16. Epilepsy and AEDs Flashcards
Define epilepsy
A neurological disorder that represents a brain state that supports recurrent, unprovoked seizures
Has neurobiological, cognitive, psychological and social consequences
What are seizures?
Abnormal, paroxysmal changes in the electrical activity of the brain - they reflect large scale synchronous discharge of neuronal networks
What is epileptogenesis?
The process by which normal brain function progresses towards generation of abnormal electrical activity
Give the classification of the different epileptic seizures (done in more detail in PBL)
Focal seizures:
Simple focal seizures
Complex focal seizures
Generalised seizures: Tonic-clonic Absence Clonic Tonic Atonic Myoclonic
What is meant by ‘status epilepticus’?
This is a (life threatening) medical emergency
This is a form of epilepsy in which seizures last more than 5 minutes - can be 15, 20 minutes and there is no resolution OR might be that there is more than one seizure in 5 minutes
State the general features of a tonic-clonic seizure aka. grand mal seizure
Premonition - vague sense that a seizure is imminent e.g. funny smell, feel sick
Pre-tonic clonic phase - a few myoclonic jerks i.e. few very short jerky movements
Tonic phase - massive contraction, often an epileptic cry is heard as the muscles of the throat becomes strangulated, contraction of the jaw muscles, cyanosis
Clonic phase - Jerks of increasing amplitude followed by relaxation, sphincter opening may occur
Postictal period - generalised lethargy, decreased muscle tone, headaches, muscle soreness, drowsiness, confusion, nausea
What are the outlines for an epilepsy diagnosis?
The patient must have an occurrence of two or more seizures in the past - the patient will generally not recall this and so a witness account of the seizure is essential
Investigations may also be used - EEG, MRI, PET, ECG
What are the cellular mechanisms linked to the the development of epilepsy and causing seizures?
Abnormal neuronal excitability - ion channels
Decreased inhibition of neurones (GABA-dependent)
Increased excitation of neurones (glutamate dependent)
Glial cell abnormalities may also play a role - these have an important role in glutamate transport
What structural changes can the brain undergo due to epilepsy?
Reorganisation of the tissue i.e. the hippocampus in temporal lobe epilepsy - loss of cells and receptors for neurotransmitters
Abnormal sprouting of fibres - when some cells are lost, some of the remaining neurones then sprout and there is the development of abnormal circuits and an abnormal excitation of neurones occurs
Loss of chandelier cells - these are GABAergic - express high levels of GABA transporter GAT-1 - interneurones which control the activity of cortical pyramidal cells - synapse on the AIS (axon initial segment) of pyramidal cells
What is secondary epilepsy?
Where epilepsy is secondary to another event e.g. stroke, brain tumours, infections
This occurs via the process of epileptogenesis - gradual process of development
What is a channelopathy?
This is where voltage gated or ligand gated ion channels undergo structural change due to mutations
This alters their activity and excitability in the brain
Results in changes in e.g. potassium, sodium and calcium channels - alters the potential difference of the neurone
What are the different targets for antiepileptic drugs?
Sodium channels (major target) Calcium channels GABAa receptor Neurotransmitter release Neurotransmitter uptake Neurotransmitter synthesis Neurotransmitter receptors
GO THROUGH THE INDIVIDUAL DRUGS AND THEIR MECHANISM OF ACTION AND THEIR TARGETS - THESE ARE ON THE COLOURED SQUARED PAPERS AS FLASHCARDS - NEED TO KNOW FOR SAQS!!!!
GO THROUGH THE INDIVIDUAL DRUGS AND THEIR MECHANISM OF ACTION AND THEIR TARGETS - THESE ARE ON THE COLOURED SQUARED PAPERS AS FLASHCARDS - NEED TO KNOW FOR SAQS!!!!
Which drugs have an action on hepatic enzymes and what is the consequence of this on their dosage?
Phenytoin and carbamazepine increase the hepatic enzymes
This means that they increase their own metabolism and so you need to up the dosage slightly to compensate for this
What is the imperative treatment for status epilepticus?
Intravenous benzodiazepine
What other non-pharmacological treatment methods are their for epilepsy?
Vagal nerve stimulation
Deep brain stimulation
Surgical - lobe resection, corpus callostomy, functional hemispherectomy
Ketogenic diet
What is an abnormal paroxysmal shift?
This is a wave of depolarisation occurring at the start of a seizure
Neuronal membrane depolarises by about 30-40mV and remains depolarised for a few seconds before returning to normal
This depolarisation results in a burst of action potentials - these are stimulated via the activation of NMDA glutamate receptors
What are the general aims of AEDs?
To increase the neural inhibition or to decrease the neural excitation
What is the action of AEDs at sodium channels?
Na+ channels are normally inactivated - AEDs bind to them to keep them inactive for longer to reduce the excitability of the neurone - do this by causing them to close at a lower membrane potential than normal - an increased refractory period
What is the action of AEDs at GABAa receptors?
Expressed post-synaptically
AEDs causes them to remain open for longer e.g. benzodiazepines and leads to hyperpolarisation of the neurone - reduced excitability
What is the action of AEDs at GABAb receptors?
Activation of these leads to inhibition of adenyl cyclase, VGCA2+ channels and an activation of K+ channels
Presynaptic activation inhibits the release of glutamate at excitatory synapses
What is the action of AEDs at potassium channels?
Influences the resting potential
AEDs have poor effect on these channels
What is the effect of AED usage on pregnancy?
All AEDs are potentially teratogenic but carbamazepine and lamotrigine are perceived to be the safest
BUT coming off of the medication and suffering seizures can also be potentially harmful to the baby
What is the inheritance/genetic basis of epilepsy
Inheritance is polygenic - poorly understood
30% of patients with epilepsy have a patient who also suffered
What is the standard anti-convulsant prescribed or epilepsy?
Carbamazepine
What is the kinetic order of phenytoin?
Zero-order kinetics
Receptor involved in absence seizures
T type calcium channel receptors
Action of pregabalin and gabapentin on epilepsy and mechanism of action
Act to increase extracellular levels of GABA
Bind to the A2O receptors on VG calcium channels
This acts to increase the GABA transporter proteins
Hence, acts to increase extracellular levels of GABA
