1. Women Issues in Epilepsy
Olgica Laban-Grant, MD
Northeast Regional Epilepsy Group
NEREG 2014

2. Epilepsy
54%
women - 41 cases per 100,000
men cases per 100,000

3. Gender issues Men and women have similar risk for recurrent seizure
likelihood of ultimate remission of epilepsy

4. Gender issues Generalized epilepsy is more common in women (58%)
Mostly juvenile absence epilepsy and juvenile myoclonic epilepsy syndromes

5. hormones
seizures
AED’s

6. Major sex steroid hormones in women are estrogen and progesteron released by ovaries

7. Hypothalamic-pituitary-gonadal (HPG) axis

8. HPG axis

9. Effect of seizures on hormones
AED’s

10. Effect of seizures on hormones
Libido (sexual desire)
Fertility
Menstrual cycle regularity
Onset of menopause

11. Fertility and Epilepsy
Women with epilepsy have fewer children
Conflicting data regarding fertility
Possible explanations:
Choice (fear of having child with birth defect)
Seizures and/or AED’s may affect reproductive system
Sexual dysfunction
More frequent disorders of menstrual cycle
Polycystic Ovary Syndrome (PCOS)

12. Menstrual disorders
Menstrual disorders are estimated to occur in 1 of 3 women with epilepsy compared with 1 in 7 in the general population
One third of menstrual cycles in women with generalized seizures are anovulatory (ovaries do not release an egg)

13. Polycystic Ovary Syndrome (PCOS) and epilepsy
Syndrome is twice as common in women with epilepsy
10-25% in WWE compared to 7% in general population

14. Polycystic Ovary Syndrome (PCOS) and epilepsy
Multiple cysts in ovaries
High male hormone levels
Excessive facial hair and acne
Other features
Obesity
Irregular menstrual periods
More frequent anovulatory cycles

15. Polycystic Ovary Syndrome (PCOS) and epilepsy
Possible explanations:
Seizure activity in brain alters the production of hormones
Valproic acid (Depakote) causes features similar to PCOS

16. Epilepsy in adolescence
Certain types of epilepsy start at approximate age (JME) or improve (benign rolandic epilepsy, absence epilepsy)
Rapid growth may account for poor seizure control
Most seizure disorders are not altered by onset of puberty

17. Epilepsy and menopause
Premature menopause is more common
14% of WWE compared to 3.7 % in general population
Menopause occurred on average 3 years earlier
Correlated with estimated life time number of seizures
No influence of AED’s

18. Effect of hormones on seizures
AED’s

19. Effect of hormones on seizures
Hormones change the excitability of the brain and alter the threshold for seizures

20. Effect of hormones on seizure threshold
PROGESTERONE
Increases
seizure threshold
ESTROGEN
Decreases

21. Effect of hormones on frequency of seizures
PROGESTERONE
Decreases frequency of
seizures
ESTROGEN
Increases frequency of

22. Hormon sensitive seizures Catamenial epilepsy
Defined as doubling of frequency of seizures in relation to menstrual period. In 1/3 of women with epilepsy there is substantial relationship between seizures and menstrual cycle.

23. Hormon sensitive seizures Catamenial epilepsy
May occur in any type of seizures or epilepsy syndrome Three major patterns were described

24. Catamenial epilepsy Pattern 1 (most common type)
Just before menstruation
(3 days before – until day 3 of menstrual period)
Possibly due to steep decline in progesterone

25. Catamenial epilepsy Pattern 2 Just before ovulation
Approximately day 14 of menstrual period
Possibly due to steep elevation in estrogen

26. Catamenial epilepsy Pattern 3 In second half of anovulatory
menstrual cycle
Anovulatory cycles (ovulation does not occur) are more frequent in women with epilepsy
There is no elevation of progesterone

27. Catamenial Epilepsy High levels of estrogen Low levels of progesterone
Fluid and electrolyte imbalance
Psychological Stress
Decrease in levels of AEDs
30-50% women with epilepsy experience menstrual cycle-related seizures
Near menst. B/c progesterone w/drawal
Near ovulation: surge of estrogen

28. Management of Catamenial Seizures
Increase in doses of antiseizure medications during particular time of menstrual cycle
Intermittent dosing with benzodiazepines
Diamox-limited data to support benefit but low risk
Supplementation with reproductive hormones
Progesterone lozenges in second half of cycle
Adverse effects -sedation, breast tenderness, depression, increased appetite and weight, breakthrough menstrual bleeding. Progesterone has been implicated in breast cancer, lipid elevations, and hypercoagulability.
Suppression of menstrual cycle
Oral contraceptive pills
Medroxyprogesterone injections
Natural progesterone suppositories or lozenges
Synthetic IM
No longer recommended for heart disease. Increase stroke, breast/uterine cancer

29. Catamenial epilepsy and menopause
Perimenopause
erratic hormone levels
Menopause
low estrogen and progesterone levels

30. Effect of AED’s on hormones
seizures
hormones

31. Birth control and epilepsy
Some of the antiseizure medication decrease efficacy of birth control pills and other hormonal birth control
This may result in birth control failure and unplanned pregnancy
Liver enzyme inducing AED at least 6% failure rate per year for oral hormonal contraceptive pills
Reduces concentration of biologically active steroid hormone
Most commonly used oral contraceptives contain 35 mcg or less or estrogen
Topamax at doses of 200 mg or more interact with oral contraceptives 31

32. Hormonal birth control and epilepsy
Antiseizure medications that interfere with birth control:
Carbamazepine (Tegretol)
Phenobarbital
Phenytoin (Dilantin)
Primidone
Rufinamide (Banzel)
Onfi (Clobazam)
Topiramate (Topamax) *higher doses
Oxcarbazepine (Trileptal) *higher doses
Liver enzyme inducing AED at least 6% failure rate per year for oral hormonal contraceptive pills
Reduces concentration of biologically active steroid hormone
Most commonly used oral contraceptives contain 35 mcg or less or estrogen
Topamax at doses of 200 mg or more interact with oral contraceptives

33. Hormonal birth control and epilepsy
AED’s that have no influence on levels of steroids
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Tiagabine (Gabatril)
Zonisamide (Zonegran)
Pregabalin (Lyrica)
Lacosamide (Vimpat)

34. Hormonal birth control and epilepsy
Solutions:
Using antiseizure medications that do not interact with birth control pills
Using alternative birth control methods
Using birth control pills with higher dose of estrogen (Pitfalls: No proof that higher dose of estrogen is sufficient to prevent pregnancy)
Breakthrough bldg. May indicate contraception not completely effective

35. IUD (intrauterine device)
Two types are available:
Copper IUD
Hormone releasing (Mirena – progesterone) – since the effect is based on local influence of hormone on uterus lining it is unlikely to be affected by AED’s

36. Effect of hormones on AED’s
seizures
AED’s

37. Lamotrigine (Lamictal)
Female hormones can decrease levels of Lamictal (lamotrigine)
Pronounced effect in pregnancy
Lamictal blood levels reduced by 50% in setting of OC use.
Lamictal category C D in some areas/countries

38. Epilepsy and Pregnancy
Over 90% of babies born to women with epilepsy will be healthy.
Although low, birth defect rate is still about twice
(4-7%) of rate in general population ( %).

39. Most common birth defects
Neural tube defects
Heart abnormalities
Orofacial clefts
Source: CDC

40. Prenatal Testing
Testing that may be done to detect some of birth defects:
Maternal serum alpha-fetoprotein at weeks of gestation
Level II ultrasound (structural) at weeks of gestation
Amniocentesis at weeks of pregnancy

41. Why Prenatal Testing?
Some birth defects require special attention during pregnancy or during delivery
Some birth defects may require surgery immediately after delivery or even before delivery

42. Some other health problems that are more frequent:
Low birth weight/reduced growth potential
Neurodevelopmental problems
Higher risk for epilepsy
Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed.
Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 42

43. Pregnancy Risk is increased by:
Seizures (especially convulsive seizures)
Antiseizure medications
Genetic predisposition? (mothers who had babies with birth defect have higher risk in subsequent pregnancies)
Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed.
Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 43

44. Seizures in Pregnancy
Women who have better control of seizures prior to pregnancy (9 months) usually have fewer seizures during pregnancy.
Repetitive convulsions are associated with:
Cognitive problems
Small for gestational age
Folic acid important for nerves/neural tube defects affect brain and spinal cord. Spinal column not completely closed.
Folic acid—leafy dark green vegetables, citrus fruits/juices, lentils 44

45. Seizures in Pregnancy
Approximately 35% of women have increase in seizure frequency
Reasons for increase in seizures
Noncompliance
Nausea/vomiting
Pharmacokinetic changes
Sleep deprivation

46. Seizures in Pregnancy Reasons for increase in seizures Noncompliance
Nausea/vomiting
Pharmacokinetic changes
Sleep deprivation

47. AED’s during pregnancy
Levels of AED’s drop in second trimester due to:
Increase in drug clearance
Increase in maternal plasma volume
Decreased protein binding
Frequent testing (monthly) and adjustment in dose of medication may be necessary

48. AED’s in pregnancy Risk increased with:
Polypharmacy (two or more AED’s)
Higher levels of medications
Specific AED’s

49. Not all AED’s are the same
Prevalence of Malformations
lamotrigine (Lamictal®) % (1.4 to 2.8%)
carbamazepine (Tegretol®) % (2.1 to 4.2%)
phenytoin (Dilantin®) % (1.5 to 5.0%)
levetiracetam (Keppra®) % (1.2 to 4.3%)
topiramate (Topamax®) % (2.4 to 6.8%)
valproate (Depakote®) % (6.4 to 13.0%)
phenobarbital (Luminal®) % (2.8 to 9.7%)
oxcarbazepine (Trileptal®) % (0.6 to 5.5%)
gabapentin (Neurontin®) % (0.02 to 3.8%)
zonisamide (Zonegran®) 0% (0.0 to 3.3%)
clonazepam (Klonopin) % (0.4 to 10.8%)
Unexposed % 0.37 to 2.6%
NorthAmerican pregnancy registry spring 2012

50. Not all AED’s are the same
Depakote (valproic acid)
Consistently associated with high risk (5-fold higher)
- birth defects
- neurodevelopmental abnormalities (learning disability, autistic spectrum disorder, ADD/ADHD)
Topamax(topiramate)
- Increased risk for facial clefts (10-fold higher)

51. Epilepsy & Pregnancy AED National Pregnancy Registry
Tracks use of AEDs and pregnancy outcomes
All information confidential
Can greatly improve our knowledge

52. Folic acid
Folic deficiency is associated with increased risk of neural tube defects.
Folic acid should be initiated before conception and continued throughout pregnancy
AED’s that are linked to folic acid malabsorption/metabolism are
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Barbiturates
Valproate (Depakote)

53. Hemorrhagic disorder of neonate
AED’s compete with vitamin K across the placenta
Associated with in utero exposure to
Carbamazepine (Tegretol)
Barbiturates (phenobarbital and primidone)
Phenytoin (Dilantin)
Discuss with your Ob need for vitamin K in last month of pregnancy

54. Postpartum issues
AED levels may rise – close monitoring of levels is still necessary
Sleep deprivation and stress may increase frequency of seizures
Child safety/lifestyle adaptation

55. Breastfeeding
Benefits of breastfeeding are felt to outweigh potential risk of continued exposure of neonate and infant to AEDs (AAN and AAP)
Protein bound drugs have low concentrations in breast milk
Observe breastfeeding infant for irritability, poor sleep patterns, or inadequate weight gain
Dilantin, gabitril, depakote extensively protein bound—low concentrations in breast milk
Tegretol, phenobarb, lamictal, topamax, zonegran low-mod protein blinding—low-mod breast milk
Neuronin and keppra no protein binding equal amounts in blood and milk

56. Epilepsy & Bone health
Altered bone density due to AED’s is associated with:
Phenytoin (dilantin)
Carbamazepine (tegretol)
Barbiturates
Valproate (depakote)

57. Epilepsy & Bone health Prevention and therapy >6months on AEDs
- exercise, balanced diet, stop smoking, moderate alcohol, moderate caffeine
- calcium and vitamin D supplements
- measure Ca, ALP, 25-hydroxy vit D yearly
Baseline bone density scan
- Referral to endocrinologist if osteopenia/osteoporosis is diagnosed

58. Northeast Regional Epilepsy Group
THANK YOU!
Northeast Regional Epilepsy Group
epilepsygroup.com

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60. Please join us Safe and effective core exercises for epilepsy patients
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Bergen/Ramapo Room
Safe and effective core exercises
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