Lecture 29; Epilepsy Flashcards by Calum Macindoe

What essentially is epilepsy?

An imbalance between excitation and inhibition

Very simplistic overview.

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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)

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What is epilepsy a symptom of?

Epilepsy is a symptom of brain dysfunction

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What are the possible causes of epilepsy?

Syndrome with many possible causes;
structural
genetic
metabolic / functional

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Define why epileptic seizures occur

Seizures occur as a result of abnormal synchronous activation of large numbers of hyperexcitableneurons which are connected in networks

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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)

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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.

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What are the two broad categories of electroclinical seizures?

Focal and Generalised

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Define focal seizures;

Focal

partial part of the brain

manifestations depend on which part of brain involved

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Describe generalised seizures;

generalised

Networks involving extensive regions of both hemispheres

Manifestations vary greatly

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What is the main functional test for seizures?

EEG

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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

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What does EEG identify?

EEG is important in identifying the seizure type and hence the correct seizure syndrome for an individual patient

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Describe what types of conscious focal seizures there are?

Consciousness may be preserved (Simple Partial)

Focal motor
Visual
Somatosensory
Auditory
Psychic

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What may lead to an impaired consciousness seizure?

Consciousness may be impaired

Complex partial - (aka) Dyscognitive

Patient is unresponsive with subsequent amnesia

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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 plusSCN1A SCN1B SCN2A

Early onset absence seizures SCN1B

Genotype doesnt have consistent phenotype.

What causes absence epilepsy?

Absence seizures and Ca++ channelsAbsence 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 epilepsydensity, 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 ephenytoin lamotrigin esodium valproate ```

What drugs enhance GABA transmission?

``` vigabatrin tiagabine sodium valproat ebenzodiazepines (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 seizuresFacio-brachial dystonicseizuresHyponatraemi

What results from anti-NMDA receptor antibodies?

Psychiatric features | DyskinesiasFocal (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 excitationusually 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