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Seronegative autoimmune autonomic ganglionopathy: case report A 60-year-old man developed seronegative autoimmune autonomic ganglionopathy during treatment with ipilimumab and nivolumab for metastatic melanoma. The man presented with rectal discomfort and bleeding. Subsequent investigations led to the diagnosis of metastatic melanoma. Therefore, palliative transanal excision of the rectal mass was performed, following which he started receiving ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks [routes not stated]. The treatment was scheduled for four doses. However, after cycle 3, he presented with nausea, constipation, fatigue, weight loss and hypotension (seated systolic BP as low as 70mm Hg). Ipilimumab and nivolumab were withheld, and the man was hospitalised for further investigation. He was administered normal saline; however, his BP did not improve. Examination was otherwise negative apart from orthostatic hypotension. He had no family history of neurologic disorders, including dysautonomia. No evidence of volume depletion was detected. Formal autonomic testing revealed low BP (91/50mm Hg) and supine resting HR (51 bpm). Slow deep breathing demonstrated blunted amplitude (4.5 bpm) at a low HR range (45–52 bpm). Valsalva maneuver showed normal HR responses (Valsalva ratio 1.38–1.57) but an absent phase-4 overshoot profile and a ’flat top’ BP. This constellation of findings was suggestive of significant sympathetic dysfunction, resulting in parasympathetic predominance. Cold-pressor test led to no change in HR and only a modest rise in BP (91/52 to 108/63mm Hg), also suggestive of poor sympathetic reserve. On orthostatic testing, systolic BP fell from supine average of 92mm Hg to 68mm Hg within 30s of standing, and further down to 57mm Hg by 50s, at which time, the test was terminated. His HR improved from 49 at baseline to 63 bpm at termination of orthostasis. Peripheral resistance averaged 860 dyn.s.cm-5 at baseline and increased only minimally (to~990 dyn.s.cm-5) with standing. At the same time, stroke volume decreased from 83mL supine to 54mL at the end of standing (50s), indicative of excessive venous pooling. His chronotropic incompetence, hypotension, impaired increase in vascular resistance, suboptimal baroreflex-mediated responses and significant venous pooling suggested a loss of sympathetic tone, compatible with acute autonomic dysfunction due to an acute autonomic ganglionopathy which was thought to be autoimmune in nature due to its development while on ipilimumab and nivolumab. Therefore, he was treated with methylprednisolone, followed by prednisone and immune globulin. He also received midodrine, fludrocortisone and sodium chloride. Thereafter, his BP gradually improved, and after several months, fludrocortisone and sodium chloride were tapered off, while the dose of midodrine was tapered and immune globulin was discontinued. He continued receiving prednisone, and his systolic BP ranged between 100–130mm Hg with minimal orthostatic changes on variable doses of midodrine alone. Restaging