Absence Seizure

Etiology

A genetic component exists for all generalized epilepsies and, specifically, for absence epilepsy. The inheritance pattern is not strictly autosomal recessive or dominant and is considered to be multifactorial and polygenic. In 1951, Lennox reported that 66% of monozygotic twins showed concordance for the EEG pattern of 3-Hertz spike and wave discharges. These can be voltage-gated (CACNA1H, CACNG3, CLCN2) or ligand-gated (CHRNA4, GABRA1, GABRB3, GABRG2, GRM4).[7] CAE is linked to many genetic variations, including at the following locations: [7]

• Calcium-channel genes: CACNA1H and CACNG3 (especially in Han Chinese) [8]                                                       
• GABA-A and GABA-B receptors: GABA is an inhibitory neurotransmitter highly involved in epileptogenesis. GABRA1, GABRB3, and GABRG2 are variants relating to CAE.[3][4][9]                                                 
• Glutamate receptor: Mutations in GRM4 alter glutamate and GABA regulation.                                               
• µ-Opioid Receptor: OPRM1 is an opioid receptor where mutations can cause thalamic hyperexcitability.                                
• Solute transfer receptor: SLC6A3/DAT1 are 2 genes in this category encoding a dopamine transporter.

Also, some copy number variants (CNVs), for example, 15q11.2, 15q13.3, and 16p13.11 microdeletion, have been described in patients with CAE.[10] However, the mode of inheritance and the majority of genes implicated in CAE are still unknown.[4]

Epidemiology

The incidence of CAE is approximately 6.3 to 8.0 children per 100,000 individuals per year.[10][11][12] CAE is a common pediatric epilepsy syndrome. Among all cases of epilepsy in school-aged children, 10% to 17% are due to CAE.[1] The age of onset for CAE is typically between 4 and 10 years, with a peak between ages 5 and 7. Girls have CAE more frequently than boys; however, some of this evidence is conflicting.[4]

Pathophysiology

The pathophysiological mechanism of the development of absence seizures is not yet fully understood. However, the cortico-thalamic-cortical circuit is believed to play a significant role in the pathophysiology of absence seizures.[13]

Some of the neurons involved in the cortico-thalamic-cortical system include the following:  

• Cortical glutamatergic neurons originating on cortical layer VI and projecting to the nucleus reticularis of the thalamus
• Thalamic relay neurons with excitatory projections to cortical pyramidal neurons                                                            
• Neurons from the thalamic nucleus reticularis containing inhibitory GABA-ergic projections that connect with other neurons from the same nucleus and with thalamic relay neurons. These neurons do not connect directly with the cortex.[4]

Neurons from the thalamic nucleus reticularis can fire in an oscillatory pattern (eg, rhythmic bursts involved in generating sleep spindles) or continuously in single spikes (tonic firing during wakefulness). Shifts between these 2 firing patterns in the thalamic nucleus reticularis are modulated by spikes in thalamocortical networks and neurons from the thalamic nucleus reticularis. These are mediated through low-threshold transient calcium channels known as T-type channels. After depolarization, T-type channels briefly allow calcium inflow before becoming inactivated. Reactivation requires a relatively long hyperpolarization facilitated by GABA-B receptors. Therefore, abnormal oscillatory rhythms can originate from T-type channel abnormality from increased GABA-B activity.[4]

As explained by the genetics of absence epilepsy, genes coding for T-type calcium channels and GABA receptors have been associated with the etiopathogenesis of this type of epilepsy. Medications that suppress T-type calcium channels, such as ethosuximide and valproate, are effective anti-absence drugs. Conversely, medications that increase GABA-B activity (eg, vigabatrin) exacerbate the frequency of absence seizures. In contrast, GABA-A agonists (eg, benzodiazepines) that preferentially enhance GABA-ergic activity in neurons from the thalamic nucleus reticularis can suppress absence seizures.[4]

More recent research on penicillin-induced models of epilepsy in cats favors the cerebellum's role in long-term electrical stimulation in absence epilepsy.[14]

History and Physical

The age of onset of CAE is usually between 4 and 10 years, with a peak between the ages of 5 and 7.[4] The onset of absence epilepsy before age 4 should raise concern for an underlying glucose transporter type 1 (GLUT1) deficiency.[4] About 10% to 15% of patients with CAE have a history of febrile seizures.[14]

Regarding the clinical presentation, family members and teachers usually describe brief spells in which the child has a loss of awareness, is unresponsive, and has a behavioral arrest. Bystanders often describe the patient during these spells as having “a blank stare.”[2] Episodes frequently occur, often 10 to 30 times throughout the day. Most children stop their activity completely, but some can continue it more slowly or unusually.[1] Some children have 3-Hz regular eyelid fluttering.[1][2] Clinical presentation can also vary in the same individual.[7]

Oral automatisms can also occur, especially with prolonged seizures or during hyperventilation. Children frequently have mild clonic or tonic movements in the first few seconds of the spell. Pallor is commonly reported.[1] Urinary incontinence is rare. Spells usually last between 4 and 30 seconds. Hyperventilation, a state of arousal, sleep deprivation, and medication use can affect the duration of the seizure.[1] These seizures are not preceded by an aura and do not have a postictal state.[13]

On physical examination, hyperventilation can trigger absence seizures. To test this, the examiner asks the child to blow repetitively for at least 2 minutes. Using a pinwheel or paper can be helpful because this encourages the child to cooperate more during testing. If hyperventilation is done successfully, the patient may develop seizures that can be seen clinically or on EEG. There is some evidence that absence seizures are more easily provoked when the person is in a sitting position.[15]

For JAE, the age of onset is classically between 10 and 19 years, with a peak at 15 years.[4] Seizures are less frequent than in CAE but tend to last longer.[3][4]

Absence status consists of generalized, nonconvulsive seizures characterized by impairment of awareness and intermittently has other manifestations such as automatisms or subtle myoclonic, tonic, atonic, or autonomic phenomena. Patients usually have a previous diagnosis of generalized epilepsy. Absence status presents as a nonconvulsive seizure lasting between a half hour and several days. It usually ends spontaneously and suddenly but should be treated with antiseizure medications at the time of diagnosis.[16]

Evaluation

EEG is the main diagnostic tool for the evaluation of absence epilepsy. In the case of childhood absence seizures, EEG shows bilaterally synchronous and symmetrical 3-Hz spike and wave discharges that start and end abruptly (see Image. EEG Showing the Characteristic 3-Hz Spike and Wave Discharges Seen in Absence Epilepsy). These discharges sometimes have maximum frontal amplitude or begin with unilateral focal spikes.[2] In 50% of seizures in CAE, the initial discharge seen has a typical spike and wave morphology. The remaining 50% can show a single spike, polyspikes, or an atypical, irregular, generalized spike and wave on a normal background.[1][4]

Atypical absence seizures show a more insidious onset and offset, slower spike and wave paroxysms (slower than 3 Hz), and an abnormal interictal background.[4] In JAE, EEG demonstrates paroxysms of generalized 3- to 4-Hertz spike-and-wave or polyspike and wave discharges.[4]

Neuropsychological testing has shown that patients with CAE have a higher rate of cognitive deficits, especially involving attention, executive function, and verbal and visuospatial memory. Difficulty with language and reading is also commonly reported. Depression, anxiety, and attention-deficit/hyperactivity disorder also have been reported more frequently in patients with CAE.[1] 

In the case of absence status, EEG shows continuous or nearly continuous generalized spike and wave or polyspike and wave discharges at 2 to 4 Hz. In patients with a new diagnosis of absence seizures, brain imaging is indicated to assess for structural abnormalities.

Treatment / Management

The first-line treatment for absence epilepsy is ethosuximide. A randomized controlled trial in 2010 that included 446 children with CAE showed that ethosuximide and valproic acid were superior to lamotrigine.[17] However, this study had a low seizure-free rate, with 53% of patients in the ethosuximide group, 58% in the valproic acid group, and 29% in patients taking lamotrigine. The group that received valproic acid had significantly lower scores on attentional measures compared to the ethosuximide and lamotrigine groups. For this reason, ethosuximide is the preferred agent for treating absence epilepsy. A study showed that only one-quarter of children with absence epilepsy became seizure-free with levetiracetam. If effective, levetiracetam can control absence epilepsy at a relatively low dose (usually <40 mg/kg/d). Increasing doses are not effective if levetiracetam is not initially effective.[18] (A1)

The most frequent adverse effects of ethosuximide are abdominal pain and nausea. For this reason, ethosuximide should be taken with meals. Other medications that can be used to manage CAE include valproate, lamotrigine, and topiramate. Second-line medications that can be used as adjunct therapy include valproic acid, zonisamide, and levetiracetam. It is important to note that some sodium channel blockers like phenytoin, carbamazepine, gabapentin, pregabalin, and vigabatrin can worsen absence seizures.[4]

Women of childbearing age not using contraception should not be treated with valproic acid; the preferred agent is ethosuximide.

Some experts suggest that a ketogenic or a medium-chain triglyceride diet may be beneficial, but strong evidence to support their use is lacking.

Differential Diagnosis

The differential diagnosis for staring spells includes absence epilepsy, focal seizures with alteration of awareness, and nonepileptic paroxysmal events. 

Focal epilepsy with alteration of awareness (previously called complex partial epilepsy) can also present with behavioral arrest and automatisms. However, these seizures are usually less frequent than absence seizures. Patients can have generalized seizures with focal epilepsy. The semiology of automatisms can vary depending on the area of the cerebral cortex where the seizures originate. 

A study that evaluated nonepileptic staring spells using video-EEG monitoring found that these episodes were often characterized by arrest of all activity, vague facial expressions, and vision fixed on 1 point without blinking. When the duration of the events was quantified, staring episodes lasted between 3 and 74 seconds. In most children, it was difficult to determine the onset and end of the event. Most parents could not regain the child’s attention by waving their hands in front of the child. Other more energetic measures like hand clapping or other loud sounds successfully stopped the events in all children. A significant percentage of children (41%) were inactive at the onset of the stare, and 18% were watching television when the event began.[19]

A retrospective chart review performed in a tertiary care epilepsy center showed that among 276 patients in the epilepsy monitoring unit, only 11% were deemed to have seizures.[20] Therefore, most staring spells are nonepileptic in nature. Clinicians should be careful when patients present with staring spells and not tell parents or other providers that these episodes are “absence seizures” before EEG evaluation is completed. The study mentioned above developed a tool to determine the pretest probability of seizures in children presenting with staring spells. This tool accounts for patient variables such as results of previous EEG, previous use of antiseizure medications or treatments for psychiatric conditions, and duration of the spells.[20]

Prognosis

Typical CAE occurs in childhood and resolves by adolescence. Seizure freedom is reported in 57% to 74% of the patients. Compared with controls, the risk for accidental injuries during absence seizures is well-reported.[19] As mentioned before, these patients have problems in the areas of attention, executive function, and verbal and visuospatial memory. Difficulty with language and reading is also commonly reported. Depression, anxiety, and ADHD have also been reported more frequently in patients with CAE.[1]

Complications

Some activities can be dangerous for people with absence seizures because of the temporary loss of awareness accompanying these episodes. Swimming, operating hazardous machinery, and driving during an absence seizure might result in drowning or an accident. Patients may need to restrict certain activities until their seizures are under control. Some states may also have laws regarding how long a patient must go without a seizure before resuming driving.