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

Background and Objectives:Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P) with the latter been characterized by diffuse anhidrosis in prospective study including patients in late stage of disease.We aimed to evaluate morphological and functional postganglionic sudomotor involvement in patients with new diagnosis MSA-P and PD to identify possible biomarkers that might be of help in differentiating the two conditions in early stage.Methods:One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At time of recruitment, questionnaires to assess non-motor, autonomic and small fiber symptoms were administered and patients underwent post-ganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor and pilomotor nerve fibers was measured on confocal images using dedicated software. A follow-up visit twelve months after recruitment was performed to confirm the diagnosis.Results:We recruited 57 patients with PD (M/F=36/21; age 63.5±9.4years) and 43 patients with MSA-P (M/F=27/16; age 62.3±9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in MSA-P compared to PD patients. Sweating output and intraepidermal, pilomotor and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in MSA-P patients. Pilomotor and sudomotor nerve density correlated with sweating function and with non-motor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers, efficiently separated the two populations, the receiver operating characteristics showing an area under the curve of 0.83.Discussion:Dynamic sweat test and the quantification of cutaneous autonomic nerves provided to be a sensitive morpho-functional approach to assess postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to early differentiate the two conditions.Classification of Evidence:This study provides Class II evidence that post ganglionic sudomotor morpho-functional assessment accurately distinguish PD from MSA-P patients.

Background: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. Objective: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p). Methods: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. Results: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression. Conclusion: Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.