Etiology

The most likely etiology for absence epilepsy syndromes is genetic, with complex, multifactorial inheritance.[22] A study published in 1991 evaluated 671 first-degree relatives of 151 patients with either childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE). Of those, 4.9% had some form of epilepsy, with one third of the affected relatives having an absence seizure. Of note, this does not correspond with the 25% expected chance of inheriting an autosomal recessive disorder.[23]

Epilepsies with atypical absence seizures, such as Lennox-Gastaut syndrome, may be secondary to a variety of congenital or acquired brain disorders, such as hypoxia-ischemia, trauma, central nervous system infection, cortical malformations, or inborn errors of metabolism.

Pathophysiology

The current understanding of the pathogenesis of absence seizures is based on animal models that generate generalized spike-and-wave discharges on EEG. A reverberating circuit between the thalamus and cortex is the basis for this model, with the hypothesis being that aberrant rhythmic oscillations are generated in the circuit, analogous to a mechanism that generates normal sleep spindles. The reticulothalamic nucleus of the thalamus has been particularly implicated and contains a predominance of inhibitory GABA-containing interneurons. In this case, GABA-mediated activity may trigger absence seizures by inducing prolonged hyperpolarization and activating low-threshold Ca^2+ currents.[24][25] The concept of "t-type" or "low-threshold" calcium channels playing a role in absence seizures is supported by the responsiveness of typical absence seizures to medications such as ethosuximide, which is known to block these channels.

Multiple studies have been conducted in an attempt to identify a single gene locus for childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), or generalized epilepsies (GE). Most identified genes associated with GE involving absence seizures are for different types of ion channels (channelopathies). A gene for a component of GABA^A receptor has been implicated in a large family with JME with autosomal dominant inheritance.[26] To date, CAE has been associated with defects in GABA^A receptor gamma2 subunit and voltage-gated Ca^2+ channel alpha-1A subunit (CACNA1A), among others.[25][27] Mutations in a gene that encodes voltage-gated chloride channel CLC-2 has been associated with CAE, juvenile absence epilepsy (JAE), and JME.[28] Studies have demonstrated that a loci on chromosome 6p and chromosome 15q may predispose to JME; 15q maps to the alpha-7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7).[27] Some cases of early-onset absence epilepsy have been attributed to mutations in the GLUT1 glucose transporter.[29]

Classification

International League Against Epilepsy (ILAE) classification of seizures[3][4]

  1. Generalized onset seizures

    • Motor

      • Tonic-clonic

      • Clonic

      • Tonic

      • Myoclonic

      • Myoclonic-tonic-clonic

      • Myoclonic-atonic

      • Atonic

      • Epileptic spasms

    • Non-motor (absence)

      • Typical

      • Atypical

      • Myoclonic absence

      • Eyelid myoclonia

  2. Focal onset seizures

  3. Unknown onset seizures

Electroclinical syndromes and other epilepsies[5]

Electroclinical syndromes arranged by age at onset

  • Neonatal period

    • Benign familial neonatal seizures (BFNS)

    • Early myoclonic encephalopathy (EME)

    • Ohtahara syndrome

  • Infancy

    • Epilepsy of infancy with migrating focal seizures

    • West syndrome

    • Myoclonic epilepsy in infancy (MEI)

    • Benign infantile epilepsy

    • Benign familial infantile epilepsy

    • Dravet syndrome

    • Myoclonic encephalopathy in nonprogressive disorders

  • Childhood

    • Febrile seizures plus (FS+)

    • Panayiotopoulos syndrome

    • Epilepsy with myoclonic atonic (previously astatic) seizures

    • Benign epilepsy with centrotemporal spikes (BECTS)

    • Autosomal-dominant nocturnal frontal lone epilepsy (ADNFLE)

    • Late-onset childhood occipital epilepsy (Gastaut type)

    • Epilepsy with myoclonic absences

    • Lennox-Gastaut syndrome

    • Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)

    • Landau-Kleffner syndrome (LKS)

    • Childhood absence epilepsy (CAE)

  • Adolescence

    • Juvenile absence epilepsy (JAE)

    • Juvenile myoclonic epilepsy (JME)

    • Epilepsy with generalized tonic-clonic seizures alone

    • Progressive myoclonus epilepsies (PME)

    • Autosomal dominant epilepsy with auditory features

    • Other familial temporal lobe epilepsies

  • Less specific age relationship

    • Familial focal epilepsy with variable foci (childhood to adult)

    • Reflex epilepsies

Distinctive constellations

  • Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS)

  • Rasmussen syndrome

  • Gelastic seizure with hypothalamic hamartoma

  • Hemiconvulsion-hemiplegia-epilepsy

Epilepsies attributed to and organized by structural-metabolic causes

  • Malformations of cortical development

  • Neurocutaneous syndromes

  • Tumor

  • Infection

  • Trauma

Angioma

  • Perinatal insults

  • Stroke

Epilepsies of unknown cause

Conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se

  • Benign neonatal seizures (BNS)

  • Febrile seizures (FS)

International League Against Epilepsy (ILAE) Commission 1989: inclusion criteria for childhood absence epilepsy[6]

Inclusion criteria:

  1. Children of school age (peak manifestations 6 to 7 years)

  2. Very frequent (several to many per day) absences

  3. EEG with bilateral, synchronous, and symmetrical spike-waves, usually at 3 Hz

  4. Development of generalized tonic-clonic seizures often occurs during adolescence.

A more stringent set of inclusion and exclusion criteria has been proposed but not widely accepted.[7] There is also debate about its distinction from juvenile absence epilepsy (JAE).

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