Aetiology

Generalised seizures may be genetic, or may be due to an underlying metabolic or immune disease, or less commonly may occur in the presence of a structural abnormality, typically diffuse, of the brain (in which case there may also be focal seizures), or their aetiology may be unknown. The International League Against Epilepsy (ILAE) uses the following aetiological classification system.[1]

Genetic

  • Seizures result directly from a known or presumed pathogenic genetic variant. The epilepsies in which a genetic aetiology has been implicated are quite diverse. Although well over 100 epilepsy-associated genes or loci have been identified, in most cases the underlying genes are not yet known. Examples of genetic epilepsies include Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+). There is usually not a specific inheritance pattern, but rather a complex inheritance, often with age-dependent penetrance.​[6]

  • The term 'genetic generalised epilepsies' is used for the broad group of epilepsies with generalised seizure types and generalised spike-wave, based on a presumed genetic aetiology. This includes the subgroup of 'idiopathic generalised epilepsies', which refers to the four syndromes of childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalised tonic-clonic seizures alone, which are the most common syndromes within the generalised genetic epilepsies.[1][3][7]​​​

Structural

  • Refers to abnormalities visible on structural neuroimaging, where the electroclinical assessment together with the imaging findings lead to a reasonable inference that the imaging abnormality is the likely cause of the patient's seizures. Structural aetiologies may be acquired (e.g., stroke, trauma, and infection), or genetic (e.g., many malformations of cortical development). When a structural aetiology has a well-defined genetic basis, both aetiological terms (genetic and structural) can be used.[1] Identification of a subtle structural lesion requires appropriate magnetic resonance imaging (MRI) studies using specific epilepsy protocols.

Metabolic

  • Generalised seizures can be due to a known or suspected metabolic disorder or neurodegenerative disorder (epilepsy is then part of a generalised encephalopathy).

Immune

  • Seizures result directly from an immune disorder in which seizures are the core symptom of the disorder. An immune aetiology should be suspected when there is evidence of autoimmune-mediated central nervous system inflammation. Examples include anti-NMDA (N-methyl-D-aspartate) receptor encephalitis and anti-LGI1 encephalitis (although these are more commonly associated with focal seizures).

Infectious

  • Seizures result directly from a known infection in which seizures are the core symptom of the disorder. The most common aetiology worldwide is where epilepsy occurs as a result of an infection. An infectious aetiology refers to a patient with epilepsy, rather than with seizures occurring in the setting of acute infection such as meningitis or encephalitis. Examples include neurocysticercosis, tuberculosis, HIV, cerebral malaria, subacute sclerosing panencephalitis, cerebral toxoplasmosis, and congenital infections such as Zika virus and cytomegalovirus.

Unknown

  • When the generalised epilepsy cannot be classified as one of the four idiopathic generalised epilepsy syndromes or evidence is lacking for a genetic basis, the epilepsy can be classified as having an unknown basis.

Pathophysiology

Our current understanding of the pathophysiology is rather limited. During an epileptic seizure, an alteration in central nervous system function leads to a paroxysm of electrical discharges in the cortex or brainstem. Excitatory and inhibitory neurotransmitters play a role in the development of seizure discharges. In general, increased neuronal excitability and synchronicity is thought to be responsible for seizure initiation and propagation. Change in the synaptic function and intrinsic properties of neurons may be the cause of hyper-excitability. This in turn can be the result of a change in balance between the glutamate and gamma-aminobutyric acid (GABA) neurotransmitter systems. Catecholaminergic neurotransmitter systems and opioid peptides are also shown to play a role in epileptogenesis. A variety of genetic and structural abnormalities can contribute to groups of neurons developing this state.

Increasingly, the role of functional networks as opposed to structural anatomical networks is seen as relevant, with epilepsies being perceived as 'a disorder of cortical network organisation'.[8] A model involving circuitry of cortical and thalamic neurons has been suggested for absence epilepsy. Within this circuit there are 'fast-spiking neurons' and interconnecting inhibitory neurons, the activity of both being modulated by GABA.[9] In addition to this thalamo-cortical network, other models include a limbic, a neocortical, and a brainstem network.

Classification

ILAE seizure type[2]

The International League Against Epilepsy (ILAE) system classifies generalised-onset seizures into the following types based on motor or non-motor clinical manifestations:

  • Non-motor: absence; interruption in the child's activities, often with a blank stare or inattention (i.e., behavioural arrest)

    • Typical

    • Atypical

    • Myoclonic absence

    • Eyelid myoclonia

  • Motor:

    • Clonic: rhythmic, muscular jerking movements with or without impaired consciousness

    • Tonic: tonic extension or flexion of the extremities

    • Tonic-clonic: this usually starts with a tonic phase and the patient becoming unconscious, possibly falling to the ground, and extension or flexion of extremities. It may be preceded by aura. The clonic phase consists of often violent muscle contractions resulting in apparent shaking.

    • Myoclonic: brief, arrhythmic, muscular jerking movements involving one or a group of muscles

    • Myoclonic-atonic

    • Myoclonic-tonic-clonic

    • Atonic: brief loss of muscle tone causing what are known as 'drop attacks', where the patient falls to the ground

    • Epileptic spasms

ILAE aetiological classification[1]

The ILAE classifies seizures as being due to genetic, structural, immune, infectious, metabolic, or unknown aetiology. For further details, see Aetiology.

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 etiological findings (structural, genetic, metabolic, immune, and infectious)".[3]

In clinical practice, the clinical features including age of onset of seizures, other signs, symptoms, and electroencephalogram findings help make an electroclinical syndromic diagnosis. Different syndromes have different natural histories, and at times the syndromic diagnosis can guide treatment. Important features to identify include how responsive seizures are to treatment and the degree of developmental impairment.

The previous term 'symptomatic generalised epilepsy', often used to refer to epilepsy with rapid bilateral network involvement due to an underlying cause, is now replaced by the term 'developmental and/or epileptic encephalopathy', which can consist of generalised, focal, or a combination of both types of seizures. The concept of epileptic encephalopathy implies that the epilepsy is directly impacting development, causing cognitive and behavioural plateau and regression. In developmental and epileptic encephalopathies, the specific genetic, structural, or other acquired aetiologies of the epilepsy are associated with developmental impairment, which is then further impacted by the epilepsy.[1]

The following are the more common epilepsy syndromes (i.e., not an exhaustive list) with predominantly generalised seizures that are recognised in childhood, sub-divided by typical age of onset as defined by the ILAE.[3]

Onset in infancy (1 month to 2 years)

  • Genetic epilepsy with febrile seizures plus (GEFS+) spectrum

  • Myoclonic epilepsy in infancy (MEI)

  • Early infantile developmental and epileptic encephalopathy (EIDEE) (includes Ohtahara syndrome)

  • Infantile epileptic spasms syndrome (IESS) (includes West syndrome)

  • Dravet syndrome

Onset in childhood (usually 2-12 years)

  • Epilepsy with myoclonic-atonic seizures (EMAtS)

  • Lennox-Gastaut syndrome (LGS)

  • Childhood absence epilepsy (CAE)

  • Epilepsy with myoclonic absence (EMA)

  • Epilepsy with eyelid myoclonia (EEM)

Onset at a variable age (usually 10-14 years)

  • Juvenile myoclonic epilepsy (JME)

  • Juvenile absence epilepsy (JAE)

  • Epilepsy with generalised tonic-clonic seizures alone (GTCA)

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