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“Update on Treatment of Seizures & Epilepsy”

Bassel F. Shneker, MDComprehensive Epilepsy Program

The Ohio State University October 24, 2009

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Outline

• Definition of Seizures and Epilepsy

• Treatment with AEDs

• Newly Approved AEDs

• New information about AEDs– Generic AEDs– Suicidality and AEDs– Pregnancy and AEDs

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Definition of Seizures

• Time-limited paroxysmal events that result from abnormal, involuntary, rhythmic neuronal discharges in the brain

• Seizures are usually unpredictable

• Seizures usually brief ( < 5 minutes) and stop spontaneously

• Convulsion, ictus, event, spell, attack and fit are used to refer to seizures

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Right Temporal Lobe Seizure

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Etiology of Seizures

• Seizures are either provoked or unprovoked• Provoked Seizures: Triggered by certain

provoking factors in otherwise healthy brain– Metabolic abnormalities (hypoglycemia and hyperglycemia,

hyponatremia, hypocalcemia)

– Alcohol withdrawal

– Acute neurological insult (infection, stroke, trauma)

– Illicit drug intoxication and withdrawal

– Prescribed medications that lower seizure threshold (theophylline, TCA)

– High fever in children

• Unprovoked Seizures: Occur in the setting of persistent brain pathology

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Definition of Epilepsy

• A disease characterized by spontaneous recurrence of unprovoked seizures (at least 2)

• Seizures are symptoms, while epilepsy is a disease, so those terms should not be used interchangeably

• Epilepsy = “seizure disorder”• Epilepsy is a syndromic disease• Each epilepsy syndrome is determined based on;

Type of seizures, age at seizure onset, family history, physical exam, EEG findings, and neuroimaging

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Etiology of Epilepsy

• Any process that alters the structure (macroscopic or microscopic) or the function of the brain neurons can cause epilepsy

• Processes that lead to structural alteration include;

• Congenital malformation• Degenerative disease• Infectious disease• Trauma• Tumors• Vascular process

• In majority of patients, the etiology is proposed but not found

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Treatment of Seizures

• Provoked Seizures– Treatment directed to the provoking factor

• Unprovoked Seizures– First Seizure

• Usually no treatment• Treatment can be initiated if risk of recurrence is high or if a

second seizure could be devastating

– Second Seizure• Diagnosis of epilepsy is established and risk of a third Seizure

is high• Most physician treat at this stage• In children, some may wait for a third seizure

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Treatment of Established Epilepsy

• First Line – Approved Anti-Epileptic Drugs (AEDs)

• Second Line (intractable epilepsy)– Epilepsy Surgery– Vagus Nerve Stimulation Therapy

• Exeprimental Treatment– AEDs– Devices

• Deep Brain Stimulator (DBS)• Responsive Neuro Stimulator (RNS)

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Antiepileptic Drugs (AED)

First Generation Second Generation

Unconventional

Carbamazepine (Tegretol)

Clonazepam (Klonopin)

Clorazepate (Tranxene)

Ethosuximide (Zarontin)

Phenobarbital

Phenytoin (Dilantin)

Primidone (Mysoline)

Valproic acid (Depakote)

Felbamate (Felbatol)

Gabapentin (Neurontin)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal) Pregabalin (Lyrica)

Tiagabine (Gabitril)

Topiramate (Topamax)

Zonisamide (Zonegran)

Adrenocorticotropic hormone (ACTH )

Acetazolamide (Diamox)

Amantadine (Symmetrel)

Bromides

Clomiphene (Clomid)

Ethotoin (Peganone)

Mephenytoin (Mesantoin)

Mephobarbital (Mebaral)

Methsuximide (Celontin)

Trimethadione (Tridione)

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What is New in AEDs World?

• 3 AEDs are approved in 2009– Rufinamide (Banzel®)– Lacosamide (Vimpat®)– Vigabitrin (Sabril®)

• Discussion about generic vs. brand AEDs

• Suicidality and AEDs

• Pregnancy and AEDs

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AED Generic (Trade) Abbreviations

• Phenobarbital/Primidone– PB / PRM

• Phenytoin (Dilantin)– PHT

• Carbamazepine (Tegretol)– CBZ

• Valproic Acid (Depakote)– VPA

• Felbamate (Felbatol)– FBM

• Gabapentin (Neurontin)– GBP

• Lamotrigine (Lamictal)– LTG

• Topiramate (Topamax)– TPM

• Tiagabine (Gabitril)– TGB

• Oxcarbazepine (Trileptal)– OCBZ (OXC)

• Levetiracetam (Keppra)– LEV (LVT)

• Zonisamide (Zonegran)– ZNS

• Pregabalin (Lyrica)– PGB

• Rufinamide (Banzel)– RUF

• Lacosamide (Vimpat)– LCM

• Vigabatrin (Sabril)– VGB

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AED Therapy

1900 1920 1940 1960 1980 2000

PB PHT CBZVPA

FBM

GBP

LTG

FOS

TPM

TGB

OCBZ

LEV

ZNSPGB

LCMRUF

VGB

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Generic vs. Brand AEDs

• Advantage– Lower cost– Increase access to treatment

• Disadvantage– Lower level seizures

– Higher level CNS toxicity

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Generic Drug- FDA Requirements

• Generic drug must: – Contain same active ingredients – Identical in strength, dosage form, and route of

administration – Same use indications– Bioequivalent – Same batch requirements for identity, strength,

purity, and quality – Manufactured under the same strict standards of

FDA's good manufacturing practice regulations required for innovator products

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Bioequivalence Requirement

• “A generic product has to be bioequivalent to the brand (reference) product by demonstrating the same in vivo performance”– Mainly absorption

• Two drugs are bioequivalent if the ratio of means of the primary PK responses such as AUC and Cmax between the two formulations of the same drug or the two drug products is within (80%, 125%) with 90% assurance.

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FDA Bioequivalence

70

80

90

100

110

120

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Brand Generic 1 Generic 2 Generic 3

70

80

90

100

110

120

130

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Questions about Generic AEDs

• Switch between generics

• Controlled vs. uncontrolled epilepsy patients

• Data about negative impact of generics

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Suicidality and AEDs

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FDA Alert – Results (1)

• Data from 199 placebo-controlled trials– 43,892 total patients

• 27,863 drug-treated patients • 16,029 placebo-treated patients

• Indications:– Epilepsy: 62 trials (31%)– Psychiatric Indications: 56 trials (28%)– Other Indications: 81 trials (41%)

• Analyzed AEDs (11): CBZ, FBM, GBP, LTG, LEV, OXC, PGB, TGB, TPM, VPA, ZNS

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FDA Alert – Results (2)

Indication Drug Patient Events per

1000

Placebo Patient Events

per 1000

Risk Difference

Relative Risk

Epilepsy 3.5 1.0 2.5 3.6

Psychiatric 8.3 5.2 3.1 1.6

Other 2.0 0.8 1.1 2.3

Total 4.3 2.2 2.1 2.0

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FDA Alert – Results (3)

• Drug-treated subjects had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with placebo-treated subjects (0.22%)

• Risk was higher in epilepsy group compared to other groups

• Risk difference 2.1 per 1000 (95% CI: 0.7, 4.2)• Increased risk observed throughout time periods

for which data was obtained• No clear pattern of risk across age groups• Results generally consistent across all drugs

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FDA Alert – 12/16/2008

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FDA Alert, So What?

• “The mean scores for the FDA alert clarity, appropriateness, and impact on clinical practice (on a scale from 1 to 10) were low, at 5.3, 4.1, and 3.6. Almost 46% did not feel the alert is going to change their practice “

Shneker, Neurology 2009

• Concerns about– What to do– Patient safety from stopping AEDs

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AEDs & Pregnancy

• Discussion about effect of AEDs on Fetus– Malformations– Cognitive side effects

• Latest Information– AED Pregnancy Registry– Neurodevelopmental Effects of Antiepileptic

Drugs (NEAD) study

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Background on AED Pregnancy Registry

• For pregnant women taking any AED• For epilepsy or non-epilepsy purpose

– Patients call 1-888-AED-AED4– www.aedpregnancyregistry.org

• Three telephone calls– Initial (10 min), 7 months (5 min), Post-partum (5

min)

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AED Pregnancy Registry Enrollment Data

www.AEDpregnancyregistry.org Winter 2009 Newsletter

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Registry Changes ProcedurePreliminary Findings 6 AEDs

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What do we know now?

• Risk of Major Malformations– Polytherapy = ↑ risk– Specific AEDs

• General population = 1.6%• Phenobarbital = 6.5%• Valproic Acid = 10.7%

• August 2006 Neurology (Meador, et al.)– NEAD Study with 333 pregnancies

• Serious adverse outcomes (major malfs, fetal death)– CBZ (8.2%), LTG (1.0%), PHT (10.7%), VPA (20.3%)

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Lamotrigine Recent Findings

• AED Pregnancy Registry Data– 564 infants LTG monotherapy 1st trimester– Between 1997 & March 2006

• Major malformations 2.7% – vs. 1.6% unexposed

• 5 infants cleft lip/palate = 1:113 – vs. 1:6,160 unexposed

– Relative risk LTG = 32.8

• Other AED registries = 1:405

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AEDs & Neurodevelopment

• “Although we’ve had a great deal of information in the past 2 years on anatomical teratogenicity from AED in utero exposure, we have had much less with regard to cognitive outcomes. Animal studies of AEDs clearly show behavioral teratogenesis at dosages less than those required to produce anatomical teratogenicity.”

Meador KJ. 2006

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AEDs & Neurodevelopment

Adab 2001 (UK)Additional Educational NeedsVPA = 30%, CBZ = 3.2%

Adab 2004 (UK)Verbal IQ lower in VPA-exposed than other AEDs

Failey 2002 (FIN)Mean Verbal IQ Scores

VPA 82, CBZ 96, Controls 95

Eriksson 2005 (FIN)Low intelligence

VPA 19% vs. CBZ 0%

NEAD Study

Prospective evaluation of long

term cognitive and behavioral

development

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AEDs & Neurodevelopment

• NEAD Study– Pregnant women on monotherapy

• CBZ, LTG, PHT or VPA

– Long-term goal = examine cognition at age 6• Planned interim analyses at 3 yrs

– Mental Scale of the Bayley Scales of Infant Development

– CBZ (n=73), LTG (n=84), PHT (n=48), VPA (n=53)

– Children’s Mental Development Index (MDI)

» Controlled (Mom’s IQ, AED levels, Sz type, etc)

Meador et al. N Engl J Med 2009;360:1597-1605.

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AEDs & Neurodevelopment

• VPA-exposed kids significantly lower IQ scores– Dose-dependent

– Conclusion• “. . .recommendation that valproate not be used as a 1st choice drug in

women of childbearing potential.”

AED Mean IQ

VPA 92

PHT 99

CBZ 98

LTG 101

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AEDs & Pregnancy – Take Home Messages

• No Safe AEDs

• Optimization of pre-pregnancy treatment– Monotherapy– Lowest dose

• Advise women to plan pregnancy

• Avoid VPA

• All childbearing age women should be on folic acid

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Acknowledgment

• James McAuley, PhD– Co-investigator, slides

• John Elliott, MPH

• Janet Renner

• Stephanie Renner