Management of Epilepsy in Women - Hospital Physician · questionnaires, found that knowledge about...

Hospital Physician Board Review Manual www.turner-white.com

Management of Epilepsy in Women

Author InforMAtIon 1

IntroductIon 2

cAtAMEnIAL EPILEPSY 2

rEProductIon dISordErS 6

contrAcEPtIon 8

PrEGnAncY 9

BrEAStfEEdInG 11

PErIMEnoPAuSE And MEnoPAuSE 12

BonE hEALth 13

concLuSIon 14

BoArd rEVIEW QuEStIonS 14

rEfErEncES 14

table of contents

www.turner-white.com Epilepsy Volume 3, Part 2 1

Author InforMAtIon

EPILEPSY BoArd rEVIEW MAnuAL

contributor:

Mona Sazgar, MDAssociate Clinical Professor, Department of Neurology, Comprehensive Epilepsy Program, University of California, Irvine

Statement of Editorial Purpose

The Epilepsy Board Review Manual is a study guide for trainees and practicing physicians preparing for board examinations in epi-lepsy. Each manual reviews a topic essential to the current management of patients with epilepsy.

note from the Publisher

This publication has been developed without involvement of or review by the Amer ican Board of Psychiatry and Neurology.

Publishing Staff

PRESIDENT, GRoUP PUBLISHERBruce M. White

SENIoR EDIToRRobert Litchkofski

ExECUTIvE vICE PRESIDENTBarbara T. White

ExECUTIvE DIRECToR of oPERATIoNSJean M. Gaul

Copyright 2015, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and produc-tion of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.

M a n a g e m e n t o f E p i l e p s y i n W o m e n

2 Hospital Physician Board Review Manual www.turner-white.com

EPilEPsy BoaRd REviEw Manual

Management of Epilepsy in womenMona Sazgar, MD

IntroductIon

cASE VIGnEttE

S.B. is a 28-year-old woman with a long-standing history of focal epilepsy of right frontal lobe origin due to cortical dysplasia. She used to experience clus-ters of seizures 2 days prior to and throughout her menstrual bleed. Some of her seizures progressed to generalized tonic-clonic activity. In the past 2 years, she has been stable and seizure free on oxcarbaze-pine 900 mg twice daily with no reported seizure recurrence. She was put on folic acid 1 mg daily by her neurologist as soon as she started dating. She got married last year and is taking a birth control pill (combined estradiol/progesterone oral contra-ceptive). She comes to her neurologist’s office and informs her that her pregnancy test came back posi-tive. She also has experienced 2 episodes of her typi-cal aura in the past 2 weeks. She is worried and has many questions regarding the reason for contracep-tive failure, her seizure recurrence, the effects of her seizure medication on her baby, and future directions.

Epilepsy affects approximately 1% of the popu-lation. Women comprise approximately half of the epilepsy population, including about 1.5 million women of childbearing age who live with epilepsy in the United States. Approximately 24,000 women with epilepsy in United States give birth every year. Women with epilepsy face specific challenges across their life cycle. Health care professionals involved in the care of women with epilepsy need to address difficult questions and concerns related

to menses, birth control, conception, pregnancy, childbirth, breastfeeding, childcare, bone health, and menopause. However, 2 published surveys of health care professionals by Long et al, the Knowl-edge of Women’s Issues in Epilepsy (KoWIE) questionnaires, found that knowledge about treat-ing epilepsy in women is lacking among health care providers.1 A total of 202 health care providers responded to the survey, 92% of whom identified themselves as physicians. few understood the ef-fects of endogenous steroid hormones on seizure threshold (24%) and that epilepsy is associated with an increased incidence of female sexual dys-function (37%).2 Most respondents could not iden-tify which seizure medications interfere with oral contraceptives. As these results indicate, there is a great need to educate health care professionals and patients with epilepsy about women’s issues in epilepsy.

catamenIal epIlepsy

In the majority of women and men with epilepsy, seizures do not occur randomly,3 but rather they tend to cluster, with more than 50% of cases show-ing temporal rhythmicity.4 Women with catamenial epilepsy show cyclical exacerbation of their sei-zures with temporal relationship to their menstrual cycles. The word catamenial is derived from the Greek word katamenios, meaning “monthly.” Sir Charles Locock first described the seizures associ-ated with the menstrual cycle in 1857. Seizure ex-acerbation may occur either at the time of menstru-



ation or ovulation and is attributed to fluctuations of estrogen and progesterone and their neuroactive properties.5 As a rule, estrogens are proconvulsant and progesterone has anticonvulsant properties. Catamenial epilepsy is thought to be related to dif-ferent responses of neurons in the cerebral cortex to sex hormones. Recent investigations by Herzog and colleagues have demonstrated the existence of at least 3 patterns of catamenial seizure exacer-bation (figure 1): perimenstrual (C1: days –3 to 3) and periovulatory (C2: days 10 to –13) in ovulatory cycles and entire luteal phase (C3: Days 10 to 3) in anovulatory cycles, where day 1 is the first day of menstrual flow and day 14 is the day of ovulation.5,6 These 3 patterns can be demonstrated simply by charting menses and seizures and obtaining a midluteal phase (days 20–22) serum progester-one level to distinguish between normal and inad-equate luteal phase cycles (<5 ng/mL) (table 1). Management of seizures in patients with catame-nial epilepsy can be challenging and may include

targeting the specific dates of hormonally related seizure exacerbation by increasing the baseline antiepileptic drugs (AEDs) on those dates, use of progesterone products, use of benzodiazepines such as clobazam and clonazepam, and use of acetazolamide.

MEchAnISM

Catamenial epilepsy may result from fluctuations in levels of endogenous sex hormones (neuros-teroids). Endogenous neurosteroids that modulate seizure susceptibility such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDoC) could play a critical role in catamenial epilepsy.7–9 It is hypothesized that the withdrawal of progesterone- derived neurosteroids can lead to enhanced excit-ability and predispose to seizure exacerbation.7 on the other hand, the plasticity in GABAA recep-tor subunits may play a role in enhanced sus-ceptibility for seizures in women with catamenial epilepsy. In animal models, prolonged exposure

figure 1. Three patterns of catamenial epilepsy as suggested by Herzog and colleagues: perimenstrual (C1) and periovulatory (C2) exacerbations during normal ovulatory cycles and the entire second half of the cycle, and (C3) exacerbation during inad-equate luteal phase cycles where day 1 is the first day of menstrual flow and day –14 is the day of ovulation. (Adapted with permis-sion from Herzog AG. Catamenial epilepsy: definition, prevalence, pathophysiology and treatment. Seizure 2008;17:152.)

Patterns of catamenial Epilepsy

f o L M f o L M

catamenial type catamenial type

normal cycle Inadequate Luteal Phase cycleEstradiol µg/mL

Progesterone ng/mL Estradiol µg/mLProgesterone ng/mLc2 c1

CyclePhase

CyclePhase

c3

day of the cycle day of the cycle

1 3 5 7 9 11 1 3 5 7 9 11 -14 -12 -10 -8 -6 -4 -2 1 3-14 -12 -10 -8 -6 -4 -2 1 3

30

25

20

15

10

5

0

25

20

15

10

5

0

P P

Seru

m h

orm

one

leve

ls

Seru

m h

orm

one

leve

ls

150

100

50

100

80

60

40

20

E2 E2



to allopregnanolone followed by withdrawal, which mimics menstruation, causes marked increase in expression of α4 and δ subunits, which are linked to enhanced neuronal excitability and seizures.10,11 The reduced inhibition and enhanced excitability caused by neuroendocrine fluctuations can be a key factor in predisposition to catamenial seizures.

Abnormalities in the hPo AxisThe brain is involved in regulating sex hormones

through the hypothalamic-pituitary-ovarian axis (HPo). The hypothalamus secretes gonadotropin-releasing hormone (GnRH), thereby stimulating the release of follicle-stimulating hormone (fSH) and luteinizing hormone (LH) by the pituitary. fSH stimulates formation and growth of the ovarian follicles, which secrete estradiol (the main form of estrogen) as they develop. Estrogen, through a negative feedback mechanism, inhibits fSH but stimulates GnRH. This leads to a surge of LH, which induces oocyte maturation, ovulation, and conversion of the follicle into the corpus luteum. ovulation marks the end of the follicular phase and the beginning of the luteal phase. following ovulation, the corpus luteum secretes progester-

one, which inhibits secretion of GnRH, fSH, and LH. If there is no pregnancy, the corpus luteum regresses and production of progesterone and es-tradiol declines. With lower levels of progesterone, GnRH inhibition decreases and the cycle repeats (figure 2).

Epilepsy itself and the medications used to treat epilepsy can have direct effects on regulation of the HPo axis. Epilepsy and AEDs can target a number of brain structures, including the limbic system, amygdala, hypothalamus, pituitary gland, and peripheral endocrine glands.12 In women with epilepsy, there are abnormalities in the levels of sex hormones, thyroid hormones, prolactin, and vitamin D related to dysregulation of the HPo axis. The shifting levels of estrogen and progesterone can affect the seizure frequency and severity by directly affecting brain excitability.

trEAtMEnt

To date there is no specific treatment approved by the US food and Drug Administration (fDA) for catamenial epilepsy. However, there are several op-tions that can be beneficial for patients with catame-nial seizure exacerbation (table 2). Acetazolimide, which has been in use for more than 50 years, is one of the oldest treatment options for catamenial epilepsy. There have not been any randomized clini-cal trials to prove the efficacy of acetazolamide in treating catamenial epilepsy. It is common practice to use 250 or 500 mg twice daily for approximately 10 days around the time of catamenial seizure ex-acerbation.

Benzodiazepines such as clonazepam and clo-bazam are used in the treatment of seizure clusters during hormonally related exacerbation of seizures. Benzodiazepines are positive allosteric modulators of GABAA receptor and broad-spectrum anticon-vulsant medications. In a double-blind, placebo-

table 1. Patterns of Catamenial Epilepsy

Perimenstrual or c1 patternSignificant increase in average seizure frequency around day –3 to day +3 of menstrual cycle, as compared with the rest of the menstrual cycle

Periovulatory or c2 patternSignificant increase in average seizure frequency during ovulation around days 10 to 15, as compared with the rest of the menstrual cycle

Inadequate luteal phaseSignificant increase in average seizure frequency between day 10 of 1 cycle and day 3 of the next cycle, which includes ovulatory, luteal and menstrual phases in women with inadequate and anovulatory luteal phase

Based on paradigm suggested by Andrew G. Herzog, MD.5



controlled cross-over study, clobazam resulted in complete control in the majority of women during the 10-day trial period.13,14 In this study, clobazam was effective when used at a dose of 20 to 30 mg/day, administered intermittently starting 2 to 4 days be-fore menses. The most common adverse effects of clobazam are sedation and depression.

Certain seizure medication doses can be tempo-rarily increased during the catamenial seizure ex-acerbation period. This approach may not be safe with some seizure medications such as phenytoin and carbamazepine.

Synthetic progestin depot medroxyprogester-one acetate (DMPA) at a dose of 150 mg every 3 months has been used for reducing seizure exacerbation in catamenial epilepsy. Reductions in seizure frequency of up to 39% over a 1-year

period have been reported.15,16 There is a risk for osteoporosis with prolonged use of DMPA, and the effects of DMPA on fertility last up to 1 year.

A National Institutes of Health–sponsored clini-cal trial led by Herzog and colleagues17 assessed the response to treatment with natural progester-one lozenges in women with medically refractory catamenial partial epilepsy. This was a random-ized, double-blind, placebo-controlled phase 3 multicenter trial. In 294 patients randomized 2:1 to progesterone or placebo, a post hoc analy-sis showed significantly higher responder rate in women with perimenstrual seizure exacerbation (C1) as compared with the periovulatory (C2) and anovulatory (C3) groups. Progesterone may pro-vide a clinically important benefit for this subset of women with perimenstrual catamenial epilepsy,

figure 2. Hypothalamic-pituitary-ovarian (HPo) axis. fSH = follicle-stimulating hormone; LH = luteinizing hormone; GnRH = gonadotropin- releasing hormone.

hypothalamus

Anterior pituitary

ovaries

Gnrh

LhfSh

negative feedback

negative feedback

Estrogen/Progesterone

GnRH neurons

Kisspeptin neurons Hypothalamus

GnRH

Pituitary

LSfSH

Gonad

EstrogenProgesterone

Hypothalamus



which is the most prevalent form of catamenial epilepsy. The recommended dose is 200 mg 3 times daily, which can be used around the days of hormonally related seizure exacerbation or days 14 to 28 of the cycle, with consideration for tapering up from a lower dose for 2 to 3 days at the onset of treatment and tapering down 2 to 3 days before discontinuing the therapy.

Novel treatment for catamenial epilepsy in the future may include neurosteroids that are devoid of hormonal side effects. one candidate is ganaxo-lone, a synthetic analog of the neuroactive steroid allopregnanolone that has sedative, anxiolytic, and anticonvulsant effects. It is a potent and selective positive allosteric modulator of the GABAA receptor. Ganaxolone has protective antiseizure activity in ro-dent models of epilepsy and is being evaluated for treatment of epilepsy in humans.18 Ganaxolone has been tested in various clinical trials to assess its effi-cacy in the treatment of epilepsy.19,20 However, there

is only limited anecdotal information supporting the efficacy of ganaxolone in women with catamenial epilepsy.21

reproductIon dIsorders

dIrEct EffEct of EPILEPSY

Decreased libido and infertility, polycystic ovar-ian syndrome (PCoS), and early menopause are among the reproductive disorders associated with epilepsy. Epileptiform discharges can alter the level of sex hormones at the hypothalamic and pituitary level.22 The amygdala, a structure closely associ-ated with temporal lobe epilepsy, has extensive reciprocal connections with the hypothalamus. Seizures originating from the amygdala can cause disruption of the GnRH-producing cells in the pre-optic area of the hypothalamus and abnor-mal release of fSH and LH and sex hormones as a consequence. Seizures in this way disrupt

table 2. Suggested Algorithm for Treatment of Women with Catamenial Epilepsy

1. determine true catamenial epilepsya. Establish whether the seizures are in fact catamenial in nature using seizure diaries. Ask the patient to chart daily seizure type and frequency

with simultaneous recording of ovulation and menstruation status using an ovulation kit or basal body temperature recording for 3 menses.

b. Determine whether there is an increase in number and severity of seizures by two-fold or higher during specific days of the patient’s menstrual cycle and establish C1, C2, or C3 type of catamenial epilepsy.

2. Progesterone lozenges/natural progesterone for c1 patternfor the C1 type, consider using progesterone lozenges 200 mg 3 times daily around the days of seizure exacerbation or days 14 to 28 of the cycle.

3. Synthetic progestinConsider oral daily synthetic progestin or intrauterine device with progestin versus depot medroxyprogesterone acetate (DMPA).

4. AcetazolamideConsider using 250 mg twice daily or 500 mg twice daily around the 7 to 10 days of seizure exacerbation as determined by the seizure diary.

5. clobazamConsider using 20 to 30 mg divided twice a day or 1 dose at night for 10 days 2 days prior to and throughout the identified seizure exacerbation

dates.

6. Small increase in baseline antiepileptic drug Consider increasing dose 2 days prior to the identified period of seizure exacerbation for up to 10 days. Be cautious about phenytoin, carbam-

azepine, or other medications with higher risk for toxicity.



the menstrual cycle and affect fertility.23 In 50 consecutive patients with temporal lobe epilepsy, Herzog et al found 56% with amenorrhea, oligo-menorrhea, or abnormally long or short menstrual cycle intervals, and 68% with clearly identifiable reproductive endocrine disorders such as PCoS, hypoandrogenism, premature menopause, and hyperprolactinemia.23 Since the disorders of sexual function can be common in women with epilepsy, questions about sexual function should be part of the routine evaluation in the outpatient clinic.

EffEct of AEdS

The medications used to treat epilepsy can also alter reproductive function. AEDs that induce he-patic enzyme metabolism (EIAEDs) can affect the concentration of sex hormones (table 3). EIAEDs affect liver cytochrome P450 isoforms and result in enhanced metabolism of sex hormones and potential for seizure exacerbation in women with catamenial epilepsy.24 In a prospective, randomized, double-blinded study by Lossius and colleagues, re-versible endocrine changes in sex steroid hormone levels were observed after withdrawal of AEDs.25 Carbamazepine was the most commonly used drug, and withdrawal led to significant increases in serum testosterone concentrations, which resulted in sexual dysfunction.

AEDs can significantly alter circulating sex hor-mone levels. Morrell and flynn studied sexual func-tion and hormones in women aged 18 to 40 years with partial onset epilepsy and primary generalized epilepsy along with non-epilepsy controls.26 Com-pared to the controls, women with partial onset epilepsy had significantly higher sexual dysfunction scores, lower mean arousal, and higher depression scores. Women on EIAEDs had statistically higher sexual dysfunction and lower sexual arousal com-pared to controls. overall, non-EIAEDs have a more

favorable profile in terms of effect on sexual function.EIAEDs can also lower the efficacy of oral and

hormonal contraceptives by enhancing metabo-lism of both the estrogen or progesterone compo-nents.27,28 Women with epilepsy should be aware of the increased risk for contraceptive failure when taking EIAEDs and should use additional methods if they desire to avoid getting pregnant. on the other hand, pregnancy and start of contraceptive medications with an estrogenic component can significantly reduce baseline lamotrigine levels by

table 3. Interactions Between AEDs and Reproductive Hormones

AEds that decrease sex hormones/cause contraceptive failure (EIAEds):

Carbamazepine (Tegretol)

Phenytoin (Dilantin)

Phenobarbital (Luminal)

Primidone (Mysoline)

Topiramatea (Topamax)

oxcarbazepine (Trileptal)

Rufinamide (Banzel)

Perampanela (fycompa)

Clobazam (onfi)

AEds with least effect on sex hormones and contraceptive failure (nEIAEds):

Ethosuximide (Zarontin)

Gabapentin (Neurontin)

valproateb (Depakote)

Lamotrigine (Lamictal)

Levetiracetamc (Keppra)

Zonisamide (Zonegran)

Pregabalin (Lyrica)

Lacosamide (vimpat)

Tiagabine (Gabitril)

a Weak enzyme inducers.b Decreased free testosterone concentrations in men and increased andro-gen concentrations in women taking valproate.c Increased testosterone concentrations reported in men on levetiracetam.

AED = antiepileptic drug.



increased clearance of this medication (>50%) and result in seizure breakthroughs unless the dose is adjusted.29,30

The use of valproic acid is associated with in-creased risk for PCoS.31–34 PCoS is characterized by enlarged ovaries with multiple small cysts and a hypervascularized, androgen-secreting stroma leading to the associated signs of androgen excess (hirsutism, alopecia, acne), obesity, and menstrual- cycle disturbance (oligorrhea or amenorrhea).35 PCoS occurs in approximately 4% to 7% of women of reproductive age in the general popu-lation, but in 10% to 25% of women with epi-lepsy.36,37 The increased rate of PCoS among women with epilepsy is likely due to altered modulation of the HPo axis by the temporo-limbic system.

contraceptIon

Hormonal contraception is used in a variety of formulations including oral contraceptive tablets, topical patches, intramuscular depot injections, im-plants, and intrauterine devices. The mechanism of action of contraceptives involves inhibiting ovula-tion and fertilization. Combined oral contraceptives (CoC), which contain both synthetic estrogen and progestin, are the most commonly used method of contraception. The most recent CoC agents con-tain only 20 to 35 mg of ethinyl estradiol, which is not sufficient to suppress ovulation but can control the menstrual cycle. The progestin component is responsible for the contraceptive effect of CoC, including inhibition of ovulation, increased viscos-ity of the cervical mucus, and reduced endome-trial suitability for ovum implantation.38 There are complex interactions between hormonal contra-ception and seizure medications. Individualized counseling is needed for women with epilepsy to

avoid reducing the efficacy of AEDs or failure of contraception.

EIAEDs such as phenytoin, carbamazepine, phe-nobarbital, primidone, oxcarbazepine, and eslicar-bazepine can result in contraceptive failure (Table 3). Perampanel and topiramate are less potent he-patic enzyme inducers and can cause contraceptive failure at higher doses.39–41 However, levetirace-tam, gabapentin, pregabalin, vigabatrin, tiagabine, zonisamide, and lacosamide have no known inter-actions with oral contraceptives (Table 3).

The oral contraceptive failure rate is 1% in healthy women, but 3% to 6% in the population of women with epilepsy.42–44 fairgrieve and col-leagues reported that less than 55% of women with epilepsy had planned their pregnancy and contraceptive failure was the cause of 1 in 4 un-planned pregnancies.38,43 Women taking EIAEDs need to take a combination of oral contraceptive pills with at least 50 µg of estrogen, but this can significantly increase side effects including the risk for blood clots.

Progestin-only tablets are unlikely to be effective in women who take EIAEDs, and women who use this method are at risk for contraceptive failure. There is no evidence as to whether EIAEDs reduce the efficacy of DMPA injections, although there is a theoretical risk and it is common practice to ad-minister the injections every 10 weeks in women using EIAEDs, as opposed to the recommended 12-week intervals for women in the general popu-lation.

Another method of contraception is levonor-gestrel implants. Levonorgestrel subdermal cap-sules are also at risk for failure with concurrent use of EIAEDs. In a study comparing levonorgestrel subdermal implants in a control group versus a group of women with epilepsy, after 1 year 2 of the 9 women with epilepsy had become pregnant dur-



ing contraception with levonorgestrel subdermal implants.45 They were both on phenytoin, and their plasma concentrations of levonorgestrel were low at the time of conception. No pregnancies had oc-curred in 10 women in the control group.

finally, intrauterine devices (IUDs) are T-shaped devices that are fitted into the uterus. The 2 common types are copper IUD (non-hormonal) and levonorg-estrel IUD (Mirena or Skyla). These devices work locally by causing thickening of the cervical mucus. They are highly efficacious and are not affected by EIAEDs. Therefore, these devices are an effective form of contraception in women with epilepsy.

pregnancy

Each year an estimated 24,000 women with epi-lepsy in the United States become pregnant. Sei-zures during pregnancy can pose a significant risk to the fetus. fortunately, in the majority of women pregnancy has no effect or a protective effect on their seizure frequency. However, an increased seizure risk is reported in 20% to 25% of women with epilepsy during pregnancy.46,47 There is an increased incidence of seizures during labor and delivery, with approximately 3% to 4% of women with epilepsy experiencing seizures during child-birth. About half of these seizures are generalized tonic-clonic in nature.48–50

Seizure recurrence during pregnancy can result from sleep deprivation, anxiety, and stress pro-voked by the pregnancy. An increased estrogen-to-progesterone ratio, especially around weeks 8 to 16 when it reaches its peak, may also be a contributing factor. Some women may reduce or discontinue AEDs once they discover they are pregnant out of fear of harming their babies. The most common cause of seizure recurrence in pregnancy is likely reduced plasma concentration of the AEDs.

Carbamazepine levels during pregnancy were studied by Tomson and colleagues, who found that in 8 of 35 women taking carbamazepine during pregnancy total concentration of carbamazepine decreased by 9% in the second trimester and 12% in the third trimester compared to baseline. How-ever, free carbamazepine levels did not change significantly during pregnancy compared to base-line.51 In the same study, in 22 women taking phenytoin monotherapy total phenytoin concentra-tion decreased in all 3 trimesters from baseline (maximum of 61%). free phenytoin concentrations decreased in the third trimester by 16%. Sufficient monotherapy data are not available to provide evi-dence for a change in levels or clearance during pregnancy for phenobarbital, valproic acid, primi-done, ethosuximide, and other AEDs.

Lamotrigine metabolism through hepatic gluc-uronidation is enhanced during pregnancy by elevated concentrations of sex hormones. Declin-ing plasma concentrations of lamotrigine during pregnancy, therefore, result in increased seizure frequency for more than 40% of patients.48,52–54 Lamotrigine clearance during pregnancy is 2 to 3 times higher than before pregnancy. The levels after delivery reach pre-pregnancy levels within 1 to 3 weeks.

oxcarbazepine levels are also significantly affect-ed by pregnancy,46,48 and there is a need for dosage adjustment during pregnancy. The plasma concen-tration of the active form of oxcarbazepine (mono-hydroxy derivative) declines by 36% to 50% in the late stages of pregnancy55 and is associated with increased seizure frequency in 50% of women.56

The elimination rate of levetiracetam is sig-nificantly increased during pregnancy due to in-creased renal glomerular filtration in late preg-nancy. The clinical relevance of this finding is unknown, but given the increased elimination rate



therapeutic monitoring of levetiracetam levels dur-ing pregnancy may be valuable.57

The American Academy of Neurology (AAN) practice guidelines suggest checking AED levels at baseline before conception and monthly thereafter. Dose adjustment should be considered to maintain an effective and stable level throughout pregnancy, at least for women with epilepsy who are on la-motrigine, oxcarbazepine, levetiracetam, carba-mazepine, and phenytoin.47 The lack of evidence for changes in other AED levels during pregnancy should not discourage monitoring the levels during pregnancy.

fEtAL rISkS WIth SEIzurE rEcurrEncE durInG PrEGnAncY

A generalized tonic-clonic seizure and postictal hypoxia can result in significant lactic acidosis as a result of lack of respiratory oxygen. Lactic acid can transfer to the fetus and result in fetal hypoxia and acidosis. Teramo and colleagues studied 3 women with epilepsy who experienced generalized tonic-clonic seizure during labor.58 There were marked changes in fetal heart rate for up to 60 minutes after the seizure. There was also a risk for increased uter-ine contractions during and after a seizure, resulting in decreased arterial blood flow to the placenta. A fall as a result of seizure may result in trauma to the uterus and possible placental abruption. The number of stillbirths (fetal death after 22 completed weeks of pregnancy) is slightly increased—1.2 to 1.3 times—in women with epilepsy.49

To avoid the potential harmful effects of con-vulsive or prolonged partial seizures on the fetus and expectant mother, all efforts must be made to avoid these types of seizures during pregnancy. This means that AED use is indicated in the major-ity of women with epilepsy, despite potential risk for fetal malformation.59 Pre-pregnancy counseling

and planning should include discussing the need for medication, type of medication, use of mono-therapy, and obtaining baseline levels of AEDs. The levels should be monitored monthly during pregnancy and adjusted in case of significant drop or signs of seizure recurrence. In case of any seizure recurrence and fall, the patient should be immediately evaluated by the obstetrician clinic to ensure maternal and fetus well-being. The delivery should be arranged in a hospital that can handle the possibility of seizure recurrence during preg-nancy and delivery.

In summary, for a pregnant woman with epi-lepsy, her neurologist should work closely with her high-risk obstetrician to manage her throughout the pregnancy, delivery, and immediate postpar-tum period. Proper management will minimize the risk for both mother and fetus.

tErAtoGEnIc EffEctS of AEdS

The majority of women with epilepsy give birth to normal, healthy children. There is a modestly increased risk for major congenital malformations, about 1.5- to 2-fold, among offspring of women treated for epilepsy during their pregnancy. In-creased risk for congenital malformations in children of women with epilepsy was reported as early as the 1960s.60 Since then, numerous studies con-firmed a greater risk for major congenital malforma-tions among children of mothers treated for epilepsy during their pregnancy. The overall prevalence of congenital malformations in children of women with epilepsy was systematically reviewed during a meta-analysis of 59 studies, and the risk was estimated to be increased 3 times compared with healthy women.61 This increased risk could be a re-sult of AEDs used during pregnancy or other factors related to maternal epilepsy. overall, in a pooled analysis of data from 26 studies, the malformation



rate was 6.1% in children of women with epilepsy, as compared with 2.8% in children of untreated women with epilepsy and 2.2% in healthy women in the general population.62 Polytherapy in women with epilepsy carries a higher risk of fetal malformation of approximately 6.8%, as compared with monothera-py with a risk of 4%.62 The teratogenic side effects of AEDs appear to be dose dependent. There is an increased risk due to high doses as opposed to low doses of valproic acid, carbamazepine, pheno-barbital, and lamotrigine. With valproic acid, the risk increases at doses above 700 mg/day.

In the North American AED Pregnancy Reg-istry (NAAPR), lamotrigine monotherapy during pregnancy was associated with a 1.9% risk for malformation in the fetus.63 Carbamazepine mono-therapy carried a risk of 3.0%, phenytoin 2.9%, phenobarbital 6.5%, and valproic acid 10.7% in the offspring of women with epilepsy. Polytherapy with lamotrigine and valproic acid resulted in a mal-formation rate of 9.1%, and with carbamazepine and valproic acid the rate was 15.4%. A recent meta-analysis of women exposed to topiramate during their pregnancy confirms that first-trimester exposure to topiramate is associated with a 6-fold increased risk of oral clefts.64 In March 2011, the fDA moved topiramate to a category D pregnancy label. Data on other newer AEDs are insufficient but so far do not indicate an alarmingly high risk with gabapentin, oxcarbazepine, and levetirace-tam.

In summary, the majority of women with epilepsy will require continuing their AEDs during preg-nancy to prevent seizures and potential harmful effects to their baby. A planned pregnancy and pre-pregnancy counselling should include simplify-ing the medication regimen and an attempt to use monotherapy at the lowest effective dose to mini-mize the teratogenic effects of AEDs.

foLIc AcId SuPPLEMEntAtIon

Some AEDs, such as valproic acid, carbam-azepine, phenobarbital, phenytoin, and primidone, alter folic acid metabolism and may decrease folic acid levels in the blood.65 folic acid deficiency can increase the risk of neural tube defects and folic acid supplementation is recommended for women with epilepsy who are planning pregnancy, as it is for all women of childbearing age when not using contraception. The effective dose of folic acid is a matter of debate as there is insufficient data for clear advice regarding the dose. A systematic review by Wald et al concluded that 5 mg of folic acid daily in women without epilepsy renders 85% protection against neural tube defects.66 folic acid studies in women with epilepsy do not show con-vincing evidence regarding the dosage needed in this population. The dose recommended by the AAN is a minimum of 0.4 mg folic acid supplemen-tation daily prior to conception and throughout the pregnancy.67 A dose of 4 to 5 mg daily in women taking carbamazepine, phenobarbital, phenytoin, primidone, and valproic acid is common practice.

BreastFeedIng

Breastfeeding is associated with reduced risk of lower respiratory tract infections, atopic dermatitis, asthma, acute otitis media, gastroenteritis, obesity, diabetes, childhood leukemia, sudden infant death syndrome, and necrotizing enterocolitis. Despite the clearly known benefits of breastfeeding, many women with epilepsy hesitate to breastfeed their newborns due to the potential risk of exposure of their infants to AEDs through breast milk. All AEDs can pass into the breast milk to a certain degree, but the amount transferred through breast milk is much less than the amount transmitted through the placenta to the fetus. Most medications have



a low transfer rate into the breast milk, especially the medications with higher protein binding affinity such as carbamazepine, phenytoin, and valproic acid.

Serum levels of valproic acid in infants of moth-ers who breastfed their babies were measured to be 0.9% to 2.3% of the mother’s serum level.68 There is only one known adverse report associ-ated with valproic acid use during breastfeeding, where an infant developed thrombocytopenia and anemia while breastfed on valproic acid. The Neu-rocognitive Effects of Antiepileptic Drugs (NEAD) study did not demonstrate any deleterious effects of breastfeeding during valproate therapy on cog-nitive outcomes in children who were previously exposed to valproate during their mother’s preg-nancy.69 This study also did not find any neurocog-nitive side effects of carbamazepine, lamotrigine, and phenytoin in breastfed infants.

for phenytoin, the drug levels in infants are lower than 5% of maternal plasma concentrations. one report in 1954 described decreased suck, drowsiness, and methemoglobinemia in an infant breastfed on phenytoin.70

Plasma levels of carbamazepine in breastfed infants are very low, with a milk/maternal plasma ratio of 0.64 to 0.79.71 only 2 reports of liver dys-function exist in breastfed infants of mothers who were taking carbamazepine.72

Lamotrigine shows a milk/maternal plasma ratio of 41.3%, with an infant plasma concentration of 18.9% of maternal plasma concentrations.73 Mild thrombocytosis was the only reported side effect in breastfed infants of mothers who continued la-motrigine while breastfeeding.

Levetiracetam shows a milk/maternal serum ratio of 1.05 (range 0.78–1.55), and the infant’s level is approximately 13% of the mother’s serum level.57 Despite the high transfer rate, the infant

serum level stays low, suggesting that the amount the infant absorbs is low.

Topiramate shows a milk/maternal plasma ratio of 0.86 (range 0.67–1.1).74 Between 2 and 3 weeks after delivery, the infant’s serum level of topiramate is barely detectable and no clear adverse events are reported in breastfed infants of mothers taking topiramate. Zonisamide also has not been associ-ated with any adverse events in breastfed infants.75

for barbiturates and benzodiazepines, the risk–benefit ratio should be evaluated more carefully. Despite low levels of phenobarbital and primidone in breast milk, there are reports of sedation, lethar-gy, weight loss, and higher drug levels in the child than in the mother.76

In summary, breastfeeding is encouraged in women with epilepsy who took AEDs during pregnancy. Except for barbiturates and benzo-diazepines, the reported side effects in infants who are breastfed on other AEDs have been rare or infrequent, and the benefit may outweigh the risks.

perImenopause and menopause

Perimenopause is characterized by decreased ovarian progesterone secretion, resulting in in-creased occurrence of anovulatory menstrual cy-cles. During the early stages of perimenopause, estrogen secretion remains high, which creates an excitatory environment and contributes to seizure exacerbation in women with catamenial epilepsy. When menopause establishes due to the dimin-ished levels of fSH and hypogonadal state, sei-zures stabilize.

Harden and colleagues reported the results of a questionnaire which was sent to women with epi-lepsy currently in menopause and perimenopause seeking information regarding the course of their



epilepsy and treatment.77 Two thirds of women with “hot flashes” and recent onset of menstrual changes reported an increase in seizures. A high percentage of these women took synthetic hor-monal replacement therapy (HRT), which was sig-nificantly associated with seizure exacerbation. A history of catamenial seizures also correlated with seizure exacerbation during the perimenopause state. The menopausal group reported decreased seizure frequency.

A follow-up randomized, double-blind, placebo-controlled trial of HRT in menopausal women with epilepsy using 0.625 mg conjugated equine es-trogen/2.5 mg medroxyprogesterone (CEE/MPA) found that seizure frequency significantly increased in a dose-related manner with the use of HRT in this formulation. The study was terminated after a small number of participants were randomized due to increased risk of breast cancer with this form of HRT.78

Women with epilepsy are at risk for early ovar-ian failure due to HPo axis dysfunction. Klein and colleagues reported a premature ovarian failure rate of 14% in women with epilepsy as compared with a rate of 3.7% in healthy control women.79 Women with premature ovarian failure and early menopause were more likely to have a history of frequent seizures as well as catamenial epilepsy.

In summary, women with catamenial epilepsy are at risk for seizure exacerbation during the perimenopause state. Their seizure medications may need to be adjusted to higher therapeutic levels. once menopause is achieved, the doses may be reduced back to their baseline. The CEE/MPA formulation of HRT needs to be avoided in these patients; for women in whom hot flashes are disturbing sleep, consultation with the patient’s gy-necologist is warranted to explore other hormonal treatment approaches.

Bone HealtH

Long-term treatment with AEDs can put patients with epilepsy at increased risk for bone loss, low bone mineral density (BMD), and fractures. Abnor-mal bone health is associated with epilepsy and independently with EIAEDs. Cytochrome P450-inducing AEDs are reported to be associated with bone loss. Persons with epilepsy have a risk for fracture that is 2 to 6 times higher than that of the general population.80,81 falls as a result of seizure or secondary to AED-induced loss of balance can increase fracture risk.

Phenytoin and phenobarbital are most consis-tently associated with low BMD.81–85 Long-term ga-bapentin use in several studies was associated with bone loss at the hip and spine.86–88 findings with carbamazepine and valproic acid and lamotrigine are mixed. In a systematic review of the literature, vestergaard reported that only 3 out of 11 carba-mazepine monotherapy studies and 6 out of 11 valproic acid monotherapy studies showed a signifi-cant reduction in BMD.89 Pack and colleagues stud-ied the effect of AED monotherapy on bone density after 1 year of treatment in premenopausal women. In 23 women who were taking lamotrigine mono-therapy, there was no detectable adverse effects on bone turnover or BMD.84 However, Guo et al examined bone mass in children treated with long-term valproate and combination lamotrigine therapy. They reported that this combination was associated with short stature, low BMD, and reduced bone for-mation. They suggested that these alterations may be mediated primarily through reduced physical ac-tivity rather than through a direct link to the valproic acid or lamotrigine therapy.90 oxcarbazepine and topiramate were studied for their effects on BMD, and no significant bone loss was found.91,92 Koo et al studied 61 patients with recent-onset epilepsy re-



ceiving monotherapy with levetiracetam, and found no decrease in BMD.93

Levels of active vitamin D metabolites such as 25-hydroxy-vitamin D may be low in people with epilepsy who are on EIAEDs. Elevated bone turn-over markers in these patients reflect increased bone remodeling and are associated with a higher rate of bone loss and are independent predictors of bone fracture81,83,94–97

Monitoring of calcium and vitamin D metabolites is important in patients who take EIAEDs. Current guidelines suggest that 25-hydroxyvitamin D con-centrations should be above 30 ng/mL. A higher dose of vitamin D supplementation may be needed in these patients. Dual energy x-ray absorptiome-try (DExA) scan should be performed periodically to monitor BMD. If osteopenia or osteoporosis is detected, consideration should be given to start-ing bisphosphonates or other therapeutic agents, increasing calcium and vitamin D supplementation, and/or replacing EIAEDs. The patient may benefit from referral to an endocrinologist.

conclusIon

Women with epilepsy face challenges across their life cycle. The challenges start with puberty and menses, and continue throughout their life, including birth control, conception, pregnancy, childbirth, breast feeding, childcare, bone health, and menopause. Health care professionals must remain informed and up to date regarding the spe-cific issues in the care of women with epilepsy. In the case of patient S.B., her seizures were consis-tent with catamenial epilepsy (C1 or perimenstrual type). She should have been informed of the risk of contraceptive failure with EIAEDs such as ox-carbazepine and offered an additional alternative contraception method such as IUD. She needs

counseling regarding the potentially teratogenic side effects of oxcarbazepine and the fact that it is a pregnancy category C medication; however, the risk of seizures during this pregnancy may be higher than the risk to the fetus from exposure to oxcarbazepine. Detailed level 4 ultrasound at around week 17 of pregnancy and close follow up with a neurologist/epileptologist and high-risk ob-stetrician are recommended throughout her preg-nancy. other investigations, including assessment of serum alpha-fetoprotein level and amniocente-sis, may be offered to her depending on detection of any fetal abnormalities with the ultrasound. She needs monthly monitoring of her oxcarbazepine levels and adjustment of the dose in case of a significant drop in the medication levels. She may need immediate dose adjustment for oxcarbaze-pine since her auras, which are simple partial sei-zures, have recurred, likely secondary to hormonal changes in her body and her pregnancy.

reFerences

1. Long L, McAuley JW, Shneker B, Moore JL. The validity and reliability of the Knowledge of Women’s Issues and Epilepsy (KoWIE) Questionnaires I and II. J Neurosci Nurs 2005;37:88–91.

2. Long L, Montouris G. Knowledge of women’s issues and epilepsy (KoWIE-II): a survey of health care professionals. Epilepsy Behav 2005;6:90–3.

3. Tauboll E, Lundervold A, Gjerstad L. Temporal distribution of seizures in epilepsy. Epilepsy Res 1991;8:153–65.

4. velez A, Eslava-Cobos J. Epilepsy in Colombia: epide-miologic profile and classification of epileptic seizures and syndromes. Epilepsia 2006;47:193–201.

5. Herzog AG, Klein P, Ransil BJ. Three patterns of catame-nial epilepsy. Epilepsia 1997;38:1082–8.

6. Herzog AG, Harden CL, Liporace J, et al. frequency of

Click to test your knowledge of this topic with

Epilepsy Board Review Questions.

http://www.turner-white.com/brqs/bepil/brqs_bepilV3P2_Q1.php



catamenial seizure exacerbation in women with localiza-tion-related epilepsy. Ann Neurol 2004;56:431–4.

7. Reddy DS. The role of neurosteroids in the pathophysiol-ogy and treatment of catamenial epilepsy. Epilepsy Res 2009;85:1–30.

8. Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 2010;186:113–37.

9. Reddy DS. Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. front Endocrinol (Lausanne) 2011;2:38.

10. Smith SS, Shen H, Gong QH, Zhou x. Neurosteroid regulation of GABA(A) receptors: focus on the alpha4 and delta subunits. Pharmacol Ther 2007;116:58–76.

11. Gangisetty o, Reddy DS. Neurosteroid withdrawal regu-lates GABA-A receptor alpha4-subunit expression and seizure susceptibility by activation of progesterone recep-tor-independent early growth response factor-3 pathway. Neuroscience 2010;170:865–80.

12. Herzog AG. Intermittent progesterone therapy and fre-quency of complex partial seizures in women with men-strual disorders. Neurology 1986;36:1607–10.

13. feely M, Gibson J. Intermittent clobazam for catamenial epilepsy: tolerance avoided. J Neurol Neurosurg Psychia-try 1984;47:1279–82.

14. feely M, Calvert R, Gibson J. Clobazam in catamenial epilepsy. A model for evaluating anticonvulsants. Lancet 1982;2:71–3.

15. Zimmerman AW, Holden KR, Reiter Eo, Dekaban AS. Medroxprogesterone acetate in the treatment of seizures associated with menstruation. J Pediatr 1973;83:959–63.

16. Mattson RH, Cramer JA, Caldwell Bv, Siconolfi BC. Treat-ment of seizures with medroxyprogesterone acetate: pre-liminary report. Neurology 1984;34:1255–8.

17. Herzog AG, fowler KM, Smithson SD, et al. Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology 2012;78:1959–66.

18. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT xII). Epilepsy Res 2015;111:85–141.

19. Reddy DS. Pharmacology of catamenial epilepsy. Methods find Exp Clin Pharmacol 2004;26:547–61.

20. Reddy DS, Rogawski MA. Neurosteroids as endogenous regulators of seizure susceptibility and use in the treatment of epilepsy. Epilepsia 2010;51:84.

21. McAuley JW, Long L, Heise J, et al. A Prospective Evalu-ation of the Effects of a 12-Week outpatient Exercise Program on Clinical and Behavioral outcomes in Patients with Epilepsy. Epilepsy Behav 2001;2:592–600.

22. Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 2008;17:101–10.

23. Herzog AG, Seibel MM, Schomer DL, vaitukaitis JL,

Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. Arch Neurol 1986;43:347–50.

24. Isojarvi JI, Tauboll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs 2005;19:207–23.

25. Lossius MI, Tauboll E, Mowinckel P, et al. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy–a prospective randomized double-blind withdrawal study. Epilepsia 2007;48:1875–82.

26. Morrell MJ, flynn KL, Done S, et al. Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs. Epi-lepsy Behav 2005;6:360–5.

27. Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia 2005;46 Suppl 9:117–24.

28. Harden CL, Leppik I. optimizing therapy of seizures in women who use oral contraceptives. Neurology 2006;67:S56–8.

29. Sabers A, ohman I, Christensen J, Tomson T. oral con-traceptives reduce lamotrigine plasma levels. Neurology 2003;61:570–1.

30. Sabers A. Pharmacokinetic interactions between contra-ceptives and antiepileptic drugs. Seizure 2008;17:141–4.

31. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329:1383–8.

32. Isojarvi JI, Pakarinen AJ, Myllyla vv. Thyroid function in epileptic patients treated with carbamazepine. Arch Neurol 1989;46:1175–8.

33. Isojarvi JI, Rattya J, Myllyla vv, et al. valproate, lamotrigi-ne, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998;43:446–51.

34. Isojarvi JI, Turkka J, Pakarinen AJ, et al. Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy. Epilepsia 2001;42:930–4.

35. Balen A. Pathogenesis of polycystic ovary syndrome--the enigma unravels? Lancet 1999;354:966–7.

36. Bauer J, Cooper-Mahkorn D. Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol 2008;83:135–55.

37. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Preva-lence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a pro-spective study. J Clin Endocrinol Metab 1998;83:3078–82.

38. Reimers A, Brodtkorb E, Sabers A. Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. Seizure 2015;28:66–70.

39. Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 2013;54:11–27.



40. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol 2011;10:446–56.

41. Brodie MJ, Kwan P. Newer drugs for focal epilepsy in adults. BMJ 2012;344:e345.

42. Coulam CB, Annegers Jf. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979;20:519–25.

43. fairgrieve SD, Jackson M, Jonas P, et al. Population based, prospective study of the care of women with epi-lepsy in pregnancy. BMJ 2000;321:674–5.

44. Johnston CA, Crawford PM. Anti-epileptic drugs and hor-monal treatments. Curr Treat options Neurol 2014;16:288.

45. Haukkamaa M. Contraception by Norplant subdermal cap-sules is not reliable in epileptic patients on anticonvulsant treatment. Contraception 1986;33:559–65.

46. Sabers A. Influences on seizure activity in pregnant women with epilepsy. Epilepsy Behav 2009;15:230–4.

47. Harden CL, Pennell PB, Koppel BS, et al. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Stan-dards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009;50:1229–36.

48. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry. Neurology 2006;66:354–60.

49. Hiilesmaa vK. Pregnancy and birth in women with epi-lepsy. Neurology 1992;42:8–11.

50. Bardy AH. Incidence of seizures during pregnancy, labor and puerperium in epileptic women: a prospective study. Acta Neurol Scand 1987;75:356–60.

51. Tomson T, Lindbom U, Ekqvist B, Sundqvist A. Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carba-mazepine and phenytoin. Epilepsia 1994;35:122–30.

52. ohman I, Beck o, vitols S, Tomson T. Plasma concentra-tions of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia 2008;49:1075–80.

53. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology 2008;70:2130–6.

54. de Haan GJ, Edelbroek P, Segers J, et al. Gestation-in-duced changes in lamotrigine pharmacokinetics: a mono-therapy study. Neurology 2004;63:571–3.

55. Christensen J, Sabers A, Sidenius P. oxcarbazepine concentrations during pregnancy: a retrospective study in patients with epilepsy. Neurology 2006;67:1497–9.

56. Petrenaite v, Sabers A, Hansen-Schwartz J. Seizure de-terioration in women treated with oxcarbazepine during

pregnancy. Epilepsy Res 2009;84:245–9. 57. Tomson T, Palm R, Kallen K, et al. Pharmacokinetics of

levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia 2007;48:1111–6.

58. Teramo K, Hiilesmaa v, Bardy A, Saarikoski S. fetal heart rate during a maternal grand mal epileptic seizure. J Peri-nat Med 1979;7:3–6.

59. Adab N, Kini U, vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75:1575–83.

60. Meadow SR. Anticonvulsant drugs and congenital abnor-malities. Lancet 1968;2:1296.

61. Meador K, Reynolds MW, Crean S, fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a sys-tematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 2008;81:1–13.

62. Shorvon SD, Tomson T, Cock HR. The management of epilepsy during pregnancy--progress is painfully slow. Epi-lepsia 2009;50:973-974.

63. Hernández-Díaz S, Smith CR, Shen A, et al. North Ameri-can AED Pregnancy Registry; North American AED Preg-nancy Registry. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78:1692–9.

64. Alsaad AM, Chaudhry SA, Koren G. first trimester ex-posure to topiramate and the risk of oral clefts in the offspring: A systematic review and meta-analysis. Reprod Toxicol 2015;53:45–50.

65. Dansky Lv, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurol-ogy 1992;42:32–42.

66. Wald NJ, Hackshaw AD, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation to neural tube defects. Br J obstet Gynaecol 1996;103:319–24.

67. Harden CL, Hopp J, Ting TY, et al. Practice parameter up-date: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the Ameri-can Academy of Neurology and American Epilepsy Soci-ety. Neurology 2009;73:126–32.

68. Piontek CM, Baab S, Peindl KS, Wisner KL. Serum valpro-ate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry 2000;61:170–2.

69. Meador KJ, Baker GA, Browning N, et al. Effects of breast-feeding in children of women taking antiepileptic drugs. Neurology 2010;75:1954–60.

70. Steen B, Rane A, Lonnerholm G, et al. Phenytoin excretion in human breast milk and plasma levels in nursed infants. Ther Drug Monit 1982;4:331–4.

71. Shimoyama R, ohkubo T, Sugawara K. Monitoring of car-



bamazepine and carbamazepine 10,11-epoxide in breast milk and plasma by high-performance liquid chromatogra-phy. Ann Clin Biochem 2000;37(Pt 2):210–5.

72. Chaudron LH, Jefferson JW. Mood stabilizers during breastfeeding: a review. J Clin Psychiatry 2000;61:79–90.

73. Newport DJ, Pennell PB, Calamaras MR, et al. Lamotrig-ine in breast milk and nursing infants: determination of exposure. Pediatrics 2008;122:e223–31.

74. ohman I, vitols S, Luef G, Soderfeldt B, Tomson T. Topira-mate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 2002;43:1157–60.

75. Kawada K, Itoh S, Kusaka T, Isobe K, Ishii M. Pharma-cokinetics of zonisamide in perinatal period. Brain Dev 2002;24:95–7.

76. Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979;7:624–7.

77. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999;40:1402–7.

78. Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a random-ized, double-blind, placebo-controlled study. Epilepsia 2006;47:1447–51.

79. Klein P, Serje A, Pezzullo JC. Premature ovarian failure in women with epilepsy. Epilepsia 2001;42:1584–9.

80. Souverein PC, Webb DJ, Petri H, et al. Incidence of frac-tures among epilepsy patients: a population-based retro-spective cohort study in the General Practice Research Database. Epilepsia 2005;46:304–10.

81. Pack AM. Treatment of epilepsy to optimize bone health. Curr Treat options Neurol 2011;13:346–54.

82. verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli f. Bone and calcium metabolism and antiepileptic drugs. Clin Neu-rol Neurosurg 2010;112:1-10.

83. Pack AM, Walczak TS. Bone health in women with epi-lepsy: clinical features and potential mechanisms. Int Rev Neurobiol 2008;83:305-328.

84. Pack AM, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008;70:1586–93.

85. valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral

density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994;9:631–7.

86. El-Hajj fuleihan G, Dib L, Yamout B, et al. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone 2008;43:149–55.

87. vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics and sedatives and risk of fractures: effects of half-life. Calcif Tissue Int 2008;82:34–43.

88. Ensrud KE, Walczak TS, Blackwell TL, et al. Antiepileptic drug use and rates of hip bone loss in older men: a pro-spective study. Neurology 2008;71:723–30.

89. vestergaard P. Effects of antiepileptic drugs on bone health and growth potential in children with epilepsy. Paediatr Drugs 2015;17:141–50.

90. Guo CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001;42:1141–7.

91. Cetinkaya Y, Kurtulmus YS, Tutkavul K, Tireli H. The effect of oxcarbazepine on bone metabolism. Acta Neurol Scand 2009;120:170–5.

92. Cansu A, Yesilkaya E, Serdaroglu A, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol 2008;39:266–71.

93. Koo DL, Hwang KJ, Han SW, et al. Effect of oxcarbaze-pine on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res 2014;108:442–7.

94. Samaniego EA, Sheth RD. Bone consequences of epi-lepsy and antiepileptic medications. Semin Pediatr Neurol 2007;14:196–200.

95. verrotti A, Greco R, Morgese G, Chiarelli f. Increased bone turnover in epileptic patients treated with carbamaze-pine. Ann Neurol 2000;47:385–8.

96. verrotti A, Greco R, Latini G, et al. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiv-ing carbamazepine. Epilepsia 2002;43:1488–92.

97. verrotti A, Agostinelli S, Coppola G, et al. A 12-month longitudinal study of calcium metabolism and bone turn-over during valproate monotherapy. Eur J Neurol 2010;17: 232–7.

Date post:	15-Sep-2018
Category:	Documents
Upload:	lethu
View:	212 times
Download:	0 times

Management of Epilepsy in Women - Hospital Physician · questionnaires, found that knowledge about...

Documents