Can Phenytoin Cause Hallucinations?
Yes, phenytoin can cause hallucinations, though this is a less commonly recognized manifestation of toxicity compared to typical neurological signs like nystagmus and ataxia. 1
Mechanism and Clinical Presentation
Hallucinations associated with phenytoin typically occur as part of a broader spectrum of central nervous system toxicity. The FDA drug label explicitly lists "mental confusion" as a dose-related CNS manifestation, and notes that serum levels sustained above the optimal range may produce "confusional states referred to as 'delirium,' 'psychosis,' or 'encephalopathy.'" 1
Visual hallucinations are the most commonly reported type of hallucinatory experience with phenytoin. 2, 3 These can be complex visual hallucinations that may mimic other conditions such as delirium tremens. 2
Key Risk Factors for Phenytoin-Induced Hallucinations
Hypoalbuminemia (Critical Risk Factor)
- Patients with low serum albumin (<25 g/L) are at particularly high risk because phenytoin is 90-95% protein-bound, and hypoalbuminemia dramatically increases free (unbound) phenytoin levels. 4, 5
- Toxic free phenytoin levels (>2 mg/L) can occur even when total phenytoin levels appear therapeutic (8-20 mg/L), leading to severe neurological side effects including hallucinations, disorientation, and myoclonia. 5
Supratherapeutic Dosing
- Phenytoin exhibits saturation (zero-order) kinetics, meaning small dose increases can lead to disproportionate rises in serum levels. 4, 6
- The American College of Emergency Physicians notes that dose-related adverse effects include cognitive changes requiring close monitoring. 7
Drug Interactions
- Multiple medications can increase phenytoin levels by inhibiting metabolism or displacing it from protein binding sites, including: amiodarone, chloramphenicol, cimetidine, disulfiram, fluoxetine, isoniazid, omeprazole, phenothiazines, sertraline, and sulfonamides. 1
Atypical Presentations
Importantly, hallucinations can occur even with subtherapeutic phenytoin levels, particularly in pediatric patients, suggesting idiosyncratic reactions independent of traditional toxicity mechanisms. 2 A documented case of a 4-year-old child developed acute complex visual hallucinations and psychomotor agitation while serum phenytoin concentrations were below therapeutic range. 2
Clinical Management Algorithm
When Hallucinations Develop:
- Immediately check both total AND free phenytoin levels (not just total levels, especially if albumin is low). 5
- Assess for hypoalbuminemia - if albumin <25 g/L, interpret total phenytoin levels with extreme caution. 5
- Review all concurrent medications for potential interactions that increase phenytoin levels. 1
- At the first sign of acute toxicity including hallucinations, dose reduction is indicated; if symptoms persist, termination of phenytoin is recommended. 1
- Consider alternative antiepileptic drugs such as carbamazepine, oxcarbazepine, or levetiracetam, particularly in patients with intellectual disability or pre-existing neurological vulnerability. 4
Special Populations at Higher Risk
- Patients with intellectual disability are particularly susceptible to cognitive dysfunction and should have phenytoin replaced with alternative agents. 4
- Elderly patients and those with hepatic impairment may show early signs of toxicity due to altered metabolism. 1
- Pediatric patients may develop idiosyncratic reactions including hallucinations even at subtherapeutic levels. 2, 3
Common Pitfall to Avoid
The most critical error is relying solely on total phenytoin levels in patients with hypoalbuminemia. Always measure free phenytoin levels (therapeutic range 0.5-2 mg/L) in patients with albumin <25 g/L, as total levels may appear falsely reassuring while free levels are dangerously elevated. 5 This can lead to severe neurological toxicity including hallucinations, disorientation, myoclonia, and even coma. 5