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

BackgroundAutoimmune Autonomic Ganglionopathy (AAG) is a rare, immune-mediated condition characterised by subacute pandysautonomia. 50% have auto-antibodies to the ganglionic nicotinic acetylcholine receptor (gAChR), affecting synaptic transmission at autonomic ganglia.MethodsWe describe 13 patients (5 female, median age 47) presenting with widespread autonomic failure, confirmed on cardiovascular, sudomotor and pupillometry testing at the National Hospital for Neurology and Neurosurgery (NHNN), and high gAChR antibody levels (>200 pm) measured by radioimmunoprecipitation assay at Oxford University.ResultsOf the 13 patients, 8 had other autoimmune conditions, 3 had antecedent infection and 3 were paraneoplastic. All had orthostatic hypotension, gastro-intestinal and urinary symptoms, 11 had documented pupillary abnormalities (9 mixed sympathetic and parasympathetic deficits, 2 subclinical sympathetic deficits), 11 had secretomotor dysfunction, 8 had generalised/partial anhidrosis, 8 had sexual dysfunction and 7 had evidence of small fibre dysfunction on neurophysiology.Ten received immunomodulatory treatment; 6 plasma exchange and 4 combination treatment including intravenous immunoglobulin, mycophenolate and rituximab. Earlier treatment was associated with greater clinical response.DiscussionPatients with AAG and high gAChR antibody levels have widespread dysfunction of the autonomic nervous system, which can respond dramatically to immunomodulation. Further research is needed to develop robust clinical biomarkers to guide treatment and monitor response.