Blanca Vazquez, MD

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Women's Issues in Epilepsy: Across the Reproductiv

Women's Issues in Epilepsy: Across the Reproductiv

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  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • PCOS: National Institutes of Health Diagnostic Criteria. In the United States, PCOS is defined with diagnostic criteria developed by the National Institutes of Health (NIH) as an ovulatory dysfunction with clinical evidence of hyperandrogenism and/or hyperandrogenemia. 3,4 For the condition to be diagnosed, related disorders, such as those that affect adrenal or thyroid function (eg, androgen-secreting neoplasms), must be excluded. 1-3 The diagnosis of PCOS is generally made through a combination of clinical, ultrasonographic, and biochemical criteria. 2 This definition excludes the finding of polycystic ovaries (PCO), multifollicular ovaries, or hyperandrogenism in isolation. Outside of the United States, the diagnosis is usually based on ovarian morphology, and affected women may be further subgrouped by ovulatory status. Because the anovulatory subgroup may demonstrate more profound insulin resistance, differences in diagnostic criteria may explain many of the divergent findings between US and European studies of patients with this disorder. 3 References 1. Bauer J, et al. Epilepsy Res . 2000;41:163-167. 2. Chappell KA, et al. Ann Pharmacother . 1999;33:1211-1216. 3. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 4. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Clinical Features of PCOS. Hyperandrogenism. Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair. 1 Reference 1. Lobo RA, et al. Ann Intern Med . 2000;132:989-993. Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years
  • 2001 Novartis Core T3 Martha J. Morrell M.D. Blanca Vazquez, MD Women's Issues in Epilepsy: Across the Reproductive Years

Transcript

  • 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