Epilepsy - Clinical Lecture Flashcards

1
Q

What are seizures?

A
  • External manifestation (and primary symptom) of epilepsy
  • Clinical manifestation of an abnormally excessive and hypersynchronous activity of neurones located predominantly in the cerebral cortex.
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2
Q

What are the 2 basic mechanisms underlying seizures?

A
  1. Excitation (too much)

2. Inhibition (too little)

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3
Q

How can excitation lead to a seizure?

A

o Ionic –> enhanced Na+, Ca2+ influx into neurons

o Neurotransmitter –> increased release of glutamate, aspartate (excitatory neurotransmitters) into synaptic cleft

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4
Q

Which 2 excitatory neurotransmitters can lead to seizures?

A

glutamate, aspartate

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5
Q

How can inhibition lead to seizures?

A

o Ionic –> insufficient Cl- influx into neuron, or insufficient K+ efflux
o Neurotransmitter –> insufficient release of GABA (inhibitory neurotransmitter)

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6
Q

What is the main inhibitory neurotransmitter in the CNS?

A

GABA

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7
Q

Is increased excitability always synonymous with seizure? Why?

A

No - the increased excitability could be in inhibitory neurons

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8
Q

What are inhibitory interneurones?

A

These brain cells allow activity to spread in one direction, but not to spread out sideways (counterbalance hyperexcitability)

  • When the brain is working normally, very small numbers of brain cells are active at any given time
  • The activity is kept tightly focussed as it flows through successive brain regions and is not allowed to spread out (by inhibitory interneurones)
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9
Q

What happens if inhibitory interneurones are dysfunctional?

A

• If inhibitory interneurones are dysfunctional, the localised hyperexcitability is not counterbalanced and can involve more and more neurones, causing a seizure
o When activity spreads out sideways, too many cells become active at one –> epileptic seizure

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10
Q

Which ion is used as a measure of excitation?

A

Ca2+

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11
Q

Which inhibitory neurotransmitter do inhibitory interneurones release?

A

GABA

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12
Q

How is magnesium involved in epilepsy?

A

Magnesium is a potential modulator of seizure activity because of its ability to antagonise excitation. Some studies have shown that people with epilepsy have lower magnesium levels than people without epilepsy.

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13
Q

What are anti-epileptic drugs?

A

A drug that decreases the frequency and/or severity of seizure sin people with epilepsy by treating the symptoms of seizures, not the epileptic condition

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14
Q

What is essential for correct AED selection?

A

Correct classification of the seizure

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15
Q

What are the 3 main modes of action of AEDs?

A
  1. Suppress action potential
  2. Enhance GABA transmission
  3. Suppress excitatory transmission
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16
Q

What are the 2 ways in which an AED can suppress action potential?

A

 Block sodium channel or modulate it

 Potassium channel opener

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17
Q

What are 2 examples of AEDs that block sodium channel or modulate it in order to suppress action potential?

A

Carbamazepine, oxcarbamazepine

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18
Q

Mechanism of action of Carbamazepine?

A

Carbamazepine is a sodium channel blocker. It binds preferentially to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential.

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19
Q

What are the 2 ways in which an AED can enhance GABA transmission?

A

 GABA uptake inhibitor OR inhibit GABA transaminases

 GABA mimetics, enhance action of GABA receptors

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20
Q

What are GABA transaminases?

A

GABA transaminase enzymes comprise a family of transaminases which degrade the neurotransmitter GABA

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21
Q

What is an example of an AED that inhibits GABA transaminases?

A

vigabatrin

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22
Q

What is an example of an AED that inhibits GABA uptake?

A

tiagabine

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23
Q

What are GABA mimetics?

A

GABA-like drugs (inhibitory effect) –> enhance action of GABA receptors

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24
Q

What are 2 classes of AEDs that function as GABA-mimetics?

A
  • Barbiturates

* Benzodiazepaines e.g. clonazepam

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25
Q

How can AEDs suppress excitatory transmission?

A

Via a Glutamate receptor antagonist

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26
Q

In practice, the most common AEDs used have which mechanisms of action?

A
  • Enhancement of GABAergic transmission
  • Inhibition of Na+ channels
  • Mixed actions –> Combination of some or all of the above and also inhibiting neurotransmitter release
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27
Q

What is a partial simple seizure?

A

A partial seizure happens when unusual electrical activity affects a small area of the brain –> does NOT affect awareness

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28
Q

What is a partial complex seizure?

A

Seizures that ARE associated with impairment in consciousness

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29
Q

First line of AEDs in partial simple and partial complex seizures?

A

Carbamazepine
Phenytoin
Valproic Acid

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30
Q

What is a tonic-clonic seizure?

A

Tonic-clonic seizures involve both tonic (stiffening) and clonic (twitching or jerking) phases of muscle activity.

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31
Q

First line of AEDs in tonic-clonic seizure?

A

Carbamazepine
Phenytoin
Valproic Acid

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32
Q

What is an absence seizure?

A

Where you lose awareness of your surroundings for a short time –> causes you to blank out or stare into space for a few seconds.

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33
Q

First line of AEDs in an absence seizure?

A

Ethosuximide

Valproic acid

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34
Q

What is an atonic seizure?

A

A type of seizure that causes sudden loss of muscle strength - can cause the person to fall to the ground.

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35
Q

What is a myoclonic seizure?

A

Myoclonic seizures are characterised by brief, jerking spasms of a muscle or muscle group. They often occur with atonic seizures, which cause sudden muscle limpness.

36
Q

First line AEDs for atypical absence, atonic and myoclonic seizures?

A

Valproic acid

37
Q

What are febrile seizures?

A

affect infants – caused by fever

38
Q

First line AEDs for febrile seizures?

A

Diazepam - given rectally (or IV)

39
Q

What is the most widely used anti-epileptic drug?

A

Valproic acid

40
Q

What is GABA?

A
  • Major inhibitory neurotransmitter

* Found at ~30% of synapses

41
Q

Via which receptors does GABA act?

A

via GABA(A) or GABA(B) receptors

42
Q

Which GABA receptor is most relevant regarding seizures and epilepsy?

A

GABA(A)

43
Q

What type of receptor is GABA(A)?

A

Ligand-gated chloride channel receptor

44
Q

What type of receptor is GABA(B)?

A

G protein-coupled receptor

45
Q

What happens when GABA binds to GABA(A)?

A

GABA is released into presynaptic cleft from presynaptic neuron and binds to GABAA receptors on postsynaptic neuron

Binding of GABA causes GABAA receptor to form a chloride channel –> Allows Cl- ions to enter cell

46
Q

What are the 3 methods of enhancing GABAergic transmission?

A
  1. Enhance action of GABAA receptors
  2. Inhibit GABA transaminase
  3. Inhibit GABA uptake
47
Q

Which 2 drugs enhance the action of GABA(A) receptors?

A
  1. barbiturates e.g. phenobarbital

2. benzodiazepines e.g. clonazepam

48
Q

What is an example of a drug that inhibits GABA transaminase?

A

vigabatrin

49
Q

What is an example of a drug that inhibits GABA uptake?

A

tiagabine

50
Q

What are the 3 main benzodiazepines?

A
  1. Clonazepam
  2. Clorazepate
  3. Diazepam (Valium) and Iorazepam
51
Q

What type of seizures is Clonazepam effective in?

A

generalised tonic-clonic, absence and partial seizures

52
Q

What type of seizures is Clorazepate effective in?

A

effective against partial seizures, used in conjunction with other drugs

53
Q

What type of seizures is Diazepam effective in?

A

effective against status epilepticus when given IV

54
Q

What is status epilepticus (SE)?

A

A life-threatening condition in which the brain is in a state of persistent seizure

55
Q

What defines a persistent state of seizure?

A
  • More than 30 minutes continuous seizure activity OR

* Two or more sequential seizures with no recovery within 30mins)

56
Q

What does SE confers greater future risk for?

A

unprovoked seizures

57
Q

Treatment for SE?

A

diazepam (GABA agonist)

58
Q

Mechanism of benzos?

A

Increases affinity of receptor to GABA:
 Increases chloride current (opening frequency)
 Suppresses seizure focus by raising action potential threshold
 Strengthens surround inhibition, prevents spread of excitation

59
Q

What are the effects of benzos?

A
o	Sedative (calming)
o	Hypnotic (initiates or prolongs sleep)
o	Anxiolytic (reduces anxiety)
o	Anticonvulsant (reduces epileptiform activity)
o	Muscle relaxant
o	Amnesic (anterograde – after drug administration)
60
Q

What are the unwanted side effects of benzos?

A

o Sedation
o Addictive, avoid long-term use
o Tolerance and dependence - avoid long term use
o Can get respiratory depression if used IV
o Drowsiness, confusion, amnesia, poor co-ordination
o Long acting (e.g. diazepam) – next day

61
Q

When can benzos be lethal in overdose?

A

When taken with other CNS depressants e.g. ethanol –> can lead to respiratory depression

62
Q

In cases of benzo overdose, what drug is used as treatment?

A

flumazenil (a benzo antagonist)

63
Q

Why should benzos only be used for short term treatment?

A

Withdrawal –> hard to wean patients off BZs if used long term

64
Q

Voltage-gated sodium channels can be

a) closed
b) open
c) inactivated.

Describe the cause for each of these states?

A

a) closed; at the resting potential
b) open: in response to a nerve impulse, the gate opens and Na+ enters cell
c) inactivated; for a brief period following activation (depolarisation), the channel does not open in response to a new signal (Na+ channels do not recover from the inactivated state until the membrane has repolarised)

65
Q

What is the trigger for voltage-gated sodium channels to open?

A

Voltage change

66
Q

Mechanism of action of Phenytoin?

A

A sodium channel blocker!

Binds to voltage-gated sodium channels when they are in an inactivated state to slow down its recovery

67
Q

Why is inhibition of voltage-gated sodium channels (e.g. by Phenytoin) considered ‘use-dependent’?

Benefits of this?

A

Phenytoin only binds to Na+ channels to inactivated channels; these channels have to have been recently opened

Only rapidly firing neurons are blocked and thus does not interfere with normally firing neurons

68
Q

What is tonic blockade?

How does it differ from phasic blockade?

A

Tonic blockade –> When there are long intervals between impulses, the level of inhibition of each impulse is the same

Phasic blockade –> When intervals between impulses is short, the level of inhibition increase with each impulse

69
Q

How is phenytoin taken?

A

Orally - well absorbed

70
Q

Describe if phenytoin is highly protein bound or not?

If so, which plasma protein is it primarily bound to?

A

Very highly protein bound (plasma proteins, primarily albumin) 80-90% –> only 10-20% free

71
Q

What is the danger of phenytoin alongside valproate?

A

Phenytoin and Valproate have the same binding sites.

If taken together produces more “free” phenytoin (the ‘free phenytoin’ is the active moiety and able to interact with receptors –> has high affinity of binding with the Na+ channel)

Tends to increase hepatic clearance of the drug so effects can be unpredictable

72
Q

How is phenytoin metabolised?

A

Highly metabolised (95%) in the liver to an inactive metabolite

BUT Metabolism is saturable; liver may not be able to metabolise anymore once saturated

73
Q

Why can a small increase in the dose of phenytoin lead to lead to large increase in plasma concentration?

A

Phenytoin is highly bound (only 10-20% ‘free’ - a slight increase in the amount of ‘free’ phenytoin can have a large effect).

Elimination can become saturated

Phenytoin kinetics are nonlinear and saturable, resulting in highly variable concentrations even with minor dosage changes

A slight increase in phenytoin bioavailability can lead to a marked increase in serum level and thus to adverse effects, especially when the level is more than 15/mg/L

74
Q

What are the mild unwanted effects of phenytoin?

A

Include vertigo, ataxia, headache and nystagmus

75
Q

What are the severe unwanted effects of phenytoin?

A

 Confusion, intellectual deterioration – acute and reversible
 Hyperplasia of the gums, hirsutism – gradual
 Megaloblastic anaemia – folate metabolism
 Hypersensitivity and rashes – quite common
 Hepatitis
 Foetal malformations – cleft palate “foetal hydantoin syndrome”

76
Q

What can phenytoin during pregnancy lead to?

A

Can cause foetal hydantoin syndrome

77
Q

What is Foetal hydantoin syndrome?

A

Up to 30% of children whose mothers are taking phenytoin during pregnancy typically have:
o intrauterine growth restriction with microcephaly
o minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges (birth defects)
o a smaller population will have growth problems and developmental delay, or mental retardation
• Heart defects and cleft lips

78
Q

What 2 drugs can cause foetal hydantoin syndrome if taken during pregnancy?

A
  1. Phenytoin

2. Carbamazepine (less common)

79
Q

Why is Valproate (valproic acid) unusual as an AED?

A
  • Not related chemically to the other classes of anti-epileptics
  • Unusual in that it is effective against both tonic-clonic and absence
  • Can also be useful in bipolar depressive illness
80
Q

Valproate/valproic acid has 3 mechanisms of actions.

What are these?

A
  1. Inhibits sodium channels (weaker than phenytoin)
  2. Decreases GABA turnover through:
     Inhibition of succinic semialdehyde dehydrogenase and GABA transaminase
     May lead to increased synaptic GABA levels
  3. Blocks neurotransmitter release by blocking T-type calcium channels
81
Q

Why is valproic acid effective against many different seizure types?

A

Due to many different mechanisms of action

82
Q

What are the dangers of valproate if taken during pregnancy?

A

Foetal valproate syndrome:
o Can cause learning difficulties and autism
o These findings must be balanced against the treatment benefits for women who require valproate for epilepsy control

83
Q

What is the mechanism behind valproic acid leading to Foetal valproate syndrome?

A

 Valproate is a HDAC (histone deacetylase) inhibitor
 The inhibition of HDAC activity results in the hyperacetylation of chromatin, associated with the altered transcription of specific genes, e.g. GRP78 (up to 2% of all expression).
 Thus, VPA inhibition of HDAC provides an epigenetic mechanism for FVS.

84
Q

What % of seizure patients are seizure free with one drug?

A

70%

85
Q

What is refractory epilepsy?

A

Epilepsy that cannot be controlled by drugs