Women Issues in Epilepsy Olgica Laban-Grant, MD Northeast Regional Epilepsy Group NEREG 2014

Epilepsy 54% women - 41 cases per 100,000 men - 49 cases per 100,000

Gender issues Men and women have similar risk for recurrent seizure likelihood of ultimate remission of epilepsy

Gender issues Generalized epilepsy is more common in women (58%) Mostly juvenile absence epilepsy and juvenile myoclonic epilepsy syndromes

hormones seizures AED’s

Major sex steroid hormones in women are estrogen and progesteron released by ovaries

Hypothalamic-pituitary-gonadal (HPG) axis

HPG axis

Effect of seizures on hormones AED’s

Effect of seizures on hormones Libido (sexual desire) Fertility Menstrual cycle regularity Onset of menopause

Fertility and Epilepsy Women with epilepsy have fewer children Conflicting data regarding fertility Possible explanations: Choice (fear of having child with birth defect) Seizures and/or AED’s may affect reproductive system Sexual dysfunction More frequent disorders of menstrual cycle Polycystic Ovary Syndrome (PCOS)

Menstrual disorders Menstrual disorders are estimated to occur in 1 of 3 women with epilepsy compared with 1 in 7 in the general population One third of menstrual cycles in women with generalized seizures are anovulatory (ovaries do not release an egg)

Polycystic Ovary Syndrome (PCOS) and epilepsy Syndrome is twice as common in women with epilepsy 10-25% in WWE compared to 7% in general population

Polycystic Ovary Syndrome (PCOS) and epilepsy Multiple cysts in ovaries High male hormone levels Excessive facial hair and acne Other features Obesity Irregular menstrual periods More frequent anovulatory cycles

Polycystic Ovary Syndrome (PCOS) and epilepsy Possible explanations: Seizure activity in brain alters the production of hormones Valproic acid (Depakote) causes features similar to PCOS

Epilepsy in adolescence Certain types of epilepsy start at approximate age (JME) or improve (benign rolandic epilepsy, absence epilepsy) Rapid growth may account for poor seizure control Most seizure disorders are not altered by onset of puberty

Epilepsy and menopause Premature menopause is more common 14% of WWE compared to 3.7 % in general population Menopause occurred on average 3 years earlier Correlated with estimated life time number of seizures No influence of AED’s

Effect of hormones on seizures AED’s

Effect of hormones on seizures Hormones change the excitability of the brain and alter the threshold for seizures

Effect of hormones on seizure threshold PROGESTERONE Increases seizure threshold ESTROGEN Decreases

Effect of hormones on frequency of seizures PROGESTERONE Decreases frequency of seizures ESTROGEN Increases frequency of

Hormon sensitive seizures Catamenial epilepsy Defined as doubling of frequency of seizures in relation to menstrual period. In 1/3 of women with epilepsy there is substantial relationship between seizures and menstrual cycle.

Hormon sensitive seizures Catamenial epilepsy May occur in any type of seizures or epilepsy syndrome Three major patterns were described

Catamenial epilepsy Pattern 1 (most common type) Just before menstruation (3 days before – until day 3 of menstrual period) Possibly due to steep decline in progesterone

Catamenial epilepsy Pattern 2 Just before ovulation Approximately day 14 of menstrual period Possibly due to steep elevation in estrogen

Catamenial epilepsy Pattern 3 In second half of anovulatory menstrual cycle Anovulatory cycles (ovulation does not occur) are more frequent in women with epilepsy There is no elevation of progesterone

Catamenial Epilepsy High levels of estrogen Low levels of progesterone Fluid and electrolyte imbalance Psychological Stress Decrease in levels of AEDs 30-50% women with epilepsy experience menstrual cycle-related seizures Near menst. B/c progesterone w/drawal Near ovulation: surge of estrogen

Management of Catamenial Seizures Increase in doses of antiseizure medications during particular time of menstrual cycle Intermittent dosing with benzodiazepines Diamox-limited data to support benefit but low risk Supplementation with reproductive hormones Progesterone lozenges in second half of cycle Adverse effects -sedation, breast tenderness, depression, increased appetite and weight, breakthrough menstrual bleeding. Progesterone has been implicated in breast cancer, lipid elevations, and hypercoagulability. Suppression of menstrual cycle Oral contraceptive pills Medroxyprogesterone injections Natural progesterone suppositories or lozenges Synthetic IM No longer recommended for heart disease. Increase stroke, breast/uterine cancer

Catamenial epilepsy and menopause Perimenopause erratic hormone levels Menopause low estrogen and progesterone levels

Effect of AED’s on hormones seizures hormones

Birth control and epilepsy Some of the antiseizure medication decrease efficacy of birth control pills and other hormonal birth control This may result in birth control failure and unplanned pregnancy Liver enzyme inducing AED at least 6% failure rate per year for oral hormonal contraceptive pills Reduces concentration of biologically active steroid hormone Most commonly used oral contraceptives contain 35 mcg or less or estrogen Topamax at doses of 200 mg or more interact with oral contraceptives 31

Hormonal birth control and epilepsy Antiseizure medications that interfere with birth control: Carbamazepine (Tegretol) Phenobarbital Phenytoin (Dilantin) Primidone Rufinamide (Banzel) Onfi (Clobazam) Topiramate (Topamax) *higher doses Oxcarbazepine (Trileptal) *higher doses Liver enzyme inducing AED at least 6% failure rate per year for oral hormonal contraceptive pills Reduces concentration of biologically active steroid hormone Most commonly used oral contraceptives contain 35 mcg or less or estrogen Topamax at doses of 200 mg or more interact with oral contraceptives

Hormonal birth control and epilepsy AED’s that have no influence on levels of steroids Gabapentin (Neurontin) Lamotrigine (Lamictal) Levetiracetam (Keppra) Tiagabine (Gabatril) Zonisamide (Zonegran) Pregabalin (Lyrica) Lacosamide (Vimpat)

Hormonal birth control and epilepsy Solutions: Using antiseizure medications that do not interact with birth control pills Using alternative birth control methods Using birth control pills with higher dose of estrogen (Pitfalls: No proof that higher dose of estrogen is sufficient to prevent pregnancy) Breakthrough bldg. May indicate contraception not completely effective

IUD (intrauterine device) Two types are available: Copper IUD Hormone releasing (Mirena – progesterone) – since the effect is based on local influence of hormone on uterus lining it is unlikely to be affected by AED’s

Effect of hormones on AED’s seizures AED’s

Lamotrigine (Lamictal) Female hormones can decrease levels of Lamictal (lamotrigine) Pronounced effect in pregnancy Lamictal blood levels reduced by 50% in setting of OC use. Lamictal category C D in some areas/countries

Epilepsy and Pregnancy Over 90% of babies born to women with epilepsy will be healthy. Although low, birth defect rate is still about twice (4-7%) of rate in general population (1.6-3.2%).

Most common birth defects Neural tube defects Heart abnormalities Orofacial clefts Source: CDC

Prenatal Testing Testing that may be done to detect some of birth defects: Maternal serum alpha-fetoprotein at 15-22 weeks of gestation Level II ultrasound (structural) at 16-20 weeks of gestation Amniocentesis at 15-20 weeks of pregnancy

Why Prenatal Testing? Some birth defects require special attention during pregnancy or during delivery Some birth defects may require surgery immediately after delivery or even before delivery

Some other health problems that are more frequent: Low birth weight/reduced growth potential Neurodevelopmental problems Higher risk for epilepsy Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed. Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 42

Pregnancy Risk is increased by: Seizures (especially convulsive seizures) Antiseizure medications Genetic predisposition? (mothers who had babies with birth defect have higher risk in subsequent pregnancies) Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed. Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 43

Seizures in Pregnancy Women who have better control of seizures prior to pregnancy (9 months) usually have fewer seizures during pregnancy. Repetitive convulsions are associated with: Cognitive problems Small for gestational age Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed. Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 44

Seizures in Pregnancy Approximately 35% of women have increase in seizure frequency Reasons for increase in seizures Noncompliance Nausea/vomiting Pharmacokinetic changes Sleep deprivation

Seizures in Pregnancy Reasons for increase in seizures Noncompliance Nausea/vomiting Pharmacokinetic changes Sleep deprivation

AED’s during pregnancy Levels of AED’s drop in second trimester due to: Increase in drug clearance Increase in maternal plasma volume Decreased protein binding Frequent testing (monthly) and adjustment in dose of medication may be necessary

AED’s in pregnancy Risk increased with: Polypharmacy (two or more AED’s) Higher levels of medications Specific AED’s

Not all AED’s are the same Prevalence of Malformations lamotrigine (Lamictal®) 2.0% (1.4 to 2.8%) carbamazepine (Tegretol®) 3.0% (2.1 to 4.2%) phenytoin (Dilantin®) 2.9% (1.5 to 5.0%) levetiracetam (Keppra®) 2.4% (1.2 to 4.3%) topiramate (Topamax®) 4.2% (2.4 to 6.8%) valproate (Depakote®) 9.3% (6.4 to 13.0%) phenobarbital (Luminal®) 5.5% (2.8 to 9.7%) oxcarbazepine (Trileptal®) 2.2% (0.6 to 5.5%) gabapentin (Neurontin®) 0.7% (0.02 to 3.8%) zonisamide (Zonegran®) 0% (0.0 to 3.3%) clonazepam (Klonopin) 3.1% (0.4 to 10.8%) Unexposed 1.1% 0.37 to 2.6% NorthAmerican pregnancy registry spring 2012

Not all AED’s are the same Depakote (valproic acid) Consistently associated with high risk (5-fold higher) - birth defects - neurodevelopmental abnormalities (learning disability, autistic spectrum disorder, ADD/ADHD) Topamax(topiramate) - Increased risk for facial clefts (10-fold higher)

Epilepsy & Pregnancy AED National Pregnancy Registry Tracks use of AEDs and pregnancy outcomes All information confidential Can greatly improve our knowledge

Folic acid Folic deficiency is associated with increased risk of neural tube defects. Folic acid should be initiated before conception and continued throughout pregnancy AED’s that are linked to folic acid malabsorption/metabolism are Phenytoin (Dilantin) Carbamazepine (Tegretol) Barbiturates Valproate (Depakote)

Hemorrhagic disorder of neonate AED’s compete with vitamin K across the placenta Associated with in utero exposure to Carbamazepine (Tegretol) Barbiturates (phenobarbital and primidone) Phenytoin (Dilantin) Discuss with your Ob need for vitamin K in last month of pregnancy

Postpartum issues AED levels may rise – close monitoring of levels is still necessary Sleep deprivation and stress may increase frequency of seizures Child safety/lifestyle adaptation

Breastfeeding Benefits of breastfeeding are felt to outweigh potential risk of continued exposure of neonate and infant to AEDs (AAN and AAP) Protein bound drugs have low concentrations in breast milk Observe breastfeeding infant for irritability, poor sleep patterns, or inadequate weight gain Dilantin, gabitril, depakote extensively protein bound—low concentrations in breast milk Tegretol, phenobarb, lamictal, topamax, zonegran low-mod protein blinding—low-mod breast milk Neuronin and keppra no protein binding equal amounts in blood and milk

Epilepsy & Bone health Altered bone density due to AED’s is associated with: Phenytoin (dilantin) Carbamazepine (tegretol) Barbiturates Valproate (depakote)

Epilepsy & Bone health Prevention and therapy >6months on AEDs - exercise, balanced diet, stop smoking, moderate alcohol, moderate caffeine - calcium and vitamin D supplements - measure Ca, ALP, 25-hydroxy vit D yearly Baseline bone density scan - Referral to endocrinologist if osteopenia/osteoporosis is diagnosed

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