Cerebellar Syndrome as the Dominant Manifestation of Severe Chronic Phenytoin Toxicity

Abstract

Background: Phenytoin continues to be widely prescribed for seizure disorders despite its narrow therapeutic index and saturable hepatic metabolism, resulting in dose-dependent non-linear pharmacokinetics. Consequently, relatively small increases in dose may lead to disproportionate elevations in serum phenytoin concentrations and increase the risk of toxicity. Chronic phenytoin toxicity predominantly manifests with neurological features, including cerebellar dysfunction, nystagmus, dysarthria, and altered sensorium. As these manifestations are often nonspecific, drug toxicity should be considered in the differential diagnosis of patients presenting with unexplained acute or subacute cerebellar syndromes, particularly in those receiving long-term antiseizure therapy. Furthermore, the severity of neurological impairment in chronic phenytoin toxicity does not consistently correlate with serum phenytoin concentrations, making clinical assessment and therapeutic drug monitoring equally important. We report a case of chronic phenytoin toxicity presenting predominantly with cerebellar dysfunction despite markedly elevated serum phenytoin levels.
Case Presentation: A 50-year-old man with a seizure disorder on long-term phenytoin therapy (600 mg/day) presented with a one-week history of progressive gait imbalance, tremors, dysarthria, and altered sensorium. Examination revealed cerebellar signs, including gait ataxia, dysdiadochokinesia, intention tremor, horizontal gaze-evoked nystagmus, along with diffuse gingival hyperplasia. Magnetic resonance imaging of the brain excluded an acute cerebrovascular event. Serum phenytoin concentration was markedly elevated at 53.90 µg/mL, confirming chronic phenytoin toxicity. Phenytoin was discontinued and replaced with levetiracetam. The patient underwent one session each of hemoperfusion and hemodialysis. Serial therapeutic drug monitoring demonstrated a decline in serum phenytoin concentration to 24 µg/mL, which was accompanied by significant improvement in cerebellar signs and normalization of sensorium. He remained seizure-free and was discharged on levetiracetam with advice for regular follow-up.
Conclusion: This case highlights that chronic phenytoin toxicity may present predominantly with cerebellar dysfunction despite markedly elevated serum phenytoin concentrations. Drug toxicity should remain an important differential diagnosis in patients with unexplained neurological symptoms, and therapeutic drug monitoring should complement clinical assessment to facilitate timely diagnosis and management.