Dr Parth Sarthi Deb

MD, DM

Epilepsy in Women

Epilepsy in women

Women

AEMEpilepsy

Outline1. Menarche

2. Menstrual cycle

3. Fertility

4. Weight gain

5. Poly Cystic Ovarian Syndrome

6. Oral contraceptive

7. Pregnancy

8. Fetus

9. Breast feeding

10. Menopause

11. Calcium and bones

Menarche

Few seizure appear during this age like JME, JAE 25%

Few childhood seizure change pattern

Sporadic seizure may become cyclical

Benign rolandic , Absence seizure may remit

Menstrual Cycle

• Menorrhagia• Oligomenorrhea• Metrorrhagia

• Simple partial• Complex partial

VAL+-CBZ

PCODWt. gain

Catamenial epilepsy

10-70% of epilepsy in women Type-I (Perimenstrual) Type-II (Periovulatory) Type-III (Second half of MC in

anovlulatory cycle ) Estrogen is pro-convulsant and Progesterone is anticonvulsant Cyclical use of Anticonvulsant Clobazam has show to be most

effective (60-80%) Natural progesteron 200mg tid is

effective used intermittently Clomifen also has shown effective

Effect of AEDs on Weight

Drug Weight gainValproate >50%

Carbamazepine 15-25%

Gabapentin 15%

Lamotrigine No

Levetiracetam No

Topiramate Loss in 45-85%

Mechanism of change in Weight

Alteration in appetite Alteration in lipid metabolism Alteration in insulin concentration Alteration in thyroid hormone Change in leptin (a compound or neurochemical very

much associated with regulation of appetite and metabolism)

Clinical Implication of weight gain

Obesity

Non compliance

Glucose intolerance

psychogenic

Dyslipidemia and Heart disease

Cancer

Sleep apnea

Polycystic ovary syndrome

More prevalent in epileptics 41% GTCS 26% Focal S

VAL. May contribute to PCOS (43%)

Rx with Clomiphene

Fertility

Reduced due to temporal and frontal lobe affection, hypothalamic dysfunction

Effect of AED on reproductive control system

Change in release of LH, prolactin and adrenal steroidal hormones

OCD dose adjustment is required with AED (CBZ, PHY, PHB,

Contraceptive in epileptic

PHY, PHB, CBZ, OXC induces hepatic P450 enzyme and cause contraceptive failure in 6-10%

Topiramate is weak enzyme induce

BNZ, LMT, VIG, GPT do no induces P-450

Epilepsy and Pregnancy

3-4 /1000 pregnancy has epilepsy

Effects of Pregnancy on Epilepsy

1. Seizure frequency may increase: i. Sleep deprivation, hormonal changes of

pregnancy (high Estrogen),

ii. associated psychological and emotional stress of pregnancy: all lower threshold for seizures.

iii. Nausea and vomiting.

2. Seizure frequency may decrease:

i. Improved compliance with drug regimen in some patients.

3. Seizure frequency may remain unchanged.

Effect of Epilepsy On Pregnancy

1. Data on 1st trimester losses, PROM (preturn rupture of membrane) ante-partum hemorrhage, operative vaginal delivery and CS are inconclusive.

2. Increased incidence of IUGR(intra uterine growth retardation), cognitive dysfunction, microcephaly and perinatal mortality (1.2 - 3 times normal).

3. Increased incidence of congenital malformations.

Effects of Epilepsy on Neonate

1. There is increased risk for infants of epileptic mothers to have epilepsy. The risk of neonatal susceptibility depends on:

i. Nature of the mother’s seizure disorder.

ii. Genetic factors.

iii. Seizures arises during pregnancy.

iv. Metabolic & toxic consequences of seizures and AEDs.

2. Increase perinatal morbidity.

Effects of Pregnancy on AED

1. Enhanced metabolism & increased drug clearance associated with pregnancy can result in decreased serum drug concentration.

2. Increased volume of distribution of the AED.

3. Increased serum binding proteins.

4. Decreased or non-compliance with medication.

Effects of AED on PregnancyAnatomic and behavioral teratogenesis Mechanisms:

1. Direct drug toxicity: due to accumulation of the drug metabolites (reactive intermediates) which are embryotoxic.

2. Antifolate effect: Phyntoins, carbamazepine & barbiturates impair folic acid absorption. Valproic acid interferes with the production of folinic acid.

3. Genetically determined deficiency of the detoxifying enzyme epoxide hydroxylase.

4. Possible genetic link between maternal epilepsy and malformations.

Neural tube defects

3-9% (N 1-3%) Often skin covered Anencephaly rare Spina bifida

predominantly – low lumber or sacral

Fetal Hydantoin Syndrome

11% of infants exposed will have the syndrome.

There is pre and postnatal growth deficiency, dysmorphic facies and mental retardation.

Fetal Valproate Syndrome:

Brachycephaly with high forehead, shallow orbits, small nose, small mouth & low posterior ears.

Long overlapping fingers & toes & hyperconvex nails.

Cleft palate & congenital heart diseases.

.

Behavioral Teratogenesis

In utero AED exposure can produce long-term behavioral changes:

In a retrospective Danish study, babies exposed in utero to phenobarbital had a 7-point decline in verbal IQ.

A prospective Finnish study found the mean verbal IQ score following in utero exposure to valproate was 82 compared with 96 for carbamazepine and 95 for healthy controls.

In a retrospective UK study of school-aged children exposed to in utero AEDs, 30% of children exposed to valproate monotherapy had additional educational needs compared with 3.2% of children exposed to carbamazepine monotherapy and 6.5% for other ani-epileptics.

Necessity for antiepileptic drugs Is the diagnosis of epilepsy well established? may show that the patient does not have epilepsy

or may reveal a treatable cause before pregnancy Does the patient require AEDs and if so, is she on

the most appropriate medications and the minimum dose to maintain seizure control

Withdrawing Antiepileptic Drugs

Many physicians will consider withdrawal of AEDs after a period of two years without seizures. The frequency of seizure recurrence within six and twelve months of discontinuing therapy is 12 and 32 percent, respectively.

Thus, if a woman has been seizure-free for a satisfactory period, a taper and withdrawal of AEDs at least six months prior to becoming pregnant is suggested

Approved use of AEDs

Drug SPS, CPS P/S GS Absence Myoclonic

Carbamazepine Yes Yes No No

Phenytoin Yes Yes No No

Valproate Yes Yes Yes Yes

Lamotrigine Yes Yes Yes Yes

Topiramate Yes Yes Yes ?

Levetiracetam Yes Yes ? ?

AED- Mono Versus Polytherapy

It is better to prescribe the lowest possible dose of a single drug to prevent and control fits.

Studies have shown higher incidence of malformations with polytherapy compared to montherapy.

If large daily doses are needed, then frequent smaller doses or extended-release formula may be helpful to avoid high peak levels. Dose should be divided into 3-4 doses/day. This is because high peak plasma levels of the drug is more teratogenic.

Newer AEDs fetal risk? There is limited human information on the fetal

risks of the newer antiepileptic drugs (eg, gabapentin, felbamate, topiramate, tiagabine, levetiracetam, pregabalin).

Animal studies shows them to be safer than older drugs

Failure of AEDs

An AED's failure to reduce seizures can be attributed to factors such as:1-Wrong dosing. 2-Improper timing. 3-Rapid administration of the drug. 4-Ignoring conditions that precipitated the seizure.5-Instability of the drugs. Many drugs disintegrate easily with moisture.

AEDs should be stored in a dry place and kept away from heat.6-Toxicity. 40% of patients experience toxic effects from older AEDs

which often causes them to withdraw. Among the most distressing are sleepiness, problems in coordination and weight gain.

7-About a quarter of patients who do not respond to AEDs actually have nonepileptic seizures that in many cases are caused by psychiatric conditions (e.g., panic attack, personality disorders).

AED: Clinical Or Subclinical Coagulopathy

Factors II,VII,IX & X are decreased.

Factors V, VIII & fibrinogen are normal.

PT & PTT should be determined at delivery.

If values are low or clinical coagulopathy develops in the neonatal period, TTT is by the infusion of FFP or concentrates of deficient factors in addition to the routine administration of vitamin K1.

Pre-conceptional Care:

A-Counseling: explain to the patient that: There is a chance of 90% of having normal child. Increased chance of having epileptic child (2-5%). Increased pregnancy complications. Increased unfortunate outcome if seizures arises during

pregnancy. Increased risk of congenital malformations.

B - Measurement of the free unbound anti-epileptic drug level in maternal serum.

C - Preconceptional folate supplementation: 5 mg daily.

Antenatal Care: Supplementation

A-Folic acid supplements.: 0.5-15mg throughout gestation B-Morning sickness: If hyperemesis gravidarum, consider giving

alternative route if vomiting is severe or prolonged.

C-Vitamin K:

Oral 20mg daily is prescribed from 36 weeks until delivery to mothers taking hepatic enzyme-inducing drugs (phenytoin, phenobarbitone, primidone, carbamazepine and topiramate - Not necessary with sodium valproate).

Antenatal - Monitoring

•Followup tests

Weeks

•AED levels (free and total), serum folate level

6-10

•Maternal serum AFP, amniocentesis,* AED levels

15-16

•Ultrasound for neural-tube defects

18-19

•Ultrasound for oral clefts and heart anomalies

22-24

•AED levels

28

•AED levels, maternal vitamin K

34-36

Labor and Delivery

“The risk of developing a seizure during labor is 9 times that during the rest of pregnancy”.

A. Check levels of AEDs. B. Consider seizure prophylaxis with intravenous

benzodiazepines or phenytoinC. Manage seizures acutely with intravenous benzodiazepines

(4-8 mg of Lorazepam), then load Phenytoin (1 g loaded over 1 h).

D. Start administration of vitamin K1 for the infant, and send the cord blood for clotting studies..

Postnatal CareA. Infant:

A. Inspected for malformation.B. Vitamin k 0.1mg/kg IM at birth reduces risks of hemorrhagic

disease. B. Bathing:

A. Never should be performed alone, as a brief lapse in attention can result in a fatal drowning. Wet sponge not water bath. Changing diapers and clothes are performed best on the floor rather than on an elevated changing table.

Postnatal Care: Breast feeding

No studies on the effects of AED on either quantity or quality of breast milk.

Breast feeding should be stopped if obvious sedation develops in an infant and is likely to relate to the presence of AED in breast milk.

Carbamazepine 40% Phenobarbital 36% Phenytoin 18% Valproic acid 5% Topiramate,Gabapentin,

?? Lamotrigine

Postnatal Care

D. Sleep: If the mother is breastfeeding, sleep deprivation may be unavoidable. The mother should make up any missed sleep during the infant's daytime naps, whenever possible.

E. Anticonvulsant: Any increase in drugs during pregnancy will need to be decreased slowly to pre-pregnancy doses over 3-4 weeks to avoid toxicity.

F. Contraceptions:

A. Barriers and IUDs are recommended.

B. Dose of OCD should be adjusted depending on types of AED

Summary Epilepsy in Pregnancy

1-Epileptic woman can get pregnant. They are not different than other women population.

2-Epilepsy and its medications increases the incidence of malformations 2-3 times normal. However; there is 90% chance of having a normal child.

3-The most common malformations are cleft lip, left palate and congenital heart diseases.

Summary Epilepsy in Pregnancy

4. A woman should not stop AED unless she has not had seizures for 2 years; gradual discontinuation can then be attempted.

5. A pregnant should not stops her AED Since most malformations develop during the 1st trimester.

6. Current AEDs are considered to be a necessary evil until newer drugs become available.

Menopause

Early menopause in some Increased estrogen /

progesterone increases seizure frequency

Reduced frequency of catamenial epilepsy

Bone health

AEDs may decrease bone mineral density and result in osteopenia, osteoporosis, and fractures, more likely in postmenopausal