A 30 year-old female patient has been maintained on phenytoin 100 mg TID for the past 5 years

with good control of her idiopathic generalized seizure.

She is 3 months pregnant when she visited your clinic.

MISSING DATA

• (+) / (-) Frequency and Severity

Associated with: •Subtherapeutic anticonvulsant levels

•Nausea and vomiting leads to missed doses•Expanded intravascular volume lowers serum drug levels•Hepatic, plasma and placental enzymes increase drug metabolism•Increased glomerular filtration hastens drug clearance

• (+) / (-) Frequency and Severity

Associated with:

•Lower seizure threshold

•“Exhaustion from sleep deprivation”

•(+) / (-) Diabetes

•(+) / (-) Hypertension

•(+) / (-) Intake of folic acid

SALIENT FEATURES

•30 year old, female

•1st trimester pregnancy

•Phenytoin 100 mg TID for the past 5 years

CLINICAL IMPRESSION

IDIOPATHIC GENERALIZED SEIZURE DISORDER

IDIOPATHIC GENERALIZED SEIZURE DISORDER

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

• Prodromal symptoms– Occurring hours or days before a seizure– Mood changes, sleep disturbances, lightheadedness,

anxiety, irritability, difficulty concentrating and, rarely, an ecstatic feeling, abdominal pain, facial pallor, or headache. Most patients lose consciousness without any premonitory symptoms

– Patients with generalized tonic-clonic seizures do not have auras. An aura represents a simple partial seizure

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

• The patient may have completely nonfocal findings on neurologic examination when not having seizures. Seizures typically are divided into tonic, clonic, and postictal phases– Tonic phase

• The tonic phase begins with flexion of the trunk and elevation and abduction of the elbows. Subsequent extension of the back and neck is followed by extension of arms and legs. This can be accompanied by apnea, which is secondary to laryngeal spasm.

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

• Autonomic signs are common during this phase and include increase in pulse rate and blood pressure, profuse sweating, and tracheobronchial hypersecretion

• Although urinary bladder pressure rises, voiding does not occur because of sphincter muscle contraction

• This stage lasts for 10-20 seconds

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

– Clonic phase• The tonic stage gives way to clonic convulsive movements, in

which the tonic muscles relax intermittently, lasting for a variable period of time.

• A generalized tremor occurs at a rate of 8 tremors per second, which may slow down to about 4 tremors per second. Each spasm is accompanied by pupillary contraction and dilation. Some patients may have tongue or cheek bites

• The atonic periods gradually become longer until the last spasm. Voiding may occur at the end of the clonic phase as sphincter muscles relax. The atonic period lasts about 30 seconds. The patient continues to be apneic during this phase

• The convulsion, including tonic and clonic phases, lasts for 1-2 minutes.

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

– Postictal state• A variable period of unconsciousness during which the

patient becomes quiet and breathing resumes.• The patient gradually awakens, often after a period of

stupor or sleep, and often is confused, with some automatic behavior.

• Headache and muscular pain are common. The patient does not recall the seizure itself.

GENERALIZED SEIZURES

• Involve both hemispheres of the brain simultaneously and may be preceded by an aura before an abrupt loss of consciousness

• Strong hereditary component

GENERALIZED TONIC-CLONIC SEIZUREGENERALIZED TONIC-CLONIC SEIZURE

• Most generalized epilepsies are idiopathic, but a definite genetic locus has been found for some of these generalized types of epilepsy.

• Unusual sensations suggesting an aura• Seizure manifestations

HISTORYHISTORY

SUBTYPE MANIFESTATIONS

Absence seizure Brief staring spells with arrest of activity, often w/ eye fluttering,

which just last a few seconds

Myoclonic seizure Very brief isolated body jerks that tend to occur in the

morning

Generalized tonic-clonic seizure

Convulsions of the whole body lasting 1-2 minutes

• Ask about the first and any subsequent seizures

• Duration• Frequency• Sequential evolution• Longest & shortest interval between seizures• Aura• Postictal state• Precipitating factors

HISTORYHISTORY

• Risk factors• Prior head trauma or CNS infection• Drug use or withdrawal • Alcohol withdrawal• Non-adherence to anticonvulsants• Family history of seizures or neurologic disorders

• Rare triggers• Repetitive sounds• Flashing lights• Touching certain parts of the body

HISTORYHISTORY

• Sleep deprivation• Can lower the seizure threshold

• A bitten tongue, incontinence (eg, urine or feces in clothing), or, in patients who have lost consciousness, prolonged confusion, suggest seizure.

PHYSICAL EXAMPHYSICAL EXAM

Physical examination rarely indicates the cause when seizures are

idiopathic but may provide clues when seizures are symptomatic.

Intellectual functions, neurologic

exam and imaging (MRI) are normal.

Diagnostic evaluation must determine whether the event was a

seizure vs. pseudoseizure or syncope.

ELECTROENCEPHALOGRAM (EEG)

• The only definitive test to confirm the diagnosis.

• Represents a recurrent, sudden, excessive discharge of cortical neurons

• When abnormal, it’s very characteristic:• Interictal symmetric bursts of 4- to 7-Hz epileptiform activity

• Interictal spike-and-wave abnormalities without any clinical seizure activity

ELECTROENCEPHALOGRAM OF SUBTYPES

SUBTYPE EEG CHANGESAbsence seizure Very characteristic

pattern wave complexesMyoclonic seizure Bilateral polyspike and

wave abnormality at a rate of 4- to 6-Hz

Generalized tonic-clonic seizure

Can show either of the above patterns or generalized spikes

SEIZURE & PREGNANCY

• A woman with a seizure disorder can carry a pregnancy safely.

• Seizures can harm the developing fetus by reducing the blood supply to the placenta.

• For most pregnant women who have epilepsy, seizures remain the same. For a few, seizures become less frequent. For others — particularly women who have poorly controlled epilepsy — pregnancy increases the number of seizures.

COMPLICATIONSCOMPLICATIONS• Severe morning sickness• Anemia• Vaginal bleeding during and after pregnancy• Abruptio placenta• Pre-eclampsia• Premature baby• LBW baby

The occurrence of seizures in the first trimester poses the greatest risk of

congenital malformation and developmental delay in the offspring.

For babies whose mothers take seizure medication, the risk of birth defects is 4 to 8 percent — compared with 2 to 3

percent for all babies.

An antifolate effect on bloodand interference with vitamin K

metabolism have been reported,for which reason pregnant women taking

phenytoin shouldbe given vitamin K before delivery and

the newborn infant shouldreceive vitamin K as well to prevent

bleeding.

The obstetrician and neurologist should work together prior to conception and throughout the pregnancy to closely

monitor seizures and contributing factors (eg, sleep deprivation and medication

compliance).

AEDs & PREGNANCY

Phenytoin• fetal hydantoin syndrome

– craniofacial anomalies, distal digital hypoplasia, epicanthal folds, hypertelorism, low-set ears, and developmental delay

• mothers received phenytoin monotherapy during pregnancy demonstrated slightly delayed locomotor development

Phenobarbital

• fetal hydantoin syndrome and fetal alcohol syndrome

Valproic Acid• syndrome of specific craniofacial

abnormalities and long, thin digits with hyperconvex nails

• neural tube defects

Carbamazepine

• craniofacial abnormalities and hypoplastic nails

• neural tube defects and cardiac abnormalities

Trimethadione

• epicanthal folds, low-set ears, microcephaly, short stature, and irregular teeth

• rarely used in the treatment of epilepsy and should certainly be discontinued during pregnancy

PREVENTION &TREATMENT

Phenytoin: Fetal Hydantoin Syndrome

A 30 year-old female patient has been maintained on phenytoin 100 mg TID for the past 5 years with good control of her idiopathic generalized seizure. She is 3 months pregnant when she visited your clinic.

Because exposure to multiple antiepileptic drugs (AEDs) seems to be more teratogenic than

monotherapy, patients are advised to switch to a single AED prior to conception and taper to the

lowest possible dose.

Supplemental folate has been shown to decrease neural tube defects in patients

without epilepsy and decrease other congenital anomalies in women with epilepsy.

4 mg of folic acid should be taken daily starting two to three months prior to

pregnancy and be continued through the first trimester.

A fetal echocardiogram should be performed at 19 to 20 weeks’ gestation with careful

attention to cardiac anomalies.Because of the increased risk neural tube

defects, a maternal serum AFP and acetylcholinesterase screening test should be

offered.

Preconceptual management of women with epilepsy

• Attempt to decrease pharmacotherapy to monotherapy.• Taper dosages of AEDs to the lowest possible dose.• In women who have not had a seizure for 2-5 years, attempt complete withdrawal of pharmacotherapy.• Establish the level of total and free AEDs necessary for achieving good clinical control.• Consider preconceptual genetic counseling.• Supplement the diet with folate at 4 mg/d.

Management of women with epilepsy during pregnancy

• Check total and free levels of AEDs monthly.• Consider early genetic counseling.• Check maternal MSAFP levels and perform a level II fetal survey and ultrasonography at 19-20 weeks' gestation.• Consider amniocentesis for alpha-fetoprotein and acetylcholinesterase.

Gabapentin, lamotrigine, felbamate, topiramate, and oxcarbazepine

These newer anticonvulsants have not been studied extensively in pregnancy, though the use of pregnancy registries for AEDs are providing larger sample sizes.

The benefits and risks between congenital anomalies and seizure control needs to be considered when preparing the women with epilepsy for pregnancy. The new anticonvulsants generally have a better pharmokinetic profile and are not metabolized to known teratogens.

All of these anticonvulsants are considered US Food and Drug Administration pregnancy category C. Of note, they are still known to both cross the placenta and into breast milk.