Transcript Neurological Diseases & Pregnancy

“Update on Treatment of
Seizures & Epilepsy”
Bassel F. Shneker, MD
Comprehensive Epilepsy Program
The Ohio State University
October 24, 2009
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Outline
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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;
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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
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Phenobarbital/Primidone
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– PB / PRM
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Phenytoin (Dilantin)
– TGB
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– PHT
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Carbamazepine (Tegretol)
Valproic Acid (Depakote)
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Felbamate (Felbatol)
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Gabapentin (Neurontin)
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Lamotrigine (Lamictal)
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Topiramate (Topamax)
– TPM
Rufinamide (Banzel)
– RUF
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– LTG
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Pregabalin (Lyrica)
– PGB
– GBP
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Zonisamide (Zonegran)
– ZNS
– FBM
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Levetiracetam (Keppra)
– LEV (LVT)
– VPA
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Oxcarbazepine (Trileptal)
– OCBZ (OXC)
– CBZ
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Tiagabine (Gabitril)
Lacosamide (Vimpat)
– LCM
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Vigabatrin (Sabril)
– VGB
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AED Therapy
TGB
TPM
FOS
LTG
GBP
PB
1900
PHT
1920
1940
CBZ
1960
VPA
FBM
1980
PGB
ZNS
LEV VGB
OCBZ RUF
LCM
2000
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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
130
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100
90
90
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70
Brand
Generic 1
Generic 2
Generic 3
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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 Procedure
Preliminary 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 Needs
VPA = 30%, CBZ = 3.2%
Adab 2004 (UK)
Verbal IQ lower in VPAexposed than other AEDs
NEAD Study
Prospective evaluation of long
term cognitive and behavioral
development
Failey 2002 (FIN)
Mean Verbal IQ Scores
VPA 82, CBZ 96, Controls 95
Eriksson 2005 (FIN)
Low intelligence
VPA 19% vs. CBZ 0%
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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
AED
Mean IQ
VPA
92
PHT
CBZ
99
98
LTG
101
– Conclusion
• “. . .recommendation that valproate not be used as a 1st
choice drug in women of childbearing potential.”
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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
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