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Women with Epilepsy

Basics

Description

- Prolonged depolarization of neuronal cell membranes - Many possible mechanisms: - Dysfunction of excitatory (glutamate) or inhibitory (GABA) neurotransmitters - Defective ion channels

- Signs and symptoms: - Preceding the seizure (aura): - Dej vu - Rising epigastric sensation - Olfactory hallucinations

- During the seizure (ictal): - Automatisms: Lip smacking, picking - Unresponsiveness or aphasia - Focal or generalized clonic movements - Oral laceration - Urinary incontinence

- After the seizure (postictal): - Confusion, agitation, psychosis - Amnesia of the event

- Physiological: - Syncope - Transient ischemic attack (TIA) - Complicated migraine - Sleep disorder - Movement disorder: Tremor, tics - Transient metabolic disturbance

- Psychiatric: - Conversion disorder - Panic attacks - Attention deficit hyperactivity disorder (ADHD)

- Traditional antiepileptic drugs (AEDs) - Carbamazepine, phenobarbital, phenytoin, primidone, valproate - Advantages - Once daily dosing available with most preparations (except carbamazepine) - Can be rapidly titrated or loaded intravenously (except carbamazepine) - Inexpensive/generic available

- Second-generation AEDs - Gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide - Advantages - Few drug interactions due to predominantly nonhepatic metabolism and low protein binding - Fewer side effects - Broad-spectrum coverage of all seizure types (lamotrigine, levetiracetam, topiramate, zonisamide) - Generic formulations available for most

- Disadvantages - Slow titration rate (except lacosamide, levetiracetam, gabapentin) - Only levetiracetam and lacosamide available in IV formulation - Degree of teratogenic risk unknown except for lamotrigine (see below)

- Vagus nerve stimulation - For patients refractory to medications and not surgical candidates - Stimulator implanted subcutaneously in the chest with electrode to the left vagus nerve - Provides seizure reduction and shortened seizure duration but rarely complete seizure control

- Fetal risk - Major malformations in 4 " 8% (twice the general population) of pregnant women taking AEDs - Risks of maternal seizures include injury to fetus, abruption, or miscarriage secondary to maternal trauma. - Potential harm of untreated seizure disorder to a pregnant woman and her fetus usually greater than risk of AED use - Congenital malformations: - Cleft lip/palate, congenital heart defects, neural tube defects, urogenital defects (3)[A] - Most strongly associated with use of polytherapy and valproate (3)[A] - Data regarding use of other newer agents lacking except lamotrigine associated with possible increased risk of cleft lip/palate

- Infertility - Number of births decreased by 33 " 66% - Anovulatory cycles increased - Also occurs in women on no AEDs

- Decreased bone mineral density - Reported with phenobarbital, mysoline, phenytoin, carbamazepine, and valproate - Consider screening with DXA scan - Supplement calcium and vitamin D to ensure adequate daily intake (vitamin D minimum 1,000 IU/day)

  • A seizure is defined as an abrupt alteration in behavior or perception and is often a symptom of underlying CNS or metabolic dysfunction.
  • Epilepsy is a disease characterized by recurrent, unprovoked seizures (2 or more).

Epidemiology

Incidence

  • Seizures:
  • Epilepsy:Average: 45/100,000Highest incidence under age 10 and over age 60 (>70 cases per 100,000)Cumulative lifetime incidence: 3.1% by age 80

Prevalence

  • Seizures:
  • Epilepsy:Point prevalence: 0.5 " 1.0% (highest in underdeveloped countries)

Risk Factors

History of any of the following:

  • Perinatal or gestational insults including prematurity
  • Febrile seizures
  • Family history of epilepsy
  • Encephalitis or meningitis
  • Stroke or subarachnoid hemorrhage
  • Head trauma involving loss of consciousness
  • CNS tumor
  • Dementia

Genetics

  • Contribution of genetics unknown in most epilepsy syndromes
  • Some idiopathic epilepsy syndromes linked to defects in ion channels via mendelian or complex inheritance

General Prevention

Avoid conditions that lower seizure threshold:

  • Sleep deprivation
  • Alcohol intoxication or withdrawal
  • Illicit drugs: Cocaine, amphetamines
  • Prescription drugs: Antipsychoticstricyclic antidepressants, bupropion, SSRIs, demerol, penicillins

Pathophysiology

  • Prolonged depolarization of neuronal cell membranes
  • Many possible mechanisms:Dysfunction of excitatory (glutamate) or inhibitory (GABA) neurotransmittersDefective ion channels

Etiology

  • Idiopathic: 65.5%
  • Vascular: 10.9%
  • Congenital: 8.0%
  • Trauma: 5.5%
  • Neoplastic: 4.1%
  • Degenerative: 3.5%
  • CNS infection: 2.5%
  • Underlying etiology varies by age. Most common identified etiology:<15 years: Congenital abnormalities5 " 24 years: Head trauma25 " 44 years: Brain tumor>45 years: Stroke

Diagnosis

History

  • Assess for underlying risk factors
  • Inquire about seizure frequency and duration
  • Ask about catamenial pattern:Increased seizures in periovulatory and perimenstrual period seen in up to1/3 of women
  • Signs and symptoms:Preceding the seizure (aura):Dej vuRising epigastric sensationOlfactory hallucinationsDuring the seizure (ictal):Automatisms: Lip smacking, pickingUnresponsiveness or aphasiaFocal or generalized clonic movementsOral lacerationUrinary incontinenceAfter the seizure (postictal):Confusion, agitation, psychosisAmnesia of the event

Physical Exam

  • Focal neurological findings may provide clues to underlying CNS etiology.
  • Postictal period: Todd 's paralysis, positive Babinski, dilated pupils
  • Nystagmus and ataxia often seen with toxicity from anticonvulsant medications

Tests

Lab

Initial or acute onset seizures:

  • Blood glucose
  • Electrolytes: Sodium, calcium, magnesium, phosphate
  • CBC
  • Urine drug screen

Imaging

Initial or acute onset seizures:

  • Head CT without contrast to exclude conditions requiring urgent intervention (hemorrhage, tumor)
  • Brain MRI, performed in follow-up as outpatient to exclude more subtle structural lesions

Surgery

  • EEG:Aids in classification of seizure type and localization of seizure onsetInitial EEG normal in up to 50%Normal EEG does not exclude epilepsy.
  • Lumbar puncture:All HIV+ patients with new onset seizure(s)Any patient with fever, elevated WBC, or suspicion of infection

Differential Diagnosis

  • Physiological:SyncopeTransient ischemic attack (TIA)Complicated migraineSleep disorderMovement disorder: Tremor, ticsTransient metabolic disturbance
  • Psychiatric:Conversion disorderPanic attacksAttention deficit hyperactivity disorder (ADHD)

Treatment

Medication

  • Traditional antiepileptic drugs (AEDs)Carbamazepine, phenobarbital, phenytoin, primidone, valproateAdvantagesOnce daily dosing available with most preparations (except carbamazepine)Can be rapidly titrated or loaded intravenously (except carbamazepine)Inexpensive/generic availableDisadvantagesDrug interactionsCNS side effectsTeratogenicityLong-term effectsSerum monitoring required
  • Second-generation AEDsGabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamideAdvantagesFew drug interactions due to predominantly nonhepatic metabolism and low protein bindingFewer side effectsBroad-spectrum coverage of all seizure types (lamotrigine, levetiracetam, topiramate, zonisamide)Generic formulations available for mostDisadvantagesSlow titration rate (except lacosamide, levetiracetam, gabapentin)Only levetiracetam and lacosamide available in IV formulationDegree of teratogenic risk unknown except for lamotrigine (see below)

Additional Treatment

General Measures

2/3 of patients can be controlled with medications

Issues for Referral

Refer to neurologist or epileptologist if:

  • Refractory to 1st or 2nd medication trial
  • Suspicion of pseudoseizures
  • Pregnant or considering pregnancy

Complementary and Alternative Medicine

  • Vagus nerve stimulationFor patients refractory to medications and not surgical candidatesStimulator implanted subcutaneously in the chest with electrode to the left vagus nerveProvides seizure reduction and shortened seizure duration but rarely complete seizure control
  • Maternal riskModerately increased risk of cesarean delivery (1)[B]No clear evidence that seizure frequency increases during pregnancy (1)[B]Declining AED levels due to altered pharmacokinetics (lamotrigine, phenytoin and carbamazepine) (2)[B]
  • Fetal riskMajor malformations in 4 " 8% (twice the general population) of pregnant women taking AEDsRisks of maternal seizures include injury to fetus, abruption, or miscarriage secondary to maternal trauma.Potential harm of untreated seizure disorder to a pregnant woman and her fetus usually greater than risk of AED useCongenital malformations:Cleft lip/palate, congenital heart defects, neural tube defects, urogenital defects (3)[A]Most strongly associated with use of polytherapy and valproate (3)[A]Data regarding use of other newer agents lacking except lamotrigine associated with possible increased risk of cleft lip/palatePoor cognitive outcome associated with valproate, possibly phenytoin and phenobarbital (3)[B]Increased risk of small for gestational age (3)[B]Some AEDs are transferred into breast milk but no evidence to support adverse effects on newborn (2)[C]
  • RecommendationsMonotherapy at the lowest dose needed to control seizures (3)[B]Avoid polytherapy as well as monotherapy with valproate (3)[A]Folic acid supplementation: 1 " 4 mg/day (start prior to conception) (2)[B]Monthly serum drug levels for women taking lamotrigine, phenytoin, and carbamazepine after conception (2)[B]Breastfeeding is not contraindicated but should be monitored (2)[C].Prenatal testingMaternal serum alpha-fetoprotein at 15 " 20 weeksLevel II (structural) ultrasound at 16 " 20 weeks

Surgery

  • Focal brain resection in patients with partial onset seizures refractory to trials of 2 or more medications (alone or in combination)
  • Most successful in patients with focal lesions seen on MRI and/or temporal lobe seizures
  • Up to 70% seizure freedom rate

In-Patient Considerations

Admission Criteria

  • Status epilepticusContinuous seizure activity >5 " 10 minutes or ≥2 seizures without return to baseline in between
  • Prolonged postictal state

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • CBC and liver function testsAll patients taking carbamazepine, phenobarbital, phenytoin, and valproate due to risk of agranulocytosis and hepatotoxicity
  • SodiumRisk of hyponatremia in patients taking carbamazepine and oxcarbazepine, especially elderly and patients on salt-wasting diuretics
  • Serum drug levelsAvailable for all AEDsAids in monitoring for toxicity, noncompliance

Prognosis

  • Classification into appropriate epilepsy syndrome aids in prognosisSome generalized epilepsy syndromes will remit in childhood (childhood absence, benign rolandic).Juvenile myoclonic epilepsy and adult onset temporal lobe epilepsy least likely to remit

Complications

  • InfertilityNumber of births decreased by 33 " 66%Anovulatory cycles increasedAlso occurs in women on no AEDs
  • Decreased bone mineral densityReported with phenobarbital, mysoline, phenytoin, carbamazepine, and valproateConsider screening with DXA scanSupplement calcium and vitamin D to ensure adequate daily intake (vitamin D minimum 1,000 IU/day)
  • Contraception
  • AEDs that decrease the efficacy of hormonal contraception: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate (>200 mg/day)
  • Oral contraceptives may decrease lamotrigine serum levels by up to 50%.
  • Intrauterine devices should be considered to avoid these potentially serious drug interactions.

References

1Harden CL, Hopp J, Ting T. Management issues for women with epilepsy: Obstetrical complications and change in seizure frequency. Epilepsia. 2009;50(5):1229 " 1236. [View Abstract]2Harden CL, Pennell PB, Koppel BS. Management issues for women with epilepsy: Vitamin K, folic acid, blood levels and breast feeding. Epilepsia. 2009;50(5):1247 " 1255. [View Abstract]3Harden CL, Meador KJ, Pennell PB. Management issues for women with epilepsy: Teratogenesis and perinatal outcomes. Epilepsia. 2009;50(5):1237 " 1246. [View Abstract]

Additional Reading

1Crawford P. Managing epilepsy in women of child bearing age. Drug Safe. 2009;32(4):293 " 307. [View Abstract]2LaRoche SM. A new look at the second-generation antiepileptic drugs: A decade of experience. Neurologist. 2007;12(3):133 " 139.

Additional Reading see also

  • Epilepsy Foundation. Website: www.efa.org
  • North American Pregnancy Registry. Website: www.aedpregnancyregistry.org

Codes

ICD9

  • 345.90 Epilepsy, unspecified, without mention of intractable epilepsy
  • 649.40 Epilepsy complicating pregnancy, childbirth, or the puerperium, unspecified as to episode of care or not applicable

ICD10

  • G40.909 Epilepsy, unsp, not intractable, without status epilepticus
  • O99.350 Diseases of the nervous sys comp pregnancy, unsp trimester

SNOMED

  • 84757009 epilepsy (disorder)
  • 199297006 disease of nervous system complicating pregnancy, childbirth and puerperium (disorder)

Clinical Pearls

  • Patients with a single seizure and risk factors for seizure recurrence should be considered for treatment.
  • Second-generation anti-epileptic drugs have similar efficacy but are better tolerated than the traditional agents.
  • Pre-conceptual counseling aids in optimizing treatment to reduce maternal and fetal complications.