Mechanism of Seizure Generation from Abnormal Electrical Activity
Seizures result from abnormal excessive or synchronous neuronal activity in the brain, fundamentally caused by an imbalance between excitatory and inhibitory neurotransmitter systems, leading to uncontrolled electrical discharges across cortical neuronal networks. 1
Core Pathophysiological Mechanism
Neurotransmitter Imbalance
The fundamental mechanism involves disruption of the delicate balance between:
- Excitatory forces: Primarily mediated by glutamate acting on N-methyl-D-aspartate (NMDA) receptors, which promotes neuronal firing 2, 3
- Inhibitory forces: Primarily mediated by gamma-aminobutyric acid (GABA) acting on GABA-A and GABA-B receptors, which suppresses neuronal activity 1, 2, 3
When excitatory neurotransmission overwhelms inhibitory restraint, neurons fire excessively and synchronously, producing the clinical manifestations of a seizure. 4, 2
Initiation and Propagation Pattern
Recent evidence clarifies how seizures begin and spread:
- Seizures initiate in circumscribed zones of relative hyperexcitation, where excitatory neurons are both more prevalent and more readily recruited compared to inhibitory neurons 5
- Once initiated, seizures propagate to surrounding brain regions after overwhelming the inhibitory restraint in adjacent areas 5
- Focal seizures arise within networks of a single cerebral hemisphere and may remain localized or subsequently become more widely distributed 1
- Generalized seizures rapidly affect both hemispheres simultaneously, even when caused by a focal lesion 1
Molecular and Cellular Mechanisms
Ion Channel Dysfunction
Multiple ionic mechanisms contribute to abnormal electrical activity:
- Sodium (Na+) channels: Lack of negative regulation leads to excessive neuronal depolarization 1
- Calcium (Ca2+) channels: Dysregulation affects neurotransmitter release and neuronal excitability 2
- Chloride (Cl-) and Potassium (K+) channels: Alterations disrupt the resting membrane potential and repolarization 2
Receptor and Synaptic Alterations
- GABA receptor dysfunction reduces inhibitory neurotransmission, with alterations detectable via 11C-flumazenil PET imaging 1
- Glutamate receptor overactivity amplifies excitatory signaling 2, 3
- Presynaptic dysfunction causes abnormal neurotransmitter release patterns 1
- Expressional alterations in receptors and ion channels can lead to epilepsy pathogenesis 3
Contributing Neurotransmitter Systems
Beyond the primary GABA-glutamate axis, other neurotransmitters modulate seizure susceptibility:
- Opioids: Can reduce electrical activity spread and have anticonvulsant effects, assessable with 11C-carfentanil 1
- Serotonin: Provides anticonvulsant effects, evaluable with 18F-MPPF 1
- Dopamine: Receptor changes associate with various epilepsy forms, assessable with 18F-fallypride 1
- Acetylcholine: Dysfunction of nicotinic receptors in hippocampal and cortical neurons significantly contributes to epilepsy pathogenesis 3
- Neuropeptides: Help rectify neurotransmitter imbalances and regulate seizure activity 4
Clinical Implications
Important Caveats
- Despite extensive research, the basic mechanism of epileptic seizures has not been fully elucidated, which is why seizure classification remains operational rather than mechanism-based 1
- The same imbalance mechanism applies to both provoked and unprovoked seizures, though the underlying causes differ (structural lesions, metabolic derangements, toxins, or primary epilepsy) 1, 2, 6
- Prolonged seizure activity can cause irreversible neuronal damage through excitotoxicity and metabolic depletion 3
Structural Correlates
Certain structural abnormalities predispose to seizures by creating zones of hyperexcitability: