Planning for Womanhood transition topics for teen girls with epilepsy Elizabeth E. Gerard, MD Associate Professor Department of Neurology Feinberg School of Medicine Director, Women with Epilepsy Program Co-Director, Women’s Neurology Center

Special Concerns for Teen Girls with Epilepsy Birth Control Pregnancy Hormones and seizures Medication Side-Effects Self-Esteem

Birth Control

It is always a good idea to discuss contraception BEFORE it is needed Birth Control It is always a good idea to discuss contraception BEFORE it is needed Contraception may be indicated for teens with epilepsy for many reasons: To prevent pregnancy To regulate menstrual cycles To control acne/symptoms of PCOS To control heavy periods

Birth Control What kind of birth control is right for me? Can my medications affect my birth control? Can birth control affect my seizures?

Intrauterine device minimal systemic hormones Mirena Appropriate for women of all ages (including women who have not given birth) Releases progesterone locally Periods often stop Helps relieve painful periods Lasts 5 years Skyla Similar to Mirena Lasts 3 years Paraguard (Copper IUD) No hormones. Lasts 10 years May get heavy periods

Intrauterine device minimal systemic hormones Mirena Appropriate for women of all ages (including women who have not given birth) Releases progesterone locally Periods often stop Helps relieve painful periods Lasts 5 years Skyla Similar to Mirena Lasts 3 years Paraguard (Copper IUD) No hormones. Lasts 10 years May get heavy periods

Intrauterine device minimal systemic hormones VERY effective for preventing pregnancy (99%) Does NOT protect against Sexually transmitted diseases Does NOT treat PCOS symptoms +

LARC

Birth Control What to know about birth control and seizure medications: 1. MOST seizure medications can make many HORMONAL forms of contraception less effective

? Hormonal Contraception ✗ ✗ ✗

Seizure medications that reduce the effect of hormonal contraception Enzyme-inducing anti-seizure medications Carbamazepine (Tegretol, Carbatrol) Clobazam (Onfi) Eslicarbazepine (Aptiom) Felbamate (Felbatol) Oxcarbazepine (Trileptal) Phenobarbital (Phenobarbital, Primidone) Phenytoin (Dilantin) Perampanel (Fycompa) Topiramate (Topamax) More than half of the commonly used anti-epileptic medications induce hepatic metabolism and compromise the efficacy of all hormonal contraception. These enzyme-inducing medications include carbamazepine, phenytoin, phenobarbital, oxcarbazepine, esclicarbazepine, perampanel, clobazam, and felbamate. They should not be combined with COCs, the vaginal ring, birth control patch and etonorgestrel implant. The efficacy of Depo-medroxyprogesterone may also be compromised by these medications, but sometimes the dose can be increased and the interval decreased to cause amenorrhea when used in combination with mild enzyme-inducers. Topiramate is a hepatic enzyme inducer that can decrease levels of the synthetic estrogen ethinyl estradiol. This effect has only been documented at higher doses of topiramate, raising controversy over whether lower doses can be used with COCs. Never the less, the World Health Organization recommends an IUD as the optimal form of contraception for patients taking topiramate and all of the above enzyme-inducing AEDs. Of note both copper and progesterone IUDs are appropriate. The local effect of the hormone in the progesterone IUDs is not affected by hepatic-enzyme induction.   Lamotrigine has unique interactions with hormonal contraception. Lamotrigine does not affect synthetic estrogens but does decrease the levels of certain progestins in women taking COCs. It is not known if this compromises efficacy of the pills but caution with this and other progesterone based contraception is advised. In addition, however, the synthetic estrogen in COCs (or birth control patch or ring) induces the metabolism of lamotrigine causing lamotrigine levels to drop by up to 50%. This can lead to break-through seizures in women who were previously at a stable dose/level of lamotrigine. Additionally, a woman taking lamotrigine and COC will have a significant increase in her lamictal levels during her pill-free week which can lead to increased side-effects. In general alternatives to COCs are recommended for patients on lamotrigine. An IUD is a highly effective option.

Birth control & enzyme-inducing medications Not effective Birth control pills “Mini-pill” Vaginal ring Birth control patch Nexplanon (implant) ? Plan B (need to use higher dose) Effective IUD Condoms Depo-provera (possibly with more frequent dosing intervals) Pregnancy has been reported with implanon and cbz DMPA is ok by WHO Have had to double the depo provera dose to 300 mg and give q 6 weeks (instead of 12) to keep women suppressed without menses/seizures

Birth Control What to know about birth control and seizure medications: 1. MOST seizure medications can make many HORMONAL forms of contraception less effective 2. Hormonal contraception that contains ESTROGEN can make certain seizure medications less effective

Birth Control & Lamotrigine

Birth control & Lamotrigine Lamictal

Birth control & Lamotrigine Birth control methods that contain estrogen (birth control pills, nuvaring, birth control patch) LOWER lamotrigine (Lamictal) levels If you start any of these methods while on lamotrigine your doctor needs to adjust your lamotrigine dose to keep your blood levels from falling If you take placebo week lamotrigine levels will rise this week Lamotrigine may affect how well the progesterone part of your birth control works Most experts recommend an IUD for patients taking lamotrigine The hormone containing IUDs (mirena, skyla) will not interfere with lamotrigine

Birth Control What to know about birth control and seizure medications: 1. MOST seizure medications can make many HORMONAL forms of contraception less effective 2. Hormonal contraception that contains ESTROGEN can make certain seizure medications less effective 3. Hormonal contraception may change your seizure patterns or seizure frequency (??)

Seizure - European Journal of Epilepsy Fig. 1 Relative risks for seizure increase on various categories of contraception in comparison to barrier category which had the lowest rate at 3.2%. Hormonal contraception was the only category that showed a significantly greater risk (****p<0.0001). Hormonal category also had a significantly greater risk for seizure increase than tubal (p<0.05), IUD (p<0.0001) and withdrawal (p<0.0001). Andrew G. Herzog  Seizure - European Journal of Epilepsy  Volume 28, Pages 71-75 (May 2015) DOI: 10.1016/j.seizure.2015.02.011 Seizure - European Journal of Epilepsy 2015 28, 71-75DOI: (10.1016/j.seizure.2015.02.011) Copyright © 2015 British Epilepsy Association Terms and Conditions

Epilepsy & Birth Control What you can do: Talk to your doctors about how your medications affect your birth control and vice-versa Discuss what your needs and concerns about birth control Consider notifying your doctor in advance that you would like some time alone to discuss (Discussing contraception does not mean you are sexually active) If you are sexually active always use condoms in addition to any hormonal form of birth control or an IUD

Pregnancy & Epilepsy Will I be able to have healthy children? Will my seizure medications be ok when I want to get pregnant?

Pregnancy & Epilepsy Women with epilepsy should NOT be discouraged from carrying children The majority of women with epilepsy will have normal, healthy babies Pregnancy in epilepsy should be PLANNED well in advance to minimize risks to mom and baby If possible it is a good idea to choose medications with low risk in pregnancy even as a teen

Pregnancy & Epilepsy Seizures Medications

Pregnancy and Epilepsy Pregnancy Registries AED Pregnancy Registry Massachusetts General Hospital 121 Innerbelt Road, Room 220 Somerville, MA 02143 Phone: 888-233-2334 (TOLL FREE) Fax: 617-724-8307 www.aedpregnancyregistry.org

Pregnancy & Epilepsy Major Congenital Malformations Fetal malformations which affect physiologic function or require surgery Best studied outcomes to date Risk in general population 1-3% Minor congenital malformations Slight irregularities of fingers or face that don’t require surgery Cognitive development

Major Congenital Malformations (MCMs) Mention hypospadias

Pregnancy & Epilepsy Tissues Malformations Postconceptual Age CNS Major congenital malformations occur early in the 1st trimester Tissues Malformations Postconceptual Age CNS Neural tube defect 28 days Heart Ventricular septal defect 42 days Face Cleft lip 36 days Cleft palate 70 days Post conception is right: be sure to say postconception – we tend to think gestational age which adds two weeks to cover time from last menses to conception But 28 day is 2 weeks after her missed menses (which is 14 days after conception) a pregnancy test can be positive at 12-14 days. So soften the statement to “malformations may occur before women know that they are pregnant.” Do you need the word maxillary palate – cleft palate is simpler Malformations MAY occur BEFORE a woman knows she is pregnant Pregnancies must be PLANNED in advance in order to minimize the risk of malformations

Epilepsy & Pregnancy AED Risk of Malformations with Monotherapy Valproic Acid (>3000 pregnancies) 5-14%: HIGHEST among all AEDs Topiramate (328 pregnancies) 3-9% Carbamazepine (>5000 pregnancies) 3-6% Lamotrigine (>6000 pregnancies) 2-5 % Levetiracetam (938 pregnancies) 3% Specifically: CBZ and depakote associated with neural tube defects, oral clefts associated with topiramate and potentially even lamictal, and “Fetal Hydantoin Syndrome” with phenytoin and phenobarb UK pregnancy registry saw 7 MCM in topirmate monotherapy and 13 in topiramate polytherapy Topiramate: don’t have a lot of information on it but we avoid it. Make sure to comment that you are presenting this for educational purposes but not realistic at this point to discuss switching medications with this patient.

Pregnancy & Epilepsy For most seizure medications, the risk of malformations increases with HIGHER doses of medications Taking more than one medication during pregnancy often increases the risk of malformations especially if one of the medications is valproic acid (Depakote) or topiramate (Topamax) It is less clear if all combinations of seizure medications increase the risk of malformations

Pregnancy & Epilepsy Cognitive Development Valproic acid (Depakote) exposure during pregnancy has been consistently associated with poorer cognitive outcomes: Decreased IQ (10 points on average) Increased risk of Autism Likely dose-related Other drugs are still being studied; more data is needed So far IQ does not be significantly affected in children exposed to Carbamazepine, lamotrigine or levetiracetam

Pregnancy & Epilepsy What you can do: Talk to your doctors about your medications and how they would affect a future pregnancy If possible, change to a medication known to have a lower risk to a pregnancy (The best medication is still the medication that that best controls your seizures at the minimal effective dose) Make sure you have adequate contraception if you are sexually active Take folic acid 0.4-4mg a day Folic acid 1mg can be given by prescription General multivitamins usually have 0.4mg of folic acid Women’s multivitamins have 0.8mg of folic acid

Hormones & Epilepsy Can seizures affect my menstrual cycle? Can my menstrual cycle affect my seizures?

Can seizures affect my menstrual cycle? Hormones & Epilepsy Can seizures affect my menstrual cycle? Can my menstrual cycle affect my seizures? SEIZURES HORMONES

Hormones & Epilepsy Women with epilepsy have a higher likelihood of having a menstrual disorders than other women Polycystic Ovary Syndrome (PCOS) Irregular mentrual cycles Acne Excess face and body hair Loss of hair on the head Difficulty loosing weight More common in temporal lobe epilepsy More common with valproic acid (Depakote) use PCOS 5x more likely Another study found that women with epilepsy were only 37% as likely to have had a pregnancy as unaffected female siblings.33 This lower rate was maintained even among married women, whereas the similarly decreased fertility seen among men in the study was primarily attributable to a smaller proportion of men with epilepsy who had ever married. Sukumaran Neurology 2010

Hormones & Epilepsy Progesterone Enhances GABA synthesis Increased number of GABA receptor subunits

PROGESTERONE ESTROGEN Hormones & Epilepsy Progesterone Enhances GABA synthesis Increased number of GABA receptor subunits

Catamenial Epilepsy Hormones & Epilepsy Seizures fluctuate with the menstrual cycle Approximately 1/3 of women with epilepsy have one type of hormonal catamenial pattern In these women hormone fluctuates acts like another seizure trigger Defined as 2 fold increase during these periods of time

Three Patterns of Catamenial Epilepsy Hormones & Epilepsy Three Patterns of Catamenial Epilepsy Perimenstrual (C1) Seizures occur primarily around the time of the start of the menstrual cycle Typically 5 days before to 3 days after start of menses Periovulatory (C2) Seizures occur primarily around ovulation Typically cycle days 10-14 in most women Luteal (C3) Occurs more commonly in cycles where ovulation does not occur seizures increase in the second half of the cycle Defined as 2 fold increase during these periods of time When strictly defined, at least 1/3 of women have hormonally sensitive epilepsy known as catamenial epilepsy. Three patterns of catamenial epilepsy have been defined and are described below. In order to meet this standardized definition of catamenial epilepsy, a woman must have twice as many seizures during the defined period than in the rest of the cycle. These patterns are outlined to demonstrate the influence of hormones on seizures; it is not necessary to memorize the various patterns. C1 pattern- Seizures occur primarily peri-menstrually from cycle day -5 to cycle day +3 (five days before to 3 days after the start of menses). This is the most common catamenial pattern and is felt to be due to the withdrawal of progesterone prior to menses. C2 pattern- Seizures occur primarily during ovulation (days 10 to 14 in most women). This is felt to be due to the rise in estrogen levels at this time or an increase in the estrogen to progesterone ratio. C3 pattern- This pattern is seen in women who have anovulatory cycles. (Anovulatory cycles and polycystic ovary syndrome are more common in women with epilepsy due to effects of seizures on the hypothalamic-pituitary-ovarian axis.) When no egg is released the ovary does not form a corpus luteum. Thus progesterone stays low and the estrogen/progesterone ratio stays high throughout the later half of the cycle. Women with the C3 pattern demonstrate an increase in seizure activity for the later 1/2 of the menstrual cycle, starting with ovulation. Note that a common feature to all catamenial patterns is that seizure frequency should be lowest between days 4 to 10-14 of the cycle.

Hormones & Epilepsy Hormonal treatments do NOT replace standard epilepsy treatments for patients with catamenial epilepsy First-line treatments still include: anti-seizure medications surgery if appropriate Hormonal treatments can be given in addition to some standard therapies Evidence for these hormonal treatments is limited Oral Progesterone: - early trial – 55% improvement – recent - only for C1 type, still decrease in seizures was not > 50% Depo-Provera: - two trials – 120-150 mg q 6-12 - Fredrickson 1996, Mattson 1984 – decrease about 40% (19 women) -Zimmerman Depo-Lupron: ? Other GnRH analogue (Triptorelin): 3/10 sz free, 4/10 decrease 50%, - best in pt w perimenstrual sz -Bauer, J eta l J Neurol (1992) 239:284-286 Diamox : Seizure reduction of 40% and Seizure severity 30% (8-30mg/kg/day) in divided doses, up to 1 gm a day (Lim et al 2001) Clobazam: 20-30mg, redcution of >50% or seizure freedom in 78% of patients (Feeley 1982, 1984)

Hormones & Epilepsy What you can do: Keep track of your period and your seizures Seizuretracker.com Mobile App Period Trackers Be extra careful around times when you are vulnerable to seizures Take your medication on time Get enough sleep Talk to your doctor about additional treatments if standard treatments haven’t worked

Self Esteem & Epilepsy Medication side-effects Acne Weight gain Low energy Social Stigma Driving Restrictions Depression

Self Esteem & Epilepsy What you can do: Educate and engage friends and teachers about epilepsy Teachers Close Friends College Dorm Advisors Disability Office Discuss medication side-effects and your feelings with your doctors Seek out a counselor or other mental health provider for you to talk to Connect with peers with epilepsy Exercise and eat healthy

Questions?

Extra Slides

Hormones & Epilepsy Current Treatments: Depo-Provera Oral Progesterone Timed doses of anti-seizure medications Benzodiazepines (Clobazam, Clonazepam) Acetozolamide (Diamox) On the Horizon: Ganaxolone (allopregnenalone) Oral Progesterone: - early trial – 55% improvement – recent - only for C1 type, still decrease in seizures was not > 50% Depo-Provera: - two trials – 120-150 mg q 6-12 - Fredrickson 1996, Mattson 1984 – decrease about 40% (19 women) -Zimmerman Depo-Lupron: ? Other GnRH analogue (Triptorelin): 3/10 sz free, 4/10 decrease 50%, - best in pt w perimenstrual sz -Bauer, J eta l J Neurol (1992) 239:284-286 Diamox : Seizure reduction of 40% and Seizure severity 30% (8-30mg/kg/day) in divided doses, up to 1 gm a day (Lim et al 2001) Clobazam: 20-30mg, redcution of >50% or seizure freedom in 78% of patients (Feeley 1982, 1984)

Very Brief Review of Female Sex Hormones

Scales are justified Estradiol ug/ml Progesteron ng/ml Per Cate – don’t call inadequate luteal phase Luteal phase with elevated estradiol/progesterone ratio Herzog et al. Epilepsia 38 (10) 1997

Hormones & Epilepsy Current Treatments: Depo-Provera Oral Progesterone Timed doses of anti-seizure medications Benzodiazepines (Clobazam, Clonazepam) Acetozolamide (Diamox) On the Horizon: Ganaxolone (allopregnenalone) Oral Progesterone: - early trial – 55% improvement – recent - only for C1 type, still decrease in seizures was not > 50% Depo-Provera: - two trials – 120-150 mg q 6-12 - Fredrickson 1996, Mattson 1984 – decrease about 40% (19 women) -Zimmerman Depo-Lupron: ? Other GnRH analogue (Triptorelin): 3/10 sz free, 4/10 decrease 50%, - best in pt w perimenstrual sz -Bauer, J eta l J Neurol (1992) 239:284-286 Diamox : Seizure reduction of 40% and Seizure severity 30% (8-30mg/kg/day) in divided doses, up to 1 gm a day (Lim et al 2001) Clobazam: 20-30mg, redcution of >50% or seizure freedom in 78% of patients (Feeley 1982, 1984)