Epilepsy - Clinical Lecture Flashcards
What are seizures?
- External manifestation (and primary symptom) of epilepsy
- Clinical manifestation of an abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex.
What are the 2 basic mechanisms underlying seizures?
- Excitation (too much)
2. Inhibition (too little)
How can excitation lead to a seizure?
o Ionic –> enhanced Na+, Ca2+ influx into neurons
o Neurotransmitter –> increased release of glutamate, aspartate (excitatory neurotransmitters) into synaptic cleft
Which 2 excitatory neurotransmitters can lead to seizures?
glutamate, aspartate
How can inhibition lead to seizures?
o Ionic –> insufficient Cl- influx into neuron, or insufficient K+ efflux
o Neurotransmitter –> insufficient release of GABA (inhibitory neurotransmitter)
What is the main inhibitory neurotransmitter in the CNS?
GABA
Is increased excitability always synonymous with seizure? Why?
No - the increased excitability could be in inhibitory neurons
What are inhibitory interneurones?
These brain cells allow activity to spread in one direction, but not to spread out sideways (counterbalance hyperexcitability)
- When the brain is working normally, very small numbers of brain cells are active at any given time
- The activity is kept tightly focussed as it flows through successive brain regions and is not allowed to spread out (by inhibitory interneurones)
What happens if inhibitory interneurones are dysfunctional?
• If inhibitory interneurones are dysfunctional, the localised hyperexcitability is not counterbalanced and can involve more and more neurones, causing a seizure
o When activity spreads out sideways, too many cells become active at one –> epileptic seizure
Which ion is used as a measure of excitation?
Ca2+
Which inhibitory neurotransmitter do inhibitory interneurones release?
GABA
How is magnesium involved in epilepsy?
Magnesium is a potential modulator of seizure activity because of its ability to antagonise excitation. Some studies have shown that people with epilepsy have lower magnesium levels than people without epilepsy.
What are anti-epileptic drugs?
A drug that decreases the frequency and/or severity of seizure sin people with epilepsy by treating the symptoms of seizures, not the epileptic condition
What is essential for correct AED selection?
Correct classification of the seizure
What are the 3 main modes of action of AEDs?
- Suppress action potential
- Enhance GABA transmission
- Suppress excitatory transmission
What are the 2 ways in which an AED can suppress action potential?
Block sodium channel or modulate it
Potassium channel opener
What are 2 examples of AEDs that block sodium channel or modulate it in order to suppress action potential?
Carbamazepine, oxcarbamazepine
Mechanism of action of Carbamazepine?
Carbamazepine is a sodium channel blocker. It binds preferentially to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential.
What are the 2 ways in which an AED can enhance GABA transmission?
GABA uptake inhibitor OR inhibit GABA transaminases
GABA mimetics, enhance action of GABA receptors
What are GABA transaminases?
GABA transaminase enzymes comprise a family of transaminases which degrade the neurotransmitter GABA
What is an example of an AED that inhibits GABA transaminases?
vigabatrin
What is an example of an AED that inhibits GABA uptake?
tiagabine
What are GABA mimetics?
GABA-like drugs (inhibitory effect) –> enhance action of GABA receptors
What are 2 classes of AEDs that function as GABA-mimetics?
- Barbiturates
* Benzodiazepaines e.g. clonazepam
How can AEDs suppress excitatory transmission?
Via a Glutamate receptor antagonist
In practice, the most common AEDs used have which mechanisms of action?
- Enhancement of GABAergic transmission
- Inhibition of Na+ channels
- Mixed actions –> Combination of some or all of the above and also inhibiting neurotransmitter release
What is a partial simple seizure?
A partial seizure happens when unusual electrical activity affects a small area of the brain –> does NOT affect awareness
What is a partial complex seizure?
Seizures that ARE associated with impairment in consciousness
First line of AEDs in partial simple and partial complex seizures?
Carbamazepine
Phenytoin
Valproic Acid
What is a tonic-clonic seizure?
Tonic-clonic seizures involve both tonic (stiffening) and clonic (twitching or jerking) phases of muscle activity.
First line of AEDs in tonic-clonic seizure?
Carbamazepine
Phenytoin
Valproic Acid
What is an absence seizure?
Where you lose awareness of your surroundings for a short time –> causes you to blank out or stare into space for a few seconds.
First line of AEDs in an absence seizure?
Ethosuximide
Valproic acid
What is an atonic seizure?
A type of seizure that causes sudden loss of muscle strength - can cause the person to fall to the ground.
What is a myoclonic seizure?
Myoclonic seizures are characterised by brief, jerking spasms of a muscle or muscle group. They often occur with atonic seizures, which cause sudden muscle limpness.
First line AEDs for atypical absence, atonic and myoclonic seizures?
Valproic acid
What are febrile seizures?
affect infants – caused by fever
First line AEDs for febrile seizures?
Diazepam - given rectally (or IV)
What is the most widely used anti-epileptic drug?
Valproic acid
What is GABA?
- Major inhibitory neurotransmitter
* Found at ~30% of synapses
Via which receptors does GABA act?
via GABA(A) or GABA(B) receptors
Which GABA receptor is most relevant regarding seizures and epilepsy?
GABA(A)
What type of receptor is GABA(A)?
Ligand-gated chloride channel receptor
What type of receptor is GABA(B)?
G protein-coupled receptor
What happens when GABA binds to GABA(A)?
GABA is released into presynaptic cleft from presynaptic neuron and binds to GABAA receptors on postsynaptic neuron
Binding of GABA causes GABAA receptor to form a chloride channel –> Allows Cl- ions to enter cell
What are the 3 methods of enhancing GABAergic transmission?
- Enhance action of GABAA receptors
- Inhibit GABA transaminase
- Inhibit GABA uptake
Which 2 drugs enhance the action of GABA(A) receptors?
- barbiturates e.g. phenobarbital
2. benzodiazepines e.g. clonazepam
What is an example of a drug that inhibits GABA transaminase?
vigabatrin
What is an example of a drug that inhibits GABA uptake?
tiagabine
What are the 3 main benzodiazepines?
- Clonazepam
- Clorazepate
- Diazepam (Valium) and Iorazepam
What type of seizures is Clonazepam effective in?
generalised tonic-clonic, absence and partial seizures
What type of seizures is Clorazepate effective in?
effective against partial seizures, used in conjunction with other drugs
What type of seizures is Diazepam effective in?
effective against status epilepticus when given IV
What is status epilepticus (SE)?
A life-threatening condition in which the brain is in a state of persistent seizure
What defines a persistent state of seizure?
- More than 30 minutes continuous seizure activity OR
* Two or more sequential seizures with no recovery within 30mins)
What does SE confers greater future risk for?
unprovoked seizures
Treatment for SE?
diazepam (GABA agonist)
Mechanism of benzos?
Increases affinity of receptor to GABA:
Increases chloride current (opening frequency)
Suppresses seizure focus by raising action potential threshold
Strengthens surround inhibition, prevents spread of excitation
What are the effects of benzos?
o Sedative (calming) o Hypnotic (initiates or prolongs sleep) o Anxiolytic (reduces anxiety) o Anticonvulsant (reduces epileptiform activity) o Muscle relaxant o Amnesic (anterograde – after drug administration)
What are the unwanted side effects of benzos?
o Sedation
o Addictive, avoid long-term use
o Tolerance and dependence - avoid long term use
o Can get respiratory depression if used IV
o Drowsiness, confusion, amnesia, poor co-ordination
o Long acting (e.g. diazepam) – next day
When can benzos be lethal in overdose?
When taken with other CNS depressants e.g. ethanol –> can lead to respiratory depression
In cases of benzo overdose, what drug is used as treatment?
flumazenil (a benzo antagonist)
Why should benzos only be used for short term treatment?
Withdrawal –> hard to wean patients off BZs if used long term
Voltage-gated sodium channels can be
a) closed
b) open
c) inactivated.
Describe the cause for each of these states?
a) closed; at the resting potential
b) open: in response to a nerve impulse, the gate opens and Na+ enters cell
c) inactivated; for a brief period following activation (depolarisation), the channel does not open in response to a new signal (Na+ channels do not recover from the inactivated state until the membrane has repolarised)
What is the trigger for voltage-gated sodium channels to open?
Voltage change
Mechanism of action of Phenytoin?
A sodium channel blocker!
Binds to voltage-gated sodium channels when they are in an inactivated state to slow down its recovery
Why is inhibition of voltage-gated sodium channels (e.g. by Phenytoin) considered ‘use-dependent’?
Benefits of this?
Phenytoin only binds to Na+ channels to inactivated channels; these channels have to have been recently opened
Only rapidly firing neurons are blocked and thus does not interfere with normally firing neurons
What is tonic blockade?
How does it differ from phasic blockade?
Tonic blockade –> When there are long intervals between impulses, the level of inhibition of each impulse is the same
Phasic blockade –> When intervals between impulses is short, the level of inhibition increase with each impulse
How is phenytoin taken?
Orally - well absorbed
Describe if phenytoin is highly protein bound or not?
If so, which plasma protein is it primarily bound to?
Very highly protein bound (plasma proteins, primarily albumin) 80-90% –> only 10-20% free
What is the danger of phenytoin alongside valproate?
Phenytoin and Valproate have the same binding sites.
If taken together produces more “free” phenytoin (the ‘free phenytoin’ is the active moiety and able to interact with receptors –> has high affinity of binding with the Na+ channel)
Tends to increase hepatic clearance of the drug so effects can be unpredictable
How is phenytoin metabolised?
Highly metabolised (95%) in the liver to an inactive metabolite
BUT Metabolism is saturable; liver may not be able to metabolise anymore once saturated
Why can a small increase in the dose of phenytoin lead to lead to large increase in plasma concentration?
Phenytoin is highly bound (only 10-20% ‘free’ - a slight increase in the amount of ‘free’ phenytoin can have a large effect).
Elimination can become saturated
Phenytoin kinetics are nonlinear and saturable, resulting in highly variable concentrations even with minor dosage changes
A slight increase in phenytoin bioavailability can lead to a marked increase in serum level and thus to adverse effects, especially when the level is more than 15/mg/L
What are the mild unwanted effects of phenytoin?
Include vertigo, ataxia, headache and nystagmus
What are the severe unwanted effects of phenytoin?
Confusion, intellectual deterioration – acute and reversible
Hyperplasia of the gums, hirsutism – gradual
Megaloblastic anaemia – folate metabolism
Hypersensitivity and rashes – quite common
Hepatitis
Foetal malformations – cleft palate “foetal hydantoin syndrome”
What can phenytoin during pregnancy lead to?
Can cause foetal hydantoin syndrome
What is Foetal hydantoin syndrome?
Up to 30% of children whose mothers are taking phenytoin during pregnancy typically have:
o intrauterine growth restriction with microcephaly
o minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges (birth defects)
o a smaller population will have growth problems and developmental delay, or mental retardation
• Heart defects and cleft lips
What 2 drugs can cause foetal hydantoin syndrome if taken during pregnancy?
- Phenytoin
2. Carbamazepine (less common)
Why is Valproate (valproic acid) unusual as an AED?
- Not related chemically to the other classes of anti-epileptics
- Unusual in that it is effective against both tonic-clonic and absence
- Can also be useful in bipolar depressive illness
Valproate/valproic acid has 3 mechanisms of actions.
What are these?
- Inhibits sodium channels (weaker than phenytoin)
- Decreases GABA turnover through:
Inhibition of succinic semialdehyde dehydrogenase and GABA transaminase
May lead to increased synaptic GABA levels - Blocks neurotransmitter release by blocking T-type calcium channels
Why is valproic acid effective against many different seizure types?
Due to many different mechanisms of action
What are the dangers of valproate if taken during pregnancy?
Foetal valproate syndrome:
o Can cause learning difficulties and autism
o These findings must be balanced against the treatment benefits for women who require valproate for epilepsy control
What is the mechanism behind valproic acid leading to Foetal valproate syndrome?
Valproate is a HDAC (histone deacetylase) inhibitor
The inhibition of HDAC activity results in the hyperacetylation of chromatin, associated with the altered transcription of specific genes, e.g. GRP78 (up to 2% of all expression).
Thus, VPA inhibition of HDAC provides an epigenetic mechanism for FVS.
What % of seizure patients are seizure free with one drug?
70%
What is refractory epilepsy?
Epilepsy that cannot be controlled by drugs
