Mechanism of epilepsy: understand brain seizure activity

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Contents

• Mechanism of seizures in epilepsy
• Neurons and neurotransmitters in epilepsy

Epilepsy is a chronic and recurring neurological disease characterised by recurrent unprovoked seizures.^1-3 Several neurobiological, cognitive, psychological and social factors might contribute to recurrent seizures.^2,3 As epilepsy is a heterogeneous condition with multifactorial causes, a wide range of treatment options are available to help manage and treat it.³

During a seizure, there is sudden, abnormally high, coordinated, and sustained neuronal excitability localised in the grey matter of the cerebral cortex or subcortex.³ The underlying pathophysiology of seizures in epilepsy has not been fully explained, but it is thought to involve abnormalities in neuronal signalling, neurotransmitter systems, and ion channel function.³

In patients with epilepsy, the inhibitory ion exchange and membrane conductance of synapses are altered, which causes hyperexcitability of the pathological neurons and leads to increased coordinated activity (hypersynchrony), resulting in seizures.³ Pathological inactivation of neuronal signalling pathways causes dysregulation of neuronal membrane excitability, which can provoke electrical bursts in the affected neurons and trigger paroxysmal depolarising shifts (PDS).³ Additionally, loss of surround inhibition results in the recruitment of neighbouring neurones and seizure propagation.²

Abnormal brain activity during seizures can be captured using electrophysiological recordings, which also detects abnormalities in the interictal state (between seizures).⁴ Interictal electroencephalography (EEG) is used in the diagnosis of epilepsy.⁴ Interictal activity may include high-frequency oscillations, interictal spikes (also known as interictal epileptiform discharges), and slow wave activities.⁴

Epilepsy involves two key processes: ictogenesis and epileptogenesis. Ictogenesis refers to the transition process from interictal to ictal (seizure) state.⁴ Epileptogenesis is the progressive process through which a structurally or functionally normal brain undergoes changes that increase its susceptibility to seizures.⁴

Mechanisms of generalised and focal seizures

Seizures are classified according to their onset as focal, generalised, or unknown.⁵ This classification reflects the anatomical origin of abnormal electrical activity in the brain during a seizure and is informed by investigations such as EEG.^5,6

• In focal onset seizures, abnormal activity originates within networks limited to one hemisphere of the brain.⁶
  • A subtype, focal-to-bilateral tonic-clonic seizures, occurs when ictal activity starts in a focal region, and subsequently propagates to both hemispheres.⁶ These were previously called partial onset with secondary generalisation seizures.⁷
• In generalised seizures, abnormal activity originates within bilaterally distributed networks from the outset.⁶
• In seizures of unknown onset, there is insufficient information to determine the point of origin.⁶

Seizures can be further classified by level of consciousness (preserved or impaired) and by seizure semiology, including the presence or absence of observable manifestations such as tonic–clonic motor activity.⁶

Epilepsy types are defined by the predominant seizure types experienced by the patient.⁸ Patients with generalised epilepsy typically show features of generalised seizures on EEG and may present with multiple seizure types such as absence, myoclonic, atonic, tonic, and tonic-clonic seizures.⁸ In contrast, patients with focal epilepsy present with seizures arising from one hemisphere, including focal aware seizures, focal impaired awareness seizures, focal motor seizures, focal non-motor seizures, and focal to bilateral tonic-clonic seizures.⁸

The mechanisms underlying seizure generation are not yet fully understood.² Current evidence suggests that seizures result from an imbalance between neuronal excitation and inhibition.⁵ There are six general causative mechanisms that have been proposed in epilepsy: genetic, structural, metabolic, infectious, immune, and unknown.⁵ This page focuses on the role of neurons, neurotransmitters and ion channels in epilepsy.

For more information on treatment approaches for patients with difficult-to-control seizures, explore our page on tackling refractory epilepsy with improved seizure control.

Neuronal rewiring is thought to contribute to ictogenesis by promoting recruitment of excitatory neuronal networks.¹ This can happen after events such as damage to normal neuronal homeostasis, brain injury (e.g. traumatic injury or stroke) or space-occupying lesions (e.g. brain tumours).^2,5

Alterations in intracellular signalling pathways have also been implicated. Mutations in the PI3K, IGF, and mTOR pathways have been associated with structural brain abnormalities observed in epilepsy.⁹ The mTOR pathway, in particular, regulates outgrowth of afferent and efferent neuronal processes, and its overactivation may lead to aberrant synaptic reorganisation, increased neuronal connectivity, and epilepsy.⁹

Neurotransmitters in epilepsy

Disruption of excitatory and inhibitory neurotransmission is a central feature of epilepsy.³ Evidence from animal models indicates that both GABAergic (inhibitory) and glutamatergic (excitatory) synapses are involved in seizure generation.⁹ Decreased activity of inhibitory signalling and increased activity of excitatory signalling can shift the balance towards neuronal hyperexcitability, facilitating seizure activity.^3,9

Mutations in proteins involved in neurotransmitter vesicle fusion in presynaptic neurons have also been associated with epilepsy.⁹ An example of this are mutations in the presynaptic calcium channels and docking proteins.⁹ These are targets for antiepileptic drugs.⁹

Learn more about how antiseizure medications can help reduce seizure frequency and support seizure freedom in patients with epilepsy.

Postsynaptic dysfunction is also associated with epilepsy.⁹ These include receptor desensitisation and receptor modifications affecting neurotransmitter affinity and subsequent protein translocation for ion channel opening or closing.⁹ Examples include mutations in genes encoding components of AMPA-type glutamate receptors, as well as dysfunction of the glutamate NMDA receptor and the inhibitory GABA_A receptor.⁹

Receptor regulation itself can shift the excitatory:inhibitory balance. Impaired clearance of AMPA and NMDA glutamate receptors can lead to irregular, heightened excitatory signalling and calcium influx, while reduced surface presentation of GABA_A receptors decreases inhibitory "braking," together disrupting the balance between excitatory and inhibitory neurotransmission.³

The role of sodium channels in epilepsy

Mutations in voltage-gated sodium channels (VGSCs) in neurons have been implicated in the disturbance of neuronal homeostasis and epilepsy.^9,10 VGSCs are responsible for generating and propagating action potentials and play a key role in the regulation of neuronal excitability and neuronal activity.¹⁰

More than 1,250 pathogenic variants in voltage-gated sodium channels have been found in patients with epilepsy, the majority located in the SCN1A gene, with additional mutations identified in SCN2A, SCN8A, and SCN1B.¹¹ Fast-firing inhibitory interneurons are disproportionately affected by VGSC mutations.⁹ It has been proposed that decreased functioning of these channels results in reduced activity and impaired inhibition from interneurons involved in neuronal homeostasis.⁹

Alternative mechanisms have also been proposed. Studies in rat cortical pyramidal neurons suggest that dysfunctional distribution of VGSCs may lower the neuronal threshold for action potential generation, causing aberrant action potential propagation and altering network excitability.¹⁰ In addition, VGSC dysfunction has been associated with paroxysmal depolarising shifts.³ Disrupted channel inactivation may alter neuronal membrane excitability and provoke electrical bursts in the affected neurons, contributing to seizure generation.³

Although many VGSC mutations have been studied in isolation, epilepsy is often polygenic, with multiple genetic variants contributing to disease onset and phenotype.¹⁰

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = gamma-aminobutyric acid; EEG = electroencephalography; NMDA = N-methyl-D-aspartate; PDS = paroxysmal depolarising shifts; SCN = Sodium Voltage-Gated Channel gene; VGSC = voltage-gated sodium channels.

MAT-UKI-0511-P | September 2026