Women Epilepsy

8/7/2019 Women Epilepsy

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WOMEN & EPILEPSY

Jeanne Ann King, MD


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ISSUES FACING THE NEUROLOGIST

IN TREATING EPILEPSY IN THE

FEMALE PATIENT

Relationshipbetween female

hormones andseizures

Contraception

Folate

Fertility

Seizure controlduring pregnancy

Risk of birthdefects

Prenatal testing Pregnancy

complications

Vitamin K

Breast feeding

Parenting advice


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THE SCOPE OF THE PROBLEM

0.6%-1.0% of general population haveepilepsy

Over 1 million WWE (USA)in theirreproductive years

3-5/1000 births to WWE (1/250)

20,000 babies/year

One of the most common chronicdisorders affecting women of reproductiveage

WWE=women with epilepsy


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REPRODUCTIVE STEROID HORMONES

VS SEIZURES: a reciprocal problem

Hormones effect excitability of theCNS and can increase seizures

Spread of seizure activity tosubcortical structures effects thehypothalamus and pituitary and

interferes with reproductive health


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RELATIONSHIP BETWEEN FEMALE

HORMONES AND SEIZURES

Pituitary hormones: FSH, LH, &prolactin

Developing ovarian follicle: estrogen

Corpus luteum: progesterone

Estrogen is excitatory; progesterone

is inhibitory


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HORMONES AND SEIZURES:basic science evidence

Estrogen

Reduces effectiveness of GABA transmission at

the GABA A receptor Enhances excitation at the glutamate receptor

Increases the number of excitatory synapses.

Progesterone

Enhances GABA mediated inhibition Increases GABA synthesis

Increases GABA-A receptors


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HORMONES AND SEIZURES:

Clinical

Women with epilepsy (WWE)experience changes in seizures

during: Puberty

Over the menstrual cycle

Pregnancy Menopause


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CATAMENIAL SEIZURES:

CLINICAL CHARACTERISTICS

Most common just before or at onsetof menses

Also occur with ovulation

30% (10-70%) of patients

Not related to seizure type

Seizures more severe duringanovulatory cycles


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SEIZURES DURING

MENSTURAL CYCLE

Ovulation: ovulatory estrogen surgewhen progesterone is relatively low

Perimenstrual period: progesteronewithdrawal

Anovulatory cycles: estrogen level

remains high without the protectiveeffect of progesterone, which isnormally secreted by the corpus

luteum


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CATAMENIAL SEIZURES:

TREATMENT

First-line AED appropriate for seizure type

Adjust levels one week before menses

Diamox Progesterone

Ganaxolone

Not helpful

Menopause Hysterectomy

BCP


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CONTRACEPTION

OCPs do not worsen seizure control

Contraceptive failure is higher (6%-

20%/year) if inducing AEDs are used(PB, PRM, PHT, CBZ, OXC and TPM)

Binding and metabolism of steroid

hormones is increased Mini-pill (35 micrograms) is not

enough


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EFFECTS OF AEDS ON STEROID

HORMONE CONCENTRATION

Reduce: PB, PRM, PHT, CBZ,OXC,TPM

No effect or increase: VPA, FBM

No effect: GBP, LTG,TGB, LEV, ZNM,VGB

This effect is seen with levonorgestrel implants as well

as with injectable depoprovera!


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CONTRACEPTION

Mid cycle spotting may be a sign ofovulation and the potential for

contraceptive failure *Women taking enzyme inducingAEDs should use alternative

contraception, or receivecontraceptives containing 50micrograms or more of the estrogencomponent.


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Folate Deficiency

This is one hypothesis for thepathogenesis of congenital malformations

and anomalies in infants of WWE PHT, CBZ and PB impair folate absorption

VPA inhibits glutamate formyl transferase

Preconceptional folate supplementationclearly reduces risk of neural tube defectsfor women without epilepsy


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SPINA BIFIDA

1%-2% risk with VPA monotherapy orpolytherapy

0.5%-1% risk with CBZ polytherapy Avoid VPA and CBZ in patients with

positive family history of NTD


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PRECONCEPTION COUNSELING

Just do it!


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FERTILITY

Reduced by 1/3-2/3

Social issues/stigma

Misinformation/Fear

Transmitting epilepsy

Birth defects from AEDs

Unfit parents

Physiologic


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PHYSIOLOGIC FACTORS

Pituitary hormone abnormalities

Due to disruption in hypothalamic input topituitary due to seizures resulting ininappropriate release

Results in anovulatory cycles (esp.TLE),polycystic ovaries and fetal loss (regulatesendometrial lining)

Prolactin levels are increased 3-5 times aftercomplex partial and GTC seizures


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PHYSIOLOGIC FACTORS

*Disturbances in LH concentrationand pulsatile release

Anovulatory cycles (1/3 of cycles)

Irregular cycles

Abnormal cycle length (35

days)

Premature ovarian failure


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POLYCYSTIC OVARY SYNDROME

Hyperandrogenic chronic anovulation

Hirsutism, acne, obesity, hypofertility,hyperandrogenemia, & menstrual disorders

Polycystic ovaries and/or hyperandrogenism:20% incidence in general population; 40% inWWE

? Increased with VPA

POS is associated with DM, cardiovasculardisease and endometrial carcinoma


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PHARMACOKINETIC CHANGES

Total levels decline for allAEDs

Decreased totalbound levels due to:

Increased volume of distribution

Increased hepatic metabolism

Increased renalclearance

Increased free levels due to:

Drop in serum proteins

*Levels rise in postpartum period


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AED LEVELS

For highly protein bound drugs, monitorthe free level

No consensus regarding frequency, butmonitor at least prepregnancy, eachtrimester, in the last month, and within 8weeks post-partum

Since many of the newer AEDs are renallyexcreted, and renal clearance is increasedduring pregnancy, monitoring isrecommended


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RISK OF BIRTH DEFECTS

Minor congenital anomalies also 2xas likely

Hypertelorism, epicanthal folds,shallow philtrum, broad nasal bridge,distal digital hypoplasia and simian

creasesFetal AED syndrome

May be outgrown in early childhood


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MECHANISMS OF TERATOGENICITY

Genetic predisposition

Free radical (oxide) metaboliteformation

Folate deficiency

Other?


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RISK OF BIRTH DEFECTS

Standard drugs: Category D

(+ evidence of risk)

Newer drugs: Category C

(dont know, cant rule out)

Animal studies are reassuring (ZNM?)

Human experience is limited


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RISK OF BIRTH DEFECTS WITH

NEW AEDS

Not enough experience to beconclusive

Information from postmarketingsurveys

Need 2000 pregnancies to know

whether a drug is teratogenic Prospective AED pregnancy registries

established


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RISK OF BIRTH DEFECTS WITH

NEW AEDS

In the meantime, selection of anewer AED is appropriate if this

achieves the most efficacious andbest-tolerated outcome

Refer pregnant patients taking AEDs

to the North American AEDPregnancy Registry. (1-888-233-2334 or 1-888-AED-AED4;http://neuro-www2.harvard )


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TERATOGENICITY:

AEDS VS EPILEPSY

1986-1993

128,049 deliveries

anticonvulsant embryopathy

major malformations

growth retardation

hypoplasia of the midface and fingers

Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, and Ryan LM. The

teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-1138.


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TERATOGENICITY:

AEDS VS EPILEPSY

223 infants exposed to one AED(20.6%)

93 infants exposed to two or more AEDs

(28%)

98 infants whose mothers had epilepsybut took no AEDs (no increase)

508 controls (8.5%) (unexposed to AEDsand mothers did not have epilepsy)

Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, and Ryan LM.

The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-1138.


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TERATOGENICITY:

Effect of Seizures

Same incidence of majormalformations if maternal seizures

involved loss of consciousness vsother types of szs

Same incidence of major

malformations if AEDs were used fornon-seizure indications

Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, and Ryan LM. The

teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-1138.


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PRENATAL DIAGNOSIS

Maternal serum alpha-fetoprotein at 14-16 weeks - 20% false negatives

Hi resolution ultrasound at 16-20 weeks -90% accuracy

Both increases accuracy to 95%

Amniocentesis at 16-18 weeks - 95%accuracy; but only in select cases (age>35or + family Hx)


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PREGNANCY COMPLICATIONS:

Hyperemesis gravidarum

Vaginal bleeding

Anemia


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PREGNANCY COMPLICATIONS

Due to Seizures:

Trauma from fallsor burns

Premature labor Abruptio placentae

Miscarriages

Intracranialbleeding

Developmental orlearning difficulties

Fetal anoxia Acidosis

Heart ratesuppression


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PREGNANCY COMPLICATIONS

During Labor and Delivery:

Premature labor

Failure to progress

Abruptio placentae

Increased rate of Caesarean sections

Seizures during labor are anindication for c-section


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ADVERSE OUTCOMES IN INFANTS OF

MOTHERS WITH EPILEPSY

Decreased viability

Stillbirths, miscarriages

Neonatal, infant mortality

Decreased growth parameters

Intrauterine growth retardation, low

birth weight Microcephaly


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NEONATAL COAGULOPATHY

Neonatal hemorrhage in the first 24 hours of life

Mild vitamin K deficiency related to AEDs

PB, PRM, CBZ & PHT competitively inhibitVitamin K transport across the placenta

Infant has prolonged PT and PTT due todeficiency in clotting factors II, VII, IX, & X.

The AAN recommends the mother receiveVitamin K1 10 mg/day in the last4 weeks ofpregnancy.


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GOOD OUTCOMES IN INFANTS OF

MOTHERS WITH EPILEPSY

Despite all this negative information,over 90% of children born to WWE

are normal! Most women experience no change

in their seizures during pregnancy or

post-partum complications.


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BREAST-FEEDING

AEDs appear in breast milk in amounts inverselyproportional to their protein binding

In some cases, a therapeutic level is achieved Sedation, feeding difficulties and rarely adverse

hepatic or hematological effects occur

Not contraindicated; in fact, encouraged, but

infants should be monitored for sedation,irritability, feeding & weight gain


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AEDs IN BREAST MILK

PB 40%

PRM 60%

PHT 30% CBZ 45%

VPA 2%

ESM 90%

FBM present

GBP ?/no PB

LTG 65%

TPM ?/13-17%PB

TGB ?/96% PB LEV ?/


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PARENTING ADVICE

In general:

Enlist the help of others for nightfeedings to avoid sleep deprivation

If no support is available, use a homehealth agency


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PARENTING ADVICE

For those who lose consciousness:

Fence yards Use safety gates and playpens

Use a child harness or wrist bungeecord, especially when traveling

Use a potty chair rather than a childbooster seat on the toilet


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PARENTING ADVICE

For those who fall with seizures

Change diapers on the floorAvoid carrying the infant when alone

Avoid the use of front or back infantcarriers

Use an umbrella stroller for transport


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PARENTING ADVICE

Bathing

Set water thermostats low

Bathe infants only with another adultpresent/or sponge baths on the floorwith a separate container of water


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MENOPAUSE

Though estrogen levels decline with cessation of

ovarian function, so do progesterone levels 30% improve, 30% worse

AEDs influence replacement hormonal therapy,just as they do OCP

Hormonal replacement with estrogen mayworsen seizures

Natural progestin replacement may improveseizures


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AEDs and BONE HEALTH

Altered bone metabolism and bonedensity associated with PHT, CBZ &

PB Osteoporosis, osteopenia,

osteomalacia & fractures especially

in menopausal women Hormonal replacement, calcium

supplementation, regular weight-bearing exercise


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RECOMMENDATIONS

Choice of AED is based on seizure type

Monotherapy

Optimize AED therapy before conception

Discuss effectiveness of contraception

Use at least 50 micrograms of ethinyl

estradiol or mestranol if hormonalcontraception is chosen


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RESOURCES AVAILABLE

AED (Harvard)Pregnancy Registry forpregnant women taking any AED:1-888-

233-2334 or 1-888-AED-AED4 (toll free) EFA: literature or information sheets

available for patients and health care

providers on hormones, sexualrelationships, fertility, family planning,pregnancy, parenting, teenage girls,menopause and more


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RESOURCES AVAILABLE (CONT.)

Quality Standards Subcommittee ofthe American Academy of Neurology.

Practice Parameter: managementissues for women with epilepsy(summary statement). Neurology1998;51:944-948.

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