epilepsy Flashcards

1
Q

what is epilepsy

A

repeated occurance of sudden excessive or synchronous discharges in cerebral cortical neurones resulting in a disruption of consciousness, disturbance of

characterised by recurrent epileptic seizures

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2
Q

what causes epileptic seizures

A

seizures resulting from excessive activity of neurones in the brain

seizures are sudden short events involving a change in a persons awareness of where they are or what they are doing

epileptic attacks result from abnormal hyperexcitability of neurones, often originating in a localised area of the brain, called the epileptic focus

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3
Q

what are 2 types of epilepsy, what causes them

A

symptomatic or idiopathic

symptomatic indicates a probable cause exists such as: cerebrovascular lesions, perinatal or postnatal trauma, CNS infections, tumours or congenital malformations of the CNS

idiopathic indicates no obvious cause can be found; usually due to another neurological condition, gene factors are probably responsible

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4
Q

what are 2 main categories of seizures

A

partial: begins with local discharge in one area of the brain

primary generalised: begins with widespread electrical discharge that involves both sides of brain at once

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5
Q

what are subcategories of primary generalised seizures and how are they characterised

A

primary generalised

absence (petit mal): brief interruption of consciousness and motor activity, thalami-cortical mechanism

tonic-clonic (grand mal): loss of consciousness, convulsions

myoclonic: brief contraction of muscle groups, may accompany other seizures
atonic: sudden loss of muscle tone, may be widespread or local

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6
Q

what are the subcategories of partial seizures

A

simple partial: motor spasms, sensory hallucination, most common in frontal cortex

complex partial: impaired consciousness, possible automatisms, most common in temporal lobes

secondary generalised: partial spreading to generalised

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7
Q

what is status epilepticus

A

repeated seizures with no recovery between attacks

causes additional problems such as metabolic disturbance and neuronal damage

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8
Q

what to brain happens during epileptogenesis

A

the epileptic focus in some neurones may undergo synchronous, repetitive depolarisations called paroxysmal depolarisation shifts, this synchronous activity is propagated to connected brain regions

transition from normal spiking paroxysmal depolarisation shifts may involve changes in intrinsic properties of neurones

increase in calcium and sodium channel activity and decrease in potassium channel activity can promote bursting

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9
Q

how does epileptogenesis effect synapses

A

causes changes in synaptic efficacy:

more EPSPs lead to excessive activation of NMDARs, fewer IPSPs result in loss of GABA mediated inhibition

paroxysmal depolarisation shifts may all cause changes in synaptic connectivity

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10
Q

what are mutations that can possibly cause idiopathic epilepsy

A

mutations in voltage gated sodium channels e.g in gene SCN1A, mutations cause gain of function causing impaired inactivation

mutations in voltage gated potassium channels e.g in gene KCNA1, causing loss of function, reducing potassium efflux which causes repolarisation of neurone

voltage gated chloride channels e.g in gene CCLCN2, mutations causing loss of function of these cause decrease in IPSPs

GABAa receptor: mutation in genes examples GABRA1, causing reduction in function due to increased desensitisation or failed insertion into membrane

nAchRs: mutation in gene such as CHRNA4, mutations causing gain of function such as prolong opening

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11
Q

what is the aim of anti epileptic drugs

A

must dampen the neuronal hyperexcitability that leads to or sustains an epileptic attack, this can be done by reducing excitation or enhancing inhibitory influences

reduction in excitation can result from decreased activity of voltage gated sodium and calcium channels or decreased efficacy of excitatory synapses

enhanced inhibition is acheived by increased efficacy of inhibitory synapses or increase in potassium channel activity

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12
Q

what are categories of establised (older) anti epileptics, give an example of each

A

hydantoins: phenytoin
dibenzapines: carbamazepine
succinimides: ethosuximide
barbiturates: phenobarbitone
bentos: diazepam, clonazepam
fatty acids: sodium valproate

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13
Q

what are examples of newer anti epileptics

A

lamotrigine, gabapentin

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14
Q

how do anti epileptics effect sodium channels, which drugs do this

A

inhibition of sodium channels in hyperexcitable cells can be achieved without affecting normal electrical activity

phenytoin and carbamazepine have this action

lamotrigine is an example of a newer drug which also has this action

ethosuximide reduces excitability by action on voltage gated sodium channels and possibly clacium channels in the thalamus which explains its effectiveness against absence seizures generated by thalamic oscillations

gabapentin was developed as a GABA agonist, however does not bind to GABA receptors, it is effective in partial and generalised seizures possibly by modifying sodium channels, main effect is block of calcium channels though

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15
Q

what drugs target chloride channels, what is their mechanism

A

phenobarbitone may hyperpolarise neurones by directly increasing chloride influx, through stimulation of GABA receptors with and without presence of GABA, this action is not restricted to the epileptic focus and results in general sedation

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16
Q

how are glutamate receptors drug targets for anti epileptics

A

NMDA receptor antagonists are effective experimentally and are more selective for hyperexcitable neurones but have not passed clinical trials

AMPA receptor antagonists potentially inhibit most excitatory transmission but would disrupt normal function

17
Q

how do anti epileptics target GABA receptors

A

tiagabine is an anticonvulsant which inhibits membrane transporters responsible for GABA reuptake, thus prolonging GABA action

na valproate inhibits GABA metabolism after uptake, increasing GABA levels present in neurone, has drug action in most forms of epilepsy

vigabatrin is a selective GABA-transaminase inhibitor, it is more active in partial generalised seizures but may exacerbate absence seizures

musicmol is an example of drugs which activate GABAa receptor directly, however these drugs are of limited benefit since they act on inhibitory and excitatory cells and are not selective for hyperexcitable regions

increased postsynaptic efficacy of GABA can be acheived with barbiturates and benzos, e.g phenobarbitone and diazepam, these bind to modulatory site on GABAa receptor, however benzos can result in tolerance, they are used via i.v in emergency situations such as status epilepticus

18
Q

what are frequent side effects of anti epileptics

A

all anti epileptics display side effects, frequent ones are sedation and ataxia

anti epileptic side effects are usually dose related

19
Q

how are anti epileptics used

A

dictated by type of seizure and efficacy but also tolerability

usually given as monotherapy but may be used in combination

after failure of 2 anti epileptics patients may be considered for surgery

20
Q

why might one of the newer drugs be used as opposed to an established one

A

may be given if older drugs have not helped or older drugs may not be suitable because:

there are contraindications to the drugs, they could interact with other drugs such as oral contraceptives, they are poorly tolerated or the person is a woman of childbearing potential

21
Q

what drugs are given for partial seizures

A

carbamazepine is principle drug given

others include na valproate, phenytoin and lamotrigine

22
Q

what drugs are given for generalised tonic-clonic seizures

A

na valproate is principel drug given

others include carbamazepine, phenytoin and lamotrigine

23
Q

for generalised absence what drugs are given

A

ethosuximide is principle drug given

na valproate, clonazepam and lamotrigine are also given

24
Q

what is given for status epilepticus

A

clonazepam

25
Q

what are considerations for women of childbearing potential in anti epileptics

A

changes in oral contraceptive metabolism: pharmacokinetic effects are due to enzyme induction

drugs of choice are phenytoin, phenobarbital and carbamazepine for women on oral contraceptives

however all anti-epileptic drugs show some teratogenicity (cause foetal mutations and malformations), major congenital malformations are 2-4 times more likely on anti-epileptics

drug with particular concern of teratogenicity is na valproate

lamotrigine is drug of choice for women of childbearing potential