A Case of Myasthenia Gravis: A Paraneoplastic Syndrome or an Immune-Related Disorder?

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable muscle weakness. While commonly linked to acetylcholine receptor (AChR) antibodies, other reported antibodies include muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), agrin, striated muscle, myosin, ryanodine receptor, and titin. Notably, titin antibodies are being highlighted for their role in MG pathogenesis, as they have been associated with increased disease severity. Immune checkpoint inhibitors (ICIs), while highly effective for solid tumors, can rarely induce immune-related myasthenia gravis (irMG), a neurological adverse effect with higher mortality than classic MG. We present a case of MG with atypical serology, highlighting the challenges of classifying and treating classic MG, paraneoplastic syndromes, and irMG. A 68-year-old man with a history of stage IV left renal cell carcinoma (RCC) with lung metastases after undergoing left nephrectomy and right segmental lung lobectomy presented with one month of palpebral ptosis, shortness of breath, dysphagia, and generalized muscle weakness. He had recently received two doses of 200 mg pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor. Physical examination revealed bilateral palpebral ptosis, symmetric, primarily proximal weakness, including bulbar and facial muscles with fatigability, and normal reflexes. Serum studies were positive for anti-striated muscle (>1:2560) and anti-titin (>2.71) antibodies, suggesting irMG or a paraneoplastic syndrome, with negative anti-AChR and anti-MuSK antibodies. Computed tomography (CT) of the chest showed no thymic disease. The patient improved with high-dose steroids followed by plasma exchange and intravenous immunoglobulin (IVIG). Repeated striated muscle antibodies were decreased, but anti-titin antibodies were persistently elevated. He is neurologically stable on pyridostigmine 60 mg, 3 liters of nasal cannula oxygen, and nighttime bilevel positive airway pressure (BiPAP) but experiences residual muscle weakness that requires wheelchair use. In summary, we present a case of MG with the presence of titin and striated muscle antibodies in a patient with metastatic RCC undergoing checkpoint immunomodulating therapy. Management remains challenging in patients with underlying malignancy treated with ICIs.