ICIs are monoclonal antibodies increasingly used for advanced malignancies. While generally well tolerated, they can provoke immune-related adverse events (irAEs), including rare but disabling neurologic complications. Overlapping central and peripheral nervous system involvement is uncommon but critical to recognize.

A 58-year-old man with Merkel cell carcinoma, recently treated with pembrolizumab every three weeks, developed progressive bilateral lower extremity weakness, sensory changes, and bowel/bladder dysfunction after five weeks of first infusion, which progressively worsened over six weeks. Examination revealed paraplegia with spasticity, lower extremity symmetric hyperreflexia (3+), sensory level at T11 and upgoing plantar responses bilaterally. Initial differentials were transverse myelitis, demyelinating lesion, paraneoplastic disease, spinal cord infarct, etc. MRI demonstrated non-enhancing T2 hyperintense intramedullary lesions in the cervical and thoracic cord with cord edema. Cerebrospinal fluid analysis showed lymphocytic pleocytosis, elevated protein, increased IgG with monoclonal banding, and oligoclonal bands. Serum testing revealed CRMP-5 IgG and ANNA-3 antibodies but not detected in CSF studies. Electromyography demonstrated acute demyelinating polyradiculoneuropathy, consistent with concurrent peripheral nerve involvement. The patient was treated with high-dose corticosteroids, intravenous immunoglobulin, and plasma exchange with partial recovery.  Spasticity improved with diazepam. He continued to gain function with continued rehabilitation and on 3 months outpatient follow up, he regained the ability to move his legs side-to-side and wiggle toes although still unable to stand or ambulate.