antiepileptics lecture Flashcards
Seizure
Seizure – a discrete clinical event that results in the abnormal discharge of a set of neurons in the brain
– “A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.”
one seizure=epilepsy?
A single seizure does NOT mean someone has epilepsy!
Epilepsy
Epilepsy – at least 2 unprovoked seizures
– Network disease and not a localized brain abnormality (no specific cortex)
Convulsive Status Epilepticus
Convulsive Status Epilepticus – failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures.
– length of seizure beyond 5 minutes
– second seizure without recovery from the first
– repeated seizures lasting 30 minutes or longer
likley contributor to Convulsive Status Epilepticus
defect in GABA
how can we use signs present in a seizure to localize it in the cortex?
by using the different fucntions of the cortex (occipital vas motor, etc.)
motor cortex signs
twitching/jerking in arms, face, shoulder, legs
frontal lobe invovlement signs
planning, actions,
reward, abstract
loss of these
auditory cortex involvment
ringing or buzzing sounds
temporal lobe involvment
fear, depression, joy, anger
wernickes area involvment
understanding or
forming speech
occipital lobe invovlment
hallucinations
somatosensory or association cortex involvment
numbness or tingling
epilepsy epidemiolgy
* Impacts and estimated?
– new cases diagnosed each year
– greater mortality (sudden unexplained death)
* Most often presents in?
– % of US population experience seizure in lifetime
* distribution?
* Risk increased with?
* costs
- Impacts and estimated 2 to 3 million Americans (1%)
– 150,000 to 200,000 new cases diagnosed each year
– 2 to 3 times greater mortality (sudden unexplained death) - Most often presents in infancy and childhood
– 0.5 % - 1% children have epilepsy
– 10% of US population experience seizure in lifetime - Bimodal distribution of occurrence
– Newborn/young children and > 65 years of age - Risk increased with traumatic brain injuries
- > $12.5 billion is estimated in indirect and direct costs
International League Against
Epilepsy (ILAE) Epilepsy Etiologies
- Genetic
- Structural
- Infectious
- Metabolic
- Immune
- Unknown
genetic seizures causes
Genetic – usually present at a young age
– Dravet Syndrome – mutations in sodium channel, type I alpha subunit
– Childhood Absence Epilepsy – mutations in T-Type Ca2+ channels and GABA receptor subunits
structural seizure causes
Structural – abnormalities found with neuronal imaging, e.g.
cortical dysplasia, posttraumatic epilepsy
Infectious seizure causes
Infectious – neurocysticercosis (parasite), meningitis, encephalitis
Metabolic seizure causes
Metabolic – abnormal glycogen metabolism (Lafora Disease)
immune seizure causes
anti-NMDA receptor encephalitis (autoimmune)
important action potential numbers
-70 and -55mV
Seizure Pathophysiology:
* Excessive excitation?
– Neuronal hyperexcitability -
– Alterations in?
– Defects in?
– Abnormal?
- Excessive excitation of cortical neurons (hyperexcitable / hypersynchronization)
– Neuronal hyperexcitability - Enhanced predisposition of neuronal depolarization and discharge when stimulated
– Alterations in the properties of ion channels in the neuronal membrane
– Defects in ion transport (ATPases) across neuronal membranes
– Abnormal synaptic vesicle protein 2-A
Alterations in the properties of ion channels in the neuronal membrane
* which ions?
* Carbamazepine and Phenytoin help how?
* Benzodiazepines help how?
* Genetic mutations?
- K+, Na+, Ca2+, Cl-
- Carbamazepine and Phenytoin reduce neuronal excitability by binding sodium channels in the inactive state and slow channel recovery from inactivation, preventing hyperexcitable neurons from rapidly and repetitively firing
- Benzodiazepines bind gamma subunit of GABA-A and increase chloride ion conductance
- Genetic mutations have been identified in these ion channels
Defects in ion transport (ATPases) across neuronal membranes
- Sodium / Potassium / Calcium / Chloride
- Abnormality in potassium conductance
Abnormal synaptic vesicle protein 2-A
targeted by?
- Normally responsible for fusion of vesicles to membrane, but get upregulated in some epilepsies (levetiracetam and brivaracetam target)
Additional Considerations of seizure pathophys
– modification of receptors?
– Modulation of ?
– Changes in ?
– NT uptake/metab?
* GABA-T?
– Modifications in the?
Additional Considerations
– Biochemical modification of receptors
– Modulation of second messaging systems and gene expression
– Changes in extracellular ion concentrations
– Alterations in neurotransmitter uptake and metabolism in glial cells
* GABA-T inhibition to increase GABA
– Modifications in the ratio and function of inhibitory circuits
Transitory imbalance in neurotransmitters
– Enhanced excitatory neurotransmission
* Glutamate / Aspartate
Ionotropic glutamate receptors:
NMDA / AMPA / Kainate
Additional Seizure
Etiological Considerations
- Cerebrovascular abnormality
- Tumors
- Head trauma
- Infection
- Hypoxia
- Fever
- Medications and Seizure medications
- Drug Intoxication
- Metabolic disturbance
- Electrolyte disturbance
- Alcohol withdrawal
- Sleep deprivation
- Hormonal changes
- Stress
- Prenatal or birth injury
- Congenital malformation
drug intoxication causing seizures
cocaine/ephederine
what rx could induce seizures/lower threshold
clozapine
bupropion
carbamazepine
TCAs
tramadol used with ssri
metabolic disturbamces causing seizures
high/low glucose
electrolyte distrubances causing lower threshold
Ca, Na, Mg
Seizure Recurrence Risk Factors:
* EEG?
* Seizure occurs during?
* family?
* Prior?
* Down’s Syndrome and cerebral palsy?
+ for these may indicate>?
- Abnormal EEG
- Seizure occurs during sleep
- Positive family history (sibling)
- Prior acute seizure
- Down’s Syndrome and cerebral palsy
– No clear association of seizure type
– No association with seizure length
– No association with age of onset
positive for these you may consider tx after only 1 seizure
ILAE Classification of Seizure Types
Generalized Seizures
- Originate at some point within and rapidly engage bilaterally distributed networks
- Can include cortical and subcortical structures but not necessarily the entire cortex
- all involve loss of consciousness and both hemispheres
Focal Seizures
- Originate within networks limited to one hemisphere
- May be discretely localized or more widely distributed and become geberalized
focal onset seizure types
generalized seizure onset types
seizure terminology:
* tonic:
* atonic:
* myoclonic:
* clonic?
Childhood Epilepsy
* Many children who experience a seizure, become?
* Most seizures are?
* Rarely do seizures cause?
* Medications may cause?
* Children with idiopathic first seizure and normal EEG have?
* Rule-out:
- Many children who experience a seizure, become seizure free
- Most seizures are brief
- Rarely do seizures cause long-term brain damage without neurologic insult
– Hypoxia in first 24-48 hours increases risk - Medications may cause long-term side effects
- Children with idiopathic first seizure and normal EEG have favorable prognosis
- Rule-out: fever, infection, trauma
What do EEG’s Tell Us?
- Graphical representation of cortical electrical activity
- Provides high temporal resolution, poor spatial resolution of cortical disorder
- Most important neuropsychological assessment tool for diagnosis, and subsequent treatment
Importance of Detailed History for seizures:
* Identifiable source?
* Precipitating events?
* Age?
* EEG?
* Severity?
* Family?
* Observe and note the?
questions to ask pt
- Identifiable source (infection /trauma/medication)
– *Phenothiazines, TCA’s, clozapine, bupropion
– *Unmasking: CBZ, Phenytoin, gabapentin, Phenobarbital (absence) - Precipitating event (stress)
– Labs: hypoglycemia, hyponatremia, infection - Age of onset / frequency
- EEG patterns
- Severity
– Describe the type of movements, sounds, visual observations - Family history – genetic considerations
- Observe and note the before, during, and after suspected seizure activity (post-ictal)
When is Seizure Treatment
Appropriate??
- After two or more seizures.
- Treat after first seizure if:
– Idiopathic and abnormal EEG
– Symptomatic and abnormal EEG
– Prior neurologic abnormality
– Positive family history
Treatment Goals for seizures
1) Prevent occurrence of seizures (no seizure)
2) Prevent or reduce drug side effects and drug interactions
3) Prevent the development of neurologic changes
4) Improve the patient’s quality of life
Prevent occurrence of seizures goals
– Decrease frequency and severity
Preventing the development of neurologic changes
– Longer seizures =
– Increased glutamate exposure =
– Repeated GTC or Status Epilepticus =
– Longer seizures = more ischemia
– Increased glutamate exposure = neuronal damage
– Repeated GTC or Status Epilepticus = cognitive decline
Improving the patient’s quality of life with seizure tx
– Provide cost-effective care (limit polypharmacy)
– Ensure patient satisfaction
– Prevent toxicity
– Ability to participate and complete ADL’s
Targets for Treatment of seizures
Reasons Treatments Don’t Work
1) Inappropriate treatment
Select the wrong drug
2) Inappropriate dose (phenyotin suspension)
3) Poor compliance / lack of education
Drug storage issues (CBZ)
Drug administration issues (phenytoin suspension)
4) Drug interactions
Cytochrome P450
P-glycoprotein
5) Seizure refractoriness
When can you consider stopping medication treatments?
* Seizure free for? differences with type?
* neuro exam/IQ
* EEG
* Epilepsy of?
– History of control within?
* No?
When can you consider stopping
medication treatments?
* Seizure free 2 to 4 years depending on seizure type
– 2 years for absence
– 4 years for partial, tonic-clonic
* Normal neurological exam / normal IQ
* Normal EEG with treatment
* Epilepsy of single seizure type
– History of control within one year
* No juvenile or myoclonic epilepsy
