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PMCOL 371 - Cellular Neuroscience > 14 - epilepsy > Flashcards

14 - 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
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?
* 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 _GABA_A 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 - Cellular Neuroscience (19 decks)

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