Epilepsy Flashcards
Stigma around epilepsy
That epilepsy is a mental illness/intellectual disability
Causes misunderstandings, and prevents those who suffer from getting help
ILAE definition of epilepsy
- Having two unprovoked seizures occurring >24hrs apart
- Having one unprovoked seizure and a probability ≥60% of having further seizures
Seizure definition
Transient occurrence of symptoms due to abnormal, excessive, synchronised electrical discharge
Focal seizures
originate within networks limited to one hemisphere
- patients can be aware or have impaired awareness
- motor or non-motor
- can shift to bilateral
Generalised seizures
originate at a point and rapidly engage bilaterally distributed networks
- impaired awareness
- motor = ‘tonic clonic’ or ‘other motor’
- non motor = absence seizures
Tonic clonic seizure
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
Absence seizures
defined by behavioural arrest and sharp wave discharge on EEG
- no post-ictal confusion or awareness of seizure
Main mutation type associated with epilepsy
Ion channels (ligand and voltage gated)
Anti-epileptic drugs
- effective in 70%
- decrease seizure incidence, but do not cure epilepsy or stop seizure once it has started
Non pharmaceutical treatment options for epilepsy
- 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
Precision medicine
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
Absence seizures
brief episodes (~10s) of behavioural arrest and unresponsiveness associated with a generalised 2-4Hz spike wave discharge in EEG
Treatment for CAE
- Ethosuxamide
- Lamotrigine & Valproate
Mechanism of ethosuxamide
Inhibition of T-type Ca2+ channels in the thalamus
Mechanism of Valproate
- Inhibition of T-type Ca2+ channels in the thalamus
- inhibition of Na+ channels
- increasing GABAergic inhibition
Mechanism of Lamotrigine
research has shown that lamotrigine selectively binds sodium channels, stabilising presynaptic neuronal membranes and inhibiting glutamate release
Side effects of valproate
nausea, weight gain, attention issues, and (rarely) severe hepatic toxicity + congenital birth defects
What drugs should not be used for absence seizures
Carbamazepine, tiagabine and vigabatrin exacerbate absence seizures
Mechanism of carbamazepine
Antagonises voltage-gated Na+ channels
Mechanism of vigabatrin
selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA.
Mechanism of tiagabine
Potent inhibitor of GABA uptake into neurons and glial cells
Stargazer rat model
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
AMPA receptors (subunit and activation pattern)
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
NMDA receptor (subunits and activation pattern)
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+
Gria4-/- mouse model
Lacks the GluA4 subunit
- exhibits characteristic absence seizure pathology
- loss of AMPA receptors at inhibitory feed forward synapses
Mechanism of absence epilepsy
Loss of feedforward inhibition in CTC pathway
- Decreased AMPA expression
GAERS rat model
A polygenetic rat model that has deficiency GAT-1 activity
- impaired GABA clearance
- elevated extracellular GABA
- enhanced extra-synaptic tonic GABA inhibition
Perampanel and Talampanel
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
RTN
reticular thalamic nuclei
- an inhibitory shell surrounding the thalamus
- maintains normal oscillatory rhythm of the CTC
DREADDS
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
