UMA MENON, MD, MBA (HEALTHCARE) OCHSNER COMPREHENSIVE EPILEPSY CENTER MARCH, 18, 2017

Transcription

1 UMA MENON, MD, MBA (HEALTHCARE) OCHSNER COMPREHENSIVE EPILEPSY CENTER MARCH, 18, 2017

2 DISCLOSURES NONE Borrowed lots of images from Google

3 OUTLINE Background Gender and epilepsy Hormones and epilepsy Contraception Pregnancy and outcomes Lactation Menopause Other issues in women

4 BACKGROUND

5 COMMONEST NEUROLOGICAL DISORDERS Headache Stroke Alzheimer s disease EPILEPSY

6 GLOBAL BURDEN OF DISEASE A meta-analysis of 65 studies in 2010 found that the median prevalence of lifetime epilepsy (LTE) globally was: in developed (high-income) countries: 5.8 per 1,000 population in resource-poor (lower-income) countries: 10.3 per 1,000 in urban areas 15.4 per 1,000 in rural areas Ngugi AK, Bottomley C, Kleinschmidt I, et al. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 2010;51:

7 IOM REPORT 2010: EPILEPSY ACROSS THE SPECTRUM million people in the US (based on 2012 census: ~ 313 million) and > 65 million world-wide have epilepsy 150,000 new cases diagnosed annually in the US 1 in 26 in the US will develop epilepsy at some point in their lifetime Risk of death increases with epilepsy 10 years of life lost with a known cause of epilepsy 2 years of life lost with epilepsy of unknown cause The annual (2004) direct medical care cost of epilepsy in the US was $9.6 Billion not including the indirect costs (Newer estimate: 2014: $ 15B) 2016 estimated population is ~ 322 million, according to US Census Bureau

8 GENDER & EPILEPSY

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10 IS THERE A GENDER DIFFERENCE IN EPILEPSY? Certain types of epilepsies are more common in women: IGE (Idiopathic Generalized Epilepsy) Photosensitive epilepsy Mutations in X chromosome (ex: Rett syndrome) Certain types of abnormalities are more common in men (associated with epilepsy): focal cortical dysplasias perinodular heterotopias Ref: McHugh and Delanty, 2008; Taylor et al, 2007; Oritz-Gonzalez at al, 2013, Sisodiya et al, 1999; Galanopoulou, 2008a,b; Briggs and Galanopoulou, 2011; Akman et al., 2014

11 GENDER DIFFERENCE IN THE BRAIN There is some data to suggest that there may be an inherent difference in the neurons of several areas in the cortex of the female versus the male Possible cause for the difference: differences in the organizational phase of neurodevelopment (role of BDNF and GABAergic signaling, role of neonatal androgens, corticosterones)

12 HORMONES & THE BRAIN Hormonal effects on the brain are complex: have more than one biological effect the effects of estradiol varies during development, adulthood, and aging. it may have direct and indirect effects affecting diverse targets, which may result in varied effects. Implications: a drug that acts on GABA A receptors may always have effects in males, but may not be as consistent in women because at the end of the luteal phase of the menstrual cycle, there are changes in GABA A receptor subunits.

13 WOMEN WITH EPILEPSY (WWE)

14 WWE Marriage rate is lower in WWE ~ one half million WWE are of child-bearing age (based on US population and prevalence of epilepsy) Childbearing rates are per 1000 lower - in WWE (compared with 67.6 per 1000 in women without epilepsy) [Childbirth rates are lower in both men and women with epilepsy] According to 2010 US Census population: million were female (50.8 percent); million were male (49.2 percent); G. Luef / Epilepsy & Behavior 15 (2009) 78 82

15 WWE: HORMONES & EPILEPSY

16 CATAMENIAL EPILEPSY Defined as an increase in seizures around the time of the menses, either just before or during the first few days of menstruation Occur in about 10% of WWE Ovulatory cycles may have 2 seizure peaks: Peri-menstrually and Mid-cycle Anovulation -> increased seizures, in the 2 nd ½ of the cycle

17 CATAMENIAL EPILEPSY Estrogen Excitatory Progesterone Inhibitory Changes in hormonal levels: Directly affect seizure threshold Effects related to AEDs Ref: Foldvary

18 WWE: FERTILITY ISSUES

19 SEXUAL DYSFUNCTION few studies; small series 20 30% of WWE (IGE as well as LRE) are more likely to suffer from sexual dysfunction; more frequent with right TLE (in both men and women) both the desire and arousal phases may be inhibited AEDs (older, enzyme-inducers) more likely to contribute to dysfn due to influence on the hypothalamic-pituitary-gonadal axis -> changes in hormone levels, influencing sexual behavior Herzog et al, 1986; Daniele et al, 1997; Baird et al, 2003

20 REPRODUCTIVE DYSFUNCTION Disorders include: polycystic ovary syndrome hypothalamic amenorrhea functional hyperprolactinemia premature menopause May be due to epilepsy itself or related to AEDs can target a number of substrates to impact hormone levels: limbic system, hypothalamus, pituitary, peripheral endocrine glands, liver, and adipose tissue Herzog, 1989; Herzog et al, 2003

21 REPRODUCTIVE DYSFUNCTION There is decreased fertility among women with epilepsy (level II) The true prevalence of PCOS among WWE (even if they are not taking AEDs - VPA) may be higher than in women without epilepsy (level II) Anovulation is associated with poorer seizure control > one-third of cycles in women with localization-related epilepsy (LRE) are anovulatory (compared to 8 10% in controls) Anovulatory cycles are also common in IGE (possibly more than LRE conflicting evidence) Cummings et al, 1995; Herzog and Friedman, 2002; Morrell et al, 2002; Lofgren et al, 2007

22 CONTRACEPTION & AEDs The bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (COCs) pose potential risks of unintended pregnancy, as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased risk of contraceptive failure Sabers A. Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure 2008;17:141 4

23 CONTRACEPTION FOR WWE Individualized plan best strategy LARC (long-acting reversible contraceptives) preferred IUD ideal other options: Progestin implant Depot medroxyprogesterone acetate Sterilization - permanent Morrell MJ. Ann Neurol 2008; 64:

24 WWE: CONCEPTION, PREGNANCY & OUTCOMES

25 PRE-CONCEPTION COUNSELING Should be available to all WWE Discussion should include: genetics, teratogenicity of AEDs, supplementation, labor, breast-feeding, childcare, overall impact on seizures Genetic predisposition: low risk in majority IGE: the risk of a WWE having an affected child is ~ 9 12% In general, the risk of one parent with epilepsy -> child with epilepsy is % (x 2-fold than general population) Some studies show mothers > fathers pass on epilepsy absolute risk of % for children born to WWE Winawar and Shinnar, 2005

26 PRE-PREGNANCY Pre-conception Folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs Supplementing WWE with at least 0.4mg Folic acid before they become pregnant maybe considered (level C) There is insufficient evidence to support or refute a benefit of prenatal vitamin K supplementation for reducing the risk of hemorrhagic complications in the newborns of WWE (Level U) AAN Practice parameter 2009

27 PRE-PREGNANCY SEIZURE CONTROL Seizure freedom for at least 9 months prior pregnancy is probably associated with a high likelihood (84 92%) of being seizure-free during pregnancy (2 Class II studies) Therefore seizure freedom is paramount in all WWE AED changes should be made and completed, well before conception

28 PREGNANCY 8 46 % of WWE have an increase in seizure frequency during pregnancy several factors may be responsible: (hyper)emesis -> low AED levels Inappropriate decrease in dose or discontinuation of AED Pregnancy-related fall in plasma conc: PHT, CBZ, PB, LTG Tomson et al, 1997

29 PREGNANCY & AEDs Goal: use of the lowest effective dose of the most appropriate AED Preferably mono-therapy

30 PREGNANCY, AEDs & TERATOGENECITY Risk of significant fetal malformation is: approximately 3% if one AED is taken (slightly above the background risk) up to 17 % if two or more AEDs are taken Most major malformations occur in the early stages of pregnancy, often before the woman knows she is pregnant Betts, Crawford, 1998; Nakane et al, 1980; Morrow et al, 2004; Vajda et al, 2004

31 CHOICE OF AEDs

32 AEDs TO AVOID: Valproate highest teratogenicity Topiramate Valproate + Lamotrigine combo Others: Carbamazepine, Phenytoin, Phenobarbital

33 NEAD: Neurodevelopmental Effects of Antiepileptic Drugs

34 NEAD FINDINGS: VPA Exposure in-utero = lower IQ in children (6-9 points lower than other AEDs -> persisted > 3 years) ** dose-dependent, but unclear safe dose Verbal > non-verbal scores (for all 4 AEDs studied) but persistent for VPA Thought to be related to impairment in cerebral lateralization (possibly through effects on apoptosis or alteration of neuronal physiology) at age 6 years, high doses of Valproate were negatively associated with verbal ability, non-verbal ability, memory, and executive function (not seen at age 6 yrs with the other AEDs assessed CBZ, LTG, PHT) Cognitive domains Children s Memory Scale (CMS), Behavior Rating Inventory of Executive Function (BRIEF), Developmental Neuropsychological Assessment (NEPSY), expressive one-word picture vocabulary test, and Developmental Test of Visual Motor Integration (DTVMI).

35 NEWER AEDs

36 LAMOTRIGINE LTG + COC -> low(er) LTG conc -> increased seizures LTG + progestin-only pill -> no effect on LTG levels LTG during pregnancy -> increased clearance of LTG - > increased seizures (therefore need higher doses/frequent adjustments) LTG after delivery -> high/toxic plasma levels (therefore, needs quick taper down to pre-pregnancy doses) Sabers et al, 2001; Sishu et al, 2006; Christensen et al, 2007; Ohman et al, 2007

37 LEVETIRACETAM Some data to show that serum concentrations of LEV decrease significantly (50% of baseline values) in the third trimester of pregnancy and increase rapidly after delivery Pennell et al, 2005; Tomson et al, 2007; Westin et al, 2007

38 OBSTETRIC CARE DURING PREGNANCY Best done in collaboration with Obstetrician in high-risk setting High-quality ultrasound scan at ~18 weeks to look for malformations Monitor AED levels: lamotrigine, carbamazepine and phenytoin levels during pregnancy should be considered (Level B) Levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C) Bardy, 1982; AAN practice parameter 2009

39 LABOR & DELIVERY

40 LABOR & DELIVERY 1-2% of WWE will have a GTC seizure during labor a further 1 2% will have a seizure in the following 24 h GTC seizures -> hypoxia-> deleterious effects on the fetus sleep deprivation, over-breathing, pain, and emotional stress -> increased risk of seizures during labor consider epidural anesthesia early-on

41 DELIVERY For WWE on AEDs, there is probably no substantially increased risk (> x 2 expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (> x 1.5 expected) of premature contractions or premature labor and delivery. There is (possibly) a substantially increased risk of premature contractions and premature labor and delivery in WWE who smoke (level C) AAN Practice parameter 2009

42 NEW-BORNS OF WWE Carbamazepine and Valproate are associated with higher risk of low birth weight -> persisted until age 3 years There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Newborns exposed to enzyme-inducing AEDs in-utero routinely receive vitamin K at delivery, as is the routine practice for all newborns NEAD study, 2013; AAN practice parameter 2009

43 LACTATION

44 WWE & BREAST FEEDING All WWE should be encouraged to breastfeed The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy Note: LTG: 30% infant levels compared w maternal plasma conc (2 wks post-delivery) ZNS similar conc as maternal plasma levels LEV significantly lower levels in infant BDZ and PB - > drowsiness Nau et al, 1982; Ohman et al, 2000; Liporace et al, 2004; Greenhill et al, 2004

45 MENOPAUSE

46 IMPACT ON SEIZURES Menopause occurs significantly earlier in women with high seizure frequency During menopause: 40% have worsening 27% improve 30% have no change Abbasi et al, 1999; Crawford et al, 1999; Harden, 2003; Harden et al, 2004

47 HORMONE REPLACEMENT THERAPY (HRT) HRT increases seizure activity in post-menopausal WWE It is dose-related one RCT Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate) Harden et al, 2006

48 OTHER ISSUES

49 BONE HEALTH

50 BONE HEALTH Changes in bone associated with epilepsy and AEDs are not gender specific. No single mechanism to explain all the changes in bone in association with epilepsy and AEDs No consensus on whom/when to screen as well as whom/how to treat. Alison Pack, Seizure 2008.

51 BONE HEALTH Bone turnover includes osteoblastic (bone formation) and osteoclastic (bone resorption) functions: elevation in markers for these functions are seen with AED treatment Increased bone turnover -> bone loss over time Low BMD (bone mineral density) is noted in: those treated with AEDs for >2 years persons treated with enzyme inducing AEDs those older than age 40

52 AEDs AND BONE HEALTH AED exposure increases the risk of osteoporosis, may impact bone quality, and increases the risk of falls -> fractures 2- to 6-fold increased risk of fractures in PWE treated with AEDs Cyt P-450 enzyme-inducing AEDs are most commonly associated with a negative impact on bone, but studies also suggest an effect of Valproate (Cyt P-450 inhibitor) Topiramate and Zonisamide CA inhibitors bone-sparing effect carbonic anhydrase potentiates the action of osteoclasts Mattson and Gidal, 2004; Alison Pack, 2008

53 BONE HEALTH Currently the most sensitive predictor of fracture is BMD (bone mineral density) Consider obtaining BMD measurements in all WWE (+/-AEDs) BMD screening by dual energy X-ray absorptiometry the more risk factors that are present, the higher the risk of fracture especially with low BMD other risk factors: family hx, small body frame, tobacco smoking, Caucasian or Asian race Cummings et al, 1995

54 TREATMENT OF BONE DISEASE IN WWE Limited info and no consensus Bisphosphonates: known to increase BMD and reduce the risk of fracture However, BP is not routinely recommended in pre-menopausal women because of unknown teratogenic potential Vitamin D: high-dose (4000IU/day) vitamin D therapy substantially increased bone mineral density at several skeletal sites 2 RCT Mikati et al, 2006;

55 CARE OF CHILDREN

56 CARING FOR CHILDREN much anxiety about the possible risks to a child from the mother s epilepsy risk of the child being harmed depends on: the type of seizure and its severity and frequency Ex: JME = sleep deprivation, early awakening and myoclonic jerking Betts, Fox, 1999

57 PSYCHIATRIC ISSUES

58 PSYCHIATRIC ISSUES In general, there is higher co-morbidity of psychiatric conditions in epilepsy: % (vs. 18% general population) Depression: 30 % (vs. 15%) Bipolar disorder: 10 % (1%) Schizophrenia: 10% ( %) Karouni et al, 2010; NIH 2015

59 DEPRESSION: Bidirectional relationship 4-fold increase in newly-diagnosed patients 17-fold increase in partial seizures Left sided significant higher depression scores in MTS independent of the lateralization of the lesion risk of suicide has been estimated to be 10 times higher than that in the general population history of depression is associated with a 4- to 6-fold greater risk of developing epilepsy Quiske, 2000; Kanner, 2003

60 WWE Up to 1 in 3 have a lifetime risk of depression no gender difference in d+e, but some studies suggest F > M Post-partum depression in % (vs %) When severe and with psychosis = psychiatric emergency increased risk of suicide and infanticide Tx is the same as for those without epilepsy: Citalopram, Sertaline, Paroxetine, Nortriptyline: 1 st line agents (undetectable levels in breast milk) Psychotherapy counseling and CBT also highly efficacious CANMAT guidelines, 2009

61 ANXIETY AND BIPOLAR DISORDER ANXIETY: Lifetime prevalence in epilepsy is 39% (vs. 9-16%) Most common is GAD (general anxiety disorder) Others: panic disorder, agarophobia and social phobias Highly co-morbid with depression BIPOLAR DISORDER: Prevalence is 10 12% with no gender difference Phenotype is modified by the use of AEDs Karouni, 2010; Jackson and Turkington, 2012; Lau et al, 2012

62 SUICIDE IN EPILEPSY 3-fold higher risk for death by suicide in PWE: in the absence of psychiatric disorders Higher risk with TLE No gender difference in attempt vs. completion in PWE (Note: in general population, women x9 more likely to attempt than complete) Role of AEDs in Suicidality: FDA issued safety warning in 2008; but flawed analysis Several studies subsequently showed no additional suicide risk with AEDs Jones et al, 2003; Kanner, 2009; Hecimovic et al, 2011; Arana et al, 2010; Bagary, 2011; Mula and Hesdorffer, 2011

63 PSYCHOGENIC NON-EPILEPTIC EVENTS/SEIZURES % of admissions to EMU and up to 50% of patients with medically refractory epilepsy Predominantly Female (F:M:: 3:1) Categorized as Somatoform disorder (DSM IV) Typically associated with history of trauma: sexual abuse or other High incidence (25-40%)of associated borderline personality disorder Whitworth and Fleischhacker, 1995; Reuber, 2008

64 THANK YOU!