Absence Seizures

Background: Absence seizures are a type of generalized seizures. They were first described Poupart in 1705, and later by Tissot in 1770, who used the term petit access. In 1824, Calmeil used the term absence. In 1935, Gibbs, Davis, and Lennox described the association of impaired consciousness and 3-Hz spike-and-slow-wave complexes on electroencephalograms (EEGs).

Absence seizures occur in both idiopathic and symptomatic generalized epilepsies. Among the idiopathic, or primary, generalized epilepsies (ie, with age-related onset), absence seizures are seen in childhood absence epilepsy (CAE, or pyknolepsy), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME, or impulsive petit mal seizures). The seizures in these conditions are called typical absence seizures and usually associated with 3-Hz spike-and-slow-wave complexes on EEG. In CAE, seizures are frequent and brief, lasting just a few seconds (pyknoleptic). Some children can have hundreds of such seizures per day. In other epilepsies, particularly those with an older age of onset, the seizures can last several seconds to minutes and may occur only a few times a day (called nonpyknoleptic or spanioleptic absence seizures). Myoclonic and tonic-clonic seizures may also be present, especially in syndromes with an older age of onset. In these syndromes, the discharge frequency may be faster than 3 Hz.

In the symptomatic generalized epilepsies, absence seizures are often associated with slow spike-wave complexes of 1.5-2.5 Hz; these are also called sharp-and-slow-wave complexes. These seizures are termed atypical absence seizures.

Pathophysiology: The etiology of idiopathic epilepsies with age-related onset is genetic. About 15-40% of patients with these epilepsies have a family history of epilepsy; concordance in monozygotic twins is 75%. Family members may have other forms of idiopathic or genetic epilepsy (eg, febrile convulsions, generalized tonic-clonic [GTC] seizures).

Several animal models demonstrate the genetic basis for absence seizures. A strain of Wistar rat, ie, genetic absence epilepsy rats from Strasbourg (GAERS), is a polygenetic model in which all animals have clinical seizures consisting of a behavioral arrest with twitching of facial muscles. This is associated with bilateral synchronous spike-wave discharges. Several single-gene loci in mice, when mutated, result in generalized spike-wave epilepsy. The tottering (chromosome 8), lethargic (chromosome 2), stargazer (chromosome 15), mocha (chromosome 10), and ducky (chromosome 9) loci all have generalized 6-per-second spike-wave EEG paroxysms that are associated with clinical seizures consisting of behavioral arrest. All types respond to ethosuximide (ETX), but the underlying cellular mechanisms for the generation of the discharges are not identical.

Several mutations of genes which encode protein subunits in various ion channels have been found in patients and family members with idiopathic epilepsies. Some forms of JME and absence epilepsy have been shown to result from mutations in Ca⁺⁺ channels.

In symptomatic generalized epilepsies, absence seizures are due to a wide variety of causes that, at an early stage of neural development, result in diffuse or multifocal brain damage. The causes of secondary generalized epilepsies and the other seizure types that accompany them, and their management, are not discussed in this article.

The pathophysiology of absence seizures is not fully understood. In 1947, Jasper and Droogleever-Fortuyn electrically stimulated nuclei in the thalami of cats at 3 Hz and produced bilaterally synchronous spike-and-wave discharges on EEG. In 1953, bilaterally synchronous spike-and-wave discharges were recorded by using depth electrodes placed in the thalamus of a child with absence seizures.

In 1977, Gloor demonstrated that the bilaterally synchronous 3-Hz spike-wave discharges in the feline penicillin model of absence seizures were generated in the cortex. This led to the corticoreticular theory of primarily generalized seizures.

Abnormal oscillatory rhythms are believed to develop in thalamocortical pathways. This involves GABA-B–mediated inhibition alternating with glutamate-mediated excitation. The cellular mechanism is believed to involve T-type calcium currents. T channels of the GABAergic reticular thalamic nucleus neurons appear to play a major role in the spike-wave discharges of the GABAergic thalamic neurons. GABA-B inhibition appears to be altered in absence seizures, and potentiation of GABA-B inhibition with tiagabine (Gabitril), vigabatrin (Sabril), and possibly gabapentin (Neurontin) results in exacerbation of absence seizures. Enhanced burst firing in selected corticothalamic networks may increase GABAB receptor activation in the thalamus, leading to generalized spike-wave activity.

Frequency:

• In the US: The incidence is 1.9-8 cases per 100,000 population.

Mortality/Morbidity:

• No deaths result directly from absence seizures. Accidents from driving or operating dangerous machinery during absence may result in death. In children with absence seizures due to secondary generalized epilepsies, death is related to the underlying disease.

• The morbidity from typical absence seizures is related to the frequency and duration of the seizures, as well as to the patient's activities; effective treatment ameliorates these factors. Educational problems and behavioral problems are sequelae of unrecognized, frequent seizures.

Race: No racial predilection is known.

Sex:

• Absence seizures are generally believed to be more common in females and in males, with some studies showing a 2:1 female-to-male ratio. Other studies have shown no difference between the sexes.

• Absence epilepsy with myoclonus has a male predominance.

Age: The generalized idiopathic epilepsies have age-related onset. Onset of absence seizures in children with symptomatic generalized epilepsies depends on the underlying disorder. While many of these disorders may have their onset at an early (prenatal, perinatal, or postnatal) age, absence seizures do not appear until later in childhood.

An example is the Lennox-Gastaut syndrome. The cause may be a genetic disorder or a perinatal insult, but the absence seizures do not present until age 1-8 years.

• CAE onset is at age 4-8 years, with peak onset at age 6-7 years.

• JAE onset is at age 7-14 years, with peak onset at age 10-12 years. Onset of JAE with myoclonus averages about age 7 years.

• JME has a more varied age of onset (8-26 y), but 79% of patients have an onset at age 12-18 years. Because the absence and myoclonic seizures are brief, they often go unrecognized, and many patients do not present until they experience a tonic-clonic seizure.

Treatment

Medical Care: Treatment involves antiepileptic drugs (AEDs). Once the proper diagnosis (ie, of the specific epilepsy syndrome) is made, the likelihood of other coexistent seizure types, such as myoclonic or tonic-clonic, should be considered and an appropriate medication selected.

• ETX (Zarontin) is effective only against absence seizures.

• Valproic acid (VPA; Depakene, Depacon) and divalproex sodium (Depakote) is considered a broad-spectrum AED because it is effective against absence, myoclonic, and tonic-clonic (as well as partial) seizures.

• Newer broad-spectrum medications, not yet approved by the US Food and Drug Administration (FDA) for treatment of absence seizures, include lamotrigine (LTG, Lamictal), topiramate (TPM, Topamax), zonisamide (ZNS, Zonegran), and levetiracetam (LEV, Keppra).

• Symptomatic generalized epilepsies are often refractory to first-line AEDs. LTG is approved by the FDA as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (at least aged 2 y). Clonazepam (Klonopin, felbamate (Felbatol), TPM, and the ketogenic or medium-chain triglyceride diet have been attempted to reduce seizure frequency. However, these adjunctive therapies have limited efficacy.

• Treatment with tiagabine (Gabitril), vigabatrin (Sabril), and possibly gabapentin (Neurontin) has been associated with the exacerbation of absence seizures. The use of carbamazepine (Tegretol) has also been associated with the exacerbation of absence seizures in some patients.

Consultations: All patients with suspected absence seizures should be examined by a neurologist who has expertise in diagnosing epileptic syndromes. Patients with refractory seizures, especially those with symptomatic epilepsies, may need to be referred to an epileptologist for prolonged EEG-video monitoring and medication adjustments.

Diet: Patients with medically intractable seizures may be tried on a ketogenic or medium-chain triglyceride diet. The results are often only temporary, and these diets are difficult to maintain. Children in whom such diets are being considered should be referred to a center with specialized dietary services.

Activity: Physical activity should not be restricted any more than necessary. Activities in which a seizure might pose a threat, such as swimming or rock climbing, may be allowed with appropriate supervision. A child with epilepsy should not be unnecessarily handicapped. Patients with uncontrolled absence seizures should not be allowed to drive. The situation may be unclear when the patient's clinical seizures are controlled but the EEG still shows some spike-wave activity.

Medication
Most AEDs are relatively toxic. Patients often take them every day, usually several times a day, for many years. Therefore, the decision to start such a medication is difficult. Once a patient has more than one unprovoked seizure, the decision to start medication is straightforward; EEG studies can help to confirm this decision.

Most AEDs are not effective against absence seizures. Also, many patients have both absence and generalized convulsive (myoclonic and GTC) seizures. Only 2 first-line AEDs are currently used for absence seizures.

Drug Category: Antiepileptics -- If the patient has only absence seizures, then ETX (Zarontin) is an appropriate medication. This may be the case for patients with CAE. ETX also may be used in conjunction with an anticonvulsive AED, such as phenytoin (PHT, Dilantin) for patients at risk of tonic-clonic seizures in whom VPA is contraindicated.

Drug Name	ETX (Zarontin) -- Succinimide AED effective only against absence seizures. No effect on GTC, myoclonic, atonic, or partial seizures. Mechanism of action based on reducing current in T-type calcium channels on thalamic neurons. Spike-and-wave pattern during petit mal seizures thought to be initiated in thalamocortical relays by activation of these channels. Available in large 250-my capsules, which may be difficult for some children to swallow, and as syrup (250 mg/5 mL).
Adult Dose	250 mg PO bid; increase by 250-mg increments q4-7d until seizures controlled or maximum daily dose reached; not to exceed 1.5 g/d
Pediatric Dose	<6> >6 years: Administer as in adults Maintenance dose: 15-40 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; blood dyscrasias; renal or hepatic disease
Interactions	Generally minimal; enzyme-inducing drugs (eg, PHT, carbamazepine, phenobarbital) may lower levels by 15-25%; valproic acid may elevate levels; has weak enzyme-inhibiting effect, usually insignificant with respect to metabolism of other drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Blood dyscrasias may occur and may be fatal (monitor CBC); caution in hepatic or renal disease; abrupt withdrawal may precipitate absence status

Drug Name	Valproic acid (Depakene, Depacon, Depakote, Depakote ER) -- DOC for patients who have absence and GTC and/or myoclonic seizures; aliphatic compound, carboxylic acid. Discovery was serendipitous; used as solvent potential AEDs, and all test compounds seemed to work. Mechanism of action not known but believed related to ability to increase brain GABA. May inhibit rapid opening of sodium channels and block T-type calcium channels. VPA (Depakene) available as syrup (250 mg/5 mL), 250- or 500-mg capsules, and IV preparation (100 mg/5 mL; Depacon). Divalproex sodium (Depakote) available as 250- or 500-mg tab and 125-mg capsule (Depakote Sprinkles), which can be opened and mixed with food. Syrup rapidly absorbed through stomach and produces gastric irritation. Rapidly produces high serum levels and may cause peak-dose toxicity. Must be given in 3-4 divided doses. Other oral preparations absorbed more slowly from GI tract and better tolerated. Because of slower absorption, some patients who have achieved control may be treated with bid dosing. Highly protein bound; protein binding is level dependent. At 40 mg/mL, 90% bound, but at 130 mg/mL, 80% bound. Therefore, as total level increases from 40 to 130 mg/mL, free level increases from 4 to 26 mg/mL. Therapeutic range originally 50-100 mg/mL; patients with hard-to-control seizures may require higher level. Depakote ER is extended-release product intended for once-a-day oral administration. When converting from Depakote to Depakote ER, dose 8-20% higher than total daily dose of Depakote is needed. IV Depacon may be given as maintenance therapy; amount mixed with at least 50 mL of compatible diluent and infused at rate not >20 mg/kg/min over at least 60 min; research ongoing concerning IV loading at more rapid rates.
Adult Dose	10-15 mg/kg/d PO initially; increase by 5-10 mg/kg/d weekly until seizures controlled or adverse effects develop; not to exceed 60 mg/kg/d divided tid/qid
Pediatric Dose	15 mg/kg/d PO initial dose, increasing by 5-10 mg/kg/d weekly until seizures controlled or adverse effects develop; maximum recommended dosage 60 mg/kg/d divided tid/qid; for select patients with complete control, bid dosing may be tried
Contraindications	Documented hypersensitivity; hepatic disease or dysfunction; because of teratogenicity, first trimester of pregnancy and in women of childbearing age who are not on adequate birth control, unless it is clearly the most effective drug for a woman planning pregnancy and aware of risks
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin, phenytoin, phenobarbital, and carbamazepine may significantly reduce levels; in children, salicylates decrease protein binding and metabolism; carbamazepine may result in variable changes of carbamazepine concentrations with possible toxicity or loss of seizure control; may increase diazepam and ETX toxicity (monitor closely); may increase phenobarbital and phenytoin levels; may displace warfarin from protein-binding sites (monitor coagulation tests) and can displace phenytoin, resulting in transient increase in free levels; may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Hepatic dysfunction may occur (more common in children taking multiple AEDs) during first 6 mo of therapy, and may be fatal; assess liver function test (LFT) results before therapy and at frequent intervals during first 6 mo; clinical symptoms (loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, vomiting) may precede LFT abnormalities; hyperammonemia reported and may be occur despite normal LFTs; may cause lethargy or coma; when asymptomatic elevations of ammonia are present, more frequent monitoring indicated; carnitine supplementation may be beneficial in addition to platelet dysfunction, thrombocytopenia may occur and associated with high doses; pancreatitis may occur, even after several years of therapy; perform appropriate tests in patients with malabsorption, abdominal pain, or other GI symptoms; spina bifida in 1-2% of children born to women taking VPA during first 12 wk of pregnancy; women planning to become pregnant should take folic acid 1-5 mg/d, and consider crossing over to ETX before conception; for women with have GTC seizures, ETX and anticonvulsant AED can be used