Epilepsy Across the Reproductive - PowerPoint Presentation

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Epilepsy Across the Reproductive Years

Blanca Vazquez, MDDirector of Clinical TrialsDirector of International ProgramNYU Epilepsy CenterNYU Medical CenterNew York, NY

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Epilepsy in Women

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Epilepsy – What Can We Do?Diagnosistherapy

HistoryNeuroimagingMRI is mainstayElectrophysiologyEEG is mainstayHigh density EEGMagnetoencephalographyIntracranial EEG“Functional” ImagingfMRI – BOLD changesSPECT – perfusionPET – glucose metabolism or other ligandsCognitive AssessmentsNeuropsychological testingWada 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

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Video EEG Monitoring

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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)

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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 freedomTreatment Goal Maximize QoL Long-term seizure control Minimize AED side effects Maximize adherenceAED Trial 2 Monotherapy or PolytherapyNewly DiagnosedRefractory EpilepsyVideo EEGEpilepsy SurgeryVNS Therapy AEDs (Polytherapy) Ketogenic Diet

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Considerations in

Epilepsy ManagementAge andGender

Seizure

Frequency

Underlying

Pathology

Comorbidities

Medication

Side Effects

Syndrome

vs

Seizure Type

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Liver

Gonads

Hypothalamus

Pituitary

Estrogen

Progesterone

Testosterone

LH/FSH

GnRH

Amygdala

Reproductive Endocrine Axis Disturbances

Hypothalamus

Altered secretion of GnRH

PituitaryAltered LH releaseGonadalAltered steroid metabolism/bindingGnRH=gonadotropin-releasing hormone; LH=luteinizing hormone; FSH=follicle-stimulating hormone

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Sex Steroid Hormones and Epilepsy Estrogen may be a proconvulsant Reduces inhibition at GABAA receptorAlters mRNA for GAD and inhibits GABA synthesis

Progesterone may be an anticonvulsantIncreases inhibition at GABAA receptorAttenuates excitation of glutamate in hippocampusAlters mRNA for GAD and increases GABA synthesisGABA =



-aminobutyric acid; mRNA = messenger ribonucleic acid;

GAD = glutamic acid decarboxylase.

Morrell MJ.

Neurology

. 1999;53(suppl 1):S42-S48.

Woolley CS, Schwartzkroin PA.

Epilepsia.

1998;39(suppl 8):S2-S8.

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Reproductive Problems and AEDs

Problem

Associated with

some AEDs

Polycystic ovaries

Mixed reports

Sex hormone level alterations

Yes

Menstrual cycle abnormalities

Yes

Anovulatory

cycles

Fertility

YesYes

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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.

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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

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Evaluation of Ovulatory FailurePredictors

Predictors included:Primary generalized epilepsyUse of valproate ever or within the past 3 yearsHigh free testosteroneFewer numbers of LH pulsesValproate use in primary generalized epilepsy (19/35) was associated with:Relatively increased free testosteroneAnovulatory cycles

Morrell M, et al.

Ann Neurol

. 2002;52(6):704-711.

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AEDs and ContraceptionHigh potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4OCs 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

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Contraception Choices for Women with EpilepsyHormonal contraceptionContraceptive pills

Injectables and depotsPatchesRingsBarrier methodsIntrauterine contraceptive devices (IUCDs)Surgical sterilizationNatural methods

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Family Planning for Women on Antiepileptic Drugs (AEDs): Interaction With Hormonal ContraceptionPossible Interaction No InteractionCarbamazepine Gabapentin

Felbamate LacosamideOxcarbazepine* LevetiracetamPhenobarbital Tiagabine

Phenytoin Valproate

Topiramate

*

Zonisamide

Lamotrigine

*At higher dosage.

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Catamenial SeizuresChanges in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b30%-50% have epileptic patterns that correspond

to their menstrual cycleb,cVulnerability to seizures is highest just before and during flow and at ovulation (relatively high estrogen and low progesterone levels)

a

Herzog AG, et al.

Epilepsia.

1997;38:1082-1088.

b

Cramer JA, Jones EE.

Epilepsia.

1991;32(suppl 6)S19-S26.

c

Morrell MJ. In: Wyllie E, ed.

The Treatment of Epilepsy: Principles and Practice.

2nd ed. Baltimore, Md: Williams & Wilkins; 1997:179-187.

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Treatment of Catamenial EpilepsyDifficult to control with AEDs

Increasing doses of AEDs premenstrually may be beneficialImportant to monitor serum levels to avoid under- or overdosingAcetozolamide of limited benefitNatural progesterone for women with regular menses

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PREGNANCY & EPILEPSYClinical Dilemma

Drugs generally contraindicated in pregnancyWomen with epilepsy are unable to stop using AEDsIncreases risk of seizuresInjuryMiscarriageDevelopmental delayLoss of job or driving privilegesRisk of cognitive decline

Complications of pregnancy and labor

Risk of congenital malformations may be increased by AED therapy

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Pregnancy Complications in Women With EpilepsyEclampsia1Increased rate of obstetric intervention (such as C-section)

1Increased birth asphyxia2Neonatal hemorrhage3Increased perinatal mortality2,4,5

Yerby MS, et al.

Epilepsia.

1985;26:631-635.

Frederick J.

Br Med

J.

1973;2:442-448.

Kohler HG.

Lancet.

1966;1:267.

Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:245-248.Waters CH, et al. Arch Neurol. 1994;51:250-253.

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Major Malformations Associated with Commonly Used AEDs

DrugPhenytoin

Phenobarbital

Valproic Acid

Carbamazepine

Cardiac defects

Yes

Yes

Yes

Orofacial clefting

Yes

Yes

Yes

GU defectsYesYesNT defectsYesYesDysmorphic syndromeYesYesYesYesGU=genitourinary; NT=neural tube

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Congenital Anomalies Associated with Commonly Used AEDsDysmorphism ~10%Dysmorphic features (mid-face)Hypertelorism

Upturned nasal tipFlat nasal bridgeLong philtrumFull lipsDistal digital hypoplasia

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Fetal Anticonvulsant SyndromeNot drug specificFeatures modify as child growsCan be seen with newer as well as older AEDs Lamotrigine, topiramate

Clinically indistinguishable from fetal alcohol syndrome

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Risk Factors for Major MalformationsPolytherapyHigh AED plasma concentrationsMechanisms Toxic metabolites

Folic acid deficiencyEpoxide metabolitesFree-radical formation

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Managing Pregnancy and EpilepsyVerify need for AEDDiagnosisSurgical lesions

RemissionDetermine “best” AED for individual patientPreconception teachingPreconception supplementation

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Folate and Neural Tube DefectNumerous studies of vitamin supplementation Pivotal study1Supplementation began at least 28 days before conception and continued at least until second missed mensesFewer 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

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Folate SupplementationCenters for Disease Control and Prevention recommends preconceptional folic acid0.4 mg/d for all women4.0 mg/d for women with a history of previous NTD

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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 advantageChoose the best AED for the seizures

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Zahn CA, et al.

Neurology. 1998;51:949-956.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 binding

1

PB and other sedating AEDs may cause sedation or poor feeding

1

American Academy of Neurology encourages breastfeeding with close observation of baby

2

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Role of Pregnancy RegistriesTo facilitate monitoring fetal outcomes of pregnant women1 Systematic epidemiology study2Collection and assessment of postmarketing data on potential adverse health effects to the mother, fetus, or infant caused by exposure to a drug or other biological agent during pregnancy

2Provides information that can be included in product labeling2Can assess suspected or unknown risks21Lamotrigine [product information]. Research Triangle Park, NC: GlaxoSmithKline, 2003.2

FDA Guidance for Industry: Establishing Pregnancy Registries. Draft Guidance.

http://www.fda.gov/cber/gdlns/pregnancy.pdf. Accessed June 27, 2002.

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Effects of AEDs on Body WeightWeight change important considerationLeads to health hazards

Impairs body image and self-esteemLeads to noncomplianceMost data anecdotalActual incidence and magnitude unknownMechanisms unclear

Biton V.

CNS Drugs

. 2003;17(11):781-791.

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Effects of AEDs on Body Weight

GainNeutral

Loss

Valproate

Lamotrigine

Topiramate

Gabapentin

Levetiracetam

Zonisamide

Carbamazepin

Phenytoin

Felbamate

Pregabaline

Lacosamide

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Manifestations of Bone DiseaseOsteopenia/Osteoporosis

AEDs reported as a secondary cause Increased rates at multiple sites including hip and lumbar spineOsteomalacia Increased osteoid or unmineralized boneMost studies in institutionalized personsConfounded 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.

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Epilepsy at Menopause PerimenopauseFluctuations in ovarian steroid levels may exacerbate or diminish seizuresa,bMenopauseSeizures may improvebImprovement most likely in those with catamenial pattern

bHRT with menopause may worsen seizuresbHRT= hormone replacement therapyaAbbasi F, et al. Epilepsia. 1999;40(2):205-210.

b

Harden CL, et al.

Epilepsia.

1999;40(10):1402-1407.

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Intractable

seizures

Excessive

drug burden

Neurobio-

chemical

changes

Unsatisfactory

quality of life

Restricted

lifestyle

Dependent

behavior

PsychosocialdysfunctionCognitivedeclineIncreasedmortalityDimensions of Refractory EpilepsyKwan 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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