Aetiology
The ‘genetic generalised epilepsies’, which include the idiopathic generalised epilepsies childhood absence epilepsy, juvenile myoclonic epilepsy, and juvenile absence epilepsy, as well as epilepsy with myoclonic absence and epilepsy with eyelid myoclonia, have a presumed genetic aetiology. Inheritance is complex, with a polygenic basis with or without an environmental contribution, making pathogenic variants difficult to identify.[9][14][18]
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-ischaemia, trauma, central nervous system infection, cortical malformations, or inborn errors of metabolism. Pathogenic variants in many genes, as well as a range of chromosomal abnormalities and copy number variants, have also been associated with Lennox-Gastaut syndrome.[14]
Pathophysiology
Understanding of the pathogenesis of absence seizures is based on animal models that generate generalised 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 hyperpolarisation and activating low-threshold Ca²⁺ currents.[19][20] 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 drugs such as ethosuximide, which is known to block these channels.
The exact anatomical origin of absence seizures is unknown at this time; however, there are several theories.[21] The centrocephalic theory suggests that seizures originate in the thalamus and then propagate to the cortex.[22] Another possibility is the generalised corticoreticular theory, which postulates that reticular projections to the cortex are necessary for seizure onset.[23] Yet another theory, the cortical focus theory, suggests there may be a cortical focus that results in corticothalamic oscillations.[24]
Most identified genes associated with generalised epilepsies involving absence seizures are for different types of ion channels (channelopathies), such as gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors, and sodium, potassium and chloride channels.[9][14][18][25] Some cases of early-onset absence epilepsy have been attributed to pathogenic variants in SLC2A1, leading to glucose transporter type 1 deficiency syndrome, as well as a variety of other pathogenic variants.[14][26][27]
Classification
International League Against Epilepsy (ILAE) classification of seizures[1]
Generalised seizure
Absence seizure
Typical
Atypical
Myoclonic absence
Eyelid myoclonia with or without absence
Other generalised seizure
Myoclonic
Negative myoclonic
Clonic
Epileptic spasms
Tonic
Myoclonic-atonic
Atonic
Focal seizure
Unknown whether focal or generalised
Epilepsy syndromes[3]
In 2022 the ILAE published a classification and definition of epilepsy syndromes. An epilepsy syndrome is defined as 'a characteristic cluster of clinical and electroencephalographic features, often supported by specific aetiological findings (structural, genetic, metabolic, immune, and infectious)'.[4]
Syndromes in which absence seizures are prominent include:
Lennox-Gastaut syndrome (LGS)
Childhood absence
epilepsy (CAE)
Epilepsy with myoclonic absence (EMA)
Epilepsy with eyelid myoclonia (EEM)
Juvenile absence epilepsy (JAE)
Juvenile myoclonic epilepsy (JME)
Dravet syndrome
Epilepsy with myoclonic-atonic seizures (EMAtS)
ILAE aetiological classification[5]
The ILAE classifies seizures as being due to genetic, structural, immune, infectious, metabolic, or unknown aetiology.
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