Can a provider add Dilantin (phenytoin) to the medication regimen of a male patient with a history of epilepsy since age two, who has a shunt in place, is currently taking Keppra (levetiracetam) and gabapentin for anxiety management, and is experiencing breakthrough seizures?

Adding Dilantin (Phenytoin) to Keppra for Breakthrough Seizures

Adding phenytoin to levetiracetam (Keppra) is not the optimal approach for this patient with breakthrough seizures—the priority should be optimizing the current levetiracetam dose before considering polytherapy, and if a second agent is needed, phenytoin is not the preferred choice due to its significant drug interactions and side effects.

Immediate Priorities Before Adding Any Medication

Assess Current Levetiracetam Dosing and Compliance

• Check serum levetiracetam levels to verify medication compliance and assess whether therapeutic levels are being achieved, as non-compliance is a common cause of breakthrough seizures 1.
• The patient's current Keppra dose is not specified in the scenario, but standard maintenance dosing for epilepsy is 1500-3000 mg daily in divided doses 1, 2.
• Each 1000 mg increase in levetiracetam dose raises odds of seizure control by 40%, and doses of 500 mg/day are NOT more effective than placebo 3.

Identify Precipitating Factors for the Recent Seizure

• The patient attributes his recent seizure to "feeling ill," which suggests a provoked seizure from acute illness 1.
• Search for reversible causes including infection, metabolic derangements (hypoglycemia, hyponatremia), medication non-compliance, sleep deprivation, or the recent gabapentin discontinuation 1.
• The patient has run out of gabapentin, which he takes for anxiety—abrupt benzodiazepine or gabapentinoid withdrawal can lower seizure threshold 1.

Why Not Add Phenytoin as the Next Step

Phenytoin Has Significant Limitations

• Phenytoin is an enzyme-inducing antiepileptic drug (EIAED) that affects the cytochrome P450 system and should be avoided where possible 4.
• Phenytoin requires continuous ECG and blood pressure monitoring due to cardiovascular risks, with a 12% risk of hypotension even in acute settings 1.
• The FDA label for phenytoin warns of serious allergic reactions, blood disorders, liver toxicity, and suicidal thoughts 5.
• 95% of neurologists recommend phenytoin/fosphenytoin for benzodiazepine-refractory status epilepticus, but this patient is NOT in status epilepticus—he had a single breakthrough seizure days ago 1.

Better Second-Line Options Exist

If optimization of levetiracetam monotherapy fails and a second agent is truly needed:

• Valproate (20-30 mg/kg/day) has 88% efficacy with 0% hypotension risk and does not significantly interact with levetiracetam 1.
• Lamotrigine or lacosamide are alternative adjuncts recommended by the American Academy of Neurology 1.
• However, valproate must be avoided in women of childbearing potential due to teratogenicity 1.

Evidence Against Routine Polytherapy Without Optimizing Monotherapy

Guidelines Prioritize Monotherapy Optimization First

• WHO guidelines recommend monotherapy with standard antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproic acid) for convulsive epilepsy, with the decision to add a second drug made only after adequate monotherapy trials 4.
• Antiepileptic drug polytherapy should be avoided where possible due to increased drug interactions, adverse effects, and complexity 4.
• The American Academy of Neurology recommends optimizing the first AED before adding a second agent 1.

Combination Therapy Increases Risks

• Combination therapy introduces increased risk of drug interactions, higher adverse event burden, and greater complexity affecting compliance 1.
• The concurrent use of phenytoin and levetiracetam has no randomized controlled trial evidence demonstrating superior efficacy for non-ICU patients with breakthrough seizures 6.

Recommended Management Algorithm

Step 1: Optimize Levetiracetam Monotherapy (Current Priority)

• Increase levetiracetam to therapeutic doses (1500-3000 mg daily in divided doses) if not already at this level 1, 2.
• Verify compliance by checking serum drug levels 1.
• Refill gabapentin to prevent withdrawal-related seizure risk and address anxiety that may affect compliance 1.

Step 2: Address the Shunt and Establish Neurology Care

• The patient has a shunt in place and hasn't established care since moving—this is a critical gap 4.
• Shunt malfunction or CNS structural issues could be contributing to breakthrough seizures and require neuroimaging evaluation 4.
• Establish care with a local neurologist who can comprehensively evaluate the shunt, review neuroimaging, and optimize AED therapy 4.

Step 3: Investigate the Recent Seizure

• The patient had auras before the seizure and remained postictal for several hours, confirming this was a true epileptic event 4.
• One breakthrough seizure after years of control does NOT automatically warrant adding a second AED—it warrants investigation of precipitating factors 4.
• The American College of Emergency Physicians recommends searching for reversible causes including acute illness, which the patient endorsed 1.

Step 4: Consider Second-Line Agent Only If Monotherapy Fails

If seizures continue despite:

• Optimized levetiracetam dosing (up to 3000 mg daily)
• Verified compliance with therapeutic drug levels
• Correction of precipitating factors
• Adequate trial period (at least 2-3 months)

Then consider adding:

• Valproate (if male or not of childbearing potential): 20-30 mg/kg/day, 88% efficacy, no hypotension risk 1
• Lamotrigine or lacosamide: Alternative adjuncts with favorable side effect profiles 1
• NOT phenytoin as first choice due to drug interactions and monitoring requirements 4, 1

Critical Pitfalls to Avoid

• Do not add a second AED without first optimizing the first AED to maximum tolerated doses 1.
• Do not ignore the gabapentin discontinuation as a potential precipitating factor for the breakthrough seizure 1.
• Do not skip neuroimaging and shunt evaluation in a patient with structural CNS abnormalities and new breakthrough seizures 4.
• Do not assume one breakthrough seizure after years of control represents treatment failure—investigate reversible causes first 4, 1.

Special Considerations for This Patient

The Shunt Complicates Management

• Patients with CNS structural abnormalities (including shunts) have higher seizure recurrence risk and may require long-term AED therapy 4.
• Shunt malfunction can present with seizures and requires urgent evaluation 4.

The Recent Illness as Precipitating Factor

• The patient attributes the seizure to "feeling ill," suggesting a provoked seizure 1.
• Provoked seizures do not necessarily require AED escalation—treating the underlying condition may be sufficient 4, 1.

Gabapentin Withdrawal Risk

• Abrupt discontinuation of gabapentin (a GABAergic agent) can lower seizure threshold 1.
• Refilling gabapentin is a priority to prevent withdrawal-related seizures 1.