Gastrointestinal Dysautonomia: A Rare Immune-Related Adverse Event That Requires Early Recognition and High-Dose Immunosuppression

Gastrointestinal (GI) immune-related adverse events (IrAEs) are relatively common following immune checkpoint inhibitor (ICI) therapy; however, GI dysautonomia is a very rare IrAE which manifests as pseudo-obstruction, gastroparesis, and/or achalasia. We present a case of seronegative GI dysautonomia secondary to pembrolizumab for metastatic melanoma, with symptoms of constipation, early satiety, and abdominal distension emerging within days of his second cycle, approximately five weeks after the initiation of therapy, which required temporary total parenteral nutrition. Concurrently, he developed autonomic features including blurred vision, dry mouth, and disabling orthostatic hypotension, suggesting a multi-system presentation. A full investigational work-up excluded a paraneoplastic cause, and autoantibodies (anti-Hu and anti-nicotinic acetylcholine receptor) were negative, indicating a seronegative presentation. Treatment with high-dose pulsed methylprednisolone, followed by a slow taper of prednisolone and initiation of maintenance mycophenolate, enabled recovery and re-establishment of oral nutrition. This case underscores that atypical GI IrAEs, such as dysautonomia, may necessitate early, high-intensity immunosuppression beyond current guideline-directed therapy. Rapid escalation of treatment may be life-saving and the only method to achieve functional and nutritional recovery.