Seizure pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]

Normally, seizures do not occur because the membrane stability of neurons is maintained, and the discharges that lead to seizures are prevented from transferring. In a normal brain, some circumstances can provoke seizures, such as: hyponatremia, drug withdrawal, and hypoglycemia. Abnormalities in different parts of the nervous system may cause seizure, such as: brain regions, cells, ions, networks, and receptors. The imbalance of excessive excitation and reduced inhibition can cause seizures and is also responsible for prolonging it if the imbalance persists. Glutamate is the most common excitatory neurotransmitter and acts on the N-methyl-D-aspartate (NMDA) receptor. However, NMDA antagonist drugs have not been clinically successful. Gamma-aminobutyric acid (GABA) is the most common inhibition neurotransmitter. GABA inhibits excess excitation of the neurons by activating the GABAA receptor. Increasing the inhibition of GABA (even if the inhibition is not damaged) may be helpful in a seizure, since it may overwhelm the excess excitation of the seizure. Examples of GABA-enhancing drugs are benzodiazepines, barbiturates, propofol, and some anesthetics. However, these drugs are not suitable for long term therapy since patients usually become tolerant to their effect.

Normally, seizures do not occur because the membrane stability of neurons is maintained, and the discharges that lead to seizures are prevented from transferring.^[1]

In a normal brain, some circumstances can provoke seizures, such as:^[1]

• Hyponatremia: Disrupion in electrochemical gradients across cell membranes causse instability.
• Drug withdrawal: Benzodiazepines, barbiturates, and alcohol may sensitize inhibitory GABAA receptors and stimulate a seizure.
• Hypoglycemia: Causes changes in the metabolism of cells.

Abnormalities in different parts of the nervous system may cause seizure, such as:^[1]

• Brain regions
• Cells
• Ions
• Networks
• Receptors

For example:

• Generalized tonic-clonic seizures is caused by abnormalities of the sodium channels or calcium channels.^[2]
• Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in the acetylcholine receptor.^[3]
• The most common form of temporal lobe epilepsy is caused by abnormalities of cellular growth in that region.^[4]
• Local brain malformations cause abnormal networks of cells.^[5]

Pathophysiology of generalized tonic-clonic seizures

• Generalized tonic-clonic seizure initiates with an excessive excitation of neurons, leading to synchronous discharges of more neurons, and affects a part of the brain that causes the clinical signs and symptoms of the seizure.
• An imbalance in excessive excitation and reduced inhibition causes and maintains a seizure.^[6]

N-methyl-D-aspartate (NMDA) Receptor

• Glutamate is the most common neurotransmitter that causes excitation.^[7]
• Glutamate excitation effects are by the N-methyl-D-aspartate (NMDA) receptor.
• However, NMDA antagonist drugs have not been clinically successful, probably due to their effects on learning and memory.

Gamma aminobutyric acid (GABA) Receptor

• Gamma-aminobutyric acid (GABA) is the most common neurotransmitter that causes inhibition.^[6]
• In normal circumstances, GABA inhibits excess excitation of the neurons by activating the GABAA receptor.
• Increasing the inhibition of GABA (even if the inhibition is not damaged) may be helpful in a seizure, since it may overwhelm the excess excitation of the seizure.
  • Examples of GABA-enhancing drugs are benzodiazepines, barbiturates, propofol, and some anesthetics.
    • However, these drugs are not suitable for long term therapy since patients usually become tolerant to their effect, probably due to upregulation of GABA receptors or changes in receptor sensitivity.