, the frequency of symptoms, extra-autonomic manifestations (coexistence with autoimmune rheumatic diseases and tumours, brain involvement, sensory disturbance, and endocrine disorders), laboratory findings, and prognosis of AAG remain largely unknown [3,4]. Approximately 50% of patients with AAG possess autoantibodies (Abs) against the gAChR [5,6]. Originally, gAChR Abs found in patients with AAG were thought to be specific for acetylcholine receptors (AChRs) containing the α3 subunit and were not assumed to bind non-specifically to nicotinic AChRs (nAChRs). Several previous reports have described the autonomic symptoms of gAChR Ab-positive AAG as severe, widespread, and predominantly post-ganglionic in distribution. Moreover, such studies have revealed that Ab levels are correlated with disease severity and pathogenesis [7,8]. Our previous study was the first to identify a subunit-specific Ab for gAChR (i.e., anti-gAChRβ4) [6]. Another subunit-specific Ab for gAChR, anti-gAChRα3, has been associated with several autonomic dysfunctions in an experimental model of AAG [[9], [10], [11], [12]]. Despite our previous findings, the clinical characteristics of patients with AAG who are seropositive for the gAChRβ4 Ab remain unknown. Therefore, we evaluated the frequency of individual autonomic symptoms and extra-autonomic manifestations such as sensory disturbance, central nervous system (CNS) involvement, endocrine disorders, and comorbid diseases (i.e., autoimmune diseases, tumours) in patients with AAG testing positive for gAChRα3 Abs, gAChRβ4 Abs, or both [3,13].

Differentiating AAG from other neurological disorders presenting with autonomic dysfunction via clinical and laboratory tests is often difficult [14]. In addition to anti-gAChR Ab levels, effective clinical tools are required to improve AAG diagnosis and monitoring. Neuroimaging data may aid in identifying clinically relevant post-ganglionic denervation. Metaiodobenzylguanidine (MIBG) is a physiological analogue of noradrenaline, which is taken up by the myocardium and actively transported into the noradrenaline granules of sympathetic nerve terminals by the noradrenaline transporter. Indeed, ¹²³I-MIBG myocardial scintigraphy may assist in evaluating damage to postganglionic fibres of the cardiac sympathetic nerve based on decreases in the heart-to-mediastinum (H/M) ratio. We previously mentioned the usefulness of ¹²³I-MIBG myocardial scintigraphy for AAG diagnosis [3]. Myocardial scintigraphy is generally used to evaluate autonomic function in patients with suspected Lewy body disease or autonomic neuropathies such as diabetic neuropathy or familial amyloid polyneuropathy [[15], [16], [17], [18]]. However, no similar studies have been performed among patients with AAG. Therefore, the secondary aim of the present study was to determine the value of ¹²³I-MIBG myocardial scintigraphy for AAG diagnosis, relative to other laboratory evaluations.

The present study aimed to determine the clinical characteristics of patients with AAG testing positive for gAChRβ4 Ab. We examined the frequency of autonomic and extra-autonomic manifestations in 179 patients with AAG testing positive for gAChRα3 Abs, gAChRβ4 Abs, or both Abs. Furthermore, our study highlights the value of ¹²³I-MIBG myocardial scintigraphy for AAG diagnosis.

Section snippets

Standard protocol approvals and patient consent

All patients provided written, informed consent before participating in the present study. The Human Ethics Committees at the Nagasaki Kawatana Medical Center and Kumamoto University Hospital (Japan) approved this study (approval number 2011-21 and 1281, respectively).

Study design and participants

We obtained 1787 serum samples (from 1381 patients) from teaching and general hospitals throughout Japan between January 2012 and August 2018 (Supplementary data 1). Clinical diagnoses were made in each hospital. All hospitals

Clinical features of patients with seropositive AAG

Although patients were divided into subgroups based on the time course of their illness, chronic AAG was the predominant subtype in our study (133/179, 74%) (Table 1). Among those with chronic AAG, 12 patients (12/133, 9%) experienced an antecedent event, whereas 13 of 46 (28%) patients in the acute AAG group experienced an antecedent event. Twenty-five patients (14%) reported antecedent events shortly before the start of autonomic symptoms: flu-like symptoms (n = 11), enterocolitis (n = 9),

Discussion

In the present study, we investigated the clinical symptoms involving autonomic and extra-autonomic manifestations, and laboratory findings among a diagnosed cohort of 179 patients with AAG who tested positive for gAChRα3 Abs, gAChRβ4 Abs, or both. The gAChR Abs have the potential to physiologically block the ganglionic synaptic transmission in the both of sympathetic and parasympathetic nervous system [1,12]. Our findings indicated that autonomic and extra-autonomic dysfunction (i.e., sicca

Declaration of competing interest

None of the authors have any conflicts of interest to disclose.

Acknowledgements

The authors would like to thank Dr. S. Orimo (Department of Neurology, Kanto Central Hospital, Tokyo, Japan) for helpful discussions.

The authors are grateful to Drs. Masataka Umeda, Kunihiro Ichinose, Hideki Nakamura, Hitomi Minami, Hajime Isomoto, Akio Ido, Kiyoshi Migita, and Kazuhiko Nakao for useful discussions. The authors are indebted to members of Kumamoto University Hospital Department of Neurology and Nagasaki Kawatana Medical center Department of Neurology for discussing some issues

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Citation Excerpt :
Finally, the introduction of any protein-based label (in this case, GL8990) can introduce sites for specific or non-specific binding of antibodies; indeed, false positive autoantibody results in Gaussia-luciferase LIP systems have been described [11]. Furthermore, from a clinical perspective, results of the LIP assay do not correlate with objective measures of autonomic failure [57]. These limitations for the LIP approach in detecting gnACHR antibodies may be responsible for the observed high rate of seropositivity for either α3 or β4 subunit autoantibodies in a wide range of unrelated disorders, many of which do not have objective findings consistent with true AAG (Table 2).
Autoimmune Autonomic Ganglionopathy (AAG) is a rare immune-mediated disease of the autonomic nervous system. The incidence of AAG is unknown and diagnosis is often difficult due to the multicompartmental nature of the autonomic nervous system - sympathetic, parasympathetic and enteric components – with variable severity and number of components affected. Diagnostic confidence is increased when ganglionic acetylcholine receptor (gnACHR) autoantibodies are detected. Three gnACHR autoantibody diagnostic assays have been described (two binding assays, one receptor immunomodulation assay), but cross-validation between assays is limited. The prevalence of gnACHR autoantibodies in AAG is not known, with application of different clinical and laboratory criteria in the few studies of AAG cohorts and large retrospective laboratory studies of positive gnACHR autoantibodies lacking adequate clinical characterisation. Furthermore, the rate of unexpected gnACHR autoantibody positivity in conditions without overt autonomic dysfunction (false positive results) adds to the complexity of their interpretation. We review the pathophysiology of gnACHR autoantibodies and assays for their detection, with immunomodulation and high titer radioimmunoprecipitation results likely offering better AAG disease identification.
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A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Standard protocol approvals and patient consent

Study design and participants

Clinical features of patients with seropositive AAG

Discussion

Declaration of competing interest

Acknowledgements

J. Neuroimmunol.

Exp. Neurol.

Mayo Clin. Proc.

Auton. Neurosci.

Auton. Neurosci.

Lancet

Transl. Res.

Auton. Neurosci.

Handb. Clin. Neurol.

Mayo Clin. Proc.

Mult. Scler. Relat. Disord.

J. Nucl. Cardiol.

Prog. Neurobiol.

Auton. Neurosci.

Exp. Neurol.

Handb. Clin. Neurol.

Auton. Neurosci.

Extra-autonomic manifestations in autoimmune autonomic ganglionopathy: a Japanese survey

J. Neurol. Neurosurg. Psychiatry

Autoimmune autonomic ganglionopathy: an update on diagnosis and treatment

Expert Rev. Neurother.

Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies

N. Engl. J. Med.

Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients

PLoS One

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

J. Clin. Investig.

Experimental autoimmune autonomic neuropathy

J. Neurophysiol.

Passive transfer of autoimmune autonomic neuropathy to mice

J. Neurosci.

Invited article: autonomic ganglia: target and novel therapeutic tool

Neurology