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

Epilepsy in Women 1 2 3 4 5 6 Hormonal contraception Menstrual cycle regularity 3 Fertility and ovulatory function 4 Pregnancy/breastfeeding 5 Sexuality 6 Bone health

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

Video EEG Monitoring

What are some of the AEDs that are currently available? First Generation AEDs Second Generation AEDs Carbamazepine (Carbatrol®, Carbatrol® XR, Tegretol®, Tegretol XR®) Felbamate (Felbatol®) Gabapentin (Neurontin®) Clonazepam (Klonopin®) Lacosamide (Vimpat®) Ethosuximide (Zarontin®) Lamotrigine (Lamictal®) Lorazepam (Ativan®) Levetiracetam (Keppra®, Keppra® XR) Phenobarbital (Luminal®) Oxcarbazepine (Trileptal®) Phenytoin (Dilantin®, Phenytek®) Pregabalin (Lyrica®) Primidone (Mysoline®) Rufinamide (Banzel®) Valproate (Depakote®, Depakene®) Tiagabine (Gabitril®) Topiramate (Topamax®) Zonisamide (Zonegran®) Key: Generic (Brand Names)

Treatment Goals for Epilepsy* Newly Diagnosed Refractory Epilepsy AED Trial 1 Monotherapy Video EEG VNS Therapy AEDs (Polytherapy) Ketogenic Diet AED Trial 2 Monotherapy or Polytherapy Epilepsy Surgery Goal of this slide is to distinguish the treatment goals for patients with refractory epilepsy versus newly diagnosed/surgical candidates. Seizure freedom is not the likely outcome and, therefore, other quality of life enhancing factors play more of role. For patients still having seizures, factors other than seizure frequency are more predictive of improved quality of life Depression Mood Adverse AED side effects 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.

Considerations in Epilepsy Management Underlying Pathology Age and Gender Syndrome vs Seizure Type Comorbidities Seizure Frequency Medication Side Effects

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 2001 Novartis Core T3 Martha J. Morrell M.D. Liver Gonads Estrogen Progesterone Testosterone

Sex Steroid Hormones and Epilepsy Progesterone may be an anticonvulsant Increases inhibition at GABAA receptor Attenuates excitation of glutamate in hippocampus Alters mRNA for GAD and increases GABA synthesis Estrogen may be a proconvulsant Reduces inhibition at GABAA receptor Alters mRNA for GAD and inhibits GABA synthesis GABA = -aminobutyric acid; mRNA = messenger ribonucleic acid; GAD = glutamic acid decarboxylase. Morrell MJ. Neurology. 1999;53(suppl 1):S42-S48. Woolley CS, Schwartzkroin PA. Epilepsia. 1998;39(suppl 8):S2-S8.

Reproductive Problems and AEDs Associated with some AEDs Polycystic ovaries Mixed reports Sex hormone level alterations Yes Menstrual cycle abnormalities Anovulatory cycles Fertility

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) 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. Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

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

Evaluation of Ovulatory Failure Predictors 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 Morrell M, et al. Ann Neurol. 2002;52(6):704-711.

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

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

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

Catamenial Seizures 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) 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.

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

PREGNANCY & EPILEPSY 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

Pregnancy Complications in Women With Epilepsy Eclampsia1 Increased rate of obstetric intervention (such as C-section)1 Increased birth asphyxia2 Neonatal hemorrhage3 Increased perinatal mortality2,4,5 Yerby MS, et al. Epilepsia. 1985;26:631-635. Frederick J. Br Med J. 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.

Major Malformations Associated with Commonly Used AEDs Drug Phenytoin Phenobarbital Valproic Acid Carbamazepine Cardiac defects Yes Orofacial clefting GU defects NT defects Dysmorphic syndrome GU=genitourinary; NT=neural tube

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

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

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

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

Folate and Neural Tube Defect 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) Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835

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 NTD

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

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

Role of Pregnancy Registries To facilitate monitoring fetal outcomes of pregnant women1 Systematic epidemiology study2 Collection and assessment of postmarketing data on potential adverse health effects to the mother, fetus, or infant caused by exposure to a drug or other biological agent during pregnancy2 Provides information that can be included in product labeling2 Can assess suspected or unknown risks2 1Lamotrigine [product information]. Research Triangle Park, NC: GlaxoSmithKline, 2003. 2FDA Guidance for Industry: Establishing Pregnancy Registries. Draft Guidance. http://www.fda.gov/cber/gdlns/pregnancy.pdf. Accessed June 27, 2002.

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.

Effects of AEDs on Body Weight Gain Neutral Loss Valproate Lamotrigine Topiramate Gabapentin Levetiracetam Zonisamide Carbamazepin Phenytoin Felbamate Pregabaline Lacosamide

Manifestations of Bone Disease 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 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.

Epilepsy at Menopause Perimenopause Menopause Fluctuations in ovarian steroid levels may exacerbate or diminish seizuresa,b Menopause Seizures may improveb Improvement most likely in those with catamenial patternb HRT with menopause may worsen seizuresb HRT= hormone replacement therapy aAbbasi F, et al. Epilepsia. 1999;40(2):205-210. bHarden CL, et al. Epilepsia. 1999;40(10):1402-1407.

Dimensions of Refractory Epilepsy Intractable seizures Excessive drug burden Neurobio- chemical changes Unsatisfactory quality of life Restricted lifestyle Dependent behavior Psychosocial dysfunction Cognitive decline Increased mortality Overall quality of life is a fundamental measure of successful treatment in patients with epilepsy Dimensions of Pharmacoresistant Epilepsy Refractory epilepsy can be classified as a condition with multi-faceted dimensions that affect a patient’s quality of life. Intractable seizures are only 1 dimension of refractory epilepsy affecting patients, including cognitive decline, dependent behavior, psychosocial dysfunction, increased mortality, excessive drug burden, and neurobiochemical changes.1 [Kwan and Brodie 2002, p 77, abstract, lines 1-3, p 78, Table 1; p 77, col 2, para 1, lines 16-19] Reference 1. Kwan P and Brodie MJ. Seizure. 2002;11:78. Kwan P and Brodie MJ. Seizure. 2002;11:78.