Women with epilepsy WWE BY GAMAL YOUSOF MD

Women with epilepsy (WWE) BY GAMAL YOUSOF MD. NEUROLOGY KAFR EL SHEIKH GENERAL HOSPITAL COPY

Can you answer these questions? � 1 -Is epilepsy affected by menstruation and why? � 2 -What to do when your patient wants to get pregnant, stop drugs , reduce dose , or change the drug. or what else , how to protect the fetus? � 3 -How to prepare your patient for delivery. are there any precautions to do , what? � 4 -Is there any care for the newborn of epileptic mother? � 5 -Can epileptic mother lactate her baby while she is taking AEDs?

Epilepsy and hormonal cycle The hormones estrogen and progesterone are produced in a woman's body at puberty. • There are times in a woman's life when changes in hormone levels and hormone balance happen: – during her periods, – during pregnancy – throughout the menopause. .

Puberty is a common time for epilepsy to start.

Menarche -Certain genetically determined epilepsies (i. e. , JAE and JME) will present around puberty, -some nongenetic partial epilepsies may worsen causing them to come to medical attention at this time. -Childhood absence and benign rolandic epilepsy may remit at puberty

At menarche -pituitary gonadotropins (FSH and LH) and ovarian � steroids (estrogen and progesterone) increase in overall concentration

Catamenial epilepsy Menstrual cycles and periods Some women find their seizures often happen just before and during their period. Others may find their seizures regularly occur at another particular time during their cycle, such as at cycle (ovulation)

Estrogen is epileptogenic � but progesterone is antiepileptic

Catamenial epilepsy When women have seizures only during their periods and at no other time, this is called catamenial epilepsy. Women with catamenial epilepsy might benefit from taking an extra type of medication during the week before and for the first few days of their period.

patterns of Catamenial epilepsy 1 -Perimenstrual (both are low) 2 -Periovulatory(estrogen and progestrone ) 3 -Inadequate luteal phase(inadequate progestrone) inadequate luteal periovulatory perimenstrual

Treatment 1 -Increase AEDs doses 2 -Add acetazolamid (cidamex) 3 -Premenstrual BZD 4 -Pthers OCS natural progesterone, and estrogen receptor antagonist clomiphen, or hysterectomy and oophorectomy.

Fertility Fluctuations of luteinizing hormone and pulsatile release of prolactin and sex steroids have been observed in temporal relation to some seizures The most common symptoms are – hyperandrogenism, – menstrual disorders with ovulatory failure, – polycystic ovary-appearing ovaries or polycystic ovary syndrome, and hyperinsulinemia • These symptoms may be secondary to epilepsy or to AED treatment, particularly with valproate

Fertility Epilepsy and antiepileptic drug-related changes in hypothalamic, pituitary, and gonadal hormones have been associated with: increased rates of infertility, anovulatory cycles, menstrual irregularity, polycystic ovaries.

polycystic ovarian syndrome Polycystic ovarian syndrome is widely believed to be common in women with epilepsy, but the actual prevalence and the pathogenesis of PCOS in this population are disputed.

PCOS For women with PCOS, ova are not released and they stay in the ovary and form cysts. This syndrome also causes a higher level of the hormone testosterone than normal.

PCOS can cause – irregular or infrequent periods – weight gain – increased hair growth. – It may also make becoming pregnant more difficult

PCOs Valproate, may directly cause PCOS or indirectly lead to the disorder by causing weight gain that triggers insulin resistance, increased testosterone levels, and other reproductive abnormalities

Preconception Starting a family • Pre-conception counselling • Risks during pregnancy, associated with epilepsy and anti-epileptic drugs • Risks of major congenital malformations related to specific anti-epileptic drugs

women should not be discouraged from becoming pregnant During pregnancy the major risks to mother and child result from loss of seizure control an elevated risk of major congenital malformations due to antiepileptic drug treatment

Pregnancy The goal of the antiepileptic drugs is to achieve good control of seizures with minimal side effects for fetus and mother Any change of AEDs should Be before getting pregnant

Starting a family Folic acid • Folic acid supplements of 800 umg up to 5 mg a day should bebtaken by women with epilepsy who are planning a family. These should start before conception and be continued § throughout the first three months of pregnancy. • As accidental pregnancies are common, some doctors suggest that any woman with epilepsy who could become pregnant should take 5 mg of folic acid daily all the time.

Starting a family Folic acid There is some evidence, however, that folic acid can interact with phenytoin and primidone, MAKING THEM LESS EFFECTIVE.

Once your pateint get pregnant Current evidence suggests that unborn babies are only very rarely harmed by their mothers' seizures, unless the mother falls and injures the baby. For this reason, it is a good idea to aim to have as few seizures as possible during pregnancy.

Pregnancy During pregnancy, the seizure frequency was unchanged, or the change was for the better in the majority (83%) of the patient No significant differences between Women With Active Epiepsy and controls in the incidence of preeclampsia, preterm labor, or in the rates of caesarean sections, perinatal mortality, But some said that there may be increase of the incidence of these complication

Pregnancy The rate of small-for-gestational-age infants was significantly higher, and the head circumference was significantly smaller in WWAE. The frequency of major malformations was 4. 8% in the 127 children of WWAE.

Pregnancy � Increased incidence of IUGR, cognitive dysfunction, microcephaly and perinatal mortality (1. 2 - 3 times normal).

Pregnancy Major Congenital Anomalies (MCA). Children who are born to women with epilepsy have a higher risk of birth defects, probably related to inutero exposure to antiepileptic drugs Because available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of Major Congenital Anomalies (MCA). Establishing definite evidence of teratogenicity with a particular drug is difficult. Valproic acid is associated with a greater incidence of MCAs than other AEDs.

Pregnancy Major Congenital Anomalies (MCA). • VPA has been associated with a variety of major and minor malformations, an increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism. increases • Polytherapy treatment in epileptic pregnant women the risk of teratogenicity in offspring Always use monotherapy when possible (tegretol) • There is an established relationship between VPA dose and adverse outcome.

drugs Carbamazepine (goody) � Sodium Valproate (baddy) � Lamotrigine (goody/baddy) �

Pregnancy • Fetal valproate syndrome results from in utero � exposure to valproic acid. It is � • Characterized by a distinctive facial � appearence, a cluster of minor and major � anomalies, and central nervous system � dysfunction. �

Teratogenicity Antiepileptic drugs (AEDs) have the potential to produce both anatomic and behavioral teratogenesis. Mechanisms: 1 -Direct drug toxicity: due to accumulation of the drug metabolites 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.

Specific Syndromes Of Malformations 1 -Fetal Hydantoin Syndrome: 11% of infants exposed will have the syndrome. � There is pre and postnatal growth deficiency, � dysmorphic facies mental retardation � Facial features of the fetal hydantoin syndrome. � Note broad, flat nasal ridge, epicanthic folds, � mild hypertelorism, and wide mouth � with prominent upper lip. . � � 3 -Barbiturates Withdrawal Symptoms Starts 1 week after birth & includes restlessness, constant crying, irritability, difficult sleeping & vasomotor instability.

Low birth weight

Withdrawal of medication? !!!!! Should she discontinue the carbamazepine? � If seizure free for two years (all types) withdrawal � can be considered Refer to neurologist if still want to consider drug � withdrawal. Need to discuss risk/benefit in detail.

Pregnancy • Investigations – Ultrasound High resoultion at 11 -13 weeks -Serum alpha fetoprotein at 16 weeks -Second trimester ultrasonic at 18 -22 weeks -Amniocentesis and measuring alpha fetoprotein to exclude anomalies – Blood levels especially in women whose epilepsy is normally difficult to control

The last months Third trimester -Maximum dose can be used Last month -Monitoring of serum levels of the AEDs -Vitamin K to mother to avoid vaginal bleeding and --protect the infant against hemorrhagic disease of the mothers taking hepatic enzyme-inducing drugs (phenytoin, phenobarbitone, primidone, carbamazepine and topiramate - Not necessary with sodium valproate).

Labor

Giving birth • Epilepsy should not prevent having a normal � labour and delivery. � • Anti-epileptic drugs (AEDs) should be taken as � The usual schedule during labor -I. V or-I. M forms may be needed(BZD. PHYENTOIN) -2 -4 weeks after delivery AEDs doses may return to normal.

Giving birth • Epidural anaesthesia/analgesia can be used in � labour. � • Some doctors feel Pethidine is probably best � avoided as this may trigger seizures. � • Entanox, nitrous oxide and oxygen is safe, so � long as the mother does not over-breathe when � using it, since over-breathing can trigger � seizures in some people. �

At labor Start administration of vitamin K 1 for the infant, � and send the cord blood for clotting studies. Management of a pregnant patient in status epilepticus: Establish the ABCs, and check vital signs. � Assess the fetal heart rate. � Rule out eclampsia. � Administer a bolus of lorazepam (0. 1 mg/kg, ie, 5 - � 10 mg) at no faster than 2 mg/min. (ttt as usual)

A nice girl from your nice management

lactation

Breast-feeding • The decision whether to breast-feed is up to the � mother. Unless the baby is born prematurely, the � small amount of anti-epileptic drug (AED) that � gets into breast milk is very unlikely to affect the � baby. � • In prematures it is advisable to discuss � breastfeeding with your baby's paediatrician, because � some AEDs may accumulate in the baby's body � and may cause them problems �

He searchs for his food in spite of your prevention

Contraception There are many different methods of contraception to prevent pregnancy. There are no contraindications to the use of non hormonal methods of contraception in women with epilepsy

Barrier methods of contraception include condoms, diaphragms and caps. These methods are not affected by taking AEDs.

Intrauterine devices (IUDs) and intrauterine systems (IUSs) • IUCDs (often called 'the coil'). • The Mirena coil is an IUSs which contains the hormone progesterone (in a slow release form called levonorgestrel). Like barrier methods such as condoms and diaphragms, IUDs and IUSs are not affected by AEDs.

Contraception There is no evidence that the contraceptive pill affects epilepsy or AEDs. But some AEDs can affect how well the pill works. This depends on which AED is being taken

Contraception. AEDs can be divided into two groups, enzyme inducing drugs and non enzyme-inducing drugs. The AED that is being taken may affect what contraception is chosen.

Contraception • Non enzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. . Hepatic microsomal-inducing EIAEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. -. 5 to 6 folds failure rate of OCS

The combined oral contraceptive pill ' • Enzyme-inducing AEDs cause the hormones in the pill to be broken down more quickly, so the pill is less effective. • If a woman is taking an enzyme-inducing AED she may be given the pill with a higher amount of estrogen. Even with this higher dose, the pill can still be unreliable. • To be effective it is often best to use other methods of contraception.

Contraceptives �Lamotrigen is exception of EIAED �LTG OCs

The combined oral contraceptive ' Usually when a woman's estrogen levels are high, there is a higher risk of seizures happening. But when the levels of estrogen are higher because of the pill, the risk of seizures is not higher. This is because the body gets rid of the estrogen from the pill quickly. If bleeding happens between periods, it means that the dose of estrogen is not enough and the pill may not be reliable against becoming pregnant.

Sleep is forbidden Sleep for babies only

What is Menopause? Some prefer to define menopause as a rose

but some prefer to define menopause like that

Menopause � menopause can alter seizure control. Women who have had reproducible catamenial patterns are more likely to experience improved seizure control after menopause. � perimenopausal time results in erratic fluctuations in gonadal steroids, which can temporarily worsen seizures. Once hormone levels stabilize, such effects should improve, but exogenous hormones and the increasing risk of cerebrovascular disease may obscure this benefit. � Postmenopausal estrogen replacement has been reported to exacerbate seizures in some women with epilepsy. � therapy (HRT) can be of benefit to them.

Bone health � AEDs may decrease bone mineral density and result in osteopenia, osteoporosis, and fractures. Although these risks are present in both men and � women treated with AEDs for more than several years, postmenopausal women are especially susceptible due to the added risk factor of hormonal depletion.

Bone health Cytochrome p-450 enzyme-inducing agents � (phenytoin, phenobarbital, primidone, carbamazepine) increase vitamin-D metabolism, leading to decreased calcium absorption in the intestine, and increased parathyroid hormone, causing bone calcium stores to be mobilized. - Reports suggest that non-enzyme-inducing AEDs, � such as valproate, may also result in decreased bone mineral density, though to a lesser degree

Bone health Calcium supplements are most helpful when used in � conjunction with vitamin C (which promotes absorption of calcium) and vitamin D

Advice for pregnancy for miss ﺍﻣﻴﺮﺓ One and a half years her epilepsy is well-controlled – she has had one fit only since then. She and her husband want to start a family but she has come to you for advice – should she discontinue the carbamazepine?

miss ﻣﺮﻭﺓ Has become unexpectedly pregnant while taking � AEDs. She had a coil but unfortunately it fell out. What do you tell her and what care is she offered in pregnancy

miss ﻣﺮﻭﺓ Had a successful pregnancy and in the third trimester asks your advice about the birth. She has read that people can have fits during delivery and she is worried about this, and she is also concerned about breast feeding while taking medication. How might you advise her?

Antiepileptic Drug Effects on Oral Contraceptives Antiepileptic Drug Effects on Oral � Contraceptives � • Agents that induce liver enzymes and may compromise Oral � Contraceptive efficacy � – Carbamazepine � – Felbamate � – Phenytoin � – Phenobarbital � – Primidone � – Oxcarbazepine � – Topiramate � • Agents that do not compromise Oral Contraceptive efficacy � – Gabapentin � – Levetiracetam � – Lamotrigine � – Tiagabine � – Valproate � – Zonisamide �