Association between neurosarcoidosis with autonomic dysfunction and anti-ganglionic acetylcholine receptor antibodies

Journal of Neurology https://doi.org/10.1007/s00415-021-10551-4 ORIGINAL COMMUNICATION Association between neurosarcoidosis with autonomic dysfunction and anti‑ganglionic acetylcholine receptor antibodies Makoto Oishi1 · Akihiro Mukaino1,2 · Misako Kunii3 · Asami Saito3 · Yukimasa Arita4 · Haruki Koike5 · Osamu Higuchi6 · Yasuhiro Maeda1 · Norio Abiru7 · Naohiro Yamaguchi8 · Hiroaki Kawano9 · Eiko Tsuiki10 · Tomonori Tanaka11 · Hidenori Matsuo6 · Masahisa Katsuno5 · Fumiaki Tanaka3 · Akira Tsujino1 · Shunya Nakane2 Received: 25 December 2020 / Revised: 1 April 2021 / Accepted: 5 April 2021 © The Author(s) 2021 Abstract 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. Keywords Neurosarcoidosis · Autonomic dysfunction · Anti-ganglionic acetylcholine receptor antibodies · Small fiber neuropathy 7 Department of Endocrinology and Metabolism, Unit of Advanced Preventive Medical Sciences, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan 8 Department of Psychiatry, Nagasaki University Hospital, Nagasaki, Japan 9 Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan Department of Cardiology, Nagasaki University Hospital, Nagasaki, Japan 10 4 Department of Neurology, Matsuyama Red Cross Hospital, Ehime, Japan Department of Ophthalmology, Nagasaki University Hospital, Nagasaki, Japan 11 5 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan 6 Department of Clinical Research, Nagasaki Kawatana Medical Center, Nagasaki, Japan * Akihiro Mukaino 1 Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan 2 Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, 1‑1‑1, Honjo, Chuo‑ku, Kumamoto 860‑8556, Japan 3 13 Vol.:(0123456789) Journal of Neurology Introduction Sarcoidosis presents with multiple non-caseating granulomas throughout the body, and neurological symptoms are thought to occur in 5–13% of the patients [1, 2]. Approximately 15% of patients with neurosarcoidosis develop peripheral neuropathy [3]. Small fiber neuropathy (SFN), characterized by sensory disturbance and autonomic failure due to damage to the myelinated Aδ and unmyelinated C fibers, is particularly common and has been reported in 44% of patients with sarcoidosis, potentially decreasing their quality of life [4–6]. Autoimmune autonomic ganglionopathy (AAG) is a rare disease characterized by various autonomic symptoms. The ganglionic neuronal nicotinic acetylcholine receptor (gAChR), consisting of two α3 and three β4 subunits, mediates fast synaptic transmission in all peripheral autonomic ganglia in the autonomic nervous system [7]. Antibodies against gAChR are detected in approximately 50% of patients with AAG. Although the clinical features of neurosarcoidosis with dysautonomia are similar to those of AAG, the exact mechanism by which these symptoms arise remains unclear. Herein, we aimed to elucidate the relationship between neurosarcoidosis with autonomic dysfunction and the presence of anti-gAChR antibodies. Methods Patients We examined 1,787 serum samples of 1,381 patients from teaching and general hospitals throughout Japan between January 2012 and August 2018. We detected serum gAChRα3 and β4 antibodies using the Luciferase Immunoprecipitation System assay and retrospectively identified cases that fulfilled the diagnostic guidelines for sarcoidosis [8, 9]. In the present study, antibody levels were expressed as an antibody index (AI), which was calculated as follows: AI = (measured value in the serum sample [in relative luminescence units (RLU)])/(cut-off value [in RLU]). The normal AI value, established based on data from healthy individuals, was < 1.0. We used the criteria for SFN proposed by Lacomis et al. [10], who stated that the diagnosis of SFN consists of three components: (1) symptoms of peripheral paresthesia that are typically painful, (2) specialized electrodiagnostic testing (normal nerve conduction studies and electromyogram), and (3) pathological findings [decreased intra-epidermal nerve fiber density (IENFD)]; these criteria are used to 13 classify SFN as possible (one item positive), probable (two items positive), or definite (three items positive). Clinical data were obtained by reviewing the case records at each hospital. All patients provided written informed consent for the storage and use of their serum and clinical information for research purposes. The study was approved by the Human Ethics Committees at the Nagasaki Kawatana Medical Center and Kumamoto University Hospital (Japan) (approval number 2011–21 and 1281, respectively). Histological analysis of skin biopsy A 3-mm punch biopsy was performed under local anesthesia (1% lidocaine) in the right lower abdomen and medial surface of the right lower leg. Then, 50-μm thick sections were immunostained using anti-human PGP 9.5 rabbit polyclonal rabbit antibody (Bio-Rad formerly AbDserotec #7863–0504, Hercules, CA), and horseradish peroxidase-conjugated antirabbit polyclonal immunoglobulin G secondary antibody (#424,144, NICHIREI BIOSCIENCES INC, Tokyo, Japan). We counted the number of small fibers in the dermis. Literature review A systematic review of the literature was cond (...truncated)