Neurological adverse effects from Immune Checkpoint Inhibitors (ICIs) are rare, with seizures and movement disorders reported in less than 1% of patients. We present a case of ICI-associated breakthrough seizures and worsening drug-induced Parkinsonism in a patient with medically refractory Epilepsy.

A 56-year-old Caucasian man with Epilepsy (FPC-focal preserved consciousness) and cutaneous Squamous Cell Carcinoma (SCC) presented in August 2025 with left eye twitching consistent with focal seizures. EEG showed frequent generalized, frontally predominant spike-and-wave discharges at 2–3 Hz lasting 3–7 seconds. His seizures had been well controlled on Lacosamide and Lamotrigine with good compliance; Valproate had been discontinued a year earlier due to Parkinsonian side-effects. Previously, multiple alternative antiseizure medications including Carbamazepine, Gabapentin, Ethosuximide, Zonisamide, and Levetiracetam were ineffective or poorly tolerated.

The patient had received two cycles of Cemiplimab (March–April 2025) for SCC, after which his tremors and rigidity progressively worsened. Concern for ICI-induced neurotoxicity prompted initiation of steroids, yielding minimal improvement. Examination revealed facial hypomimia, bilateral rigidity, postural and action tremors, and global hypokinesia. Clobazam was added during hospitalization, and steroids were continued. No further clinical or electrographic seizures were noted. Neuroimaging (including DAT scan), skin biopsy, EMG, and autoantibody panels (Anti-GAD65 Ab, Anti-Amphiphysin Abs) were inconclusive. The patient reported improved mobility and seizure control weeks later at outpatient follow-up. 

Breakthrough seizures and worsening parkinsonian symptoms following ICI therapy suggested immune-mediated neuronal hyperexcitability. Addition of Clobazam controlled seizure burden and reduced extrapyramidal features, supporting a role for GABAergic modulation in stabilizing ICI-induced neuronal excitability. Paraneoplastic and autoimmune causes were considered, and ruled out.

This case underscores that seizures and subacute parkinsonism are rare, but significant ICI related complications. Symptom stabilization was achieved with a combination of Lacosamide, Lamotrigine, Clobazam, and Corticosteroids after other antiepileptics were poorly tolerated.