Download - 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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RELATIONSHIP BETWEEN FEMALE
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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RELATIONSHIP BETWEEN FEMALE
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.