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Y2 CONTROL & MOVEMENT > Epilepsy > Flashcards

Epilepsy Flashcards

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1
Q

What are the 2 different situations which can lead to a seizure?

A

Excitation (too much):

  • ionic - Na+ or Ca2+ influx
  • neurotransmitter - glutamate or aspartate release

Inhibition (too little):

  • ionic - Cl- influx or K+ efflux
  • neurotransmitter - GABA release

either situation can result in too much neuronal activity and cause a seizure

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2
Q

When the brain is working normally, how many brain cells are active?

What is their activity like?

A

when the brain is working normally, very small numbers of brain cells are active at any given time

the activity is tightly focussed as it flows through successive brain regions and is not allowed to spread out

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3
Q

What is the role of inhibitory interneurones in the brain?

A

a group of brain cells called inhibitory interneurones allow activity to spread in one direction, but not to spread out sideways

they release the inhibitory neurotransmitter - GABA

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4
Q

What % of neurones in the brain are interneurones?

A

interneurones represent 10-20% of the total number of neurones

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5
Q

In a seizure, what happens to activity that is controlled by the inhibitory interneurones?

A

the initially localised hyperexcitability spreads into surrounding neuronal networks

it might be counterbalanced by inhibitory mechanisms

or, after involving more and more neurones, cause a clincially visible seizure

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6
Q

What is GABA?

How does it exert an effect?

A

gamma-aminobutyric acid

it is a major inhibitory neurotransmitter

it is found at 30% of synpases

it acts via GABAA or GABAB receptors

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7
Q

What is the difference between GABAA and GABAB receptors?

A

GABAA receptors are ligand-gated chloride channels

GABAB receptors are G protein-coupled receptors

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8
Q

What is the structure of the GABAA receptor protein?

A

it is pentameric

the typical in vivo subunit composition is two alpha, two beta and one gamma or delta subunit

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9
Q

Why is GABA receptor subunit composition important?

A

it determines the intrinsic properties of each channel

this also determines the affinity they have for certain drugs / molecules

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10
Q

What are the types of epilepsies caused by mutations in GABAA receptor subunits?

A
  • childhood absence epilepsy (CAE)
  • pure febrile seizures (FS)
  • generalised epilepsy with febrile seizures plus (GEFS+)
  • Dravet syndrome (DS) / severe myoclonic epilepsy in infancy (SMEI)
  • juvenile myoclonic epilepsy (JME)
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11
Q
A
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12
Q

What is the significance of the y2(390X) nonsense mutation?

A

it has been identified in 2 separate pedigrees with epilepsy, including Dravet syndrome

it produces a truncated subunit with the loss of 78 C-terminal amino acids

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13
Q

What mutation is present in people with Dravet syndrome?

A

GABRG2 (Q390X) mutation

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14
Q

What types of seizures do people with Dravet syndrome tend to have?

A

first start with febrile seizures, then tonic-clonic seizures (TCS), myoclonic seizures (MS), absence seizures (AS), complex partial seizures (CPS) and tonic seizures (TS)

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15
Q

What is status epilepticus?

A

status epilepticus (SE) is a life-threatening condition in which the brain is in a state of persistent seizure

more than 30 mins continuous seizure activity

OR

two or more sequential seizures spanning this period without full recovery between seizures

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16
Q

What is the risk of status epilepticus?

A

SE is a medical emergency because the longer the seizure lasts, the less likely it is to stop on its own

SE confers a greater risk for future unprovoked seizures

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17
Q

What is the treatment for status epilepticus?

A

GABAA receptor agonist

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18
Q

What is seen in animals in the post-status epilepticus models?

A

a single episode of status epilepticus is used to incite epileptogenesis

an episode of self-sustained SE is induced in previously healthy animals using an intraperitoneal injection of the pro-convulsant drug pilocarpine

this is a non-selective muscarinic receptor agonist

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19
Q

How does SE alter the expression of GABA receptor subunits?

A

SE alters the abundance of a1 and a4 subunits in y2-containing GABAA receptors in dentate granule cells

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20
Q

How may the SE-induced alterations in the expression of GABA receptor subunits affect the brain?

A

the change in receptor subtype from a1by2 to a4by2 may have dramatic effects on brain inhibition

a4 containing GABA receptors have been shown to desensitise rapidly, especially when assembled with b3 subunits

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21
Q

What is one way that may be used to prevent epileptogenesis after SE?

A

GABA receptor 1 over-expression

modulation of GABAA receptor subunit composition by gene transfer is one approach that may prevent epileptogenesis

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22
Q

How can GABA receptor over-expression be acheived?

A

injection to the dentate granule cells of the hippocampus of a viral vector containing the a1 subunit

this increases a1 subunit expression

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23
Q

What was seen in rats with an increased a1 subunit expression?

A

a1 subunit viral vector-treated rats showed both increased latency time and decreased rates of seizure development

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24
Q

What is meant by epileptogenesis?

A

the gradual process by which a normal brain develops epilepsy

this is a chronic condition in which seizures occur

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25
What are antiepileptic drugs? What do they treat?
a drug which decreases the **frequency** and/or **severity** of seizures in people with epilepsy they treat the **symptom of seizures** and not the underlying epileptic condition correct classification of seizures leads to correct AED selection
26
What are the 3 modes of actions of antiepileptic drugs?
1. suppress action potential 2. enhance GABA transmission 3. suppression of excitatory transmission
27
What types of antiepileptic drugs suppress action potentials?
* sodium channel blocker or modulator * potassium channel opener
28
What types of antiepileptic drugs will enhance GABA transmission?
* GABA uptake inhibitor * GABA mimetics
29
What type of antiepileptic drug will suppress excitatory transmission?
* glutamate receptor antagonist
30
What are the main mechanisms of action of anticonvulsants?
* enhancement of GABAergic transmission * inhibition of Na+ channels * mixed actions - combination of some or all of the above and also inhibiting neurotransmitter release
31
What is meant by a partial seizure? What are the 2 different types?
in a partial seizure, the electrical disturbance is limited to a **specific area** of **one** cerebral hemisphere partial seizures can be **_simple_** or **_complex_**
32
What is the difference between a partial simple and a partial complex seizure?
**partial simple:** * consciousness is retained **partial complex:** * consciousness is impaired or lost they both only affect a single area of the brain
33
What are the 3 antiepileptic drugs of choice in a partial simple or partial complex seizure?
* carbamazepine * phenytoin * valproic acid
34
What is a "generalised tonic clonic" seizure?
a disturbance in the functioning of both sides of the brain this disturbance is caused by electrical signals spreading through the brain inappropriately it produces bilateral, convulsive tonic and clonic muscle contractions
35
What is meant by tonic and clonic muscle contractions?
**tonic seizures:** * involve sudden stiffening and contraction of the muscles **clonic seizures:** * involve rhythmic twitching or jerking of one or several muscles tonic-clonic seizures are a combination of these 2 types in a specific pattern
36
What are the 3 antiepileptic drugs of choice in generalised tonic clonic seizures?
* carbamazepine * phenytoin * valproic acid **alternatives:** * lamotrigine * topiramate * phenobarbital
37
What is meant by an absence seizure?
absence seizures cause lapses in awareness, sometimes with staring they are a type of generalised onset seizure, meaning they begin in both sides of the brain at the same time they begin and end abruptly, lasting only a few seconds
38
What are the epileptic drugs of choice used to treat absence seizures?
* ethosuximide * valproic acid **alternatives:** * lamotrigine * clonazepam
39
What is an atypical absence seizure?
it has a less abrupt onset and offset of loss of awareness than a typical absence seizure they tend to last longer (30 seconds) they are often associated with other features such as loss of muscle tone of the head, trunk or limbs (gradual slump) and subtle myoclonic jerks
40
Why are atypical absence seizures referred to as "atonic" and "myoclonic"?
**atonic:** * this means loss of muscle tone * in an atonic seizure, a person suddenly loses muscle tone and their head and body becomes limp **myoclonic:** * there is sudden, involuntary jerking of a muscle or group of muscles
41
What are the antiepileptic drugs of choice in an atypical absence seizure?
* valproic acid * clonazepam can be used as an alternative
42
What is a febrile seizure?
a seizure associated with a high body temperature (fever) but without any serious underlying health issue they commonly occur in children between the ages of 6 months and 5 years
43
What are the antiepileptic drugs of choice used to treat febrile seizures?
* diazepam - rectal **alternatives:** * diazepam - IV * valproic acid
44
What are the 4 methods of enhancing GABA action? What are examples of antiepileptic drugs that work in these ways?
* enhance action of GABAA receptors with **barbiturates** e. g. **phenobarbital** * enhance action of GABAA receptors with **benzodiazepines** e. g. **clonazepam** * inhibit GABA transaminase - **vigabatrin** * inhibit GABA uptake - **tiagabine**
45
What arethe major binding sites on the GABAA receptor? What ion passes through the channel?
46
What are the 3 main benzodiazepines?
* clonazepam * clorazepate * diazepam (valium) and lorazepam
47
When is clonazepam used?
it is effective in generalised tonic-clonic, absence and partial seizures
48
When is clorazepate used?
it is effective against partial seizures it is used in conjunction with other drugs
49
When is diazepam (valium) used?
it is effective against status epilepticus when given IV
50
What is the mechanism of action of benzodiazepines?
**they increase the affinity of GABA for its receptor** they increase the Cl- current (opening frequency) they suppress seizure focus by raising action potential threshold they strengthen surround inhibition to prevent spread
51
What are the unwanted effects and drawbacks of using benzodiazepines?
* the main unwanted effect is **sedation** * significant problem of **tolerance** and **dependence** so long-term use is avoided * if given IV, **respiratory depression** may result
52
What are the main antiepileptic drugs that will inhibit Na+ channels?
several of the most frequently used anti-epileptic drugs act in this way: * phenytoin * carbamazepine and oxcarbamazepine * lamotrigine
53
During an action potential, in what 3 states does the voltage-dependent Na+ channel exist?
* **closed** - before activation * **open** - during depolarisation * **inactivated** - shortly after the peak of depolarisation
54
What is the mechanism of action of phenytoin?
Na+ channels do not recover from the inactivated state until the membrane has repolarised phenytoin **binds to the inactivated state** and slows down its recovery
55
What are the 3 main antiepileptic drugs that have mixed actions?
* gabapentin * valproate (valproic acid) * levetiracetam
56
What are the properties of valproate? What is it used to treat?
it is taken orally and is well-absorbed it is effective against both tonic-clonic and absence seizures it can be used in bipolar depressive illness
57
What are the 3 different mechanisms of action of valproate?
* inhibits Na+ channels - (weaker than phenytoin) * decreases GABA turnover * blocks neurotransmitter release by blocking T-type Ca2+ channels
58
How does valproate decrease GABA turnover?
it inhibits **succinic semialdehyde dehydrogenase** this leads to indirect inhibition of **GABA transaminase** this may lead to **increased synaptic GABA** levels
59
What is the advice given to pregnant women with epilepsy?
seizures are very harmful for pregnant women every pregnant woman with epilepsy is recommended to be given **folic acid**
60
What antiepileptics should and should not be used in pregnancy?
**monotherapy** is usually better than drug combination phenytoin and valproic acid are absolutely contraindicated oxcarbamazepine is better than carbamazepine
61
What can taking phenytoin during pregnancy lead to?
**foetal hydantoin syndrome** which may also include heart defects and cleft lip
62
What are the features of foetal hydantoin syndrome?
* intrauterine growth restriction with microcephaly * minor dysmorphic craniofacial features and limb defects including hypoplastic nails and distal phalanges * some may have growth problems and developmental delay, or mental retardation
63
What is the definition of foetal hydantoin syndrome?
a group of defects caused to the developing foetus by exposure to the teratogenic effects of **phenytoin**, or more rarely, **carbamazepine** reports of adverse effects from carbamazepine in pregnancy have been less common
64
What is the risk associated with foetal valproate syndrome?
6-9% risk of congenital malformations in infants exposed to valproate prenatally, compared to 2-3% in the general population
65
What % of the population are seizure free with one or two drugs?
70% are seizure free with one drug 5-10% are seizure free with two or more drugs 20% still have seizures - refractory epilepsy
66
What is meant by refractory epilepsy?
when medicines do not work well, or at all, to control the seizures
67
What is meant by optogenetics?
a biological technique that involves the use of light to control cells in living tissue this typically involves neurones that have been genetically modified to express light-sensitive ion channels
68
What is epilepsia partilais continua?
a rare type of brain disorder the patient experiences recurrent **motor epileptic seizures** that are focal (hands and face) they recur every few seconds or minutes for extended periods (days or years)
69
What usually causes epilepsia partialis continua?
it is usually due to large, acute brain lesions resulting from strokes in adults and focal cortical inflammatory processes in children
70
What is the therapy goal in epilepsia partialis continua?
the seizures are very medication and therapy-resistant the primary therapeutic goal is to stop **secondary generalisation**
71
What would happen in a rodent model of epilepsia partialis continua when a tetanus toxin is injected into the motor cortex?
* tetanus toxin decreases neurotransmitter release and predominantly affects **inhibitory GABAergic synapses** * loss of inhibition results in **focal seizure acitivity**, which progresses over 3-7 days * after time, the tetanus toxin is cleared but the seizure activity continues
72
How was seizure activity suppressed a week after the tetanus toxin injection?
seizure activity was suppressed using light activation of the light-activated chloride-pump, **halorhodopsin**, transfected into pyramidal cells in the focus **lentiviral vectors** are used to transfect pyramidal neurones with halorhodopsin
73
What are lentiviruses?
retroviruses that can transfect nondividing cells
74
What happens once the pyramidal neurones have been transfected with halorhodopsin?
by selecting the appropriate gene promoter (*Camk2a*), it is possible to restrict gene expression to particular subsets of neurones e.g. pyramidal cells
75

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