Ganglionic Acetylcholine Receptor Antibodies Research Articles

The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study.

Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent gastrointestinal symptoms. Clinically, FD and IBS often resemble gastrointestinal dysmotility caused by autoimmune autonomic neuropathy. We examined the seropositive frequency of autoantibodies against ganglionic nicotinic acetylcholine receptors (gnAChRs) in patients presenting with FGIDs. To elucidate the seropositivity of gnAChR antibodies and the clinical features of seropositive FD and IBS. We measured autoantibodies against the gnAChR α3 and β4subunits using luciferase immunoprecipitation systems. Serum samples from patients with any autonomic symptoms were obtained from hospitals in Japan between January 2012 and August 2018 (1787 serum samples of 1381 patients). We selected FD and IBS patients and compared the clinical characteristics and prevalence of autonomic symptoms between those with seropositive and seronegative IBS and FD. Nine IBS and two FD cases (one comorbid case with IBS) were found. We found four patients (36.4%) in whom gnAChR antibodies were positive in these eleven patients. Sicca symptoms were observed in three of four cases (75%) of seropositive FGID compared with zero of seven cases (0%) of seronegative FGID. We found patients with gnAChR antibodies in FD and IBS patients. These data will be valuable for elucidating the pathophysiology of these FGIDs and developing new treatment strategies.

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

A Flow Cytometric Assay to Detect Functional Ganglionic Acetylcholine Receptor Antibodies by Immunomodulation in Autoimmune Autonomic Ganglionopathy.

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.

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy.

The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

Ganglionic acetylcholine receptor antibodies in autoimmune autonomic ganglionopathy: Characteristics, clinical features and outcomes

Ganglionic acetylcholine receptor antibodies in autoimmune autonomic ganglionopathy: Characteristics, clinical features and outcomes

Alpha 3 ganglionic acetylcholine receptor antibody associated refractory status epilepticus

Autoimmune encephalitides are a group of syndromes that may present with subacute onset of disorientation, personality changes, memory loss and most prominently seizures. Earlier reports of this entity were from patients with paraneoplastic limbic encephalitis, however autoimmune etiologies have also been described in patients with non-paraneoplastic encephalitis [1]. The Alpha 3 ganglionic acetylcholine receptor autoantibody (a3-AChR Ab) mainly causes autoimmune dysautonomia that is either subacute or insidious in onset. A direct relationship betweenantibody titer and severity of dysautonomia occurs in both experimental animals and patients [2]. Most of these cases have been paraneoplastic (mainly adenocarcinomas) however a few cases have been linked to other autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome. Patients who are seropositive for a3-AChR Ab may present with less common neurological manifestations such as peripheral neuropathies, encephalopathy and subacute neuropsychiatric presentations. This report presents a unique case of refractory new-onset status epilepticus associated with a3-AChR antibody which responded to immunotherapy.

Clinical experience of seropositive ganglionic acetylcholine receptor antibody in a tertiary neurology referral center.

Antibody against the acetylcholine receptor of autonomic ganglia (gAChR-Ab) is implicated in the pathogenesis of autoimmune autonomic ganglionopathy (AAG) and several other disorders. This study was a retrospective evaluation of 95 patients positive for gAChR-Ab. Twenty-one (22%) patients had AAG, with a greater median gAChR-Ab level (0.21 nmol/L) and higher percentage (57%) of antibody levels >0.20 nmol/L when compared with the remaining 74 patients without autonomic manifestations (non-AAG group, 0.10 nmol/L and 15%, respectively). Only 2 new cases of malignancy were diagnosed after gAChR-Ab detection. The non-AAG group was associated with high frequencies of neurological and non-neurological autoimmunity, but also included 23 (31%) patients with mostly degenerative disorders. Detection of gAChR-Ab, especially at a higher level, is helpful for the diagnosis of AAG in patients with corresponding autonomic symptoms. However, its value is limited for predicting cancer risk and for diagnosis and management of patients without autonomic symptoms.

Autoimmune autonomic ganglionopathy

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder of widespread autonomic failure. Approximately half of the patients with AAG have the autoantibodies against the neuronal nicotinic acetylcholine receptor (AChR) in autonomic ganglia. These ganglionic AChR antibodies have the potential to mediate the synaptic transmission in sympathetic, parasympathetic, and enteric ganglia. Therefore, seropositive AAG patients exhibit various autonomic symptoms. Extra-autonomic manifestations (coexistence with brain involvement, sensory disturbance, endocrine disorders, autoimmune diseases and tumors) are present in many patients with AAG. The nicotinic AChRs comprise a family of abundantly expressed ligand-gated cation channels found throughout the central and peripheral nervous systems. Moreover, limited manifestations of autoimmune dysautonomia including autoimmune gastrointestinal dysmotility are newly recognized clinical entity. Although combined immunomodulatory therapy is beneficial for almost all patients with AAG, several case reports of some AAG patients with small benefit exist. This review focuses on the recent progress in the clinical approaches of AAG and its related disorders involving the role of autoantibodies and clinical practice.

Paraneoplastic sensory neuropathy and ganglionic acetylcholine receptor antibody

Paraneoplastic sensory neuropathy and ganglionic acetylcholine receptor antibody

Recent advances in autoimmune autonomic ganglionopathy

This review highlights recent advances in our understanding of autoimmune autonomic ganglionopathy (AAG) including serological diagnosis, clinical observations, pathophysiology, and treatment. Classical AAG is a subacute disorder associated with antibodies against ganglionic acetylcholine receptors. Recent observations demonstrate that these antibodies cause a specific inhibition of synaptic transmission in autonomic ganglia and antibody levels correlate in a predictable way with severity of autonomic failure. Ganglionic acetylcholine receptor antibodies can be associated with other neurological disorders including chronic or restricted forms of autonomic dysfunction and with neurological or paraneoplastic disorders unrelated to the autonomic nervous system. Treatment of AAG is based on case reports. It is clear that AAG patients respond to immunomodulatory treatments but combination immunotherapy may be required to achieve a clinical response. Recently, additional clinical observations indicate that AAG patients may also show signs of treatment-responsive cognitive impairment. The pathophysiology and varied clinical presentation of AAG are becoming more clear. AAG is a treatable antibody-mediated disorder of autonomic ganglionic synaptic transmission. Future studies will continue to define the optimal diagnostic and therapeutic approach to autoimmune autonomic disorders.

Isolated Sympathetic Failure With Autoimmune Autonomic Ganglionopathy

A 16-year-old boy had a gradual onset of post-exercise myalgia with progressive fatigue and dizziness. He had bradycardia (37 beats/minute) with low supine and normal standing norepinephrine levels (56 and 311 pg/mL, respectively). He had absent sympathetically mediated vasoconstrictor responses during Valsalva maneuver testing. Circulating ganglionic acetylcholine receptor antibodies were identified. Response was gradual to treatment with intravenous immunoglobulin combined with aggressive symptomatic interventions (permanent pacemaker implantation and treatment with pyridostigmine, midodrine, and modafinil). After the intravenous immunoglobulin treatment, his autoantibody levels decreased and the autonomic abnormalities resolved. After a reconditioning exercise program and eventually undetectable antibody titers, he achieved complete recovery. The patient continued to do well after his pacemaker was removed and his medications were discontinued. Thus, severe isolated sympathetic nervous system failure can occur in adolescents with autoimmune autonomic ganglionopathy, and multifaceted treatment can be effective.

Autoimmune autonomic ganglionopathy with Sjögren's syndrome: Significance of ganglionic acetylcholine receptor antibody and therapeutic approach

Autoimmune autonomic ganglionopathy (AAG) is a disorder defined by antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia. We report two patients with chronically progressing dysautonomia with Sjögren's syndrome (SS). The first case showed elevated titer of ganglionic acetylcholine receptor (AChR) antibody and improved with oral intake of prednisolone. In contrast, the second case showed no elevation of ganglionic AChR antibody titer and had poor response to immunomodulatory therapy. These two cases indicate that chronic AAG may be treatable by immunomodulatory therapy, and have relevance to SS.

Antibody testing as a diagnostic tool in autonomic disorders

Some forms of peripheral autonomic dysfunction (especially enteric neuropathy and subacute panautonomic failure) occur as autoimmune phenomena either in isolation or in the context of cancer. Autoimmune autonomic ganglionopathy is an example of a severe, but potentially treatable, antibody-mediated form of autonomic failure. Diagnostic evaluation of autonomic disorders can be supplemented by testing for paraneoplastic antibodies and antibodies against membrane receptors. The diagnostic antibodies most commonly associated with dysautonomia are paraneoplastic antibodies (anti-Hu and CRMP-5) and ganglionic acetylcholine receptor antibodies.

Characterization of ganglionic acetylcholine receptor autoantibodies

In myasthenia gravis (MG), autoantibodies bind to the α1 subunit and other subunits of the muscle nicotinic acetylcholine receptor (AChR). Autoimmune autonomic ganglionopathy (AAG) is an antibody-mediated neurological disorder caused by antibodies against neuronal AChRs in autonomic ganglia. Subunits of muscle and neuronal AChR are homologous. We examined the specificity of AChR antibodies in patients with MG and AAG. Ganglionic AChR autoantibodies found in AAG patients are specific for AChRs containing the α3 subunit. Muscle and ganglionic AChR antibody specificities are distinct. Antibody crossreactivity between AChRs with different α subunits is uncommon but can occur.

Evaluation and Management of Autonomic Nervous System Disorders

Autonomic nervous system dysfunction may manifest with a variety of symptoms, with orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweating abnormalities (increased or decreased sweating) being common problems requiring medical evaluation and treatment. Determination of the underlying diagnosis for these symptoms is critical in terms of classification of the disorder and its prognosis. Recent advances in evaluation of patients with these conditions and treatment modalities have enabled physicians to improve overall management of patients with these disorders. These advances include testing for ganglionic acetylcholine receptor antibody in patients with suspected autoimmune autonomic neuropathy and use of pyridostigmine for treatment of patients with orthostatic hypotension or tachycardia.

Antibodies to muscle and ganglionic acetylcholine receptors (AchR) in celiac disease

Background: About 2.5% of patients with idiopathic peripheral neuropathy or idiopathic dysautonomia have underlying celiac disease (CD). Antibodies to ganglioside have been reported in CD patients with neuropathy. No data are so far available on the presence in CD of acetylcholine receptor (AChR) antibodies. Muscle AChR antibodies are found in patients with myasthenia gravis, and ganglionic AChR antibodies in patients with autoimmune autonomic neuropathy.Objective: To determine the frequency of AChR antibodies in CD patients and assess possible correlations with neurological manifestations.Methods: Seventy CD patients (16 M, 54 F, mean age 36 years) underwent neurological and electrophysiological evaluation. AChR antibodies were detected with radioimmunoprecipitation assay. Sera from 15 age-matched patients with systemic lupus erythematosus (SLE) and 10 with Sjogren syndrome were studied as controls.Results: None of our CD patients complained of autonomic symptoms or fatigable weakness. Borderline titres (0.03–0.05 nmol/l) of ganglionic AChR antibodies were present in 4 patients, one affected with type I diabetes and one with subclinical neuropathy. Three of the 4 patients underwent cardiovascular autonomic function tests, which showed no abnormalities. Low levels of ganglionic AChR antibodies (0.05–0.10 nmol/l) were found in 2 SLE control patients, one of whom had a severe sicca complex. Muscle AChR antibodies (>1.0 nmol/l) were found in two CD patient and one control patient with SLE. Neither had symptoms or signs of myasthenia gravis.Discussion and conclusions: CD is occasionally associated with neurologic disease, and with antibody reactivity to neuronal antigens. None of our CD patients had autonomic failure or significant levels of ganglionic AChR antibodies. Two CD patient and one control with SLE had muscle AChR antibodies without clinical evidence of myasthenia. The presence of antibodies in CD and in SLE patients may reflect a non-specific autoimmune response in these patients or may indicate subclinical autoimmune autonomic and neuromuscular involvement.

Whole-Body Tremulousness

Acquired generalized repetitive myoclonus may be mistaken for tremor. Distinguishing myoclonus has etiologic and therapeutic implications. To describe isolated generalized polymyoclonus and the outcomes of etiologic evaluations at the time of diagnosis. Computer search of the Mayo Movement Neurophysiology Laboratory database and medical records linkage system. Department of Neurology, Mayo Clinic. Nineteen adults with generalized repetitive myoclonus confirmed using surface electromyography (burst duration <50 milliseconds), and other neurologic features minimal or absent. Treatment of myoclonus and underlying causes. Clinical presentation and underlying etiologies. We identified 19 patients with isolated generalized polymyoclonus resembling whole-body tremor. Onset was most often subacute (12 patients), mean symptom duration was 1.8 years, and mean age at onset was 55 years. Referral diagnoses or patient complaints were tremor, tremulousness, or shaking in all but 5 patients. All the patients had repetitive myoclonus of all limbs, impairing gait in 14 patients. Surface electromyography confirmed nonperiodic muscle burst durations of less than 50 milliseconds, typical of myoclonus. Clinical and serologic screening for cancer and autoimmunity revealed metastatic breast cancer in 2 patients (1 positive for ganglionic acetylcholine receptor antibody) and antibody profiles implicating neurologic autoimmunity in 3 patients (CRMP-5 IgG or neuronal voltage-gated potassium channel antibodies). Medications known to occasionally trigger myoclonus (opioids, selective serotonin reuptake inhibitors, and a serotonin-norepinephrine reuptake inhibitor) were being taken by 7 patients. Myoclonus resolved after discontinuation of selective serotonin reuptake inhibitor therapy in 1 patient; drug discontinuation was declined and follow-up was inadequate in the other 6. Isolated whole-body tremulousness should raise the suspicion of generalized polymyoclonus, confirmed using routine surface electromyography. Recognition is important because the differential diagnosis includes autoimmunity and drug-induced myoclonus.

Postural Orthostatic Tachycardia Syndrome: The Mayo Clinic Experience

To evaluate the prevalence and pathogenetic mechanisms of postural orthostatic tachycardia syndrome (POTS). We reviewed the medical records of patients with POTS seen at the Mayo Clinic in Rochester, Minn, from January 1, 1993, through December 31, 2003. All patients were required to have had a full autonomic reflex screen. The results of the following additional tests were evaluated: thermoregulatory sweat test, plasma catecholamine measurement, serum ganglionic (a3) acetylcholine receptor antibody detection, and 24-hour urinary sodium measurement. We identified 152 patients (86.8% female; mean +/- SD age, 30.2+/-10.3 years) with a mean duration of symptoms of 4.1 years. The mean orthostatic heart rate increment was 44 beats/min. Half the patients had sudomotor abnormalities (apparent on both the quantitative sudomotor axon reflex test and thermoregulatory sweat test), and 34.9% had significant adrenergic impairment, indicating that at least half of the patients had a neuropathic pattern of POTS. In 13.8% of patients, onset was subacute, and ganglionic acetylcholine receptor antibody was detected in 14.6%, suggesting an autoimmune origin in at least 1 in 7 patients. Hyperadrenergic status was documented in 29.0% of patients (standing plasma norepinephrine level 2600 pg/mL), and at least 28.9% were presumably hypovolemic (24-hour urinary sodium level <100 mEq/24h). The lack of correlation between urinary sodium and standing norepinephrine levels suggests that mechanisms other than hypovolemia accounted for the hyperadrenergic state. Our findings suggest a neuropathic basis for at least half the cases of POTS and that a substantial percentage of cases may be autoimmune. Hyperadrenergic and hypovolemic correlates are likely compensatory or exacerbating.

Passive transfer of autoimmune autonomic neuropathy to mice.

Autoimmune autonomic neuropathy (AAN) is an acquired, often severe, form of dysautonomia. Many patients with AAN have serum antibodies specific for the neuronal ganglionic nicotinic acetylcholine receptor (AChR). Rabbits immunized with a fusion protein corresponding to the N-terminal extracellular domain of the ganglionic AChR alpha3 subunit produce ganglionic AChR antibodies and develop signs of experimental AAN (EAAN) that recapitulate the cardinal autonomic features of AAN in man. We now demonstrate that EAAN is an antibody-mediated disorder by documenting sympathetic, parasympathetic, and enteric autonomic dysfunction in mice injected with rabbit IgG containing ganglionic AChR antibodies. Recipient mice develop transient gastrointestinal dysmotility, urinary retention, dilated pupils, reduced heart rate variability, and impaired catecholamine response to stress. The autonomic signs are associated with a reversible failure of nicotinic cholinergic synaptic transmission in superior mesenteric ganglia. Mice injected with IgG from two patients with AAN (of three tested) demonstrated a milder phenotype with evidence of urinary retention and gastrointestinal dysmotility. The demonstration that ganglionic AChR-specific IgG causes impaired autonomic synaptic transmission and autonomic failure in mice implicates an antibody-mediated pathogenesis for AAN. The antibody effect is potentially reversible, justifying early use of immunomodulatory therapy directed at lowering IgG levels and abrogating IgG production in patients with AAN.