Lecture 29; Epilepsy Flashcards
What essentially is epilepsy?
An imbalance between excitation and inhibition
Very simplistic overview.
What is the hallmark characteristic of epilepsy?
Abnormal, excessive electrical discharge from neurones (hypersynchronized discharge from the brain)
Often associated with Loss of Consciousness
But
Does not always produce Loss of Consciousness
Not all Loss of Consciousness due to epilepsy (people who faint can jerk a bit)
What is epilepsy a symptom of?
Epilepsy is a symptom of brain dysfunction
What are the possible causes of epilepsy?
Syndrome with many possible causes;
structural
genetic
metabolic / functional
Define why epileptic seizures occur
Seizures occur as a result of abnormal synchronous activation of large numbers of hyperexcitableneurons which are connected in networks
What pathways typically are seizure forming?
epiltogenesis
Seizures may be propagated via both normal and abnormal pathways
Seizures spread through synaptic and non synaptic pathways
- gap junctions (Bipasses synapses)
Everyone has neuronal circuitry that can generate seizures(ECT, Drugs)
How many people have epilepsy and how does this differ from epilepsy?
0.5 –1 % of the population has epilepsy.
1 in 20 people will have a seizure at some time in their life.
Epilepsy is as a tendency to recurrent seizures.
What are the two broad categories of electroclinical seizures?
Focal and Generalised
Define focal seizures;
Focal
partial part of the brain
manifestations depend on which part of brain involved
Describe generalised seizures;
generalised
Networks involving extensive regions of both hemispheres
Manifestations vary greatly
What is the main functional test for seizures?
EEG
What is EEG and what does it show?
An EEG is a 30 minute recording from 21 electrodes placed in standard positions on the scalp.
A single EEG will show epileptiform activity in 29-70% of patients with proven epilepsy.
Sensitivity improved by recordings during sleep.
Incidental epileptiform abnormalities are found in 0.5% of healthy young adults
What does EEG identify?
EEG is important in identifying the seizure type and hence the correct seizure syndrome for an individual patient
Describe what types of conscious focal seizures there are?
Consciousness may be preserved (Simple Partial)
Focal motor Visual Somatosensory Auditory Psychic
What may lead to an impaired consciousness seizure?
Consciousness may be impaired
Complex partial - (aka) Dyscognitive
Patient is unresponsive with subsequent amnesia
What sorts of brain lesions can be associated with focal seizures?
Cavernous Angionma
Focal Cortical Dysplasia
Hippocampal Sclerosis
Subependymall Hetrotopia
What does GABA transmission do and what drugs allosterically bind to it / treat epilepsy?
x2 GABA bind - Cl in hyperpolarises
Allosteric binding sites for Benzodiazepines and Barbiturates (antiepileptic drugs)
Are ion channels permanent?
No, they are all very plastic.
Ion channels demonstrate frequency dependent changes in synaptic efficiency
Excitatory synapses are potentiated when fire repetitively Inhibitory synapses decrease in efficacy when fire repetitively
NMDA LTP may be involved in long term chronic seizures.
What does mutations in K channels lead to?
Mutations in voltage gated K channels
Benign familial neonatal epilepsy (children grow out of them)
2 different K channel mutations
What can mutations in Na channels lead to?
Severe Myoclonic Epilepsy of Infancy (Dravet’sSyndrome) SCN1A
Benign familial Neonatal Epilepsy SCN2A
Generalised Epilepsy with Febrile Seizures plusSCN1A SCN1B SCN2A
Early onset absence seizures SCN1B
Genotype doesnt have consistent phenotype.
What causes absence epilepsy?
Absence seizures and Ca++ channelsAbsence seizures due to abnormal activation of T-type calcium channels in the thalamus
Hyperpolarisation of thalamic relay neurones produces synchronous depolarisation of the cortex via excitatory neurones
GAERS rats –mutations of T-type calcium channel
What are the possible mutations in ligand gated ion channels?
AutosomalDominant Nocturnal Frontal Lobe Epilepsy Mutation of Nicotinic AChreceptor
Generalised Epilepsy with Febrile Seizures plus Mutation of GABAa receptor
Angelman’s syndrome
- Deletion of part of Chr15 -contains genes for several GABAareceptor subunits
What does surgery on epileptics show?
Surgically resected temporal lobe specimens show changes in the ratio and function of Na channels
What do epileptic animal models show in terms of changes in brain structure?
Overexpression of low threshold Ca currents in thalamic neurones in rats produces model of human absence epilepsydensity, distribution, molecular structure and function of ion channels is altered after seizures
What can induce seizures?
Blocking Gaba a receptors
Activating glutamate receptors
Blocking some K channels
What drugs block GABAa receptors?
Blockade of GABAa receptors
bicuculline(competitive antagonist)
picrotoxin(non-competitive antagonist),
penicillin –enters open GABA channels and occludes them
What activates glutmate receptors? causing siezures
kainate, domoicacid unblocking of NMDA receptors by low Mg2+
What antiepileptic drugs target Na channels?
Na+ channel blockers –presynaptic
Prevent sustained repetitive firing from extended depolarisation
i.e carbamazepin ephenytoin lamotrigin esodium valproate
What drugs enhance GABA transmission?
vigabatrin tiagabine sodium valproat ebenzodiazepines (diazepam, lorazepam) barbiturates (phenobarbitone) topirimate
What drugs act on Ca channels?
Ethosuxamide
Sodium valproate
What drugs block glutamate?
Topirimate
Lamotrigine
Felbamate
Perampanel (AMPA receptors)
What are some autoantibody induced epileptic syndromes
?
Anti-voltage gated potassium channels (LGI1):
Anti-NMDA receptor
What results from Anti-voltage gated potassium channels (LGI1):?
Limbic encephalitis, (prominent amnesia)Focal (dyscognitive) seizures –complex partial seizuresFacio-brachial dystonicseizuresHyponatraemi
What results from anti-NMDA receptor antibodies?
Psychiatric features
DyskinesiasFocal (dyscognitive) seizures –complex partial seizures
What are the effects of seizures?
Kindling (theory)
Repetitive exposure to (initially) subthreshold electrical stimulation eventually produces spontaneous seizures
Theory that seizures may beget seizures
How do seizures affect the neuronal circuits?
Anatomic rearrangements of local circuits
Excitatory axons have collateral branches feedback inhibition and / or excitationusually inhibition more powerful
With neuronal death, there is sprouting of unlesioned axons occurs to fill in dendritic regions
How do seizures affect the dengate gyrus?
Mossy fibres of granule cells in dentate gyrusinnervate pyramidal cells of CA3 region (inappropriate)
When granule cells die, surviving neurons develop collaterals that form new connections
Form recurrent excitatory connections - alter normal balance between feedback inhibition and excitation
What did they find in sprouting in epilepsy associated with?
Degree of sprouting correlates with number of evoked seizures
Sprouting may occur even in the absence of overt cell death
