This document summarizes special considerations for women with epilepsy across the reproductive years, including effects on sexuality, mood, menstruation, fertility, bone health, pregnancy, breastfeeding, and menopause. It discusses how epilepsy and antiepileptic drug use can impact these areas through mechanisms like hormonal changes, drug interactions, teratogenic risks, and bone loss. Management involves counseling, supplementation, contraception guidance, monitoring for side effects, and registry participation for pregnant patients.

1. Women and Epilepsy Across the Reproductive Years Blanca Vazquez,MD Director of Clinical Trials Comprehensive Epilepsy program NYU Medical Center

2. Special Considerations in woman With Epilepsy Sexuality Mood Menstrual cycle regularity Hormonal contraception Fertility Bone health Pregnancy/breastfeeding Morrell MJ. Epilepsia. 1996;37(suppl 6):S34-S44. Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.

3. Epilepsy and Sexuality

4. Psychosis -- Ictal, Interictal, Post-Ictal Anxiety Mood Disorders Behaviour/Personality NES AEDs’ Psychotropic Effects

5. Puberty Several primary generalized seizure syndromes often begin in teens and early 20’s Juvenile myoclonic epilepsy Juvenile absence epilepsy Levels of steroid hormones, specifically testosterone, increase during puberty Testosterone is converted to: Estrogen, which is proconvulsant 3  -androstanediol, which is anticonvulsant

6. 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.

7. 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

8. AEDs and Contraception High potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4 OCs 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

9. Contraception Choices for Women with Epilepsy Hormonal contraception Contraceptive pills Injectables and depots Patches Rings Barrier methods Intrauterine contraceptive devices (IUCDs) Surgical sterilization Natural methods

10. Family Planning for Women on Antiepileptic Drugs (AEDs): Interaction With Hormonal Contraception Possible Interaction No Interaction Carbamazepine Gabapentin Felbamate Oxcarbazepine* Levetiracetam Phenobarbital Tiagabine Phenytoin Valproate Topiramate* Lamotrigine Zonisamide *At higher dosage.

11. Catamenial Seizures Changes in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cycle a,b 30%-50% have epileptic patterns that correspond to their menstrual cycle b,c Vulnerability 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.

12. Seizure Frequency in Normal Cycle Average Number of Seizures Per Day Menstrual 0.3 0.4 0.5 0.6 Follicular Ovulatory Luteal * P <0.001 vs. ovulatory or luteal and ovulatory and luteal combined Number of seizures=1324 Number of cycles=98 * * Mean number of seizures/day Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

13. Treatment of Catamenial Epilepsy Difficult to control with AEDs Increasing doses of AEDs premenstrually may be beneficial Important to monitor serum levels to avoid under- or overdosing Acetozolamide of limited benefit Natural progesterone for women with regular menses

14. Effects of AEDs on Body Weight Weight change important consideration Leads to health hazards Impairs body image and self-esteem Leads to noncompliance Most data anecdotal Actual incidence and magnitude unknown Mechanisms unclear Biton V. CNS Drugs . 2003;17(11):781-791.

15. Effects of AEDs on Body Weight Gain Neutral Loss Valproate Lamotrigine Topiramate Gabapentin Levetiracetam Zonisamide Carbamazepine Phenytoin Felbamate Tiagabine

16. Retrospective Analysis Of Bone Density Retrospective analysis of bone density in 153 men and women with epilepsy treated with enzyme-inducing AEDs in an outpatient practice Density at femoral neck determined by DXA scan Pack AM, et al. Epilepsy Behav . 2003;4(2):169-174.

17. Possible Mechanisms Induction of cytochrome P450 enzyme system Impaired absorption of calcium Impaired bone resorption and formation Inhibition of response to parathyroid hormone (PTH) Hyperparathyroidism Vitamin K deficiency Calcitonin deficiency Feldcamp J, et al. Exp Clin Endocrinol Diabetes . 2000;108(1):37-43. Koch KH, et al. Epilepsia . 1972;13(6):829-834. Onodera K, et al. Life Sci. 2002;70(13):1533-1542. Valimaki MJ, et al. J Bone Miner Res . 1994;9(5):631-637. Vernillo AT, et al. Matrix. 1990;10(1):27-32. Weinstein RS, et al. J Clin Endocrinol Metab. 1984;58(6):1003-1009.

18. Conclusion PHT, CBZ, and VPA are associated with low calcium PHT is associated with increased bone turnover Vitamin D levels are normal suggesting that there are other mechanisms for AED-associated bone disease

19. Treatment of AED Associated Bone Disease Multiple therapies available for bone disease Calcium Vitamin D supplementation Bisphosphonates Hormone replacement Calcitonin Few studies evaluating the effect of therapies in AED-associated bone disease

20. Calcium RDA Adolescents/Young Adults 11-24 years 1,200-1,500 mg calcium Men 25-65 years 1,000 Over 65 years 1,500 Women 25-50 years 1,000 Over 50 years (postmenopausal) On estrogens 1,000 Not on estrogens 1,500 Over 65 years 1,500 Pregnant and nursing 1,200-1,500

21. Fetal Anticonvulsant Syndrome Not drug specific Features modify as child grows Can be seen with newer as well as older AEDs Lamotrigine, topiramate Clinically indistinguishable from fetal alcohol syndrome

22. Clinical Dilemma Drugs generally contraindicated in pregnancy Women with epilepsy are unable to stop using AEDs Increases risk of seizures Injury Miscarriage Developmental delay Loss of job or driving privileges Risk of cognitive decline Complications of pregnancy and labor Risk of congenital malformations may be increased by AED therapy

23. Pregnancy Impact on Maternal Seizures Etiology: declining AED concentration Decreased protein binding Increased clearance Increased plasma volume Increased renal blood flow All AEDs decline The more weakly bound, the greater the decline 50% of women with epilepsy have seizures when AED levels fall below therapeutic range Krishnamurthy KB, et al. Epilepsia. 2002;43(suppl 7):232-233.

24. Folate and Neural Tube Defect Numerous studies of vitamin supplementation Pivotal study 1 Supplementation began at least 28 days before conception and continued at least until second missed menses Fewer malformations in vitamin supplemented group (13.3 vs. 22.9 per 1000) Fewer NT defects in vitamin supplemented group (0 vs. 6) Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835.

25. Folate Supplementation Centers for Disease Control and Prevention recommends preconceptional folic acid 0.4 mg/d for all women 4.0 mg/d for women with a history of previous NT defect

26. North American AED and Pregnancy Registry Toll-free number: 888-233-2334 Established in 1996 Higher than expected risk of malformations with phenobarbital and valproate Prospective surveillance of AED in pregnancy

27. 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 advantage Choose the best AED for the seizures

28. 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 Zahn CA, et al. Neurology. 1998;51:949-956. Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.

29. Menopausal Women Epilepsy Pattern Increase Decrease No change Catamenial pattern Percent of women *Significantly associated with a decrease in seizures ( P =0.013) Harden CL, et al. Epilepsia. 1999;40(10):1402-1407. *

30. AEDs and Menopause Fluctuation in seizure frequency and severity may necessitate adjustments to dosing No statistically significant association between premature ovulatory failure (early menopause) and AEDs

31. Women Treated with AEDs Conclusion Counsel regarding symptoms and signs of reproductive dysfunction Monitor bone health If patient develops reproductive health dysfunction, bone disease, or excessive weight gain, consider changing to alternate AED Provide prophylactic folic acid, calcium, and vitamin D supplementation Cooperate with pregnancy registry efforts