What is the first-line treatment for a patient experiencing generalized tonic-clonic seizures (GTCS)?

Treatment of Generalized Tonic-Clonic Seizures

For first-line treatment of generalized tonic-clonic seizures (GTCS), benzodiazepines (lorazepam 4 mg IV) should be administered immediately for active seizures, followed by a second-line agent such as levetiracetam 30 mg/kg IV, valproate 20-30 mg/kg IV, or fosphenytoin 20 mg PE/kg IV if seizures continue. 1, 2 For chronic management in patients with primary GTCS, sodium valproate is the most effective first-line agent, though lamotrigine and levetiracetam are appropriate alternatives, particularly in women of childbearing potential. 3, 4

Acute Seizure Management (Active Seizure)

First-Line: Benzodiazepines

• Administer IV lorazepam 4 mg at 2 mg/min immediately for any patient actively seizing, with 65% efficacy in terminating status epilepticus 2
• Lorazepam is preferred over diazepam due to superior efficacy (59.1% vs 42.6% seizure termination) and longer duration of action 2
• Have airway equipment immediately available before administration, as respiratory depression can occur 2
• Check fingerstick glucose simultaneously and correct hypoglycemia while administering treatment 2

Second-Line Agents (If Seizures Continue After Benzodiazepines)

Select one of the following based on patient factors:

• Valproate 20-30 mg/kg IV over 5-20 minutes: 88% efficacy with 0% hypotension risk—superior safety profile compared to phenytoin 2, 1
• Levetiracetam 30 mg/kg IV over 5 minutes: 68-73% efficacy with minimal cardiovascular effects and no cardiac monitoring requirements 2, 1
• Fosphenytoin 20 mg PE/kg IV at maximum rate of 50 mg/min: 84% efficacy but 12% hypotension risk requiring continuous ECG and blood pressure monitoring 2, 1
• Phenobarbital 20 mg/kg IV over 10 minutes: 58.2% efficacy but higher risk of respiratory depression 2

Valproate appears to be the optimal second-line choice due to its superior efficacy (88%) and minimal hypotension risk (0%) compared to fosphenytoin's 84% efficacy and 12% hypotension risk 2

Refractory Status Epilepticus (Seizures Continuing Despite Benzodiazepines and One Second-Line Agent)

Initiate continuous EEG monitoring and select an anesthetic agent:

• Midazolam infusion (preferred): 0.15-0.20 mg/kg IV load, then 1 mg/kg/min continuous infusion, titrate up by 1 mg/kg/min every 15 minutes to max 5 mg/kg/min—80% efficacy with 30% hypotension risk 2
• Propofol: 2 mg/kg bolus, then 3-7 mg/kg/hour infusion—73% efficacy with 42% hypotension risk, requires mechanical ventilation but shorter ventilation time (4 days vs 14 days with barbiturates) 2
• Pentobarbital: 13 mg/kg bolus, then 2-3 mg/kg/hour infusion—highest efficacy at 92% but 77% hypotension risk requiring vasopressors and prolonged mechanical ventilation 2

Chronic Management (Seizure Prevention)

For Primary Generalized Tonic-Clonic Seizures

Sodium valproate is the most effective first-line treatment for primary GTCS, but should be avoided in women of childbearing potential due to teratogenicity and neurodevelopmental risks 3, 4, 5

First-line options in order of preference:

• Sodium valproate: Most efficacious for primary GTCS in males and postmenopausal women, avoid in childbearing-age women 4, 3
• Lamotrigine: Appropriate first-line alternative, particularly for women of childbearing potential 4, 3
• Levetiracetam: Equally appropriate first-line alternative with favorable safety profile 4, 3
• Topiramate: Effective but concerns regarding cognitive and memory adverse effects 4, 5

High-certainty evidence shows no significant differences in treatment failure between sodium valproate, lamotrigine, and levetiracetam for generalized onset seizures 3

For Secondary Generalized Tonic-Clonic Seizures (Focal Onset)

Lamotrigine and levetiracetam demonstrate the best profiles for focal seizures with secondary generalization 3

First-line options:

• Lamotrigine: Performs better than most other treatments including carbamazepine in terms of treatment failure 3
• Levetiracetam: No significant difference from lamotrigine, both perform better than other AEDs 3
• Carbamazepine: Traditional first-line but higher treatment failure rates than lamotrigine 3

All AEDs approved for focal epilepsies may be used for secondary GTCS, including lacosamide, perampanel, and topiramate 5

Newer Agents

• Perampanel: FDA-approved as adjunctive therapy for primary GTCS in patients ≥12 years, starting dose 2 mg once daily at bedtime, titrate by 2 mg weekly to maintenance dose of 8 mg daily 6, 7
• Warning: Serious psychiatric and behavioral reactions including aggression, hostility, and homicidal ideation reported with perampanel—closely monitor during titration 6

Critical Pitfalls to Avoid

• Never use sodium channel blockers (carbamazepine, phenytoin, oxcarbazepine) as initial treatment for unclassified GTCS unless focal onset is clearly confirmed, as they may aggravate primary GTCS 8
• Do not skip to third-line anesthetic agents (pentobarbital, propofol) until benzodiazepines and a second-line agent have been tried 2
• Never use neuromuscular blockers alone (rocuronium)—they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 2
• Avoid valproate in women of childbearing potential due to significantly increased risks of fetal malformations and neurodevelopmental delay 3, 4
• Do not initiate antiepileptic medication in the ED for patients with a single unprovoked seizure without evidence of brain disease or injury—outpatient follow-up is appropriate 1

Special Monitoring Considerations

• Continuous vital sign monitoring is essential during acute treatment, particularly respiratory status and blood pressure 2
• Simultaneously search for and treat underlying causes: hypoglycemia, hyponatremia, hypoxia, drug toxicity, CNS infection, ischemic stroke, intracerebral hemorrhage, and withdrawal syndromes 2
• Prepare for respiratory support regardless of administration route when using benzodiazepines or anesthetic agents 2
• Use continuous EEG monitoring in refractory status epilepticus to guide titration and detect ongoing electrical seizure activity 2