Lecture 16: Epilepsy

Question 1

What are epileptic seizures and their general causes?

Answer 1

• An attack caused by abnormal, excessive electrical discharge from neurons in the brain often associated with loss of consciousness but not always.
• Can be caused from structure, genetic or metabolic/functional abnormalities.

Question 2

Epileptogenesis?

Answer 2

• Occur as a result of abnormal synchronous activation of large numbers of hyperexcitable neurons which are conected in networks.
• Propogated via both normal and abnormal pathways
• Spread through synaptic and non synaptic pathways (eg. gap junctions)
• Everyone has the circuitry to generate a seizure. (ECT, drugs)

Question 3

Prevelance of epilepsy?

Answer 3

0.5-1% of the population

1 in 20 people will have a seizure in their life

Question 4

Classification of epilepsy?

Answer 4

Electroclinical

• Focal (or Partial) - manifestations depend on part of brain
• Generalised seizures - Networks involving extensive regions of both hemispheres.

Question 5

Focal seizures?

Answer 5

Consciousness may be preserved = Focal aware seizure

• focal motor, visual, somatosensory auditory, psychic

Consciousness may be impaired = focal imparied awareness s.

Question 6

Neuronal Ion channel variations?

Answer 6

1. voltage gated vs ligand gated (generally allow wider range of ions to pass through)
2. excitatory vs inhibitory
3. different localisation of channels along axons and around synapes
4. regional differences in density of different recpetors
5. Composition of between 2-6 subunits

Question 7

Ionotropic excitatory Amino Acid Rcpetors- Glutamate Receptors?

Answer 7

non-NMDA

• 2 major types are AMPA and Kainate
• rapidly activate and inactivate
• Allow any cation to pass
• Relatively impermeable to Ca²⁺

NMDA

• Relatively slow activation
• relatively selective for Ca²⁺
• Mg²⁺ normally blocks channel when polarised but expelled when membrane is partially depolarised

Question 8

Inhibitory Transmission?

Answer 8

GABA

• Involved in 70% of synapses
• GABAa receptors bind 2 molecules of GABA
• Opens Cl- channels to hyperpolarise neurons and mediated inhibition promote neuronal synchronisation
• allosteric binding sites for benzodiazapines and barbituates

Question 9

Do ion channels exhibit plasticity?

Answer 9

Yes

They are not permanent and are rather constantly changing, especially as we mature leading to childhood epilepsy that you can grow out of.

Eg. mutations in voltage gated K+ channels that change to different channels after a few months of life = benign familial neonatal epilepsy

However, issues with Na channels that begin at 6 months triggered by a fever of some kind = Dravet’s syndrome

Question 10

Absence seizures?

Answer 10

Occur due to abnormal activation of T-type calcium channels in the thalamus

Patients usually knows they have happened and are just not “with it” for a breif period of time.

Question 11

Other mutations of genes encoding for ligand gated ion channels causing epilepsy?

Answer 11

Nicotinic ACh receptor = Nocturnal frontal lobe epilepsy

GABAa receptor = Generalized epilepsy with febrile seizures

Deletion of part of Ch 15 = Angelman’s syndrome

Question 12

Drugs that induce seizures?

Answer 12

Blockades of GABAa recpetors

-eg. penicillin enters open GABA channels and occludes them

Activtion of Glutamate recpetors

• Demoic acid (a toxin) that is sometime found in shellfish

Blockade of K currents

- with 4-aminopyridine (can be used to treat Multiple sclerosis)

Question 13

Drugs that help stop prolonged seizures?

Answer 13

Na+ channel blockers - Presynaptic

= Phenytoin, carbamazepine, lamotrigine

GABA inhibitors - enhance GABA transmission (inhibition)

= vigabatrin was the first but toxic to the retina

= Benzodiazapines (Diazapam, lorazapam)

= Barbiturates (Phenobarbitone)

Ca²⁺ Channel blockers -especially for absent seizures

Glutamate transmission blockers

Question 14

Antibody-induced epilepsy syndromes?

Answer 14

Can have antibodies that develop that are against the voltage gated K+ channels or NMDA receptors

Typically get focal seizures that for unkown reason are normally in the temporal lobe.

Also can get ones that are anti-GAD, AMPA receptor, GABA

Question 15

The effect of seizures?

Answer 15

Kindling

• Repetitive exposure to subthreshold electrical stimulation eventually produces spontaneous seizures.
• Theory that seizures may beget seizures

Anatomical rearrangement of local circuits

• excitatory axons have collateral branches
• With neuronal death, there is sprouting of unlesioned axons that fill in dendritic regions.
• E.g. mossey fibres of granule cells in dentate gyrus of hippocampus