Antiepileptic Drug (AED) Adverse Effects

1. Drug-by-Drug Adverse Effect Profile

Phenytoin

• CNS (dose-related): Nystagmus, ataxia, diplopia, cognitive dulling - primarily affecting the cerebellum and vestibular system. The elderly are highly susceptible.
• Gingival hyperplasia: Gums grow over the teeth with chronic use (Figure 19.9, Lippincott).
• Peripheral neuropathy and osteoporosis: With long-term use (CYP induction accelerates vitamin D metabolism).
• Nonlinear (zero-order) kinetics: Small dose increases can produce disproportionately large rises in plasma concentration, making toxicity unpredictable.
• Teratogenicity: Fetal hydantoin syndrome (cleft palate, digital hypoplasia).
• Note: IM phenytoin causes tissue necrosis - use fosphenytoin for parenteral dosing instead.

Carbamazepine

• CNS: Diplopia, dizziness, ataxia, sedation.
• Hyponatremia (SIADH): Clinically significant, especially in the elderly.
• Dermatological: Rash, and - critically - Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN). Strongly associated with HLA-B*15:02 in Han Chinese and Southeast Asian populations. Screening before use is now standard in these populations.
• Hematological: Aplastic anemia (rare), agranulocytosis - CBC monitoring recommended.
• Hepatotoxicity: Mild transaminase elevations are common; fulminant hepatic failure is rare.
• Teratogenicity: Spina bifida and neural tube defects.
• Drug interactions: Strong CYP3A4 inducer - reduces efficacy of many co-administered drugs.

Valproate (Valproic acid / Divalproex)

• Hepatotoxicity: Potentially fatal, especially in children under 2 and those with mitochondrial disorders (Alpers syndrome - absolute contraindication).
• Weight gain and polycystic ovarian syndrome (PCOS)/hyperandrogenism in women.
• Pancreatitis (rare but serious).
• Tremor, hair loss (alopecia)
• Thrombocytopenia, coagulopathy (inhibits platelet aggregation).
• Teratogenicity - highest among AEDs: Neural tube defects (1-2%), cognitive impairment in offspring (lowest IQ at age 6 among CBZ, LTG, PHT, VPA - see below). Folic acid supplementation is imperative.
• Drug interactions: Inhibits lamotrigine glucuronidation - doubles lamotrigine half-life from ~25 to ~60 hours, requiring dose reduction of lamotrigine.

Phenobarbital / Primidone

• CNS: Drowsiness, mental dullness, nystagmus, ataxia (dose-related).
• Behavioral: Hyperactivity and behavioral problems in children and developmentally delayed patients.
• Connective tissue disorders: Frozen shoulder, Dupuytren contractures with long-term use.
• Strong CYP450 inducer: Extensive drug interactions.
• Teratogenicity: ~5.5% - comparable to other first-line drugs.

Lamotrigine

• Rash: Occurs in ~12% of patients; life-threatening SJS/TEN in ~1%. Risk is highest when the dose is escalated too rapidly or when used with valproate. Slow titration significantly reduces incidence.
• Reversible chorea: Rare, especially with concurrent phenytoin.
• Favorable profile: No weight gain, less teratogenic than valproate or carbamazepine; no enzyme induction.
• Drug interaction note: Valproate inhibits its metabolism (increase half-life to ~60 hours); enzyme-inducing AEDs reduce its levels.

Levetiracetam

• Psychiatric/behavioral: Irritability, agitation, depression, and suicidal ideation - the most clinically limiting adverse effect.
• CNS: Somnolence, dizziness at high doses.
• Advantages: No significant drug interactions (SV2A mechanism, renally excreted); favorable teratogenic profile; safe in hepatic failure/polypharmacy.

Carbamazepine analogues - Oxcarbazepine / Eslicarbazepine

• Hyponatremia (more pronounced with oxcarbazepine than carbamazepine).
• CNS: Dizziness, somnolence, diplopia, headache.
• Rare: rash, psychiatric effects.

Topiramate

• Cognitive impairment: "Dopamax effect" - word-finding difficulty, slowed thinking; common and dose-dependent.
• Weight loss, anorexia (useful side effect in some patients).
• Paresthesia (carbonic anhydrase inhibition).
• Nephrolithiasis (kidney stones): ~1.5%; more in men.
• Oligohidrosis (decreased sweating) and hyperthermia: Especially in children.
• Acute angle-closure glaucoma (rare but acute; must be recognized promptly).
• Teratogenicity: Oral clefts.

Gabapentin / Pregabalin

• Sedation, dizziness, ataxia, weight gain, peripheral edema.
• Generally well tolerated with few drug interactions (renally excreted, no protein binding).
• Nonlinear kinetics with gabapentin (saturable gut transport); pregabalin has more linear kinetics.
• Dosage adjustment required in renal impairment.
• Abuse potential with pregabalin (Schedule V in the US).

Ethosuximide

• GI disturbances: Nausea, vomiting, anorexia.
• CNS: Sedation, headache, hiccups.
• Fewer cognitive side effects than valproate when used for absence seizures.
• Virtual use limited to absence seizures.

Tiagabine

• Sedation, weight gain, fatigue, headache, tremor, dizziness, anorexia.
• Multiple drug interactions.

Vigabatrin

• Visual field defects / peripheral retinal damage (photoreceptor loss) - irreversible; the main reason for its restricted use (no longer used in adults; only through SHARE pharmacies in the US).
• Somnolence, fatigue, weight gain, peripheral neuropathy, anemia.

Felbamate

• Aplastic anemia (~1 in 4,000) and hepatic failure - limits use to refractory epilepsy (Lennox-Gastaut syndrome) only.

Zonisamide

• Nausea, anorexia, ataxia, confusion, sedation, paresthesia.
• Oligohidrosis and hyperthermia (shared with topiramate; carbonic anhydrase inhibition).
• Cognitive complaints; fewer than topiramate per some reports.

Lacosamide

• Headache, diplopia, dizziness.
• PR interval prolongation - caution in cardiac disease/conduction abnormalities; ECG check recommended before use.

Rufinamide

• QT interval shortening (rare but potentially arrhythmogenic).
• Multiple drug interactions.

Cenobamate

• Fatigue, headache, dizziness, double vision.

Fenfluramine

• Requires regular echocardiograms to monitor for valvulopathy and pulmonary hypertension.

Stiripentol

• Somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, insomnia.
• Neutropenia and thrombocytopenia possible.

2. Class-Wide / Common Adverse Effects

3. Teratogenicity - Key Comparison

• Neural tube defects: Valproate (1-2%), carbamazepine
• Fetal hydantoin syndrome: Phenytoin
• Oral clefts: Topiramate, phenobarbital
• Folic acid supplementation (4-5 mg/day) is recommended for all women on AEDs who may become pregnant.

4. Skin Reactions From AEDs - Special Note

5. Quick Memory Reference