Osama RagabAss.lec of NeurologyFaculty of Medicine

Tanta University2013

Having a diagnosis of epilepsy can make you re-question your whole life plan

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Approximately one-half million women withepilepsy are of childbearing age.

It has been estimated that3–5 births per 1000 willbe to women with epilepsy.

Women with epilepsy are at an increased risk ofgestational hypertension, but not preeclampsia.

There is a possible additive effect of epilepsy andsmoking on the rates of preterm delivery.

Seizures, including status epilepticus, duringpregnancy can be fatal to both mother andfetus.

The overall likelihood of major congenitalmalformations in neonates exposed to anyAED ranges from 2.2% up to 11%.

Infants born to women with epilepsy who aretaking AEDs have twice the risk of being smallfor gestational age and low Apgar scores .

AEDs have been associated with a higher rate ofspontaneous abortion (2 times normal)

PREGNACY & FETUS

Neurons and glia are equipped for local de novoproduction of steroid hormones mainly in thehippocampus .

Neurosteroids are known for their non-genomic acuteeffects by direct modulation of NMDA receptorsand GABAA receptors.

Neurosteroids are responsible mainly for “finetuning” of neuronal excitability by acting atsynaptic and extrasynaptic receptors.

Neurosteroids also play an important role in neuronalsurvival in developing as well as aging brain .

Disturbances in the neurosteroid production havebeen detected in sclerotic hippocampal tissue frompatients with temporal lobe epilepsy, and otherneurodegenerative disorders (such as Alzheimer'sdisease or multiple sclerosis).

Sex hormones are critical for regulating neuronalexcitability and survival.

in some women with epilepsy, seizure exacerbation canbe related to periodical hormonal fluctuationsduring the ovarian cycles.

Seizures also often change pattern, expression or onsetat the time of natural hormonal changes such asadolescence . pregnancy , and during theperimenopause and menopause .

Some epileptic syndromes may either remit (benignrolandic epilepsy, childhood absence) or have theironset (juvenile myoclonic epilepsy) in adolescence,indicating the likely influence of hormonal changesand maturation occurring around puberty.

The dramatic irregular fluctuations in gonadalhormones during the onset of menopause(perimenopausal stage) and their loss at menopauseare likely to influence seizure frequency.

Chronic administration of progesterone has anti-seizure effect related to its metaboliteallopregnanolone which modulate GABAAreceptors .

chronic administration of allopregnanolone contributesto a paradoxical agrevate seizure by increasing theexpression of α4 subunit of GABAA receptors.

The agrevation could be related to progesterone-induced increase in dendritic spine density withmushroom like spines .

Estradiol has mixed effects when administered acutelyranging from no effect, mild anticonvulsant toproconvulsant effects depending whether physiologicalor supraphysiological doses have been used.

Seizure limiting effects linked mainly to regulation ofneuropeptide Y (NPY) in the hippocampus . (powerfulinhibitory peptide) .

The neuroprotective effects of estradiol on seizure-induceddamage were linked to the regulation of NPYexpression.

Unlike estradiol, progesterone has only anticonvulsant butnot neuroprotective effects.

Effects of epilepsy on

reproductive hormones

The hypothalamus receives many direct connectionsfrom parts of the temporal lobe that are involved inthe generation of seizures.

Increased frequency of pulsatile secretion of luteinizinghormone (LH) has been observed in women withepilepsy and may contribute greatly to alterations inovarian cycle.

Higher LH pulse frequencies positively correlateespecially with localization of the focus in the lefttemporal lobe compared to lower LH pulsefrequencies in patients with the right side foci .

A significant increase in allopregnanolone serum levelwas observed in both male and female prepubertalchildren, independent on the type of epilepsy,during the post-ictal phase but not during the inter-ictal phase.

AEDs that induce hepatic microsomal enzymes(EIAEDs) also interact with hormonalcontraceptives to increase estrogen’s metabolismand progesterone’s protein binding, therebydecreasing concentrations of both hormones andthus reducing contraceptive efficacy .

A large number of women with epilepsy have somedegree of sexual and/or reproductive dysfunction .

Sexual dysfunction may include difficulty with libido,arousal, and orgasm.

Libido difficulties are reported more often inindividuals with complex partial than generalizedseizures.

Some women report normal sexual desire but difficultor painful coitus (dyspareunia).

Some women report normal sexual desire but difficultor painful coitus (dyspareunia).

Physiologically, the areas of the brain that mediatesexual behavior are the same areas that are involvedin common forms of focal epilepsy.

A recent study found improvement in sexual functionfor both women and men associated withlamotrigine (LTG) therapy .

Resective brain surgery as a treatment for medicallyrefractory seizures has also been shown to restoresexual function.

Sildenafil is also being studied to improvevasocongestion in women .

Women with epilepsy have a fertility rate 60–80% thatof women without epilepsy.

One-third to one-half of women with temporal lobeepilepsy report difficulties with their menstrualcycle, with 20% having amenorrhea ,oligomenorrhea. Some women experienceanovulatory cycles.

Women with epilepsy are at risk for polycystic ovaries,a major contributor to infertility

The association between epilepsy and reproductiveendocrine disorders is a matter of controversy.

Epilepsy is associated with these disorders by itself.But AED therapy may have a greater effect onendocrine function.

Women with epilepsy are eligible for fertility treatmentwhether or not they are taking AEDs.

An in-depth history should delineate the duration ofepilepsy, frequency of seizures, the use of AEDs,their type, and the response to these medications.

Attention should be given to past obstetrical historyincluding maternal as well as neonatal outcomes,with stresses congenital anomalies.

If the patient has been seizure free for more than oneyear, then discontinuation of AEDs can beconsidered.

If the seizure-free interval is less than 1 year,monotherapy of the least teratogenic drug at thelowest effective dose is recommended.

Women who decide with their doctor to trytapering off AED therapy should begin atleast 6 months prior to becoming pregnant.

Changes in AEDs should also be made prior toa planned pregnancy to ensure seizurecontrol.

The adverse structural and functional effects of inutero exposure to AEDs are dose dependent.

The lowest effective dose to control seizureactivity should be used.

Anticonvulsant level, drawn prior to morningdose of AED, to identify the serumconcentration at which seizures are maximallycontrolled. This level will then be used forfuture comparison during pregnancy.

the American College of Obstetricians andGynecologists recommends 4.0 mg of folic aciddaily for women at risk of having offspringwith neural tube defects (including womentaking AEDs).

Pregnancy has a variable and unpredictable effecton epilepsy.

It is difficult to predict the change in seizurefrequency during pregnancy with the rate ofseizures decreasing in 3–24% of patients,increasing in 14–32%, and unchanged in 54–80%.

Remaining seizure free for at least nine monthsprior to conception is associated with greaterlikelihood (84–92%) of remaining seizure freeduring pregnancy.

Seizure frequency may increase: due to:

-Enhanced metabolism & increased drug clearance associated withpregnancy can result in decreased serum drug concentration.

-Increased volume of distribution of the AED.

-Increased serum binding proteins.

-Decreased or non-compliance with medication.

-Sleep deprivation, hormonal changes of pregnancy and associatedpsychological and emotional stress of pregnancy: all lowerthreshold for seizures.

-Nausea and vomiting.

If a patient presents to prenatal care and did notreceive preconceptual drug therapyoptimization, withdrawal of medication shouldnot be attempted as this may provoke maternalseizures and possibly status epilepticus.

In addition, changes in medication expose thefetus to polytherapy and thus increase the riskof malformations.

Maternal plasma drug levels should be monitoredmonthly and compared to pre-pregnancylevels, if possible . Medication dosage is thenadjusted according to both plasma levels andseizure activity.

Supplemental folic acid should be started prior toconception and then discontinued after twelveweeks of gestation

The pharmacokinetic and pharmacodynamic effects ofall AEDs can change during pregnancy .

Throughout pregnancy, the plasma volume increaseswhich will change the drug distribution. Cardiacoutput and renal blood flow increase, thusincreasing renal clearance of medications.

Pregnancy induces the cytochrome p450 (CYP 450) super-families in the liver, thus liver metabolism of certain drugs increases.

Conversely, fat storage increases thus fat-soluble drugelimination slows down.

Total drug levels may decrease due to a decrease inAED transporters including albumin and alpha1-acid glycoproteins, but the unbound concentrationdoes not change.

The unbound form of the drug determines thetherapeutic, toxic, and teratogenic effects.

Among the AEDs, there is no single best choice fortreatment of seizures.

The drug with the lowest risk of teratogenesis incombination with the ability to control seizures withthe lowest dose and monotherapy form is ideal.

primarily metabolized in the liver by the CYP450 enzyme.

The rate of major congenital malformations withphenytoin monotherapy use ranges 0.7–7.4%.

The Fetal Hydantoin Syndrome ,hypoplasia and irregularossification of the distal phalanges, facial dysmorphismepicanthal folds, hypertelorism, broad and depressednasal bridge, an upturned nasal tips,intrauterinegrowth restriction, and intellectual disability.

The free plasma concentration varies significantly duringthe second and third trimesters.

Metabolism urs predominantly in the liver by thecytochrome p450 superfamily.

The free plasma concentration of carbamazepineincreases in a non-significant manner duringpregnancy. Monthly monitoring of carbamazepinelevels is not recommended.

The rate of congenital malformations withcarbamazepine monotherapy use ranges 2.2–6.3%.

The specific congenital malformation associated with inutero carbamazepine use cardiac malformations andoral clefts

Valproate exposure is associated with a 1–2% risk ofneural tube defects (i.e. a 10–20-fold increase over thegeneral population), an increased risk ofneurodevelopmental deficits.

The most common birth defects with valproate use,orofacial clefts, congenital heart defects, hypospadias,and skeletal abnormalities, reduced verbal abilities, andlower IQ.

In comparison to other AEDs, valproate has the highestrisk of major congenital malformations.

Valproic Acid use in pregnancy should be avoided ifpossible.

Metabolism of lamotrigine occurs throughglucuronidation in the liver.

Several studies suggest that lamotrigine clearanceincreases by about 65–94% and therefore should bemonitored frequently during the second and thirdtrimesters.

The prevalence of fetal congenital malformations within utero exposure to lamotrigine is 2–3%, with themost common malformation being cleft lip/palate.

Excreted primarily through the kidneys.

Pregnancy appears to enhance the elimination oflevetiracetam resulting in marked decline in plasmaconcentration, which suggests that therapeuticmonitoring may be of value.

Rate of major congenital malformation of 0.70%.

Cognitive defects have not been seen in childrenexposed to levetiracetam or lamotrigine.

Plasma concentrations of topiramate vary greatlyduring pregnancy, therefore it is necessary tocarefully monitor serum levels.

The rate of major congenital malformations withtopiramate monotherapy ranges 2–3.8%, with cleftlip and palate occurring most frequently.

Gabapentin It is renally excreted.

There is no data that describes the pharmacokinetics ofgabapentin during pregnancy, thus obtainingmonthly serum levels may be of benefit.

Data regarding the teratogenic effects of gabapentin isvery limited and inconclusive, with rates of majorcongenital malformation uncertain (0–6%).

Seizures can lead to reduced placental circulation andsecondary ischemia in the fetus.

Optimal reperfusion after the circulation is restoredcan lead t o increased oxidative stress, which inturn could exert teratogenic effects.

AED usage may lead to folate deficiency which inturn may predispose to neural tube defects.

AEDs increase the levels of arene oxides as abyproduct of its metabolism. Arene oxide is apotent teratogen.

Alteration in the homeobox (HOX) genes, retinoicacid signaling pathways, histone deacetylators andpolymorphisms involving AED transporters.

Neural tube closure occurs at about Day 26 ofpregnancy, often before a woman is aware that she ispregnant. Neural tube and cardiac defects occur inthe first 28 days following conception, so folatesupplementation should begin before conception isattempted and continue throughout the pregnancy.If the folate supplement is begun more than 30 daysafter conception, it will not provide protectionagainst a NTD.

Current recommendations For any sexually activewoman of childbearing potential, recommendeddaily allowances of folic acid have been increased to400 μg/day for nonpregnant women, 600 μg/day forpregnant women and 500 μg/day for lactatingwomen.

Many epileptologists recommend higher doses (800 μgto 4 mg/day) for women with epilepsy.

The reported frequency of status epilepticus in pregnantwomen with epilepsy ranges from 0% to 1.8%.

The aim of management in status epilepticus is to achievecontrol of the seizures as rapidly as possible.

There are four main categories of drugs that are used totreat status epilepticus: benzodiazepines, phenytoin (orfosphenytoin), barbiturates, and propofol.

Benzodiazepines are the first-line treatment of statusepilepticus due to their fast onset of action. Lorazepam(0.02–0.03 mg/kg IV) is the initial drug of choice.

Women with generalized epilepsy are more at risk forseizures during delivery than are those with partialepilepsy .

It is important to remind women with epilepsy to bringtheir AEDs to the hospital during labor and to takeregular doses during this period under thesupervision of hospital staff.

Intravenous (Phenobarbital [PB], VPA, LEV)administration may be needed if the woman is notable to keep down oral medication.

Hyperventilation and maternal exhaustion should beavoided

Generalised tonic clonic seizures are associated withhypoxia, and continuous CTG tracing isrecommended in the event of a seizure

An intravenous benzodiazapene (e.g. lorazepam ordiazepam) is recommended to terminate the seizure

Women should deliver in a centre with adequatefacilities for maternal and neonatal resuscitation

Emergency C.S. should be performed when repeatedGTCSs cannot be controlled during labor .

Obstetric analgesia may be used to allow for rest beforedelivery.

Pethidine should never be used because it is metabolised tonorpethidine, which is epileptogenic. Diamorphine is anoption.

Few cases of postpartum seizures were reported followingepidural analgesia.

It is suggested that oral vitamin K supplementation at 10–20 mg/day be prescribed during the last month ofpregnancy and 0.5 mg administered intramuscularlyimmediately after delivery.

This is particularly important for women taking EIAEDsassociated with alterations in vitamin K metabolism.

Vitamin K is recommended for all neonates at birth;however, neonates born to women with epilepsy shouldbe monitored for bleeding.

The recommended dosage for neonates is 1 mgintramuscularly or intravenously at birth.

AED therapy should be continued postpartum.

For most AEDs, the pharmacokinetics in the motherwill return to pre-pregnancy levels within 10–14days after delivery.

Regardless of the AED, patients should be monitoredfor signs/symptoms of toxicity closely and doseadjustments to pre-pregnancy levels are likely.

Lamotrigine clearance decreases quickly in the firstweek postpartum, and dose adjustments should bemade sooner.

The dose incrementally reduced at postpartum days 3,7, and 10, with return to preconception dose orpreconception dose plus 50 mg to help counteractthe effects of sleep deprivation.

Patients must be advised of the importance of adequaterest, sleep, and compliance with drug therapy.

Precautions must be taken to protect the infant in theevent the mother has a seizure.

Patients should not bathe their child while they arehome alone, they need to avoid climbing stairs whilecarrying baby.

All of the AEDs are measurable in breast milk. Thereported percentage of maternal plasma levels inbreast milk varies depending on the drug.

Lamotrigine, one of the newer AEDs, is excretedextensively in breast milk. No adverse events inthese infants exposed to lamotrigine duringlactation were observed in the first postnatal year.

n.

Small studies of levetiracetam, topiramate, andgabapentin have found that while present in breastmilk in concentrations similar to maternal plasma,the concentrations in infant plasma were low,suggesting rapid eliminatio

Most experts believe that taking AEDs does notgenerally contradict breastfeeding.

Infant serum anticonvulsant levels should bemonitored if acute changes in behavior occur.

It has been estimated that more than 40% of womenwith epilepsy have unplanned pregnancies .

Most hormonal OCs combine synthetic estrogen andprogesterone.

In fact, most studies have shown that estrogen-basedcontraceptives do not affect seizure frequency

Some first- and second-generation AEDs inducehepatic cytochrome P450 enzyme activity andincrease the metabolism of both estrogen andprogesterone.

Women taking hepatic microsomal EIAEDs may haveas much as a five- to six fold increase in the COCfailure rate.

Most drugs that inhibit or have no effect on thecytochrome P450 enzyme system do not affect theefficacy of hormonal contraception .

LTG is the exception; though it is not an EIAED, it isreported to interact with COCs and may reducecontraceptive effectiveness, and the contraceptivemay interfere with seizure control by reducing theLTG blood level by as much as 40–60% .

Fully effective contraception cannot be guaranteedwith either LTG or topiramate (TPM) (>200mg/day).

One suggestion for patients taking AEDs that interferewith COCs is to use a barrier method ofcontraception, such as a condom, the diaphragm, orthe cervical cap, in addition to the COC.

Non EIAED interactwith COCs.

EIAED interact withCOCs.

Non EIAED nointeraction with COCs.

LamotrigenbarbiturateClozepam ,Clonazepam

CBZValporoate

OXCLVT

TOPVigapatrin , GBP

PHTFelbamate

PRIMETHX

Zonisamide

It is recommended that injections be administeredevery 10 weeks (and some clinicians prefer every 6–8 weeks) rather than the usual 12 weeks for womenwith epilepsy.

Intrauterine devices (IUDs) that secrete progestin maybe used by women with epilepsy and does not appearto be affected by EIAEDs . A copper IUD, is alsoeffective for women with epilepsy taking EIAEDs.

EIAEDs appear to reduce the effectiveness of the patchbecause of the low progestin dose and increasedmetabolism of the steroid components.

Combined OCs can increase the elimination of drugsthat are metabolised by glucuronidation.

Among AEDs, this metabolic pathway has beenstudied most intensively for lamotrigine.

The metabolism of lamotrigine is acceleratedapproximately 50% by co-treatment with combinedOCs .

A drop in the plasma level of the AED followinginitiation of OCs may lead to increased seizureactivity