Erfan Bashar
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Epilepsy — Pathophysiology

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

A seizure begins when the balance between excitation and inhibition in cortical networks tips toward runaway excitation. Two pillars carry the process: membrane depolarization and hypersynchrony. The first explains why a neuron fires when it should not. The second explains why that firing becomes a seizure rather than background noise.

Depolarization is a shift in the neuronal membrane potential toward rapid, prolonged, intense firing. The two principal transmitters holding this balance are glutamate, the main excitatory transmitter, and GABA, the main inhibitory one. More glutamatergic drive or less GABAergic restraint makes neurons depolarize more easily. Seizure threshold sits on a continuum. Anyone can seize under extreme provocation such as cocaine intoxication or severe electrolyte disturbance, while people with epilepsy live with an abnormally low threshold because their neurons are hyperexcitable.

Hypersynchrony turns abnormal firing into a seizure. One misfiring neuron produces nothing detectable. A seizure needs thousands of neurons discharging simultaneously enough to summate into a scalp signal. That is what the EEG records as spikes and sharp waves. Visible spikes represent only a small fraction of total brain activity, yet their synchronized timing makes them clinically decisive. In generalized seizures the discharge engages both hemispheres rapidly through cortical and subcortical networks. In focal seizures it stays within one hemisphere unless it spreads.

The substrate: channels, pumps, and transmitters

The abnormalities underlying hyperexcitability are defects in voltage-dependent sodium, potassium, and calcium channels, failure of membrane ATPase with its sodium-potassium pump, impaired GABA-mediated inhibition, and heightened glutamate and aspartate transmission. Many genetic epilepsies are channelopathies: sodium channel mutations that let neurons fire too easily, potassium channel mutations that prevent clean repolarization, and calcium channel mutations that drive rhythmic thalamocortical firing in absence seizures.

Structural damage creates the same endpoint by a different road. After a stroke, seizures arise not from dead neurons in the infarct core but from surviving peri-infarct neurons that depolarize more readily, particularly during hyperperfusion. Roughly 1 in 10 stroke patients develops seizures. Development adds its own twist. In the immature brain, NMDA-mediated excitation is prolonged and GABAergic signalling can be depolarizing rather than hyperpolarizing. This helps explain why seizures are common in children and why most remit as the brain matures.

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