epilepsy · 2018. 6. 11. · choosing antiepileptic drugs •! seizure type •! epilepsy syndrome...
TRANSCRIPT
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Epilepsy
Dr.Yotin Chinvarun M.D., Ph.D.
Comprehensive Epilepsy and Sleep disorder Program
PMK hospital
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Definitions
•! Seizure: the clinical manifestation of an abnormal
and excessive excitation of a population of cortical
neurons
•! Epilepsy: a tendency toward recurrent seizures
unprovoked by systemic or neurologic insults
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Epidemiology of Seizures and Epilepsy
•! Seizures
–!Incidence: approximately 80/100,000 per year
–!Lifetime prevalence: 9%
(1/3 benign febrile convulsions)
•! Epilepsy
–!Incidence: approximately 45/100,000 per year
–!Point prevalence: 0.5-1%
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Classification of epilepsy
•! Seizure classification is important, guiding the
investigation, therapy, and prognosis of seizure
types. The major subdivisions are
•! Primarily generalised seizures
•! Partial seizures
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International classification of epilepsies
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International classification of epilepsies
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International classification of epilepsies
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Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily
Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
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Partial Seizures
•! Simple
•! Complex
•! Secondary generalized
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Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily Generalized
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Simple Partial Seizure Subclassification
•! With motor signs
•! With somatosensory or special sensory symptoms
•! With autonomic symptoms or signs
•! With psychic symptoms (disturbance of higher cerebral function)
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EEG: Simple Partial Seizure
•! Left parietal-
posterior
temporal
seizure
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Seizures
Partial Generalized
Simple Partial
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! Impaired
consciousness
! Clinical manifestations vary
with site of origin and
degree of spread
•! Presence and nature
of aura
•! Automatisms
•! Other motor activity
! Duration typically < 2
minutes
Seizures
Partial Generalized
Complex Partial
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Complex Partial Seizures
•! Impaired consciousness
•! Clinical manifestations vary with site of origin and degree of
spread
–! Presence and nature of aura
–! Automatisms
–! Other motor activity
•! Duration (15 sec.—3 min.)
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! Begins focally, with or without focal neurological symptoms
! Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases
! Typical duration 1-3 minutes
! Postictal confusion, somnolence, with or without transient focal deficit
Seizures
Partial Generalized
Secondarily
Generalized
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Secondarily Generalized Seizures
•! Assumed or observed to begin as simple and/or complex partial
seizures
•! Variable symmetry, intensity, and duration of tonic (stiffening)
and clonic (jerking) phases
•! Usual duration 30-120 sec.
•! Postictal confusion, somnolence, with or without transient focal
deficit
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Right temporal
seizure with
maximal phase
reversal in the
right sphenoidal
electrode
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Continuation of same
seizure
Right temporal
seizure with maximal
phase reversal in the
right sphenoidal
electrode
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Seizures
Partial Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
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! Brief staring spells (“petit mal”) with impairment of awareness
!! 3-20 seconds
!! Sudden onset and sudden resolution
!! Often provoked by hyperventilation
!! Onset typically between 4 and 14 years of age
!! Often resolve by 18 years of age
! Normal development and intelligence
! EEG: Generalized 3 Hz spike-wave discharges
Seizures
Partial Generalized
Absence
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Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily
Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
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Primary generalized seizures
•! Have a bilateral symmetrical onset.
•! The clinical manifestations are diverse, and include:-
•! Tonic,
•! clonic, or
•! tonic-clonic(‘grand mal’)
•! Absence
•! Myoclonus
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EEG: Absence Seizure
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! Brief staring spells with variably reduced responsiveness
!! 5-30 seconds
!! Gradual (seconds) onset and resolution
!! Generally not provoked by hyperventilation
!! Onset typically after 6 years of age
! Often in children with global cognitive impairment
! EEG: Generalized slow spike-wave complexes (<2.5 Hz)
! Patients often also have Atonic and Tonic seizures
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! Brief, shock-like jerk of a muscle or group of muscles
! Epileptic myoclonus
!! Typically bilaterally synchronous
!! Impairment of consciousness difficult to assess (seizures <1 second)
!! Clonic seizure – repeated myoclonic seizures (may have impaired awareness)
! Differentiate from benign, nonepileptic myoclonus (e.g., while falling asleep)
! EEG: Generalized 4-6 Hz polyspike-wave discharges
Seizures
Partial Generalized
Myoclonic
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Tonic seizures
!! Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck
!! Duration - 2-20 seconds.
!! EEG – Sudden attenuation with generalized, low-voltage fast activity (most common) or generalized polyspike-wave.
Atonic seizures
!! Sudden loss of postural tone
!! When severe often results in falls
!! When milder produces head nods or jaw drops.
!! Consciousness usually impaired
!! Duration - usually seconds, rarely more than 1 minute
!! EEG – sudden diffuse attenuation or generalized polyspike-wave
Seizures
Partial Generalized
Tonic
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!! Associated with loss of consciousness and post-ictal confusion/lethargy
!! Duration 30-120 seconds
!! Tonic phase
!! Stiffening and fall
!! Often associated with ictal cry
!! Clonic Phase
!! Rhythmic extremity jerking
!! EEG – generalized polyspikes
Seizures
Partial Generalized
Tonic-
Clonic
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Epilepsy Syndrome
Grouping of patients that share similar:
•! Seizure type(s)
•! Age of onset
•! Natural history/Prognosis
•! EEG patterns
•! Genetics
•! Response to treatment
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Epilepsy Syndromes
•! Partial epilepsies
–! Idiopathic (genetic related)
–!Symptomatic (lesion)
–!Cryptogenic (unknown cause)
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Epilepsy Syndromes (cont.)
•! Generalized epilepsies
–! Idiopathic
–! Symptomatic
–! Cryptogenic
•! Undetermined epilepsies
•! Special syndromes
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Etiology of Seizures
and Epilepsy
•! Infancy and childhood
–! Birth injury
–! Inborn error of metabolism
–! Congenital malformation
•! Childhood and adolescence
–! Idiopathic/genetic syndrome
–! CNS infection
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Etiology of Seizures
and Epilepsy (cont.)
•! Adolescence and young adult
–! Head trauma
–! Drug intoxication and withdrawal*
•! Older adult
–! Stroke
–! Brain tumor
–! Acute metabolic disturbances*
–! Neurodegenerative
*causes of acute symptomatic seizures, not epilepsy
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Questions Raised by a
First Seizure
•! Seizure or not?
•! Focal onset?
•! Evidence of CNS dysfunction?
•! Metabolic precipitant?
•! Seizure type? Syndrome type?
•! Studies?
•! Start AED?
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Seizure Precipitants
•! Low (less often, high) blood glucose
•! Low sodium
•! Low calcium
•! Low magnesium
•! Stimulant/other proconvulsant intoxication
•! Sedative or AEDs withdrawal
•! Severe sleep deprivation
•! Stress
•! Infection, fever
•! Concussion, closed head trauma
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Evaluation of a First Seizure
•! History, physical
•! Blood tests: CBC, electrolytes, glucose, Ca, Mg,
hepatic and renal function
•! Lumbar puncture only if meningitis or encephalitis
suspected and potential for brain herniation is ruled out
•! Blood or urine screen for drugs
•! Electroencephalogram
•! CT or MR brain scan
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EEG Abnormalities
•! Background abnormalities: significant asymmetries and/or
degree of slowing inappropriate for clinical state
•! Transient abnormalities associated with seizures and epilepsy
–! Spikes
–! Sharp waves
–! Spike-wave complexes
•! May be focal, lateralized, generalized
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Medical Treatment of
First Seizure
Whether to treat first seizure is
controversial
•! 16-62% will recur within 5 years
•! Relapse rate is reduced by antiepileptic drug treatment
•! Abnormal imaging, abnormal EEG or family history
increase relapse risk
•! Quality of life issues are important
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Choosing Antiepileptic Drugs
•! Seizure type
•! Epilepsy syndrome
•! Pharmacokinetic profile
•! Interactions/other medical conditions
•! Efficacy
•! Expected adverse effects
•! Cost
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!! Limited placebo-controlled trials available, particularly of newer AEDs
!! In practice, several drugs are commonly used for indications other than those for which they are officially approved/recommended
!! Choice of AED for partial epilepsy depends largely on drug side-effect profile and patient’s preference/concerns
!! Choice of AED for primary generalized epilepsy depends on predominant seizure type(s) as well as drug side-effect profile and patient’s preference/concerns
!! ILAE and AAN recommendations indications listed in the appendix
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Broad-Spectrum Agents
Valproate
Felbamate
Lamotrigine
Topiramate
Zonisamide
Levetiracetam
Rufinamide*
Narrow-Spectrum Agents
Partial onset seizures
Phenytoin
Carbamazepine
Oxcarbazepine
Gabapentin
Pregabalin
Tiagabine
Lacosamide*
Absence
Ethosuximide
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Choosing Antiepileptic Drugs (cont.)
•! Partial onset seizures
phenytoin* gabapentin
carbamazepine* phenobarbital
valproate primidone
lamotrigine felbamate**
topiramate
Tiagabine
Lacosamide
* considered by many as drugs of choice
**associated with aplastic anemia and hepatic failure
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Monotherapy for Partial Seizures
Best evidence and FDA indication:
Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate
Similar efficacy, likely better tolerated:
Lamotrigine, Gabapentin, Levetiracetam
Also shown to be effective:
Valproate, Phenobarbital, Felbamate, Lacosamide
Limited data but commonly used:
Zonisamide, Pregabalin
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Choosing Antiepileptic Drugs (cont.)
•! Generalized onset seizures
Absence: valproate* = ethosuximide
Myoclonic: valproate, clonazepam
Tonic-clonic: valproate = phenytoin
Seizures in Lennox-Gastaut Syndrome:
valproate, lamotrigine, felbamate**
* the risk of valproate-induced hepatic failure must be carefully
weighed in young children
** associated with aplastic anemia and hepatic failure
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Monotherapy for Generalized-Onset Tonic-Clonic Seizures
Best evidence and FDA Indication:
Valproate, Topiramate
Also shown to be effective:
Zonisamide, Levetiracetam
Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )
Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies
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Absence seizures
Best evidence:
Ethosuximide (limited spectrum, absence only)
Valproate
Also shown to be effective:
Lamotrigine
May be considered as second-line:
Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam
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Myoclonic Seizures
Best evidence: Valproate
Levetiracetam (FDA indication as adjunctive tx)
Clonazepam (FDA indication)
Possibly effective:
Zonisamide, Topiramate
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Lennox-Gastaut Syndrome
Best evidence/FDA indication*:
Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide
* FDA approval is for adjunctive treatment for all except clonazepam
Also effective:
Valproate
Some evidence of efficacy:
Zonisamide, Levetiracetam
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Antiepileptic Drug Monotherapy
•! Simplifies treatment, reduces adverse effects
•! Conversion to monotherapy from polytherapy
–! Eliminate sedative drugs first
–! Withdraw antiepileptic drugs slowly over
several months
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!! Drugs that may induce metabolism of other drugs:
!! carbamazepine, phenytoin, phenobarbital, primidone
!! Drugs that inhibit metabolism of other drugs:
!! valproate, felbamate
!! Drugs that are highly protein bound:
!! valproate, phenytoin, tiagabine
!! carbamazepine, oxcarbazepine
!! topiramate is moderately protein bound
!! Other drugs may alter metabolism or protein binding of antiepileptic drugs (especially antibiotics, chemotherapeutic agents and antidepressants)
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Drugs that may decrease the efficacy of hormonal contraception
–! Phenytoin
–! Carbamazepine
–! Phenobarbital
–! Topiramate*
–! Oxcarbazepine*
–! Felbamate*
*at high doses
“High-dose” birth control pills are recommended for patients taking
these medications.
Lamotrigine levels decreased by hormonal contraception
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“Therapeutic Range” of AED Serum
Concentrations
A guide not a goal
•! Limited data
•! Broad generalizations
•! Individual differences
•! Useful in:
–! Providing initial target in patients with infrequent
seizures
–! Understanding unexpected seizures or side effects,
especially with polypharmacy
–! Verifying compliance
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Often dose-related:
Dizziness
Fatigue
Ataxia
Diplopia
Irritability
!! levetiracetam
Word-finding difficulty
!! topiramate
Weight loss/anorexia
!! topiramate, zonisamide, felbamate
Weight gain
!! valproate (also associated with polycystic ovarian syndrome in young women)
!! carbamazepine, gabapentin, pregabalin
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Typically idiosyncratic:
Renal stones
!! topiramate, zonisamide
Hyponatremia
!! carbamazepine, oxcarbazepine
Aplastic anemia
!! felbamate, zonisamide, valproate, carbamazepine
Agranulocytosis
!! carabamazepine
Hepatic Failure
!! valproate, felbamate, lamotrigine, phenobarbital
Anhydrosis, heat stroke
!! topiramate
Acute closed-angle glaucoma
!! topiramate
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!! 15.9% patients ever experienced a rash attributed to an AED
!! Average rate of AED-related rash for a given AED 2.8%, 2.1% causing AED discontinuation.
!! Predictors significant in multivariate analysis: !! occurrence of another AED-rash
Arif H et al. Neurology 2007!59 60
Stevens-Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TENS)
!! severe life threatening allergic reaction
!! blisters and erosions of the skin, particularly palms/soles and
mucous membranes
!! fever and malaise
!! rare: severe risk roughly 1-10/10,000 for many AEDs
!! rapid titration of lamotrigine especially in combination with
valproate increases risk
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