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PMCOL 371 > 15 - Epilepsy > Flashcards

15 - Epilepsy Flashcards

1
Q

What is a seizure?

A

Finite period of brain dysfunction resulting from abnormal discharge of cerebral neurons

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2
Q

What are three causes of seizures?

A
  1. Exces of excitation - glutamate major player
    - Some drugs work to reduce glutamate release
  2. Insufficient inhibition
    - Some drugs work to enhance inhibition, mainly via GABAA receptors
  3. Elevated excitability
    • Some drugs work to reduce this at several levels
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3
Q

Normal activity - ____ amplitude, ____ frequency

A

Normal activity - low amplitude, high frequency

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4
Q

Synchrony - sometimes natural such as ____

Occur during:

A

Synchrony - sometimes natural such as hippocampal sharp waves

Occur during:
- immobility
- Consummatory behaviour
- Sleep

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5
Q

Epilepsy results from inappropriate ____

A

Epilepsy results from inappropriate synchrony

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6
Q

What are mechanisms of synchrony:

  • Neuronal networks of ____ system are pre-wired for some synchrony
  • Synchrony aided by ____ and other ____
  • Simultaneous activation and input ideal for ____
A

What are mechanisms of synchrony:
- Neuronal networks of limbic system are pre-wired for some synchrony
- Synchrony aided by theta and other global rhythms
- Simultaneous activation and input ideal for synaptic plasticity
- Synchrony makes this more likely to occur

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7
Q

Reciprocal excitation can result in ____

A

Reciprocal excitation can result in epileptiform events

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8
Q

Hippocampal network patterns predict ____

A

Hippocampal network patterns predict behaviour

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9
Q

Hippocampal network patterns predict ____

A

Hippocampal network patterns predict behaviour

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10
Q

Synchronous, rhythmic discharge of interneurons regulates timing of ____

A

Synchronous, rhythmic discharge of interneurons regulates timing of pyramidal cell discharge

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11
Q

What is a Sharp wave ripple?

A

50-60,000 neurons discharge in concert in the CA3-CA1-subiculum-presubiculum-EC axis

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12
Q

Neuronal networks in the limbic system:
- Normally provide mechanisms for ____
- ____ can recruit other regions
- ____ is intrinsic
- Subverted by imbalances in ____

A

Neuronal networks in the limbic system:
- Normally provide mechanisms for consolidation of memories, behaviours
- Local synchronous activity can recruit other regions
- Mechanism for spread is intrinsic
- Subverted by imbalances in excitation/inhibition

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13
Q

What are two electrical diagnostic tools used for epilepsy?

A

Electroencephalogram (EEG)

Telemetry (EEG + Video)

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14
Q

What are five imaging diagnostic tools used for epilepsy?

A

CT

MRI

fMRI

SPECT

PET

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15
Q

What does a sudden high amplitude discharge on an EEG indicate?

A

Generalized seizure = ictal

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16
Q

What are pros and cons of a surface EEG?

A
  • Pros
    • Simple to implement
    • Localization possible
    • Diagnostic
  • Cons:
    • limited range (surface of cortex - not as precise as other methods)
    • Signal very small (micro volts)
    • Signal-Noise relatively poor
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17
Q

And intracranial EEG can identify ____

A

And intracranial EEG can identify* damaged tissue causing seizures and remove* - must record 1+ seizures brain exposed electrodes placed on sterile sheet

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18
Q

Pros and cons of Intracranial EEG

A
  • Pros:
    • Much larger signals
    • Better localization
    • Lower noise
  • Cons
    • Much more difficult (major surgery - risk infection)
    • Risk of complications
    • Only used when there is no other option and they’re confident it will work
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19
Q

How are MRI images used to diagnose epilepsy?

A

Look for temporal lobe lesions - repeated seizures kills tissue

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20
Q

Pros and Cons of MRI images - TL lesions?

A
  • Pros
    • Good resolution
    • Picks up clear lesions
    • Frequently diagnostic
  • Cons:
    • Poor at diffuse lesions (eg small heterotopias - nerve cells from neocortex end up in hippocampus (don’t speak same language))
    • Interpretation sometimes ambiguous
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21
Q

What is SPECT?

A

Single Proton Emission Computed Tomography

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22
Q

How is SPECT used to identify seizure?

A

Seizure = increased glucose uptake

  • inject radioactive marker 99Tc or 201Th
  • Uptake of tracer greater where activity is greater (local perfusion increase) - results in more tracer in an area
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23
Q

Pros and Cons of SPECT?

A

Single Proton Emission Computed Tomography

  • Pros:
    - Shows area of activity
    - Possible to differentiate ambiguous foci
  • Cons
    - Resolution limited
    - Requires injection of tracer during seizure
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24
Q

What is positron emission tomography? (PET)

A

Positron (anti-electron) emitting atoms - short lived isotopes, some with 20 min half life

  • monitor uptake
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25
Q

What isotopes are used in positron emission tomography? What are their half lives?

A
  • Carbon - 11 (20 min)
  • Nitrogen-13 (10min)
  • Oxygen-15 (2 min)
  • Fluorine-18 (110min)
26
Q

Pros and Cons of Positron emission tomography?

A
  • Pros:
    • Very good spatial resolution
    • Activity mapping possible
    • Metabolic studies possible
  • Cons:
    • Tracer must be injected during seizure
    • Very expensive
    • Instruments rare
    • Competition with other types of patients
    • PET used for cancer diagnosis (tumour have high glucose uptake)
27
Q

What are medical tx of epilepsy?

A

Pharmacotherapy

28
Q

Non medical tx of epilepsy?

A
  • Surgical
  • Vagal nerve stimulators
29
Q

What types of drugs are used for generalized T-C?

A

MES1

Maximal electroshock - increase threshold for seizure (gen/partial)

30
Q

What types of drugs are used for absence seizures?

A

PTZ2

Pentylenetretrazole

31
Q

Why is seizure classification important for treatment?

A

Classification determines tx

Wrong diagnosis = poor control

Poor control = elevated dosage

Elevation of wrong drugs = toxicity

32
Q

How are seizures classified?

A
  1. Partial Seizures
    • Localized onset (clinical obs, EEG)
    • Simple
    • Complex
  2. Generalized Seizures
    • Localization not possible
33
Q

What are the two types of Partial Seizures?

A
  • Simple Partial
    - Abnormal discharge, minimal spread, consciousness preserved (recall what happened during)
    - Electrographically classified = no spread
  • Complex Partial:
    • Localized discharge, wider spread (usually bilateral)
    • Sometimes “aura” - sense that seizure is starting
    • Alteration in consciousness, automatisms (fragmented behaviours - lip smacking, swallowing etc)
34
Q

Simple Partial
- Discharge
- Spread
- Consciousness
- Classified by?

A

Simple Partial
- Abnormal discharge, minimal spread, consciousness preserved (recall what happened during)
- Electrographically classified = no spread

35
Q

Complex Partial:
- Discharge
- Spread
- Aura?
- Consciousness

A

Complex Partial:
- Localized discharge, wider spread (usually bilateral)
- Sometimes “aura” - sense that seizure is starting
- Alteration in consciousness, automatisms (fragmented behaviours - lip smacking, swallowing etc)

36
Q

Partial seizures can ________ secondarily

A

Partial seizures can generalize secondarily

Complex partial seizures can generalize to generalized tonic-clonic seizures

37
Q

What are the types of Generalized Seizures?

A
  • Generalized tonic clonic (GTC - Grand mal)
  • Absence (petit mal)
  • Myoclonic Jerks
  • Atonic
  • Infantile Spasms
38
Q

Generalized tonic clonic (GTC - Grand mal)
- presentation
- lasting
- Post
- Drugs used to tx are essentially same as used for ____

A

Generalized tonic clonic (GTC - Grand mal)
- Full blown attack, rigidity, (tonus) followed by alternating relaxation and rigidity, then jerking of the body (clonus)
- gradual (1-2 min)
- Postictal stupor (brain is exhausted)
- Drugs used to tx are essentially same as used for complex partial seizures

39
Q

Absence (petit mal)
- ____ onset and cessation
- Presentation
- Often?
- Characteristic ____ EEG

A

Absence (petit mal)
- Sudden onset and cessation = brief
- Staring, altered consciousness, sometimes mild jerking of eyelids, extremities
- Frequent (up to 100’s/day)
- Characteristic 3 Hz spike and wave EEG

40
Q

Myoclonic Jerks (generalized seizure)

A

Symptom of variety of seizures - but entity by itself

41
Q

Atonic Generalized seizure

A
  • sudden loss of postural tone
  • Pt drops to floor
    • often results in injuries
    • Linked to childhood epilepsy syndromes
42
Q

Infantile spasms (generalized seizures)

A
  • Syndrome - heterogeneous
  • Associated with mental retardation
  • Drugs effect in some cases only
  • Successful tx rarely helps retardation
43
Q

Mechanisms of Anticonvulsant drugs:

A
  • voltage-dependent channels
    • T-type Ca++ channels supression
  • ligand-gated channels
    • GABAA receptor potentiation
44
Q

Mechanisms of antiepileptic Drugs:

A

Voltage-Dependent Channels

  • Effects on Na+ channels - prolong inactivation
    • makes repetitive firing more difficult
  • Protect against focal (partial) seizures
    • Phenytoin
    • Carbamazepine
    • Lamtrigine
45
Q

3 examples of antiepileptic drugs?

A
  • Phenytoin
  • Carbamazepine
  • Lamotrigine

Idea is to find drug that targets inactivated Na+ channels
- Preferentially inhibits overly active Na+ channels = prevent repetitive firing

46
Q

How do voltage-dependent anticonvulsant drugs work?

A
  • Target T-type Ca++ channels - suppress activity
  • Stops oscillatory behaviour (bursts)
  • Ethosuxamide
  • Dimethadione
  • (meds like carbamazepine do NOT help)
47
Q

2 examples of anticonvulsant drugs that target Voltage dependent channels (T-Type Ca++)

A
  • Ethosuxamide
  • Dimethadione
  • (meds like carbamazepine do NOT help)
48
Q

Ligand-Gated channels anticonvulsant drug mechanisms:

A
  • Target GABAA receptor - potentiate action
  • Directly:
    • Benzodiazepines
    • Barbiturates
    • Topiramate
  • Indirectly:
    • via reduce reuptake/metabolism of GABA
      - Gabapentin
      - Tiagabine
      - Vigabatrin
49
Q
  • Anticonvulsant Drugs used to target Ligand-Gated channels (GABAA)
  • Directly: (3)
  • Indirectly: (2) - mechanism?
A

Target GABAA receptor - potentiate action
- Directly:
- Benzodiazepines
- Barbiturates
- Topiramate
- Indirectly:
- via reduce reuptake/metabolism of GABA
- Gabapentin
- Tiagabine
- Vigabatrin

50
Q

Phenytoin:

  • Acts on:
  • Blocks:
  • Useful against:
A

Phenytoin:

  • Oldest nonsedative antiseizure drug
  • Acts on:
    - Na+, K+, Ca++ conductances
  • Blocks:
    - Repetitive firing (binds to inactive state to prevent activation)
    - Use-dependent block of Na+ channel
    - Binds preferentially to inactive state
  • Useful against:
    - partial and Generalized Tonic Clonic seizures (especially when secondary to other type)
51
Q

Carbamazepine:

  • Related to ____ antidepressants
  • Action similar to ____
  • Preferred first-line drug for ____ seizures
  • Can be combined with ____
A

Carbamazepine:

  • Related to tricyclic antidepressants
  • Action similar to phenytoin
    - Acts on:
    - Na+, K+, Ca++ conductances
    - Blocks:
    - Repetitive firing (binds to inactive state to prevent activation
    - Use-dependent block of Na+ channel
    -> Binds preferentially to inactive state
  • Preferred first-line drug for partial seizures
  • Can be combined with phenytoin for refractory epilepsies
52
Q

Ethosuximide:

  • Acts via suppression of ____
  • Effective for ____ seizures
  • Suppresses characteristic ____
A

Ethosuximide:

  • Acts via suppression of* T-type Ca++ channels (support bursting)*
  • Effective for absence seizures
  • Suppresses characteristic 3Hz spike-and-wave (thalamocortical oscillations)
53
Q

Valproic acid/Na+ Valproate
- Effective against ____ seizures
- Mechanism:

A

Valproic acid/Na+ Valproate
- Effective against absence, myoclonic seizure, primarty GTC seizures
- Mechanism: unknown
- May involve increasing expression of inhibitory peptides in brain (increase release NPY - suppress presynaptic glutamate release)
- May cause developmental issues in offspring

54
Q

Phenobarbital:

  • Potentiates ____ action
  • Drug of choice only in patients age ____
  • Suppresses ____
A

Phenobarbital:

  • Potentiates GABAA action
  • Drug of choice only in patients age < 2 y.o
  • Suppresses excitatory transmission => increase inhibition caused by GABA
  • Heavily sedates
55
Q

____ is a prodrug that is converted to phenobarbital

A

Primidone is a prodrug that is converted to phenobarbital

56
Q

Efficacy of primidone vs carbamazepine, phenytoin?

A

Primidone is less effective than carbamazepine, phenytoin

57
Q

Benzodiazepines:

  • examples: (3)
  • Used for ____
  • 2 biggest problems:
A

Benzodiazepines:

  • examples: (3)
    • Diazepam, lorazepam, clonazepam etc
  • Used for status epilepticus - rarely used longterm
  • 2 biggest problems:
    • Tolerance - shift if types of GABA receptors in Brain
    • Sedation
58
Q

Tiagabine:

  • inhibits:
  • preference for ____
  • Useful as ____
A

Tiagabine:

  • inhibits: GABA uptake - rational design
  • preference for GAT-1 (forebrain and hippocampus)
  • GABA remains in synapse longer
  • Useful as adjunctive therapy, some use as monotherapy

*GAT-1 takes GABA into cell => good for limbic system seizures

59
Q

Why is tiagabine good for limbic system seizures?

A

Preference for GAT-1 => GAT-1 take GABA into cell

Tiagabine inhibits GABA reuptake

GAT-1 is found in forebrain and hippocampus

60
Q

Lamotrigine

  • Action like ____ on ____ and ____ channels
  • Effective in ____ and ____ epilepsies
  • Most studies as ____
  • Pediatric patient off-target effect
A

Lamotrigine

  • Action like phenytoin on Ca++ and Na+ channels
  • Effective in partial and absence epilepsies
  • Most studies as add-on therapy, monotherapy now more common for partial seizures
  • Pediatric patient off-target effect
    - Potentially life-threatening Rash

PMCOL 371 (18 decks)

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