eMedicine Specialties > Neurology > Seizures and Epilepsy

Absence Seizures

Scott Segan, MD, Director of SBH Stroke Center and Attending Neurologist, St Barnabas Hospital

Updated: Apr 7, 2009

Introduction

Background

Absence seizures are a type of generalized seizures.^1,2 They were first described by Poupart in 1705, and later by Tissot in 1770, who used the term petit access. In 1824, Calmeil used the term absence.³ In 1935, Gibbs, Davis, and Lennox described the association of impaired consciousness and 3-Hz spike-and-slow-wave complexes on electroencephalograms (EEGs).⁴

Absence seizures occur in both idiopathic and symptomatic generalized epilepsies.⁵ Among the idiopathic generalized epilepsies, absence seizures are seen in childhood absence epilepsy (pyknolepsy), juvenile absence epilepsy, and juvenile myoclonic epilepsy (impulsive petit mal).⁶ The seizures in these conditions are called typical absence seizures and are usually associated with generalized 3-4 Hz spike-and-slow-wave complexes on EEG.⁷

In childhood absence epilepsy, seizures are frequent and brief, lasting just a few seconds (pyknoleptic). Some children can have many 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 cryptogenic or symptomatic generalized epilepsies, absence seizures are often associated with slow spike-wave complexes of 1.5-2.5 Hz⁶ ; these are also called sharp-and-slow-wave complexes. These seizures may be associated with loss of axial tone and head nodding or a fall may occur. Increased tone, autonomic features, and automatisms may also be seen. Absence seizures associated with slow spike-wave complexes are called atypical absence seizures.⁸

Pathophysiology

Etiology

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; overall concordance in monozygotic twins is 74% with a 100% concordance during the peak age of phenotypic expression.⁹ Family members may have other forms of idiopathic or genetic epilepsy (eg, febrile convulsions, generalized tonic-clonic seizures).

Several animal models demonstrate the genetic basis for absence seizures. A strain of Wistar rat, genetic absence epilepsy rats from Strasbourg (GAERS), is a polygenetic model¹⁰ 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, but the underlying cellular mechanisms for the generation of the discharges are not identical.¹¹

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 discussed elsewhere (Epilepsy in Children with Mental Retardation, Lennox-Gastaut Syndrome), and 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.²³ In 1953, bilaterally synchronous spike-and-wave discharges were recorded by using depth electrodes placed in the thalamus of a child with absence seizures.²⁴

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.²⁵ 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.²⁶ 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 GABA-B receptor activation in the thalamus, leading to generalized spike-wave activity.

Frequency

United States

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. Up to two thirds of children with childhood absence epilepsy are girls.^9,27
• Absence epilepsy with myoclonus has a male predominance.²⁸

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.²⁹

• Childhood absence epilepsy onset is at age 4-8 years, with peak onset at age 6-7 years.²⁷
• Juvenile absence epilepsy onset is generally around puberty. Actual age of onset may vary, depending on whether pyknoleptic (8.3 ± 4.5 years) or nonpyknoleptic seizures occur (14.8 ± 8.3 years).³⁰
• Juvenile myoclonic epilepsy has a more varied age of onset (8-26 y), but 79% of patients have an onset at age 12-18 years.³¹ 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.

Clinical

History

• Children with idiopathic generalized epilepsies may present with a history of staring spells, but infrequent absence seizures may not be diagnosed until a generalized tonic-clonic seizure has occurred.
  • Other symptoms, such as behavioral problems, may be the presenting complaint. Although the brief attacks are unrecognized, the lapses of awareness interfere with attention; as a result, the child becomes frustrated.
  • Decline in school performance may be an indication of the onset or breakthrough of absence seizures.
• In symptomatic generalized epilepsies, atypical absence seizures often occur in the setting of developmental delay or mental retardation. (See Table 1 for features of typical and atypical absence seizures.) Other seizure types can be present, such as myoclonic, tonic, atonic, tonic-clonic, and even partial seizures.

Physical

• Physical and neurologic findings are normal in children with idiopathic generalized epilepsies. Having the child hyperventilate for 3-5 minutes can often provoke absence seizures. This procedure can easily be performed in the clinic or office, and the result is diagnostic.
• Ictal features
  • On clinical examination, typical absence seizures appear as brief staring spells.
    • Patients have no warning or postictal phase, and if engaged in gross motor activity, such as walking, they may stop and stand motionless or they may continue to walk.
    • Children are not responsive during the seizure and have no memory of what happened during the attack; they are generally unaware that a seizure has occurred.
    • Table 1. Clinical and EEG Findings in Typical and Atypical Absence Seizures* (Adapted from Dreifuss, 1997³² .)
      
      

      Type of Clinical Seizure		EEG Findings
      Typical absence	Impairment of consciousness only	Usually regular and symmetrical 3 Hz, possible 2- to 4-Hz spike-and-slow-wave complexes, and possible multiple spike-and-slow-wave complexes
      	Mild clonic components
      	Atonic components
      	Tonic component
      	Automatisms
      	Autonomic components
      Atypical absence	Changes in tone more pronounced than those of typical absence seizure	EEG more heterogeneous than in typical absence; may include irregular spike-and-slow-wave complexes, fast activity, or other paroxysmal activity; abnormalities bilateral but often irregular and asymmetric
      	Nonabrupt onset or cessation abrupt

      *May be seen alone or in combination.
  • Absence seizures may be confused with complex partial seizures, especially in cases of prolonged seizures with automatisms (see Table 2). The occurrence of automatisms is dependent on duration of the seizure; the longer the seizure, the more likely automatisms are to occur (see Media file 1).³³
    
    

    

    Percentage of absence seizures with automatisms as a function of duration in seconds. (Data gathered from Penry et al, 1975 ³³.)

    
    
  • Atypical absence seizures, which occur in patients with symptomatic generalized epilepsies, are usually longer than typical absences and often have more gradual onset and resolution.
  • Although absence seizures may share many clinical features with complex partial seizures, the abrupt ending of typical absence seizures, without a postictal phase, is the most useful clinical feature in distinguishing the 2 conditions. Table 2. Differentiating Features of Complex Partial and Absence Seizures

    Feature	Complex Partial	Absence
    Onset	May have simple partial onset	Abrupt
    Duration	Usually >30 s	Usually <30 s
    Automatisms	Present	Duration dependent
    Awareness	No	No
    Ending	Gradual postictal	Abrupt

• In symptomatic generalized epilepsies, physical and neurologic findings may be abnormal, reflecting the underlying disorder.
  • Physical examination may reveal stigmata of a genetic disease, such as a neurocutaneous disorder (eg, tuberous sclerosis) or an inborn error of metabolism.
  • Neurologic examination may show signs of developmental delay or more specific signs, such as spastic paresis in cerebral palsy.

Causes

After noncompliance with treatment, lack of sleep is the most frequent cause of seizure exacerbations. Drugs that lower the seizure threshold (eg, alcohol, cocaine, high-dose penicillin, isoniazid [INH] overdose, neuroleptics) are most likely to cause seizures in patients with epilepsy. Withdrawal of alcohol, benzodiazepines, and other sedatives are also common causes.

Differential Diagnoses

Other Problems to Be Considered

Breath-holding spells
Nonconvulsive generalized status epilepticus

Workup

Laboratory Studies

• When evaluating a child for staring spells, laboratory tests for metabolic abnormalities or toxic or drug ingestion (especially in older children) may be indicated. If a clear history of the episodic nature of the attacks is obtained, then the EEG can be diagnostic and laboratory tests may not be necessary.
• When evaluating a child with a developmental delay, or if the EEG reveals atypical absences, then a full work-up for the underlying cause of a symptomatic generalized epilepsy is indicated.

Imaging Studies

• Neuroimaging findings are normal in idiopathic epilepsies by definition^1,34 and therefore neuroimaging is not indicated if the typical clinical pattern is present.
• Neuroimaging is often ordered by primary care providers and the emergency department, especially if a child presents with a generalized tonic-clonic seizure, to rule out significant structural causes of seizures. A normal result helps support the diagnosis of idiopathic epilepsy. For cryptogenic and symptomatic generalized epilepsies, neuroimaging can help in diagnosing of any underlying structural abnormality.
• If imaging is performed, MRI is preferred to CT scanning. MRI is more sensitive for certain anatomic abnormalities. A review of 134 MRIs in patients with idiopathic generalized epilepsies found nonspecific abnormalities in 24%.³⁵

Other Tests

The only diagnostic test for absence seizures is the EEG.

• Findings in typical absence seizures include the following:
  • Background activity is normal.
    • In syndromes with frequent absence seizures, such as childhood absence epilepsy, a routine awake recording is often pathognomonic.
    • Bursts of frontally predominant, generalized 3-Hz spike-and-wave complexes are seen during the seizures.⁴
    • In syndromes with less frequent absence seizures (juvenile absence epilepsy or juvenile myoclonic epilepsy), an awake recording may be normal; a sleep or sleep-deprived recording may be needed.
  • Typical absence seizures have generalized 3-Hz spike-and-wave complexes (see Media file 2).
    
    

    

    EEG of a typical absence seizure with 3-Hz spike-and-wave discharges.

    
    
    
    • The spike frequency is often faster at the onset, with a slight deceleration at the end.²⁷ They can range from 2.5-6 Hz, with the faster frequencies seen in syndromes with older age of onset.
    • Bursts of generalized polyspikes and waves (multiple spike-and-slow-wave complexes) may also be seen³¹ , especially during sleep and in syndromes with older age of onset.
    • The onset and ending of these seizures are abrupt; no postictal EEG slowing is noted.
    • Hyperventilation often provokes these seizures and should be a routine part of all EEGs in children.
    • Photosensitivity may be present in idiopathic generalized epilepsies  and is more often seen in juvenile myoclonic epilepsy and childhood absence epilepsy than juvenile absence epilepsy.³⁰
    • EEG video monitoring demonstrates that clinical seizure manifestations may lag behind the start of ictal EEG activity; bursts lasting less than 3 seconds are usually clinically silent. During the absence seizure, rhythmic eye blinks and mild clonic jerks may be present. As a seizure progresses, automatisms may be seen.³³
    • Clinical and EEG features may vary considerably in different children.³⁶
• Findings in atypical absence seizures include the following:
  • Seizures are characterized by slow spike-and-wave paroxysms, classically 2.5 Hz (see Media file 3). The onset may be difficult to discern, and postictal EEG slowing may be noted.
    
    

    

    Slow spike-and-wave discharges (2.5 Hz). This is an interictal pattern in a child with seizures and developmental delay.

    
    
  • Background activity is often abnormal, reflecting the diffuse or multifocal underlying encephalopathy of symptomatic generalized epilepsy.
  • Generalized polyspike-and-wave complexes also may be present, and focal features may be observed.
  • The clinical correlation of generalized spike-and-wave complexes with clinical seizures is not as clear-cut as in typical absence seizures. Generalized slow spikes and waves may be present as an interictal pattern, as in Lennox-Gastaut syndrome.
  • EEG-video monitoring can show a more varied alteration of consciousness than in typical absence seizures. If the patient has underlying mental retardation, discerning changes in mental status also may be more difficult in atypical absence.
  • Changes in postural tone, most noticeably head nods, are common.

Ambulatory EEG monitoring over 24 hours may be useful to quantitate the number of seizures per day and their most likely times of occurrence.

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. Since altered awareness occurs with even brief bursts of spike-wave paroxysms on EEG, treatment should be titrated to suppressing all epileptiform activity.³⁷

• Ethosuximide (Zarontin) is effective only against absence seizures.
• Valproic acid (Depakene, Depacon) and divalproex sodium (Depakote, Depakote ER) are considered broad-spectrum AEDs because they are effective against absence, myoclonic, tonic-clonic, and partial seizures.
• Symptomatic generalized epilepsies are often refractory to first-line AEDs. Lamotrigine (Lamictal) and topiramate (Topamax) are approved by the FDA as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (³ 2 y). Clonazepam (Klonopin, felbamate (Felbatol), topiramate, and the ketogenic or medium-chain triglyceride diet have been attempted to reduce seizure frequency. However, these adjunctive therapies have limited efficacy.
• Some AEDs can aggravate seizures, especially in cryptogenic or symptomatic generalized epilepsies.³⁸ Treatment with carbamazepine (Tegretol, Tegretol XR, Carbatrol)^39,40 and oxcarbazepine (Trileptal)⁴¹ has been associated with the exacerbation of absence seizures. Gabapentin (Neurontin) is ineffective against absence seizures⁴²  and tiagabine (Gabitril) and vigabatrin (Sabril) have been associated with the exacerbation of absence or myoclonic seizures in some patients.^43,44

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 ketogenic⁴⁵ or medium-chain triglyceride diet⁴⁶ . Although these diets are difficult to maintain, there is evidence for their effectiveness.⁴⁷ 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

The decision to start antiepileptic medication must be made with great care. Most AEDs are relatively toxic and can have sedative and cognitive side effects. Children with absence seizures may need to be on medication for many years, and in some for life. EEG can usually confirm the diagnosis and the presence of spontaneous seizures can be documented on routine EEG or with longer recordings (ie, 24-hour ambulatory EEG or EEG video monitoring).

Most AEDs are not effective against absence seizures. Also, many patients have both absence and generalized convulsive (myoclonic and generalized tonic-clonic) seizures and need an AED with efficacy for both. Only 2 first-line AEDs have FDA approval to be indicated for absence seizures: ethosuximide and valproic acid. Ethosuximide has efficacy for absence only and valproic acid has efficacy for absence, generalized tonic-clonic, and myoclonic seizures.

Of the newer AEDs, lamotrigine, topiramate, and levetiracetam have been shown to have efficacy against seizures in idiopathic generalized epilepsy^48,49 and have received FDA approval to be indicated for adjunctive therapy of generalized tonic-clonic seizures in idiopathic generalized epilepsy in children 2 and older (for lamotrigine and topiramate) and in children 6 and older (for levetiracetam). Lamotrigine and topiramate are also approved as adjunctive therapy in Lennox-Gastaut syndrome in children 2 years and older. Topiramate has also received FDA approval as initial monotherapy for generalized tonic-clonic seizures in children 10 years and older with idiopathic generalized epilepsy. Studies have shown these medications to have anti-absence efficacy, but the data are incomplete.⁵⁰

Antiepileptics

If the patient has only absence seizures, then ethosuximide (Zarontin) is an appropriate medication. This may be the case for patients with childhood absence epilepsy. Ethosuximide may also be used in conjunction with an anticonvulsive AED, such as phenytoin (Dilantin) for patients at risk of tonic-clonic seizures in whom valproic acid is contraindicated.

Lamotrigine (Lamictal)

Triazine derivative used in neuralgia. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membrane.

Dosing

Adult

Monotherapy:
Initial: 50-100 mg/day PO bid
Maintenance: 100-400 mg/day PO divided in 1-2 doses, not to exceed 500 mg/day

Adjunct therapy with valproic acid:
Initial dose: 25 mg PO qod
Maintenance: 50-200 mg/day in 1-2 divided doses, not to exceed 200 mg/day

Pediatric

<2 years: Not established
2-12 years:
Added to regimens Weeks 1-2: 0.6 mg/kg/day PO divided q12h, rounded down to nearest 5 mg (ie, to nearest whole tablet)
Weeks 3-4: 1.2 mg/kg/day PO divided q12h, rounded down to nearest 5 mg
Maintenance: 5-15 mg/kg/day PO; not to exceed 400 mg/day PO divided q12h
To achieve maintenance dose, increase doses q1-2wk as follows:
Calculate 1.2 mg/kg/day and round down to nearest 5 mg; add this amount to previously administered daily dose

Concomitant therapy with valproic acid:
Weeks 1-2: 0.15 mg/kg/day PO qd or divided bid, rounded down to nearest 5 mg
If initial calculated daily dose is 2.5 to 5 mg, take 5 mg on alternate days for first 2 wk
Weeks 3-4: 0.3 mg/kg/day PO qday or divided bid, rounded down to nearest 5 mg
Maintenance: 1-5 mg/kg/day PO qday or divided bid, not to exceed 200 mg/day
To achieve maintenance dose, increase doses q1-2wk as follows:
Calculate 0.3 mg/kg/day, and round down to nearest 5 mg; add amount to previously administered qday dose
Added to AED regimens that do NOT include carbamazepine, phenytoin, phenobarbital, primidone, or valproate:
Weeks 1-2: 0.3 mg/kg/day PO qday or divided bid, rounded down to nearest 5 mg
Weeks 3-4: 0.6 mg/kg/day PO divided q12h, rounded down to nearest 5 mg
Maintenance: 4.5-7.5 mg/kg/day PO; not to exceed 300 mg/day PO divided q12h
To achieve maintenance dose, increase doses q1-2wk as follows:
Calculate 0.6 mg/kg/day and round down to nearest 5 mg; add this amount to previously administered daily dose
>12 years:
Added to regimens that include carbamazepine, phenytoin, phenobarbital, or primidone:
Weeks 1-2: 50 mg/day PO
Weeks 3-4: 100 mg/day PO divided bid
Maintenance: 300-500 mg/day PO divided bid; to achieve maintenance, increase doses by 100 mg/day q1-2wk

Concomitant therapy with valproic acid:
Weeks 1-2: 25 mg PO every other day
Weeks 3-4: 25 mg PO qday
Maintenance: 100-400 mg/day PO qday or divided bid
To achieve maintenance dose, may increase by 25-50 mg/day q1-2wk

Added to AED regimens that do NOT include carbamazepine, phenytoin, phenobarbital, primidone, or valproate:
Weeks 1-2: 25 mg PO qday
Weeks 3-4: 50 mg PO qday
Maintenance: 225-375 mg/day PO qday or divided q12h

Interactions

Acetaminophen increases renal clearance of medication, decreasing effects; similarly, carbamazepine, phenobarbital, and phenytoin increase lamotrigine metabolism causing a decrease in lamotrigine levels; succinimide anticonvulsants (eg, methsuximide, phensuximide) decrease lamotrigine levels; estrogen-containing oral contraceptives increase elimination (most patients require up to a 2-fold dose increase of lamotrigine); rifampin decreases lamotrigine levels; administration of valproic acid with lamotrigine increases half-life and serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired renal or hepatic function

Ethosuximide (Zarontin)

Succinimide AED effective only against absence seizures. No effect on generalized tonic-clonic, 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-mg capsules, which may be difficult for some children to swallow, and as syrup (250 mg/5 mL).

Dosing

Adult

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/day

Pediatric

<6 years: 15 mg/kg/day PO divided bid initially; initial dose not to exceed 250 mg; may increase to effect q4-14d
>6 years: Administer as in adults
Maintenance dose: 15-40 mg/kg/day PO divided bid

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

Contraindications

Documented hypersensitivity; blood dyscrasias; renal or hepatic disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Blood dyscrasias may occur and may be fatal (monitor CBC); caution in hepatic or renal disease; abrupt withdrawal may precipitate absence status

Valproic acid (Depakene, Depacon, Depakote, Depakote ER)

DOC for patients who have absence and generalized tonic-clonic 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 to be related to ability to increase brain GABA. May inhibit rapid opening of sodium channels and block T-type calcium channels.
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 the 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.

Dosing

Adult

10-15 mg/kg/day PO initially; increase by 5-10 mg/kg/day weekly until seizures controlled or adverse effects develop; not to exceed 60 mg/kg/day divided tid/qid

Pediatric

15 mg/kg/day PO initial dose, increasing by 5-10 mg/kg/day weekly until seizures controlled or adverse effects develop; maximum recommended dosage 60 mg/kg/day divided tid/qid; for select patients with complete control, bid dosing may be tried

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 ethosuximide 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

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

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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 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 is 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 valproic acid during first 12 wk of pregnancy; women planning to become pregnant should take folic acid 1-5 mg/day, and consider crossing over to ethosuximide before conception; for women who have generalized tonic-clonic seizures, ethosuximide and anticonvulsant AED can be used

Follow-up

Further Outpatient Care

• Children with absence seizures should be monitored closely during titration or crossover of AEDs. The dose of the medication should be increased weekly until seizures are controlled or adverse effects develop.
• The aim in therapy is to control seizures completely with the minimum required amount of medication to minimize adverse effects.
• The therapeutic effect of valproic acid for absence seizures may lag several weeks behind reaching a therapeutic level.⁵¹
• Liver function test, amylase and/or lipase, and CBC results should be monitored during drug treatment to watch for adverse reactions.
• Drug levels should be monitored to ensure compliance and to watch for toxic levels in patients who are too young or too developmentally disabled to articulate subjective adverse effects.

Complications

Absence status epilepticus may occur spontaneously, as a result of a concurrent illness, or after the administration of a drug that lowers the seizure threshold.

• On clinical evaluation, the patient appears to be in a dreamy state with partial responsiveness and automatisms; at times the presentation may be more subtle, with only mild encephalopathy. The diagnosis is made by EEG confirmation of generalized 3-Hz spike-and-wave complexes, although the discharges may be slower and less regular than with isolated seizures.
• Treatment has been intravenous benzodiazepines. In some patients, this may be replaced by or supplemented with intravenous valproic acid because intravenous benzodiazepines have been reported to produce tonic status in patients with symptomatic generalized epilepsy.⁵²

Prognosis

• The prognosis for the primary generalized epilepsies depends on the particular epileptic syndrome. Because seizures, particularly generalized tonic-clonic seizures, may occur well after patients appear to achieve good control, a long seizure-free period should be achieved before discontinuation of therapy is considered.
• The remission rate for childhood absence epilepsy is good; 80% respond to medication. Complete remission rates vary widely, perhaps dependent on the length of follow-up. 
  • Generalized tonic-clonic seizures may develop in up to 40% of children with childhood absence epilepsy.²⁷
  • Persistence of seizures is more likely in those with generalized tonic-clonic seizures.
  • Early onset of absence seizures, quick response to therapy⁵³ , and normal EEG background are good prognostic signs.
• Juvenile myoclonic epilepsy carries a high risk of generalized tonic-clonic seizures.
  • Despite excellent control with relatively small doses of an AED, the relapse rate is greater than 90%.⁵⁴
  • Patients with juvenile myoclonic epilepsy generally need to be treated for life, though occasional patients achieve control with careful attention to lifestyle issues (eg, adequate sleep, abstinence from alcohol).

Patient Education

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

Miscellaneous

Medicolegal Pitfalls

• The 2 main pitfalls in treatment of absence seizures both involve incorrect diagnosis.
  • On occasion, a patient without epilepsy is identified as having epilepsy.
  • Staring spells, daydreaming, migraine equivalents, and panic and/or anxiety attacks all may be confused with nonconvulsive seizures.
• Certain epileptic syndromes are often undiagnosed or misdiagnosed.
  • Patients who present with a generalized tonic-clonic seizure are often given an AED without efficacy against absence or myoclonic seizures. Their generalized tonic-clonic seizures may be controlled, but they may have unrecognized absence or myoclonic seizures.
  • Patients with absence seizures may be identified as having complex partial seizures, and vice versa. This leads to incorrect treatment and an inaccurate understanding of the prognosis.
• Careful history taking and EEG studies can help avoid these pitfalls.

Special Concerns

• Patients who are old enough to drive should be warned about driving and operating heavy machinery. Physicians should be familiar with state laws concerning driving with epilepsy; inform patients concerning these legal matters.
• Women of childbearing age who are not using adequate birth control should not be treated with valproic acid, if equally effective alternatives are available for them.
  • If a woman taking valproic acid wishes to become pregnant, treatment may be crossed over to ethosuximide if only absence seizures are present, and she may be given folic acid 1-5 mg/d before conception. After the first trimester, treatment may be switched back to valproic acid.
  • Women with generalized tonic-clonic seizures may be crossed over to lamotrigine, and given folic acid 1-5 mg/d before conception.
  • Most clinicians believe that women treated with valproic acid or any hepatic enzyme-inducing AED should be treated with vitamin K before delivery.

Multimedia

Media file 1: Percentage of absence seizures with automatisms as a function of duration in seconds. (Data gathered from Penry et al, 1975 ³³.)

Media file 2: EEG of a typical absence seizure with 3-Hz spike-and-wave discharges.

Media file 3: Slow spike-and-wave discharges (2.5 Hz). This is an interictal pattern in a child with seizures and developmental delay.

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Keywords

absence seizure, petit mal seizures, generalized seizures, idiopathic generalized epilepsy, symptomatic generalized epilepsy, seizure treatment, epilepsy treatment, idiopathic generalized epilepsies, childhood absence epilepsy, pyknolepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, impulsive petit mal seizures, typical absence seizures, symptomatic generalized epilepsies, nonpyknoleptic seizures, spanioleptic absence seizures

Contributor Information and Disclosures

Author

Scott Segan, MD, Director of SBH Stroke Center and Attending Neurologist, St Barnabas Hospital
Scott Segan, MD is a member of the following medical societies: American Academy of Neurology and American Epilepsy Society
Disclosure: UCB Pharma Honoraria Speaking and teaching

Medical Editor

Edward B Bromfield, MD, Associate Professor of Neurology, Faculty Member, Division of Sleep Medicine, Harvard Medical School; Chief, Division of EEG, Epilepsy and Sleep Neurology, Consulting Neurologist, Brigham and Women's Hospital
Edward B Bromfield, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association, and Massachusetts Medical Society
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
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