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Lect 14: Epilepsy (Classification of epilepsies (Partial -> focal &…
Lect 14: Epilepsy
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Defn: J.Hughlings-Jackoson (1873) occasional, sudden, excessive, rapid & local discharges of grey matter
- Sudden, xs high freq neuronal discharge
- Discharges x random but highly synched
- Essentially disorder of cerebral cortex
- Involve loss of consciousness
- Behavioural changes related to discharge site -> clinical pov -> what part of brain gen seizures
Synaptic balance
- Intrinsic excitability & also in terms of connections bet brain cells
- Excitation (pre-synaptic terminal -> glutamate released acts on postsynaptic neuron on ionotropic glutamate receptors -> cause depolarisation -> excitatory post synaptic potential (EPSP)
- Other side Inhibition -> inhibitory pre-synaptic terminal -> GABA main NT -> released and acting on post-synaptic GABAA receptors -> hyperpolarised -> take cell away from resting membrane potential inhibitory post synaptic potential (IPSP)
Epilepsy
- Dynamic balance in cortical networks
- Excitation controlled by inhibition
- At level of cell membrane
- At level of integrated neuronal network
- Normal processing dep on dynamic alterations
- Xs changes in any direction -> cause pathological synchronisation
Facts & figures
- Children & elderly susceptible
- Seizure not epilepsy
- Pharmacoresistant -> neurosurgery
Causes
- 70% idiopathic/cryptogenic
- Genetic -> rare familial disorders
- Congenital -> structural abnormalities
- Birth trauma -> ischaemia
- Neurological -> elderly
- Head trauma -> penetrating/non-penetrating
- Metabolic -> glucose/electrolyte imbalance
- Disease -> meningitis, cancer
Recording epilepsy
- Electro-EncephaloGraphy (EEG)
- Non-invasive technique -> electrodes on scalp -> record sync electric activity gen by neurons within brain measured
- Gold standard
- Electrode fixed to scalp -> connects to an amplifier as the changes in neurons must get thru think layer of tissue (scalp, skull, dura arachnoid, subarachnoid space)
- Unsynch brain -> normal brain
- Summit -> low amplitude background noise
- Sync activity
- large synced summit activity -> pathological scenario
- Human Epileptic EEG
- Left temporal lobe seizure
- Rapidly synced discharges
- Tonic phase
- Pathological activity propagates & generalises across brain
- Clonic phase
- Generalised but slightly different
- Post-ictal phase
- X synched but activity is quiet -> patient at confused state
Neuron -> intrinsic excitability -> excited due to ionic conductance within membrane
- Na+ & Ca2+ (into cell) (destabilising: promote excitation) & Cl- (into cell) & K+ (out) (promote hyperpolarisation of cell membrane)
- Low threshold Ca-currents (IT) in pyramidal neurons
- IT activated during membrane depolarisation from rest
- Underlies burst mode firing in pyramidal neurons
- Blocked by voltage gated Ca channel blockers
- IT increased in epilepsy
- Dendritic IH in epilepsy
- IH -> mixed Na/K current
- Helps to set membrane potential around -70mV (resting membrane potential) if -60 -> more excited -> causing network to be excited
- Limits summation of excitatory synaptic inputs
- Reduction leads to increase in cortical pyramidal cell excitability
- Changes in intrinsic excitability in epilepsy
- IT increased leading to more burst mode firing (pathological activity) & lowered threshold
- IH decreased leading to greater summation of excitatory inputs
- Polymorph causing mutations in Na channel subunits, K channels & voltage gated Ca & Cl channels
Excitatory cortical synapses
- Excitatory cortical neurone -> receives Excitatory glutamate input (afferent axons onto dendrites) -> release glutamate -> 2 types of post synaptic glutamatergic receptors activated -> acting on AMPA which mediates fast excitatory neurotransmission & NMDA receptors which gives slower amplitude
- Inhibitory interneuron -> provide inhibitory synaptic connection onto excitatory pyramidal cell -> getting excitatory input which helps drive cell
- When GABA is released onto dendrite -> acting on post synaptic GABA receptors -> GABAA (fast response) & GABAB (slow)
Intrinsic excitability (Ability of neuron to control excitation) & Synaptic balance (neurons communication with each other)
Network interactions (diff types of cells -> inhibitory interneurons -> provide inhibition onto pyramidal cell but in turn they provide excitation on inhibitory interneurons
- Epilpesy seen on a network level
- Changes in intrinsic level + synaptic level -> alter network func
Temporal overlap of inhibition & excitation
- Changes in dynamics -> network synaptic response -> becomes pathological
Within cortical networks
- Pyramidal neurons excited by glutamate inputs
- Pyramidal neurons excite interneurons
- Interneurons inhibit pyramidal cells
- Pyramidal neurons can excite each other
- Loss of inhibition result in increased excitation
- Increased excitation can override inhibition
Deafferentation induced axon sprouting
- In epilepsy -> lose some afferent axons -> axonal sprouting -> aberrant -> x connecting to each other in right manner
- Esclapez et al (1999) -> increased glutamate release in epileptic animals
- Basal dendrites lost
- Main difference -> More extensive in axons aberrant axonal sprouting
- Dynamic balance shifted towards excitation
Dormant inhibitory neurone hypothesis
- Cell x longer driven -> x able to inhibit excitatory cell -> network compensates by increased excitation
- Hirsch et all (1999) -> decreased GABA release in epileptic animals
Summary
- Loss of excitatory drive result in increased reciprocal excitation in pyramidal cells
- Loss of excitatory drive causes decreased inhibition in pyramidal cells
- Combination can lead to abnormal synchrony
- Effects compounded by increased destabilising/loss of intrinsic stabilising currents
- Other evidence suggests changes in receptor efficacy e.g. increased NMDA receptor activity, compromised GABAA receptors