Epilepsy Flashcards
What are seizures?
Clinical manifestation of an abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex (ie. excessive neuronal firing)
Why do convulsions occur?
The cortical discharges from the excessive neuronal activity of the seizures can be transmitted to the muscles causing twitches or convulsions
Do seizures always manifest in the same way?
No, epileptic seizures manifest in different ways depending on their site of origin
What are the 3 main classifications of seizures - what does each refer to?
Based on the origin and spread of activity
1) Generalised - with initial activation of neurons throughout both hemispheres
2) Partial - with initial activation of a limited number of neurons in a part of one hemisphere
3) Secondary generalised - a partial seizure that later spreads to involve the majority of the 2 cerebral hemispheres
What is a myoclonic seizure?
Jerking movements of the body
What is a tonic-clonic seizure?
Stiffening, falling and jerking of the body
What is an atonic seizure?
Falling heavily to the ground
What is an absence seizure?
Staring and blinking without falling
What are the 5 sub-types of generalised seizure?
1) Absence
2) Myoclonic
3) Tonic-clonic
4) Tonic
5) Atonic
What are the types of partial seizures - what does each refer to?
1) Simple - seizure activity whilst the person is alert
2) Complex - Seizure activity with change in awareness of surroundings
3) With secondary generalisation - seizure activity begins in one area and spreads
What is the manifestation of a partial seizure originating in the parietal lobe?
Tingling in or jerking of arm, leg and face
What is the manifestation of a partial seizure originating in the frontal lobe?
Jacksonian seizure (tingling feeling in the hand or arm)
What is the manifestation of a seizure beginning in the frontal lobe?
Adversive seizures - eyes or head both turn to one side
What is the manifestation of a seizure beginning in the occipital lobe?
Flashing lights or spots, vomiting
What is the manifestation of a seizure originating in the temporal lobe?
Strange smell or taste, altered behaviour, de ja vu, lip smacking or chewing movements
What does electroencephalography (EEG) do?
Scalp electrodes record the electrical activity along the scalp produced by the firing of neurones within the brain - this converts the electrical impulses into waves (Spike-wave discharges) which can be monitored and analyzed
What is the difference in appearance of a partial and generalized seizure on EEG?
Partial - only half of the electrodes show the amplified waves of excessive activity
Generalised - all of the electrodes show the amplified waves of excessive activity
What is status epilepticus?
Life threatening condition in which the brain is in a state of persistent seizure - more than 30 mins continuous seizure activity or 2 or more sequential seizures spanning this period without full recovery between seizures
Why is status epilepticus a medical emergency?
Its a medical emergency because the longer the seizure lasts, the less likely it is to stop on its own. SE confers greater risk for future unprovoked seizures
How is epilepsy defined?
Epilepsy can be defined as a condition in which seizures recur, usually spontaneously; a single seizure episode is not considered as epilepsy - ie. need 2 or more unprovoked seizure
What are the 2 basic mechanism underlying seizures?
1) Excitation (too much)
- Ionic - Na+, Ca2+ influx
- Neurotransmitter - glutamate, aspartate release
2) Inhibition (too little)
- Ionic - Cl- influx, K+ efflux
-Neurotransmitter - GABA release
Either situation can result in too much neuronal activity and cause a seizure
What neurons are involved in preventing seizures physiologically, how?
Inhibitory interneurons - allow activity to spread in one direction, but not to spread out sideways
They do so by releasing the inhibitory neurone GABA
How are interneurones involved in the manifestation of a seizure?
Have initial localized hyperexcitability which spreads into surrounding neuronal networks - this may be counterbalanced by inhibitory mechanisms or, after involving more and more neurones, can cause a clinically visible seizure
What is GABA, where is it found?
Major inhibitory neurotransmitter - found at ~30% of synapses
What are the 2 GABA receptors and what kinds are they?
GABAa - ligand-gated chloride channel receptor
GABAb - G protein-coupled receptor
What is the structure of GABAa receptor?
Pentameric - typical in vivo subunit composition is 2 alpha, 2 beta and 1 gamma or delta subunit
How can GABAa receptor structure affect drug therapies?
GABAR subunit composition determines the intrinsic properties of each channel - different subunits have different affinities for different drugs
What are the 5 currently known epilepsies caused by GABAa receptor mutations?
1) CAE - childhood absence epilepsy
2) FS - pure fibrile seizures
3) GEFS+ - generalised seizures with febrile seizures plus
4) JME - juvenile myoclonic epilepsy
5) DS - dravet syndrome (also known as SMEI - severe myoclonic epilepsy in infancy)
How many transmembrane domains does each GABA receptor subunit have?
4
The mutation GABRG2(Q390X) is found in what epilepsy syndrome?
Dravet syndrome
Which subunit is mutated in Dravet syndrome - what does the mutation cause?
Gamma 2 - get a change from a transmembrane protein to a globular cytosolic protein
What have animal models shown as to why an episode of status epilepticus can lead to the development of epilepsy?
1) Status epilepticus alters the abundance of alpha 1 and alpha 4 sub units in gamma2-containing GABAa receptors in dentate granule cells - reduction in alpha 1 and increase in alpha 4
2) Alpha 4 containing GABAa receptors have been shown to desensitize rapidly, especially when assemble with beta 3 subunits - thus higher chance of seizures
How have animal models showed that epileptogenesis following status epilepticus may be able to be prevented using gene therapy?
Modulation of GABAa receptor subunit composition by gene transfer - ie. use of a viral vector containing the alpha 1 subunit thereby increasing alpha 1 subunit expression
What is an antiepileptic drug?
A drug which decreases the frequency and/or severity of seizures in people with epilepsy - treats the symptoms of seizures, not the underlying epileptic condition
Why is correct classification of the seizures important in therapy?
Correct classification of seizures leads to correct anti-epileptic drug selection
What are the 3 modes of action of anti-epileptic drugs?
1) Suppress action potential: sodium channel blocker or modulator, potassium channel opener
2) Enhance GABA transmission: GABA uptake inhibitor, GABA mimetics
3) Suppression of excitatory transmission: glutamate receptor antagonist
What are the 3 categories of anti-convulsants and what are they based on?
Based on main mechanisms of action
1) Enhancement of GABAnergic transmission
2) Inhibition of Na+ channels
3) Mixed actions - combination of some or all of the above and also inhibiting neurotransmitter release
In partial simple and partial complex seizures what are the 3 drugs of choice?
1) Carbamazepine
2) Phenytoin
3) Valproic acid
In generalised tonic clonic seizures what are the 3 drugs of choice?
1) Carbamazepine
2) Phenytoin
3) Valproic acid
In absence seizures what are the 2 drugs of choice?
1) Ethosuximide
2) Valproic acid
In atypical absence, atonic and myoclonic seizures what is the drug of choice?
Valproic acid
In febrile seizures what is the drug of choice and how should it be given?
Diazepam, rectal
What are febrile seizures?
Child has a fit due to raised temperature
What 2 types of anti-epileptics enhance the action of GABAa receptors?
1) Barbiturates - phenobarbital
2) Benzodiazepines - clonazepam
What anti-epileptic drug acts by inhibiting GABA transaminase?
Vigabatrin
What anti-epileptic drug inhibits GABA uptake?
Tiagabine
What kind of receptor is the GABAa receptor, is it inhibitory or excitatory?
Ligand gated chloride channel
Inhibitory
What is the mechanism of action of benzodiazepines?
Increase affinity of GABA for its receptor thus increasing the Cl- current, suppresses seizure focus by raising action potential threshold - this strengthens surround inhibition and prevents spread
What are the 3 possible side effects of benzodiazepines?
1) Main unwanted effect = sedation
2) Significant problem of tolerance and dependence (avoid long term use)
3) Can get respiratory depression if used IV
What is the mechanism of action of phenytoin?
- During an action potential the voltage-dependent Na+ channel exists in 3 stages:
1) Closed - before activation
2) Open - during depolarisation
3) Inactivated - shortly after the peak of depolarisation - Na+ channels do not recover from the inactivated state until the membrane has repolarised
- Phenytoin binds to the inactivated state and slows down its recovery
Why is valproate an unusual anti-epileptic?
Not related chemically to the other classes of anti-epileptics
Unusual in that it is effective against both tonic-clonic and absence
In addition to epilepsy, what other condition can valproate be used to treat?
Bipolar depressive illness
How is valproate taken?
Orally - as is well absorbed
What is the mechanism of action of valproate?
- Has more than one mechanism
- Inhibits Na+ channels but weaker than phenytoin
- Decreases GABA turnover - inhibition of succinic semialdehyde dehydrogenase and thereby indirectly inhibiting GABA transaminase, may lead to increased synaptic GABA levels
- Blocks neurotransmitter release by blocking T-type Ca2+ channels
What type of AEDs are Clonazepam, Clorazepate, Diazepam (Valium) and lorazepam?
Benzodiazepines
The AEDs Phenytoin, Carbamazepine and oxcarbamazepine and Lamotigine act in what way?
Inhibition of Na+ channels
Which 3 AEDs have mixed action?
1) Gabapentin
2) Valproate (valproic acid)
3) Levetiracetam
Why is it important to use AEDs in epileptic pregnant women, how should this be done?
- Seizures are very harmful for pregnant women
- Monotherapy is better than drug combination
- Folic acid is recommended to be given for every pregnant woman with epilepsy
Which 2 AEDs are contra-indicated in pregnancy?
1) Phenytoin
2) Valproic acid
Which AED is a better alternative to carbamazepine in pregnant women?
Oxcarbamazepine
What is foetal hydantoin syndrome?
A group of defects caused to the developing foetus by the tetratogenic effects of phenytoin or more rarely carbamazepine. (occurs in up to 30% of children whose mothers take phenytoin during pregnancy)
What are the 7 possible features of foetal hydantoin syndrome?
1) Intrauterine growth restriction with microcephaly
2) Minor dysmorphic craniofacial features
3) Limb defects including hypoplastic nails and distal phalanges
4) Small population have growth problems
5) Small population have developmental delay or mental retardation
6) Heart defects may be featured
7) Cleft lip may be featured
What is foetal valproate syndrome?
Congenital malformations caused in infants exposed to valproate prenatally - risk is 6-9% compared to 2-3% in population - the tetratogenic effects of valproate are known the exact mechanism is however unclear
What percentage of patients with epilepsy are seizure free with one drug?
70%
What percentage of patients with epilepsy are seizure free with 2 or more drugs?
5-10%
What percentage of patients with epilepsy still have seizures despite treatment with AEDs, and what is this called?
10% - refractory epilepsy
What is optogenetic stimulation?
Gene therapy - insert the opsin gene using a viral vector, - produce a protein called halorodhopsin which acts in a similar way to GABAa receptors but is different as its not ligand-gated, it is activated by light
What is epilepsia partialis continua?
Rare type of brain disorder where the patient experiences recurrent motor epileptic seizures that are focal (hands and face), they recur every few seconds or minutes for extended periods (days or years)
What is epilepsia partialis continua caused by?
Large, acute brain lesions resulting from strokes in adults, and focal cortical inflammatory processes in children
Can epilepsia partialis be treated with AEDs?
No, they are very medication and therapy-resistant, the primary therapeutic goal is to stop secondary generalisation
How can epilepsia partialis continua be produced in an animal model?
By injection with tetanus toxin - this decreases neurotransmitter release predominantly affecting GABAergic synapses
This loss of inhibition results in focal seizure activity which progresses over about 3-7 days, after time, the tetanus toxin is cleared but the seizure activity continues
How have animal models shown that optogenetics may be a viable treatment for epilepsia partialis continua?
In animal models seizure activity was suppressed using light activation of the light-activated chloride pump, halorhodopsin, transfected into pyramidal cells in the focus of the seizures
In the animal models what vectors were used to transfect the halorhodopsin gene?
Lentiviral vectors - these are retroviruses which can transfect non-dividing cells
How have animal models shown you can restrict gene expression of halorhodopsin to the appropriate cells in the brain?
By selecting the appropriate gene promoter - Camk2a
