Epilepsy

Question 1

Epilepsy

Answer 1

Neurological disorder that represents a brains state that supports recurrent, unprovoked seizures
–> neurological, cognitive, psychosocial and social consequences

Question 2

Seizures

Answer 2

Abnormal, paroxysmal changes in electrical activity of brain

–> reflect large scale synchronous discharges of neuronal networks

Question 3

Epileptogenesis

Answer 3

Process by which normal brain function progresses towards generation of abnormal electrical activity

Question 4

What proportion of patients are resistant to treatment

Answer 4

1/3rd

Question 5

Status epilipticus

Answer 5

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

Question 6

Tonic-clonic seizures phases

Answer 6

Premonition
Pre-tonic-clonic phase
Tonic phase
Clonic phase
Postictal phase

Question 7

Premonition phase

Answer 7

Vague sense that seizure is imminent

Peculiar smell, sense of doom

Question 8

Pre-tonic-clonic phase

Answer 8

Few myoclonic jerks or brief clonic seizures

Question 9

Tonic phase

Answer 9

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

Question 10

Clonic phase

Answer 10

Jerks of increasing amplitude followed by relaxation

Sphincter opening may occur

Question 11

Postictal phase

Answer 11

Generalised lethargy
Decreased muscle tone
Headache
Muscle soreness

Question 12

Diagnosis- clinical history

Answer 12

Occurrence 2 or more seizures

Witness account

Question 13

Structural changes in epilepsy

Answer 13

Prominent loss of cells in CA2 and CA3 hippocampal areas

Question 14

Hippocampal analysis

Answer 14

Loss of neurones
Distortion + compression of layers
Gliosis
Different tract organisation
Sclerotic hippocampus

Question 15

Hippocampus + medial temporal lobe

Answer 15

Hippocampal sclerosis
Sprouting of the mossy fibres of granule cell
May lead to reverberant excitatory circuits
Neurogenesis may also occur

Question 16

Chandelier cells

Answer 16

Special population of interneurones which are GABAergic
Control activity of cortical pyramidal cells
Synapse on axon initial segment (AIS) of pyramidal cells

Question 17

Chandelier cells in epilepsy

Answer 17

Loss of inhibitory chandelier cells increases risk of abnormal excitatory activity

Question 18

Conditions/procedures with high risk of developing epilepsy

Answer 18

Craniotomy
Traumatic brain injury
Stroke
Aneurysm
Brain tumour
Status epilepticus
CNS infection

Question 19

Cellular mechanisms underlying seizure

Answer 19

Abnormal neuronal excitability (ion channels)
Decreased inhibition (GABA-dependent)
Increased excitation (Glu-dependent)

Question 20

Paroxysmal depolarising shift

Answer 20

Neurones in epileptic focus burst firing potentials

Particular role of NMDA glutamate receptor

Question 21

Glial cells

Answer 21

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

Question 22

Dentate gyrus

Answer 22

Within hippocampus
Has granule cell layer
Damaged in epilepsy

Question 23

Mossy fibres

Answer 23

Axons of dentate cells in hippocampus

Question 24

Mossy fibre sprouting

Answer 24

Axons of dentate cells in hippocampus develop collaterals that grow into abnormal locations
–> inner 1/3rd of dentate gyrus molecular layer

Question 25

Epilepsy + Activation of distinct major signalling pathways

Answer 25

mTOR or REST pathway mTOR --> major regulator of growth + homeostasis REST --> leads to negative regulation of expression of many genes in CNS

Question 26

Mutation in SCN1B

Answer 26

Codes for sodium channel Generalised epilepsy with febrile seizures More Na+ into cell --> more depolarisation

Question 27

Mutation in KCN Q2 or 3

Answer 27

Codes for M type potassium channel subunit More K+ out of cell--> more depolarisation Benign familial neonatal convulsions

Question 28

Sodium channel targets

Answer 28

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

Question 29

Phenytoin

Answer 29

``` Anticonvulsant Na channels 0 order kinetics Inducer of hepatic microsomal enzymes Not used in absence seizures ```

Question 30

Carbamazepine

Answer 30

Anticonvulsant Na channels Inducer of hepatic microsomal enzymes Not used in absence seizures

Question 31

Valproate

Answer 31

Na channels | Used in all types of seizures

Question 32

Topiramate

Answer 32

Na channels | Augmentation of GABAa and inhibition of glutamate AMPA/kainite signalling

Question 33

Lamotrigine

Answer 33

Na channels Also activity at Ca channels Presynaptic inhibition of glutamate release

Question 34

Zonisamide

Answer 34

Na channels

Question 35

L-type calcium channels drugs

Answer 35

``` Mainly expressed post-synaptically, allowing post-depolarisation Ca efflux Phenytoin Carbamazepine Valproate Topiramate ```

Question 36

N and P/Q type calcium channels drugs

Answer 36

Expressed pre-synaptically where they mediate Ca entry necessary for neurotransmitter release Topiramate Levetiracetam --> selectively inhibits only N type Lamotrigine

Question 37

T type calcium channels drugs

Answer 37

Require less depolarisation to be activated | Ethosuximide--> used preferentially in treatment of absence seizures

Question 38

All Ca channels drugs

Answer 38

AED blocks Alpha 2 Delta subunit on calcium channel Gabapentin Pregabalin

Question 39

GABAa receptor

Answer 39

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

Question 40

Benzodiazepines- Clonazepam (sedation)

Answer 40

GABAa receptor | Positive allosteric modulators of the receptors + increase frequency of receptor opening

Question 41

Barbiturates

Answer 41

GABAa receptor Positive allosteric modulators of receptor Cause prolonged opening times + can directly activate channels at high concentrations

Question 42

Phenobarbitone

Answer 42

Barbiturate | Leads to microsomal enzyme induction

Question 43

Levetiracetam

Answer 43

Binds to synaptic protein SV2A | Modulates neurotransmitter release

Question 44

Tiagabine

Answer 44

Increases extracellular levels of GABA by blocking GABA transporter GAT1 Add on therapy in partial seizures

Question 45

Vigabatrin

Answer 45

Inhibits GABA metabolism by inhibiting GABA transaminase | --> stops it getting broken down

Question 46

Perampanel

Answer 46

Selective non-competitive agonist of AMPA receptors

Question 47

Felbamate

Answer 47

Inhibits NMDA receptors + possible GABAa receptors

Question 48

Focal seizure

Answer 48

Carbamazepine Lamotrigine Valproate

Question 49

Tonic-clonic seizure

Answer 49

Carbamazepine Lamotrigine Valproate

Question 50

Absence seizure

Answer 50

Ethosuximide | Valproate

Question 51

Myoclonic seizure

Answer 51

Valproate Clonazepam Levetiracetam

Question 52

Other epilepsy treatments

Answer 52

Vagal nerve stimulation DBS Ketogenic diet (high fat and low carbs)