What is the next best step in managing a patient with refractory seizures and increasing frequency despite high doses of antiepileptics, including Oxcarbazepine (Trileptal), Levetiracetam (Keppra), and Clobazam, with normal MRI findings?

Management of Refractory Epilepsy with Increasing Seizure Frequency

This patient requires immediate evaluation for autoimmune encephalitis with CSF analysis and serum/CSF autoantibody testing, followed by consideration of immunotherapy if positive, while simultaneously optimizing antiepileptic therapy by adding a third-line agent with a different mechanism of action rather than further dose escalation of current medications. 1

Immediate Diagnostic Workup

This 35-year-old male with refractory seizures despite therapeutic doses of three antiepileptic drugs (AEDs) and normal MRI requires urgent evaluation for potentially treatable causes before assuming primary drug-resistant epilepsy:

Autoimmune Encephalitis Evaluation

• Perform lumbar puncture immediately to test for inflammatory markers (oligoclonal bands, IgG index, IgG synthesis rate) and neuronal autoantibodies in CSF 1
• Send serum autoantibody panel including NMDAR, LGI1, CASPR2, GABA-B, and AMPA receptor antibodies 1
• Consider brain FDG-PET if CSF and antibody testing are uninformative but clinical suspicion remains high 1
• Screen for underlying malignancy with CT chest/abdomen/pelvis with contrast, as paraneoplastic syndromes can present as refractory seizures 1

Why This Matters

Young adults with new-onset refractory epilepsy and normal structural imaging should raise suspicion for autoimmune encephalitis, which requires immunotherapy rather than additional AEDs 1. Missing this diagnosis leads to progressive neurological damage and continued seizures despite escalating antiepileptic medications 1.

Antiepileptic Drug Optimization

Critical Pitfall: Avoid Further Dose Escalation

Do not increase current AED doses beyond their current levels. Research demonstrates that patients with refractory epilepsy treated in the lowest quartile of the dose range had significantly better long-term seizure reduction compared to those in higher dose quartiles 2. Escalating to maximally tolerated doses in non-responders often worsens seizure frequency rather than improving control 2.

Add a Third-Line Agent with Different Mechanism

Since this patient is already on three AEDs (sodium channel blocker, synaptic vesicle protein modulator, and GABA enhancer), add an agent with a novel mechanism:

Perampanel 2 mg once daily at bedtime is the optimal choice 3:

• Non-competitive AMPA glutamate receptor antagonist—completely different mechanism from current regimen 3
• FDA-approved for partial-onset seizures with secondary generalization in adults 3
• Titrate by 2 mg increments weekly based on response, with maintenance dose of 8-12 mg daily 3
• Critical monitoring: Watch for psychiatric adverse reactions (aggression, hostility, irritability) particularly during titration 3

Alternative option: Valproate 20-30 mg/kg/day if Perampanel is not tolerated 4:

• Broad-spectrum mechanism with multiple targets 4
• 88% efficacy in refractory cases with minimal hypotension risk 4
• Can be loaded IV if seizures are frequent or clustering 4

Why Not Further Optimize Current Medications?

• Oxcarbazepine 1200 mg/day is already at high therapeutic dose 2
• Levetiracetam 3000 mg/day is at maximum recommended dose 4
• Clobazam 10 mg at bedtime is adequate for adjunctive therapy 2
• Evidence shows that responders to a given AED are typically identified at low-to-moderate doses, and non-responders often experience worsening seizures with dose escalation 2

If Seizures Continue or Cluster: Acute Management

For Seizure Clusters or Status Epilepticus

If the patient develops seizure clusters or status epilepticus:

First-line: IV lorazepam 0.1 mg/kg (or IM midazolam 10 mg if no IV access) 4

Second-line (if seizures persist after 5-10 minutes):

• Valproate 30 mg/kg IV over 5-20 minutes is preferred over fosphenytoin given the patient is already on oxcarbazepine (cross-reactivity concern) 4
• Alternative: Levetiracetam 30 mg/kg IV (but patient already on high-dose oral levetiracetam) 4

Third-line for refractory status epilepticus:

• Midazolam infusion: 0.15-0.20 mg/kg IV load, then 1 mcg/kg/min continuous infusion 5, 4
• Titrate by 1 mcg/kg/min every 15 minutes to maximum 5 mcg/kg/min 5
• Causes hypotension requiring pressors in 30% (versus 77% with pentobarbital) 5
• Requires continuous EEG monitoring to detect ongoing electrical seizures 5

Immunotherapy Protocol (If Autoimmune Etiology Confirmed)

If autoantibodies are positive or clinical suspicion remains high despite negative antibodies:

First-line immunotherapy (start once infection ruled out by basic CSF analysis) 1:

• High-dose methylprednisolone 1000 mg IV daily for 5 days 1
• OR IVIG 0.4 g/kg/day for 5 days (preferred if patient is agitated or has bleeding disorder) 1
• OR plasma exchange 5-10 sessions every other day (preferred if severe hyponatremia or high thrombotic risk) 1

Consider combination therapy from the start given severity of presentation with increasing seizure frequency 1

Second-line immunotherapy (if no improvement 2-4 weeks after first-line) 1:

• Rituximab 375 mg/m² weekly for 4 weeks for antibody-mediated disease (NMDAR, LGI1, etc.) 1
• Cyclophosphamide 750 mg/m² monthly for cell-mediated disease 1

Common Pitfalls to Avoid

1. Do not use neuromuscular blockers alone (e.g., rocuronium) as they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 4

2. Do not skip directly to third-line agents like pentobarbital without trying appropriate second-line options 4

3. Do not assume drug-resistant epilepsy without ruling out autoimmune encephalitis in a young adult with normal MRI 1

4. Do not continue escalating doses of failing medications—this often worsens outcomes in refractory epilepsy 2

5. Do not delay immunotherapy if autoimmune etiology is suspected, as early treatment significantly improves outcomes 1

Monitoring Requirements

• Continuous EEG monitoring if seizures are frequent or patient develops status epilepticus 5
• Psychiatric monitoring when starting Perampanel, particularly for aggression and mood changes 3
• Serum drug levels to confirm therapeutic ranges before declaring treatment failure 2
• Repeat autoantibody testing if initial testing negative but clinical suspicion remains high 1

Prognosis and Counseling

Patients with truly drug-resistant epilepsy (failing 2-3 appropriate AED trials) have only a 5-10% chance of achieving seizure freedom with additional medications 6, 7. The risks of uncontrolled seizures—including SUDEP, injuries, cognitive decline, and psychosocial dysfunction—often outweigh the risks of more aggressive treatments including immunotherapy or epilepsy surgery evaluation 7. This patient should be referred to a comprehensive epilepsy center for consideration of surgical evaluation if medical management continues to fail 7.