1. 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

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

3. Birth Control

4. 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

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

6. 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

7. 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

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

9. LARC

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

11. ?
Hormonal
Contraception ✗ ✗ ✗

12. 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.

13. 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

14. 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

15. Birth Control & Lamotrigine

16. Birth control & Lamotrigine
Lamictal

17. 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

18. 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 (??)

19. 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 (May 2015)
DOI: /j.seizure
Seizure - European Journal of Epilepsy  , 71-75DOI: ( /j.seizure )
Copyright © 2015 British Epilepsy Association Terms and Conditions

20. 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

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

22. 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

23. Pregnancy & Epilepsy
Seizures
Medications

24. Pregnancy and Epilepsy
Pregnancy Registries
AED Pregnancy Registry Massachusetts General Hospital 121 Innerbelt Road, Room 220 Somerville, MA Phone: (TOLL FREE) Fax:

25. 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

26. Major Congenital Malformations
(MCMs)
Mention hypospadias

27. 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 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

28. 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.

29. 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

30. 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

31. 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

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

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

34. 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

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

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

37. 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

38. 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 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 of the cycle.

40. 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 – mg q 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:
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)

41. 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

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

43. 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

44. Questions?

45. Extra Slides

46. 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 – mg q 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:
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)

47. Very Brief Review of Female Sex Hormones

48. 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

49. 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 – mg q 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:
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)