Epilepsy Flashcards
Epilepsy
Neurological disorder that represents a brains state that supports recurrent, unprovoked seizures
–> neurological, cognitive, psychosocial and social consequences
Seizures
Abnormal, paroxysmal changes in electrical activity of brain
–> reflect large scale synchronous discharges of neuronal networks
Epileptogenesis
Process by which normal brain function progresses towards generation of abnormal electrical activity
What proportion of patients are resistant to treatment
1/3rd
Status epilipticus
Form of epilepsy which is a life-threatening medical emergency
Seizure lasts more than 5 minutes or multiple seizures within 5 minutes without regain of consciousness
Tonic-clonic seizures phases
Premonition Pre-tonic-clonic phase Tonic phase Clonic phase Postictal phase
Premonition phase
Vague sense that seizure is imminent
Peculiar smell, sense of doom
Pre-tonic-clonic phase
Few myoclonic jerks or brief clonic seizures
Tonic phase
Tonic contraction of axial musculature
Upward eye deviation and pupillary dilatation
Tonic contraction of limbs
Cyanosis
Resp. muscle contraction Epileptic cry- tonic contraction of jaw muscles
Clonic phase
Jerks of increasing amplitude followed by relaxation
Sphincter opening may occur
Postictal phase
Generalised lethargy
Decreased muscle tone
Headache
Muscle soreness
Diagnosis- clinical history
Occurrence 2 or more seizures
Witness account
Structural changes in epilepsy
Prominent loss of cells in CA2 and CA3 hippocampal areas
Hippocampal analysis
Loss of neurones Distortion + compression of layers Gliosis Different tract organisation Sclerotic hippocampus
Hippocampus + medial temporal lobe
Hippocampal sclerosis
Sprouting of the mossy fibres of granule cell
May lead to reverberant excitatory circuits
Neurogenesis may also occur
Chandelier cells
Special population of interneurones which are GABAergic
Control activity of cortical pyramidal cells
Synapse on axon initial segment (AIS) of pyramidal cells
Chandelier cells in epilepsy
Loss of inhibitory chandelier cells increases risk of abnormal excitatory activity
Conditions/procedures with high risk of developing epilepsy
Craniotomy Traumatic brain injury Stroke Aneurysm Brain tumour Status epilepticus CNS infection
Cellular mechanisms underlying seizure
Abnormal neuronal excitability (ion channels) Decreased inhibition (GABA-dependent) Increased excitation (Glu-dependent)
Paroxysmal depolarising shift
Neurones in epileptic focus burst firing potentials
Particular role of NMDA glutamate receptor
Glial cells
Abnormalities may be involved
Have important role in glutamate transport + clearance through glutamate transporters e.g. EAAT1 and EAAT2
–> don’t clear glutamate
–> glutamate overexcites post-synaptic cell
Dentate gyrus
Within hippocampus
Has granule cell layer
Damaged in epilepsy
Mossy fibres
Axons of dentate cells in hippocampus
Mossy fibre sprouting
Axons of dentate cells in hippocampus develop collaterals that grow into abnormal locations
–> inner 1/3rd of dentate gyrus molecular layer
Epilepsy + Activation of distinct major signalling pathways
mTOR or REST pathway
mTOR –> major regulator of growth + homeostasis
REST –> leads to negative regulation of expression of many genes in CNS
Mutation in SCN1B
Codes for sodium channel
Generalised epilepsy with febrile seizures
More Na+ into cell –> more depolarisation
Mutation in KCN Q2 or 3
Codes for M type potassium channel subunit
More K+ out of cell–> more depolarisation
Benign familial neonatal convulsions
Sodium channel targets
AEDs block voltage gated Na+ channels preferentially in their inactive state
- -> channels become inactive at lower membrane potentials + time taken to return to resting state is delayed
- -> refractory period increased
- -> inhibits sustained repetitive firing
Phenytoin
Anticonvulsant Na channels 0 order kinetics Inducer of hepatic microsomal enzymes Not used in absence seizures
Carbamazepine
Anticonvulsant
Na channels
Inducer of hepatic microsomal enzymes
Not used in absence seizures
Valproate
Na channels
Used in all types of seizures
Topiramate
Na channels
Augmentation of GABAa and inhibition of glutamate AMPA/kainite signalling
Lamotrigine
Na channels
Also activity at Ca channels
Presynaptic inhibition of glutamate release
Zonisamide
Na channels
L-type calcium channels drugs
Mainly expressed post-synaptically, allowing post-depolarisation Ca efflux Phenytoin Carbamazepine Valproate Topiramate
N and P/Q type calcium channels drugs
Expressed pre-synaptically where they mediate Ca entry necessary for neurotransmitter release
Topiramate
Levetiracetam –> selectively inhibits only N type
Lamotrigine
T type calcium channels drugs
Require less depolarisation to be activated
Ethosuximide–> used preferentially in treatment of absence seizures
All Ca channels drugs
AED blocks Alpha 2 Delta subunit on calcium channel
Gabapentin
Pregabalin
GABAa receptor
Activation leads to early rapid component of inhibitory transmission
Receptors are permeable to Cl- ions
As ECF Cl- conc. higher than intracellular conc., opening leads to hyperpolarisation
Benzodiazepines- Clonazepam (sedation)
GABAa receptor
Positive allosteric modulators of the receptors + increase frequency of receptor opening
Barbiturates
GABAa receptor
Positive allosteric modulators of receptor
Cause prolonged opening times + can directly activate channels at high concentrations
Phenobarbitone
Barbiturate
Leads to microsomal enzyme induction
Levetiracetam
Binds to synaptic protein SV2A
Modulates neurotransmitter release
Tiagabine
Increases extracellular levels of GABA by blocking GABA transporter GAT1
Add on therapy in partial seizures
Vigabatrin
Inhibits GABA metabolism by inhibiting GABA transaminase
–> stops it getting broken down
Perampanel
Selective non-competitive agonist of AMPA receptors
Felbamate
Inhibits NMDA receptors + possible GABAa receptors
Focal seizure
Carbamazepine
Lamotrigine
Valproate
Tonic-clonic seizure
Carbamazepine
Lamotrigine
Valproate
Absence seizure
Ethosuximide
Valproate
Myoclonic seizure
Valproate
Clonazepam
Levetiracetam
Other epilepsy treatments
Vagal nerve stimulation
DBS
Ketogenic diet (high fat and low carbs)
