A patient on phenytoin experienced a single generalized tonic‑clonic seizure; what is the next step in management?

Management of Breakthrough Seizure in Patient on Phenytoin

Check the phenytoin level immediately and obtain brain imaging (CT or MRI) to exclude new structural pathology, then adjust management based on whether the level is subtherapeutic, therapeutic, or supratherapeutic. 1

Immediate Diagnostic Steps

Check Phenytoin Level

• Draw serum phenytoin level stat to determine if the breakthrough seizure is due to inadequate dosing, noncompliance, or paradoxical toxicity 1
• Therapeutic range is 10-20 mcg/mL (total) or 1-2 mcg/mL (free phenytoin), though some patients require levels at the upper end (>15 mcg/mL) for adequate control 2

Obtain Neuroimaging

• Perform CT or MRI in the emergency department to exclude new structural lesions, hemorrhage, tumor progression, or other acute pathology that could explain increased seizure frequency 1
• This is critical as breakthrough seizures may indicate new intracranial pathology rather than medication failure

Assess for Precipitating Factors

• Screen for acute alcohol intake, which can paradoxically increase phenytoin levels and cause seizures from toxicity 1, 3
• Evaluate for drug interactions that may alter phenytoin metabolism or protein binding 1, 4
• Consider compliance issues, malabsorption, or need for higher maintenance doses (200-700 mg/day) 1

Management Algorithm Based on Phenytoin Level

If Level is Subtherapeutic (<10 mcg/mL)

• Administer IV loading dose of 18-20 mg/kg at maximum rate of 50 mg/min in adults to rapidly achieve therapeutic levels 2
• Alternatively, use fosphenytoin at 150 PE/min (three times faster than phenytoin with fewer adverse events) 2
• Increase maintenance dose incrementally by 100-200 mg/day at weekly intervals, monitoring for efficacy and toxicity, with maximum typical adult dose of 1200 mg/day 2
• Address compliance issues and assess for drug interactions or malabsorption 1

If Level is Therapeutic (10-20 mcg/mL)

• Consider that the patient may be one who requires higher levels (>15 mcg/mL) for adequate seizure control 2
• Add a second antiepileptic agent rather than pushing phenytoin to toxic levels 5, 3
• Valproate is more effective than phenytoin for primary generalized tonic-clonic seizures (66% vs 42% seizure control, NNT 4.3) 5
• Levetiracetam is a reasonable alternative add-on agent 3

If Level is Supratherapeutic (>20 mcg/mL)

• Hold phenytoin immediately and temporarily add another anticonvulsant, as supratherapeutic levels can paradoxically cause breakthrough seizures 3
• Start levetiracetam or another agent while phenytoin level returns to therapeutic range 3
• Monitor for signs of phenytoin toxicity: nystagmus, ataxia, cognitive changes, dizziness 2, 3
• Resume phenytoin at lower maintenance dose once level normalizes 3

Special Considerations and Pitfalls

Phenytoin Encephalopathy Risk

• Long-term phenytoin use can cause cognitive impairment and cerebellar syndrome, particularly in patients with intellectual disability or pre-existing balance disturbances 6
• Consider switching to carbamazepine or oxcarbazepine in patients susceptible to cognitive dysfunction 6

Status Epilepticus Management

• If patient presents in status epilepticus, lorazepam is superior to phenytoin alone (65% vs 44% success rate) 5
• For benzodiazepine-refractory status epilepticus, IV valproate (30 mg/kg) is more effective than phenytoin (18 mg/kg) with 66% vs 42% seizure control 5
• High-dose phenytoin (mean 23.8 mg/kg) controls seizures in only 38% of refractory cases 5

Monitoring After Intervention

• After IV loading, check level at 2-4 hours to confirm therapeutic range achievement 2
• Approximately 50% of patients have subtherapeutic levels at 12 hours post-loading, making this a critical monitoring timepoint 2
• Watch for dose-related adverse effects: ataxia, nystagmus, tremor, somnolence, cognitive impairment 2