Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs).
METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI.
RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature.
CONCLUSIONS: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

UNASSIGNED: Autoimmune autonomic ganglionopathy (AAG) is characterized by serum autoantibodies against the ganglionic acetylcholine receptor (gAChR). Immunomodulatory treatments may alleviate AAG symptoms, but the most appropriate treatment strategy is unclear.
UNASSIGNED: This study aimed to confirm the effectiveness of treatments, particularly immunotherapy, in patients with seropositive AAG in Japan, as well as to determine the most effective treatment and the best assessment method for clinical response to treatment.
UNASSIGNED: We collected data from a previous cohort study of patients with seropositive AAG. The clinical autonomic and extra-autonomic symptoms were objectively counted and subjectively assessed using the modified Composite Autonomic Symptom Score. Post-treatment changes in the gAChR antibody level were evaluated.
UNASSIGNED: Thirty-one patients received immunotherapy. Among them, 19 patients received intravenous methylprednisolone; 27, intravenous immunoglobulin; 3, plasma exchange; 18, oral steroids; 2, tacrolimus; 1, cyclosporine; and 1, mycophenolate mofetil. Patients who received immunotherapy showed improvements in the total number of symptoms (from 6.2 ± 2.0 to 5.1 ± 2.0) and modified Composite Autonomic Symptom Score (from 37.4 ± 15.3 to 26.6 ± 12.8). Orthostatic intolerance, sicca, and gastrointestinal symptoms were ameliorated by immunotherapy. Immunotherapy decreased the antibody levels (gAChRα3 antibodies, from 2.2 ± 0.4 to 1.9 ± 0.4, p = 0.08; gAChRβ4 antibodies, from 1.6 ± 0.1 to 1.0 ± 0.2, p = 0.002), but antibody levels increased in 10 patients despite immunotherapy. The rate of improvement in the total number of symptoms was higher in patients with combined therapy than in patients with non-combined therapy (70.7% vs 28.6%).
UNASSIGNED: The scores in many items on the rating scale decreased after immunotherapy in patients with seropositive AAG, particularly in the combined immunotherapy group. However, more accurate assessment scales for clinical symptoms and multicenter randomized, placebo-controlled prospective studies are warranted to establish future treatment strategies.

Autoimmune autonomic ganglionopathy (AAG) is a rare post-ganglionic disorder that causes a range of symptoms, often including gastrointestinal disorders. Patients may be seropositive or seronegative for antibodies against the nicotinic acetylcholine receptor. Here, we describe the case of a 56-year-old woman with a previous diagnosis of sensorimotor peripheral neuropathy who presented with severe constipation that was not responsive to laxative therapy. The evaluation showed diffuse colonic hypomotility, rectal hypersensitivity, and type IV pelvic floor dysfunction. The patient was diagnosed 10 months after the presentation as having seronegative AAG, and she responded well to treatment with intravenous methylprednisolone and apheresis.

Commercially available antibodies that bind to the human muscle acetylcholine receptor (ACHR) have been validated previously for flow cytometric use (Keefe et al., 2009; Leite et al., 2008; Lozier et al., 2015). Despite a multitude of commercially available antibodies to other nicotinic ACHRs, validation in a wide variety of immunoassay formats is lacking; when studied, a large proportion of these antibodies have been deemed not fit for most research purposes (Garg and Loring, 2017). We have recently described a flow cytometric immunomodulation assay for the diagnosis of Autoimmune Autonomic Ganglionopathy (AAG) (Urriola et al., 2021) that utilises the monoclonal antibody mab35(Urriola et al., 2021) which is specific for ganglionic ACHR (gnACHR) that contain α3 subunits (Vernino et al., 1998). Other fluorescent ligands for α3-gnACHR have not been validated for flow cytometric use. We investigated 7 commercially sourced antibodies and 3 synthetic fluorescent novel conotoxins purported to specifically bind to the extracellular domains of the gnACHR, and compared the results to staining by mab35, using flow cytometry with the neuroblastoma cell line IMR-32. We also evaluated the degree of non-specific binding by depleting the cell membrane of the relevant acetylcholine receptor with a pre-incubation step involving the serum from a patient with Autoimmune Autonomic Ganglionopathy containing pathogenic antibodies to the ganglionic acetylcholine receptor. None of the assessed conotoxins, and only one antibody (mab35) was found to perform adequately in flow cytometric staining of the native ganglionic acetylcholine receptor.

Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. An early systematic analysis of autonomic dysfunction following COVID-19 is lacking and may provide initial insights into the spectrum of this condition.
We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021.
We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%); 22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy.
Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.

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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.

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.