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Epilepsy
20 notes available
1 Last Minute Review 2 Seizure Semiology & Localization 3 Epilepsy Diagnostic Workup 4 Neonatal & Infantile Encephalopathies 5 Childhood Epileptic Encephalopathies 6 Self-Limited & Absence Epilepsies 7 Temporal Lobe & Focal Epilepsies 8 Idiopathic Generalized Epilepsies 9 Progressive Myoclonic & Reflex Epilepsies 10 First Seizure & Acute Symptomatic 11 Status Epilepticus 12 Autoimmune Epilepsy 13 ASM Selection & Treatment 14 Individual ASM Profiles & PK 15 Presurgical Evaluation 16 Epilepsy Surgery 17 Neuromodulation (VNS, RNS, DBS) 18 Special Populations & SUDEP 19 Driving Regulations 20 Epilepsy Mimics & DDx
Clinical › Epilepsy

ASM Selection & Treatment

ASM Selection & Treatment Principles

What You'll Learn

  • Focal epilepsy first-line: lamotrigine (SANAD I + II), with alternatives such as levetiracetam, carbamazepine/oxcarbazepine, and lacosamide depending on patient factors. Cenobamate is a high-efficacy option for drug-resistant focal epilepsy or selected later-line use, with slow titration for DRESS risk — not routine first-line.
  • Generalized epilepsy first-line: valproate (SANAD I + II); use LTG or LEV in women of childbearing potential
  • Broad-spectrum ASMs (VPA, LEV, LTG, TPM, ZNS, clobazam, perampanel) are preferred when classification is uncertain, but selection remains syndrome-specific: LTG can worsen myoclonus in JME; TPM is not a preferred absence drug; ethosuximide is absence-only; narrow Na⁺ channel blockers can worsen IGE and Dravet.
  • Seizure freedom probability: ~45–47% with first ASM (Chen 2018 update), ~13% with second, 2–5% each subsequent; cumulative ~64%
  • Drug-resistant epilepsy (ILAE 2010): failure of 2 tolerated, appropriately chosen and used ASMs → refer for surgical evaluation
  • Synergistic combination with strongest evidence: LTG + VPA (but VPA doubles LTG levels — dose adjust)
  • Withdrawal: consider after 2–5 years seizure-free; recurrence ~30–40% overall; JME >80–90% relapse → generally lifelong treatment
HighYield Pearls
  • ILAE drug-resistant epilepsy: failure to achieve sustained seizure freedom after adequate trials of 2 well-chosen, well-tolerated ASMs (mono- or combo) → refer for epilepsy surgery evaluation — not after 5, not after 10
  • Women of childbearing age: AVOID valproate (lowest offspring IQ, NTDs, dose-related teratogen, lifelong cognitive risk) and topiramate (cleft lip/palate); lamotrigine & levetiracetam safest per NAAED registry; folic acid 0.4–4 mg preconception
  • Lamotrigine in pregnancy: levels DROP markedly (glucuronidation induction) → check monthly and titrate UP; reduce postpartum to avoid toxicity
  • OCP-interacting enzyme inducers: CBZ, PHT, PB, PRM, TPM (>200 mg), OXC (high-dose) reduce many systemic hormonal contraceptives. Prefer copper IUD or LNG-IUD; DMPA is generally acceptable. Do not rely on POPs, combined OCPs, patch/ring, or implant with strong enzyme inducers. These ASMs also induce DOACs, warfarin, and transplant immunosuppressants.
  • VPA + LTG combo: VPA inhibits glucuronidation → doubles LTG levels → halve the LTG dose and titrate extra-slowly to avoid SJS/TEN
  • Dravet syndrome: Na⁺ channel blockers (CBZ, OXC, PHT, LTG, lacosamide) CONTRAINDICATED — worsen seizures; use VPA + clobazam ± stiripentol/CBD/fenfluramine
  • HLA-B*15:02 screening in Asian-ancestry patients before CBZ, PHT, OXC (SJS/TEN risk); HLA-A*31:01 for European ancestry on CBZ
  • Elderly: start low, go slow — LTG, LEV, GBP favored; AVOID IV PHT loading (cardiac arrhythmia, hypotension, purple-glove); avoid TPM/ZNS (cognition); renal-dose LEV/GBP/PGB/LCM/ZNS
  • Hepatic disease: avoid VPA (hepatotoxicity, hyperammonemia), CBZ, felbamate; LEV, GBP, and PGB have the lowest hepatic burden. Lacosamide may be used cautiously with dose adjustment in mild/moderate hepatic impairment (about 25% max-dose reduction per labeling), but avoid in severe hepatic impairment.
  • Psychiatric comorbidity: LEV & perampanel → irritability/aggression/depression (pyridoxine may mitigate LEV behavioral SE); mood-friendly choices: LTG, VPA, CBZ; always counsel SUDEP in DRE
🔍 Quick ReferenceBy syndrome · Special populations · "Avoid" pairs
First-line by syndrome
  • Focal epilepsy → lamotrigine (SANAD II noninferior to LEV; alternatives: LEV, CBZ, OXC, lacosamide). Cenobamate is reserved for drug-resistant focal epilepsy or selected later-line use, not routine first-line.
  • Generalized tonic-clonic / JME / JAE → valproate (most effective; LEV or LTG if WOCA)
  • Childhood absence (CAE) without GTC → ethosuximide (Glauser CAE trial: ETX = VPA > LTG; ETX preferred — fewer attentional AEs)
  • Lennox-Gastaut (LGS) → VPA + clobazam, rufinamide, cannabidiol, fenfluramine; callosotomy for drop attacks
  • Dravet syndrome → VPA + clobazam ± stiripentol, cannabidiol, fenfluramine (STICLO: 71% vs 5%)
  • Infantile spasms (non-TSC) → ACTH; TSC → vigabatrin first-line
Special populations
  • Pregnancy / WOCA → lamotrigine or levetiracetam safest (NAAED registry); folic acid 0.4–4 mg; monitor LTG levels monthly
  • Elderly new-onset focal epilepsy → lamotrigine, levetiracetam, or gabapentin (best tolerability; renal dose adjust)
  • Hepatic dysfunction → levetiracetam, gabapentin, pregabalin have the lowest hepatic burden. Lacosamide: cautious use with dose adjustment in mild/moderate hepatic impairment, avoid/not recommended in severe.
  • Renal dysfunction → favor LTG, CBZ, VPA, PHT (hepatic); dose-reduce LEV/GBP/PGB/LCM/ZNS
  • Asian ancestry before CBZ/PHT/OXC → HLA-B*15:02 screen (SJS/TEN risk); consider HLA-A*31:01 in European/Japanese ancestry for CBZ (SJS/TEN, DRESS, maculopapular rash)
  • Depression/mood disorder → favor LTG (mood-stabilizing); avoid LEV, perampanel, TPM, ZNS
  • Drug-resistant epilepsy after 2 failed ASMs → surgical evaluation, VNS, RNS, or DBS; counsel SUDEP
"Avoid in" pairings
  • Valproate → AVOID in women of childbearing age, hepatic disease, urea-cycle disorders, mitochondrial disease (POLG)
  • Topiramate → AVOID in pregnancy (cleft lip/palate), nephrolithiasis, cognitive concerns, glaucoma
  • Na⁺ channel blockers (CBZ, OXC, PHT, LTG, lacosamide) → AVOID in Dravet syndrome, absence, myoclonic, atonic (IGE)
  • Levetiracetam / perampanel → AVOID with active depression, psychosis, irritability/aggression
  • Enzyme inducers (CBZ, PHT, PB, PRM) → AVOID with OCPs, DOACs, warfarin, transplant immunosuppressants
  • VPA + lamotrigine → halve LTG dose & titrate slowly (SJS/TEN risk from doubled LTG levels)
  • IV phenytoin loading in elderly → AVOID (cardiac arrhythmia, hypotension, purple-glove syndrome) — use fosphenytoin or LEV
  • Carbamazepine / phenytoin / oxcarbazepine in Asian patients → check HLA-B*15:02 first
Broad-Spectrum vs. Narrow-Spectrum ASMs

Classification by Spectrum

SpectrumASMsIndicationsKey Caveat
Broad-spectrumVPA, LEV, LTG, TPM, ZNS, clobazam, perampanelPreferred when classification is uncertain; selection still syndrome-specificLTG may worsen myoclonus in JME; TPM is not a preferred absence drug; ethosuximide is absence-only
Narrow-spectrum (focal)CBZ, OXC, ESL, PHT, lacosamide, GBP, PGBFocal epilepsy onlyMay worsen absence, myoclonic, atonic — AVOID in IGE
Narrow-spectrum (absence)EthosuximideAbsence seizures onlyNo efficacy for other seizure types; first-line for CAE without GTC
  • Rule: if seizure type uncertain → always choose broad-spectrum ASM
  • Na+ channel blockers exacerbate generalized absence/myoclonic seizures via enhanced thalamocortical synchronization
  • Gabapentinoids (GBP, PGB) may worsen myoclonus and absence seizures
ASM Selection by Seizure Type & Syndrome

Master Selection Table

Seizure Type / SyndromeFirst-LineAlternativesKey Evidence / Notes
Focal seizuresLTGLEV, CBZ, OXC, lacosamide (cenobamate reserved for drug-resistant focal or selected later-line)SANAD I + II: LTG best for time to remission and treatment failure
Generalized tonic-clonicVPALTG, LEVSANAD I + II: VPA superior; LTG/LEV preferred in women of childbearing potential
Absence (CAE without GTC)EthosuximideVPA, LTGGlauser NEJM 2010 (CAE trial): ETX = VPA > LTG; ETX preferred due to fewer attentional AEs vs VPA.
Absence (with GTC)VPALTG, LEVETX ineffective for GTC → VPA covers both seizure types
MyoclonicVPALEV, clobazamLEV has Class I evidence for myoclonic seizures; VPA most effective overall
Infantile spasms (non-TSC)ACTHVigabatrin, prednisoloneACTH superior to VGB for non-TSC spasms
Infantile spasms (TSC)VigabatrinACTHVGB first-line in TSC: 65–95% response. EPISTOP showed preemptive VGB (before clinical spasms) reduced IS incidence in TSC infants with abnormal EEG; not yet universal standard of care.
LGSVPAClobazam, rufinamide, CBD, fenfluramineCBD (GWPCARE3/4); fenfluramine FDA-approved; callosotomy for drop attacks
Dravet syndromeVPA + clobazamStiripentol, CBD, fenfluramineNa+ channel blockers CONTRAINDICATED; stiripentol (STICLO: 71% vs. 5%)
JMEVPA (most effective)LEV (women), LTG (caution)LTG may worsen myoclonus; lifelong treatment required (>80–90% relapse)
💎 Board Pearl
  • Ethosuximide is first-line for CAE WITHOUT GTC; if GTC present, use VPA (ETX has no GTC efficacy)
  • LTG in JME: acceptable for GTC prevention but may paradoxically worsen myoclonic jerks — use with caution
  • Cenobamate: up to 21% seizure-free during 12-month maintenance at 400 mg in open-label phase 3 (Sperling 2020); pivotal RCT (Krauss 2020) reported 50% responder rates — unprecedented for adjunctive therapy
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