Flashcards in Symposium 5: Epilepsy Deck (40):
What is a seizure?
The clinical manifestation of an abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex.
What causes the manifestations of seizures?
The cortical discharges can be transmitted to the muscles, causing twitches or convulsions: epileptic seizures manifest themselves in different ways depending on their site of origin and subsequent spread.
How are seizures broadly classified?
- Generalized (with initial activation of neurones throughout both hemispheres)
- Partial (with the initial activation of a limited number of neurones in a part of 1 hemisphere)
- Secondary generalized (a partial seizure that later spreads to involve the majority of the 2 cerebral hemispheres)
What are the different types of partial seizure?
Simple or complex with secondary generalisation
What are the different types of generalised seizure?
What is a simple seizure?
Partial seizure activity while the person is alert.
What is a complex seizure?
Partial seizure activity with a change in awareness.
What is secondary generalisation?
Seizure begins as partial but spreads to generalised.
What is an absence seizure?
Staring and blinking without falling. No awareness of surroundings.
What is a myotonic seizure?
Jerking movements of the body. No awareness of surroundings.
What is a tonic-clonic seizure?
Stiffening, falling and jerking of the body. No awareness of surroundings.
What is a tonic seizure?
Stiffening and falling. No awareness of surroundings.
What is an atonic seizure?
Falling heavily to the ground. No awareness of surroundings.
What will the manifestation of a temporal lobe partial seizure be?
- Strange smell or taste
- Altered behaviour
- Deja vu
- Lip smacking or chewing movements
What will the manifestation of a frontal lobe partial seizure be?
- Anterior - Adverse seizures (eyes or head both turn to one side)
- Posterior - Jacksonian seizure (tingling feeling in hand or arm)
What will the manifestation of a parietal lobe partial seizure be?
Tingling in or jerking of leg, arm, face.
What will the manifestation of an occipital lobe partial seizure be?
Flashing lights or spots, vomiting.
What is electroencephalography?
By placing electrodes on the scalp, a series of electrical impulses originating in the brain are amplified and summed into waves (Spike-wave discharges) that can be monitored and analyzed.
What is status epilepticus?
Status epilepticus (SE) is a life-threatening condition in which the brain is in a state of persistent seizure
More than 30 mins continuous seizure activity OR
Two or more sequential seizures spanning this period without full recovery between seizures
Why is status epilepticus a medical emergency?
- the longer a seizure lasts, the less likely it is to stop on its own
- SE confers greater risk for future unprovoked seizures
What is the definition of epilepsy?
Epilepsy can then be defined as a condition in which seizures recur, usually spontaneously; a single seizure episode is not considered as epilepsy, i.e. 2 or more unprovoked seizures
What are the basic mechanisms underlying seizures?
- Excitation (too much)
- Ionic—Na+, Ca2+ influx
- Neurotransmitter—glutamate, aspartate release
- Inhibition (too little)
- Ionic—CI- influx, K+ efflux
- Neurotransmitter—GABA release
What is the function of inhibitory interneurones?
- Allow activity to spread in one direction, but not to spread out sideways
- They release the inhibitory neurotransmitter GABA
What might be the pathophysiology underlying epilepsy?
- The initially localized hyperexcitability spreads into surrounding neuronal networks
- it might be either counterbalanced by inhibitory mechanisms
- or, after involving more and more neurones, cause a clinically visible seizure
What is GABA?
- GABA (g-aminobutyric acid)
- Major inhibitory neurotransmitter
- Found at ~30% of synapses
- Acts via GABA-A or GABA-B receptors
What types of epilepsies are caused by GABA-A mutations?
- CAE (childhood absence epilepsy)
- FS (pure febrile seizures)
- GEFS+ (generalized epilepsy with febrile seizures plus)
- JME (juvenile myoclonic epilepsy)
- DS (Dravet syndrome – also know as SMEI (severe myoclonic epilepsy in infancy))
What is the significance of the Gabrg2(Q390X) mutation?
The mutant γ2(Q390X) subunit had more hydrophilic surface area than the wild-type subunit, thereby changing the subunit from a transmembrane protein to a globular cytosolic protein.
What is a post-status epilepticus model.
A single episode of status epilepticus is used to incite epileptogenesis
An episode of self-sustained SE is induced in previously healthy animals, e.g. an intraperitoneal (IP) injection of the pro-convulsant drug pilocarpine, a non-selective muscarinic receptor agonist
What are the results of the post-SE model?
- GABAR α1 subunit mRNA expression decreases and α4 subunit mRNA expression increases in dentate granule cells of the hippocampus
- Decrease in α1 and increase in α4 subunit protein abundance of γ2-containing GABAARs after pilocarpine-induced SE
- Conclusion: SE alters the abundance of α1 and α4 subunits in γ2-containing GABAARs in dentate granule cells
What is the relevance of the results of the post-SE model?
- The change in receptor subtype from α1βγ2 to α4βγ2 may have dramatic effects on brain inhibition
- α4 containing GABARs have been shown to desensitize rapidly, especially when assembled with β3 subunits
What are the possible modes of action of
1. Suppress action potential:
Sodium channel blocker or modulator
Potassium channel opener
2. Enhance GABA transmission:
GABA uptake inhibitor
3. Suppression of excitatory transmission:
Glutamate receptor antagonist
What are the categories of anticonvulsants?
- Enhancement of GABAergic transmission
- Inhibition of Na+ channels
- Mixed actions
- Combination of some or all of the above and also inhibiting neurotransmitter release
What are the various methods of enhancing GABAergic transmission.
- Enhance action of GABAA receptors with barbiturates e.g. phenobarbital
- Enhance action of GABAA receptors with benzodiazepines e.g. clonazepam
- Inhibit GABA transaminase - vigabatrin
- Inhibit GABA uptake - tiagabine
What is the mechnism of action for benzodiazepines?
- Increase affinity of GABA for its receptor
- Increases Cl- current (opening frequency)
- Suppresses seizure focus by raising action potential threshold
- Strengthens surround inhibition – prevents spread
What is the mechanisms of action for phenytoin?
Phenytoin binds to the inactivated state and slows down its recovery
What is the mechanism of action for valproate?
- Inhibits Na+ channels but weaker than phenytoin
- Decreased GABA turnover
- May lead to increased synaptic GABA levels
Blocks neurotransmitter release by blocking T-type Ca2+ channels
What is foetal hyantoin syndrome?
- intrauterine growth restriction with microcephaly
- minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges (birth defects)
- a smaller population will have growth problems and developmental delay, or mental retardation
- heart defects and cleft lip may also be featured
What is foetal valproate syndrome?
- There is a 6-9% risk of congenital malformations in infants exposed to VPA prenatally, compared to 2-3% in the general population
What percentage of people with epilepsy are seizure free on medication?
- 70% seizure free with one drug
With careful monitoring and adjustment
- 5% to 10% seizure free with two or more drugs
- 20% still have seizures (refractory epilepsy)