Seizure disorders

Seizure disorders, epilepsy

1. What every clinician should know

Seizures are paroxysmal behavioral spells caused by disorderly discharge of cortical nerve cells and can range from clinically undetectable abnormal patterns on electroencephalography (EEG) to generalized convulsions. Patients are defined as having epilepsy when they experience recurrent or unprovoked seizures, or have brain alterations increasing the likelihood of future seizures.

Clinical features and incidence

The incidence of epilepsy in pregnant women is 0.3-0.6%. In pregnant women with epilepsy, 33-45% experience increased seizure frequency, 5% decreased seizure frequency and 54-80% experience no change in seizure frequency.

Anticonvulsant drugs can have interactions with oral contraceptive agents, decreasing the efficacy of the contraceptives. Women with epilepsy should be strongly counseled to take precautions to avoid unplanned pregnancy. Nonhormonal methods of birth control are recommended, but if oral contraceptives are used, higher dose oral contraceptive pills (at least 50 micrograms of estrogen) are preferred.

For patients who have been seizure free for at least 9 months prior to conception, the likelihood of remaining seizure free during pregnancy is 84-92%. Women with poorly controlled epilepsy are more likely to have increased seizure frequency in pregnancy. Women with idiopathic generalized epilepsies are more likely to remain seizure-free than women with localization-related epilepsy. Worsening in seizure control from the first to second or third trimester may occur in 15% of pregnancies. Sleep deprivation may also decrease seizure threshold.

It has been suggested that women with seizure disorders are at risk of increased adverse pregnancy outcomes because of changes in placental blood flow during seizure activity or post-ictal phase leading to hypoxia or acidosis. During seizures, fetal bradycardia, decreased fetal heart rate variability have been reported.

2. Diagnosis and differential diagnosis

Diagnostic criteria

Pregnant women experiencing new onset of seizures (two or more) merit anticonvulsant treatment, EEG and MRI of the head to exclude an underlying structural lesion. MRI (without gadolinium) should be considered, even in the first trimester, if necessary to aid in diagnosis when the benefits outweigh the risks of imaging.

It is important to classify the patient’s seizure type based on clinical presentation, EEG and MRI findings as well as lab data. Seizures are either generalized or partial/focal, depending on which portion of the brain is involved. Partial seizures may be classified as complex if consciousness is impaired. Manifestations of partial seizures include jerking or repetitive movements, auras, clouded consciousness and staring. Generalized seizures are most commonly tonic-clonic (grand mal), absence (petit mal) or myoclonic seizures.

It is important to identify triggers, such as sleep deprivation, alcohol and stress, that may be modifiable. It is usually appropriate to refer patients to a neurologist to establish the diagnosis and guide management.

Differential diagnosis

Eclamptic seizures must always be considered when a pregnant woman experiences seizures. Other types of seizures can be distinguished from eclampsia by the lack of elevated blood pressure, proteinuria and edema.

Status epilepticus rarely complicates pregnancy and may lead to fatal outcomes for mother or fetus. Status epilepticus is treated with IV diazepam (10-30 mg) or lorazepam (4-8mg), as well as IV fosphenytoin. (20 mg phenytoin equivalents per kg loading dose, up to 150 mg phenytoin equivalents per kg infusion.)

Other entities that may mimic seizures include syncope, transient ischemic attacks, psychogenic nonepileptic seizures, sleep disorders and delirium.

3. Management

Antepartum

Preconception counseling should be recommended to women of reproductive age with epilepsy. They should be counseled that all anticonvulsant medications have been associated with increased risks of minor (6-20%) and major (4-6%) fetal malformations. Patients with seizure disorders should take increased folate supplementation (4 grams daily) when attempting pregnancy and during prenatal course. Patients should be referred for genetic counseling and serum screening.

Monotherapy should be a goal of treatment for most patients before conception and during the first trimester. However, altering medication after the period of organogenesis is not likely to decrease malformation rate, and may result in increased seizure activity in pregnancy.

Patients may have decreased medication compliance because of fear of adverse fetal effects or other symptoms of pregnancy, such as nausea and vomiting. Altered pharmacokinetics may impact changes in seizure rate in pregnancy. Factors that may increase drug activity are decreased plasma protein binding sites, and factors that may decrease drug activity are increased clearance and volume of distribution. It is recommended to check anticonvulsant medication levels (both total and free plasma levels) at 6 weeks, 10 weeks and then once per trimester.

Maternal serum AFP as well as ultrasound should be used to increase detection of fetal neural tube defects. Amniocentesis, specifically measurement of alpha-fetoprotein and acetylcholinesterase in amniotic fluid, can increase detection of neural tube defects.

Most physicians recommend administration of prophylactic vitamin K1 (10 to 20 mg/day) during the last month of pregnancy to women treated with anti-epileptic drugs (AEDs) to protect the child against severe postnatal bleeding due to a deficiency in vitamin K-dependent clotting factors

Intrapartum

Most women can experience a normal labor and delivery. If a patient has a history of status epilepticus in the setting of severe stress or frequent seizures in the third trimester, a cesarean delivery may be considered. 1-2% of women experience generalized seizures during labor. Continued treatment with anticonvulsant medication is recommended on the patient’s regular schedule during the course of labor and delivery.

Convulsive seizures during labor should be treated with IV benzodiazepines (usually lorazepam) and IV phenytoin should be considered. Continuous fetal heart rate monitoring is recommended during and after seizure activity. Infants in mothers receiving benzodiazepines, barbiturates or primidone should be monitored carefully for withdrawal symptoms after delivery.

Magnesium sulfate is not appropriate treatment for epileptic seizures; however, it may be difficult to distinguish eclampsia from epileptic seizures in the third trimester or delivery, and in those cases, magnesium sulfate may be warranted during the initial evaluation process as presumptive treatment for eclampsia.

Postpartum

1-2% of women with epilepsy experience seizures during the first 24 hours postpartum.

In patients experiencing seizure activity and requiring medication adjustment during pregnancy, continued measurement of serum levels of anticonvulsant drugs is recommended until 6-8 weeks postpartum.

Most physicians recommend administration of prophylactic vitamin K1 (10-20 mg/day) during the last month of pregnancy to women treated with AEDs to protect the child against severe postnatal bleeding due to a deficiency in vitamin K-dependent clotting factors.

Breastfeeding has not been shown to be deleterious to infants of mothers on anticonvulsant medication, although there is limited data. Women on phenobarbitol, clobazam, gabapentin, lamotrigine or oxcarbazepine should be monitored closely, and infant drug levels can be checked. Current guidelines do not discourage breastfeeding or recommend changing maternal drug therapy based on a decision to breastfeed. If breastfed infants develop sedation related to anticonvulsant medication intake on the part of the mother, breastfeeding should be discontinued and the infant monitored for signs of withdrawal. Maternal use of barbiturates may be associated with neonatal withdrawal symptoms (restlessness, irritability, vasomotor instability – but not seizures.)

4. Complications

Complications as a consequence of the condition

Worsening of seizure frequency (occurs in 15% of pregnancies, more likely in women with poor seizure control during the 9 months prior to conception and women with localization-related epilepsy).
Increased rates of congenital anomalies (neural tube defects, congenital heart disease, cleft lip and palate, and genitourinary defects), which may be due to teratogenic effect of seizures or antiepileptic medications. Therapeutic recommendations are in general to use the lowest effective dose, monotherapy when possible. Avoid valproate, never use trimethadione.
Adverse pregnancy outcomes (IUGR, stillbirth, pre-eclampsia or preterm delivery) related to changes in placental blood flow. Recent studies have not supported an increased risk, but monitoring of fetal growth and well-being should be considered.

Complications as a consequence of management

Major fetal malformations noccurrig in women on antiseizure medications include cleft lip/palate, congenital heart disease, neural tube defects and genitourinary defects. The most common are cleft lip/palate and congenital heart disease. Some studies have shown that women with epilepsy who are not on antiseizure medications may not have an increased incidence of malformation compared to the general population. Risk of teratogenicity increases with use of multiple medications, and monotherapy is a goal of treatment of pregnant women with epilepsy. The strongest associations are with carbamezepine, valproate and oxcarbazepine, and certain medications have been associated with particular types of fetal effects. (See Table I)

Table I.n

Rates of congenital anomalies associated with anticonvulsant medications

Fetal anticonvulsant syndrome (also known as fetal hydantoin syndrome) is seen in 11% of fetuses exposed to antiepileptic medications. The syndrome includes microcephaly, dysmorphic facies, growth restriction and mental retardation.

Neonatal hemorrhagic disease may result in infants who were exposed to anticonvulsant therapy in utero and is characterized by a deficiency in coagulation factors similar to vitamin K deficiency. Maternal vitamin K supplementation (10-20 mg orally daily from 36 weeks to delivery) may prevent this condition.

5. Prognosis and outcome

Maternal and fetal/neonatal outcomes

Prognosis for pregnancy outcome depends on control of maternal seizures as well as use of anticonvulsant medications. Certain medications commonly used to control epilepsy are associated with teratogenicity. Pregnancy may alter drug efficacy and some women experience worsening seizure frequency during pregnancy. Labor and delivery, as well as the immediate postpartum period are times of increased risk of seizures. Risk to the infant of developing epilepsy varies, but is likely quite small. Genetic factors, presence of seizures in pregnancy and anticonvulsant therapy have all been theorized to play a role.

Impact on long-term health

Epilepsy in women with recurrent or unprovoked seizures is likely to require longterm management. Prophylactic therapy with anticonvulsant medication is usually continued until a patient has been seizure-free for 2-3 years.

6. What is the evidence for specific management and treatment recommendations

Pschirrer, ER. “Seizure disorders in pregnancy”. Obstet Gynecol Clin North Am. vol. 31. 2004. pp. 373-84.

McPherson, JA, Harper, LM, Odibo, AO, Roehl, KA, Cahill, AG. “Maternal seizure disorder and risk of adverse pregnancy outcomes”. Am J Obstet Gynecol. vol. 208. 2013. pp. 378.e1-5.

Meador, KJ, Baker, GA, Browning, N, Clayton-Smith, J, Combs-Cantrell, DT. ” NEAD Study Group. Effects of breastfeeding in children of women taking antiepileptic drugs”. Neurology. vol. 75. 2010. pp. 1954-60.

Battino, D, Tomson, T, Bonizzoni, E, Craig, J, Lindhout, D. “EURAP Study Group. Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry”. Epilepsia. vol. 54. 2013. pp. 1621-7.

Creasy, RK, Resnick, R, Iams, JD, Lockwood, CJ. “Creasy & Resnick's Maternal-Fetal Medicine: Principles and practice”. 2014.

Borthen, I, Eide, MG, Veiby, G. “Obstetric outcome in women with epilepsy: a hospital-based, retrospective study”. BJOG. vol. 18. 2011. pp. 956-65.

Richmond, JR, Krishnamoorthy, P. “Anderson P et al. Epilepsy and pregnancy: an obstetric perspective”. Am J Obstet Gynecol. vol. 190. 2004. pp. 371-9.

Gabbe, S, Niebyl, J, Simpson, J. “Obstetrics: normal and problem pregnancies”. 2007.

Cummings, C, Stewart, M, Steenson, M, Morrow, J, Nelson, J. “Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine”. Arch Dis Child. vol. 643. 96. pp. 7

Hernandez-Diaz, S, Smith, CR, Shen, A, Mittendorf, R, Hauser, WA. “Comparative safety of antiepileptic drugs during pregnancy”. Neurology. vol. 78. 2012. pp. 1692-9.

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