In a healthy adult with a first unprovoked seizure, when should antiepileptic drug therapy be initiated and which agents are preferred as first‑line treatment?

Antiepileptic Drug Therapy After First Unprovoked Seizure in Adults

Primary Recommendation

Antiepileptic drugs should NOT be routinely initiated after a first unprovoked seizure in adults who have returned to baseline and have no evidence of brain disease or injury. 1, 2 The World Health Organization and American College of Emergency Physicians explicitly recommend against routine prescription, as immediate treatment does not improve long-term outcomes at 5 years despite reducing short-term recurrence risk. 1, 2

Risk Stratification Algorithm

Low-Risk Patients (Do NOT Treat)

• Unprovoked seizure without risk factors (normal neurologic exam, no prior brain disease/injury, normal MRI/EEG) carries only 20-40% recurrence risk over 5 years. 1, 2
• The number needed to treat to prevent one recurrence within 2 years is 14 patients—meaning 13 patients receive medication without benefit. 1, 2
• Treatment should be deferred to outpatient neurology follow-up rather than initiated in the emergency department. 1

High-Risk Patients (Consider Treatment)

• Unprovoked seizure WITH risk factors raises recurrence risk to 60-70% and warrants consideration of immediate therapy. 1, 2

High-risk features include: 1, 3

• Remote structural brain lesion (Level A evidence)
• Epileptiform abnormalities on EEG (Level A evidence)
• Age ≥40 years
• History of alcoholism
• Glasgow Coma Scale <15
• Nocturnal seizure (Level B evidence)
• Significant brain-imaging abnormality (Level B evidence)

• Even with high-risk features, treatment can be deferred to outpatient neurology rather than given immediately in the ED. 1

Provoked Seizures

• Do NOT treat with antiepileptics—manage the underlying cause (metabolic derangement, intoxication, acute systemic illness). 1
• The 2-year risk of subsequent unprovoked seizure after a provoked event is only ≈11%. 1

First-Line Medication Selection (When Treatment IS Indicated)

Preferred Agent

• Levetiracetam is preferred due to favorable pharmacokinetics and low adverse-effect profile. 1

Alternative First-Line Options

• Carbamazepine is recommended by WHO as preferred first-line monotherapy for partial onset seizures. 2
• Phenobarbital is suggested by WHO as cost-effective if availability is assured. 2

Critical Contraindication

• Valproate must be avoided in women of childbearing potential due to teratogenic risk. 1, 2

Key Evidence Supporting Non-Treatment Approach

• Immediate AED therapy reduces recurrence risk within the first 2 years (Level B evidence) but does not improve long-term prognosis for sustained seizure remission beyond 3 years (Level B evidence). 3
• Approximately one-third to one-half of patients will have recurrence within 5 years regardless of treatment timing. 1, 3
• AED adverse events occur in 7-31% of patients and are predominantly mild and reversible (Level B evidence). 3

Diagnostic Workup Required

• Brain MRI is preferred over CT for detailed assessment of epileptogenic lesions. 1
• Outpatient EEG should be arranged as part of neurodiagnostic work-up. 1
• Electrolyte testing only when history/physical suggests metabolic disturbance (vomiting, diarrhea, dehydration). 1
• Toxicology screening only when drug exposure or substance-use disorder is suspected. 1

Disposition

• Patients who have returned to baseline need not be admitted unless they possess recognized risk factors for recurrence. 1
• Observation for at least 6 hours is reasonable, as 85% of early recurrences happen within this timeframe. 1

Common Pitfalls to Avoid

• Do not initiate AEDs solely for patient or family anxiety—this does not improve long-term outcomes and exposes patients to unnecessary medication risks. 1
• The default should be observation and neurology follow-up, not immediate treatment, as recommended by WHO. 1, 2
• Recognize that treating 14 patients prevents only one recurrence within 2 years, meaning 13 patients receive medication without benefit. 1