What is the initial antiepileptic drug (AED) treatment for focal seizures in both inpatient (IPD) and outpatient (OPD) settings in Indian clinical practice?

Focal Seizure Management in Indian Clinical Practice

Outpatient (OPD) Prescription for Focal Seizures

For adults with focal seizures in Indian clinical practice, initiate monotherapy with carbamazepine 200-400 mg twice daily or lamotrigine 25 mg daily (titrated slowly to 100-200 mg daily), as these are the recommended first-line agents with the best evidence for treatment failure and seizure control. 1, 2

First-Line Monotherapy Options

Carbamazepine:

• Start: 200 mg twice daily (or 100 mg BD if concerned about tolerability)
• Titrate: Increase by 200 mg every 1-2 weeks
• Target maintenance: 400-600 mg twice daily (800-1200 mg/day total)
• Maximum: 1600 mg/day in divided doses
• Carbamazepine is specifically recommended as preferential treatment for partial onset seizures in low- and middle-income countries when availability can be assured 1
• High-certainty evidence shows carbamazepine performs well for time to first seizure and remission outcomes 2

Lamotrigine (preferred if better tolerability needed):

• Start: 25 mg once daily for 2 weeks
• Week 3-4: 50 mg once daily
• Week 5-6: 100 mg once daily or 50 mg BD
• Target maintenance: 100-200 mg twice daily (200-400 mg/day total)
• Lamotrigine demonstrates superior performance compared to carbamazepine for treatment failure outcomes (HR 1.26,95% CI 1.10-1.44) 2
• Slow titration is critical to prevent Stevens-Johnson syndrome 2

Levetiracetam (alternative first-line):

• Start: 500 mg twice daily
• Titrate: Increase by 500 mg every 1-2 weeks
• Target maintenance: 1000 mg twice daily (2000 mg/day total)
• Maximum: 1500 mg twice daily (3000 mg/day)
• No significant difference between lamotrigine and levetiracetam for treatment failure (HR 1.01,95% CI 0.88-1.20) 2
• Excellent tolerability profile with minimal drug interactions 3, 4

Critical Prescribing Considerations for OPD

When to start treatment:

• Do NOT routinely prescribe antiepileptic drugs after a first unprovoked seizure 1
• Initiate treatment after 2 unprovoked seizures, or after 1 seizure occurring during sleep with epileptiform EEG activity or structural brain lesion 3

Avoid phenobarbital as first-line despite cost:

• Although phenobarbital is recommended in WHO guidelines for low-resource settings due to acquisition costs 1, high-certainty evidence shows phenobarbital has significantly worse treatment failure rates (HR 1.97,95% CI 1.45-2.67 compared to lamotrigine) 2
• Phenobarbital carries higher risk of behavioral adverse effects 1

Drug selection algorithm:

1. First choice: Lamotrigine or carbamazepine - both have high-certainty evidence for focal seizures 2
2. If psychiatric comorbidity present: Lamotrigine preferred - levetiracetam should be avoided with psychiatric history 3
3. If cost is major constraint: Carbamazepine - more affordable than lamotrigine in Indian market
4. If drug interactions concern: Levetiracetam - no enzyme induction, minimal interactions 4

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Inpatient (IPD) Prescription for Acute Seizures/Status Epilepticus

For actively seizing patients or status epilepticus, immediately administer IV lorazepam 0.1 mg/kg (4 mg typical adult dose) at 2 mg/min, followed by a second-line agent if seizures persist beyond 5 minutes. 1, 5

First-Line Treatment (Immediate)

IV Lorazepam (preferred benzodiazepine):

• Dose: 0.1 mg/kg IV (typically 4 mg for adults)
• Rate: 2 mg/min
• May repeat once after 5 minutes if seizures continue
• Lorazepam is preferred over diazepam when IV access available due to longer duration of action 1, 5

If IV access not available:

• Rectal diazepam 10-20 mg (0.2-0.5 mg/kg)
• IM diazepam is NOT recommended due to erratic absorption 1
• IM midazolam 10 mg can be considered as alternative 5

Second-Line Treatment (If Seizures Continue After Benzodiazepines)

For benzodiazepine-refractory status epilepticus, administer one of the following with equivalent efficacy:

Levetiracetam (preferred for safety profile):

• Loading dose: 30 mg/kg IV (typically 2000-3000 mg for adults)
• Rate: Over 5 minutes (up to 100 mg/min)
• Efficacy: 47% cessation at 60 minutes, with only 0.7% risk of life-threatening hypotension 1, 5
• Minimal cardiovascular effects 5, 6

Fosphenytoin:

• Loading dose: 20 mg PE/kg IV
• Rate: Maximum 50 mg PE/min (or 150 mg PE/min if urgent)
• Efficacy: 45% cessation at 60 minutes, but 3.2% risk of life-threatening hypotension 1, 5
• Requires continuous ECG and BP monitoring 5

Valproate:

• Loading dose: 20-30 mg/kg IV (typically 2000-3000 mg for adults)
• Rate: Over 5-20 minutes (6 mg/kg/hour)
• Efficacy: 46% cessation at 60 minutes, with 1.6% risk of hypotension 1, 5
• 88% efficacy reported in some studies with minimal hypotension risk (0%) 5
• Avoid in women of childbearing potential and young children due to hepatotoxicity and teratogenicity 1, 6

High-certainty evidence shows levetiracetam, fosphenytoin, and valproate have similar efficacy (approximately 45-47% seizure cessation), but levetiracetam has the best safety profile with lowest hypotension risk. 1, 5

Third-Line Treatment (Refractory Status Epilepticus)

If seizures persist after adequate dosing of benzodiazepines plus second-line agent:

Midazolam infusion:

• Loading: 0.15-0.20 mg/kg IV bolus
• Infusion: 1 mg/kg/min, titrate up by 1 mg/kg/min every 15 minutes to maximum 5 mg/kg/min
• 80% overall success rate with 30% hypotension risk 5
• Requires intubation and mechanical ventilation 5

Propofol:

• Loading: 2 mg/kg IV bolus
• Infusion: 3-7 mg/kg/hour
• 73% efficacy but requires mechanical ventilation 5
• Less hypotension than pentobarbital (42% vs 77%) 5

Pentobarbital:

• Loading: 13 mg/kg IV
• Infusion: 2-3 mg/kg/hour
• Highest efficacy at 92% but 77% hypotension risk 5
• Longer ventilation time (14 days vs 4 days with propofol) 5

Critical IPD Management Pitfalls

Never use neuromuscular blockers alone:

• Rocuronium or other paralytics only mask motor manifestations while allowing continued electrical seizure activity and ongoing brain injury 5
• Always ensure adequate antiepileptic medication before paralysis

Simultaneous evaluation for underlying causes:

• Check and correct: hypoglycemia, hyponatremia, hypoxia, drug toxicity 1, 5
• Investigate: CNS infection (LP if indicated), stroke, hemorrhage, withdrawal syndromes 1

Continuous monitoring requirements:

• Vital signs, especially BP and respiratory status 5
• EEG monitoring when available to guide treatment and detect non-convulsive status 5
• Prepare for intubation regardless of medication route 5

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Sample IPD Prescription Format

Acute Seizure/Status Epilepticus:

1. Immediate (0-5 minutes):

   • Inj. Lorazepam 4 mg IV slow push over 2 minutes STAT
   • May repeat once after 5 minutes if seizures continue

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

   • Inj. Levetiracetam 2000-3000 mg (30 mg/kg) IV over 5 minutes STAT
   • Alternative: Inj. Fosphenytoin 1500-2000 mg PE (20 mg PE/kg) IV at max 150 mg PE/min with cardiac monitoring

3. Supportive care:

   • IV fluids: NS 500 mL over 4 hours
   • Monitor: Continuous vitals, oxygen saturation, cardiac monitoring
   • Check: RBS, serum electrolytes, renal function, liver function
   • Maintain airway, prepare for intubation if needed

4. Transition to maintenance (once seizures controlled):

   • Tab. Levetiracetam 500 mg BD PO (or appropriate first-line agent based on seizure type)
   • Titrate as per OPD protocol above

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Sample OPD Prescription Format

New-onset Focal Seizures (after 2nd unprovoked seizure):

Rx:

1. Tab. Levetiracetam 500 mg BD PO after food

   • Week 1-2: 500 mg BD
   • Week 3-4: 1000 mg BD (target dose)

   OR

   Tab. Carbamazepine 200 mg BD PO after food

   • Week 1-2: 200 mg BD
   • Week 3-4: 400 mg BD
   • Week 5-6: 600 mg BD (target dose)

2. Counseling provided:

   • Avoid high-risk activities (driving, swimming alone, working at heights) 1
   • First aid measures for family members 1
   • Medication compliance critical - do not stop abruptly
   • Report rash immediately (especially with lamotrigine)
   • Avoid alcohol and sleep deprivation

3. Follow-up: 2 weeks for tolerance assessment, then monthly until seizure-free for 3 months, then every 3 months

4. Discontinuation consideration: Only after 2 seizure-free years with patient/family involvement in decision 1

1, 5, 6, 3, 4, 2