Epilepsy Flashcards
What are the 2 different situations which can lead to a seizure?
Excitation (too much):
- ionic - Na+ or Ca2+ influx
- neurotransmitter - glutamate or aspartate release
Inhibition (too little):
- ionic - Cl- influx or K+ efflux
- neurotransmitter - GABA release
either situation can result in too much neuronal activity and cause a seizure
When the brain is working normally, how many brain cells are active?
What is their activity like?
when the brain is working normally, very small numbers of brain cells are active at any given time
the activity is tightly focussed as it flows through successive brain regions and is not allowed to spread out
What is the role of inhibitory interneurones in the brain?
a group of brain cells called inhibitory interneurones allow activity to spread in one direction, but not to spread out sideways
they release the inhibitory neurotransmitter - GABA
What % of neurones in the brain are interneurones?
interneurones represent 10-20% of the total number of neurones
In a seizure, what happens to activity that is controlled by the inhibitory interneurones?
the initially localised hyperexcitability spreads into surrounding neuronal networks
it might be counterbalanced by inhibitory mechanisms
or, after involving more and more neurones, cause a clincially visible seizure
What is GABA?
How does it exert an effect?
gamma-aminobutyric acid
it is a major inhibitory neurotransmitter
it is found at 30% of synpases
it acts via GABAA or GABAB receptors
What is the difference between GABAA and GABAB receptors?
GABAA receptors are ligand-gated chloride channels
GABAB receptors are G protein-coupled receptors
What is the structure of the GABAA receptor protein?
it is pentameric
the typical in vivo subunit composition is two alpha, two beta and one gamma or delta subunit
Why is GABA receptor subunit composition important?
it determines the intrinsic properties of each channel
this also determines the affinity they have for certain drugs / molecules
What are the types of epilepsies caused by mutations in GABAA receptor subunits?
- childhood absence epilepsy (CAE)
- pure febrile seizures (FS)
- generalised epilepsy with febrile seizures plus (GEFS+)
- Dravet syndrome (DS) / severe myoclonic epilepsy in infancy (SMEI)
- juvenile myoclonic epilepsy (JME)
What is the significance of the y2(390X) nonsense mutation?
it has been identified in 2 separate pedigrees with epilepsy, including Dravet syndrome
it produces a truncated subunit with the loss of 78 C-terminal amino acids
What mutation is present in people with Dravet syndrome?
GABRG2 (Q390X) mutation
What types of seizures do people with Dravet syndrome tend to have?
first start with febrile seizures, then tonic-clonic seizures (TCS), myoclonic seizures (MS), absence seizures (AS), complex partial seizures (CPS) and tonic seizures (TS)
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
What is the risk of status epilepticus?
SE is a medical emergency because the longer the seizure lasts, the less likely it is to stop on its own
SE confers a greater risk for future unprovoked seizures
What is the treatment for status epilepticus?
GABAA receptor agonist
What is seen in animals in the post-status epilepticus models?
a single episode of status epilepticus is used to incite epileptogenesis
an episode of self-sustained SE is induced in previously healthy animals using an intraperitoneal injection of the pro-convulsant drug pilocarpine
this is a non-selective muscarinic receptor agonist
How does SE alter the expression of GABA receptor subunits?
SE alters the abundance of a1 and a4 subunits in y2-containing GABAA receptors in dentate granule cells
How may the SE-induced alterations in the expression of GABA receptor subunits affect the brain?
the change in receptor subtype from a1by2 to a4by2 may have dramatic effects on brain inhibition
a4 containing GABA receptors have been shown to desensitise rapidly, especially when assembled with b3 subunits
What is one way that may be used to prevent epileptogenesis after SE?
GABA receptor 1 over-expression
modulation of GABAA receptor subunit composition by gene transfer is one approach that may prevent epileptogenesis
How can GABA receptor over-expression be acheived?
injection to the dentate granule cells of the hippocampus of a viral vector containing the a1 subunit
this increases a1 subunit expression
What was seen in rats with an increased a1 subunit expression?
a1 subunit viral vector-treated rats showed both increased latency time and decreased rates of seizure development
What is meant by epileptogenesis?
the gradual process by which a normal brain develops epilepsy
this is a chronic condition in which seizures occur
What are antiepileptic drugs?
What do they treat?
a drug which decreases the frequency and/or severity of seizures in people with epilepsy
they treat the symptom of seizures and not the underlying epileptic condition
correct classification of seizures leads to correct AED selection
What are the 3 modes of actions of antiepileptic drugs?
- suppress action potential
- enhance GABA transmission
- suppression of excitatory transmission
What types of antiepileptic drugs suppress action potentials?
- sodium channel blocker or modulator
- potassium channel opener
What types of antiepileptic drugs will enhance GABA transmission?
- GABA uptake inhibitor
- GABA mimetics
What type of antiepileptic drug will suppress excitatory transmission?
- glutamate receptor antagonist
What are the main mechanisms of action 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 is meant by a partial seizure?
What are the 2 different types?
in a partial seizure, the electrical disturbance is limited to a specific area of one cerebral hemisphere
partial seizures can be simple or complex
What is the difference between a partial simple and a partial complex seizure?
partial simple:
- consciousness is retained
partial complex:
- consciousness is impaired or lost
they both only affect a single area of the brain
What are the 3 antiepileptic drugs of choice in a partial simple or partial complex seizure?
- carbamazepine
- phenytoin
- valproic acid
What is a “generalised tonic clonic” seizure?
a disturbance in the functioning of both sides of the brain
this disturbance is caused by electrical signals spreading through the brain inappropriately
it produces bilateral, convulsive tonic and clonic muscle contractions
What is meant by tonic and clonic muscle contractions?
tonic seizures:
- involve sudden stiffening and contraction of the muscles
clonic seizures:
- involve rhythmic twitching or jerking of one or several muscles
tonic-clonic seizures are a combination of these 2 types in a specific pattern
What are the 3 antiepileptic drugs of choice in generalised tonic clonic seizures?
- carbamazepine
- phenytoin
- valproic acid
alternatives:
- lamotrigine
- topiramate
- phenobarbital
What is meant by an absence seizure?
absence seizures cause lapses in awareness, sometimes with staring
they are a type of generalised onset seizure, meaning they begin in both sides of the brain at the same time
they begin and end abruptly, lasting only a few seconds
What are the epileptic drugs of choice used to treat absence seizures?
- ethosuximide
- valproic acid
alternatives:
- lamotrigine
- clonazepam
What is an atypical absence seizure?
it has a less abrupt onset and offset of loss of awareness than a typical absence seizure
they tend to last longer (30 seconds)
they are often associated with other features such as loss of muscle tone of the head, trunk or limbs (gradual slump) and subtle myoclonic jerks
Why are atypical absence seizures referred to as “atonic” and “myoclonic”?
atonic:
- this means loss of muscle tone
- in an atonic seizure, a person suddenly loses muscle tone and their head and body becomes limp
myoclonic:
- there is sudden, involuntary jerking of a muscle or group of muscles
What are the antiepileptic drugs of choice in an atypical absence seizure?
- valproic acid
- clonazepam can be used as an alternative
What is a febrile seizure?
a seizure associated with a high body temperature (fever) but without any serious underlying health issue
they commonly occur in children between the ages of 6 months and 5 years
What are the antiepileptic drugs of choice used to treat febrile seizures?
- diazepam - rectal
alternatives:
- diazepam - IV
- valproic acid
What are the 4 methods of enhancing GABA action?
What are examples of antiepileptic drugs that work in these ways?
- 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 arethe major binding sites on the GABAA receptor?
What ion passes through the channel?
What are the 3 main benzodiazepines?
- clonazepam
- clorazepate
- diazepam (valium) and lorazepam
When is clonazepam used?
it is effective in generalised tonic-clonic, absence and partial seizures
When is clorazepate used?
it is effective against partial seizures
it is used in conjunction with other drugs
When is diazepam (valium) used?
it is effective against status epilepticus when given IV
What is the mechanism of action of benzodiazepines?
they increase the affinity of GABA for its receptor
they increase the Cl- current (opening frequency)
they suppress seizure focus by raising action potential threshold
they strengthen surround inhibition to prevent spread
What are the unwanted effects and drawbacks of using benzodiazepines?
- the main unwanted effect is sedation
- significant problem of tolerance and dependence so long-term use is avoided
- if given IV, respiratory depression may result
What are the main antiepileptic drugs that will inhibit Na+ channels?
several of the most frequently used anti-epileptic drugs act in this way:
- phenytoin
- carbamazepine and oxcarbamazepine
- lamotrigine
During an action potential, in what 3 states does the voltage-dependent Na+ channel exist?
- closed - before activation
- open - during depolarisation
- inactivated - shortly after the peak of depolarisation
What is the mechanism of action of phenytoin?
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
What are the 3 main antiepileptic drugs that have mixed actions?
- gabapentin
- valproate (valproic acid)
- levetiracetam
What are the properties of valproate?
What is it used to treat?
it is taken orally and is well-absorbed
it is effective against both tonic-clonic and absence seizures
it can be used in bipolar depressive illness
What are the 3 different mechanisms of action of valproate?
- inhibits Na+ channels - (weaker than phenytoin)
- decreases GABA turnover
- blocks neurotransmitter release by blocking T-type Ca2+ channels
How does valproate decrease GABA turnover?
it inhibits succinic semialdehyde dehydrogenase
this leads to indirect inhibition of GABA transaminase
this may lead to increased synaptic GABA levels
What is the advice given to pregnant women with epilepsy?
seizures are very harmful for pregnant women
every pregnant woman with epilepsy is recommended to be given folic acid
What antiepileptics should and should not be used in pregnancy?
monotherapy is usually better than drug combination
phenytoin and valproic acid are absolutely contraindicated
oxcarbamazepine is better than carbamazepine
What can taking phenytoin during pregnancy lead to?
foetal hydantoin syndrome
which may also include heart defects and cleft lip
What are the features of foetal hydantoin syndrome?
- intrauterine growth restriction with microcephaly
- minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges
- some may have growth problems and developmental delay, or mental retardation
What is the definition of foetal hydantoin syndrome?
a group of defects caused to the developing foetus by exposure to the teratogenic effects of phenytoin, or more rarely, carbamazepine
reports of adverse effects from carbamazepine in pregnancy have been less common
What is the risk associated with foetal valproate syndrome?
6-9% risk of congenital malformations in infants exposed to valproate prenatally, compared to 2-3% in the general population
What % of the population are seizure free with one or two drugs?
70% are seizure free with one drug
5-10% are seizure free with two or more drugs
20% still have seizures - refractory epilepsy
What is meant by refractory epilepsy?
when medicines do not work well, or at all, to control the seizures
What is meant by optogenetics?
a biological technique that involves the use of light to control cells in living tissue
this typically involves neurones that have been genetically modified to express light-sensitive ion channels
What is epilepsia partilais continua?
a rare type of brain disorder
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 usually causes epilepsia partialis continua?
it is usually due to large, acute brain lesions resulting from strokes in adults and focal cortical inflammatory processes in children
What is the therapy goal in epilepsia partialis continua?
the seizures are very medication and therapy-resistant
the primary therapeutic goal is to stop secondary generalisation
What would happen in a rodent model of epilepsia partialis continua when a tetanus toxin is injected into the motor cortex?
- tetanus toxin decreases neurotransmitter release and predominantly affects inhibitory GABAergic synapses
- loss of inhibition results in focal seizure acitivity, which progresses over 3-7 days
- after time, the tetanus toxin is cleared but the seizure activity continues
How was seizure activity suppressed a week after the tetanus toxin injection?
seizure activity was suppressed using light activation of the light-activated chloride-pump, halorhodopsin, transfected into pyramidal cells in the focus
lentiviral vectors are used to transfect pyramidal neurones with halorhodopsin
What are lentiviruses?
retroviruses that can transfect nondividing cells
What happens once the pyramidal neurones have been transfected with halorhodopsin?
by selecting the appropriate gene promoter (Camk2a), it is possible to restrict gene expression to particular subsets of neurones
e.g. pyramidal cells
