Khaled M. Zamel, MD
DESCRIPTION
- Absence seizures are generalized seizures characterized by paroxysmal loss of consciousness with brief discontinuation of activity followed by abrupt recovery with no recollection of the event. Typical absence seizures are mostly seen in idiopathic generalized epilepsies (IGEs) such as childhood absence epilepsy (CAE), Juvenile absence epilepsy (JAE) and Juvenile myoclonic epilepsy (JME). Atypical absence seizures are seen only with severe symptomatic or cryptogenic epilepsies such as in Lennox–Gastaut syndrome.
EPIDEMIOLOGY
Incidence
- The vast majority of absence seizures start between the age of 4 and 12.
- Annual incidence of CAE is about 6 to 8/100,000 per year.
- Incidence of absence seizures in adults is uncertain but in general onset of absence seizures is rare after age 20.
Prevalence
- Absence seizures account for 2–16% of seizures in all ages and are the seizure type most commonly undiagnosed.
- CAE is the most common form of pediatric epilepsy accounting for 10 to 17% of all cases of childhood onset epilepsy.
- JAE may account for about 2–3% of all adult epilepsies and up to 10% of IGEs.
- No known difference
- Absence seizures are seen more often in childhood, but they also occur in about 10–15% of adults with epilepsies, often combined with other generalized seizures.
- Some studies showed twofold preponderance in girls.
RISK FACTORS
- Family history of absence epilepsy, febrile seizures or other IGEs. In general, a family history of epilepsy is found in 15–44% of patients with generalized absence seizures.
Genetics
- Recent genetic studies linked CAE to gene mutations in the GABA-A receptor gamma 2 subunit as well as calcium channel CACNA1H.
GENERAL PREVENTION
Non-compliance with antiepileptic medications is a frequent cause of breakthrough seizures. Alcohol as well as many drugs such as neuroleptics and isoniazid can lower seizure threshold.
PATHOPHYSIOLOGY
- Not fully understood
- The thalamocortical networks are believed to be involved with abnormal oscillatory rhythms that generate the generalized spike and wave discharges that accompany the absence seizure episodes. This involves activation of the T-type calcium channels as a result of GABA-B mediated inhibition alternating with glutamate-mediated excitation.
ETIOLOGY
- There is strong evidence that genetic factors are involved in the etiology of typical absence seizures. On the other hand, acquired disorders are more common in atypical absence seizures.
COMMONLY ASSOCIATED CONDITIONS
- Later age of onset of absence seizures is linked to higher risk for developing convulsive generalized tonic-clonic (GTC) seizures.
- Attention deficit hyperactivity disorder, subtle cognitive deficits, linguistic difficulties, and anxiety disorders are more common in patients with absence epilepsy.
HISTORY
- The characteristic features of typical absences are abrupt onset of brief staring, cognitive impairment and change in facial expression. Duration is typically <20 seconds without postictal changes. Many patients have associated minor motor movements, such as eye rolling, eyelid fluttering, head nodding, or subtle oral automatisms. Less frequently, mild myoclonic jerks of the head or extremities or change in muscle tone may occur. Occasionally, autonomic features such as change in skin color, urinary incontinence, or pupillary dilation are seen. Hyperventilation for 3 minutes will provoke an absence in nearly all untreated children with CAE.
- In CAE, absence seizures begin between 4 and 8 years and may occur many times per day. Sometimes, decline in school performance is the only indication that leads to the diagnosis. About 30% of children with CAE later develop GTC seizures.
- JAE begins between 10 and 15 years. JAE patients usually have less frequent absences than those with CAE but higher risk for developing GTC seizures.
- JME usually begins in adolescence with initial manifestations of myoclonic seizures, which predominantly occur on awakenings. GTC and absence seizures usually develop later.
- Atypical absence seizures are seen most frequently in symptomatic generalized epilepsies accompanied by developmental delay or mental retardation. They are usually associated with other types of seizures
- In contrast to the typical absence, atypical absence seizures are characterized by a less abrupt clear onset and offset, which is usually progressive. Atypical absence seizures last longer and have a higher incidence of changes in postural tone.
PHYSICAL EXAM
- The neurologic examination is usually normal in patients with typical absence seizures.
- Hyperventilation for 3–5 minutes can aid the diagnosis as it frequently provokes absence seizures.
- Atypical absence seizures usually occur in children with subnormal mental function
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Video-EEG is the single most important diagnostic procedure. In CAE, the EEG has a normal background with 4–20 seconds bursts of rhythmic, generalized, high-amplitude 3-Hz spike-and-wave discharges typically exacerbated by hyperventilation. In JAE, discharges are similar but with faster frequency, mostly 4–5 Hz with frequent polyspike. JME is characterized by the occurrence of generalized polyspike and slow-wave discharges of 3–6 Hz. Atypical absences usually occur in the context of abnormal background and an ictal EEG of slow <2.5-Hz spike-and-slow wave.
Follow-Up & Special Considerations
- Questionable cases could be evaluated with long-term video-EEG monitoring to record and characterize their events.
Imaging
Initial Approach
- Patients usually have normal neuroimaging. Brain MRI, is indicated if the patient has atypical features of the seizures, developmental delay, or abnormal neurologic examination.
Diagnostic Procedures/Other
Specific investigations such as metabolic or genetic testing might be indicated in patients with atypical absence seizures to look for possible underlying metabolic or infectious etiology.
Pathological Findings
- Using advanced MRI techniques, studies in CAE patients have showed evidence of reduction in thalami, temporal lobes, the basal forebrain white matter, and the subcallosal and left orbital frontal gyri.
DIFFERENTIAL DIAGNOSIS
- Accurate diagnosis starts with a careful history: Description of the seizures, including duration, frequency, presence or absence of an aura, and postictal events. Other primary diagnostic considerations for staring spells include complex partial seizures and daydreaming. In contrast to absence seizures, complex partial seizures are much less frequent, often preceded by an aura, followed by postictal confusion and are rarely activated by photic stimulation or hyperventilation. Daydreaming usually is caused by boredom, is of variable duration, can be interrupted by stimulation, and is never associated with clonic components. Absence seizures may frequently be misdiagnosed as non-epileptic disturbances of behavior. In addition, clouding of consciousness with ocular and oromotor automatisms may occur in partial and other generalized epilepsies.
- Absence seizures comprise the primary seizure type in several epilepsy syndromes. The syndromic diagnosis is important to determine optimal treatment and prognosis.
- CAE
- JAE
- JME
- Myoclonic absence epilepsy
- Eyelid myoclonus with absences
- Perioral myoclonus with absences
- Stimulus-sensitive absence epilepsies
- Atypical absence seizures occur in children with severe symptomatic or cryptogenic epilepsies.
MEDICATION
First Line
The main antiepileptic agents for AES are ethosuximide, valproic acid (VA) and lamotrigine (LMT). The age of onset, side effect profile and presence of other accompanying types of seizures determine medication selection. Ethosuximide and VA both control absences in up to 75% of patients. LMT is less efficacious controlling absences in 30–50% of patients. This was recently confirmed in a multicenter double-blind, randomized, controlled clinical trial (1) that compared the 3 medications in 453 children with newly diagnosed CAE. This study also concluded that VA caused more attentional dysfunction than ethosuximide. When other types of generalized seizures are associated, antiepileptics other than ethosuximide should be selected.
- Ethosuximide: First drug of choice for isolated typical absences in CAE.
- For children 3 to 6 years, initial dosage is 15 mg/kg/day or 250 mg once daily, with titration to daily maintenance dose of 20 mg/kg. For older children/adults, the initial dose is 500 mg with gradual increase by 250 mg every 4–7 days until control is achieved. Serious but rare side effects include aplastic anemia, Stevens–Johnson syndrome, and hepatic impairment. Common side effects include GI disturbances, anorexia, weight loss, drowsiness, photophobia, and headache.
- VA: Effective for 75% of patients with absence seizures, as well as generalized convulsive and myoclonic seizures. In children, it is the second choice if ethosuximide fails to control absence attacks or the patient develops GTC seizures. It is the preferred drug of choice in JAE due to the high incidence of GTC seizures. It should be avoided in women of childbearing age due to risks of fetal malformations and neurodevelopmental delay.
- Initial dosage is 10–15 mg/kg/day. Maintenance dose in children is 30–60 mg/kg/day in three divided doses. Serious side effects include acute hepatic failure and acute pancreatitis. Common side effects include nausea, vomiting, dyspepsia, weight gain, polycystic ovaries, tremor, transient hair loss, and thrombocytopenia.
- LMT: Controls absences and generalized seizures in 50–60% of patients, but may worsen myoclonic jerks. LMT has less cognitive side effects. It requires long titration to establish therapeutic efficacy.
- For children ages 2–12 years taking VA, LMT could be added at 0.15 mg/kg/day and increased every 2 weeks by 0.15 mg/kg/day to a maximum of 5 mg/kg/day. In adults and children >12 years, LMT can be added to VA at a dose of 25 mg every other day and gradually increased to a maximum of 200 mg/day. LMT monotherapy can be given to patients >12 years at 25 mg daily, increased to a maximum of 100 mg/day. An allergic rash that could progress to Stevens–Johnson syndrome is the most common serious adverse effect. Other common side effects include headache, nausea, diplopia, dizziness, tremors, and ataxia. Side effects are more common with rapid titration or when combined with VA.
- VA is contraindicated for children <2 years and for patients with hepatic disease.
- Vigabatrin, tiagabine, and carbamazepine are contraindicated for treatment of absence seizures, as they tend to exacerbate the seizures and could produce absence status epilepticus. Gabapentin, phenobarbital and phenytoin are ineffective for absence.
Second Line
- Clonazepam, clobazam, and acetazolamide may be useful adjunctive drugs.
- Levetiracetam has only a modest effect against absence seizures (2) but could be a good alternative to VA in treating patients with JAE and JME due to favorable side effect profile and proven efficacy in treating GTC and myoclonic seizures.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Dietary therapies such as ketogenic or modified Atkins diet are established as an effective treatment in symptomatic epilepsies with reduction of absence seizure frequency by >50%.
IN-PATIENT CONSIDERATIONS
Admission Criteria
- Prolonged periods of stupor, impaired memory, or cognitive functions could represent absence status epilepticus. Inpatient EEG monitoring may be diagnostic by showing prolonged generalized bursts of spike-and-wave discharges. Intravenous or rectal benzodiazepines could be helpful for both treatment and diagnosis.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Patients taking ethosuximide should have blood counts to monitor for aplastic anemia. Those taking VA should be monitored for thrombocytopenia and hepatotoxicity. Therapeutic trough levels range from 40–100 mg/mL for ethosuximide and 50–100 mg/mL for VA.
PATIENT EDUCATION
- Medication compliance should be encouraged to avoid breakthrough seizures.
- Epilepsy Foundation of America.
PROGNOSIS
- Typical absence seizures generally have a favorable prognosis. CAE carries the best prognosis; up to 95% of children with CAE will have complete remission. JAE has a less favorable prognosis than CAE. JME is usually a lifelong epilepsy.
- Poor prognostic factors include history of associated GTC or myoclonic seizures or absence status, positive family history of epilepsy, abnormal EEG background, or subnormal intelligence.
The main antiepileptic agents for AES are ethosuximide, VA and LMT.
