Slide 1. Slide 2. Slide 3. Women are different than males. Viva la Difference! Patricia E Penovich MD Minnesota Epilepsy Group PA July 17, 2014

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1 Slide 1 Patricia E Penovich MD Minnesota Epilepsy Group PA July 17, 2014 Slide 2 Slide 3 Women are different than males Viva la Difference!

2 Serum Hormone Levels Serum Hormone Levels Slide 4 E2 P Estradiol mcg/ml Progesterone ng/ml Normal Cycle C2 C Day of Cycle With permission from Herzog Slide 5 E2 P Estradiol µg/ml Progesterone ng/ml Inadequate Luteal Phase Cycle C Day of Cycle With permission from Herzog, Slide women with partial seizures randomized, compared 3 month baseline to 3 months treatment 200 mg progesterone/placebo lozenges Days mg tid Days mg tid Days mg tid Measurement AED & progesterone levels mid luteal phase each cycle Criteria for catamenial: 1.69 C1, 1.83 C2, 1.62 C3 Herzog et al. Neurology 2012

3 Slide 7 Progesterone trial 1 Used cyclic natural progesterone vs placebo comparing baseline and treatment for 3 cycles No difference in combined groups for overall seizure frequency compared to placebo If catamenial seizure frequency was 3 from baseline, their was significance Herzog AG. Neurology Slide 8 Anovulatory Cycles A cycle with or without menses, irregular cycle intervals Natural menarche, menopause Metabolic induced - PCOS Slide 9 68 patients with epilepsy and 51 controls 35 VPA, 17 carbamazepine, 17 oxcarbazepine 61% off meds NS for patient off med and controls Patients on meds Higher male hormone levels (testosterone, androstendione) PCOS On meds 38%: on VPA 63%, other meds 25% Off meds 6%, controls 11% Mikkonen, et al

4 Slide 10 Gynecologic syndrome Phenotype: hirsutism, obesity, acne Infertility Endocrine abnormalities: abnormal LH, increased androgens Menstrual irregularities/anovulatory cycles Insulin resistance Frequency in general population 5% Frequency in WWE=10-20% Long-term health consequences LH=luteinizing hormone Morrell Slide 11 Weight Gain Weight Loss VPA (40%-50%) FBM (2%-75%) LTG Weight Neutral CBZ (32%) TPM (10%-20%) TGB (?) GBP (15%-20%) PGB ZNS LAC VPA=valproate; CBZ=carbamazepine; GBP=gabapentin; FBM=felbamate; TPM=topiramate; ZNS=zonisamide; LTG=lamotrigine; TGB=tiagabine; LAC=lacosamide; PGB=pregabalin Ketter, et al. 1999; Gidal, et al Slide 12 Sexual dysfunction is present in 14%-50% of women with epilepsy Deficits in libido Less interest Increased anxiety Deficits in arousal Dyspareunia Vaginismus Lack of lubrication Anorgasmia Morrell. 1997; Morrell. 2005; Morrell, et al

5 Slide 13 Enzyme-inducing drugs induce the synthesis of sex hormone binding globulin (SHBG) reducing the peripheral sex steroid hormones 117 patients (77 male, 40 female) + controls Monotherapy CBZ, LTG, LEV for >6 months Arizona Sexual Experience Scale (ASEX) Results Women experienced significantly more sexual difficulties than men Patients on CBZ experienced more difficulties than those on LTG, significant only for women Svalheim, et al Slide 14 Estrogen Control of bleeding Need mcg Progesterone Prevents ovulation and controls uterine environment and implantation Need 1 mg Hepatic enzyme inducing AEDs result in about 50-60% decrease in levels of serum hormones Slide 15 Oral contraceptive pills Combined or progestin only Nonsurgical preparations Patch, vaginal ring Surgical preparations Progesterone implant or intrauterine device Injections progestogen injection All hormonal agents affected by inducers Reddy

6 Slide 16 Decreased Hormone Concentration CBZ CLO ESLI OXC + PB PHT PRM TPM No Effect or Increased Hormone Concentration ETX PGB FBM RUF GBP TGB LCM VGB LEV VPA LTG # ZNS # Level dec by 50% with OCP use. + Dose >1200 mg. Doses >200 mg Slide 17 Birth rates reduced by 1/3 to 2/3 compared to siblings Marriage rates for women with epilepsy now equivalent to those of women without epilepsy Birth rate lower in men and women on CBZ, OXC, VPA compared to reference cohort in Finnish database Morrell. 1998; Schupf, et al Artama, et al Slide 18 Study Vinkainen Borthen MONEAD type Retro, registry Pro+ retro, Control Gestation. Delivery premie C sect Preg. Cx Infant eclampsia, bp SGA, Apgar, HC Viinikainen, et al. 2006; Borthen. 2009; 2010.

7 Slide 19 Malformation Significantly compromises health and requires surgical correction 2%-3% in general population 4%-8% in infants of women with epilepsy Anomaly Definition: a minor deviation from normal appearance 5%-10% in general population ~15% of infants of women with epilepsy Bruni Slide 20 Slide 21 embryonic period (in weeks) fetal period (in weeks) full term Period of dividing brain zygote, implantation Indicates common site of action of teratogen CNS & bilaminar embryo eye ear palate ear heart eye heart Usually not susceptible to teratogens prenatal death arm teeth leg external genitalia central nervous system heart arms eyes legs teeth palate external genitalia ear major morphological abnormalities physiological defects & morphological abnormalities

8 Slide 22 Dietary supplementation recommended 0.4 mg/d for general population beginning at age of menses (child-bearing age) Inducing AEDs 2-5 mg/d VPA 4-5 mg/d Slide 23 Polytherapy High treatment dose Folic acid deficiency Family history of birth defects AED selection Morrell. 1997; Sander, et al. 1992; Dansky, et al Slide registries reported in English between with reports of >100 patients Mean age: 29.1 years On monotherapy: 57% Rates of malformation: >2.5 times healthy population Types of malformations: Cardiovascular > musculoskeletal > ear, neck, face Congenital malformation rate: 7.08/100 pregnancies Monotherapy 5.1% Polytherapy 8.5% Meador, et al

9 Slide 25 Category C CLO ESCLI FBM GBP LAC LEV LTG OXC PGB RUF TGB VGB ZNS Adverse effect in animal studies; no human studies Risk/benefit analysis Category D VPA CBZ PHT TPM PB Positive human fetal risk Risk/benefit analysis June 2011: Cognitive delay in VPA infants. Cleft lip/palate in topiramate exposure. Slide 26 Analysis utilizing the EUROCAT database of 98,075 major malformations Almost 4 million births 14 countries, 19 registries, first trimester exposure Absolute Risk in Pop Relative Spina bifida 0.6 % 12-16x Other 2-7 ASD 0.5 Cleft palate 0.3 Hypospadias 0.7 Polydactyly 0.2 Craniosynostosis 0.1 ASD=atrial septal defect Jentink, et al Slide 27 Prospective surveillance of AED in pregnancy since enrolled; >1000 prospective monotherapy. Analysis of all monotherapies soon Higher than expected risk of malformations with phenobarbital 1 and valproate 2 Cleft lip/palate 5/684 with lamotrigine (7.3/1000 vs. 0.7/1000 in unexposed controls; RR=10.4). 3,4 All were on folate and were non-smokers. Not seen in any other registries 5 Women with epilepsy enroll by phone Toll-free: (see appendix) 1 Holmes, et al. 2001; 2 Wyszynski, et al. 2005; 3 Holmes. 2006; 4 Holmes. 2008; 5 Dolk, et al

10 Slide 28 AED Total Malf Enrolled Prevalence of Malf % 95% CI % lamotrigine carbamazepin e phenytoin leviteracetam topiramate valproate phenobarbital oxcarbazepin e gabapentin , zonisamide clonazepam Unexposed Slide 29 Control North American UK International LTG Lamotrigine Carbamazepine Valproate LTG + CBZ LTG + VPA LTG + nonvpa 3.0 na 1.9 CBZ + VPA www2.massgeneral.org/aed/winter2010; 2 Morrow. 2006; 3 Interim Report: The Lamotrigine Pregnancy Registry. GlaxoSmithKline Slide 30 VPA significantly decreased early development <age 2 1 VPA and polytherapy: children with extremely low or borderline full scale IQ on Wechsler, verbal comprehension and working memory with perceived perceptual reasoning and processing speed 2 VPA exposed showed decreased originality and decreased fluency 3 1 Bromley, et al. 2010; 2 Nadebaum. 2011; 3 McVearry

11 Slide 31 CBZ LTG PHT VPA N children Mean 6 yr IQ (95% CI) Verbal Index Nonverbal index General memory index ********Use if permission granted by Meador and NEAD study Slide 32 Meador et als by permission Slide , prospective enrollment prior to birth, testing ages 1, 3, 6 years 632 live births; 296 to women with epilepsy 7 of 10 children with autism spectrum disorder were exposed to AED in utero, 5/7 to VPA. Seven x higher than controls. N N, Autism % Controls No AED exposure 47 0 AED VPA VPA + LTG LTG CBZ PHT Bromley, et al. 2008; Dolk, et al

12 IUPC FHR Fetal Heart Rate (beats/min) Slide Time (min) Slide 35 Immediately before CPS During CPS Complex partial seizure (CPS) occurs Nei, et al Slide 36 Assess risks and benefits for individual patients Antiepileptic drug concentration in breast milk related to protein binding 1 Infant plasma levels most often very low 2 American Academy of Neurology encourages breast-feeding with close observation of baby 3 May prevent withdrawal syndrome in infant exposed to barbituates or benzos 4,5 1 Zahn, et al. 1998; 2 Tomson. 2005; 3 American Academy of Neurology, Quality Standards Subcommittee. 1998; 4 Chen, et al. 2010; 5 Rauchenzauner, et al

13 Slide 37 Unpredictable effect of MP on seizures Estrogen goes down Progesterone also goes down 30 + % worse; 30% no change; 30% better May be worse peri-menstrually for women with catamenial pattern 5 th decade of life is time of increasing frequency of seizures as well HRT replacement could worsen Onset MP earlier by as much as 10 years Slide 38 Sequelae fractures Increased risk in men, women, children 2.2X higher overall and 2.9 X if sz related Occur during sz and clumsiness 1 Evidence biopsy, DXA scan for BMD eval Factors:gait, MR, physical activity, length of AED tx 2 Mechanisms Impaired absorption Ca, Vit D Induction of P450 catabolism of vitamin D and increased estrogen metabolism 3 PB, PRM, PHT, CBZ VPA: increased resorption PTH=parathyroid hormone; PRM=primidone 1 Koppel BS Coppola G Pack AM Slide 39 No change in BMD using leviteracetam in new onset patients at one year 1 Switch from phenytoin to leviteracetam resulted in improved BMD and Vit D 2 Monotherapy: normal Vit D, Ca with LTG compared to CBZ, PHT, VPA 3 Vitamin D supplementation 4 Adult 4000 IU improved BMD Children IU improved BMD 1 Koo DL Phabpjal K Pack AM Mikati M 2006.