Phenytoin Toxicity: Clinical Manifestations and Management
Primary Clinical Presentation
Phenytoin toxicity manifests predominantly as nystagmus, ataxia, and dysarthria, with progression to confusion, lethargy, and potentially coma in severe cases. 1
Dose-Dependent Symptom Progression
The clinical features of phenytoin toxicity correlate directly with serum levels, following a predictable pattern:
- Nystagmus on lateral gaze typically appears at serum levels of 20 mcg/mL 1
- Ataxia develops at approximately 30 mcg/mL 1
- Dysarthria and lethargy emerge when plasma concentrations exceed 40 mcg/mL 1
- Severe toxicity can occur at levels above 50 mcg/mL, though marked individual variation exists 1
Complete Symptom Profile
Neurological Manifestations
The central nervous system bears the primary burden of toxicity:
- Early signs: Nystagmus, dizziness/vertigo, unsteady gait, and general weakness 2
- Progressive symptoms: Ataxia, decreased coordination, hyperreflexia, slurred speech, diplopia, and tremor 1, 3
- Advanced toxicity: Confusion, somnolence, lethargy, depressed consciousness, and coma 1, 4
Gastrointestinal Symptoms
Paradoxical Seizures: A Critical Pitfall
A less recognized but important manifestation is paradoxical seizures, where seizure frequency increases as phenytoin levels rise into the toxic range. 5 This phenomenon may occur with or without other toxicity features 5, and has been documented at levels ranging from 38.3 to 46.5 mcg/mL 5. This can lead to diagnostic errors, as clinicians may mistakenly increase phenytoin dosing when seizures worsen 6.
Cardiac Complications
Cardiac manifestations (arrhythmias and hypotension) are rare with oral ingestion but may occur with parenteral administration of phenytoin or fosphenytoin 4. The American Heart Association recommends monitoring vital signs, especially blood pressure and heart rate via ECG during IV administration 7.
Management Algorithm
Immediate Assessment and Supportive Care
The mainstay of therapy is supportive care, as there is no antidote for phenytoin toxicity. 4
- Discontinue phenytoin immediately upon recognition of toxicity 2, 6
- Ensure airway protection and adequate ventilation if consciousness is depressed 3
- Monitor vital functions closely, including respiratory and circulatory systems 1
- Manage nausea and vomiting symptomatically 4
- Implement fall precautions due to significant ataxia and unsteady gait risk 2
Gastrointestinal Decontamination
- Activated charcoal should be considered if the patient presents early after ingestion 4
- Multiple-dose activated charcoal remains controversial—experimental studies show increased clearance rates, but clinical benefit has not been demonstrated 4, 3
Enhanced Elimination: Not Recommended
There is no evidence that invasive methods of enhanced elimination provide any benefit. 4 Specifically:
- Hemodialysis, hemoperfusion, plasmapheresis, and forced diuresis are ineffective and carry unnecessary risks 4, 3
- While hemodialysis can be considered theoretically (phenytoin is not completely protein-bound), it does not improve outcomes 1
Monitoring During Recovery
The clinical course is typically uneventful with supportive care alone 2. However, due to zero-order (saturation) pharmacokinetics, phenytoin exhibits a greatly increased half-life in overdose, resulting in prolonged symptoms that may last a week or more 4, 3.
Prognosis
Deaths are unlikely after phenytoin intoxication alone, and all patients can be expected to recover fully with appropriate supportive care. 4, 2 The primary risk is injury from falls due to ataxia during the recovery period 2.
Common Causes to Prevent Future Episodes
The three leading causes of acute phenytoin intoxication are:
Patients with hepatic impairment, renal failure, hypoalbuminemia, or those taking interacting medications require more vigilant monitoring 8, 5.