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Epilepsy and AEDs. Steven C. Karceski, M.D. Assistant Professor of Neurology Director, Columbia Epilepsy Center. Treatment Goal. Complete control of seizures No side effects. effective (in all seizure types) no adverse effects no long term risks no interactions with other drugs.

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Epilepsy and aeds

Epilepsy and AEDs

Steven C. Karceski, M.D.

Assistant Professor of Neurology

Director, Columbia Epilepsy Center


Treatment goal
Treatment Goal

  • Complete control of seizures

  • No side effects


Ideal treatment

effective (in all seizure types)

no adverse effects

no long term risks

no interactions with other drugs

long lasting action

safe in pregnancy

inexpensive

Ideal Treatment


AEDs

  • Seizure/epilepsy type

  • Pharmacokinetics

    • Absorption

    • Half-life

    • Elimination

  • Side effects

  • Drug-drug interactions


J.S.

  • 35-year-old man

  • Onset: age 16

  • Seizure: aura, staring, oral automatisms

  • Frequency: up to 3/week

  • Duration: 60-120 seconds

  • Risk Factor: febrile seizure at 1 year


J.S

  • Tried Tegretol, Dilantin, Depakote, Neurontin

  • MRI: Left mesial temporal sclerosis

  • EEG: Focal left temporal epileptiform discharges

  • EMU: Left temporal onset seizures

  • Q: What should be considered next?


Seizure type partial
Seizure Type: Partial

  • Partial (onset)

    • Simple Partial (aura)

    • Complex Partial

    • Secondarily generalized

  • All AEDs are effective

    (exception: ethosuximide)


Available aeds

phenobarbital (Phenobarbital, Primidone)

phenytoin (Dilantin)

carbamazepine (Tegretol, Carbatrol)

valproic acid (Depakote, Depakene)

ethosuximide (Zarontin)

methsuximide (Celontin)

clonazepam (Klonopin)

lorazepam (Ativan)

gabapentin (Neurontin)

felbamate (Felbatol)

lamotrigine (Lamictal)

topiramate (Topamax)

tiagabine (Gabitril)

levetiracetam (Keppra)

oxcarbazepine (Trileptal)

zonisimide (Zonegran)

Available AEDs


J s temporal lobe epilepsy
J.S.: Temporal Lobe Epilepsy

  • Febrile seizure as a child, with return of partial seizures in adolescence

  • Seizures: simple and complex partial, secondarily generalized

  • Often refractory to medications


J.S.

  • Q: What are the chances that a new medication will accomplish the treatment goal?

  • A: 5-10%

  • Consider: temporal lobectomy


M.G.

  • 19-year-old woman

  • Onset: menarche (age 13)

  • Seizures: no aura

    • Generalized tonic-clonic seizures

    • Myoclonic seizures

  • Risk factor: twin sister has epilepsy


M.G.

  • Started on Depakote

    • Weight gain

    • Hair loss

    • Menstrual irregularity

  • Switched to Tegretol

    • Worsening of seizures


Seizure type generalized
Seizure Type: Generalized

  • Generalized (onset): no aura

    • GTC

    • Tonic/Atonic

    • Absence

    • Myoclonic

  • AED options are more limited


The list of aeds again

phenobarbital (Phenobarbital, Primidone)

phenytoin (Dilantin)

carbamazepine (Tegretol, Carbatrol)

valproic acid (Depakote, Depakene)

ethosuximide (Zarontin)

methsuximide (Celontin)

clonazepam (Klonopin)

lorazepam (Ativan)

gabapentin (Neurontin)

felbamate (Felbatol)

lamotrigine (Lamictal)

topiramate (Topamax)

tiagabine (Gabitril)

levetiracetam (Keppra)

oxcarbazepine (Trileptal)

zonisimide (Zonegran)

The list of AEDs (again)


M g juvenile myoclonic epilepsy
M.G.: Juvenile Myoclonic Epilepsy

  • Begins at puberty

  • Seizures: myoclonic, absence, GTCs

  • Normal intellect

  • Normal neurological examination

  • Normal MRI

  • Often responds to low doses of medications


Seizure type generalized1
Seizure Type: Generalized

  • Generalized (onset)

    • Fewer medication options

    • Some AEDs WORSEN

      generalized seizures


The list of aeds again1

phenobarbital (Phenobarbital, Primidone)

phenytoin (Dilantin)

carbamazepine (Tegretol, Carbatrol)

valproic acid (Depakote, Depakene)

ethosuximide (Zarontin)

methsuximide (Celontin)

clonazepam (Klonopin)

lorazepam (Ativan)

gabapentin (Neurontin)

felbamate (Felbatol)

lamotrigine (Lamictal)

topiramate (Topamax)

tiagabine (Gabitril)

levetiracetam (Keppra)

oxcarbazepine (Trileptal)

zonisimide (Zonegran)

The list of AEDs (again)


AEDs

  • Broad spectrum (both generalized and partial seizures): felbamate, lamotrigine, levetiracetam, topiramate, valproate, zonisamide

  • Narrow spectrum (partial seizures only): All others


Aed side effects
AED Side Effects

  • Sleepiness

  • Dizziness

  • Poor memory, concentration

  • Weight gain/loss

  • Long-term bone health issues

  • Women’s health


Newer aeds
Newer AEDs

  • Tend to cause fewer side effects (bone health, changes in weight, etc.)

  • Most are qD or BID

  • Many are broad spectrum


Aeds and rash
AEDs and Rash

  • Virtually all have been reported to cause a rash/allergic reaction

  • Usually occurs within the first 3 months of therapy

  • Related to the speed of titration


Aeds and rash1
AEDs and Rash

  • Erythematous

  • Maculopapular

  • Pruritic

  • All rashes should be evaluated carefully!

  • Not all rashes are due to medications!

    • Remember to ask about soaps, perfumes, etc.


Aeds and rash2
AEDs and Rash

  • Signs of a more serious rash

    • Fever

    • Adenopathy

    • Oral ulcerations

    • Malaise, flu-like symptoms

  • Stop the medicine immediately


Bone health
Bone Health

  • Women

  • Age

  • Exercise

  • Diet (vitamin D, calcium)

    • Need 1000 to 1500 mg per day

  • AEDs have been associated with bone loss


Aeds and bone health
AEDs and Bone Health

  • Studies are ongoing

  • May cause osteopenia, osteoporosis: phenytoin, phenobarbital, valproate, carbamazepine

  • Appear to be bone “neutral”: lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide


Evaluation of bone health
Evaluation of Bone Health

  • DEXA scan (bone density)

    • Obtain a baseline study

    • Follow-up yearly (or every other year)

  • Counseling about Calcium, vitamins, exercise


Poor bone health
Poor Bone Health

  • Osteoporosis/osteopenia

    • Start calcium, vitamins (if not already done)

    • Consider Fosamax, Miacalcin, or other agent

  • Follow-up treatment with DEXA every 6-12 months


Sleep affects seizures
Sleep affects Seizures

  • REM sleep may prevent focal seizures

    • 133 patients; 613 seizures

    • Seizures were rare during REM sleep

  • Research may identify the critical difference in REM, leading to the development of newer treatments

Herman S. Epilepsia. 2001.


Seizures affect sleep
Seizures affect Sleep

  • Seizures disrupt the sleep-wake cycle

    • Seizures cause post-ictal fatigue

    • Seizures decrease total sleep time

    • Seizures suppress REM sleep

    • Seizures prolong REM latency

  • Interictal sleep is also disordered – even brief seizures can affect sleep

Vaugn BV. Sem Neurol. 2004.


Aeds affect sleep
AEDs affect Sleep

  • Some medications cause sleepiness

  • Some medications cause insomnia

  • Others affect sleep architecture

  • The effect may be unpredictable

  • The mechanisms are unclear: is it due to neuronal inhibition? excitation?


Aeds and sleep
AEDs and Sleep

  • Newer AEDs: fewer effects on sleep

  • Gabapentin may increase sleep efficiency

    • Increases slow-wave and REM sleep

  • Levetiracetam improves subjective sleep

    • Fewer recognized awakenings

    • But still overall sleepier


Aeds and sleep1
AEDs and Sleep

  • Sleep “promoting”: gabapentin

  • Sleep “disruptive”: phenytoin, felbamate


Newer aeds and weight
Newer AEDs and weight

  • Weight gain: gabapentin, valproate

  • Weight loss: felbamate, topiramate, zonisamide

  • Weight “neutral”: lamotrigine, oxcarbazepine, levetiracetam


Newer aeds and dosing
Newer AEDs and Dosing

  • qD dosing – zonisamide

  • BID dosing – XR forms of carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate

  • TID dosing – gabapentin, tiagabine


Aeds and women s health
AEDs and Women’s Health

  • AEDs can affect oral contraceptives

    • Enzyme inducers: carbamazepine, phenobarbital, phenytoin, oxcarbazepine

  • AEDs can affect fertility

    • PCOS: valproate

  • AEDs can affect the fetus


Aeds and teratogenicity

Pregnancy “D”

Dilantin

Tegretol

Depakote

Phenobarbital

Zarontin

The “older” AEDs

Pregnancy “C”

All “newer” AEDs!

AEDs and Teratogenicity


Aeds birth defects
AEDs & Birth Defects

  • 2-3 % of normal women

  • Single AED: 4-6 %

  • Multiple AEDs: 6-9% or higher

  • Risk also increases with higher doses of AEDs


Seizures pregnancy
Seizures & Pregnancy

  • GTCs cause early delivery, fetal distress

  • One case: CPS may also cause fetal distress

  • Maintain seizure control!

  • Use a single medication at the lowest needed dose

  • Folate, folate, folate!


Aeds and aging
AEDs and Aging

  • Drug-drug interactions: the average senior takes 5-12 medications

  • Medications are absorbed differently

  • Seniors have slower metabolism (liver)

  • Seniors have slower elimination (kidneys)

  • A higher percentage is “unbound”


Aeds and aging1
AEDs and Aging

  • Dosing must be lowered accordingly!

  • A lower dose may produce the same level as in a younger adult


Summary
Summary

Age

Seizure Type

“Refractoriness”

Gender

Pharmacokinetics

Treatment


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