15 - Epilepsy Flashcards
What is a seizure?
Finite period of brain dysfunction resulting from abnormal discharge of cerebral neurons
What are three causes of seizures?
- Exces of excitation - glutamate major player
- Some drugs work to reduce glutamate release - Insufficient inhibition
- Some drugs work to enhance inhibition, mainly via GABAA receptors - Elevated excitability
- Some drugs work to reduce this at several levels
Normal activity - ____ amplitude, ____ frequency
Normal activity - low amplitude, high frequency
Synchrony - sometimes natural such as ____
Occur during:
Synchrony - sometimes natural such as hippocampal sharp waves
Occur during:
- immobility
- Consummatory behaviour
- Sleep
Epilepsy results from inappropriate ____
Epilepsy results from inappropriate synchrony
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 ____
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
Reciprocal excitation can result in ____
Reciprocal excitation can result in epileptiform events
Hippocampal network patterns predict ____
Hippocampal network patterns predict behaviour
Hippocampal network patterns predict ____
Hippocampal network patterns predict behaviour
Synchronous, rhythmic discharge of interneurons regulates timing of ____
Synchronous, rhythmic discharge of interneurons regulates timing of pyramidal cell discharge
What is a Sharp wave ripple?
50-60,000 neurons discharge in concert in the CA3-CA1-subiculum-presubiculum-EC axis
Neuronal networks in the limbic system:
- Normally provide mechanisms for ____
- ____ can recruit other regions
- ____ is intrinsic
- Subverted by imbalances in ____
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
What are two electrical diagnostic tools used for epilepsy?
Electroencephalogram (EEG)
Telemetry (EEG + Video)
What are five imaging diagnostic tools used for epilepsy?
CT
MRI
fMRI
SPECT
PET
What does a sudden high amplitude discharge on an EEG indicate?
Generalized seizure = ictal
What are pros and cons of a surface EEG?
- 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
And intracranial EEG can identify ____
And intracranial EEG can identify* damaged tissue causing seizures and remove* - must record 1+ seizures brain exposed electrodes placed on sterile sheet
Pros and cons of Intracranial EEG
- 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
How are MRI images used to diagnose epilepsy?
Look for temporal lobe lesions - repeated seizures kills tissue
Pros and Cons of MRI images - TL lesions?
- 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
What is SPECT?
Single Proton Emission Computed Tomography
How is SPECT used to identify seizure?
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
Pros and Cons of SPECT?
Single Proton Emission Computed Tomography
- Pros:
- Shows area of activity
- Possible to differentiate ambiguous foci - Cons
- Resolution limited
- Requires injection of tracer during seizure
What is positron emission tomography? (PET)
Positron (anti-electron) emitting atoms - short lived isotopes, some with 20 min half life
- monitor uptake
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)
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)
What are medical tx of epilepsy?
Pharmacotherapy
Non medical tx of epilepsy?
- Surgical
- Vagal nerve stimulators
What types of drugs are used for generalized T-C?
MES1
Maximal electroshock - increase threshold for seizure (gen/partial)
What types of drugs are used for absence seizures?
PTZ2
Pentylenetretrazole
Why is seizure classification important for treatment?
Classification determines tx
Wrong diagnosis = poor control
Poor control = elevated dosage
Elevation of wrong drugs = toxicity
How are seizures classified?
- Partial Seizures
- Localized onset (clinical obs, EEG)
- Simple
- Complex
- Generalized Seizures
- Localization not possible
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)
Simple Partial
- Discharge
- Spread
- Consciousness
- Classified by?
Simple Partial
- Abnormal discharge, minimal spread, consciousness preserved (recall what happened during)
- Electrographically classified = no spread
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)
Partial seizures can ________ secondarily
Partial seizures can generalize secondarily
Complex partial seizures can generalize to generalized tonic-clonic seizures
What are the types of Generalized Seizures?
- Generalized tonic clonic (GTC - Grand mal)
- Absence (petit mal)
- Myoclonic Jerks
- Atonic
- Infantile Spasms
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
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
Myoclonic Jerks (generalized seizure)
Symptom of variety of seizures - but entity by itself
Atonic Generalized seizure
- sudden loss of postural tone
- Pt drops to floor
- often results in injuries
- Linked to childhood epilepsy syndromes
Infantile spasms (generalized seizures)
- Syndrome - heterogeneous
- Associated with mental retardation
- Drugs effect in some cases only
- Successful tx rarely helps retardation
Mechanisms of Anticonvulsant drugs:
- voltage-dependent channels
- T-type Ca++ channels supression
- ligand-gated channels
- GABAA receptor potentiation
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
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
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)
2 examples of anticonvulsant drugs that target Voltage dependent channels (T-Type Ca++)
- Ethosuxamide
- Dimethadione
- (meds like carbamazepine do NOT help)
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
- via reduce reuptake/metabolism of GABA
- 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
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)
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
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)
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
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
____ is a prodrug that is converted to phenobarbital
Primidone is a prodrug that is converted to phenobarbital
Efficacy of primidone vs carbamazepine, phenytoin?
Primidone is less effective than carbamazepine, phenytoin
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
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
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
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
