Epilepsy in Pregnancy by Abhishek Jaguessar

8/4/2019 Epilepsy in Pregnancy by Abhishek Jaguessar

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Epilepsy in Pregnancy

BY

ABHISHEK JAGUESSAR



Learning Objectives

At the end of this presentation, you should:

1-Understand the effects of pregnancy on epilepsy and thecomplications that epilepsy may have on pregnancy,lactation and neonate.

2-Be able to outline a management plan for an epilepticpregnant woman.

3-Be aware of the different AEDs, their toxic effects and thesafest drug that can be used in pregnancy.



Definition and Incidence

Epilepsy is recurring spontaneous seizures due to

sudden excessive and disordered electrical dischargefrom the neurones of the Cerebral cortex. It is estimated

that 7% of epileptic women become pregnant andepilepsy affects about 0.5-1% of pregnant women.

Epilepsy can be partial or generalized.



Classification Of Epilepsy

A- Partial Seizures (Focal Seizures): This is the commonest type and

is subcategorized as :

1-Simple Partial Seizures (Jacksonian epilepsy): The affectedwoman does not lose consciousness but may experience confusion,

tingling, or odd mental and emotional events. Such events mayinclude déjà vu phenomenon, mild hallucinations, or extremeresponses to smell and taste.

After the seizure, the patient usually has temporary weakness in

certain muscles.




2- Complex Partial Seizures (>50% in adults): They can result in loss of judgment, involuntary uncontrolledbehavior & loss of consciousness. Prior to the actual seizure, somepeople may experience a warning aura, which can be an odd odor, afeeling of warmth, or a visual or auditory hallucination. They thenmay lose consciousness briefly and appear to others as motionlesswith a vacant stare. After a few seconds, some may begin toperform repetitive movements, such as chewing or smacking of lips.Episodes usually last no more than two minutes.

Ocassionally a simple or complex partial seizures evolve intosecondarily generalized seizures. The progress may be so rapid that

the partial stage is not even noticed.




B- Generalized SeizuresThey occur in more diffuse areas of the brain and they have more seriouseffect on the patient. They are further subcategorized as follows:

1-Tonic-Clonic (Grand Mal) Seizures: a- The tonic phase: muscles suddenly contract, causing the patient to falland lie rigidly for about 10 to 30 seconds. Some people experience aura;most, lose consciousness without warning. If the throat or larynx is affected,stridor occurs when the patient inhales.

b-The clonic phase : Seizure is said to enter this phase when the musclesbegin to alternate between relaxation and rigidity. After this phase, the

patient may lose bowel or urinary control.

The seizure usually lasts a total of two to three minutes, after which thepatient remains unconscious for a while and then awakens to confusion andextreme fatigue.




2- Absence (Petit Mal) Seizures: Petit mal or absence

seizures are brief (three to 30 seconds) losses of

consciousness and may consist of only a short cessation

of physical movement and loss of attention. Suchseizures may pass unnoticed by others. About 25% of

patients with petit mal develop grand mal seizures




C- Other Seizures:1- Atonic (Akinetic) Seizures. A person who has an atonic (or akinetic)

seizure loses muscle tone. Sometimes it may affect only one part ofthe body so that, for instance, the jaw slackens and the head drops.At other times, the whole body may lose muscle tone, and theperson can suddenly fall.

2- Simply Tonic or Clonic Seizures. Seizures can also be simply tonicor clonic. In tonic seizures, the muscles contract and consciousnessis altered for about 10 seconds, but the seizures do not progress tothe clonic phase. Clonic seizures, which are very rare, occurprimarily in young children, who experience spasms of the muscles

but not their tonic rigidity.

3- Myoclonic. Myoclonic seizures are a series of brief jerky contractionsof specific muscle groups, such as the face or trunk.




4-Gestational epilepsy: Some patients experience their first seizuresduring pregnancy. This can be a result of true gestational epilepsy, arare syndrome of seizures occurring only during pregnancy. Patientswith this syndrome have a variable presentation with single ormultiple seizures in one or more of their pregnancies. It can also bea manifestation of epilepsy that may extend beyond the pregnancy.

The workup of these patients should involve a neurologicexamination, consultation with a neurologist, CBC count, chemistrypanel (particularly for electrolytes), head MRI versus CT scan, andEEG. The differential diagnosis should include eclampsia and anypossible etiology considered in the nonpregnant patient, including

stroke, electrolyte abnormalities, tumor, trauma, drugs/withdrawal,and epilepsy



Effects Of Pregnancy On Epilepsy

Unpredictable

1-Seizure frequency may increase: due to:

-Enhanced metabolism & increased drug clearance associated with

pregnancy 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 (high E), and

associated psychological and emotional stress of pregnancy: all lowerthreshold for seizures.

-Nausea and vomiting.



Effects Of Pregnancy On Epilepsy (Cont.)

2-Seizure frequency may decrease:

Due to improved compliance with drug regimen in some patients.

3-Seizure frequency may remain unchanged.



Effect Of Epilepsy On Pregnancy

• Data on 1st trimester losses, PROM, ante-partumhemorrhage, operative vaginal delivery and CS areinconclusive.

• Increased incidence of IUGR, cognitivedysfunction, microcephaly and perinatalmortality (1.2 - 3 times normal).

• Increased incidence of congenital malformations.



Effect Of Epilepsy On Lactation

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

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



Effects Of Epilepsy On Fetus And Neonate

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

• Nature of the mother’s seizure disorder.

• Genetic factors.• Seizures arises during pregnancy.

• Metabolic & toxic consequences of seizures and AEDs.

2-Increase perinatal morbidity.



Table 1. Antiepileptic Drug Exposure Through Breast Milk Pennell PB, 2004

___________________________________ AED Breast milk/maternal conc Adult half-life NN half-life

______________________________________________________________________

Carbamazepine 0.4 –0.6 8 –25 8 –28

Phenytoin 0.18 –0.4 12 –50 15 –105

Phenobarbital 0.36 –0.6 75 –126 45 –500

Ethosuximide 0.8 –0.9 32 –60 32 –40

Primidone 0.7 –0.9 4 –12 7 –60

Valproic acid 0.01 –0.10 6 –18 30 –60

Lamotrigine 0.6 —— ___

Topiramate 0.69 –0.86 —— ___

Zonisamide 0.41 –0.93 63 61 –109

Levetiracetam 3.09 —— ___



Management

I-Preconceptional Care:

A-Re-assessment: may show that the patient does not have epilepsyor may reveal a treatable cause before pregnancy (e.g. blood vesselabnormality in the brain).

B-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.



Management

I-Preconceptional Care:

C-Measurement of the free unbound anti-epileptic drug level inmaternal serum.

D- Preconceptional folate supplementation: 5 mg daily.

E- No trial to stop AED unless the patient is seizure free at least for 2years. The AED dose should be tapered till stopped completely atleast 6 months prior to any planned pregnancy to provide some

reassurance that seizures are not going to recur.



II-Antenatal Care

A-Investigations:

• Metabolic: serum glucose, urea, electrolytes, Ca & Mg• EEK• MRI/CT scan of the head.

B-Drugs:

Monotherapy at the lowest effective dose should be employed. If large dailydoses are needed, use frequent smaller doses or extended-release formulato avoid high peak levels. Monitoring of serum AEDs level is mandatory.

Usually, women don't suspect they are pregnant until their fourth to sixthweek of pregnancy. By that time, if there are any harmful effects from their

AEDs, most of these effects would have already occurred.



II-Antenatal Care

C-Selenium supplementation: in a dose of 200 µ/day may beimportant to minimize the free radical mediated damage.

D-Folic acid supplements.

E-Morning sickness: If hyperemesis gravidarum, consider givingalternative route if vomiting is severe or prolonged.

F-Antenatal diagnosis: of congenital malformations (screening shouldbe done by detailed ultrasound and measurement of æ fetoprotein

at 18 weeks).



II-Antenatal Care (Cont.)

G-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).

Be aware of the nature of the AED you are usingwhether it is a hepatic enzyme inducing or not. Most of

the newer AEDs are not enzyme inducers).



III-Labor and Delivery (Cont.)

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

Management of women with epilepsy upon labor and

delivery:

• Check levels of AEDs.

• Inform all health care providers that the patient has

epilepsy.

• Consider seizure prophylaxis with intravenousbenzodiazepines or phenytoin.




• Manage seizures acutely with intravenous benzodiazepines (1-2 mgof diazepam), then load phenytoin (1 g loaded over 1 h).

• Labor management should be based on routine standards of care.

• Start administration of vitamin K1 for the infant, and send the cordblood 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 nofaster than 2 mg/min.




• Load phenytoin (20 mg/kg, ie, 1-2 g) at no faster than 50 mg/min,with cardiac monitoring.

• If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) atno faster than 100 mg/min.

• Check laboratory findings, including electrolytes, AED levels,glucose, and toxicology screen.

• If fetal testing results are nonreassuring, move to emergent delivery.



III-Labor and Delivery

• The majority of women who have epilepsy have a safe vaginal

delivery without seizure occurrence; provided, the AED is taken

before and throughout labor.

• Generalized tonic clonic Seizures GTCSs needs aggressiveinterference because of the high risk for the mother and fetus,

especially if they progress to status epilepticus. Oxygen should be

administered to the patient and she should be placed on her left side

to increase uterine blood flow and decrease the risk for maternal

aspiration.




• Emergency C.S. should be performed when repeated GTCSs cannot be

controlled during labor or when the mother is unable to cooperate.

• Any lady having a seizure during labour must be observed closely for thenext 72 hours.

• Obstetric analgesia may be used to allow for rest before delivery. Pethidine

should never be used because it is metabolised to norpethidine, which is

epileptogenic. Diamorphine is an option. Few cases of postpartum seizures

were reported following epidural analgesia.




• During labor, oral absorption of AEDs may be inappropriate and anyvomiting might complicate the situation. PB, PHT, and VPA can begiven IV at the same maintenance dosage. Convulsive seizures andrepeated seizures during labor should be treated promptly withparenteral lorazepam or diazepam.

• Benzodiazepines, in large doses, can cause neonatal cardiac andrespiratory depression; therefore, close monitoring for theseneonates is mandatory.



IV-Postnatal Care

A-Infant:- Inspected for malformation.-Vitamin k 0.1mg/kg IM at birth reduces risks of hemorrhagic disease.

B-Bathing: never should be performed alone, as a brief lapse inattention can result in a fatal drowning. Wet sponge not water bath.

Changing diapers and clothes are performed best on the floor ratherthan on an elevated changing table.

C-Breast Feeding: encouraged in suitable position. If excessive infantsedation is encountered, as may be seen with phenobarbital orprimidone, the infant should be weaned slowly with monitoring for

signs and symptoms of withdrawal and infant drug levels.



IV-Postnatal Care

D- The following safety issues must be taken into account:

• If the mother is likely to drop objects she is holding but

remain upright, then she should use a harness whencarrying the baby.

• If she is likely to fall, then a stroller kept at home is amust.



IV-Postnatal Care

E- 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.



IV-Postnatal Care (Cont.)

•

F-Anticonvulsant: Any increase in drugs during pregnancy will needto be decreased slowly to pre-pregnancy doses over 3-4 weeks to

avoid toxicity.

G-Contraceptions: Barriers and IUDs are recommended.

Many AEDs induce the hepatic cytochrome P-450 system, which is

the primary metabolic pathway of the sex steroid hormones. This

leads to rapid clearance of steroid hormones and allow ovulation in

women taking OCPs or other hormonal forms of birth control.



IV-Postnatal Care (Cont.)

In 1998, the American Academy of Neurology recommended theuse of an E2 dose of 50 μg or its equivalent for 21 days of eachcycle when using OCPs with the enzyme-inducing AEDs. Morerecently, however, it is recognized that this still is inadequateprotection, and a backup barrier method was recommended.

Women on low dose pills or minipills and AED may get pregnant.

Patients on hormonal contraception need to be warned thatmidcycle bleeding indicates possible birth control failure, but itsabsence does not indicate adequate birth control efficacy. The

newer transdermal patch formulation have a higher failure rate withthese AEDs. IM medroxyprogesterone provides higher dosages ofprogestin but still may require dosing at 8- to 10-week intervalsrather than 12-week intervals.



Table 2 . Antiepileptic drug effects on hormonal contraceptivesGuberman 1999., Krauss et al 1996., Rosenfeld et al 1997

________________________________________ Lower hormone level No significant effect _______________________________________________ Phenobarbital EthosuximidePhenytoin ValproateCarbamazepine GabapentinPrimidone LamotrigineTopiramate TiagabineOxcarbazepine Levetiracetam

Zonisamide



Anti-Epileptic DrugsI-Monitoring

The ideal AED serum free level must be established for each patient

before conception, and should be the level at which seizure control

is the best possible for that patient without debilitating side effects.

Levels should be repeated at the beginning of each trimester and

again in the last 4 weeks of pregnancy. Monitoring should continue

until the 6th to 8th week postpartum. In doing so, one may be able to

avoid symptoms of toxicity that result from the changes in

pharmacokinetics postpartum.



Anti-Epileptic Drugs I-Monitoring

Some authors recommend monthly monitoring, given the possibility

of rapid and unpredictable decreases in AED levels in an individual

patient.

The frequency with which levels are monitored must be tailored toeach situation, including increased monitoring for worsening seizure

control, adverse effects, and compliance issues.



Table 3: Therapeutic Levels of Anti-Epileptic Drugs (AEDs)Dichter MA, Brodie M.1996., Brodie M, Dichter MA 1996., Johannessen SI et al 2003.,

LaRoche SM et al 2004

Drug Common dose Doses Therapeutic levels

Carbamazepine 600 mg qd-qid 6-12 μ/ml

Gabapentin 300 mg Qd 70-120 μmol/L

Lamotrigine 25-30 mg Qd 10-60 μmol/L

Levetiracetama 500 –1500 mg bid 35 –120 μmol/L

Oxcarbazepine 300 –600 mg bid 50 –140 μmol/L

Phenobarbital 120 mg qd-bid 10 –40 μ/mL

Phenytoin 300 mg qd-bid 10 –20 μ/mL

Primidone 500 mg qd-bid 5 –15 μ/mL

Valproic acid 1000 mg qd-bid 50 –100 μ/mL



Anti-Epileptic Drugs

II-Teratogenicity

Antiepileptic drugs (AEDs) have the potential to produce bothanatomic 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 acidabsorption. 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.



Table 4: Timing Of Embryonic Organogenesis(Pennell PB 2003)

Organ system Defect Postconception age

CNS NTD 28 days

Face Cleft lip & palate 36 and 70 days

CVS VSD 42 days

Urogenitalsystem

Hypospadius 56 days



Prenatal Screening for Fetal Malformations

• Transvaginal U/S can be performed at 18-20 weeks to diagnose themost severe defets (face - heart). However, sensitivity is better, forcleft palate and lips, if U/S is repeated between 24-28 weeks.

• Screening for NTD: by combination of Maternal serum α –fetoproteinat 15-22 weeks and Level II,structural Ultrasound, at 16-20 weeks.

• If results are equivocal, proceed with amniocentesis withmeasurements of amniotic fluid α -fetoprotein and acetylcholine-esterase.



Anti-Epileptic Drugs (Cont.)

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 and

mental retardation.




Specific Syndromes Of Malformations

2-Facial 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.

3-Barbiturates Withdrawal SymptomsStarts 1 week after birth & includes restlessness, constant crying,irritability, difficult sleeping & vasomotor instability.




Behavioral Teratogenesis

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

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

• A prospective Finnish study found the mean verbal IQ score following inutero exposure to valproate was 82 compared with 96 for carbamazepineand 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 additionaleducational needs compared with 3.2% of children exposed tocarbamazepine monotherapy and 6.5% for other ani-epileptics.



Anti-Epileptic Drugs

III-Mono Versus Polytherapy

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

• Studies have shown higher incidence of malformations withpolytherapy compared to montherapy.

• If large daily doses are needed, then frequent smaller doses orextended-release formula may be helpful to avoid high peak levels.

Dose should be divided into 3-4 doses/day. This is because highpeak plasma levels of the drug is more teratogenic.



Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy

Study design Findings

Kaneko et al. 1988 Prospectivestudy

Malformation rates were 6.5%&15.6% for monotherapy &polytherapy (p = 0.01)

Oguni et al. 1992 Comparison of 2prospectivelyfollowed cohorts

Major malformations decreasedfrom 24.1% to 8.8% (p < 0.01),paralleling an increased no. ofpatients receiving monotherapy.

Dravet et al. 1992 Prospective studyof effects of AEDs

Malformations was higher ininfants exposed to poly (15%)compared to monoth. (5%) (p <0.01)



Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)

Study design FindingsHolmes etal. 2001

Frequency of embryopathyin control infants notexposed to AEDs (n = 508)

and in infants exposed toAED monotherapy (n =223) and AED polytherapy(n = 93) were compared

Frequency of embryopathywas higher in infants exposedto AED monotherapy vs.

nonexposed controls (20.6%vs. 8.5%; OR 2.8; 95% CI 1.1 to9.7). The frequency was alsohigher in infants exposed toAED polytherapy vs.nonexposed controls (28.0%

vs. 8.5%: OR 4.2; 95% CI 1.1 to5.1)



Table 5: Comparison of Malformation Rates During Pregnancy Monotherapy Versus Polytherapy (Cont.)

Study design Findings

Lindhout etal. 1992

Influences of changes inprescribing practices analyzedby comparing 2 cohorts,1972 –1979 and 1980 –1985, in

the Netherlands

Mean no. of drugs usedduring pregnancydecreased from 2.2 in the70s to 1.7 in the 80s.

Rates of anomalies were9.9% & 7.6% in 70s and80s cohorts, respectively.The difference did notreach stat significance

Samrén et al.1997

Pooled data from 5prospective European studies

For the AED-exposedchildren, the RR for amajor malformation was2.3 (95% CI 1.2 to 4.7) vscontrols




VI-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 neonatalperiod, TTT is by the infusion of FFP or concentrates of deficientfactors in addition to the routine administration of vitamin K1.




IV-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.



Anti-Epileptic Drugs (AEDs) (Cont.)

IV-Failure of AEDs

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 AEDswhich often causes them to withdraw. Among the most distressing

are sleepiness, problems in coordination and weight gain.




IV-Failure of AEDs

7-About a quarter of patients who do not respond to AEDs actually

have nonepileptic seizures that in many cases are caused bypsychiatric conditions (e.g., panic attack, personality disorders).



Differential Diagnosis

1-Eclamptic Seizures:

• HTN & Ptnuria are always present.

• Urine output is diminished & anuria may develop. Hemoglobinuria iscommon.

• Fever of 39º C or more indicates impending CNS hemorrhage.

2-Migraine headaches, particularly migraine with auras, maysometimes be confused with epilepsy. With epileptic seizure, thepreceding aura is often seen as multiple, brightly colored, circularspots, while migraine sufferers tend to see black, white, or colorless

lined or zigzag flickering patterns. Typically the migraine painexpands gradually over minutes toward one side.



Differential Diagnosis (Cont.)

3-Panic Attacks: One study reported on patients withpartial seizures that resembled panic disorder.Symptoms of panic disorder include palpitations,sweating, trembling, sensation of breathlessness, chest

pain, feeling of choking, nausea, faintness, chills orflushes, and fear of losing control and fear of dying.

4-Narcolepsy: a sleep disorder that causes a sudden loss of muscletone & excessive daytime sleepiness, can be confused withepilepsy.




5-Local Anesthetic Toxicity: Occurs due to either injection of the localagent into a bl. vessel or the administration of excessive amounts.Manifestations of systemic toxicity are those of C.N.S. & C.V.S.

6-Pheochromocytoma: Clinically, there is hypertensive crisis, seizuredisorder or anxiety attacks. Diagnosis is by 24 hrs VMA,metanephrines or unconjugated catecholamines. Adrenallocalization is usually successful with CT or MRI.




7-Tetany: Occurs as a part of maternal hypo-parathyroidism. Diagnosisis confirmed by low ionized calcium & parathormone levels & bymeasurement of urinary AMP excretion after administration ofparathormone.

8-Metabolic: Hypoglycemia or hyponatremia.

9-Fulminant hepatic failure: Due to acute fatty liver of pregnancy oracute viral hepatitis.





Conclusions (Cont.)

4-A woman should not stop AED unless she has nothad seizures for 2 years; gradual discontinuationcan then be attempted.

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

6-Current AEDs are considered to be a necessary evil

until newer drugs become available. However, thesafest are: Phenobarbital and phenytoins.



Thank you

Epilepsy in Pregnancy by Abhishek Jaguessar

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