Women with Epilepsy often have unique considerations when managing their condition. Hormonal fluctuations can impact seizure frequency, and some anti-seizure medications are associated with higher risks of birth defects, cognitive issues in offspring, menstrual irregularities, and bone health issues. Levetiracetam appears to carry lower risks during pregnancy and for bone health compared to other anti-seizure drugs like valproate, phenobarbital, and phenytoin, which should generally be avoided. Careful planning and medication management is important when considering pregnancy or contraception for women with epilepsy.

1. Women with Epilepsy:
Role of Newer ASDs
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.

2. Introduction
• Incidence of epilepsy in men and women is similar.
• Fundamental principles of management are the same.
• However, managing women with epilepsy (WWE) requires attention to
special considerations.
• It is estimated that 3 to 5 births per thousand will be to WWE.
Yerby MS. Neurology 2000; 55: S21–S31.

3. Case 1: Are there unusual epilepsy patterns in women?
• 20y/F, temporal lobe epilepsy with right MTS.
• CPS once in 2 months, rare secondary generalization.
• Seizures usually occur just before the periods, are more intense and longer
duration and often occur in clusters.
• Has irregular periods, heavy bleeding and oligomenorrhea.
• No PCOS.
• Not keen on surgery.
• On LEV+OXC+CLB.

4. MRI brain coronal T2 and T2F sequences show hyperintensity and atrophy of the right
hippocampus suggestive of mesial temporal sclerosis. There is poor grey-white differentiation in
the right anterior temporal lobe.

5. MD YOUSUF ALI(4820545)
Longitudinal bipolar montage of a 23 year old lady, showing frequent right temporal spikes, along
with slowing. MRI brain showed right MTS.

6. Catamenial Epilepsy
• Definition: two fold increase in daily seizure frequency in relation to certain
phases of the menstrual cycle as compared to baseline seizure frequency. This
should be demonstrated in atleast 3 consecutive months.
• Catamenial pattern is seen in around 1/3rd of women with epilepsy. In some
women seizures are purely catamenial.
• More common in focal epilepsy.
• Estrogens: seizure-promoting effect, through NMDA receptors.
• Progesterone: seizure inhibiting effect, through GABA-A receptors. .

7. Catamenial Epilepsy
• Three phases with catamenial clustering:
1. Periovulatory estrogen peak (days 10 to 13)
2. Perimenstrually with typical fall in gestagen (day 3)
3. Second half of the cycle in disorders of luteal function, i.e., inadequate
progesterone level (day 10 to day 3 of next cycle).
The Anti-Müllerian hormone is also implicated in catamenial epilepsy. It has an
anticonvulsant activity and protects against NMDA mediated excitotoxicity. Receptors
for Anti-Müllerian hormones are expressed in several brain regions including the
hippocampus and are thought to inhibit seizures. Women with active epilepsy have
lower levels of Anti-Müllerian hormone.

8. Treatment of Catamenial epilepsy
Agent Remark
Clobazam 15-20 mg of clobazam daily for 10 days starting two days prior to the
expected period of seizure exacerbation. Preferred choice.
Regular ASDs Increase in dose during periods of exacerbation. No evidence.
Acetazolamide 500-1000 mg acetazolamide daily during 7-10 days of seizure
exacerbation
Cyclical natural progesterone Day 14-25: 200 mg three times a day
Days 26-27: 100 mg three times a day
Day 28: 50 mg three times a day
Depot medroxyprogesterone 150 mg every 3 months to suppress menstruation.
GnRh analogues: Triptorelin,
Goserelin
Intramuscular every 4-12 weeks.
Ganaxolone Synthetic analogues of allopregnanolone
Combined OCPs

9. Follow up
• Perimenstrual increase in CLB: slightly beneficial.
• Perimenstrual increase in LEV: beneficial, but mood swings.
• Progesterone therapy: good reduction in seizure frequency.

10. Case 2: Does Sexual Dysfunction occur in Epilepsy?
• 28y/F, unclassified generalised epilepsy.
• On PHT 300 mg/d, PB 60 mg/d.
• No children after 6 years of marriage, fertility tests were normal.
• Referred by reproductive medicine unit to consider change of AEDs:
1. Poor libido on the part of the patient.
2. Gum hypertrophy and other cosmetic concerns.
3. Irregular periods.
4. Teratogenicity concerns.
• Normal MRI brain and EEG.

11. Sexual dysfunction
• Prevalence: of sexual dysfunction in females in the general population: 25-
63%, compared to 10- 75% in WWE.
• Risk factors: Uncontrolled seizures, longer duration of epilepsy, high seizure
frequency, focal epilepsy, polytherapy, enzyme inducing ASDs.
• Enzyme inducing AEDs (PHT, CBZ) increase SHBG and reduce level of
unbound hormone, increase metabolism of sex steroids.
• Types: Hyposexuality (reduced desire), reduced sexual arousal, orgasmic and
pain-related sexual problems.
• Newer ASDs: LEV, LTG are not associated with sexual dysfunction.

12. Follow up:
• AEDs changed to LEV 1500 mg/d.
• Gum hypertrophy improved.
• Conceived after 1 year.
• Had a breakthrough seizure in 5th month of pregnancy.
• LCS 200 mg/d was added. Seizure free since then.
• Delivered a healthy baby.

13. Case 3: Epilepsy and menstrual disturbances
• 30y/F, with epilepsy since 14 years of age.
• Focal epilepsy with impaired awareness, right hemispheric.
• Was on PHT and CLB.
• No children after 8 years of marriage.
• Oligomenorrhea, amenorrhea, weight gain.
• Perimenstrual clustering of seizures.
• Gynecological and Endocrine evaluation normal.
• Changed to PHT + LEV, and later to LEV+ LCS for seizure control.
• Better seizure control and weight reduction.

14. Menstrual disturbances
• Types: Amenorrhea (no menstruation for 6 months), oligomenorrhea,
polymenorrhea, polymenorrhagia, irregular cycles, and anovulatory cycles.
• Prevalence: One-third of WWE have menstrual irregularities (10-60%) as
compared to 12-14% of women in the general population.
• Causes: PCOS (40%), hypothalamic amenorrhea (12%), functional
hyperprolactinemia (2%), early menopause (4%).
• Can occur in WWE even if they are not on ASD.

15. Case 4: Is PCOS related to Epilepsy or its treatment?
• 23y/F, JME.
• Well controlled with VPA since 13 years of age.
• Yearly USG abdomen and pelvis normal till 18 years of age.
• Polycystic changes noted in USG at 18 years of age.
• Irregular periods, weight gain.
• Changed to LEV 1000 mg/d with good seizure control.
• USG changes resolved in a year.
• Menstrual cycles returned to normal.

16. Bipolar montage showing frontally dominant generalised polyspike and wave discharges

17. Polycystic Ovarian Syndrome (PCOS)
2 out of 3 of the following: Other features:
Polycystic ovaries on imaging Elevated LH/ FSH ratio
Oligo/ anovulation Insulin resistance
Clinical or biochemical evidence
of Hyperandrogenism
Obesity
Prevalence of PCOS in WWE is higher (10-20%) than in women
without epilepsy (5-6%), even in those not on AEDs.
PCOS is seen in 20-50% of women taking VPA, especially those
starting valproate before the age of 20. Also seen with CBZ.

18. Causes Comment
Sexual dysfunction Hyposexuality, reduced arousal
Menstrual disturbances Amenorrhoea, anovulatory cycles
PCOS Metabolic syndrome, hyperandrogenism
Social reasons Not getting married, delayed marriage, choosing not to have
children.
• Women with idiopathic or cryptogenic epilepsy are only 37% likely to become pregnant as
compared to their female siblings.
• Infertility was detected in 38% of the women.
• Polytherapy, older age, and lower education levels were risk factors for infertility.
• PB, VPA are associated with a higher risk of infertility. Avoid enzyme inducing ASDs.
Is Fertility affected by Epilepsy or its treatment?

19. Case 5: WWE requiring contraception
26y/F, with remote symptomatic focal epilepsy due to NCC.
• Seizure free on CBZ 600 mg/d, CLB 10 mg/d.
28y/F, with JME. Mother of one child.
• On LEV 1000 mg/d and LTG 300 mg/d, rare seizures with sleep deprivation.

20. Only 50% of WWE with epilepsy plan their pregnancy and approximately 25%
of the unplanned pregnancies are due to contraceptive failure.
ASDs that cause
contraceptive failure
ASDs that cause
contraceptive failure at
higher doses
ASDs whose levels
fall with hormonal
contraceptives
Phenytoin Topiramate (>200 mg/d) Lamotrigine: LTG
dose may have to be
increased by 30%.
Blood level
monitoring may be
required.
Phenobarbitone, Primidone Perampanel
Carbamazepine,
Oxcarbazepine,
Eslicarbazepine
Felbamate
Clobazam Cenobamate
Rufinamide

21. Contraception Comment
Non- hormonal methods All AEDs
IUCD All AEDs
Combined OCPs Non enzyme inducing AEDs
Combined OCPs Enzyme inducing AEDs cause rapid estrogen
metabolism and risk of contraceptive failure. Use
higher strength of ethinyl oestradiol (50-100 ug/day).
Use additional barrier methods.
Emergency contraception Higher dose is needed in case of enzyme inducing
AEDs.
Medroxyprogesterone injections Effective, but use more frequently (every 10 weeks,
instead of 12)
Progesterone only pill Contraindicated due to high failure rate.
Midcycle bleeding indicates risk of contraceptive failure.
Avoid systemic hormonal contraceptive agents in WWE. Use barrier methods or IUCD

22. Case 6: WWE planning for pregnancy
• 25y/F, focal epilepsy +/- Secondary generalisation.
• MRI negative. EEG showed left fronto-temporal spikes in the past. Latest
EEG is normal.
• Has seizures once in 3-4 months.
• On OXC 1200 mg/d + CLB 15 mg/d
• Planning for pregnancy.

23. Preparing a WWE for pregnancy
Pre conception counseling: genetics,
teratogenicity, lifestyle changes etc
Shift to AEDs that are relatively safe in pregnancy.
Folic acid of 1-5 mg/d Shift to monotherapy.
Ensure seizure freedom of atleast 9
months prior to conception.
Shift to lower doses.
• More than 90% of pregnancies in WWE have a successful outcome.
• Higher dose of folate is advised for WWE on enzyme inducing ASDs.
• In these women, Vitamin K in the dose of 10 mg intramuscularly is recommended
at 32-34 weeks of pregnancy and for the newborns at the time of birth.

24. Epilepsy related complications in WWE during Pregnancy
Seizure frequency Unchanged: 54-80%
Decreased: 3- 24%
Increased: 14- 32%
Seizure increase was more likely in partial epilepsy (29%) than
idiopathic epilepsy (7%).
Status epilepticus Frequency: 0-1.8% (no increased risk)
More likely convulsive type.
Seizure recurrence
in previously
seizure free WWE
If seizure free for >9 months prior to
pregnancy, 75-94% continue to be seizure free
during pregnancy.
Increased risk= greater than 2 times expected.

25. Case 7: AEDs and major congenital malformations
• 27y/F, with focal epilepsy, infrequent seizures.
• Seizure free with CBZ 600 mg/d, CLB 10 mg/d.
• 1st pregnancy: unplanned pregnancy resulting in stillbirth.
• 2 nd pregnancy: baby was premature, had microcephaly and cardiac defects.
Succumbed in the NICU after a surgical procedure.
• ASDs changed to LEV 1000 mg/d and CBZ 400 mg/d.
• 3rd pregnancy: Uneventful, normal baby.
• 4th pregnancy: on LEV 1000 mg/d. Uneventful, normal baby.

27. Percentage risk of major congenital malformation from in-
utero exposure to eight commonly used ASMs as
monotherapy based on EURAP study and Cochrane review.
Dose-dependent risk of major congenital malformations
with four ASMs as monotherapy based on EURAP study.

28. Risk of Teratogenicity due to first trimester AED exposure
VPA Increased risk with monotherapy, and more with
polytherapy.
Polytherapy including VPA has higher risk than
polytherapy without VPA.
VPA + LTG is particularly teratogenic.
Recommendation: Avoid VPA as monotherapy or polytherapy.
CBZ Class I: No increased risk
LTG Class I: No increased risk.
AED polytherapy has increased risk compared to monotherapy.
Minor anomalies were not included in the above studies.
Increased risk= greater than 2 times expected.

29. Common teratogenic associations of AEDs
VPA Neural tube defects, facial clefts, hypospadias.
PHT Cleft palate
CBZ Posterior cleft palate
PB Cardiac anomalies
VGB, TPM, OXC Teratogenic in animals.
Teratogenicity due to VPA occur at a daily dose of 1000 mg or more.
MCM type is not specific to any AED.

30. • 30y/F, JME, seizure free with VPA 1000 mg/d.
• Seizure control with LEV, LTG suboptimal.
• Planning for pregnancy. On folic acid 5 mg/d.
• What is the risk of poor cognitive outcomes in the offspring?
Case 8: Maternal epilepsy, AEDs and cognition of offspring

31. Maternal epilepsy, AEDs and cognition of offspring
• VPA during pregnancy is associated with lower IQ and a higher risk of ASD
and ADHD in the exposed children.
• In the NEAD study, the IQ of the children exposed to high dose VPA was 8-11
points lower compared to children exposed to other ASDs.
• However, with VPA doses of less than 1000 mg, the IQ was similar.
• A higher risk of autism was also noted in children exposed to CBZ and LTG.

32. Cognitive teratogenesis
Cognitive risk due to AEDs is present throughout pregnancy.
WWE not on AEDs No increased risk of poor cognitive outcome.
WWE on AEDs Conflicting conclusions.
CBZ No increased risk.
VPA Increased risk. Avoid in pregnancy
PHT Increased risk. Avoid.
PB Increased risk. Avoid.
Polytherapy Increased risk. Avoid.
Increased risk= greater than 2 times expected.

33. Case 9: ASDs and Bone health
• 56y/F, unclassified generalised epilepsy for the last 25 years.
• Was initially on PHT 200 mg/d and PB 30 mg/d.
• Rare breakthrough seizures.
• History of right radius fracture in the past.
• DEXA scan showed diffuse osteoporosis.
• Changed to CBZ 400 mg/d and PB 30 mg/d.
• On calcium supplements.
• Had another seizure and fall and fracture neck of femur on both sides.

34. AEDs and Bone health
• WWE have 2-6 times higher risk of fractures.
• Long-term use of enzyme-inducing ASDs is associated with low bone mineral
density in WWE.
• Risk with LEV and LTG is much lower.
• Regular exercise and cessation of smoking should be followed.
• Monitor Bone mineral density every 2 years in all postmenopausal WWE.
• Calcium (1,000 mg) and Vitamin D (800 U) supplements should be given to all
postmenopausal WWE and those on enzyme-inducing ASDs for > 3 years.

35. Pregnancy and seizure outcomes in WWE on LEV
monotherapy (personal experience)
• Study of 86 pregnancies in 80 women with epilepsy while on LEV
monotherapy.
• Between 2013 and 2017.
• One child had malformation of nasal bones.
• 1st trimester abortions= 4; 2nd trimester abortion = 2; IUD= 1 (same as
control group).
• Pregnancy and seizure outcomes were similar in the two groups.
• 55% of WWE underwent LSCS.

36. Summary and Conclusions
• LEV appears to be anti-seizure medicine of choice in WWE.
• LTG, LCS, OXC, CBZ are preferred next.
• Avoid Valproate, PB, PHT, TPM and CLB in WWE.
• Monitor for PCOD in women with epilepsy.
• Caution while using OCPs in women on enzyme inducing ASDs.
• Monitor for bone health especially with enzyme inducing ASDs.
• No contraindications for breast-feeding (caution with PB. BZD).

37. THANK YOU