Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure

Cutsforth‐Gregory, Jeremy K.; McKeon, Andrew; Coon, Elizabeth A.; Sletten, David M.; Suarez, Mariana D.; Sandroni, Paola; Singer, Wolfgang; Benarroch, Eduardo E.; Fealey, Robert D.; Low, Phillip A.

doi:10.1016/j.mayocp.2018.05.033

Cited by 24 publications

(17 citation statements)

References 37 publications

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“…These factors may explain the unexpected findings discussed above of a high proportion of gnACHR subunit specific antibody positivity in patients with SLE assessed by LIPS (9.4% ( 9 )), even without autonomic dysfunction., which was not seen in our immunomodulation assay. The RIA assay also displays great analytical sensitivity, but at the cost of specificity when the decision limit is low; the current decision limit for the gnACHR antibody RIA performed at Mayo Clinic (Rochester) is 20pM ( 25 ), although this test only starts being reasonably specific for clinically meaningful autonomic failure at 200pM, and very specific at levels above 400pM ( 8 ), which is further verified in a study by the Oxford group in which AAG patients, when seropositive for gnACHR antibodies, have levels that exceed 200pM ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

“…Binding assays include the radioimmunoprecipitation assay (RIA) and the Luciferase Immunoprecipitation assay (LIPS), that are reported to have a sensitivity and specificity of 50 and 100%, respectively ( 3 , 5 ), with antibody levels directly correlated with severity of autonomic impairment. The RIA is, however, only moderately specific (92%) in AAG with severe autonomic dysfunction, with low positive levels not associated with autonomic impairment ( 8 ). Likewise, positive results can be seen in up to 16.3% of patients with autoimmune disorders without autonomic impairment when assessed by the LIPS assay ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Fifty percent of patients have a detectable antibody to the ganglionic nicotinic acetylcholine receptor (gAChR‐Ab), which mediates fast synaptic transmission at sympathetic, parasympathetic, and enteric autonomic ganglia 1 . Higher antibody levels have been associated with a greater degree of autonomic dysfunction 2 ; whereas low titres <200 pM are nonspecific in the absence of autonomic failure 3 . Passive and active immunization studies have provided strong evidence for the pathogenicity of the ganglionic antibody 4,5 .…”

mentioning

confidence: 99%

“…Patients with AAG can respond to immunotherapy, but the response of individual patients varies and multiple immunomodulatory agents may be needed 11–14 . Previous studies have largely utilized cardiovascular and sudomotor assessments when attempting to objectively quantify the severity of autonomic failure and treatment response in patients with AAG, failing to capture the pupillary, urinary, and secretomotor deficits that are prominent in this disease 1,3,12,13,15 . For example, Iodice and colleagues described a patient with low Composite Autonomic Severity Score (CASS), derived from cardiovascular and sudomotor testing, that poorly reflected her multiple prominent autonomic symptoms, measured by the Composite Autonomic Symptom Score (COMPASS) questionnaire, and a mismatch in CASS and COMPASS changes after immunotherapy 12 .…”

mentioning

confidence: 99%

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

Koay

Vichayanrat

Bremner

et al. 2021

Annals of Neurology

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Objective 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. Methods 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. Results 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. Interpretation 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

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“…At the level of sympathetic ganglia, widespread sudomotor deficits have been described in autoimmune autonomic ganglionopathy, in which antibodies to the α3-ganglionic nicotinic acetylcholine receptor may be associated with a spectrum of generalized or limited autonomic disorders, including gastrointestinal dysmotility, orthostatic hypotension, abnormal pupillary responses, atonic bladder, postural tachycardia, and cognitive impairment. [46][47][48] Mixed postganglionic and preganglionic patterns of anhidrosis have been described, suggesting that antibody-mediated sudomotor pathology involves lesions at both the sympathetic ganglia and postganglionic axons. 49,50 Anhidrosis or hypohidrosis occurs in more than 80% of cases of Lambert-Eaton myasthenic syndrome, in which there is loss of functional P/Q-type voltage-gated calcium channels on presynaptic nerve terminals.…”

Section: Peripheral Nervous System Diseasementioning

confidence: 99%

Sudomotor Dysfunction

Cheshire

2020

Semin Neurol

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Disorders of sudomotor function are common and diverse in their presentations. Hyperhidrosis or hypohidrosis in generalized or regional neuroanatomical patterns can provide clues to neurologic localization and inform neurologic diagnosis. Conditions that impair sudomotor function include small fiber peripheral neuropathy, sudomotor neuropathy, myelopathy, α-synucleinopathies, autoimmune autonomic ganglionopathy, antibody-mediated hyperexcitability syndromes, and a host of medications. Particularly relevant to neurologic practice is the detection of postganglionic sudomotor deficits as a diagnostic marker of small fiber neuropathies. Extensive anhidrosis is important to recognize, as it not only correlates with symptoms of heat intolerance but may also place the patient at risk for heat stroke when under conditions of heat stress. Methods for assessing sudomotor dysfunction include the thermoregulatory sweat test, the quantitative sudomotor axon reflex test, silicone impressions, and the sympathetic skin response.

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Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure

Cited by 24 publications

References 37 publications

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

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

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

Sudomotor Dysfunction

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