Epilepsy Across the Reproductive Years

Blanca Vazquez, MDDirector of Clinical Trials

Director of International ProgramNYU Epilepsy CenterNYU Medical Center

New York, NY

Epilepsy in Women

•Hormonal contraception

1•M

enstrual cycle regularity

2

•Fertility and ovulatory function

3

•Pregnancy/breastfeeding

4

•Sexuality

5

•Bone health

6

Epilepsy – What Can We Do?

DIAGNOSIS THERAPY

• History• Neuroimaging

• MRI is mainstay

• Electrophysiology• EEG is mainstay• High density EEG• Magnetoencephalography• Intracranial EEG

• “Functional” Imaging• fMRI – BOLD changes• SPECT – perfusion• PET – glucose metabolism or other ligands

• Cognitive Assessments• Neuropsychological testing• Wada procedure

• AEDs• Anti-epileptic drugs

• Neuromodulation• Vagus Nerve Stimulator• Deep Brain Stimulation• Reactive Neurostimulation

• Immunomodulation• Steroids• Intravenous Immunoglobulin (IVIG)• ACTH (which is probably more than just

immune)• Plasma Exchange (PLEX)

• Epilepsy Surgery• Diet

Video EEG Monitoring

What are some of the AEDs that are currently available?

First Generation AEDs Second Generation AEDs

Carbamazepine (Carbatrol®, Carbatrol® XR, Tegretol®, Tegretol XR®)

Felbamate (Felbatol®)

Gabapentin (Neurontin®)

Clonazepam (Klonopin®) Lacosamide (Vimpat®)

Ethosuximide (Zarontin®) Lamotrigine (Lamictal®)

Lorazepam (Ativan®) Levetiracetam (Keppra®, Keppra® XR)

Phenobarbital (Luminal®) Oxcarbazepine (Trileptal®)

Phenytoin (Dilantin®, Phenytek®) Pregabalin (Lyrica®)

Primidone (Mysoline®) Rufinamide (Banzel®)

Valproate (Depakote®, Depakene®) Tiagabine (Gabitril®)

Topiramate (Topamax®)

Zonisamide (Zonegran®)

Key: Generic (Brand Names)

Treatment Goals for Epilepsy*

* Kwan P, et al. Epilepsia 2009; doi: 10.1111/j.1528-1167.2009.02397.x Gilliam F. Neurology 2002;58:s9-s19. Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008. Faught E, et al. Epilepsia 2009;50(3):501-509.

AED Trial 1 Monotherapy

Treatment Goal Seizure freedom

Treatment Goal Maximize QoL

Long-term seizure control Minimize AED side effects

Maximize adherence

AED Trial 2 Monotherapy or Polytherapy

Newly Diagnosed Refractory Epilepsy

Video EEG

Epilepsy SurgeryVNS Therapy

AEDs (Polytherapy) Ketogenic Diet

Considerations in Epilepsy Management

Age andGender

Seizure Frequency

Underlying Pathology

Comorbidities

Medication Side Effects

Syndrome vs

Seizure Type

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LiverGonads

Hypothalamus

Pituitary

EstrogenProgesteroneTestosterone

LH/FSH

GnRH

Amygdala

Reproductive Endocrine Axis Disturbances

• Hypothalamus– Altered secretion of GnRH

• Pituitary– Altered LH release

• Gonadal– Altered steroid

metabolism/binding

GnRH=gonadotropin-releasing hormone; LH=luteinizing hormone; FSH=follicle-stimulating hormone

Reproductive Problems and AEDs

Problem Associated with some AEDs

Polycystic ovaries Mixed reports

Sex hormone level alterations

Yes

Menstrual cycle abnormalities

Yes

Anovulatory cyclesFertility

YesYes

Polycystic Ovary Syndrome NIH Diagnostic Criteria

♀ Presence of ovulatory dysfunction, polymenorrhea, oligomenorrhea, or amenorrhea

♀ Clinical evidence of hyperandrogenism and/or hyperandrogenemia

♀ Exclusion of other endocrinopathies (eg, Cushing syndrome, hypothyroidism, late-onset congenital adrenal hyperplasia)

Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

Clinical Features of PCOS Hyperandrogenism

♀ Symptoms may

include:−Hirsutism

−Acne−Male pattern balding

and/or male distribution of body hair

Lobo RA, et al. Ann Intern Med. 2000;132:989-993.

Hirsutism

Acne

Evaluation of Ovulatory FailurePredictors

• Predictors included:– Primary generalized epilepsy– Use of valproate ever or within the past 3 years– High free testosterone– Fewer numbers of LH pulses

• Valproate use in primary generalized epilepsy (19/35) was associated with:– Relatively increased free testosterone– Anovulatory cycles

Morrell M, et al. Ann Neurol. 2002;52(6):704-711.

AEDs and Contraception

• High potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4

• OCs are metabolized by liver, highly protein-bound and have low and variable bioavailability

• Inducing effects of some AEDs on estradiol and progesterone may explain OC failure

Contraception Choices for Women with Epilepsy

• Hormonal contraception– Contraceptive pills– Injectables and depots– Patches

• Rings• Barrier methods• Intrauterine contraceptive devices (IUCDs)• Surgical sterilization• Natural methods

Family Planning for Women on Antiepileptic Drugs (AEDs): Interaction With Hormonal

Contraception

Possible Interaction No InteractionCarbamazepine GabapentinFelbamate LacosamideOxcarbazepine* LevetiracetamPhenobarbital TiagabinePhenytoin ValproateTopiramate*ZonisamideLamotrigine

*At higher dosage.

Catamenial Seizures• Changes in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b

• 30%-50% have epileptic patterns that correspond to their menstrual cycleb,c

– Vulnerability to seizures is highest just before and during flow and at ovulation (relatively high estrogen and low progesterone levels)

aHerzog AG, et al. Epilepsia. 1997;38:1082-1088.bCramer JA, Jones EE. Epilepsia. 1991;32(suppl 6)S19-S26.cMorrell MJ. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:179-187.

Treatment of Catamenial Epilepsy

• Difficult to control with AEDs• Increasing doses of AEDs premenstrually may

be beneficial– Important to monitor serum levels to avoid

under- or overdosing• Acetozolamide of limited benefit• Natural progesterone for women with

regular menses

PREGNANCY & EPILEPSYClinical Dilemma

• Drugs generally contraindicated in pregnancy• Women with epilepsy are unable to stop using AEDs

– Increases risk of seizures• Injury• Miscarriage• Developmental delay

– Loss of job or driving privileges– Risk of cognitive decline

• Complications of pregnancy and labor• Risk of congenital malformations may be increased by

AED therapy

Pregnancy Complications in Women With Epilepsy

• Eclampsia1

• Increased rate of obstetric intervention (such as C-section)1

• Increased birth asphyxia2

• Neonatal hemorrhage3

• Increased perinatal mortality2,4,5

1. Yerby MS, et al. Epilepsia. 1985;26:631-635.2. Frederick J. Br Med J. 1973;2:442-448.3. Kohler HG. Lancet. 1966;1:267.4. Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:245-248.5. Waters CH, et al. Arch Neurol. 1994;51:250-253.

Major Malformations Associated with Commonly Used AEDs

Drug Phenytoin PhenobarbitalValproic

Acid Carbamazepine

Cardiac defects

Yes Yes Yes

Orofacial clefting

Yes Yes Yes

GU defects Yes Yes

NT defects Yes Yes

Dysmorphic syndrome

Yes Yes Yes Yes

GU=genitourinary; NT=neural tube

Congenital Anomalies Associated with Commonly Used AEDs

• Dysmorphism ~10%• Dysmorphic features (mid-face)

– Hypertelorism– Upturned nasal tip– Flat nasal bridge– Long philtrum– Full lips

• Distal digital hypoplasia

Fetal Anticonvulsant Syndrome• Not drug specific• Features modify as child grows• Can be seen with newer as well as older AEDs

– Lamotrigine, topiramate• Clinically indistinguishable from fetal alcohol syndrome

Risk Factors for Major Malformations

• Polytherapy• High AED plasma concentrations• Mechanisms

– Toxic metabolites– Folic acid deficiency– Epoxide metabolites– Free-radical formation

Managing Pregnancy and Epilepsy

• Verify need for AED– Diagnosis– Surgical lesions– Remission

• Determine “best” AED for individual patient• Preconception teaching• Preconception supplementation

Folate and Neural Tube Defect

• Numerous studies of vitamin supplementation • Pivotal study1

• Supplementation began at least 28 days before conception and continued at least until second missed menses– Fewer malformations in vitamin supplemented group

(13.3 vs 22.9 per 1000)– Fewer NTDs in vitamin supplemented group

(0 vs 6)

Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835

Folate Supplementation• Centers for Disease Control and Prevention recommends preconceptional folic acid

– 0.4 mg/d for all women– 4.0 mg/d for women with a history of previous NTD

What Is the Safest AED in Pregnancy?

• No drug without risks

• Maternal seizures hazardous

• Valproate has an additional risk of developing an NT defect (1%–2%)

• Monotherapy (seizure control)

• Phenobarbital has no advantage

• Choose the best AED for the seizures

1. Zahn CA, et al. Neurology. 1998;51:949-956.2. Quality Standards Subcommittee of the American Academy of Neurology. Neurology.

1998;51:944-948.

Breastfeeding and AEDs

• Assess risks and benefits for individual patients• AED concentration in breast milk related to protein

binding1

• PB and other sedating AEDs may cause sedation or poor feeding1

• American Academy of Neurology encourages breastfeeding with close observation of baby2

Effects of AEDs on Body Weight

• Weight change important consideration– Leads to health hazards– Impairs body image and self-esteem– Leads to noncompliance

• Most data anecdotal• Actual incidence and magnitude unknown• Mechanisms unclear

Biton V. CNS Drugs. 2003;17(11):781-791.

Effects of AEDs on Body Weight

Gain Neutral Loss

Valproate Lamotrigine Topiramate

Gabapentin Levetiracetam Zonisamide

Carbamazepin Phenytoin Felbamate

Pregabaline Lacosamide

Manifestations of Bone Disease• Osteopenia/Osteoporosis

– AEDs reported as a secondary cause – Increased rates at multiple sites including hip and

lumbar spine• Osteomalacia

– Increased osteoid or unmineralized bone– Most studies in institutionalized persons

• Confounded by poor diet, inadequate sunlight, limited exercise

Andress DL, et al. Arch Neurol. 2002;59(5):781-786.Farhat G,et al. Neurology. 2002;58(9):1348-1353.Pack AM, et al. Epilepsy Behav. 2003;4(2):169-174.Sato Y, et al. Neurology. 2001;57(3):445-459.Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):631-637.

Intractableseizures

Excessivedrug burden

Neurobio-chemicalchanges Unsatisfactory

quality of life

Restrictedlifestyle

Dependentbehavior

Psychosocialdysfunction

Cognitivedecline

Increasedmortality

Dimensions of Refractory Epilepsy

Kwan P and Brodie MJ. Seizure. 2002;11:78.

Overall quality of life is a fundamental measure ofsuccessful treatment in patients with epilepsy

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