Pathophysiology of Seizure Flashcards
(IC3+6)
How might hyper-excitability such as rhythmic firing of a relatively large population of neurons lead to seizure?
**Abnormal activity in small areas of cortex* provide triggers for seizure
Instability in a single neuronal cell membrane or group of cells around it:
- When one axon is hyperexcitable => spread to multiple axon terminals => excitation of multiple neurons in the CNS => neurons keep firing
- Seizure is characterized by synchronized paroxysmal electrical discharges occurring in a large population of neurons within the cortex
Therefore hyper-excitability can spread from small foci in cortex to other parts to evoke seizure
(IC3)
Seizure occurs when what is compromised?
Inhibitory postsynaptic potential is compromised
- No hyperpolarization of postsynaptic membrane induced by GABA neurotransmitters
- Therefore, no control of seizures by inhibitory synapse
- Lead to epileptic focus
IC6: increased excitatory signals or decreased inhibitory signals
What are the two key concepts in seizure pathophysiology?
- Hyperexcitability: Enhanced predisposition of a neuron to depolarize
- Hypersynchronization: related to network changes
Explain hyperexcitability
- What are the factors that enhance predisposition of neuron to depolarize?
- Hyperexcitability: Enhanced predisposition of a neuron to depolarize
- Voltage- or Ligand-gated K+, Na+, Ca2+, Cl- ion channels
- Abnormalities in intracellular and extracellular substances (e.g., Na+, K+, O2, glucose)
- Excessive excitatory neurotransmitters (e.g., glutamine, acetylcholine, histamine, cytokines)
- Insufficient inhibitory neurotransmitters (e.g., GABA, dopamine)
Explain hypersynchronization
- Hypersynchronization: related to network changes
E.g., Hippocampal sclerosis (underlies temporal lobe epilepsy)
- Intrinsic reorganization of local circuits
- Contribute to synchronization and promote generation of epileptiform activity
- Hypersynchronous paroxysmal electrical discharges occurring in large population of neurons within the cortex
Neurotransmitters in the brain:
- Explain the action of the excitatory neurotransmitter, Glutamate
- Patients with epilepsy - receptor changes?
Primary receptor of Glutamate: NMDA
- NMDA responds to Glutamate by opening ion channels that let Calcium ions in
- Patients with epilepsy seem to have fast or long-lasting activation of NMDA receptors
Neurotransmitters in the brain:
- Explain the action of the inhibitory neurotransmitter, GABA
- Patients with epilepsy - receptor changes?
GABA binds to GABA receptors
- GABA inhibits the signal by opening channels that let in Chloride ions
- Patients with epilepsy seem to have genetic mutations in which their GABA receptors are dysfunctional and are hence unable to inhibit the signals; besides genetic causes, these receptors and ion channels may also be affected by brain tumors, brain injury, infection etc.
[Clinical Neurology]
Based on clinical neurology perspective, what are the 3 processes that lead to seizure
- Paroxysmal depolarization shift (short in the circuit)
- Initial seizure nidus and seizure focus
- Neuronal synchronization (driving of normal neighbors)
- Surrounding neurons co-opted into seizing
- Transition to the ictus
- Failure of inhibition, allowing seizure in one focus to spread to other areas of the brain
[Clinical Neurology]
Explain Paroxysmal Depolarization Shift (PDS)
- Initial seizure nidus and seizure focus
Involvement of astrocytes
- Astrocytes regulate homeostasis of glutamate, they can bind to glutamate released by neurons and recycle it for use
- Astrocytes can also release glutamate on their own accord to send signals to neighbouring neurons
Increased secretion of glutamate due to lack of scavenging of glutamate
- Increased excitation of neuron
- Increased calcium signalling
- Neurons become hyperexcitable
[Clinical Neurology]
How does Paroxysmal Depolarization Shift (PDS) look like on the surface EEG?
A spike and a slow wave
- The spike is the area that nidus of hyperexcitable neurons that are synchronized in their activity (neurons being excited multiple times drive that spiking activity)
[Clinical Neurology]
Explain: Neuronal synchronization (driving of normal neighbors)
- Surrounding neurons co-opted into seizing
When there’s a seizure, there’s repeated paroxysmal depolarization
This will increase extracellular potassium (in phase 5 of AP, K+ leaves the cell)
Many spikes => drive increase K+ conc. in the extracellular fluid
Increased extracellular K+ drives depolarization of surrounding neurons
- Less potassium diffuses out of neurons, neurons become partially depolarized
- Increased extracellular potassium may also flow down its conc. gradient, aid in the depolarization, contributing to partial depolarization of the neurons
[Clinical Neurology]
Explain transition to the ictus
- Failure of inhibition, allowing seizure in one focus to spread to other areas of the brain
- Loss of hyperpolarization, loss of refractory phase
- Loss of surround inhibition
- Excess glutamate stimulation
- Increase in intracellular calcium (from glutamate)
- Recurrent excitatory feedback circuit
[Clinical Neurology]
Seizures begets seizures
- How does increase in calcium over time result in long term structural and functional changes in the neurons, that could beget another seizure?
- Second messenger activity
- Changes to gene expression
- Calcium activation turns on cell death pathways that can destroy surrounding inhibitory neurons and increase excitatory tone
[Clinical Neurology]
Which part of the brain is most easily repeatedly activated, and hence is at higher risk of developing seizures + more prone to developing epilepsy? (epileptic region)
Hippocampus
