Epilepsy

Question 1

Stigma around epilepsy

Answer 1

That epilepsy is a mental illness/intellectual disability

Causes misunderstandings, and prevents those who suffer from getting help

Question 2

ILAE definition of epilepsy

Answer 2

• Having two unprovoked seizures occurring >24hrs apart
• Having one unprovoked seizure and a probability ≥60% of having further seizures

Question 3

Seizure definition

Answer 3

Transient occurrence of symptoms due to abnormal, excessive, synchronised electrical discharge

Question 4

Focal seizures

Answer 4

originate within networks limited to one hemisphere
- patients can be aware or have impaired awareness
- motor or non-motor
- can shift to bilateral

Question 5

Generalised seizures

Answer 5

originate at a point and rapidly engage bilaterally distributed networks
- impaired awareness
- motor = ‘tonic clonic’ or ‘other motor’
- non motor = absence seizures

Question 6

Tonic clonic seizure

Answer 6

Tonic phase: generalised stiffening of body and arching of limbs and back
Clonic phase: jerking of limbs, body, and head
Post-ictal confusion fatigue: limpness of limbs and body

Question 7

Absence seizures

Answer 7

defined by behavioural arrest and sharp wave discharge on EEG
- no post-ictal confusion or awareness of seizure

Question 8

Main mutation type associated with epilepsy

Answer 8

Ion channels (ligand and voltage gated)

Question 9

Anti-epileptic drugs

Answer 9

• effective in 70%
• decrease seizure incidence, but do not cure epilepsy or stop seizure once it has started

Question 10

Non pharmaceutical treatment options for epilepsy

Answer 10

• Surgery (focal only)
• Vagus nerve stimulation, which involves a ‘pace-maker’ like device
• Electrode implantation for responsive neuro-stimulation and deep brain stimulation
• Ketogenic diet
• Education and positive lifestyle changes

Question 11

Precision medicine

Answer 11

Approaching each case of a disease one individual at a time, to find the most effective treatment for that person
- applicable to diseases like epilepsy that have a diverse array of causes

Question 12

Absence seizures

Answer 12

brief episodes (~10s) of behavioural arrest and unresponsiveness associated with a generalised 2-4Hz spike wave discharge in EEG

Question 13

Treatment for CAE

Answer 13

1. Ethosuxamide
2. Lamotrigine & Valproate

Question 14

Mechanism of ethosuxamide

Answer 14

Inhibition of T-type Ca2+ channels in the thalamus

Question 15

Mechanism of Valproate

Answer 15

• Inhibition of T-type Ca2+ channels in the thalamus
• inhibition of Na+ channels
• increasing GABAergic inhibition

Question 16

Mechanism of Lamotrigine

Answer 16

research has shown that lamotrigine selectively binds sodium channels, stabilising presynaptic neuronal membranes and inhibiting glutamate release

Question 17

Side effects of valproate

Answer 17

nausea, weight gain, attention issues, and (rarely) severe hepatic toxicity + congenital birth defects

Question 18

What drugs should not be used for absence seizures

Answer 18

Carbamazepine, tiagabine and vigabatrin exacerbate absence seizures

Question 19

Mechanism of carbamazepine

Answer 19

Antagonises voltage-gated Na+ channels

Question 20

Mechanism of vigabatrin

Answer 20

selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA.

Question 21

Mechanism of tiagabine

Answer 21

Potent inhibitor of GABA uptake into neurons and glial cells

Question 22

Stargazer rat model

Answer 22

Exhibits bilateral synchronous activity and behavioural arrests that define absence seizures

Caused by a mutation in the TARP-gamma2/stargazin protein (Cacng2 gene) resulting in decreased expression of AMPA receptors in inhibitory feedforward RTN nRs

Question 23

AMPA receptors (subunit and activation pattern)

Answer 23

Composed of four subunits (GluA1-4), each of which can bind glutamate.
- Opening occurs when two sites are bound, and further binding increases current
- Rapid opening/closing (1ms) responsible for fast excitatory transmission

Question 24

NMDA receptor (subunits and activation pattern)

Answer 24

Hetero-tetramers containing 2xGluN1 and 2xGluN2/N3
- requires subsequent depolarisation to remove Mg2+ block as well as glutamate binding
- allows influx of Na+, K+, and Ca2+

Question 25

Gria4-/- mouse model

Answer 25

Lacks the GluA4 subunit
- exhibits characteristic absence seizure pathology
- loss of AMPA receptors at inhibitory feed forward synapses

Question 26

Mechanism of absence epilepsy

Answer 26

Loss of feedforward inhibition in CTC pathway
- Decreased AMPA expression

Question 27

GAERS rat model

Answer 27

A polygenetic rat model that has deficiency GAT-1 activity
- impaired GABA clearance
- elevated extracellular GABA
- enhanced extra-synaptic tonic GABA inhibition

Question 28

Perampanel and Talampanel

Answer 28

AMPA receptor antagonists
- shown to protect against all seizure types EXCEPT absence seizure due to lack of GluA4-containing AMPA available to be acted on

Question 29

RTN

Answer 29

reticular thalamic nuclei
- an inhibitory shell surrounding the thalamus
- maintains normal oscillatory rhythm of the CTC

Question 30

DREADDS

Answer 30

Designer Receptors Exclusively Activated by Designer Drugs

DREADDs have dual specificity, that is, both the ligand and the receptor are exclusive partners. The receptor is designed to be unresponsive to natively expressed ligands and is instead activated solely by a designer drug, which in turn is inert at natively expressed receptors