31/05 revision

how many drugs are there that can be used to treat epilepsy

many

what do drugs to treat epilepsy often have

more than one mechanism of action

how have almost all drugs used to treat epilepsy been found

• serendipitously

• or empirically

what are the most common mechanisms of drugs to treat epilepsy

• enhanced GABA transmission

• inhibition of Na+ channels

• inhibition of Ca2+ channels

what does inhibition of GABA signalling cause

convulsions- activation of excitatory pathways

what do benzodiazepines potentiate

• the action of GABA at GABA-A receptors by the action at the modulatory site

• e.g. clobazam and lorazepam

what do barbiturates potentiate

• the action of GABA at GABA-A receptors by action at the channel modulatory site - enhance Cl- influx

• e.g. phenobarbital

what was gabapentin designed as

• GABA-A agonist for treatment of epilepsy

• not a GABA-A agonist but IS an anticonvulsant agent acting at P/Q-type Ca2+ channels

what is vigabatrin

• GABA transaminase inhibitor

• more GABA in presynaptic terminal so more GABA to release

• therefore increases the amount of GABA available for release

what is valproate

• increases the amount of GABA in the brain

• exact mechanism of this is unclear

what is tiagabine

• GABA uptake (GAT1) inhibitor

• GABA will remain in synapse so more GABA for inhibitory effects

• therefore increases the amount of GABA following synaptic release

what are some examples of epileptic drugs that inhibit voltage-gated Na+ channels

• valproate

• phenytoin

• carbamazepine

• lamotrigine

• rufinamide

• lacosamide

what do epileptic drugs that inhibit voltage-gated Na+ channels exhibit

• use-dependency

where do epileptic drugs that inhibit voltage-gated Na+ channels act

preferentially at cells that are repetitively firing

what do epileptic drugs that inhibit voltage-gated Na+ channels block

inactivated state

what effect do epileptic drugs that inhibit voltage-gated Na+ channels have on Na+ channels

• stop action potentials and therefore the spread of neuronal activity across the brain

• slows recovery from inactivation

what are some examples of T-type Ca2+ channel blockers used in the treatment of absence seizures

• ethosuximide

• valproate

• clonazepam

example of an epileptic drug which decreases activity of the P/Q-type Ca2+ channel blockers

gabapentin

where does levetiracetam bind and what does it do

• to the synaptic vesicle protein SV2A

• modulation of NT release

what does phenobarbital inhibit

• glutamate receptors

• as well as enhancing GABA receptors and blocking Na+ channels

what does topiramate block

• AMPA receptors

• as well as blocking Na+ and Ca2+ channels and enhancing action of GABA

what was perampanel designed as

an AMPA antagonist and is one of the most recently introduced anti epileptic drugs

what are seizures due to

unregulated neuronal discharge in the brain

what does manifestation of the seizure depend on

• area of the brain that is affected by

• e.g, motor cortex, somatosensory cortex, hypothalamus, reticular system

what does epilepsy arise from

• imbalance of inhibitory and excitatory activity

• decreased inhibitory activity- GABA-A antagonists cause convulsions

• increased excitatory activity- can cause excitotoxicity

what do neurons in the focal area display

• shown to display sudden depolarisations (30mV for few second)

• paroxysmal depolarisation shift (PDS)

• burst of action potentials

what sort of activity are in the network of neurons in epilepsy

synchronous activity

what can happen in regions surrounding the focal area in epilepsy

hyper excitability

what are absence seizures

• oscillatory feedback between cortical and thalamic neurons

• involve activity of T-type voltage-gated Ca2+ channels

how many cases of epilepsy are due to specific mutations in family history

2%

what are the many mutations identified in epilepsy

• ion channels

• GPCRs

• enzymes

• neurotransmitters

how many spontaneous mutations to the voltage-gated Na+ channel have been found which are associated with epilepsy

>150

what is epilepsy

a group of neurological disorders of the CNS characterised by the occurrence of seizures

what are seizures a result of

• unregulated and synchronous neuronal activity in the brain

• hurts of high frequency action potentials

what does epilepsy manifest clinically as disturbances of

• consciousness

• behaviour

• motor function

• sensation

• emotion

• autonomic function

how many people are affected by epilepsy and where are most of these people

• 70 million worldwide

• 80% with active epilepsy are in low-middle income countries due to patients not getting appropriate treatment

what is the uk prevalence of epilepsy

5-10 cases per 1000

when can epilepsy start

• any age

• incidence with age is a u-shape curve

what are the mortality rtes for epilepsy like

• low

• some patients with epilepsy will die prematurely as a result of the disease (usually a seizure)

• can be unexplained (SUDEP)

what are most cases of epilepsy termed as

idiopathic

what is the genetic component of epilepsy

• 50-60% concordance in identical twins- if 1 twin gets it other twin has 50-60% chance to get; 15% in non-identical twins

how can epilepsy be secondary

• brain damage at birth

• brain development malformation

• head trauma

• Brian trauma

• stroke

• neurodegenerative diseases

• infections that affect the brain- e.g. meningitis

• drug or alcohol withdrawal

what can seizures be triggered by

specific events like flashing lights

what can seizures be classified as

• focal

• generalised

what are focal seizures

• occur in a discrete area and usually remain in that area- aberrant activity but remains in discrete area

• motor or non-motor

• aware v impaired awareness

what are generalised seizures

• involve all of the brain (both hemispheres)

• arise in a discrete area but activity spreads rapidly

• usually involve loss of consciousness from the onset

what are the different types of generalised seizures

• absence (non-motor)

• tonic-clonic

• myoclonic

• atonic

• tonic

• clonic

what type of onset do absence seizures have

childhood onset

how frequent are absence seizures

can be very frequent (many times per day)

what is the duration of absence seizures

approx. 3-30 seconds

what are absence seizures characterised by

• vacant staring

• stilness

• lack of awareness/responsiveness

what is the recovery like for absence seizures

rapid recovery with no after-effects

what do tonic-clonic seizures involve

immediate loss of consciousness

what are the 2 phases in tonic-clonic seizures

• tonic phase

• clonic phase

tonic phase

• lasts approx. 1 minute

• contraction of the muscles (rigidity)

• respiration stops

• involuntary cry- air passes through vocal chords

• loss of control of autonomic functions e.g. bladder

clonic phase

• lasts 2-4 minutes

• contraction and relaxation of muscle- jerky, uncontrolled movement of limbs

• tongue biting

what happens post seizure in tonic-clonic seizures

• confusion

• drowsiness

• nausea

• headache

what are seizures often preceded by and what is this termed as

• preceded by specific sensations

• termed as aura

• usually last less than 1 minute

what is status epilepticus

• prolongues seizure- over 5 minutes

• medical emergency

what can be used to identify the lesion site in epilepsy

• scans e.g. MRI, PET

• looking for glucose uptake by cells

what can help determine the type of seizure

EEG

what is the percentage of people that become seizure free with the correct medication

70-80%