Management of Women’s Issues in Epilepsy
Dr. Prithika Chary
Consultant Neurologist & Neurosurgeon
Chief, Division of Epileptology
Director, EPICENTTRE
Apollo Hospitals, Chennai
Women with epilepsy - Life stages
• Women with epilepsy face a number of problems unique to their gender.
• These special concerns, relate to menses, birth control, conception, pregnancy, childbirth, child care, and menopause.
• Care of women with epilepsy entails some special considerations as seizures are often linked to menarche, the menstrual cycle, and menopause
Sexual issues
• Sexual function and reproductive health are affected by seizures and antiepileptic drugs.
• Some of these drugs are associated with an increased failure rate of hormonal contraceptives
• Pregnancy in a woman with epilepsy carries an increased risk to both mother and child.
Seizures related to the menstrual cycle
• An increase in seizure frequency around the time of menstruation (catamenial epilepsy) was first documented more than 100 years ago
• It is variously reported in 10% to 72% of women
• Seizures are linked to menses because sex hormones alter the excitability of neurons in the cerebral cortex
• Estrogens can lower seizure threshold, resulting in an increase in the frequency of interictal spikes & seizures
• Progestins have the opposite effect and may protect against seizures
Ovulation & Seizures
The presence or absence of ovulation in any single menstrual cycle affects the likelihood of seizure, and women may exhibit different patterns of seizure exacerbation
Ovulatory cycles display two distinct patterns.
• First, seizures may increase a few days before menses and in the first 2 to 3 days of bleeding, perhaps precipitated by the rapid decline in progesterone levels.
• Second, seizure frequency may increase at the time of ovulation as a result of the rise in estrogen levels.
Ovulatory cycles protect against seizures
• In women with catamenial epilepsy there is a reduction in seizures during the luteal phase (days 17 to 24) of ovulatory cycles owing to the protection of increased progesterone levels.
• With anovulatory cycles, the progesterone-secreting corpus luteum is not formed and estrogen levels remain high.
• Anovulatory cycles are associated with a pattern of increased seizures during the entire second half of the menstrual cycle.
Diagnosis of Catamenial pattern
• To determine if a catamenial pattern is present, patients should be instructed to chart menses along with basal body temperature and seizures for several months.
• A record of basal body temperature is useful in determining ovulation.
• Progesterone levels can be measured on day 22 of the menstrual cycle (day 1 being the onset of menses). A progesterone level lower than 5 mg/mL on day 22 indicates an anovulatory cycle.
Management of catamenial seizures
• A supplemental daily dose of the maintenance antiepileptic drug at the expected time of seizure exacerbation
• Acetazolamide (Diamox), a carbonic anhydrase inhibitor, has also been used but with limited success.
• Hormonal manipulation is unconventional, but it may involve either increasing the level of progesterone or decreasing the level of estrogen
• Any treatment with hormonal manipulation should be done in collaboration with a gynecologist and in the presence of effective contraception.
Contraception
• The choice of birth control for women with epilepsy must take into account the high failure rate of hormonal contraception in women taking hepatic enzyme-inducing antiepileptic drugs
• The hepatic P-450 system also metabolizes sex steroids, and the enhanced metabolism induced by some antiepileptic drugs leads to lower hormonal levels and reduced contraceptive efficacy
Hepatic induction & Contraception
• Oral contraceptives may still be used, but higher doses are needed (ie, 50 micrograms of estrogen rather than the typical 35 micrograms
• Hepatic enzyme inducing antiepileptic drugs are Carbamazepine (Tegretol), Felbamate, Phenobarbitone Sodium, Phenytoin sodium (Dilantin), Primidone (Mysoline), Topiramate (weak)
Long acting contraceptives
• Contraceptive failure has also been reported with the use of fixed subdermal levonorgestrel (Norplant System) in women taking carbamazepine or phenytoin sodium because of a similar mechanism
• Medroxyprogesterone acetate (Depo-Provera) may provide a useful alternative . The currently recommended dose is 150 mg administered intramuscularly every 3 months.
Contraception
Contraceptive failure does not occur with
• Valproic acid ,
• Gabapentin (Neurontin),
• Lamotrigine (Lamictal),
• vigabatrin
• Benzodiazepines because they do not induce hepatic metabolism.
Sexual and reproductive health
• Complex partial seizures, are associated with overall hyposexuality and reduced libido
• Many studies have shown decreased libido or impotence in up to two thirds of men with epilepsy
• In women, dysfunctional sexual behavior was present in up to 50% Sexual Dysfunction
Important causes of sexual dysfunction include
• social and psychological influences,
• disruption of normal limbic function by epileptic discharges,
• altered pituitary or gonadal hormones,
• secondary effects of antiepileptic drugs.
Reproduction
• Reproduction in both men and women with epilepsy is lower than in the general population
• Social factors such as fear of having a child with epilepsy or a congenital malformation may significantly influence reproduction
• Women with epilepsy have fewer children than women in the general population.
• Their fertility rate is 25 to 33 % lower than average.
• Social pressures on women with epilepsy to refrain from having children may be a factor in their lower rate of childbearing.
Women with epilepsy are at higher risk for
• Reproductive endocrine disorders, such as polycystic ovarian syndrome and hypogonadotropic or hypergonadotropic hypogonadism
• Menstrual cycle disturbances that entail a higher incidence of anovulatory cycles .10% of menstrual cycles are anovulatory in healthy women,while 35% are anovulatory in women with temporal lobe epilepsy.
Infertility
• Infertility in a couple requires careful evaluation in both partners.For women with epilepsy,
• pelvic ultrasound to rule out PCOD
• Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations
• Midluteal-phase progesterone levels may help identify a treatment focus
Epilepsy & Pregnancy
• Epilepsy is the most common neurologic disorder in pregnant women
• Prevalence of epilepsy in women of child bearing age is 0.3-1.0%
• Most pregnancies are routine, and most of the children delivered are healthy
• However, both seizures and antiepileptic drugs can adversely affect the foetus
• Most women with epilepsy can conceive and deliver healthy children.
• However, their pregnancies are considered to be high risk because many of these women experience more complications than women who do not have epilepsy.
• During pregnancy, 1/4 to1/3 of women with epilepsy have an increase in seizure frequency.
• This is not related to type of seizure, how long the woman has had seizure, or how often she had seizures during previous pregnancies.
• The increase in seizure frequency seen during pregnancy is strongly associated with the changing blood levels of AEDs during pregnancy.
• Seizures, particularly GTCS (grand mal) seizures, can be hazardous in pregnancy.
• They can cause miscarriages.
• Trauma from falling is a major cause of obstetrical injury.
• GTCS place both mother and fetus at risk for hypoxia and acidosis, both of which can affect the mother's and baby's central nervous systems.
• Although rare, stillbirths have occurred following a single generalized convulsion or series of seizures.
• Status epilepticus carries a high mortality rate for mother and fetus.
• Also, generalized seizures occurring during labor can affect the baby's heart rate.
• All women have a 2-3% risk of having a child with a birth defect.
• This risk is higher in women with epilepsy, estimated at 4-6%.
• Genetic factors and taking antiepileptic medications may both play a role in this risk.
• While pregnancy presents special concerns for women with epilepsy, more than 90% of those who become pregnant give birth to normal, healthy infants.
Problems Associated with Epilepsy in Pregnancy
• CHANGES IN DRUG METABOLISM
• INCREASE IN SEIZURE FREQUENCY
• DECREASE IN FETAL VIABILITY
• INCREASED RISK OF FETAL BLEEDING
• DECREASE IN FETAL GROWTH
• DECREASE IN CHILDHOOD INTELLIGENCE
Problems Associated with Antiepileptic Drugs
• Medication
• Maternal effects
• Characteristic potential fetal/neonatal effects
• Carbamazepine (Tegretol) Drowsiness, leukopenia, ataxia, mild hepatotoxicity/ Facial dysmorphisms, neural tube defects, hypoplasia of distal phalanges
• Phenytoin (Dilantin) Nystagmus, ataxia, hirsutism, gingival hyerplasia, megaloblastic anemia / Facial clefting, hypoplasia of distal phalanges, hypertelorism, neonatal coagulopathy
• Phenobarbital Drowsiness, ataxia / Neonatal withdrawal, neonatal coagulopathy
• Primidone (Mysoline) Drowsiness, ataxia, nausea / Neonatal withdrawal, neonatal coagulopathy
• Valproic acid (Depakene) Ataxia, drowsiness, alopecia, hepatotoxicity, thrombocytopenia / Facial dysmorphisms, neural tube defects
Guidelines for Counseling Women with Epilepsy Who Are Planning Pregnancy
• The risk of major malformations, minor anomalies and dysmorphic features is 2 - 3 fold higher in infants born to women who take AEDs while they are pregnant than the risk in infants born to women who do not take these drugs.
• Some of this risk is caused by a genetic predisposition for birth defects inherent in certain families. Maternal and paternal family medical histories should be reviewed for birth defects.
• The potential for prenatal diagnosis with ultrasound and/or amniocentesis for major malformations should be discussed with the parents.
• If the patient is seizure-free for at least two years, withdrawal of the antiepileptic drug should be considered.
• If antiepileptic drug therapy is necessary, a switch to monotherapy should be made if possible.
• Effects of tonic-clonic seizures may be deleterious to the fetus, may injure the mother, and can result in miscarriage.
• The preconception diet should contain adequate amounts of folate.
• If the patient is seizure-free for at least two years, withdrawal of the antiepileptic drug should be considered.
• If antiepileptic drug therapy is necessary, a switch to monotherapy should be made if possible.
Pre-pregnancy management::
• Re-assess & confirm the diagnosis of epilepsy
• Re-evaluate the continued need for AED
• Transfer to single drug therapy if possible
• Treat with the lowest individual effective daily dose
• Change of AED if necessary
• Folic acid supplementation
• Reassurance on the altogether benign course of pregnancy, delivery and good outcome in over 90% of the cases, and on the benign prognosis of epilepsy, provided good drug compliance is maintained
Management during pregnancy
• Counsel on value of good drug compliance
• Monthly neuro check with drug monitoring
• Increase AED dose SOS, preferably based on clinical criteria I.e. sz control & side effects
• Reassure on good course & outcome of pregnancy
• Individualised obstetric monitoring, including determination of serum AFP & US
• Counsel on continued drug compliance during delivery & on breast feeding ( recommended)
Pregnancy +Epilepsy - Risks to mother
• Vaginal bleeding
• Protracted/Prolonged labour
• Usually no dramatic change in course of epilepsy
• Risks of GTCS/status epilepticus to be avoided
• Importance of good drug compliance to be emphasised
Pregnancy+Epilepsy - Risks to foetus
• Lower postnatal APGAR scores
• Increased risk for asphyxia
• Lower incidence of physiological icterus
• Lower Vit K - replacement required 1mg/Kg
• Postnatal sedation vs hyperexcitability
• Breast feeding is recommended despite associated risks
Management during peurperium
• Lower daily dose of AED in case of side effects
• Maintain a good night’s sleep despite breast feeding during the day
• Paediatric monitoring as necessary
Epilepsy & Pregnancy
• Women should undergo evaluation by their neurologist regularly during pregnancy.
• Serum AED levels should be monitored closely and adjusted if seizures occur.
• Both free and total levels of PHT & CBZ should be checked.
Investigations during pregnancy
AED levels
• 6-10 wks AED levels (free and total), serum folate level
• 15-16 wks Maternal serum AFP, amniocentesis, AED levels,Triple screen MOM
• 28 wks AED levels
• 34-36 wks AED levels, maternal vitamin K
Ultrasound
• 18-19 wks A high-level ultrasound predicts a neural-tube defect with an accuracy of more than 95%
• 22-24 wks Ultrasound for oral clefts and heart anomalies
Management during pregnancy
• Women need to obtain adequate sleep because sleep deprivation might increase seizure frequency.
• Vitamin K, 20 mg a day orally, should be administered for the 2 weeks before delivery to decrease the risk of maternal and neonatal bleeding .
• Delivery should take place in a clinic with facilities for providing specialized care to epileptic patients and with an associated neonatal intensive care unit.
• AED administration should be continued during labor.
• Parenteral medication or additional oral doses may be necessary because of decreased absorption during a prolonged labor.
Postpartum
• Monitoring of maternal antiepileptic drug levels should continue postpartum.
• Levels gradually return to baseline by 12 weeks after delivery.
• Mothers should be advised to avoid sleep deprivation.
• Breast-feeding and child-care issues should be discussed.
Serum concentrations of AEDs in breast milk
Commission on Genetics, Pregnancy & the Child 1993
Many women with epilepsy can breast-feed.
• Carbamazepine 40%-45%
• Ethosuximide 90%
• Phenobarbital 36%-40%
• Phenytoin sodium 18%-30%
• Primidone 60-70%
• Valproic acid 5%-10%
• Gabapentin , Lamotrigine , Topiramate Not known
Menopause
• Little is known about menopause and epilepsy.
• During menopause, ovarian follicles involute and levels of both estrogen and progesterone decline dramatically.
• Steroid hormones are derived from the adrenal cortex. In response to the lack of feedback inhibition, LH and FSH concentrations rise.
• Seizures become more unpredictable. Control improves in some women and worsens in others.
• One systematic study concluded that seizures are more likely to decrease if they exhibit a catamenial pattern and if they began in adult life.
• Poorly controlled seizures are likely to worsen.
• In a recent report 51% of women experienced a change in seizure frequency during menopause; increases and decreases in frequency were reported equally.
• Additional prospective studies are needed.
Menopause & HRT
• The use of supplemental estrogen raises concern because of the possibility of increased seizures
• This may be a rare occurrence, so the risks and benefits of its use need to be assessed on an individual basis
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