Case Presentation: A 78-year-old man with newly diagnosed stage IV urothelial carcinoma, recently started on enfortumab vedotin and pembrolizumab, presented with several days of progressive lower-extremity weakness, difficulty rising from a seated position, and blurry vision. Days earlier, he had presented to another facility, where labs showed a troponin of 3,009 ng/L with a normal ECG and echocardiogram. He was treated empirically with prednisone 60 mg daily for presumed immune-checkpoint inhibitor (ICI) myocarditis and discharged with close oncology follow-up.At follow-up, his weakness persisted. Repeat labs showed an up-trending troponin of 4,227 ng/L and a CK of 4,980 U/L, prompting hospital admission. Coronary angiography was normal. Neurologic examination demonstrated subtle facial weakness, incomplete eyelid closure, and lower-extremity strength of 4/5. Given the constellation of myocarditis, myositis, and myasthenic features, he was diagnosed with Triple M syndrome and treated with pulse-dose steroids and intravenous immunoglobulin. He did not develop heart block or respiratory failure. Acetylcholine receptor antibodies were negative, and cardiac MRI was unremarkable. His strength improved steadily with rehabilitation; by three weeks he was able to rise from a seated position, and by five months he was walking independently.
Discussion: As hospitalists, we increasingly encounter immunotherapy-related adverse events (irAE). Most patients present with cutaneous, endocrine, gastrointestinal, or pulmonary manifestations, and diagnosis is not as difficult as before given the increased use of immunotherapies and high prevalence of these toxicities. However, atypical presentations can be easily overlooked without awareness of rare but life-threatening toxicities.Cardiac and neuromuscular irAEs are rare but often fatal. Up to 10% of patients with ICI-associated myocarditis develop overlapping myasthenia gravis and myositis. Troponin is frequently checked in emergency evaluations, and any elevation in patients receiving ICIs should prompt consideration of overlap syndromes. We recommend checking CK, performing a focused neurologic examination, and maintaining high suspicion for bulbar, ophthalmoplegic, or motor deficits. Median time to symptom onset is approximately 34 days, typically after about three infusions. However, late presentations, even after one year of therapy, have been reported. Triple M syndrome carries a mortality rate of 40–60% because of rapid progression to life-threatening complications including cardiogenic shock, arrhythmias, and respiratory failure.
Conclusions: Clinicians should be aware of rare but life-threatening irAEs and maintain a high suspicion for overlap syndromes. Early consultation with oncology, cardiology, and neurology is the key for early diagnosis and aggressive immunosuppression to improve outcomes.