Epilepsy

  • Seizure:  brief, episodic neuronal discharge which causes changes in consciousness, movement, senses &/or behavior
    • Abnormal firing of neurons & a breakdown of normal inhibition (either at one spot in the brain or over the entire brain)
    • Seizures beget seizures–increase in frequency & new seizure types
  • Convulsion:  series of violent muscle contractions
    • All convulsions are seizures but not all seizures involve convulsions
  • Epilepsy = recurrent & ongoing seizures
  • Seizures cause an increased need for blood & oxygen demand.  If a seizure continues brain damage (ischemia) is possible
  • Causes of seizures:  mechanical, metabolic, substance withdrawal, toxins (bacterial or otherwise),hyperventilation, hereditary, idiopathic (most),  pretty much anything that causes a disruption of cell homeostasis
  • Types of seizures
    • Partial (aka focal aka local):  usually remain asymmetric but they can spread & become secondarily generalized.
      • May be either simple partial or complex partial
    • Generalized
      • Tonic-clonic  (most common)
        • Tonic = continuous muscle contraction with out a break
        • Clonic = superimposed contractions & relaxations causing the convulsions
      • Absence:  usually onset in childhood
      • Atonic:  are rare & usually are confined to childhood
      • Myoclonic:  usually onset in childhood & in combo with other seizures.  Characterized by muscle jerks.
  • Principles of drug therapy:
    • All antiepileptic drugs carry a suicide risk warning
    • The goal is to decrease the frequency of the seizures
    • Typically don’t initiate drug therapy for a single seizure but when you do start it begin low & titrate slow.  Must balance seizure control & SE.  Non-compliance is the #1 reason for therapeutic failure.
    • Use monotherapy whenever possible (works for the majority of pts)
      • Combo therapy should only be considered after the patient has failed on multiple single agents
        • Combo therapy should only be used if it’s clear that there will be a better efficacy w/ minimal/no extra SE or if there will be equal efficacy with less SE
      • Pretty much anything you see used as adjuvant therapy in seizures could also be ok for use as monotherapy
    • All anticonvulsants are considered equally efficacious
    • Therapeutic ranges should be ordered in order to establish a therapeutic baseline, if there is suspected toxicity, breakthrough seizures, if you are starting or d/c a drug that interacts with its metabolism
    • Routine monitoring isn’t needed
  • 1st generation antieplieptic drugs (carbamazepine, ethosuximide, phenobarb, phenytoin, primidone, valproic acid)
    • Familiar drugs, well documented efficacy, low cost, more adverse SE, complex pharmacokinetics (they do have identified therapeutic ranges however)
    • Significant effects on liver enzymes (inducers & inhibitors)
    • Carbamazepine:   FDA approved for partial seizures & tonic-clonic seizures
      • Not used for absence seizures
      • Inhibits Na channels
      • Autoinducer (induces its own metabolism) resulting in decreased half life
        • Also is an enzyme inducer
      • People who test positive for HLA-B*1502 shouldn’t be prescribed carbamazepine
      • SE:  CNS, rash, SJS, toxic epidermal necrolysis
        • Caution use in patients with asian descent
        • Black box warning for causing blood issues  (aplastic anemia, thrombocytopenia, leukopenia)
      • Dosage range:  400-2400 mg/day
    • Ethosuximide (Zarontin):  FDA approved for absence seizures only (DRUG OF CHOICE)
      • SE:  N/V, CNS, SHS, blood issues like carbamazepine, lupus-like syndrome
      • Dosing range is up to 1500 mg/day
  • 2nd gen drugs (gabapentin, felbamate, lamotrigine, levetiracetam, oxycarbazepine, topiramate, pregabalin, vigabatrin, zonisamide)
    • Have unique mechanisms of action, less toxic, simpler pharmacokinetic profiles, better tolerated, less research available, higher cost
    • Felbamate (felbatol):  FDA approved as adjunct for partial seizures only
      • Reserved for refractory seizures (seizures which haven’t responded well to other meds)
      • Should obtain informed consent first
      • Potentiates GABA & inhibits glutamate via NDMA receptors
      • Enzyme inhibitor–may need to reduce the dose of other anticonvulsants
      • SE:  GI, aplastic anemia & acute liver failure
      • Dosing range = 1200-3600 mg/day
    • Gabapentin (neurontin):  FDA approved for partial  seizures (adjunct)
      • Affects both Ca & GABA
      • Saturable absorption so you need to admin in divided doses & also must make dosing adjustments for renally impaired  (CrCl < 30 = once a day dosing)
      • SE (minimal compared to other drugs):  CNS, fatigue, weight gain, tremor, n/v
      • Dosing range:  1200-3600 mg/d (normal ppl)   renal dysfunction:  10-1400 mg/d
    • Lacosamide (vimpat):  FDA approved for partial seizures (adjunct) in pts > 17
      • Doesn’t have any significant DDIs noted
      • Dose adjust in renal dysfunction (CrCl < 30) & mild-moderate hepatic dysfunction (not recommended in severe hepatic dysfunction)
      • SE:  CNS (dizziness, ataxia), A-fib/flutter, asymptomatic AV block
        • Need to obtain a baseline ECG for at risk patients (any patient with pre-existing cardiovascular disease/issues)
      • Dosage range:  100-400 mg/day    (1:1 PO to IV conversion)
    • Lamotrigine (lamictal):  FDA approved as monotherapy for partial seizures (after 1st gen. agents have been tried) & as adjunct therapy for primary generalized tonic-clonic
      • Dose adjust by 50-75% in moderate & severely hepatic impairment
      • SE:  CNS (aseptic meningitis), diplopia, HA
        • Black box warning for SJS/toxic epidermal necrolysis  (especially common in kids) typically occurring within first 2-8 weeks
          • Risk is increased w/ valproic acid use
            • Decrease dose of lamictal when using these two in combo
    • Levetiracetam (Keppra):  FDA approved as adjunct therapy for partial seizures, myoclonic,  & primarily generalized tonic-clonic seizures
      • Not protein bound but you do need to dose adjust in renal dysfunction (CrCl < 50 mL/min)
      • SE:  CNS (somnolence & asthenia) & psychosis (agitation, hostility, anxiety, emotional lability, personalization, depression)
      • Maintenance dose:  1000-3000 mg/day
    • Oxcarbazepine (trileptal):  FDA approved for partial seizures
      • Don’t use in absence seizures
      • MOA:  inhibits firing of Na channels
      • Pro-drug that needs to be dose-adjusted for renal dysfunction
      • Cross-allergenic with carbamazepine but isn’t an autoinducer like carbamazepine
        • 1.5x carbamazepine dose if converting
      • SE:  CNS, GI, hyponatremia  (if the patient becomes symptomatic, decrease dose or restrict fluids)
      • Maintenance dose = 1200 mg/day
    • Phenobarb/primidone:  FDA approved for partial seizures, primarily generalized tonic-clonic but isn’t generally considered primary therapy for any seizure disorder in adults
      • Primidone is the prodrug of phenobarb
      • Enzyme inducer
      • SE:  CNS, nystagmus  (SE are the main reason that use is limited in adults)
      • Maintenance dose of phenobarb < 240 mg/day
      • Maintenance dose of primidone:  < 2000 mg/day
    • Phenytoin:  FDA approved for partial seizures & primarily generalized tonic-clonic seizures
      • Not used for absence seizures
      • Inhibits firing of Na channels
      • Takes 7-10 days to reach steady state
      • Enzyme inducer
      • Absorption is affected by particle size & concentration is saturable
        • Highly (> 90%) protein bound–kinetics are NOT linear
        • Phenytoin doses need to be corrected for patients with either LOW ALBUMIN or RENAL DYSFUNCTION
      • SE:  CNS, gingival hyperplasia, vitamin D deficiency, folic acid deficiency, peripheral neuropathy, hirsutism
        • Other dose related SE:  nystagmus > ataxia, seizures > coma
        • Rare:  SJS, lupus like syndrome, bone marrow suppression
      • Maintenance dose:  < 600 mg/day
    • Pregabalin (Lyrica–C5 drug): FDA approved for adjunct partial seizures
      • Rarely used
      • Absorption isn’t accomplished via a carrier; dose needs to be adjusted for renal dysfunction
      • SE:  new onset of seizures, dizziness, tiredness, peripheral edema, weight gain, vision changes, acute euphoria
      • Max dose = 600 mg/day   (normal)     25 mg in severely renally compromised
      • Must d/c over a minimum of 1 week      (withdrawal symptoms:  irritability, anxiety, insomnia, diarrhea)
    • Rufinamide (Banzel):  FDA indicated for seizures associated with Lennox-Gastaut syndrome
      • Take with food for better absorption
      • Avoid in patients with severe liver disease, short QT syndrome
      • May reduce the effectiveness of hormonal contraceptives
      • SE:  CNS, N/V, diplopia/nystagmus/blurred vision, tremor, HA
      • Max dose:  3200 mg/day
    • Tiagabine (gabitril):  FDA approved as an adjunct therapy for partial seizures
      • SE:   dizziness, nervousness, depression, tremor, difficulty finding appropriate words
      • Maintenance dose:  < 56 mg/day
    • Topiramate (topamax):  FDA approved for partial seizures & primarily generalized tonic-clonic seizures
      • Decrease dose in renal dysfunction
      • SE:  CNS, memory difficulties, cognitive slowing, cleft palate (if used during prego)
        • weight loss & kidney stones (aka nephrolithiasis) are common after long term use
      • Maintenance dose:  600 mg BID
    • Valproic acid (depakene)/divalproex (depakote):  FDA approved for absence seizures & partial seizures
      • 1st line therapy for mixed seizure disorders
      • Decrease dose in liver dysfunction, highly protein bound (saturable binding)
      • Enzyme inhibitor
        • DDIs are very common with valproic acid
      • SE:  alopecia, GI, weight gain or anorexia, CNS, tremor
        • Valproic acid = alopecia (hair loss)             phenytoin = hirsituism (hair growth)
        • Other SE:  hepatotoxicity (toxic metabolite; may not be irreversible), thrombocytopenia, avoid in pregnancy due to its effects on IQ
      • Maintenance dose:  < 60 mg/kg/day
    • Vigabatrin (Sabril):  FDA approved as adjunct therapy for partial seizures
      • Only used for refractory seizures
      • SE:  HA, fatigue, CNS, weight gain, permanent peripheral visual field defects (25-50% of adults within 1st year, incidence rises w/ dose)
        • Also emotional/mental disturbances, peripheral neuropathy, edema
      • Requires a ton of monitoring (REMS & SHARE programs) & only 4 pharmacies in the country can prescribe it
      • Max dose = 3000 mg/d
    • Zonisamide (zonegran):  FDA approved as adjunct therapy for partial seizures
      • Rarely used
      • Use lower starting doses for patients with liver or kidney dysfunction
      • Possible cross allergenicity with sulfa drugs
      • May cause increased risk of metabolic acidosis (if the patient develops this, alkali treatment should be considered)
      • SE:  CNS, psychotic symptoms (delusions, hallucinations, paranoia), SJS, toxic epidermal necrolysis
      • Max dose:  400 mg/day
  • Withdrawing antiepileptics:
    • Patients must be: seizure free for at least 2 years, normal neuro/IQ exam, EEG normalized on meds, seizures were under control w/in 1 year of first episode, age of onset:  2-35, only one type of seizure present (partial or tonic-clonic)
    • Taper over 2-9 months gradually, discontinuing one drug at a time
  • Prego:  plan for pregnancy in any woman of child-bearing age.
    • When pregnancy is planned, adjust med before hand & try to convert the patient to a monotherapy (multi-drug therapy is associated with worse outcomes)
    • Establish target level for prego (even with drugs that don’t usually get their levels monitored)
    • Anti-epileptic drugs have increased clearance during pregnancy
    • Serum drug levels will increase over the 8-10 weeks after prego (may need to decrease dose after they give birth)
    • Most sensitive period for fetal development is 5-11 weeks
    • Carbamazepine & low dose lamotrigine are 1st line for prego epileptics
      • Avoid valproic acid if at all possible
  • Use either intrauterine levonorgestrel (Mirena—best choice) or medroxyprogesterone acetate (depo-provera) as birth control for patients with epilepsy as antieplieptics decrease OC efficacy

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