Download Epilepsy

Seizure Disorders
Definition of seizures
 Time-limited paroxysmal events that result
from abnormal, involuntary, rhythmic
neuronal discharges in the brain
 Seizures are usually unpredictable
 Seizures usually brief ( < 5 minutes) and stop
spontaneously
 Convulsion, ictus, event, spell, attack and fit
are used to refer to seizures
 Seizures that are prolonged or repetitive can
be life-threatening
2
Definition of epilepsy
 Epilepsy is a disorder which is a symptom of
disturbed electrical activity in the brain,
which may be caused by a wide variety of
etiologies
 A collection of many different types of
seizures that vary widely in severity,
appearance, cause, consequence, and
management
Definition of epilepsy
 Not uncommonly, patients have other
comorbid disorders, including depression,
anxiety, and potentially neuroendocrine
disturbances.
 Patients with epilepsy also may display
neurodevelopmental delay, memory
problems, and/or cognitive impairment
Etiology of seizures
 Provoked Seizures: Triggered by certain provoking factors in
otherwise healthy brain
… Metabolic abnormalities (hypoglycemia and
hyperglycemia, hyponatremia, hypocalcemia)
… Alcohol withdrawal
… Acute neurological insult (infection, stroke, trauma)
… Illicit drug intoxication and withdrawal
… Prescribed medications that lower seizure threshold
(theophylline, TCA)
… High fever in children
 Unprovoked Seizures: Occur in the setting of persistent brain
pathology
5
TABLE 62.1 Common Causes of New-Onset Seizures
Primary or Acquired Neurological Disorders
Alzheimer's disease or other neurodegenerative diseases
Brain tumor
Central nervous system infection
Cerebrovascular disease
Febrile seizures of childhood
Genetic or developmental disorders
Head trauma
Idiopathic/genetic
Systemic or Metabolic Disorders
Alcohol abuse and withdrawal
Anoxia or ischemia
Drug overdose or toxicity
Eclampsia
Hepatic failure
Hypocalcemia
Hypoglycemia
Hypomagnesemia
Hyponatremia
Porphyria
Renal failure
Etiology of seizures
 Many medical conditions can cause
epilepsy.
 A genetic predisposition to seizures has
been observed in many forms of primary
generalized epilepsy.
 Patients with mental retardation, cerebral
palsy, head injury, or strokes are at an
increased risk for seizures and epilepsy
 In elderly, seizures are primarily of partial
onset associated with the focal neuronal
injury induced by strokes,
neurodegenerative disorders
7
Etiology of seizures
factors that precipitate seizures in susceptible
individuals.
 Hyperventilation can precipitate absence
seizures.
 Sleep, sleep deprivation, sensory stimuli,
and emotional stress increase the
frequency of seizures.
 Hormonal changes occurring around the
time of menses, puberty, or pregnancy.
8
Etiology of seizures
factors that precipitate seizures in susceptible
individuals.
 theophylline, alcohol, high-dose
phenothiazines, antidepressants
(especially maprotiline or bupropion), and
street drug use have been associated with
provoking seizures.
 Perinatal injuries and small gestational
weight at birth are risk factors for partialonset seizures.
9
Etiology of Epilepsy
 Any process that alters structure or function
of the brain neurons can cause epilepsy
 Processes that lead to structural alteration
include:
 Congenital malformation
 Degenerative disease
 Infectious disease
 Trauma
 Tumors
 Vascular process
10
TABLE 62.2 Drugs That Have Been Associated With Provoking or Drugs That
May Exacerbate Seizures
Antiarrhythmic agents (class 1B)
Antimicrobials
β-Lactams and related compounds
Isoniazid
Quinolones
Antivirals
Acyclovir
Ganciclovir
Drugs of abuse
Amphetamine
Cocaine
Ephedra
Methylphenidate
Psychotropic agents
Antidepressants
Antipsychotics
Lithium
Sedative-hypnotic drug withdrawal
Alcohol
Barbiturates (short-acting)
Benzodiazepines (short-acting)
Miscellaneous
Cyclosporine
Lindane
Flumazenil
Metoclopramide
Normeperdine (accumulation in renal failure)
OKT3
Radiographic contrast agents
Theophylline
Tramadol
Classification of seizures
 Traditionally divided into “ grand mal” and
“petit mal” seizures
 ILAE classification of epileptic seizures in
1981 based on clinical observation and EEG
findings
 Seizures were divided into partial and
generalized seizures based on loss of
consciousness
 Partial seizures were divided into simple
partial and complex partial based on
alteration of consciousness
12
CLASSIFICATION OF SEIZURES
Seizures
Loss of Consciousness?
Yes
No
Generalized Seizures
Partial Seizures
Alteration of Consciousness?
Yes
No
Complex Partial
Simple Partial
ILAE CLASSIFICATION OF SEIZURES
Partial Seizures
Generalized Seizures
Complex Partial Seizures (CPS)
Tonic-Clonic (primary tonic-clonic)
Absence
Myoclonic
Clonic
Tonic
Atonic
Atypical Absence
Infantile Spasm
–With automatism
–Without automatism
Simple Partial Seizures (SPS)
–Motor
oWith march
oWithout march
oVersive
oPostural
oPhonatory
–Sensory
oSomatosensory
oOlfactory
oVisual
oAuditory
oGustatory
oVertiginous
–Autonomic
–Psychiatric
oDysphasic
oDéjà vu or jamais vu
oCognitive
oAffective
oIllusions
oStructured hallucinations
Secondary Generalized Tonic-Clonic
Clinical presentation
Symptoms
 CP seizures can include somatosensory or
focal motor features.
 CP seizures are associated with altered
consciousness.
 Absence seizures can be almost nondetectable
with only very brief (seconds) periods of
altered consciousness.
 GTC seizures are major convulsive episodes
and are always associated with a loss of
consciousness.
Clinical presentation
 Signs
… between seizure episodes there are
typically no objective
 Laboratory Tests
… There are currently no diagnostic
laboratory tests for epilepsy.
… In some cases, GTC or CP), serum prolactin
levels can be transiently elevated.
… Lab tests done to rule out treatable causes
of seizures.
Clinical Presentation
Other Diagnostic Tests
 EEG is very useful in the diagnosis
 An epileptiform EEG is found in only approximately
50% of the patients who have epilepsy.
 A prolactin level within 10 to 20 mins of a tonic-clonic
seizure can be useful in differentiating seizure activity
from pseudoseizure activity but not from syncope.
 MRI is very useful (especially imaging of the temporal
lobes)
 CT scan typically is not helpful except in the initial
evaluation for a brain tumor or cerebral bleeding.
Generalized tonic-clonic seizures
 begin with tonic (rigid) flexion of the
extremities followed by extension.
 The tonic phase usually lasts 15 to 20
seconds and is quickly followed by the
clonic (jerking) phase, during which
there are spasms of the trunk and
extremities and often biting of the
tongue.
Generalized tonic-clonic seizures
 The clonic phase usually lasts 20 to 30
seconds and is followed by a postictal
state, during which the patient may
sleep or awaken confused and
disoriented.
 gradual return of consciousness and
orientation over a period of 15 to 30
minutes, after which the patient has no
recall of the event.
Generalized tonic-clonic seizures
 Increases in blood pressure and heart
rate, incontinence of urine or feces, and
a brief interruption of normal breathing
with cyanosis commonly accompany this
type of seizure.
Absence Seizures
 Occur primarily during childhood
 Characterized by an abrupt interruption
of consciousness followed by a fixed
stare.
 Automatisms (coordinated involuntary
movements such as lip smacking,
chewing, or grimacing) or mild clonic
movements may also occur.
Absence Seizures
 there is no loss of postural tone.
 lasts several seconds and ends as
abruptly
 may also cluster and occur as frequently
as hundreds of times a day.
Simple Partial Seizures
 Motor manifestations (e.g., clonic
jerking of one limb) or sensory
symptoms (e.g., a foul odour or visual
distortions).
 Patients can respond to their
environment throughout the attack.
Complex partial seizures
 impaired consciousness and a
heterogeneous group of abnormal
symptoms or behaviours.
 Auras precede complex partial seizures
in many patients.
 Unusual epigastric sensations are the
most common, although various motor,
sensory, or psychic symptoms (as
described for simple partial seizures)
may occur.
Complex Partial Seizures
 Consciousness is impaired for an
average of about 2 minutes.
 During this time, patients may exhibit
automatisms such as lip smacking,
buttoning or unbuttoning of clothing, or
wandering behaviour.
TREATMENT
Desired Outcome
 Accurately diagnose seizure type and
determine the etiology.
 Identify and eliminate patient-specific
seizure precipitants.
 Select optimal AED based on seizure type,
patient age, sex, and concomitant medical
conditions.
 Therapy should be individualized to attain
best possible seizure control
General approach to treatment
 identification of goals
 assessment of seizure type and
frequency
 development of a care plan
 a plan for follow-up evaluation
General approach to treatment
 Consider Patient characteristics such as age, medical
condition, ability to comply with a prescribed regimen
 For new-onset seizures decide whether to use drug
therapy or not.
 If a decision is made to start AED therapy,
monotherapy is preferred.
 Patient education and assurance of patient
understanding of the plan are essential.
… Detailed directions regarding titration, what to do in the
event of a treatment-emergent side effect, and what to do if a
seizure occurs
Treatment of Seizures
 Provoked Seizures
… Treatment directed to the provoking
factor
30
Treatment of Seizures
 Unprovoked Seizures
… First Seizure
 Usually no treatment
 Treatment initiated if risk of recurrence
is high or if a 2nd seizure could be
devastating
… Second Seizure
 Diagnosis of epilepsy is established and
risk of a third Seizure is high
 In children, some may wait for a third
seizure
31
When to start AED
 initiate prophylactic treatment following a
CNS insult likely to cause epilepsy (e.g.,
stroke or head trauma).
 AED may not be indicated in patients whose
seizures have minimal impact on their lives.
 a careful individual risk–benefit assessment.
 treatment is recommended in all persons
with a high risk of seizure recurrence
 the side effects of AEDs need to be
considered.
When to start AED
High-risk features for seizure recurrence
 symptomatic epilepsy with generalized
tonic–clonic seizures
 complex or simple partial seizures,
 idiopathic generalized epilepsies.
 Early treatment after a first GTCS has not
been shown to improve long-term prognosis
or lower mortality or the risk of injury
When to start AED
Good prognoses who may not even
require drug treatment
 uncomplicated febrile seizures
 benign idiopathic partial epilepsies
Table 58-2 Recurrence Risk for Patients Experiencing One Unprovoked Seizure
Type of Patient
Adults with single unproved
seizure
No CNS insult
First-Year Risk (%)
Fifth-Year Risk (%)
34
10
29
Sibling with seizure
29
46
No sibling with seizures
7
27
15
9
58
26
10
39
26
48
41
75
37
56
Influence of family history
EEG patterns
GSW on EEG
Normal EEG
Occurrence of previous seizure
Caused by an illness or
childhood febrile seizure
Remote symptomatic with
Todd paresis
Status epilepticus at onset
Nonpharmacologic therapy
 Diet
 Surgery
 vagus nerve stimulation (VNS).
Nonpharmacologic therapy
 Diet
… ketogenic diet devised in1920s.
… high in fat and low in CHO/ protein
… leads to acidosis and ketosis
… It requires strict control and parent
compliance.
… poorly tolerated by patients.
… Long-term effects have included kidney
stones, increased bone fractures, and
adverse effects on growth.
Nonpharmacologic therapy
 Surgery
… treatment of choice in selected patients with
refractory focal epilepsy.
… success rate 80% and 90% in properly selected
patients.
… surgery reduces the risk of epilepsy-associated
death, and it may also improve depression and
anxiety in refractory epilepsy patients.
… Learning and memory can be impaired
postoperatively, and general intellectual abilities
are also affected in a small number of patients.
Nonpharmacologic therapy
 Surgery
 A National Institutes of Health Consensus
Conference identified three absolute requirements
for surgery.
… an absolute diagnosis of epilepsy
… failure on an adequate trial of drug therapy
… definition of the electroclinical syndrome.
… Surgery may be particularly useful in children
with intractable epilepsy. Patients may need to
continue to receive AED therapy for a period of
time
Nonpharmacologic therapy
 vagus nerve stimulation (VNS).
… An implanted device approved as an
adjunctive for partial-onset seizures
refractory to AEDs.
… It is also used off-label in the treatment of
generalized epilepsy.
… The mechanisms of antiseizure actions of
VNS are unknown in the human.
… 23% to 50%of patients achieve > 50%
reduction in their seizure frequency
Nonpharmacologic therapy
 vagus nerve stimulation (VNS).
… The most common side effect are
hoarseness, voice alteration, increased
cough, pharyngitis, dyspnea, dyspepsia,
and nausea.
… Serious adverse effects reported include
infection, nerve paralysis, hypoesthesia,
facial paresis, left vocal cord paralysis, left
facial paralysis, left recurrent laryngeal
nerve injury, urinary retention, and lowgrade fever.
FIGURE 58-1.
Drug Therapy
ANTIEPILEPTIC DRUGS (AED)
First Generation
Second
Generation
Unconventional
Carbamazepine (Tegretol)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Ethosuximide (Zarontin)
Phenobarbital
Phenytoin (Dilantin)
Primidone (Mysoline)
Valproic acid (Depakote)
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Topiramate (Topamax)
Zonisamide (Zonegran)
Adrenocorticotropic
hormone (ACTH )
Acetazolamide (Diamox)
Amantadine (Symmetrel)
Bromides
Clomiphene (Clomid)
Ethotoin (Peganone)
Mephenytoin (Mesantoin)
Mephobarbital (Mebaral)
Methsuximide (Celontin)
Trimethadione (Tridione)
44
Choice of antiepileptic drug
the choice of first-line agents is based on
 efficacy for the seizure or epilepsy syndrome,
 Tolerability and safety,
 ease of use,
 pharmacokinetics (including current or
likely future need for concomitant
medication for comorbidity),
 cost
TABLE 62.6 Antiepileptic Drugs of Choice Based on Seizure Classification
Generalized Seizures
Generalized Tonic-ClonicAbsence
Partial Seizuresa
Myoclonic, Atonic, Atypical Absence
Drugs of choice
Carbamazepine
Phenytoin
Lamotrigine
Oxcarbazepine
Topiramateb
Valproate
Carbamazepine
Phenytoin
Topiramate
Lamotrigine
Ethosuximide
Lamotrigine
Valproate
Valproate
Lamotrigine
Alternatives
Gabapentinb
Levetiracetam
Phenobarbital
Pregabalin
Primidone
Tiagabineb
Valproate
Levetiracetam
Phenobarbital
Phenytoin
Primidone
Clonazepam
Clonazepam
Topiramate
Felbamate
a
b
Simple-partial, complex-partial, and secondarily generalized tonic-clonic seizures.
Used primarily as adjunctive therapy.
Seizure Type
First-Line Drugs
Partial seizures (newly diagnosed)
Adults & adolescents:
U.S. guidelines25,26
U.K. guidelines27,28
ILAE guidelines29
Carbamazepine
Gabapentin
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Carbamazepine
Lamotrigine
Oxcarbazepine
Topiramate
Valproic acid
Adults:
Carbamazepine
Phenytoin
Valproic acid
Children:
Oxcarbazepine
U.S. Expert Panel 200530
Elderly:
Gabapentin
Lamotrigine
Carbamazepine
Lamotrigine
Oxcarbazepine
Alternative Drugsa
Comments
FDA approved:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Adults:
Gabapentin
Lamotrigine
Oxcarbazepine
Phenobarbital
Topiramate
Children:
Carbamazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Elderly:
Carbamazepine
Levetiracetam
Partial seizures (refractory monotherapy)
U.S. guidelines25,26
Lamotrigine
FDA approved:
Oxcarbazepine
Carbamazepine
Topiramate
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Valproic acid
U.K. guidelines27,28
Lamotrigine
Oxcarbazepine
Topiramate
Partial seizures (refractory adjunct)
U.S. guidelines25,26
Adults:
U.K. guidelines27,28
FDA approved:
Gabapentin
Carbamazepine
Lamotrigine
Levetiracetam
Oxcarbazepine
Gabapentin
Lamotrigine
Levetiracetam
Tiagabine
Oxcarbazepine
Topiramate
Zonisamide
Children:
Gabapentin
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Pregabalin
Tiagabine
Valproic acid
Zonisamide
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Generalized seizures
absence (newly diagnosed)
U.S. guidelines25,26
Lamotrigine
U.K. guidelines27,28
Lamotrigine
ILAE guidelines29
None
U.S. Expert Panel 200530
Ethosuximide
Valproic acid
FDA approved:
Ethosuximide
Valproic acid
Ethosuximide
Lamotrigine
Valproic acid
Lamotrigine
Primary generalized (tonicclonic)
U.S. guidelines25,26
Topiramate
U.K. guidelines27,28
ILAE guidelines29
Lamotrigine
Topiramate
None
FDA approved:
Lamotrigine
Topiramate
Adults:
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Children:
U.S. Expert Panel 200530
Valproic acid
Carbamazepine
Phenobarbital
Phenytoin
Topiramate
Valproic acid
Lamotrigine
Topiramate
FDA approved:
Juvenile myoclonic
epilepsy
Levetiracetam
(myoclonic seizures)
ILAE29
None
Clonazepam
Lamotrigine
Levetiracetam
Topiramate
Valproic acid
Zonisamide
U.S. Expert Panel
200530
Valproic acid
Levetiracetam
Topiramate
Zonisamide
PARTIAL SEIZURES
 partial seizures do not respond to treatment as
well as seizures that are generalized.
 Carbamazepine, phenytoin, phenobarbital, and
primidone are equally effective for the
treatment of partial seizures
 carbamazepine and phenytoin are usually
tolerated better.
 Phenytoin has a long half-life that allows for
once-daily dosing
PARTIAL SEIZURES
 phenytoin is associated with cosmetic changes
that make it less desirable for the treatment of
epilepsy in children, adolescents, and women.
 Valproate is also useful for the treatment of
partial seizures, but carbamazepine provides
better seizure control and fewer long-term
adverse effects.
PARTIAL SEIZURES
 Felbamate, gabapentin, lamotrigine, tiagabine,
topiramate, levetiracetam, oxcarbazepine,
zonisamide, and pregabalin are also effective
for treating partial seizures.
 Lamotrigine and topiramate are effective as
monotherapy and appear to be better tolerated
than carbamazepine monotherapy particularly
in elderly patients.
PARTIAL SEIZURES
 Phenobarbital and primidone are also useful
in partial seizures, but sedation and cognitive
adverse effects limit their utility.
PARTIAL SEIZURES
 The first AED leads to complete seizure control
in about 50-65%% of patients
 Subsequent combination or substitution
achieve control in up to 10–15%.
 1 in 3 patients remains with uncontrolled
partial seizures.
 The other new agents are primarily used as
adjunctive therapy if monotherapy has failed
or for patients who are intolerant of standard
AEDs (e.g., carbamazepine, phenytoin, and
valproate).
PARTIAL SEIZURES
 If several single-drug or combination regimens
with these drugs have failed, surgical options
should be considered.
 If not, third-line agents are available; these are
clobazam, phenobarbital, phenytoin,
primidone, and tiagabine.
 Less often used agents with either tolerability
or safety problems or no Class I evidence for
efficacy (acetazolamide, bromide, felbamate,
sulthiame, vigabatrin) should be used as a last
resort.
GENERALIZED SEIZURES
 Valproate, lamotrigine, and topiramate are the
drugs of choice for the treatment of primary
generalized tonic-clonic seizures.
 insufficient data to support the use of any of
the new AEDs as monotherapy in newly
diagnosed primary generalized tonic-clonic
seizures
 topiramate was recently approved as initial
monotherapy for primary generalized seizures
in those older than 10 years of age.
GENERALIZED SEIZURES
 75% to 85% of patients achieve complete
seizure control during monotherapy with VPA
 Lamotrigine and topiramate are emerging as
more often used therapies in children younger
than 2 years of age because of the higher risk
of valproate-associated hepatotoxicity in this
population.
 Phenobarbital and primidone are also
effective, but because of their potential for
adverse effects, they are usually reserved for
second-line or third-line agents.
GENERALIZED SEIZURES
 Carbamazepine, phenytoin, and oxcarbazepine
can rarely exacerbate seizures in patients with
primary generalized epilepsy syndromes.
Absence seizures
 Ethosuximide, VPA and lamotrigine are
effective for the treatment of absence seizures.
 Ethosuximide may be preferred over VPA
when only absence seizures are involved
because of the potential for fewer serious
adverse effects.
 Ethosuximide is not effective against GTC
seizures; therefore, valproate and lamotrigine
are preferred if this seizure type is also
present.
Absence seizures
 70% to 90% of patients who were treated with
ethosuximide or valproate experienced
cessation or a dramatic reduction in absence
seizures.
 The combination of ethosuximide and
valproate is often effective when monotherapy
fails to yield adequate results
Absence seizures
 Clonazepam is also effective against absence
seizures.
 it should be reserved for patients in whom
ethosuximide and valproate fail because of
frequent dose-related adverse effects and the
development of tolerance
 Carbamazepine , phenobarbital, and phenytoin
are ineffective for the treatment of absence
seizures and may even exacerbate it
Myoclonic, atonic, and atypical
absence seizures
 VPA is effective for the treatment of
myoclonic, atonic, and atypical absence
seizures and is the initial drug of choice for
patients with mixed seizure types.
 It controls myoclonic seizures in 75% to 90% of
patients with generalized idiopathic and
juvenile myoclonic epilepsy.
Myoclonic, atonic, and atypical
absence seizures
 Clonazepam is also effective as monotherapy
or in combination with VPA when either drug
alone does not provide adequate seizure
control.
 Lamotrigine, topiramate, zonisamide, and
felbamate are also effective against myoclonic,
atonic, and atypical absence seizures.
Advantages of modern AEDs
 less enzyme inducing than CBZ, PHT or r
barbiturates
 less enzyme inhibiting than VPA, or do not
influence hepatic enzyme systems at all.
 causes fewer adverse drug interactions.
 fewer hormona metabolic disturbances
Advantages of modern AEDs
 malformation rate associated with LTG is
similar to CBZ or untreated women with
epilepsy and is lower than VPA.
 the absence of hypersensitivity reactions.
 a modern AED should be preferred over a
classic AED when starting drug treatment in a
patient with new-onset epilepsy.
Finding the optimal dose of AED
 The drug is titrated to the lowest effective
dose.
 If seizures continue, the daily dose is increased
by small increments to the average effective
dose
 Most AEDs work within several days to a week
of starting treatment.
Finding the optimal dose of AED
 If seizure control cannot be achieved with the
maximum tolerated dose, a dose reduction
 to the previous average dose is recommended.
If toxic symptoms or high plasma
concentrations indicate an increased risk of
toxicity before seizures are controlled, a second
AED is added.
Monitoring treatment with
antiepileptic drugs
 Target plasma AED concentrations are
available for a number of drugs.
 Plasma concentrations are less useful than the
clinical course.
 Some patients have toxic symptoms at low
concentrations, whereas others tolerate higher
concentrations without apparent clinical
symptoms.
Monitoring treatment with
antiepileptic drugs
 If treatment is ineffective, monitoring of
concentration may unmask irregular drug
compliance
 Except for PHT, for which monitoring is
strongly recommended because of the
nonlinear saturation dose kinetics, monitoring
of other AED plasma concentrations is optional
and should be individualized (e.g., poor drug
compliance or adverse events).
Monitoring treatment with
antiepileptic drugs
 The therapeutic range for AEDs can be
different for different seizure types.
… higher to control CP seizures than to control
tonic-clonic seizures.
 Patients should be monitored chronically for
seizure control, comorbid conditions, social
adjustment (including quality-of-life
assessments), drug interactions, compliance,
and adverse effects.
.
Monitoring treatment with
antiepileptic drugs
 Periodic screening for comorbid
neuropsychiatric disorders such as depression
and anxiety is also important
 Clinical monitoring involves identifying the
number and type of seizures.
…a seizure diary.
…
ADVERSE EFFECTS
 Acute effects
… dose/serum concentration–related or idiosyncratic.
… Neurotoxic adverse effects
 sedation, dizziness, blurred or double vision,
difficulty with concentration, and ataxia.
 can be alleviated by decreasing drug dose or
avoided in some cases by increasing the drug
very slowly.
… Most idiosyncratic reactions are mild, but they can
be more serious including hepatitis or blood
dyscrasias are serious but rare.
ADVERSE EFFECTS
 Acute effects
… Acute organ failure, generally occurs within the
first 6 months.
… laboratory evaluations are not helpful in predicting
or detecting the early stages and not recommended
in asymptomatic patients.
… WBC and LFTs if the patient reports an
unexplained illness (e.g., lethargy, vomiting, fever,
or rash).
… adverse effects can occur despite serum
concentrations within therapeutic range
ADVERSE EFFECTS
 Chronic effects
… osteomalacia and osteoporosis.
… ranging from asymptomatic high-turnover disease,
with normal BMD, to markedly decreased bone
BMD (osteoporosis)
… Etiology uncertain
… hypothesized that phenytoin, phenobarbital,
carbamazepine, oxcarbazepine, and valproic acid,
may interfere with vitamin D metabolism.
ADVERSE EFFECTS
Chronic effects
 osteomalacia and osteoporosis.
… ranging from asymptomatic high-turnover
disease, with normal BMD, to markedly
decreased bone BMD (osteoporosis)
… Etiology uncertain
… hypothesized that phenytoin, phenobarbital,
carbamazepine, oxcarbazepine, and valproic
acid, may interfere with vitamin D
metabolism.
ADVERSE EFFECTS
Chronic effects
 cognition impairment
… No large differences between the older drugs
… phenobarbital and primidone appear to
cause more cognitive impairment
… Phenytoin, particularly when serum
concentrations are above the commonly
accepted therapeutic range
… valproic acid may cause less impairment of
cognition.
ADVERSE EFFECTS
Chronic effects
 cognition impairment
… Patients changed from polytherapy to monotherapy
also may demonstrate improvement
… newer agents believed to cause fewer
neurobehavioral or cognitive effects.
… gabapentin and lamotrigine have been shown cause
fewer cognitive impairments as compared with
older agents
… topiramate may cause substantial cognitive
impairment, when used at high doses or during
rapid dose escalation.
ADVERSE EFFECTS
Chronic effects
 worsening of seizures
… can result from either improper selection of
an AED for a specific seizure type
… can represent a paradoxical toxic effect of
the drug
Antiepileptic drug interactions
 Older AEDs such as phenytoin,
carbamazepine, phenobarbital and valproic
acid can significantly interfere not only with
each other and other AEDs, but also with
other treatments.
 Although newer AEDs have a more
favourable pharmacokinetic profile, they are
not entirely exempt from interactions
andthey are also commonly administered in
combination with older AEDs.
Antiepileptic drug interactions
 The AEDs that most commonly cause
interactions with each other and with other
drugs are older AEDs:
 phenytoin, carbamazepine, phenobarbital,
primidone and valproic acid.
 Pharmacokinetic characteristics: they have
high protein-binding capacity, exclusively or
predominantly hepatic metabolism, potent
enzyme induction and inhibition, and active
intermediate metabolites.
Antiepileptic drug interactions
 In certain groups of patients, failure to
anticipate potential interactions of AEDs
with each other and with other drugs could
lead to a major management problem
 Patients with refractory epilepsy and
elderly people are sections of the population
in whom polypharmacy is the norm.
 The interaction of AEDs with contraceptives
is an aspect that must be taken into
consideration in young women.
Antiepileptic drug interactions
 Cancer patients, patients undergoing
treatment with immunosuppressants and
those who are HIV positive or have a
psychiatric disorder, often take drugs that
interact with AEDs.
 Antiepileptics are becoming increasingly
widely used in other common conditions
such as neuropathic pain and migraine.
Therapeutic considerations in the
elderly and young
 Avoidance of AEDs that interact with other
medications that the elderly are taking.
… Many of the drugs are inducers or inhibitors of the
CYP450 system,
 Hypoalbuminemia is common in elderly, which can
make monitoring and adjustment of serum drug
levels of highly albumin-bound AEDs, such as
phenytoin, valproic acid, and tiagabine, problematic.
 increase in fat to lean body mass or decrease in body
water, can affect the volume of distribution of some
drugs, and therefore possibly the elimination half-life
Therapeutic considerations in the
elderly and young
 declining renal and/or hepatic function require a
lower dose of the AED.
 the pharmacodynamic response to AEDs can change
as the patient ages because elderly patients may be
more sensitive to various neurocognitive adverse
effects of these drugs.
 Elderly patients may demonstrate efficacy (e.g.,
control of seizures) at relatively lower serum
concentrations as well.
Therapeutic considerations in the
elderly and young
 For neonates and infants, an increase in the total
body water to body fat ratio and a decrease in serum
albumin and -acid glycoprotein can result in volume
of distribution changes that can affect the
elimination half-life of the AEDs.
 newborns up to the age of 2 to 3 years display
decreased efficiency in renal elimination, with the
newborn having the most significant impairment.
 Hepatic activity is also reduced in this population.
 by age 2 to 3 years, hepatic activity is more robust
than in adults. Therefore, children require higher
doses than adults, whereas neonates and infants
require lower doses.
THERAPEUTIC CONSIDERATIONS
IN WOMEN
 Estrogen has a seizure-activating effect
 progesterone exerts a seizure-protective effect.
 Hepatic enzyme inducers, increase the metabolism of
steroid hormones and induce the production of sex
hormone–binding globulin.
… decreases in the unbound fraction of
the hormone.
… topiramate and oxcarbazepine at
higher doses, can cause treatment
failures in women taking oral
contraceptives.
THERAPEUTIC CONSIDERATIONS
IN WOMEN
… Valproic acid, benzodiazepines, and
most of the newer AEDs, such as
gabapentin, levetiracetam, tiagabine,
and zonisamide, are not enzyme
inducers and have not been
associated with this effect.
THERAPEUTIC CONSIDERATIONS
IN WOMEN
 In some women, vulnerability to seizures is
highest just before and during the menstrual
flow and time of ovulation.
 This can be related to progesterone
withdrawal and changes in the estrogen-toprogesterone ratio.
 Conventional AEDs should be tried first in
these women.
THERAPEUTIC CONSIDERATIONS
IN WOMEN
Intermittent acetazolamide also
has been used but with variable
and limited success.
Hormonal therapy with
progestational agents also can be
effective.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 the possibility of increased maternal
seizures, pregnancy complications, and
adverse fetal outcome.
 Approximately 25% to 30% ↓and ↑
 Increased seizure activity may result
from either a direct effect on seizure
threshold or a reduction in AED
concentration.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 An increase in clearance has been
reported for phenytoin, carbamazepine,
phenobarbital, ethosuximide,
lamotrigine, oxcarbazepine, and
clorazepate.
 Protein binding also may be altered.
… as early as the first 10 weeks of pregnancy
and can take up to 4 weeks postpartum to
return to normal.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 There is a higher incidence of adverse
pregnancy outcomes in women with
epilepsy(4% to 6%)
 barbiturates and phenytoin are
associated with congenital heart
malformations, orofacial clefts, and
other malformations.
 Valproic acid and carbamazepine are
associated with spina bifida (neural
tube defect) and hypospadias.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 the risk of neural tube defect appears to
be related to drug exposure during
gestational days 0 to 28.
 Other adverse outcomes associated
with maternal seizures, but not
necessarily caused by AEDs, are
growth, psychomotor, and mental
retardation.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 Women with epilepsy are also more
likely to have miscarriages
 Many of these teratogenic effects can be
prevented by adequate folate intake;
 Higher folate doses should be used in
women with a history of a previous
pregnancy with a neural tube defect.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 New AEDs are reported to be less
teratogenic,
 clinical data are still limited, and more
experience is needed.
 Some AEDs also can lead to neonatal
hemorrhagic disorder, which can be
prevented by the administration of
vitamin K 10 mg orally, given to the
mother daily during the last month of
pregnancy.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 Although AEDs pass into the breast
milk, the concentrations are very low,
and the infant receives a
subtherapeutic dose.
 Taking AEDs with less protein binding
results in more accumulation in breast
milk.
THERAPEUTIC CONSIDERATIONS
IN PREGNANCY
 The perimenopausal period can be
associated with worsening of seizures,
possibly owing to fluctuations in sex
hormones.
 At menopause, seizures actually can
improve
 The effect of hormone-replacement
therapy on seizure control is still
unclear.
CLINICAL CONSIDERATIONS
WITH SPECIFIC DRUGS
CARBAMAZEPINE
Advantages
 Oral immediate- and extended-release solid
and liquid dosage forms are available
 The sustained- and controlled-release dosage
forms allow for twice-daily dosing to reduce
the peak-to-trough fluctuations.
 Compared with other first-generation AEDs,
carbamazepine causes minimal cognitive
impairment.
CARBAMAZEPINE
 has an active metabolite that can contribute
to efficacy and toxicity.
 Other drugs can alter the concentration of
this metabolite without changing the
concentration of the parent carbamazepine.
 It induces its own metabolism, which
requires careful dosage titration.
 It also induces the metabolism of other
medications, and other drugs may interact
with it and/or the active metabolite
CARBAMAZEPINE
 no parenteral formulation.
 clinically meaningful CNS side effects
including sedation and nausea.
 Chronic carbamazepine use also has been
associated with alterations in bone mineral
density in some studies and decreases in 25hydoxy (OH) vitamin D.
CARBAMAZEPINE
Place in Therapy
 first-line therapy for patients with newly
diagnosed partial seizures and for patients
with primary generalized convulsive seizures
who are not in an emergent situation
GABAPENTIN
Advantages
 has multiple mechanisms of action and is
mechanistically different from firstgeneration AEDs.
 It is not metabolized and is excreted
unchanged by the kidney.
 Has a broad therapeutic index with minimal
CNS adverse effects and no drug
interactions.
 Doses can be escalated rapidly.
GABAPENTIN
Disadvantages
 absorbed by an active process that saturates
at higher doses.
 This may require more frequent daily dosing
for patients who need doses greater than
3,600 mg/day.
 Doses >3,600 mg/day may be required in
some patients to achieve seizure remission.
 There is no parenteral formulation.
GABAPENTIN
Place in Therapy
 second-line agent for patients with partial
seizures who have failed initial treatment
 may be a role in patients with less severe
seizure disorders, such as new-onset partial
epilepsy, particularly in the elderly patient.
 has been shown to be useful in the treatment
of chronic pain and other nonepileptic
conditions.
LEVETIRACETAM
Advantages
 not metabolized by the cytochrome P450
system and no significant drug interactions,
 Well tolerated, with transient sedation
LEVETIRACETAM
Disadvantages
 Dose adjustments are needed for patients
with decreased renal function
 Slower dose escalation may be needed to
avoid CNS adverse effects.
 Behavioral problems can limit therapy in
some patients.
LEVETIRACETAM
Place in Therapy
 indicated for patients with partial seizures
who have failed initial therapy.
 recently approved as adjunctive treatment
for myoclonic seizures in patients with
juvenile myoclonic epilepsy.
PHENYTOIN
 Advantages
 Phenytoin has been used for more than 65
years
 It is available in multiple dosage forms,
allowing flexibility in dosing and use in
emergent situations.
PHENYTOIN
Disadvantages
 metabolism saturates at doses given
clinically. This makes phenytoin a
challenging drug to dose.
 Phenytoin is an inducer of cytochrome P450
isozymes, is metabolized by cytochrome P450
enzymes, and is highly protein bound.
 Phenytoin is associated with multiple
significant adverse effects.
PHENYTOIN
Place in Therapy
 a first-line AED for primary generalized
convulsive and partial seizures.
 Its use in therapy may be reevaluated as
more experience is gained with newer AEDs.
TOPIRAMATE
Advantages
 Topiramate has multiple mechanisms of
action and is a broad-spectrum AED.
 The kidney mainly eliminates it, although
some liver metabolism occurs, especially if
given concomitantly with enzyme inducers.
 It has liner pharmacokinetics and few drug
interactions.
TOPIRAMATE
Disadvantages
 With rapid dosage escalation, topiramate can
compromise cognitive functioning, including
impaired word finding and short-term
memory.
 Renal stones and weight loss also have been
associated with topiramate use.
 There is no parenteral formulation.
TOPIRAMATE
Place in Therapy
 Topiramate is a first-line AED for patients
with partial seizures.
 The drug is also approved for the treatment
of tonic-clonic seizures in primary
generalized epilepsy.
VALPROIC ACID/DIVALPROEX
SODIUM
Advantages
 available in multiple dosage formulations.
The IV formulation is especially well
tolerated.
 It has a wide therapeutic index and can be
considered a broad-spectrum AED.
 It can be useful in other neurologic or
psychiatric disorders, including migraine
headache and bipolar disorder.
VALPROIC ACID/DIVALPROEX
SODIUM
Disadvantages
 Some patients report significant weight gain
which s can limit compliance.
 Associated with alopecia, tremor,
pancreatitis, polycystic ovary disease, and
thrombocytopenia.
 It has been associated with hepatic necrosis
in young children.
 It is an enzyme inhibitor and is involved in
multiple drug-drug interactions
VALPROIC ACID/DIVALPROEX
SODIUM
Place in Therapy
 Valproic acid is first-line therapy for primary
generalized seizures such as myoclonic,
atonic, and absence seizures.
 It can be used as both monotherapy and
adjunctive therapy for partial seizures
 it can be very useful in patients with mixed
seizure disorders.