Case Presentation: A 57 year-old female with a history of COPD and CKD presented with recurrent syncope. The patient reported a two year history of recurrent syncopal events and progressive worsening of orthostatic intolerance with inability to ambulate independently. She denied any gastrointestinal or urinary symptoms as well as changes in her sweating patterns. Blood pressure decreased by 51 mmHg systolic and heart rate increased by 5 BPM when standing. Her physical exam was notable for scattered ecchymoses due to falls and her neurologic exam was normal other than significant gait imbalance attributed to presyncopal symptoms. Her orthostatic hypotension persisted after rehydration, and she was not taking any culprit medications. Adrenal insufficiency was excluded. Brain MRI was unremarkable. TSH, RPR, HIV, Hemoglobin A1C, SPEP, B12, thiamine, and vitamin E were unremarkable. Serum testing for a paraneoplastic panel including Purkinje cell, CV2.1, neuronal antibodies were all negative, and she did not have any evidence of malignancy. ANA was positive at 1:320 with negative sub-serologies. Anti-ganglionic neuronal acetylcholine receptor antibodies (alpha-3AChR) were detected in the serum at high titers, consistent with a diagnosis of autoimmune autonomic ganglionopathy (AAG).
Discussion: Hospitalists frequently care for patients hospitalized due to syncope and falls, and orthostatic hypotension is a common cause of syncope. Orthostatic hypotension in the absence of volume depletion or causative medications raises concern for autonomic dysfunction, particularly if the orthostatic hypotension occurs in the absence of reflex tachycardia, as in this case. Etiologies of autonomic failure include neurodegenerative disease (including Parkinson Disease and other related synucleinopathies) and autonomic neuropathies (which can be due to diabetes, nutrient deficiencies, toxins, infections, infiltrative disease, autoimmune and paraneoplastic disease). Rarely, as in this case of autoimmune autonomic ganglionopathy (AAG), autonomic failure is due to autoantibody inhibition of the ganglionic acetylcholine receptor.AAG is a rare disease which usually presents subacutely in middle aged patients with a female predominance. Orthostatic hypotension is common and is often accompanied by other anticholinergic symptoms including dry mouth, anhidrosis, constipation, and urinary retention. Half of patients with clinically diagnosed AAG are identified to have pathologic antibodies to the alpha-3 subunit of the ganglionic nicotinic acetylcholine receptor. AAG can be a paraneoplastic phenomenon and a presenting feature of malignancy. In the absence of a paraneoplastic etiology, treatment with immunomodulators including plasma exchange, IVIG, and rituximab can be effective.
Conclusions: This case describes a middle aged woman with recurrent syncope due to severe orthostatic hypotension, which was ultimately discovered to be due to autoimmune autonomic ganglionopathy (AAG). AAG is a rare cause of autonomic failure due to pathologic antibodies inhibiting the nicotinic acetylcholine receptor at autonomic ganglia. Autonomic failure due to AAG can be treated with immunomodulatory therapy, and diagnosis of AAG may be the presenting feature of occult malignancy. In summary, hospitalists should consider AAG in patients presenting with recurrent syncope due to orthostatic hypotension, particularly in the presence of other features of autonomic failure.