Case Presentation: A 77-year-old woman with type 2 diabetes, hypothyroidism, prior stroke with residual right sided weakness, and stage I mucinous adenocarcinoma of the left lung complicated by recurrence presented with one week of severe bilateral ptosis, fatigue, dysarthria and generalized weakness six weeks after initiation of nivolumab and ipilimumab for cancer recurrence. Patient denied chest pain and dyspnea on arrival. Initial vital signs were normal other than hypertension to 139/82. Negative inspiratory force (NIF) measurement was -20 cm H2O. Physical exam was notable for a frail appearing but alert and oriented woman with severe bilateral ptosis, ophthalmoplegia in all directions, dysarthria and reduced proximal muscle strength in all extremities. Reflexes and sensation to light touch and vibration were normal. Ice pack test was positive.Labs showed hemoglobin of 11.1 g/dL, high sensitivity-troponin of 935 ng/L, creatine kinase of 909 U/L, aspartate aminotransferase of 155 U/L, alanine aminotransferase of 87 U/L, and creatinine 1.23 mg/dL (baseline 0.8-0.9). ECG showed a new-onset right bundle branch block (RBBB). Transthoracic echocardiogram (TTE) showed hyperdynamic systolic function with EF of 65-70%. Her clinical presentation was concerning for Triple M Overlap syndrome (TMOS) which is characterized by the simultaneous occurrence of myasthenia gravis, myositis, and myocarditis. Neurology was consulted and the patient was given intravenous (IV) methylprednisolone 500 mg every 12 hours for 3 days before transitioning to prednisone 60 mg daily. She underwent 7 sessions of therapeutic plasma exchange (PLEX) and was started on pyridostigmine 30 mg twice daily on day 5, increased to 60 mg three times daily on day 8. By day 10, high sensitivity-troponin had decreased to 296 ng/L and repeat TTE showed normal EF of 55-60%. Repeat ECG showed resolution of patient’s RBBB. Acetylcholine receptor antibody and muscle specific kinase antibody tests were negative. Bulbar symptoms and respiratory muscle weakness did not improve with PLEX. On day 10, patient was transferred to the intensive care unit because of her worsening respiratory status as evidenced by NIF measurement of -11 cm H2O, and hypotension. She was started on empiric antibiotics and high flow nasal cannula 40% FiO2/40 L/min. The patient and family were informed that further respiratory support would likely require intubation and a tracheostomy. Code status was switched to Do Not Resuscitate and Do Not Intubate (DNR/DNI). On day 13, chest x-ray showed atelectasis or possible aspiration pneumonia. She developed hypoxemia to 78% SpO2, despite increasing supplemental oxygen. On hospital day 15, she became somnolent and was non-participatory during examination. Her family opted to transition to comfort care and she expired.
Discussion: Although the prevalence of TMOS as a potential complication of ICI therapy is less than 1%, internists should become familiar with this diagnosis as it is associated with a mortality as high as 43.8%, significantly higher than classical myasthenia gravis. While improvement of myocarditis in these patients is necessary for preventing further cardiac morbidity, it may not prognosticate resolution of respiratory crisis.
Conclusions: -TMOS is a rare clinical entity that is increasingly recognized as a dangerous complication of immune checkpoint inhibitor (ICI) therapy.-Early goals of care discussions should guide early decision-making with regards to aggressive pursuit of therapy.