3.10 Mechanisms of Seizures

Question 1

Describe Focal Seizures (aka Partial Seizures). Difference between simple partial and complex partial?

Answer 1

–Start from a small group of localized neurons (A partial seizure has a seizure focus, a localized region of the brain where the activity starts).
–Preceded by aura, a sense of fear, a rising feeling in the abdomen, a specific odor.

–Simple partial (no alteration in consciousness)
–Complex partial (with an alteration in consciousness)
•Focal seizures can spread and generalize (secondarily generalize)

Question 2

Describe generalized seizures

Answer 2

•Generalized Seizures
–No aura.
–Involve both hemispheres from the onset.

Question 3

Which two processes need are regulated in the control of neural circuits?

Answer 3

–Excitability of individual neurons
–Local inhibition of neurons

Question 4

Seizure and neural circuits

Answer 4

•Seizure can be considered to be the loss of control of neural circuits.
–Increased excitability of neurons
–Loss of local inhibition
–Spread of excitation

Question 5

Sodium current in Central Neurons and repetitive firing

Answer 5

• The sodium current that makes up the action potential in central neurons, has a higher threshold for activation.
• The sodium current does not inactivate at resting potential. Inactivation occurs at a significantly depolarized level. Thus, sustained depolarization can produce repeated action potentials.
• Calcium currents and persistent sodium currents can keep the cell depolarized to produce the repetitive firing.

Question 6

Potassium and repeated action potential firing in central neurons

Answer 6

•Repeated action potential generation is also supported in central neurons by a fast, outward potassium current for rapid repolarization of the membrane.

Question 7

Role of Domoic acid in neuron excitability

Answer 7

• Domoic acid is a glutamate analog.
• Can be a source of outbreaks of seizure and associated amnesia through effects on the hippocampus.

Question 8

Role of Glia in Neuron Excitability

Answer 8

•Glia absorb and release glutamate.
•Calcium waves in glia.
–Permanent increase after repeated seizures
–Leads to glutamate release.
•Glia also absorb and thus modulate GABA.

Question 9

Repetitive discharge leads to:

Answer 9

•Repetitive discharge leads to:
–Increasing K+ outside the cell
•limits K+ exit from cells
•depolarizes neighboring cells
•Mechanisms under debate but could be through the activation of persistent (slowly inactivating) conductances.
•Remember that Na+ current channels are different in central neurons.

–Accumulating Ca2+ in nerve terminals leads to further synaptic release. (presynaptic)
–Ca2+ entry through NMDA glutamate channels. (postsynaptic)

Question 10

What is a paroxysmal depolarization shift?

Answer 10

Neuron in the focus (of a partial seizure) display a paroxysmal depolarization shift (PDS).

PDS- 20-40 mV positive shift in membrane potential lasting 50-200 msec.

–The shift triggers a train of action potentials at the peak of the shift.

Question 11

What causes a paroxysmal depolarizing shift (PDS)?

Answer 11

•The PDS is caused by activation of glutamate AMPA and NMDA channels, and voltage-gated Ca2+ channels.

Question 12

The burst of spikes and PDS is followed by an _______

*mech. of partial seizure*

Answer 12

Afterhyperpolarization (AHP)

Question 13

What is the afterhyperpolarization (AHP) and how does it relate to the seizure activity?

*mech. of partial seizures*

Answer 13

• The afterpolarization (AHP) limits the duration of the depolarizing shift.
• The AHP is mediated by Ca²⁺and voltage-dependent K+ channels, GABA-mediated Cl- (GABA-A) and K+ (GABA-B) conductances.

Question 14

IPSP in the cortex vs. the spinal cord

Answer 14

•Cortical inhibitory post synaptic potentials are much larger and last 10-20 times as long as the inhibitory post synaptic potentials applied in the spinal cord.

Question 15

What is an Inhibitory surround?

Answer 15

The inhibitory surround is made up of inhibitory interneurons that act to restricts the center excitability and its spread.

Question 16

Local spread of excitability is caused by ______

Answer 16

Antagonizing GABA

*Note: Penicillin can act as a weak GABA-A antagonist and can be convulsant (generalized penicillin epilepsy).

Question 17

The breakdown of the inhibitory surround

Answer 17

• The breakdown of the inhibitory surround leads to reduction of the afterhyperpolarization (AHP).
• With no AHP, the neuron will display nearly continuous high frequency firing.

Tonic:

• GABA release stops
• AMPA and NMDA channels become overactive.
• Ca²⁺conductance is prolonged

Clonic:

• When GABA resumes, the continuous discharge stops
• AMPA and NMDA channels become less active.

Side note: Afterwards
•The GABA release can be reduced by intense discharge.
•The neurons are still viable but they release less GABA.

Question 18

Why is the hippocampus prone to seizures?

Answer 18

• Excitatory feedforward connections of dentate granule cells.
• Subiculum projects to the entorhinal cortex
• Characteristic hippocampal damage leads to denervation of dentate granule cells.
• Axonal sprouting of mossy fibers leads to recurrent hyperexcitability of dentate granule cells
• Link to epilepsy has not been confirmed.

(Note: this info was found on slide titled “Mesiotemporal Epilepsy: Hippocampus)

Question 19

How does a partial seizure spread?

Answer 19

• Spread of activity through local connections
• The spread of seizure activity involves normal cortical, and subcortical circuitry.

Question 20

What are some of the symptoms that can arise during the spread of a seizure?

Answer 20

• Spread can produce aura
• A slow progression can produce a progression of clinical symptoms as in the Jacksonian march, the progressive activation of motor cortex
• Seizures with a neocortical focus have a more rapid progression compared to seizures which start in the limbic system (hippocampus or amygdala)

Question 21

How does a partial seizure generalize?

Answer 21

Seizure activity spreads from the focus to thalamus and the thalamus sends the activity bihemispherically.

Question 22

Inhibition, depolarization, and hyperpolarization of absence seizure

*Mechanisms of generalized seizures*

Answer 22

In the absence seizure, inhibition is preserved but the depolarizing and hyperpolarizing phases become stronger.

Question 23

What activates T-type Ca2+ channels in the thalamic relay cells?

*GENERALIZED SEIZURE*

Answer 23

Hyperpolarization

Question 24

What causes the hyperpolarization during generalized seizures?

Answer 24

GABAergic interneurons

Question 26

Metabolic demand during a partial seizure?

Answer 26

The metabolic demand during a partial seizure leads to a 3-fold increase in glucose and oxygen use.

Question 27

Define Status Epilepticus

Answer 27

Repeated generalized seizures without a return to full consciousness is called status epilepticus.

Question 28

__________or more of continuous convulsive seizures lead to brain injury and possibly death.

Answer 28

30 minutes

Question 29

Explain some mechanisms of brain damage caused by seizures

Answer 29

•Brain damage from excitotoxicity.
•Excessive glutamate release, leading to
–Increases in intracellular calcium.
–The calcium activates many enzymes (phosphatases, proteases, lipases) that degrade the cell.
–Lipid peroxidation leads to free radicals which damage cellular proteins and leads to cell death.
–Possible involvement of the activation of genes for programmed cell death (apoptosis.)
•Na + builds up in the cell, pulling in water and leading to swelling of the cells.
•Hippocampal cells, CA1 and CA3 pyramidal cells are particularly vulnerable.
•Stimulation of limbic structures (amygdala and hippocampus) produces an afterdischarge.
•Repeated stimulation of limbic structures can lead to stronger and stronger afterdischarge and eventually seizure, a process called kindling.
•Cell loss can be selective. Some GABAergic interneurons are spared. These cells contain calcium-binding proteins such as parvalbumin and calbindin.
•Seizures can lead to changes in gene expression.

Question 30

Mechanisms of convulsants and anticonvulsants

Answer 30

• Convulsants act by either enhancing excitation or blocking inhibition.
• Anticonvulsants act by either blocking excitation or enhancing inhibition.