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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
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
  • 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 GABA<u>A</u> 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 - Cellular Neuroscience (19 decks)

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