A 67-year-old man with NSCLC presented with 2 weeks of fatigue, encephalopathy, and upper extremity pain and weakness. Pemetrexed/carboplatin/pembrolizumab was completed 5 months prior to presentation, with ongoing pembrolizumab monotherapy. 

Examination revealed asymmetric weakness of proximal more than distal upper extremities, diminished sensation, and brisk reflexes throughout.    

Endocrinology workup was consistent with autoimmune hypophysitis. Serum CK, MRI brain and MRI c-spine were normal. MRI brachial plexus was devoid of signal abnormality, but revealed supraspinatus and infraspinatus muscle swelling, consistent with denervation. Subsequent EMG/NCS confirmed brachial plexopathy. CSF analysis: 110 WBCs, protein 207mg/dL, glucose 87mg/dL. Meningitis/encephalitis PCR and cytology were negative; anti-NMDA-R antibodies were positive.  

Treatment with methylprednisolone improved his symptoms.

Our patient’s sensorimotor involvement of both proximal and distal extremities raises suspicion for overlapping chemotherapy-induced and ICI-related neuropathies, as the latter typically presents in a non-length dependent pattern. Pemetrexed causes sensorimotor polyneuropathies, which resolve after discontinuation. Carboplatin causes chronic pure sensory neuropathies, inconsistent with our EMG/NCS results. Neither agent causes NMDA-R encephalitis. Therefore, pembrolizumab is the culprit. 

Although his NSCLC diagnosis and treatment with an anti-PD1 ICI increased the propensity to develop n-irAEs, the risk is only 3-6%, with the majority being PNS manifestations. However, our patient simultaneously developed CNS (NMDA-R encephalitis), PNS (brachial plexopathy), and endocrine (hypophysitis) ICI-related complications. While pembrolizumab-related plexopathy and NMDA-R encephalitis are recognized n-irAEs, their simultaneous occurrence has not been previously reported. We postulate co-occurring n-irAEs may be secondary to unidentified biomarkers or immunopathologic mechanisms, thereby advocating further investigation to elucidate potential indicators.