Seizures and Epilepsy Flashcards
What is the cause of a seizure?
Excessive and hypersynchronous activity in cerebrocortical neurones
What is epilepsy?
A condition that involves recurring seizures
How many people will experience a seizure in their lifetime?
Approx 9%
What is idiopathic epilepsy?
Epilepsy with no identifiable cause
What is symptomatic epilepsy?
Epilepsy with an identifiable cause
What is cryptogenic epilepsy?
Epilepsy where a cause is suspected but not confirmed
What is a generalised seizure?
A seizure that affects neurones in both cerebral hemispheres
What is a partial seizure?
A seizure that affects neurone in only one hemisphere
What is a secondary generalised seizure?
When a partial seizure which only affects one hemisphere spreads to involve both hemispheres
What is status epilepticus?
When a seizure occurs for more than 30 minutes without complete recovery
What is meant by a simple partial seizure?
A partial seizure where consciousness is retained
What is meant by a complex partial seizure?
A partial seizure where consciousness is impaired
Describe the Montreal procedure
A patient undergoes brain surgery using local anaesthetic. The surgeon stimulates different regions of the cortex to elicit a sensation. Any regions that elicit a sensation that usually precedes a seizure is surgically removed
Which neurones are typically affected during a generalised seizure?
Thalamocortical neurones
What are the symptoms of a generalised seizure?
Bilateral symmetrical muscle contractions and loss of consciousness
What are the types of generalised seizure?
Absence Myoclonic Tonic-clonic Tonic Atonic
What is the most common type of seizure?
Complex partial
How can seizures be diagnosed?
Using electroencephalography to detect the synchronous firing of cortical neurones which reads as large waves
What type of EEG waves are typically seen during a seizure?
Delta waves
What may cause seizures?
Hypoxia in utero Brain injuries Ischaemic or haemorrhagic strokes Infections Tumours Congenital abnormalities
What typically causes genetic epilepsies that follow Mendelian patterns?
Ion channelopathies
What evidence is there to suggest polygenic inheritance of epilepsy?
The majority of people with epilepsy do not have relative with epilepsy, suggesting multiple genes and environmental factors are involved
Describe the excess excitation mechanism of seizure activity
Excessive inward sodium or calcium currents
Excessive release of glutamate or aspartate
Describe the insufficient inhibition mechanism of seizure activity
Excessive inward chloride or potassium currents
Insufficient GABA release
Which neurones typically prevent hyperexcitability?
Inhibitory interneurones
Which neurotransmitter is the main inhibitory neurotransmitter?
GABA
Which channel is mainly involved in seizures?
GABAa chloride ligand channel
How many proteins make up the GABAa receptor?
5 separate proteins
Which subunits make up the GABAa receptor?
Two alpha
Two beta
One gamma
Describe how the Gamma-2 nonsense mutation results in Dravet syndrome
The nonsense mutation results in a premature stop codon which truncates the protein. The truncated protein is more hydrophilic so becomes a cytolic protein rather than a membranal protein, causing a lack of GABA receptors
How is status epilepticus treated?
Diazepam
What is the animal model for status epilepticus?
The animal is injected with pilocarpine which induces SE. 2 weeks post injection, epileptogenesis occurs where spontaneous seizures occur until death
Describe the processes underlying epileptogenesis
Alpha-1 subunit expression decreases
The receptor subtypes may change to ones that desensitise more rapidly resulting in disinhibition
What are the aims of antiepileptic drug treatment?
To suppress action potentials
To enhance GABA transmission
To suppress glutamatergic transmission
Describe the mechanism of barbiturates
Enhance GABAa receptor action
Give an example of a barbiturate
Phenobarbital, thiopental sodium
Describe the mechanism of benzodiazepines
Increases GABA’s affinity for GABAa receptors to increase the chloride current and raise the action potential inhibition
What are the actions of a benzodiazepine?
Sedation, hypnosis, anxiolysis, anticonvulsive, relaxation and amnesia
Give an example of a benzodiazepine
Diazepam, clonazepam, clorazepate, lorazepam
What seizures does clonazepam treat?
Tonic-clonic
Absence
Partial
What seizures does clorazepate treat?
Partial
What seizures does diazepam treat?
Status epilepticus
What seizures does lorazepam treat?
Status epilepticus
Which subunits may be rendered diazepam insensitive?
Alpha2, alpha3 and alpha5
Point mutation which substitutes histidine to arginine
How can a benzodiazepine overdose be treated?
Patient given flumezanil
Why are benzodiazepines preferred over barbiturates?
Barbiturates have a much narrower therapeutic window
When could a dose of benzodiazepines become lethal?
If the drug is taken alongside another depressant drug, such as alcohol, oxycodone or doxylamine
Why is treatment with benzodiazepines not preferred?
Benzodiazepines are addictive and tolerance is common
What is the mechanism of GABA transaminase inhibitors?
They inhibit GABA transaminase to prevent GABA breakdown
Give an example of a GABA transaminase inhibitor
Vigabatrin
Give an example of a GABA reuptake inhibitor
Tiagabine
What is the mechanism of a GABA reuptake inhibitor?
Prevent the reuptake of GABA into the neurone to increase the concentration in the synapse
Describe the mechanism of sodium channel inhibitors?
Inhibit sodium channels to slow recovery and prevent reactivation
Give an example of a sodium channel inhibitor?
Phenytoin, carbamazepine, lamotrigine
When will phenytoin bind to a sodium channel?
Only when it is firing, resulting in use-dependent blockade
How is phenytoin administered?
Orally
Why should phenytoin not be prescribed with an albumin binding drug?
Phenytoin is largely albumin bound
Cotherapy with another albumin binding drug, results in unpredictable concentrations of free phenytoin and hepatic clearance making it difficult to dose
What occurs to the half life of phenytoin as the dose increases?
The half life increases
Why should phenyltoin not be prescribed during pregnancy?
Risk of foetal hydrantoin syndrome
What are the symptoms of foetal hydrantoin syndrome
Microcephaly Dysmorphic craniofacial features Limb defects Developmental delays Heart defects Cleft lip
What is the mechanism of valproic acid?
Inhibits sodium channels and succinic semialdehyde dehydrogenase. The inhibition of SSD indirectly inhibits GABA transminase
Inhibition of T-type calcium channels
What is the risk of taking valproic acid during pregancy?
Foetal valproate syndrome causing congenital malformations
What causes the congenital malformations in foetal valproate syndrome
Inhibition of histone deacetylases which results in hyperacetylation of chromatin and increases gene transcription
What are the drug choices for partial seizures?
Carbamazepine
Phenytoin
Valproic acid
What are the drug choices for tonic clonic seizures?
Carbamazepine
Phenytoin
Valproic acid
What are the drug choices for absence seizures?
Ethosuximide, valproic acid
What is the drug choice for atonic seizures?
Valproic acid
What is the drug choice for myoclonic seizures?
Valproic acid
What is the drug choice for febrile seizures?
Rectal diazepam
Describe how optogenetics may be used experimentally to treat refractory epilepsy?
Halorhodopsins are a light activated chloride channel which cause hyperpolarisation in response to yellow light and can work as a GABA receptor if introduced to neurones
Which epilepsy models have optogenetics been trialled and found to be successful in rodents?
Epilepsia partialis continua
Temporal lobe epilepsy
