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Epilepsy Across the Reproductive Y ears

Epilepsy Across the Reproductive Y ears. Blanca Vazquez, MD Director of Clinical Trials Director of International Program NYU Epilepsy Center NYU Medical Center New York, NY. Epilepsy in Women. Epilepsy – What Can We Do?. Diagnosis. therapy. History Neuroimaging MRI is mainstay

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Epilepsy Across the Reproductive Y ears

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  1. Epilepsy Across the Reproductive Years Blanca Vazquez, MD Director of Clinical Trials Director of International Program NYU Epilepsy Center NYU Medical Center New York, NY

  2. Epilepsy in Women

  3. Epilepsy – What Can We Do? Diagnosis therapy • History • Neuroimaging • MRI is mainstay • Electrophysiology • EEG is mainstay • High density EEG • Magnetoencephalography • Intracranial EEG • “Functional” Imaging • fMRI – BOLD changes • SPECT – perfusion • PET – glucose metabolism or other ligands • Cognitive Assessments • Neuropsychological testing • Wada procedure • AEDs • Anti-epileptic drugs • Neuromodulation • Vagus Nerve Stimulator • Deep Brain Stimulation • Reactive Neurostimulation • Immunomodulation • Steroids • Intravenous Immunoglobulin (IVIG) • ACTH (which is probably more than just immune) • Plasma Exchange (PLEX) • Epilepsy Surgery • Diet

  4. Video EEG Monitoring

  5. What are some of the AEDs that are currently available? Key: Generic (Brand Names)

  6. Treatment Goals for Epilepsy* Newly Diagnosed Refractory Epilepsy AED Trial 1 Monotherapy Video EEG VNS Therapy AEDs (Polytherapy) Ketogenic Diet AED Trial 2 Monotherapyor Polytherapy Epilepsy Surgery Treatment Goal Maximize QoL Long-term seizure control Minimize AED side effects Maximize adherence Treatment Goal Seizure freedom * Kwan P, et al. Epilepsia 2009; doi: 10.1111/j.1528-1167.2009.02397.x Gilliam F. Neurology 2002;58:s9-s19. Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008. Faught E, et al. Epilepsia 2009;50(3):501-509.

  7. Considerations in Epilepsy Management Underlying Pathology Age andGender Syndrome vs Seizure Type Seizure Frequency Comorbidities Medication Side Effects

  8. Reproductive Endocrine Axis Disturbances • Hypothalamus • Altered secretion of GnRH • Pituitary • Altered LH release • Gonadal • Altered steroid metabolism/binding GnRH=gonadotropin-releasing hormone; LH=luteinizing hormone; FSH=follicle-stimulating hormone Hypothalamus Amygdala GnRH Pituitary LH/FSH Liver Gonads Estrogen Progesterone Testosterone

  9. Reproductive Problems and AEDs

  10. 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.

  11. Clinical Features of PCOSHyperandrogenism • Symptoms may include: • Hirsutism • Acne • Male pattern balding and/or male distribution of body hair Hirsutism Acne Lobo RA, et al. Ann Intern Med. 2000;132:989-993.

  12. Predictors included: Primary generalized epilepsy Use of valproate ever or within the past 3 years High free testosterone Fewer numbers of LH pulses Valproate use in primary generalized epilepsy (19/35) was associated with: Relatively increased free testosterone Anovulatory cycles Evaluation of Ovulatory FailurePredictors Morrell M, et al. Ann Neurol. 2002;52(6):704-711.

  13. 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 AEDs and Contraception

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

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

  16. Changes in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b 30%-50% have epileptic patterns that correspond to their menstrual cycleb,c Vulnerability to seizures is highest just before and during flow and at ovulation (relatively high estrogen and low progesterone levels) Catamenial Seizures aHerzog AG, et al. Epilepsia. 1997;38:1082-1088. bCramer JA, Jones EE. Epilepsia. 1991;32(suppl 6)S19-S26. cMorrell MJ. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:179-187.

  17. 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 Treatment of Catamenial Epilepsy

  18. 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 PREGNANCY & EPILEPSYClinical Dilemma

  19. Eclampsia1 Increased rate of obstetric intervention (such as C-section)1 Increased birth asphyxia2 Neonatal hemorrhage3 Increased perinatal mortality2,4,5 Pregnancy Complications in Women With Epilepsy • Yerby MS, et al. Epilepsia. 1985;26:631-635. • Frederick J. Br MedJ. 1973;2:442-448. • Kohler HG. Lancet. 1966;1:267. • Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:245-248. • Waters CH, et al. Arch Neurol. 1994;51:250-253.

  20. Major Malformations Associated with Commonly Used AEDs GU=genitourinary; NT=neural tube

  21. Dysmorphism ~10% Dysmorphic features (mid-face) Hypertelorism Upturned nasal tip Flat nasal bridge Long philtrum Full lips Distal digital hypoplasia Congenital Anomalies Associated with Commonly Used AEDs

  22. 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 Fetal Anticonvulsant Syndrome

  23. Polytherapy High AED plasma concentrations Mechanisms Toxic metabolites Folic acid deficiency Epoxide metabolites Free-radical formation Risk Factors for Major Malformations

  24. Verify need for AED Diagnosis Surgical lesions Remission Determine “best” AED for individual patient Preconception teaching Preconception supplementation Managing Pregnancy and Epilepsy

  25. Numerous studies of vitamin supplementation Pivotal study1 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 NTDs in vitamin supplemented group (0 vs 6) Folate and Neural Tube Defect Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835

  26. 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 NTD Folate Supplementation

  27. 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 What Is the Safest AED in Pregnancy?

  28. Assess risks and benefits for individual patients AED concentration in breast milk related to protein binding1 PB and other sedating AEDs may cause sedation or poor feeding1 American Academy of Neurology encourages breastfeeding with close observation of baby2 Breastfeeding and AEDs • Zahn CA, et al. Neurology. 1998;51:949-956. • Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.

  29. 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 Effects of AEDs on Body Weight Biton V. CNS Drugs. 2003;17(11):781-791.

  30. Effects of AEDs on Body Weight

  31. Osteopenia/Osteoporosis AEDs reported as a secondary cause Increased rates at multiple sites including hip and lumbar spine Osteomalacia Increased osteoid or unmineralized bone Most studies in institutionalized persons Confounded by poor diet, inadequate sunlight, limited exercise Manifestations of Bone Disease Andress DL, et al. Arch Neurol. 2002;59(5):781-786. Farhat G,et al. Neurology. 2002;58(9):1348-1353. Pack AM, et al. Epilepsy Behav. 2003;4(2):169-174. Sato Y, et al. Neurology. 2001;57(3):445-459. Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):631-637.

  32. Intractable seizures Excessive drug burden Neurobio-chemicalchanges Cognitivedecline Unsatisfactoryquality of life Increasedmortality Psychosocialdysfunction Restrictedlifestyle Dependentbehavior Dimensions of Refractory Epilepsy Overall quality of life is a fundamental measure of successful treatment in patients with epilepsy Kwan P and Brodie MJ. Seizure. 2002;11:78.

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