How should I start antiepileptic medication in an adult who has had a new unprovoked seizure after electrolytes, glucose, renal and liver function tests, brain imaging and electroencephalogram have been performed, taking into account seizure type, comorbidities, age, organ function and drug interactions?

Starting Antiepileptic Medications After a First Unprovoked Seizure

Do not start an antiepileptic drug (AED) in the emergency department for a first unprovoked seizure unless the patient has remote symptomatic brain disease or injury (e.g., prior stroke, traumatic brain injury >7 days ago, tumor, or chronic CNS disease). 1

Key Principle: AEDs Do Not Improve Long-Term Outcomes

• Starting an AED after a first unprovoked seizure lengthens the interval to the next seizure but does not improve five-year outcomes, remission rates, or mortality. 1
• The number needed to treat to prevent one seizure recurrence within two years is 14, meaning 13 patients are exposed to medication adverse effects without proven morbidity or mortality benefit. 1
• AED therapy reduces 1–2 year recurrence risk but does not affect long-term recurrence rates or remission. 1

When to Consider Starting an AED

High-Risk Features for Recurrence

Initiate AED therapy only when the first unprovoked seizure occurs in the setting of:

• Remote symptomatic brain disease (prior stroke, traumatic brain injury, tumor, or chronic CNS disease that occurred >7 days ago). 1
• Abnormal EEG showing epileptiform discharges, which predicts increased seizure recurrence risk. 1
• Structural brain lesion on MRI (e.g., cortical dysplasia, mesial temporal sclerosis, prior infarct). 1

Recurrence Risk Data

• Approximately 30–50% of patients experience seizure recurrence within five years after a first unprovoked seizure. 1
• Patients with remote symptomatic seizures have higher recurrence rates, supporting early AED initiation after a single event. 1
• The mean time to first recurrence is 121 minutes (median 90 minutes), and >85% of early recurrences occur within 6 hours of ED presentation. 1
• Nonalcoholic patients with new-onset seizures have the lowest early recurrence rate (9.4%). 1

Selecting the Appropriate AED

Match AED to Seizure Type and Patient Factors

When AED initiation is warranted, selection depends on seizure type, comorbidities, age, organ function, and drug interactions:

For Focal (Partial) Seizures:

• Levetiracetam is preferred in most patients due to minimal drug interactions, no hepatic metabolism, and favorable adverse effect profile. 1
• Lamotrigine is an alternative but requires slow titration (weeks) to avoid Stevens-Johnson syndrome risk. 2
• Carbamazepine is effective but has significant drug interactions (hepatic enzyme inducer) and requires monitoring. 3

For Generalized Seizures:

• Valproate (30 mg/kg loading dose) is highly effective for generalized seizures but is absolutely contraindicated in women of childbearing potential due to teratogenicity (neural tube defects, decreased IQ). 4
• Lamotrigine is preferred in women of childbearing potential for generalized seizures. 1

Critical Contraindications and Warnings

Valproate:

• Contraindicated in hepatic disease, mitochondrial disorders (POLG mutations), suspected POLG-related disorder in children <2 years, and urea cycle disorders. 4
• Black box warning for hepatotoxicity (especially in children <2 years), fetal risk (neural tube defects, major malformations, decreased IQ), and pancreatitis. 4
• Monitor serum liver tests prior to therapy and at frequent intervals. 4

Carbamazepine:

• Start at low dose (200 mg twice daily in adults >12 years) and increase weekly by 200 mg/day. 3
• Maximum dose generally 1200 mg/day in adults >15 years (up to 1600 mg/day in rare instances). 3
• Induces hepatic enzymes, reducing efficacy of oral contraceptives, warfarin, and other AEDs. 3
• Monitor blood levels to optimize efficacy and safety. 3

Dosing Strategies When Resuming AEDs in the ED

If a patient with known epilepsy presents with breakthrough seizure and subtherapeutic AED levels, loading doses may be appropriate:

Carbamazepine:

• 8 mg/kg oral suspension as a single load (IV formulation not available). 2
• Oral tablet has slow/erratic absorption; suspension preferred for loading. 2

Lamotrigine:

• 6.5 mg/kg single oral load if on lamotrigine for >6 months without a history of rash. 2
• Do not load in AED-naïve patients due to Stevens-Johnson syndrome risk. 2

Lacosamide:

• Oral and IV formulations available and safe; loading dosages not well studied. 2
• Adjunct for partial seizures; withdrawal seizures can occur with abrupt discontinuation. 2

Common Pitfalls to Avoid

• Do not start AEDs for provoked seizures (e.g., hypoglycemia, hyponatremia, alcohol withdrawal, acute stroke, acute CNS infection). 1
• Do not prescribe valproate to women of childbearing potential unless all other options are unacceptable and effective contraception is ensured. 4
• Do not discharge patients on AEDs without neurology follow-up to confirm diagnosis, optimize therapy, and monitor for adverse effects. 1
• Do not assume alcohol withdrawal seizures are benign; they should be a diagnosis of exclusion, especially in first-time seizures. 1
• Do not fail to counsel patients on driving restrictions, which vary by state but typically require 3–12 months seizure-free. 5

Disposition and Follow-Up

• Patients who have returned to baseline with normal neurologic exam, normal labs, and reliable follow-up can be safely discharged without AED initiation. 1
• Arrange outpatient neurology follow-up within 1–2 weeks for EEG and epilepsy-protocol MRI to stratify recurrence risk. 1
• Admit patients with persistent abnormal neurologic findings, abnormal investigation results requiring inpatient care, or unreliable follow-up. 1