Epilepsy (15) Flashcards
Seizures
Abnormally excessive and hyper synchronous activity of neurones located predominantly in cerebral cortex
Twitches/convulsions
Cortical discharges transmitted to muscles
Classification of seizures
- Generalised
- Partial
- Secondary generalised
Generalised
Initial activation of neurones throughout both hemispheres (tonic clonic/clonic/atonic)
Partial
Initial activation of a limited number of neurones in a part of 1 hemisphere (absence/myoclonic/simple/complex)
Secondary generalised
Partial seizure that later spread to involve majority of 2 cerebral hemispheres
Manifestation of partial seizure in parietal lobe
Tingling/jerking in leg, arm, face
Manifestation of partial seizure in occipital lobe
Flashing lights/spots, vomiting
Manifestation of partial seizure in temporal lobe
Strange smell or taste, altered behaviour, deja vu, lip smacking/chewing movements
Manifestation of partial seizure in frontal lobe
- Adversive seizures (Eyes/head both turn to one side)
- Jacksonian seizure (tingling feeling in hand/arm)
EEG
Electroencephalogram
EEG uses
Scalp electrodes to record electrical activity along scalp - firing of neurones within brain, series of electrical impulses originating in brain are amplified and summed into waves (Spike-wave discharges)
Status epliepticus
State of persistent seizure, more than 30 mins/2+ without full recovery
Why is SE a medical emergency?
The longer a seizure lasts, less likely it will stop on its own and more likely to reoccur in future
Treatment for SE
GABAa receptor agonist e.g. diazepam
Epilepsy
2 or more unprovoked seizures
Mechanisms underlying seziures
Excitation or inhibition > too much neuronal activity > seizure
Excitation (too much)
Ionic - Na+, Ca2+ influx, neurotransmitter - glutamate, aspartate release
Inhibition (too little)
Ionic - Cl-influx, K+ efflux
neurotransmitter GABA release
Inhibitory interneurones
Allow activity to spread in one direction but not sideways, release inhibitor neurotransmitter GABA
GABA
Major inhibitory neurotransmitter, found at 30% of synapses, acts via GABAa or GABAb
GABAa
Ligand-gated chloride channel receptor
GABAb
G protein-coupled receptor
What determines intrinsic properties of each channel
GABAR subunit
Types of epilepsies caused by mutation in GABAa receptor subunits
- Childhood absence epilepsy (CAE)
- FS (pure febrile seizures)
- GEFS+ (generalised epilepsy with febrile seizures plus)
- JME (juvenile myoclonic epilepsy)
- DS (Dravet syndrome - SMEI severe myoclonic epilepsy in infancy)
Dravet syndrome associated with which mutation
GABRG2(Q390X) > loss of 78 C-terminal aa (changes it from transmembrane protein to a globular cytosolic protein)
Febrile seizures
Associated with fever
Tonic-clonic/grand mal
Generalised
Myoclonic seizure
Involuntary twitching of a muscle/group of muscles
Absence seizure
Lapses of awareness, staring, last only a few seconds, common in children
Complex partial seizure
Feeling deja vu, fear, euphoria/depersonalization
Tonic seizure
Tone is greatly increased, arms/legs sudden stiff movements, during sleep usually involved most/all of brain
Post-status epileptics animal models single episode of status epileptics is used to incite
Epilpetogenesis (via pilocarpine)
Pilocarpine is a
Pro-convulsant drug, non-selective muscarinic receptor agonist
Purpose of anti epileptic drugs
Decreases frequency and/or severity of seizures in people with epilepsy, treats symptom of seizures not underlying epileptic condition
Modes of action of anti-epileptic drugs
- Suppress action potential
- Enhance GABA transmission
- Suppression of excitatory transmission
Suppress action potential using
Sodium channel blocker/modulator, potassium channel opener
Enhance GABA transmission
GABA uptake inhibitor, GABA mimetics
Suppression of excitatory transmission
Glutamate receptor antagonist
Main mechanisms of action
- Enhancement of GABAergic transmission
- Inhibition of Na+ channels
- Mixed actions
Anti epileptics for partial simple and complex seizures
Carbamazepine, phenytoin, valproic acid
Anti epileptics for Generalised tonic clonic
Carbamazepine, phenytoin, valproic acid
Anti epileptics for Absence seizures
Ethosuximide, valproic acid
Anti epileptics for Atypical absence, atonic, myoclonic seizures
Valproic acid
Anti epileptics for Febrile seizures
Diazepam, rectal
Enhancing GABAergic transmission
- Enhance action of GABAa receptors with barbiturates (phenobarbital)/benzodiazepines (clonazepam)
- Inhibit GABA transaminase (vigabatrin)
- Inhibit GABA uptake (tiagabine)
Benzodiazepines
- Clonazepam
- Clorazepate
- Diazepam (valium) and Iorazepam
Clonazepam effective against
Generalised tonic-clonic, absence and partial seizures
Clorazepate effective against
Partial seizures (used with other drugs)
Diazepam (valium) and lorazepam effective against
Status epilepticus when give IV
Mechanism of action of benzodiazepines
Increase affinity of GABA for its receptor (increases Cl- current, supresses seizure focus by raising action potential threshold, strengthens surround inhibition - prevents spread)
Problems with benzodiazepines
Sedation, tolerance and dependence, respiratory depression (iv)
Inhibition of Na channels
Phenytoin, Carbamazepine and oxcarbamazepine, Lamotrigine
Phenytoin
- During an action potential voltage-dependent Na channel (closed, open, inactivated)
- Na channels don’t recover from inactivated state until membrane has repolarised
- Binds to inactivated state and slows down its recovery
Mixed actions
Gabapentin, Valproate, Levetiracetam
Valproate effective for?
Tonic-clonic and absence (bipolar)
How is valproate taken?
Orally, well absorbed
Mechanism of action of valproate
- Inhibits Na channels
- Decreased GABA turnover (inhibition of succinic semialdehyde dehydrogenase - inhibit GABA transaminase, increased synaptic GABA)
- Blocks neurotransmitter release by blocking Ca2+ channels
Antiepileptics and pregnancy
Monotherapy, folic acid recommended, Phenytoin and Valporate not allowed, oxcarbamazepine
Foetal hydantoin syndrome caused by
Taking phenytoin (sometimes carbamazepine)
Foetal hydantoin syndrome symptoms
Intrauterine growth restriction with microcephaly, dysmorphic craniofacial features and limb defect (hypoplastic nails and distal phalanges), growth problems and developmental delay, heart defects and cleft lip
Foetal valproate syndrome (FVS)
6-9% risk of congenital defects
Optogenic stimulation used for
Partial seizures, use of halorhodopsin similar to GABAa hyperpolarise the neurone in reaction to yellow light
Epilespia partialis continua
Rare, recurrent motor epileptic seizures that are focal (hands and face)
Epilespia partialis continua caused by
Large, acute brain lesions from strokes
Treatment for Epilespia partialis continua
Medication and therapy-resistant, stop secondary generalisation
