Perspectives in Pediatric Neurology

Absence Seizures and Syndromes: An Overview

During the 1970s, Kiffin Penry and his colleagues conducted landmark studies of absence seizures, describing their characteristics in great detail.¹ Nevertheless, as the two case studies in this issue of Perspectives in Pediatric Neurology illustrate, absence seizures may continue to elude diagnosis. This often occurs because the manifestations of absence seizures can be both subtle and very brief. They are often mistaken for daydreaming. On the other hand, absence seizures with unusual or dramatic automatisms might lead to a misdiagnosis of complex partial seizures. Furthermore, as one of the cases shows, a focal-onset seizure that rapidly generalizes into an apparent absence seizure may be misdiagnosed (and inappropriately treated) as a primary generalized seizure. In still other instances, patients may have brief, unrecognized absence seizures that progress to generalized tonic-clonic seizures (GTCS). As a result, the patient receives a drug for GTCS that fails to control, and may even worsen, the absence seizures.² One of Penry's favorite anecdotes concerned a teenaged girl whose absence seizures went undetected until she obtained her driver's license. With her mother in the passenger seat, she drove through a red light at an intersection, striking another car. When her astonished mother asked her daughter what happened, the girl had no memory of the event. Thus, what had been dismissed as "daydreaming" for many years turned out to be frequent absence seizures; it took a serious accident for her to be referred for diagnosis.

Pathophysiology and clinical characteristics of typical absence seizures

While the pathophysiology of absence seizures has not been definitively established, it is generally believed that inhibitory phenomena are involved in ictal events. Absence seizures may be a response of an abnormal neocortex to synchronizing input from the brain stem and thalamus.³

Typical absence seizures are primary generalized seizures characterized by brief staring episodes, lasting two to 15 seconds (generally less than 10 seconds), with impaired consciousness and responsiveness. They begin without warning (no aura) and end suddenly, leaving the person alert and without postictal confusion. Often, the person will resume preattack activities, as if nothing had happened.² Simple absence seizures are characterized by staring spells alone. In complex absence seizures, which are more common, staring is accompanied by automatisms, such as eye blinks or lip smacking; they may include mild clonic, atonic, or autonomic components involving the facial muscles. There may also be a slight nod of the head or semi-purposeful movements of the mouth or hands. The automatisms tend to be stereotyped, with the same behaviors occurring during each seizure. Penry et al observed automatisms in 63% of all absence seizures.² However, the automatisms are less elaborate than those observed with complex partial seizures. There may also be autonomic manifestations, such as pupil dilation, flushing, tachycardia, piloerection, salivation, or urinary incontinence.³ Absence seizures are classified in Table 1.

Absence seizures can be provoked by one or two minutes of hyperventilation and may be terminated by a loud or repetitive stimulus. Sleep deprivation, drowsiness, and photic stimulation may also precipitate seizures. Total sleep deprivation may elicit absence seizures even in children who have been seizure-free for many years on medication.² Children who are active and happy experience fewer seizures than those who are anxious, inactive, or bored.⁵

Onset of absence seizures is usually between the ages of five and 10; they never occur prior to age 2 1/2 and onset is rare after age 20.⁶ Approximately 25% of affected children experience their first seizure before the age of five and 67% between the ages of five and 15. Fifty percent of patients will experience a remission of seizures following adolescence.² Forty to fifty percent of patients with recurrring absence seizures will also experience one or more generalized tonic-clonic seizures.^2,7 In 14% of patients with childhood absence epilepsy, the disorder begins with both absence and GTCS.⁸ Generalized tonic-clonic seizures are seen less often in children with an early onset of absence seizures. The prognosis is better for a child who experiences typical absence seizures alone, without other seizure types.⁹

On the EEG, typical absence seizures are associated with generalized, bilaterally synchronous, frontally predominant 3 Hz spike-and-wave discharges that begin suddenly from a normal background and end abruptly, without postictal slowing (Figure 1).^3,10 Interictal discharges do not occur.⁶

Atypical absence seizures

Atypical absence seizures usually occur in children with below average intelligence. They are often related to diffuse or multifocal structural lesions in the brain.³ Seizures usually last longer than 10 seconds, begin and end more gradually than typical absence seizures, and are not precipitated by hyperventilation. During an atypical absence seizure, consciousness may be only partially impaired and it may be difficult to distinguish the seizure from the child's usual behavior. Atonic attacks with complete collapse, rather than head nodding, often occur. These patients often have histories of clusters of generalized tonic-clonic seizures² and they have a greater tendency to develop absence status than those with typical absence seizures.³ On the EEG, atypical absences are associated with poorly organized and irregular spike-and-wave discharges of 1 to 2.5 Hz (Figure 2). The primary differential diagnosis for both typical and atypical absence seizures is complex partial seizures; their characteristics are compared in Table 2 (below).

Absence status

In absence status, one staring spell follows another without complete recovery between spells. The person wanders in a fugue state, only semi-responsive to questions and performing poorly on tasks. Approximately 10% of children with absence seizures will experience at least one episode of absence status.¹¹

Absence syndromes

Typical absence seizures occur in three generalized idiopathic epilepsy syndromes; these are listed in Table 3 (below) along with three generalized symptomatic epilepsy syndromes that include absences. The idiopathic syndromes, childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy, appear to be genetically distinct, but there is some clinical and electrographic overlap among them. It has also been noted that childhood absence epilepsy will occasionally evolve into juvenile myoclonic epilepsy.¹⁰ Childhood absence epilepsy (CAE), also known as petit mal epilepsy or pyknolepsy, is characterized by typical absence seizures in children who are apparently otherwise normal. "Pyknos" is Greek for crowded clusters, refering to the tendency of children with this syndrome to experience clusters of a few to several hundred absences per day.^7,8 While children with this syndrome have no associated neuropathologies,¹² they may have cognitive deficits related to the underlying syndrome. Certainly, it is easy to understand how several hundred absences per day can interfere with cognitive functioning. A classic example of a learning disability caused by the seizures themselves is the child who has a flurry of absence seizures during the school day. The teacher notes that she is inattentive or appears to be daydreaming, while she is actually having dozens of brief, generalized seizures that impair her consciousness and make sustained learning difficult. Every year, the epilepsy clinic on VCU's Medical College of Virginia Campus sees a few children who appear to have Attention Deficit disorder but actually have absence seizures. It isn't cost effective to perform an EEG on every child who has a learning disability in order to detect the few who have seizures. Fortunately, uncomplicated absence seizures are associated with a good prognosis for cognitive functioning once seizures are controlled. In the example above, it was attention, rather than cognition, that was impaired by the seizures. However, a recent study conducted detailed neuropsychological testing in 16 children with CAE and 16 well-matched children without epilepsy. Of the 16 patients with CAE, 11 were treated with valproate monotherapy, two with ethosuximide monotherapy, and three with both drugs. The researchers found similar, impaired neurocognitive profiles among the children with CAE; they had lower scores on measures of general cognitive functioning, visuospatial skills, and memory compared to controls, but with little impairment of verbal skills. The authors note that it is unlikely that anticonvulsant drug effects account for the cognitive deficits seen.¹³

Childhood absence epilepsy accounts for approximately 8% of childhood epilepsies and the majority of those affected are female. About one-third of affected children have a family history of epilepsy, while siblings of those affected have a 10% risk of experiencing seizures.⁷ While an autosomal dominant gene with age-dependent penetration has been identified for CAE, some degree of brain damage may be necessary to trigger the disorder.¹⁴

Juvenile absence epilepsy is much less common than the childhood form, and males and females are affected equally. In juvenile absence epilepsy, absence seizures begin at or after puberty but they occur less frequently than in childhood absence epilepsy. Absence status and generalized tonic-clonic seizures are more likely to occur in this syndrome and patients may also experience myoclonic seizures.³ Juvenile absence epilepsy is associated with spike-and-wave discharges of 3 Hz or faster.¹⁰ Absence seizures also occur in epilepsy with generalized tonic-clonic seizures on awakening³ and in approximately 25% of patients with juvenile myoclonic epilepsy.¹⁵ Atypical absence seizures are characteristic of Lennox-Gastaut syndrome.³

Prognosis

Several factors influence the prognosis of a patient with absence seizures. Patients who have no apparent acquired brain lesion and whose epilepsy is primarily genetic in origin (e.g., those with childhood absence epilepsy) generally have a good prognosis. Early onset of absence seizures and rapid response to medication are also good prognostic signs.³ By contrast, patients with absence seizures associated with brain lesions, mild retardation, abnormal background activity on the EEG, and atypical spike-wave discharges (e.g., those with Lennox-Gastaut syndrome) have a poorer prognosis.

Drug therapy

Typical absence seizures are remarkably responsive to treatment; fewer than 5% of cases are refractory.² The drugs of choice for childhood absence epilepsy and juvenile absence epilepsy are ethosuximide or valproate. The latter is preferable if the patient also has GTCS or if the physician wishes to reduce the risk of future GTCS.¹⁴ Valproate may be more effective than ethosuximide for atypical absence seizures.³ Ethosuximide is given at a dose of 20 to 40 mg/kg daily, to achieve serum levels of 40 to 100 �g/mL. The side effects of ethosuximide include anorexia, nausea, vomiting, headaches, lethargy, and dizziness. Valproate is given at a dose of 20 to 60 mg/kg, to achieve a level of 50 to 100 �g/mL. The side effects of valproate include tremor, weight gain, and transient hair loss.

Remission and drug withdrawal

Absence seizures associated with childhood absence epilepsy tend to remit in adolescence; complete remission occurs in approximately 50% of patients. If the patient has none of the signs listed above suggesting a poor prognosis, the rate for complete remission rises to 90%. The absence seizures associated with juvenile absence epilepsy are less likely to remit spontaneously, although response to medication is good.³

Because typical absence seizures tend to remit in adolescence, an attempt should be made to withdraw medication after a seizure-free period of approximately four years. Tapering should be very slow, over six months to one year.³

In summary, it can be very gratifying to treat children with typical absence seizures, because the vast majority will respond to medication. As early as 1984, Penry noted that "No form of epilepsy is easier to treat than absence seizures."² He added that, unfortunately, many patients with absence seizures remain uncontrolled, usually due to incomplete diagnosis, a situation that remains true today. The following two cases are compelling illustratrations of how incomplete diagnoses led to initial difficulties that were later overcome through a careful reconsideration of the initial diagnosis.