epilepsy in womwan

1. WOMAN WITH
EPILEPSY
Dr prashant shringi
Senior resident
Neurology

2. Introduction
• Epilepsy is a highly prevalent neurological disorder ≈1%
of the population.
• About half of the women with epilepsy are in the
reproductive age group of 15–49 years.
• 0.5% of women of child-bearing age
• Commonest chronic neurological disorder to complicate
pregnancy.

3. • National Institute for Health and Care Excellence (NICE)
has also identified women in the reproductive age group
to have specific and unique problems in managing their
epilepsy.

4. ROLE OF HORMONES IN EPILEPSY
• Female hormones change the excitability of brain and
alter the threshold for seizures.
• There are times in a woman’s life when change in
hormone levels and hormone balance happen:
 during her periods
 during pregnancy
 throughout the menopause

5. HORMONES IN EPILEPSY
ESTROGEN
• PROCONVULSANT
• REDUCES INHIBITION AT
GABA -A RECEPTOR
• ALTERS mRNA FOR GAD AND
INHIBITS GABA SYNTHESIS
•
• Woolley CS, Schwartzkroin PA. Epilepsia 1998;39(suppl 8):S2-S8
PROGESTERONE
• ANTICONVULSANT
• INCREASESINHIBITION AT
GABA -A RECEPTOR
• ATTENUATES EXCITATION
OF GLUTAMATE IN
HIPPOCAMPUS
• ALTERS mRNA FOR GAD
AND INCREASES GABA
SYNTHESIS.

7. EFFECT OF AEDS ON WEIGHT
• Drug Weight gain
• Valproate >50%
• Carbamazepine 15-25%
• Gabapentin 15%
• Lamotrigine No
• Levetiracetam No
• Topiramate Loss in 45-85%

8. PCOD
• More prevalent in epileptics
41% GTCS
26% Focal Seizures
• Valproic acid May contribute to PCOS (43%)
• Rx - Clomiphene

9. Menarche
• Few seizure appear during this age like JME, JAE in
25%.
• Few childhood seizure change pattern.
• Sporadic seizure may become cyclical.
• Benign rolandic ,Absence seizure may remit.

10. Menarche
• Pitutary gonadotrophins (FSH AND LH)- Increased
• Ovarian steroids (estrogen and progesterone) increase in
overall concentration.

11. CATAMENIAL EPILEPSY
• SEIZURES that tends to cluster in relation to menstrual
periods.
 HIGH LEVELS OF ESTROGEN
 LOW LEVELS OF PROGESTERONE
 FLUID AND ELECTROLYTE IMBALANCE
 PSYCHOLOGICAL STRESS
 DECREASE IN LEVELS OF AEDS

12. CATAMENIAL EPILEPSY
• 10-70% of epilepsy in women.
• Type-I (Perimenstrual)
• Type-II (Periovulatory)
• Type-III (Second half of MC in anovlulatory cycle )
• CLOBAZAM has shown to be most effective (60-80%).

13. MENOPAUSE & EPILEPSY
• Early menopause in some.
• Increased estrogen /progesterone increases seizure
frequency.

14. FERTILITY RATE IN WOMEN WITH
EPILEPSY (WWE)

15. FERTILITY IN WWE
• Women with epilepsy have approximately 15% fewer
children than expected.
• Reasons –
Social effects of epilepsy
-Menstrual irregularity-
-1 of 3 women with epilepsy,
-Oligo and polymenorrhea (1/3)
-Anovulatory MC(1/3) .
-Effect of some antiepileptic medications on the ovaries
-Effect of seizures/AED on reproductive hormones.

16. • Age, lower education, and polytherapy with antiepileptic
medications also risk factors (Sukumaran et al., 2010)

17. CHALLENGES:pregnency in epileptic
female
• Pregnancy is a state where pharmacokinetic changes are
more pronounced and more rapid than during any other
period of life.
• Risks with uncontrolled seizures during pregnancy need
to be balanced against potential teratogenic effects of
antiepileptic drugs .

18. • Maternal mortality is ten-times higher in women with
epilepsy than in those without.
• Edey S, Moran N, Nashef L. SUDEP and epilepsy-related mortality in pregnancy. Epilepsia2014;
55:e72–74

19. EFFECT OF EPILEPSY ON
PREGNANCY
Spontaneous miscarriage
Antepartum haemorrhage
Postpartum haemorrhage
Hypertensive disorders (preeclampsia ,eclampsia )
Induction of labour

20. Caesarean section ( increased)
Any preterm birth before 37 weeks of gestation
Fetal growth restriction
WWE had increased risk of preterm delivery
• Maternal mortality risk is increased more than 10-fold
compared to women without epilepsy
• (MacDonald SC, Bateman BT, McElrath TF, Hernandez-Diaz S. Mortality and Morbidity
DuringDelivery Hospitalization Among Pregnant Women With Epilepsy in the United
States. JAMA Neurol.2015;72(9):981-8.)

21. Pregnancy Registries
• To assess pregnancy outcomes in women with epilepsy,
different groups established epilepsy and pregnancy
registries in the late 1990s
• Prospectively enrol large numbers of pregnancies with
exposure to antiepileptic drugs

23. • UK registry enrolls pregnancies from the United Kingdom
and Ireland
• NAAPR enrolls pregnancies mainly from the United
States and Canada.
• EURAP registry-Europe, Asia, Oceania, Australia, and
South America.
• Australian registry

24. • Seizures had occurred during pregnancy in-
79.2% of pregnancies with < 1 year of pre-pregnancy
seizure freedom
23% of those with at least 1 year’s freedom
20.5% with 2 years’ freedom
19% with 3 years’ freedom
17.5% with 4 years’ freedom and in 17.7% with 5 or
more years seizure-freedom

25. Women with epilepsy versus those without (2 809 984
pregnancies) had-
 increased odds of spontaneous miscarriage (OR
1·54, 95% CI 1·02–2·32; I²=67%)
 antepartum haemorrhage (1·49, 1·01–2·20; I²=37%)
 post-partum haemorrhage (1·29, 1·13–1·49;
I²=41%)
 hypertensive disorders (1·37, 1·21–1·55; I²=23%)
 induction of labour (1·67, 1·31–2·11; I²=64%)
 caesarean section (1·40, 1·23–1·58; I²=66%), any
 preterm birth (<37 weeks of gestation; 1·16, 1·01–
1·34; I²=64%), and fetal growth restriction (1·26,
1·20–1·33; I²=1%).

26. Seizure in pregnancy
• More than 70 % of patients pass through the pregnancies
without changes in seizure frequency
• Two-third remain complete seizure-free
• Minor proportion of WWE experience reduced seizure
frequency
• Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Seizure control and
treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry.
Epilepsia.2013;54(9):1621-7

27. • One-quarter to one-third of pregnant have increased
seizure frequency or seizure recurrence during the course
of their pregnancy
• Status epilepticus occurs in 1 – 2% of pregnancies in
women with epilepsy

28. • WWE will experience a seizure during labour or within the
first 24 hours after delivery.
• Nine-fold increase in seizures compared to the risk during
pregnancy in general.

29. Seizure deterioration in pregnancy
• Women who have been seizure-free up until the
pregnancy breakthrough seizures –
1 trimester:- poor compliance
• Labour and delivery is the period with the highest risk of
seizures
• Risk of having a GTCS during labour is approximately 1 –
2%
• and when all types of seizures on average 5%.

30. • Excessive nausea
• Vomiting
• Non-compliance especially during the first trimester
• Hormonal changes, sleep deprivation, anxiety, and
psychosocial stress provoked by the pregnancy may also
influence negatively on seizure susceptibility

31. Risk factors for deteriorated seizure
control
• Each pregnancy tends to have its own seizure pattern,
which means that even if a serious worsening of seizures
occurs during one pregnancy, the woman does not need
to be discouraged if she wants to become pregnant
again(NICE 2012 GUIDELINES).

32. Highest risk of seizure worsening
Patients with focal epilepsy
Use of polytherapy
Specific AEDs (lamotrigine and oxcarbazepine)
• Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al.
Seizure control and treatment changes in pregnancy: observations from the
EURAP epilepsy pregnancy registry. Epilepsia.2013;54(9):1621-7

33. • Pregnancy can alter the pharmacokinetics of most AEDs
and lead to increased clearance of the drugs
• Fall in the plasma concentration is the most common
explanation for seizure deterioration
• Lamotrigine Oxcarbazepine and Levetiracetam have
increased clearance during pregnancy and require close
monitoring throughout pregnancy.
• Pennell PB, Peng L, Newport DJ, Ritchie JC, Koganti A, Holley DK, et al. Lamotrigine in
pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology.
2008;70

34. Treatment during pregnancy
Cochrane Database of Systematic Reviews 2004, Issue 3
It is advisable for women to continue medication during
pregnancy using monotherapy at the lowest dose required to
achieve seizure control.
Polytherapy would seem best avoided where possible.

35. Recommendations for delivery
• Vaginal delivery is recommended.
• Caesarean delivery can be considered in cases of high
risk of GTCS (1%-3%), or if prolonged or frequent CPS
make it difficult for the woman to labour.
• Epidural anaesthesia can be administered
• Using prostaglandins is not contraindicated.

36. Recommendations for delivery
• Plasma levels should be checked 2 to 3 weeks after
childbirth. If doses were changed during pregnancy, they
should be adjusted again
• Advice on sleep hygiene
Epilepsia, 50(Suppl. 1):7–23, 2009

37. INDICATIONS OF CAESAREAN
SECTION
• Frequent seizures greatly impair cooperation in
forthcoming labour and delivery.
• Generalised seizure during labour.
• Refractory status epilepticus in the third trimester.
• Sveberg L, Svalheim S, Taubøll E. The impact of seizures on pregnancy and delivery. Seizure 2015;28:35–8.-
Dubovický M. Neurobehavioral manifestations of developmental impairment of the brain. Interdiscip Toxicol
2010;3:59–67

39. ANTENATAL SCREENING

40. Neonatal outcomes
• Children of WWE have an increased risk of-
Born with low Apgar scores
Low birth weight (<2500 g)
Small for gestational age
Major congenital malformations,
Intrauterine growth retardation
long-term cognitive and behavioral dysfunction of the
offspring

41. • Relative impacts of different seizure types are difficult to
determine-
SPS have minimal effect on the fetus.
CPS may leads to injuries due to L.O.C.
GTCS are feared the most-injury, alterations in
electrolytes, blood pressure and oxygenation.

42. AED & MCM

45. • Kerala Registry of Epilepsy and Pregnancy had been
prospectively evaluating the reproductive issues of
women with epilepsy since April 1998 to 2013.

50. Terato genecity of AED
• Most serious teratogenic effects occur during the first 2.5
months of gestation.
• Changing medication before or during the first trimester is
most useful.
• The neural tube closes between 3 and 4 weeks.
• Cleft lip and palate occur with exposure before 5 and 10
weeks, respectively
• Congenital heart disease occurs before 6 weeks.

51. • Valproate doses over 800 mg/day - highly teratogenic.
• Lamotrigine has been associated with low teratogenic
risks.

52. NON-TERATOGENIC EFFECTS OF AEDS
ON CHILDREN EXPOSED , IN UTERO
• There is a longer term risk to the cognitive and
behavioural development of the child exposed in utero to
sodium valproate.
• Although less certain, there may also be risks associated
with phenobarbital and phenytoin exposure.

53. NEAD STUDY
• Neurodevelopmental Effects of Antiepileptic Drugs
(NEAD) study [Meador et al. 2013]
• NEAD was a prospective observational study of cognitive
development in children exposed in utero to VPA, LTG,
CBZ monotherapy.

54. • A 6-year follow up of 224 children showed that intelligence
quotient (IQ) at age 6 was lower in exposed to VPA (mean
97) compared with CBZ (mean 105), LTG (mean 108)
monotherapy.
• VPA exposure to doses higher than 1000 mg per day had
a negative impact on verbal ability, nonverbal ability,
executive function and memory in exposed children

55. ROLE OF FOLIC ACID IN TREATING
PREGNANT WOMEN WITH EPILEPSY
• Folic acid supplements reduce the risk of NTD
• Folic acid 5 mg once daily is the widely recommended
dose for WWE on AED.

56. PLACE OF VITAMIN K IN PREGNANCY
• All children born to mothers taking enzyme-inducing AEDs
should be given 1 mg of vitamin K parenterally at delivery.
[NICE]
• To avoid bleeding in the newborn.

57. Breast feeding
• Encourage
• Breastfed children may have a higher IQ.
• To minimize infant AED exposure,maternal AEDs should
be kept to a low effective dose, and if signs of potential
adverse reactions noted (lethargy, poor feeding), infant
serum concentrations can be monitored

58. AED concentration in breast milk

59. CONTRACEPTION IN WOMEN WITH
EPILEPSY
• Induction of hepatic cytochrome P450 enzyme activity –
Phenytoin ,Pheno.,CBZ etc
• Increases the rate of metabolism of both oestrogen and
progestogen.
• Failure rate of contraceptive pill with AEDs is about twice
that in the general population

61. WWE & CONTRACEPTION
• Depot medroxyprogesterone-acetate (MPA) injections
appear to be effective
• A/E- delayed return to fertility, impaired bone health
• Levonorgestrel intrauterine system (IUS) appears to be
effective, even in women taking EI-AEDs.

62. • In combined oral contraceptives, during the period ‘‘on the
pill’’ lamotrigine levels decrease by approximately 50%,
followed by an increase of lamotrigine levels in the
contraceptive-free week up to 80—100% of the baseline
lamotrigine level
• Result in an increased risk of seizure recurrence
especially in week 2 and 3 on the pill or in concentration-
dependent adverse effects at the end of the pill-free
interval
• Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce
lamotrigine plasma levels. Neurology August 26, 2003;61(4):570—1.

63. BONE HEALTH
• AEDS MAY DECREASE BONE MINERAL DENSITY AND
RESULT IN OSTEOPENIA, OSTEOPOROSIS, AND
FRACTURES
• Phenytoin
• Phenobarbiyone
• Valproic acid
• Carbemezepine
• Oxcarbemezepine

64. MENTAL HEALTH
• Psychiatric comorbidity is high in patients with epilepsy
often as a result of AED treatment.
• Prevalence rate of psychiatric conditions in epilepsy
ranges between 20–30%.
• Depression-M/C
• Psychosis
• Peripartum depression,
• Anxiety

65. LEGAL ISSUES
• Social stigma
• Fertility
• Economical issues
• Mental health
• Marriage
• Abortions
• Divorces

66. • Special Marriage Act of 1954 stated that a marriage under
these acts can be solemnized “if at the time of marriage,
neither party suffers from recurrent attacks of insanity or
epilepsy.”
• It took 12 years for Dr. K. S. Mani, often referred as “father
of Indian epilepsy,” and the IEA to have the word
“epilepsy” deleted from this law.

67. • Thank you

68. Refrences
• Malformation risk of antiepileptic drug exposure during
pregnancy in women with epilepsy: Results from a
pregnancy registry in South India; sv thomas et al;
Epilepsia, **(*):1–8, 2017 doi: 10.1111/epi.13632.
• Management and treatment of women with epilepsy
during pregnancy; Anne Sabers, 3rd Congress of the
European Academy of Neurology Amsterdam, The
Netherlands, June 24 – 27, 2017.
• Practice Parameter update: Management issues for
women with epilepsy—Focus on pregnancy (an evidence-
based review):Obstetrical complications and change in
seizure frequency,harden et al.

69. • Management of epilepsy during pregnancy:an
update;patel et al, Ther Adv Neurol Disord1–12DOI:
10.1177/ 1756285615623934.
• Bradleys neurology 7 edition.