PMCOL 371 > 15 - Epilepsy > Flashcards

15 - Epilepsy Flashcards

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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
What isotopes are used in positron emission tomography? What are their half lives?
- Carbon - 11 (20 min) - Nitrogen-13 (10min) - Oxygen-15 (2 min) - Fluorine-18 (110min)
26
Pros and Cons of Positron emission tomography?
- 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
What are medical tx of epilepsy?
Pharmacotherapy
28
Non medical tx of epilepsy?
- Surgical - Vagal nerve stimulators
29
What types of drugs are used for generalized T-C?
MES1 Maximal electroshock - increase threshold for seizure (gen/partial)
30
What types of drugs are used for absence seizures?
PTZ2 Pentylenetretrazole
31
Why is seizure classification important for treatment?
Classification determines tx Wrong diagnosis = poor control Poor control = elevated dosage Elevation of wrong drugs = toxicity
32
How are seizures classified?
1. Partial Seizures - Localized onset (clinical obs, EEG) - Simple - Complex 2. Generalized Seizures - Localization not possible
33
What are the two types of Partial Seizures?
- 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
**Simple Partial** - Discharge - Spread - Consciousness - Classified by?
**Simple Partial** - Abnormal discharge, minimal spread, consciousness preserved (recall what happened during) - Electrographically classified = no spread
35
Complex Partial: - Discharge - Spread - Aura? - Consciousness
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
Partial seizures can ________ secondarily
Partial seizures can *generalize* secondarily Complex partial seizures can generalize to generalized tonic-clonic seizures
37
What are the types of Generalized Seizures?
- Generalized tonic clonic (GTC - Grand mal) - Absence (petit mal) - Myoclonic Jerks - Atonic - Infantile Spasms
38
Generalized tonic clonic (GTC - Grand mal) - presentation - lasting - Post - Drugs used to tx are essentially same as used for ____
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
Absence (petit mal) - ____ onset and cessation - Presentation - Often? - Characteristic ____ EEG
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
Myoclonic Jerks (generalized seizure)
Symptom of variety of seizures - but entity by itself
41
Atonic Generalized seizure
- sudden loss of postural tone - Pt drops to floor - often results in injuries - Linked to childhood epilepsy syndromes
42
Infantile spasms (generalized seizures)
- Syndrome - heterogeneous - Associated with mental retardation - Drugs effect in some cases only - Successful tx rarely helps retardation
43
Mechanisms of Anticonvulsant drugs:
- voltage-dependent channels - T-type Ca++ channels supression - ligand-gated channels - GABAA receptor potentiation
44
Mechanisms of antiepileptic Drugs:
Voltage-Dependent Channels - Effects on Na+ channels - prolong inactivation - makes repetitive firing more difficult - Protect against focal (partial) seizures - Phenytoin - Carbamazepine - Lamtrigine
45
3 examples of antiepileptic drugs?
- Phenytoin - Carbamazepine - Lamotrigine Idea is to find drug that targets *inactivated Na+ channels* - Preferentially inhibits overly active Na+ channels = prevent repetitive firing
46
How do voltage-dependent anticonvulsant drugs work?
- Target T-type Ca++ channels - suppress activity - Stops oscillatory behaviour (bursts) - Ethosuxamide - Dimethadione - (meds like carbamazepine do NOT help)
47
2 examples of anticonvulsant drugs that target Voltage dependent channels (T-Type Ca++)
- Ethosuxamide - Dimethadione - (meds like carbamazepine do NOT help)
48
Ligand-Gated channels anticonvulsant drug mechanisms:
- Target GABAA receptor - potentiate action - Directly: - Benzodiazepines - Barbiturates - Topiramate - Indirectly: - via reduce reuptake/metabolism of GABA - Gabapentin - Tiagabine - Vigabatrin
49
- Anticonvulsant Drugs used to target Ligand-Gated channels (GABAA) - Directly: (3) - Indirectly: (2) - mechanism?
Target GABAA receptor - potentiate action - Directly: - Benzodiazepines - Barbiturates - Topiramate - Indirectly: - via reduce reuptake/metabolism of GABA - Gabapentin - Tiagabine - Vigabatrin
50
Phenytoin: - Acts on: - Blocks: - Useful against:
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
Carbamazepine: - Related to ____ antidepressants - Action similar to ____ - Preferred first-line drug for ____ seizures - Can be combined with ____
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
Ethosuximide: - Acts via suppression of ____ - Effective for ____ seizures - Suppresses characteristic ____
Ethosuximide: - Acts via suppression of* T-type Ca++ channels (support bursting)* - Effective for *absence* seizures - Suppresses characteristic *3Hz spike-and-wave (thalamocortical oscillations)*
53
Valproic acid/Na+ Valproate - Effective against ____ seizures - Mechanism:
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
Phenobarbital: - Potentiates ____ action - Drug of choice only in patients age ____ - Suppresses ____
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
____ is a prodrug that is converted to phenobarbital
*Primidone* is a prodrug that is converted to phenobarbital
56
Efficacy of primidone vs carbamazepine, phenytoin?
Primidone is less effective than carbamazepine, phenytoin
57
Benzodiazepines: - examples: (3) - Used for ____ - 2 biggest problems:
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
Tiagabine: - inhibits: - preference for ____ - Useful as ____
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
Why is tiagabine good for limbic system seizures?
Preference for GAT-1 => GAT-1 take GABA into cell Tiagabine inhibits GABA reuptake GAT-1 is found in forebrain and hippocampus
60
Lamotrigine - Action like ____ on ____ and ____ channels - Effective in ____ and ____ epilepsies - Most studies as ____ - Pediatric patient off-target effect
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
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