8 Kao EpilepsyManagement

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Update on EpilepsyManagement

Amy Kao, MD

[email protected]

Childrens National Medical Center

Center for Neuroscience and Behavioral MedicineDivision of Neurophysiology, Epilepsy, and Neurocritical Care

June 23, 2011


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Objectives

Review the general approach to seizure and

epilepsy treatment, based on epidemiologyand seizure type

Discuss antiseizure medications, side effects,

interactions, and monitoring needs Review newest antiseizure medications


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The Basics

A seizure

Sudden event caused by abrupt, uncontrolled,hypersynchronous electrical discharges ofneurons

Epilepsy A condition characterized by the tendency for

recurrent unprovoked seizures


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More Definitions

Status epilepticus Seizure activity lasting 30 minutes

Series of seizures lasting 30 min without full

consciousness regained between

A state in which seizures are of sufficient length

or are repeated frequently enough to produce afixed and lasting epileptic condition


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Classification of Seizuresby Onset

Generalized onset

GTC

Absence

Myoclonic

Tonic

Atonic

Partial/Focal Onset

Simple partial

Complex partial

Secondarily

generalized

petit mal


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Partial Seizure with 2 Generalization


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Classification of Seizuresby Syndromes

Cluster of symptoms, signs, lab findings (e.g.EEG) which is consistent and implies diagnosis,treatment, or prognosis; e.g. Infantile spasms

Lennox-Gastaut syndrome Childhood/juvenile absence epilepsy

Benign rolandic epilepsy

Juvenile myoclonic epilepsy


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Impact of Seizures/Epilepsy

Risk of having a seizure by age 20: > 4%

Risk of epilepsy by age 20: > 1%

Risk of epilepsy by age 74: 3%

Peak occurrence in childhood and over 65

Prevalence of epilepsy in kids = 5/1000


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First Unprovoked Seizure

Recurrence risk Idiopathic/cryptogenic: 30 to 50% by 2 years

Abnormal EEG: ~50%

Remote symptomatic: >50% Not different if status epilepticus

Seizure remission

No difference if med started after 1st vs 2nd


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Treatment after First Seizure

Reassurance Safety

No unsupervised baths or swimming alone

Biking with helmet and on sidewalk Baby monitor

Counseling

Appearance of seizures (e.g. complex partial)

First aid during seizure

Rescue med if prolonged seizure


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Antiseizure Medications

Mechanisms

Seizure = excitation > inhibition (Glutamate) (GABA)

Inhibit voltage-gated Na+ channels

Inhibit Na+ currents via non-NMDA receptors Inhibit Ca++ currents via NMDA receptors

Inhibit T-type voltage-gated Ca++ channels

Enhance GABAA-receptor Cl- currents

Inhibit GABA transaminase GABA


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Choice of AEDs

NO SEIZURES, NO SIDE EFFECTS

Need for labwork/levels ? Idiosyncratic versus dose-related side effects

Concern of non-compliance, optimization of med,

med interactions, baseline Seizure type

Primary generalized versus partial/focal-onset

Epilepsy syndrome


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AED and Seizure Type

OXC, LVT, LMG,TPM, PHT, ZNS,VPA, PHB, GBP,

TGB, FBM

CBZPartial with or w/o 2

generalization

LMG, TPM, LVT,ZNS, FBM, PHT,

PHT

VPAMyoclonic, GTC,atonic, tonic

VPA, LMG, ZNS,

LVT

ETXAbsence

Pred, VPA, TPM,ZNS, VGB

ACTHGeneralizedInfantile spasms

Other options1st choiceSeizure type


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AED and Epilepsy Syndrome

VPA, TPM, ZNS, VGBACTHInfantile spasms

OXC, LVT, TPM,LMG, GBP

CBZBenign rolandic

LMG, ZNS, TPM, LVTVPAJuvenile myoclonic

LMG, TPM, LVT, ZNSVPAJuvenile absence

VPA, LMGETXChildhood absenceLMG, TPM, FBM, ZNSVPALennox-Gastaut

PHT, TPM, LVTPHBNeonatal szs

Other options1st choiceSyndrome


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Absence Epilepsy


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Absence Epilepsy

ConsensusETX 1st line, VPA and LMG

other options 2010 randomized controlled study

ETX and VPA significantly more effective

VPA more negative effects on attentionalmeasures


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Specific Antiseizure Medications phenobarbital/

primidone bromides

phenytoin

carbamazepine

valproic acid

ethosuximide

benzodiazepines

felbamate

gabapentin

lamotrigine

topiramate

gabitril

levetiracetam

oxcarbazepine

zonisamide


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Newest generation AEDs

Pregabalin (Lyrica)

Lacosamide (Vimpat) Rufinamide (Banzel)

Vigabatrin (Sabril)


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phenobarbital

Benefits

Safe in neonates

Levels easy to maintain

Cost low

Side Effects Hyperactivity

Sleep difficulty

IQ decline

Bone health Hypersensitivity

Idio: megaloblastic anemia

Administration issues

Can load Q day dosing ok

Enzyme inducer

1912


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phenytoin

Benefits

Safe in neonates

Cost low

Side Effects

Gum hyperplasia

Hirsutism

Bone health

Mild LFTs Hypersensitivity rxn

Idio: blood dyscrasias

Administration Issues

Can load BID or QD dosing

Zero-order kinetics

Enzyme inducer

1938Dilantin


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carbamazepine

Benefits

Short-acting comes in

generic

Side Effects Hyponatremia

Leukopenia

Rash/hypersensitivity Bone health

Idio: aplastic anemia


Enzyme inducer Auto-induction

Liquid TID to QID

May exacerbate 1

generalized seizures

1974Tegretol, Tegretol

XR, Carbatrol


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valproic acid

Benefits

Broad spectrum

May epileptiformdischarges

Not allergenic

Side Effects

platelets (dose-related), NH3, weight gain, PCOS,bone health

Idio: Hepatic failure,pancreatitis, bone marrowsuppression


Liquid may be TID toQID

Enzyme inhibitor

IV form available

1978Depakene,

Depakote


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ethosuximide

Benefits

Effective vs absence seizures Side effects/Issues

GI upset

Idio: blood dyscrasias, lupus-like syndrome,Stevens-Johnson

1957Zarontin


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benzodiazepines Tolerance issues

Rectal valium (Diastat) Ease of use

Expensive

Nasal or buccal midazolam0.2 mg/kg 0.5 mg/kg/dose

clorazepate (Tranxene)

BID to TID

bridging or band-aid med

1960s


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felbamate

Approval Adjunctive therapy for partial or generalized

seizures in Lennox-Gastaut

Benefits Effective in Lennox-Gastaut

Side Effects/Issues

Hepatic failure, aplastic anemia Insomnia, decreased appetite

Frequent lab monitoringcbc, LFTs

1993Felbatol


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gabapentin Approval

Adjunctive tx for partial seizures (with and w/o 2

generalization) > 12 y/o Adjunctive tx for partial seizures 3 to 12 y/o

Benefits

Safe

Effective for neuropathic pain

Eliminated by kidney

Side Effects/Issues

TID dosing Less efficacy against seizures

Behavioral changes, weight gain

Neurontin 1993


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lamotrigine Approval

Adjunctive tx for partial szs 2 y/o

Primary generalized seizures 2 y/o

Adjunctive tx for generalized szs of LGS 2 y/o

Monotherapy for 16 y/o

Lamictal XR for

13 y/o Benefits

Broad spectrum

Well-tolerated; Behavioral improvement

No standard lab monitoring Side Effects/Issues

Risk of Stevens-Johnson, TEN

Slow titration

Lamictal 1994


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topiramate Approval

Adjunctive for partial or primary generalized seizures, LGS

in 2 y/o Benefits

Broad spectrum

Effective for headache prophylaxis

Eliminated by kidney

Side Effects/Issues

Paresthesias

Memory/concentration, emotional lability Decreased appetite, nephrolithiasis, hypohidrosis

Metabolic acidosis

Idio: Glaucoma

Topamax 1996


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tiagabine

Approval

Adjunctive tx of partial seizures in 12 y/o Benefits

Used for anxiety

No severe reactions reported

Side Effects/Issues

No RCTs in pediatrics

Gabitril 1997


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levetiracetam Approval

Adjunctive tx of partial seizures in

4 y/o Adjunctive of myoclonic seizures in 12 yo with JME

Adjunctive primary generalized seizures 6 yo

Keppra XR for adjunctive partial seizures 16 yo

Benefits

Broad spectrum

Bulk excreted by kidney

No interaction with other meds ? neonates

Side Effects/Issues

Behavioral issues

Keppra 2000


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oxcarbazepine

Approval

Adjunctive tx for partial seizures in 2 y/o

Monotherapy for partial seizures in 16 y/o

Benefits

Lacking toxic metabolite of carbamazepine No auto-induction

Side Effects/Issues

Rash

Hyponatremia Decreases efficacy of OCPs

Induce CYP3A enzymes

Trileptal 2000


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zonisamide Indications

Adjunctive partial seizures adults Benefits

Broad-spectrum

Effective in progressive myoclonic epilepsy Q day or BID

Side Effects/Issues

Sulfonamide derivative Behavioral changes

Nephrolithiasis

Oligohydrosis and hyperthermia

Zonegran 2000


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Acthar gel

Approved by FDA end of 2010 as monotx for

infantile spasms


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pregabalin

Structure similar to gabapentin, increased

binding affinity and linear pharmacokinetics

Indications

Adjunct Rx for partial onset seizures in adults Diabetic neuropathy, fibromyalgia, post-herpetic

neuralgia

Side Effects Weight gain, difficulty with concentration

Lyrica

2004


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lacosamide Adjunct Rx partial-onset szs in 17 years

Broad-spectrum in animal models Case reports of use in refractory status

Dose-related: Dizziness, headache, nausea,diplopia

Dose-related prolongation of PR interval

Obtain ECG before and after titration known conduction abnormalities

ischemic heart disease

heart failure

2008

Vimpat


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lacosamide No clinically-meaningful lab changes or

weight changes Not highly protein-bound

CYPC219 substrate, renally-cleared

No effect on AEDs, digoxin, omeprazole(CYPC219 inhibitor), OCPs


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rufinamide

Adjunctive therapy for LGS 4 yrs

Broad spectrum by animal models

Somnolence, vomiting, headache (slow titrationminimizes)

Rash/hypersensitivity syndrome

Contraindicated in familial short QT QT not


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rufinamide Clearance decreased by VPA

Weak inducer of CYP3A4 Decrease OCPs


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vigabatrin

Adjunctive therapy adults with refractory CPS

Infantile spasms 1 mo-2 yrs

PHT, no impact on other AED/OCPs

Drowsiness, trembling, swallowing problems,irritability, anemia

Peripheral neuropathy/edema in adults DWI/T2 hyperintense lesions in basal ganglia,

thalamus, brainstem, dentate nucleus in up to

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2009

Sabril


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vigabatrin Irreversible, bilateral concentric peripheral field

constriction in 30-50% (20-40 axial degrees) Most at least 6 mos, stable by 2 years

If no significant benefit in 2-4 weeks, stop

SHARE program Baseline and q 3 mos x 18 mos, then q 6 mos

dilated indirect ophthalmoscopy

visual fields OCT, ERG

can waive requirements


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Impact on general care Interactions with other meds

Inducing metabolism (PHB, PHT, CBZ) Inhibiting metabolism (VPA)

Competing for protein binding

Antibiotics Penicillins, ciprofloxacin, metronidazole

Oral contraceptives

Chemotherapy


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Drugs which may lower sz threshold

http://professionals.epilepsy.com/page/table_

seniors_drugs.html Antihistamines

Stimulants

Pseudoephedrine Bupropion, meperidine


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Other considerations in general care

Suicidality and AEDs

April 2009FDA approved updating oflabeling of all AEDs to warn about increasedrisk of suicidality (2x)

Pooled analysis of RCTs on 11 AEDs Epilepsy is associated with increased risk

All patients currently on or starting on any

AED should be monitored


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Other considerations in general care

Complementary/Alternative Therapies

1/3 of children with epilepsy had used CAM American hellebore, betony, blue cohosh, mugwort,

pipsissewa, skullcap, kava, melatonin, marijuana

Contradictory data in animal models

EFAacceptable as long as traditionaltherapies continue and do not conflict

National Center for Complementary andAlternative MedicineUnder guidance ofmedical professional trained in herbalmedicine


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Referral to neurology Education/reassurance

new-onset seizure groups Epilepsy camp

Epilepsy management

Nonpharmacologic treatment Vagus nerve stimulator

Ketogenic diet

Resective surgery


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Helpful references www.epilepsyfoundation.org

www.health.nih.gov www.epilepsy.com

www.talkaboutit.org


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[email protected]


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Bibliography

Buchhalter JR and Jarrar RG. Therapeutics in pediatric epilepsy,Part 2: epilepsy surgery and vagus nerve stimulation. Mayo Clin

Proc2003;78:371-378. Camfield PR et al. If a first antiepileptic drug fails to control a childs

epilepsy, what are the chances of success with the next drug? JPediatr1997;131:821-824.

Hirtz, D et al. Practice parameter: treatment of the child with a first

unprovoked seizure. Neurology2003;60:166-175. Jarrar RG and Buchhalter JR. Therapeutics in pediatric epilepsy,

Part 1: the new antiepileptic drugs and the ketogenic diet. Mayo ClinProc2003;78:359-370.

Kwan P and Brodie MJ. Early identification of refractory epilepsy. NEngl J Med2000;342:314-319.


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Bibliography

Loring DW and Meador KJ. Cognitive side effects of antiepileptic

drugs in children. Neurology2004;62:872-877. Morrell M. Brain stimulation for epilepsy: can scheduled or

responsive neurostimulation stop seizures? Curr Opin Neurol19:164-168.

Pearl PL et al. Use of complementary and alternative therapies in

epilepsy. Arch Neurol2005;62:1472-1474. Sinha SR and Kossoff EH. The ketogenic diet. The Neurologist

2005;11:161-170.

Snead OC. Surgical treatment of medically refractory epilepsy in

childhood. Brain Devel2001;23:199-207.

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