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Update on EpilepsyManagement
Amy Kao, MD
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
Administration Issues
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
Administration Issues
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
1/3
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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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.