epilepsy treatment

goals of treatment

1. control or reduce the frequency and severity of seizures

   • goal is zero but not always realistic

2. minimize side effects and ensure medication compliance

   • monotherapy is preferred

   • noncompliance is the most common reason for treatment failure

3. maintain or restore quality of life

4. manage co-morbidities

nonpharm treatment

• medical marijuana

  • cannabidol- first ever cannabis derived medication approved by the FDA to treat forms of epilepsy

    • does not contain THC

    • consider additive CNS side effect

• ketogenic diet

  • used in pts w refractory seizures

  • high in fat, normal protein, low in carbs

  • forces body to breakdown fatty acids into ketone bodies

  • ketones pass into brain, replace glucose → reduced seizure activity

• vagus nerve stimulation

  • implanted medical device that is FDA approved for use as an adjunctive therapy in reducing frequency of seizures

• surgery

  • pts w focal onset seizures who are drug resistant may be candidates for surgical resection

• embrace2 smartwatch

clinical pearls

• generally considered to have equal efficacy

• FDA warnings exists for all AEDS for increased risk of suicidality associated with use

• all have mechanisms of actions that work on CNS physiology so there is higher risk of neurotoxic events

• osteopenia or osteoporosis with long term use

• known teratogenicity or pregnancy category C

• 1st generation

  • multiple DDIs caused by metabolism by and effects on the CYP450 and UGT systems

  • inducers

    • carbamazepine, phenytoin, phenobarb/primidone

  • inhibitors

    • valproic acid

• 2nd generation

  • keppra and gabapentin are completely renally cleared

  • topamax is partially renally cleared

common broad-spectrum AEDs

• lamotrigine - lamictal

  • Na+ channel blocker

  • normal dose: varies significantly (weekly titration)

    • week 1-2: 25 mg QD

    • week 3-4: 50 mg QD

    • week 5 and on: increase by 50 mg QD every 1-2 weeks

  • BBW: serious skin rashes

    • reason for slow titration

  • AEs: alopecia, n/v, diplopia, drowsiness, ataxia, headache, rash, blood dyscrasias

  • DI: does not induce or inhibit liver enzymes

    • VPA increases lamictal conc.

    • ethinyl estradiol induces lamotrigine glucuronidation

  • dosage forms: tab, ER tab, chew tab. ODT

  • uses: focal and generalized seizures, bipolar disorder

  • pregnancy: caution advised → safer option for pregnancy

• levetiracetam - keppra

  • Ca+ channel blocker, increases GABA

  • normal dose: 500-1500 mg PO/IV Q12H

    • 1000-3000 mg PO QD ER

    • decrease dose if CrCl <80mL/min

  • AEs: sedation, fatigue, coordination difficulties, behavioral disorders, irritability, agitation, somnolence, lethargy

    • avoid in pts with baseline irritability and anger management problems

  • renal elimination

  • no significant drug interactions

  • uses: focal and generalized seizures

• topiramate - topamax, quedexy, eprontia

  • Na+ channel blocker

  • normal dose

    • IR: 200 mg BID

    • ER: 400 mg QD

    • decrease mdose if CrCl <70 mL/min

  • contraindications: avoid abrupt withdrawal

    • trokendi - alcohol use 6 hr before and after dose

    • qudexy - metabolic acidosis

  • AEs: paresthesia, cognitive impairment, nephrolithiasis, metabolic acidosis, anorexia, weight loss, ocular effects, oligohidrosis and hyperthermia

  • renal elimination

  • uses: focal and generalized seizures and migraine prophylaxis

• divalproex sodium - valproic acid - depakote

  • increases GABA

  • individualized dosing

  • therapeutic range 50-100 mcg/mL

  • contraindications: pregnancy, severe liver disease

  • BBW: increases hepatoxicity, increased risk for pancreatitis, teratogenic

  • AEs: GI complaints, weight gain, alopecia. hyperammonemia, hepatotoxicity, thrombocytopenia, tremor

  • enzyme inhibitor with nonlinear kinetics

  • uses: focal and generalized seizures, bipolar disorder, migraines

common narrow-spectrum AEDs

• carbamazepine - tegretol, epitol

  • Na+ channel blocker

  • doses:

    • IR: 800-1200 mg in divided doses

    • ER: 400-600 mg BID

    • therapeutic range 4-12 mcg/mL

    • may need to start dose at ¼ to 1/3 the anticipated dose due to auto-induction

  • contraindications: hypersensitivity to TCAs, bone marrow depression. MAOI use, cocomitant use of fefazodone or other NNRTI that are CYP3A4 substrates

  • BBW: HLA-B*1502 allele and serious dermatologic rxns, aplastic anemia and agranulocytosis

  • AEs: neurosensory side effects, nausea, hyponatremia, leukopenia

  • uses: focal and generalized seizures, bipolar disorder, neuropathies (trigeminal neuralgia)

  • food (fat) may enhance bioavailability

  • autoinducer and enzyme inducer

• oxcarbazepine- trileptal, oxtellar

  • Na+ and Ca2+ channel blocker

  • dose: 600 mg BID

    • maintenance dose is 1.5x the dose of carbamazepine

  • AEs: dizziness, nausea, headache, diarrhea, vomiting, upper respiratory tract infection, dyspepsia, ataxia, nervousness. hyponatremia

  • not an autoinducer but an enzyme inducer

  • uses: focalized seizures

• lacosamide - vimpat

  • stablizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing by enhancing the slow inactivation of sodium channels

  • dose:

    • status epi: 200-400 mg IV

    • PO: 50-200 mg BID

    • dose reduce (by 75%) in mild to moderate hepatic impairment

  • AEs: cardiovascular effects, dermatologic rxns, nausea, dizziness, drowsiness, headache

  • C-V for euphoric effects

• phenobarbital

  • enhance/potentiate GABA effect

  • dose:

    • status 15-20 mg/kg IV

    • 2mg/kg/day PO in divided doses

  • enzyme inducer

  • primidone is prodrug of phenobarb

  • contraindications: significant hepatic impairment, dyspnea or airway obstruction

  • BBW: concomitant use of BZD + opioids → sedation, respiratory depression, death and abuse, misuse, addiction, dependence

  • AEs: hypotension, bradycardia, respiratory depression, dermatologic rxns, dizziness, drowsiness, headache

  • C-IV

• phenytoin - dilantin

  • Na+ channel blocker

  • dose:

    • 100 mg TID-QID

    • therapeutic range: 10-20 mg/L total and 10% free

  • contraindications: history of prior hepatotoxicity from phenytoin

  • BBW: cardiovascular risk associated with rapid infusion due to risk of hypotension and cardiac arrhythmias

  • AEs: purple glove syndrome, hepatotoxicity, enlarged gums, nervous system effects, blood dyscrasias, teratogenic, osteoporosis, infusion effects, unwanted hair growth

  • michaelis-menten pharmacokinetics

  • CYP2C9 substrate

  • enzyme inducer

  • uses: focal and generalized seizures, status epilepticus

miscellaneous AEDs

• ethosuximide- zarontin

  • t-type Ca2+ channel blocker

  • dose:

    • 500-1500 mg QD

    • therapeutic range: 40-100 mcg/mL

  • AEs: n/v

  • metabolism occurs in the liver, 3A4 substrate

  • uses: absence seizures

• gabapentin - neurontin

  • Ca2+ channel blockers

  • dose:

    • 300-1200 mg TID

    • decrease dose if CrCl <80 mL/min

  • AEs: fatigue, somnolence, dizziness, ataxia

  • 100% renal elimination

  • uses: partial seizures, neuralgias

• pregabalin - lyrica

  • Ca2+ channel blocker

  • dose:

    • IR: 50-100 mg TID

    • ER: 165-330 mg QD

    • decrease dose if CrCl <60 mL/min

  • AEs: dizziness, somnolence, ataxia, weight gain, peripheral edema, visual distrubances, abnormal thinking

  • 90% renal elimination

  • C-5

  • uses: focal seizures, neuropathies. fibromyalgia

guidelines

• 1st line agents for adults with new-onset focal epilepsy or unclassified GTC seizures

  • lamotrigine

  • levetiracetam

  • zonisamide

• 1st line agents for adults >/= with new onset focal epilepsy or unclassified GTC seizures

  • lamotrigine

  • gabapentin

• 1st line agents for the treatment of absence seizures

  • ethosuximide

  • valproic acid

• 1st line therapy for treatment resistant adult focal epilepsy

  • IR pregabalin

  • perampanel

  • lacosamide

  • eslicarbazepine

  • ER topiramate

  • levetiracetam

• choosing an AED

  • seizure type → drug AE → comorbidities → available dosage formulations → patient preference → adherance considerations → patient access → insurance coverage

• initiate AEDs at the lowest possible dose

• assess for possible drug interactions

  • enzyme inducers: carbamazepine, oxcarbazepine. phenytoin, fosphenytoin, phenobarb, primidone

  • enzyme inhibitors: valproic acid

• assess for BBW

• assess concomitant disorders

• follow-up

  • well-controlled seizures on AED therapy can be seen in follow-up annually

  • pts with ongoing med changes, seizures, or epilepsy-related issues can be seen once every 3-4 months

• discontinuation: drug should be tapered down for several months

• pediatrics

  • require higher doses than that seen in adults

  • often weight based dosing

• geriatrics

  • common in older adult populations due to head trauma and strokes

  • lamotrigine and gabapentin should be considered over older first-generation AEDs

• pregnancy and lactation

  • folic acid supplementation

  • more frequent monitoring

  • ideal to be seizure free for over 9 months before becoming pregnant