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James Fischer, Pharm.D.
Spring 1998
Drug Therapy of Epilepsy
I.Epilepsy - Pathophysiology
Definitions / Epidemiology
Functional Anatomy of the Brain
Pathophysiology
Etiology
Diagnosis
Classification of Epileptic Seizures
Selected Epileptic Syndromes
First Aid for Seizures
I.Drug Therapy
Goal of Therapy
General Management of Epilepsy
Principles of Antiepileptic Drug (AED) Therapy
Adverse Effects
Drug Interactions
Specific Drug Therapy for Epilepsy
I.Case Study
GOALS AND OBJECTIVES
http://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#EPILEPSY%20-%20PATHOPHYSIOLOGYhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Definitions%20/%20Epidemiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Functional%20Anatomy%20of%20the%20Brainhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Pathophysiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Etiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Diagnosishttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#CLASSIFICATION%20OF%20EPILEPTIC%20SEIZUREShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Selected%20Epileptic%20Syndromeshttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#FIRST%20AID%20FOR%20SEIZUREShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#DRUGhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#GOALhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#MANAGEMENThttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#PRINCIPLEShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#ADVERSEhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#INTERACTIONShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#SPECIFIChttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#CASEhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Definitions%20/%20Epidemiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Functional%20Anatomy%20of%20the%20Brainhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Pathophysiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Etiologyhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Diagnosishttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#CLASSIFICATION%20OF%20EPILEPTIC%20SEIZUREShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#Selected%20Epileptic%20Syndromeshttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#FIRST%20AID%20FOR%20SEIZUREShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#DRUGhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#GOALhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#MANAGEMENThttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#PRINCIPLEShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#ADVERSEhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#INTERACTIONShttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#SPECIFIChttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#CASEhttp://www.uic.edu/classes/pmpr/pmpr652/Final/Fischer/epilepsy.html#EPILEPSY%20-%20PATHOPHYSIOLOGY8/2/2019 Epilepsi at Web
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1. Review the pathophysiology of epilepsy including etiology, diagnostic criteria,
factors to consider in differentiating epilepsy from other disorders, classification of
epileptic seizures and first aid measures for the patient with seizures.
2. Identify the clinical manifestations and EEG findings associated with the different
types of epileptic seizures. At the conclusion of these lectures, the student should be
able to classify a given patient's seizure type based on data provided concerning the
clinical description and EEG results.
3. Provide an understanding of the basic principles involved in the drug treatment of
epilepsy, including factors to consider in the initiation and assessment of antiepileptic
drug (AED) therapy.
4. The student should be able to recommend an initial AED regimen or alteration in
regimen (including dose schedule, monitoring parameters) for an epileptic patient
based on information concerning patient's seizure type, medical history, previous
drug therapy and pertinent laboratory data.
5. Explain the role of plasma concentration monitoring in AED therapy and be aware
of the therapeutic serum concentration range for the major AED.
6. Review the adverse effects seen during therapy with the major AED. The student
should be aware of the causative factors, clinical importance, prevention and/or
management of these adverse effects.
7. The student should be aware of the potential drug interactions that may occur
among the AED, and the mechanisms and clinical implications of these interactions.
REQUIRED READINGS
1. Fischer JH (ed). The Epilepsy Counseling Guide. MPE Communications inc., Fair
Lawn, New Jersey, 1994.
2.Garnett WR. Epilepsy, inPharmacotherapy: A Pathophysiologic Approach, 3rd ed.
Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Appleton &
Lange, Stamford, CT. 1997; 1179-1209.
EPILEPSY - PATHOPHYSIOLOGY
I. Definitions/ EpidemiologyA. Seizures are discrete, time-limited alterations in brain function - including changes
in motor activity, autonomic function, consciousness, or sensation -that result from an
abnormal and excessive electrical discharge of a group of neurons within the brain.
The clinical manifestations of a seizure reflect the area of the brain from which the
seizure begins (i.e., seizure focus) and the spread of the electrical discharge. Clinical
manifestations accompanying a seizure are numerous and varied, including
indescribable bodily sensations, "pins and needles" sensations, smells or sounds, fear
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or depression, hallucinations, momentary jerks or head nods, staring with loss of
awareness, and convulsive movements (i.e., involuntary muscle contractions) lasting
seconds to minutes. Convulsions are specific type of seizures where the attack is
primarily manifested by involuntary muscular contractions.
B. Seizures are symptoms of a disturbance in brain function. Up to 10% of the
population will experience a seizure during their lifetime. However, in the majority of
these people, seizures occur either as an isolated incident or secondary to an acute
reversible medical condition, such as fever, trauma, metabolic disorder, or alcohol or
drug intoxication. Since seizures do not usually recur in these patients once the
underlying cause has been corrected, these patients are not considered to have
epilepsy and do not require long-term antiepileptic drug therapy.
C. Epilepsy is defined as a condition characterized by recurrent (two or more)
seizures unprovoked by any immediately identifiable cause.
D. Epilepsy is the third most common neurologic disorder, following stroke and
Alzheimer=s disease. Approximately 2 million people (0.5% - 1.5% of population) inthe United States have active epilepsy. Each year 50 per 100,000 individuals in the
United States will be diagnosed with epilepsy (125,000 new cases/year), with the
highest frequency of newly identified cases occurring among children < 5 years (50-
100 cases/100,000) and adults >65 years of age (70-150 cases/100,000).
II. Functional Anatomy of the Brain
The material in sectionII. is informational only (i.e., it will not be included on test)
and is included to provide a brief overview of the neuroanatomy pertaining to
seizures and epilepsy. The upper and largest portion of the brain is referred to as the
cerebrum. The cerebrum is comprised of grey and white matter. The outer layer of
grey matter forms the cerebral cortex and consists largely of nerve cells (neurons) andsupportive glial cells. White matter, comprised of myelinated nerve fibers, lies
beneath the cerebral cortex. These myelinated fibers connect the cerebrum with other
parts of the brain (projection fibers), the front of the brain to the back portion,
different areas on the same side of the cerebrum (association fibers), and one side of
the brain to the other (commissural fibers). As shown in the figure above, the
cerebrum is incompletely divided into the left and right hemispheres by the medial
longitudinal fissure. The left and right cerebral hemispheres are interconnected by a
large fiber bundle located beneath the medial fissure, the corpus callosum. The right
hemisphere controls the left side of the body and "sees" the left half of space; the left
hemisphere controls the right side of the body and "sees" the right half of space. In
most right-handed individuals, the left hemisphere controls language functions suchas the ability to speak (frontal lobe) and understand language (temporal lobe). As
shown below, each cerebral hemisphere is divided into 5 lobes: frontal, parietal,
temporal, occipital, and the insula (located on the underside of brain). Specific areas
in each lobe are associated with different functions. Injury or abnormal functioning of
these cortical areas can cause partial seizures, with the initial symptoms of the seizure
often reflecting the function of that area.
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The neocortex (cortical area covering surface of brain), hippocampus, and other
mesial temporal frontal areas are frequent sites of seizure onset. Subcortical areas,
such as the thalamus, substantia nigra, and corpus striatum, are thought to play key
roles in the spread of seizure activity and generation of generalized seizures. In the
"normal" brain, inhibitory stimuli from these subcortical areas modulate excitatory
neurotransmission between the cortex and other brain areas and limit the spread ofabnormal electrical signals. Depression of the inhibitory activity of these areas in the
brains of patients with epilepsy may facilitate the spread of seizure activity following
an initial partial seizure or the generation of primary generalized seizures.
III. Pathophysiology
The onset of a seizures appears to occur when a small group of abnormal neurons
undergo prolonged depolarizations associated with the rapid firing of repeated action
potentials. These abnormally discharging epileptic neurons recruit adjacent neurons
or neurons with which they are connected into the process. A clinical seizure occurs
when the electrical discharges of a large number of cells become abnormally linked
together, creating a storm of electrical activity in the brain. Seizures may then spread
to involve adjacent areas of the brain or through established anatomic pathways to
other distant areas.
On a fundamental level, seizures can be viewed as resulting from an imbalance
between excitatory and inhibitory processes in the brain. Proposed mechanisms for
the generation and spread of seizure activity within the brain include abnormalities in
the membrane properties of neurons, changes in the ionic micro environment
surrounding the neuron, decreased inhibitory neurotransmission which is primarily
by gamma-amino butyric acid (GABA), or enhanced excitatory neurotransmissionwhich is primarily mediated by the acidic amino acid, glutamate. The different
antiepileptic drugs (AEDs) act by affecting one or more of these processes. Specific
mechanisms of action of the AEDs include: modulation of voltage dependent ion
channels (carbamazepine, phenytoin, valproic acid), enhancement of activity of the
major inhibitory neurotransmitter in the brain, GABA (phenobarbital,
benzodiazepines, tiagabine), and suppression of excitatory neurotransmission
(lamotrigine, felbamate).
IV. Etiology
A. In 60-70% of patients, no specific cause for their seizures can be identified.Epilepsy in these patients is referred to as being idiopathic (i.e., no definite cause).
B. Infants/children: congenital malformations, perinatal injuries or hypoxia,
developmental neurologic disorders, metabolic defects, injury, and infection are
common causes of seizures.
C. Young Adults: head trauma, brain tumors, infection, and arteriovenous
malformations are common causes of seizures.
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D. Elderly: cerebrovascular disease, CNS degenerative diseases, and brain tumors are
common causes.
E. Genetic - risk increased 2-3 times in individuals with first degree relative with
epilepsy.
V. Diagnosis
A. Steps in Diagnosis of Epilepsy
1. Confirm patient has epilepsy
a. Other conditions to consider in differential: pseudoseizures, syncope, breath
holding spells, narcolepsy, hemiplegic migraines, drug toxicity, transient ischemia
attack.
b. Following factors delineate epilepsy from above: abrupt onset, genuine loss of
consciousness (if not simple partial), brief duration, rapid recovery, stereotypic
episodes.
c. Pseudoseizures (seizures occurring on a psychogenic basis, "hysterical seizures")
present a common and difficult diagnostic problem, especially since many patients
may have both pseudoseizures and epilepsy. Factors differentiating pseudoseizures
from epilepsy include:
1. Precipitating factors with a strong emotional orpsychological component
2. "Non-physiological" seizure patterns - violent thrashing orflailing of all 4 limbs, particularly when movements
asynchronous; preservation of consciousness despite motor
activity of arms and legs; rage and directed violence as ictal
events; gradual build up and prolonged resolution of
seizure; lack of tongue biting, incontinence and postictal
confusion.
3. Personal and family history of psychiatric disease
4. Repeatedly normal interictal EEG and lack of any responseto therapeutic levels of antiepileptic drugs
5. Definitive differentiation requires use of simultaneous videoand EEG recording
2. Correct classification of seizure type and, if possible, epileptic syndrome
3. Identification of any underlying cause
B. Diagnostic Evaluation
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1. History -
a. Medical history of patient and family history
b. Description of seizure - important to obtain exact details of episode from patient
and/or observer. Description should include details on:
1. Events preceding seizure: What was happening before theseizure ? What time was it ? Does patient recognize onset of
seizure by a smell, visual disturbance, sound or odd feeling ?
2. Events during the seizure: What are the initial events ? Isconsciousness lost or altered ? What kind of body
movements occurred ? How long did the seizure last ? Did
the person urinate or bite his/her tongue ?
3. Events after the seizure (i.e., postictal period): Is the patient
alert, drowsy, or confused ? Was there any numbness orweakness ?
4. An effort should also be made to identify any precipitating
factors. Factors known to precipitate epilepsy in susceptible
patients include: sleep deprivation, fever, emotional stress,
lack of food, alcohol/drug withdrawal, pregnancy, menses,
and various sensory stimuli (i.e., photosensitivity, television,
reading, eating, music). Identification and avoidance, where
possible, of these factors may assist in reducing the
frequency of seizures.
2. Physical and Neurological Examination
3. Clinical Laboratory data
4. Electroencephalography (EEG)
a. Measurement of fluctuations in electrical activity within brain recorded from
electrodes on scalp. Role: confirm presence of epilepsy, diagnosis of seizure type, long
term prognosis.
b. EEG findings alone do not confirm or deny diagnosis of epilepsy. Important to
correlate EEG findings to clinical events.
1. Approximately 5% of patients without epilepsy haveepileptiform discharges on their EEG.
2. Of patients with epilepsy, only about 50% have epileptiformactivity on their first EEG.
c. Detection of abnormal EEG enhanced by use of multiple recordings and specific
activating techniques.
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1. photic stimulation, hyperventilation, sleep deprivation (these
are usually performed with standard EEG exam);
2. Video-EEG monitoring: provides correlation betweenclinical seizure and electrical activity in brain
3. Nasopharyngeal and sphenoidal electrodes: allows fordetection of abnormal electrical activity on underside of
cortex
d. EEG patterns having clinical correlations
1. 3 Hz spike and wave complex: Absence seizures
2. Slow spike and wave complex: minor motor seizures (i.e.,atypical absence, tonic, atonic)
3. Hypsarrhythmia: infantile spasms4. Polyspike and wave complex: myoclonic seizures
5. Neuroimaging Studies: Magnetic resonance imaging (MRI) or computed
tomography are useful in identifying structural lesions in brain. MRI appears more
sensitive in detecting lesions in patients with epilepsy. Consider in patients > age 18, in
children with partial seizures, and in presence of abnormal neurologic findings, or
focal slow-wave abnormalities on EEG.
VI. CLASSIFICATION OF EPILEPTIC SEIZURES
Seizures are classified according to their clinical features and patterns seen on theEEG. Epileptic seizures are divided into two broad categories based on the symptoms
and EEG findings observed at the outset of the seizure. If the initial onset indicates
involvement of both sides of the brain, the seizures are referred to as generalized
seizures. If the initial onset indicates involvement of only a localized area of the brain,
they are referred to as partial seizures.
A. Partial Seizures - those seizures where initial onset arises from a localized area of
brain. Partial seizures are caused by localized injury to brain and diagnostic
evaluation for the presence of a focal lesion (i.e., tumor, vascular malformation,
stroke, trauma, neurodegenerative disease) is required. However, in majority of
patients, cause will remain unknown (idiopathic). Partial seizures are further
subdivided based on whether consciousness is maintained (i.e., simple partial) or
impaired (i.e., complex partial) during the seizure. Partial seizures are most common
type experienced by adults.
1. Simple partial seizures
a. No loss of consciousness; During a simple partial seizure, the patient is alert and
able to respond to questions or commands and afterwards remembers what happened
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during the seizure. Simple partial seizures may precede complex partial or
secondarily generalized seizures, in which case they are referred to as auras.
b. Clinical manifestations of simple partial seizure usually relate to the particular
area of brain involved, and thus a wide variety of symptoms are possible, including
motor, sensory, autonomic, and psychic manifestations. For any given patient,
symptoms will be same with each seizure.
c.Motor seizures generally reflect involvement of the motor or supplementary motor
cortex and cause a change in muscle activity. Tonic (neck stiffening, sustained
deviation of eyes to one side) or clonic (jerking) movements are most common.
Abnormal movements may be restricted to one body part or spread to other muscles
on same side or both sides (secondary generalization) of the body.
d.Sensory seizures are often manifested by hallucinations or illusions involving one of
the senses - touch (paresthesia or numbness in one or more body parts), smell (patient
may smell a disagreeable odor), taste (abnormal or disagreeable taste), vision
(unformed or formed visual hallucinations), and hearing (buzzing sound, ringing inears, music, voices).
e.Autonomic seizures can cause changes in heart or breathing rate, sweating,
goosebumps, or strange or unpleasant sensation in abdomen, chest or head.
f.Psychic seizures, arising from the limbic system and neocortical areas of the frontal
and temporal lobes, affect how the patient thinks, feels, and experiences things.
Manifestations of psychic seizures include feelings of fear, anxiety, depression, deja
vu, jamais vu, and dissociative phenomena such as autoscopy (out of body
experience).
g. Duration 30 seconds or less; No postictal symptoms, although patient=s with partialmotor seizures may experience a temporary numbness or weakness in the affected
body part (Todd's paralysis)
h. EEG findings: local contralateral discharge starting over the cortical area
corresponding to symptoms
j. Prognosis: good seizure control obtained in 30-50%
2. Complex partial seizures (temporal lobe, psychomotor epilepsy)
a. Impairment of consciousness observed: In this context, consciousness refers to
patients' ability to normally interact and respond to their environment. Thus,although patients may appear to be conscious, closer examination shows that they are
unaware of their environment; fail to respond or respond inappropriately to
questions; and afterward, are unable to remember the episode. Complex partial
seizures involve portions of brain concerned with maintenance of consciousness and
memory, and generally imply bilateral involvement of temporal or frontal lobes and
limbic system.
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b. Associated with initial aura (i.e., simple partial seizure) in >50% of patients; the
aura is a simple partial seizure which may then progress to a complex partial (and/or
generalized tonic-clonic) seizure. Most common forms of aura: fear, rising epigastric
sensation, unilateral "funny feeling" or "numbness", or visual disturbances; focal
twitching of face or fingers.
c. Simple to complex automatisms (repetitive motor activity that is purposeless,
undirected, and inappropriate) are frequently observed during complex partial
seizures. Examples include repetitive chewing or swallowing, lip smacking, fumbling
movements of fingers or hands, picking at clothing, mumbling, moving about
aimlessly, purposeless behavior, and clumsy perseverance of a preceding motor act.
d. Average duration 1 to 3 minutes
e. Postictal phase - confusion, lethargy, altered behavior, amnesic for event
f. EEG findings: unilateral or, frequently, bilateral discharge in temporal or
frontotemporal region.
g. Prognosis: good seizure control in 40-60%
h. Most common seizure type seen in adult, account for up to 60% of adult epilepsies
3. Partial Seizures Secondarily Generalized - partial seizure may progress through
several stages reflecting spread of discharge to different brain areas. For example,
seizure may begin as simple partial (i.e., aura), progress to complex partial and
subsequently become secondarily generalized (tonic-clonic). The initial clinical events
of a seizure, described by patient or observer, will usually provide a reliable
indication of whether seizure is partial or generalized. Sometimes, however, the focal
onset may not be apparent from clinical data, due to either rapid spread of dischargeor location of focus in brain area not associated with an obvious behavioral function,
thus EEG findings are needed for accurate classification.
B. Generalized Seizures - those seizures where first clinical changes indicate initial
involvement of both hemispheres. The initial clinical event is a loss of consciousness.
Various types of generalized seizures differentiated by absence or presence of specific
motor activity.
1. Generalized Tonic-Clonic (Grand Mal)
a. Loss of consciousness is quickly followed by a sudden fall to ground. In the tonic
phase, muscles become rigid and the simultaneous contractions of diaphragm andchest muscles may produce the characteristic "epileptic cry". The patient's eyes roll
up or turn to the side and the tongue may be bitten. The rigidity is replaced shortly by
series of synchronous clonic movements of head, face, legs and arms. Autonomic
changes also observed included: increased blood pressure, heart rate, and bladder
pressure; pupillary mydriasis; hypersecretion of skin and salivary glands; cyanosis of
skin.
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b. Although onset may occur at any age, most commonly occurs during second decade
of life.
c. Average duration 2 to 5 minutes.
d. Postictally, patients lethargic/sleepy lasting several minutes to hours.
e. Incontinence seen in early postictal phase in approx. 35% of patients.
f. In patients with primary generalized tonic-clonic seizures, seizures seen most
commonly on awakening and to a lesser extent in evening when relaxing.
g. Prognosis: good seizure control in 70-85%.
2. Absence (Petit Mal)
a. Onset between 4 and 14 years and often resolve by age 18.
b. Clinical description - Brief episodes of staring with impairment of awareness and
responsive that begin without warning and end suddenly, leaving patient alert and
attentive. In simple absence seizures, patient only stares. In the more common
complex absence seizures, staring is accompanied by simple automatic movements
such as blinking of eyes, drooping of head, or chewing.
c. Duration - short (10-45 secs), patients usually unaware of occurrence.
d. Abrupt recovery without after effects
e. Characteristic EEG pattern of 3 per second spike and waves; may be precipitated
in large percent of patients by hyperventilation.
f. 25 to 50% of patients go on to develop generalized tonic-clonic (GTC) seizures.
g. Development and intelligence are usually normal and long term prognosis is good,
particularly in patients who do not develop GTC.
h. Important in children to differentiate from complex partial seizures, since
treatment and prognosis vary. In contrast to absence, complex partial seizures usually
have a longer duration (minutes vs. seconds), are often preceded by aura, and
typically have a brief period of postictal confusion. Also, the EEG pattern is markedly
different between the two seizure types.
3 Atypical Absence
a. Onset between 1 to 7 years of age
b. Clinical description - similar to typical absence except that loss of responsiveness
during seizure is often less complete and more gradual in onset and cessation; Also
clonic, tonic and atonic components (i.e., increase or decreases in muscle tone) are
more pronounced than in typical absence. Commonly seen in patients with Lennox-
Gaustaut syndrome in conjunction with myoclonic, atonic and tonic seizures.
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c. EEG findings: slow spike and wave (< 2.5 Hz) discharge and/or incompletely
generalized spike-waves
d. Not precipitated by hyperventilation
e. Often associated with mental retardation or structural CNS damage
f. Prognosis: response to therapy and long term prognosis dependent on presence of
underlying neurologic deficit and/or mental retardation. Good response seen only 20-
30% of patients.
4. Atonic seizures
a. Onset usually between age of 2 to 5 years
b. Clinical description- sudden and total loss of muscle tone and posture control that
causes eyelids to drop, head to nod and patient to fall to ground - "drop attack"; not
necessarily associated with loss of consciousness. Must wear helmet to protect from
head injury. May or may not have postictal symptoms.
c. Average duration 10 to 60 seconds; brief, if any, postictal symptoms
d. Other seizure types common in patients with atonic seizures. May be observed in
conjunction with myoclonic seizures and atypical absence (Lennox-Gaustaut
Syndrome)
e. Prognosis to therapy dependent on presence of underlying neurological deficit
and/or mental retardation
5. Myoclonic Seizure
a. Sudden, brief shock-like jerk of a muscle or group of muscles, often occurs in
healthy people as they fall asleep. Epileptic myoclonus usually causes synchronous
and bilateral jerks of the neck, shoulders, upper arms, body, and upper legs.
b. Myoclonic seizures occur in a variety of epilepsy syndromes.
6. Tonic seizures
a. Characterized by sudden bilateral stiffening of the body, arms, or legs. Tonic
seizures usually last less than 20 seconds and are more common during sleep.
b. Primarily seen in younger children; commonly associated with metabolic disorder
or underlying neurological deficit
c. Frequently occur with other seizure types and in various epilepsy syndromes
d. Duration 10-60 seconds; brief, if any, postictal symptoms
Note material on handout after this point will not be covered in class and you are not
responsible for this information on the test.
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VII. Selected Epileptic Syndromes
Epilepsy syndromes are defined by a cluster of characteristics, including seizure type,
EEG, neurologic status, age at seizure onset, family history, and prognosis. While
seizure type is most important determinant of drug selection, classifying the epilepsy
syndrome provides information on the responsive to drug therapy, expected duration
of drug therapy, and long term prognosis.
A. Infantile Spasms
1. Consist of sudden flexion of the head with abduction and extension of arms,
accompanied by flexion of knees and often a little grunt or cry. Spasms may also be
extension rather than flexion. Spasms commonly occur in series of 2 or more.
2. Onset most commonly between 4 to 7 months of age
3. Definite etiology can be established in 60% of patients
4. Mortality rate 11-23%; developmental retardation 80-90%
5. Characterized by spasms, developmental retardation, hypsarrhythmia pattern on
EEG.
6. Spasms may be flexor (jackknife), extensor or mixed flexor-extensor.
7. Unique among seizure types in responsiveness to ACTH/corticosteroids.
8. Poor treatment prognosis; spasms usually disappear by age 3 or 4, but child left
profoundly handicapped, retarded, and often with Lennox-Gaustaut syndrome (see
under atypical absence seizures). Patients who are normal prior to onset and who
respond to therapy have slightly better prognosis.
B. Febrile Seizures
1. Convulsions that occur with fever (> 38oC) in children between 6 months and 6
years of age, not secondary to an infection of brain or meninges.
2. Prevalence: 2 to 5% of all children will have a febrile seizure before 6 y/o; Peak
incidence at 2 years of age.
3. Etiology: strong genetic predisposition
4. Primarily occur as generalized tonic-clonic seizures, but partial seizures occur in
10-15% of patients.
5. Prognosis: febrile convulsions usually have benign course; although 2 to 4% will go
on to develop afebrile epilepsy. Intellectual dysfunction and neurologic sequelae may
occur following febrile status epilepticus.
6. Factors associated with increased risk of developing afebrile epilepsy: Preexisting
neurologic abnormality; family history of afebrile seizures; and a complicated initial
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seizure (> 20 minutes duration 2 or more seizures in same illness, and/or focal febrile
seizure).
7. Treatment
1. Symptomatic - control fever and seizures
2. Prophylactic Antiepileptic Drug Therapy - controversial;present recommendations to consider prophylactic
treatment only in patients with two or more of risk factors
above; or in patients with recurrent (3 or more) febrile
seizures who are under 3 years of age. Current
recommendation for prophylactic therapy is the intermittent
administration of rectal or oral diazepam at time of febrile
episode.
C. Lennox-Gastaut Syndrome: This syndrome is characterized by the triad of
intractable seizures, mental and developmental retardation, and slow spike and wavepattern on the EEG. Seizures (tonic, atonic, atypical absence, myoclonic, and tonic-
clonic) usually begin between ages 1 and 6 years and respond poorly to antiepileptic
drugs. Behavioral problems are common and probably result from the underlying
neurologic injury, effects of frequent seizures and head injuries, and high-dose
combinations of antiepileptic drugs.
D. Benign Rolandic epilepsy. This syndrome frequently begins in children with a
family history of epilepsy. The most characteristic sign is a partial motor or
somatosensory seizure involving the face. Tonic-clonic seizures may also occur,
especially during sleep. The seizures are infrequent (some patients require no
medications), are easily controlled with antiepileptic drug therapy, and stop
spontaneously by age 15. Mental development is unaffected.
E. Juvenile myoclonic epilepsy: These myoclonic seizures, with or without tonic-clonic
or absence seizures, usually begin shortly before or after puberty but may first occur
in early adulthood. Myoclonic and tonic-clonic seizures most often occur in the early
morning, shortly after the patient awakens. Mental developemnt is normal. In most
patients seizures are well controlled by valproic acid alone, but the disorder requires
life long therapy.
VIII. FIRST AID FOR SEIZURES
A. Generalized Tonic-Clonic Seizures
1. Prevent person from hurting himself or herself. Place something soft under the
head, loosen tight clothing, and clear area of sharp or hard objects.
2. Do not force any objects into patient's mouth.
3. Do not restrain patient's movements.
4. Turn patient on his or her side to allow saliva to drain from mouth
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5. Stay with patient until seizure ends naturally.
6. Do not pour liquids into patient's mouth or offer any food, drink or medication
until fully awake.
7. Give artificial respiration if patient does not resume breathing after seizure.
8. Provide area for patient to rest until fully awakened, accompanied by responsible
adult.
9. Be reassuring and supportive when consciousness returns.
10. While a convulsive seizure is not usually a medical emergency, presence of any of
the following signs indicate the need for immediate medical attention:
a. Seizure lasting longer than 10 minutes or occurrence ofsecond seizure.
b. Difficulty in rousing at 20-minute intervals.
c. Complaints of difficulty with vision
d. Vomiting
e. Persistent headache after a rest period
f. Unconsciousness with failure to respond
g. Unequal size pupils or excessively dilated
B. Nonconvulsive Seizures (Absence and Complex Partial)
1. Do not restrain patient.
2. Remove harmful objects from patient's path.
3. Calmly try to encourage patient to sit down or encourage him or her away from
dangerous situations. If person does not respond to these measures, force should not
be used.
4. Observe but do not approach patient who appears angry or combative.
5. Remain with patient until fully alert.
DRUG THERAPY
I. GOAL OF THERAPY
A. Primary goal of drug therapy is the complete suppression of seizures in the absence
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of disabling side-effects. Prognosis of epilepsy has improved in last decade, and at
present about 60-70% of newly diagnosed patients can be expected to achieve
complete seizure control following institution of effective monotherapy (one drug).
B. When epilepsy cannot be controlled completely, the aim of treatment is to attain
the best compromise between the desire to maximize seizure control and the need to
keep side-effects within acceptable limits for the individual patient.
C. Therapy should maintain or restore the patient=s lifestyle and ability to lead an
active life.
II. GENERAL MANAGEMENT OF EPILEPSY
A. Appropriate diagnostic evaluation
B. Identify and correct underlying cause
C. Treatment of Seizures
1. Assess necessity of drug therapy
a. Drug therapy not indicated for seizures due to acutereversible medical problem
b. Therapy not necessary for certain benign epilepsies (febrileseizures, rolandic epilepsy)
c. Following first unprovoked seizure- while some benefit may
occur by initiating therapy in high risk patients, present
consensus is to delay therapy until patient experiences a
second unprovoked seizure.
2. Institution of appropriate antiepileptic drug therapy
3. Identify and avoid if possible any precipitating factors (i.e., alcohol, lack of sleep,
emotional stress, fever, lack of food, exposure to flickering light, menstruation)
4. Evaluation for surgery or implantation of vagal nerve stimulator in patients
refractory to drug therapy.
D. Prevention of complications of seizures
1. Early control/termination of seizures
2. Avoidance of intolerable drug-induced adverse effects
3. Attention to and treatment of psychosocial complications
III. PRINCIPLES OF ANTIEPILEPTIC DRUG (AED) THERAPY
A. Select most appropriate drug based on:
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1. Seizure Type (see Table 1) - Seizure type is the primary criteria for antiepileptic
drug selection. Although not necessary for drug selection, knowledge of the epilepsy
syndrome is also useful since it provides additional information including the
expected responsiveness of the patient=s seizure disorder to drug therapy, expected
duration of drug therapy, and long term prognosis.
2. Final selection among drugs having equal efficacy for a given seizure type should be
individualized for each patient based on other factors such as potential adverse
effects, convenience of administration, cost, and patient=s lifestyle. (see Individual
drug monographs, Section VI).
B. Optimization of therapy requires individualization of dosage. Once an agent has
been selected, therapy should initiated by starting at the low end of the drug=s
recommended dosage range and slowly increasing the dose until seizures are
controlled or intolerable adverse effects develop. Following each dose increase, time
should be allowed for the drug to come to steady-state before evaluating the patient=s
clinical response at that dosage level and deciding whether further adjustments are
needed.
1. Initial Dosage: AED therapy should be gradually introduced during the first month
of therapy to minimize the gastrointestinal and neurologic side effects that commonly
occur with initiation of AED treatment. The frequency of these side effects tends to
decrease over the first few months as tolerance develops. Although seen to some
extent with all the AEDs, these initiation related side effects may be especially
troublesome with carbamazepine, ethosuximide, felbamate, lamotrigine, primidone,
tiagabine, topiramate and valproic acid. In addition to the GI and CNS effects listed
above, the occurrence of rash with lamotrigine is related to the rate of dose initiation.
To minimize these initiation related side effects, these agents are usually started at
subtherapeutic dosages and the dose gradually increased over several weeks to therecommended dose range. Specific initiation schedules for these drugs are provided in
their monographs (see section VI). If intolerable adverse effects develop during the
titration process, the dose should be reduced to the previous level that the patient
tolerated and, after symptoms subside, the titration process restarted using smaller
dosage increments. Since initiation related adverse effects are less problematic with
gabapentin, phenytoin, and phenobarbital, therapy with these agents is generally
started at dosages within the recommended dose range.
2. Before considering therapy with a given AED as a failure and switching to another
drug, the following factors should be reevaluated:
a. Diagnosis of epilepsy
b. Classification of seizure type and/or epilepsy syndrome
c. Presence of an active lesion
d. Adequate dosage and/or duration of therapy (i.e., was dosepushed to maximal tolerated level, was adequate time
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allowed for steady-state to be achieved following each dose
adjustment).
e. Compliance with medication regimen (noncompliance ismost common cause of drug failure and breakthrough
seizures)
3. If seizures continue, despite a maximally tolerated dose of the first AED, a second
AED should be selected. Therapy with the second drug should be initiated as
described above. Once the dose of the second drug has been titrated into its
recommended dose range, the initial drug should then be gradually withdrawn over
1-3 weeks (more rapid if being performed as inpatient). After the first drug has been
withdrawn, the dose of the second drug, taken alone (i.e., monotherapy), should then
be increased until seizures are controlled or intolerable side effects develop. This
process should be continued until monotherapy with two or three of the primary
drugs has failed. Only after this should combination or polytherapy be considered.
Factors to consider when combining drugs include the patient=s previous clinical
response (i.e., seizure control, side effects) to each drug alone, mechanism of action(theoretically combining drugs having differing mechanisms of action would appear
preferable), adverse effect profiles, and pharmacokinetic properties.
4. Epilepsy surgery should also be considered in patients who have failed
monotherapy with the primary drugs and an initial attempt with polytherapy.
C. Monotherapy
Monotherapy with the AEDs is preferred for most patients. Advantages of
monotherapy as compared to polytherapy (multiple drug therapy) include: equal or
superior efficacy to combination drug therapy; reduced frequency of adverse effects;
absence of drug interactions; lower cost; enhanced ability to correlate response,adverse effects, and abnormal lab values to specific drug; reduced risk of birth
defects; and improved compliance due to simpler and less intrusive regimens
D. Monitoring Therapy
1. Seizures - patients should be encouraged to keep a seizure diary and accurately
record the type, duration, and time of occurrence of any seizures. In assessing
therapy, the following seizure related parameters should be considered:
a. Change in seizure frequency - important to assess not onlychange in absolute number of seizures, but also length of
seizure-free interval
b. Change in seizure pattern or type
c. Altered time of occurrence
2. Adverse Effects: patients should be educated to the type of adverse effects that may
occur with the AEDs and to record in their seizure diary any adverse effects and the
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time of day at which they occur. Specific adverse effects that should be monitored for
include:
a. Dose-Dependent Neurological Effects - (see section V, VI) thefollowing should be assessed at each visit: mental status;
cerebellar signs (i.e., nystagmus, balance, coordination,
tremor); visual problems (blurring, double vision); cognitive
function
b. Idiosyncratic/Chronic Adverse Effects: (see section V, VI)
3. Laboratory Tests
a. Baseline (i.e. prior to starting therapy) lab tests should
include liver function tests (SGOT, SGPT, alkaline
phosphatase), serum albumin, complete blood cell count
with differential, urinalysis, and serum electrolytes.
b. In otherwise healthy and asymptomatic patients, routine
laboratory monitoring after starting therapy is unnecessary
with clinical laboratory tests only being repeated if indicated
by the patient's clinical condition. For patients with
abnormal baseline laboratory tests, further work up is
required to evaluate their cause and follow-up monitoring
performed as indicated. (i.e., for a patient with a low WBC
started on carbamazepine, a CBC should be obtained every
month for first 1-3 months, then quarterly for next year, and
then every 6-12 months thereafter).
4. AED Plasma Concentrations: When used appropriately, AED plasmaconcentrations provide a useful adjunct tool to clinical monitoring to assist in
optimizing therapy (particularly for carbamazepine, phenytoin, primidone, valproic
acid). Because of infrequent occurrence of seizures in most patients and wide
interpatient variability in AED pharmacokinetics, availability of target plasma
concentrations is helpful in guiding dose adjustments.[Please note however that the
final assessment of therapy is the patient=s clinical response (i.e., seizure control and
side effects) not what the plasma concentration is.] AED plasma concentration
monitoring also is useful in assessing medication compliance and evaluating cause of
an unexpected loss of seizure control or occurrence of drug toxicity. Role of plasma
concentration monitoring with newer AEDs is not established and is not currently
recommended.
E. Appropriate Use of AED Plasma Concentrations
1. General Guidelines for Use of AED Plasma Concentrations
a. A major problem with the use of AED plasmaconcentrations is tendency of many clinicians to treat the
published therapeutic ranges as a fixed range that is optimal
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for every patient. It is important to remember that these
ranges are derived from uncontrolled studies and at best
should be viewed as a target range to initially aim for as one
is attempting to optimize therapy in a given patient.
b. Considerable interpatient variability in therapeutic plasmaconcentrations exists for these drugs, with many patients
being controlled at levels below or above the published
ranges. An important point to remember in monitoring AED
plasma concentrations is that the therapeutic concentration
for a specific patient is that which controls seizures without
producing significant adverse effects, regardless of whether
or not it is within the published therapeutic range for that
drug.
c. AED plasma concentrations should be interpreted in termsof what is occurring clinically with patient.
d. Monitoring of AED plasma concentrations should berestricted to answering questions concerning specific clinical
problems. Routine monitoring of plasma concentrations in
otherwise stable patients serves no purpose except to tell you
what you already know and unnecessarily increases the cost
of therapy.
2. Appropriate Indications for AED Plasma Concentration Monitoring
a. Guiding dosage adjustments
b. Identifying patient=s individual therapeutic range
c. Determing cause of unexpected loss of seizure control oroccurrence of drug toxicity
d. Evaluating clinical consequences of addition/removal ofpotential interacting drug
e. Assessment of patient compliance
3. Factors to Consider Before Obtaining AED Plasma Concentration
a. Determine reason for sampling, since this will guide whenand at what time to obtain sample
b. Should the plasma sample be reflective of steady-state ?While not all plasma concentrations need to be at steady-
state, obtaining a plasma sample prior to achievement of
steady-state will not provide an accurate assessment of
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patient=s clinical response to the current drug regimen and
may result in inappropriate dosage adjustments. To ensure a
new steady-state has been reached, plasma samples should
not be obtained for at least 4-5 half lives afetr most recent
dosage adjustment or change in concurrent therapy.
c. Sampling time. In most instances, sampling time should beconsistent with times of previous samples to allow an
accurate assessment between changes in patient=s clinical
response and plasma concentrations. Obviously exceptions
to this rule exist. For example, if the indication for the
plasma level is dose related toxicity, obtaining sample at time
of peak concentration or occurrence of symptoms may be
helpful.
d. Determine need for obtaining free (unbound) plasma drugconcentration or plasma concentration of metabolite.
4. Evaluation of AED Plasma Concentrations
a. When was last dose given ?
b. Is this concentration reflective of steady-state ? (When wasdrug started, when did last dosage change occur, when were
regimens of any concurrent drugs last changed)
c. Is patient compliant ?
d. What is patient=s clinical response to this concentration ?
e. Is there an intercurrent illness or concomitant drug thatmight alter plasma concentrations or clinical response to the
AED ?
f. What are therapeutic goals for this patient ?
5. Factors Associated with Individual Variation in Therapeutic Plasma Concentration
a. Seizure Type- patients with partial seizures have been shown
to require higher plasma concentrations than patients with
primary generalized seizures (Lambie et al, 1976; Schmidt &
Haenel, 1984).
b. Severity of Epilepsy- higher plasma concentrations shown tobe required in patients with higher pretreatment seizure
frequency and patients in status epilepticus.(Lund, 1974;
Schmidt & Haenel, 1984)
c. Altered plasma protein binding- relationship between free
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and total AED plasma concentration altered. In patients
with decreased protein binding (increased free fraction),
clinical response would be expected at a lower total plasma
concentration than if patient's plasma protein binding were
normal.
d. Active Metabolites
e. Concurrent Drug Therapy: Pharmacodynamic Interactions
1). Enhancement of Concentration-Related Toxicity: Concurrent use of other AEDs
(polytherapy), alcohol, antidepressant, antihistamines, antipsychotics,
benzodiazepines, narcotic analgesics, and sedative hypnotics may result in the
occurrence of concentration-related neurotoxicity at lower than expected plasma
concentrations.
2). Drugs Antagonizing Anti-Seizure Effect of AEDs: bupropion, clozapine,
imipenem-cilastin, isoniazid, reserpine, tricyclic antidepressant, theophylline andcocaine/amphetamines may lower the seizure threshhold.
F. Evaluation of Patient with Chronic Active Epilepsy
1. Review diagnosis/etiology
2. Review compliance
a. Evaluation of compliance
1. Direct questioning of patient using open ended question (e.g.
"How do you take your medicine?" "Which dose is moredifficult to remember?"
2. Review of refill patterns
3. Pill counts
4. AED plasma concentrations
a. Approaches for Improving Compliance
1. Patient education
2. Simplification of dosage regimens
3. Flexible, patient-specific administration schedules
4. Medication calendar
5. Use of pill cups, boxes, or watch with alarm
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3. Review Drug History
AED history should include drugs, doses used, and clinical response in terms of any
beneficial effects or adverse effects.
4. Form Treatment Plan
5. Reduction of Polytherapy
a. Assess present therapy
b. Withdraw any nonessential drugs, and drugs present atsubtherapeutic plasma concentrations
c. If not present, initiate therapy with desired AED(s) andtitrate dose to therapeutic serum concentration range
d. Concurrent with above, begin reducing drugs that are
producing adverse effects or potentially toxic.
e. Once therapeutic plasma concentrations of desired drug isachieved, remove any other AED(s) as appropriate.
f. Plan should be reassessed based on clinical response andplasma concentration monitoring following each change in
drug and/or dose.
g. Anticipate changes that may occur in pharmacokinetics ofremaining drugs as potentially interacting drugs are
removed.h. Tapering Schedule for withdrawing AED therapy: To
minimize any exacerbation in seizure control or the
occurrence of withdrawal seizures, ensure that plasma
concentrations of desired drug(s) are in the usual
therapeutic range and then slowly withdrawing the
unwanted drug over several days to weeks. While the exact
time schedule for tapering the dose of the drug to be
withdrawn will depend on the patient=s clinical condition
and setting, a general recommendation would be to decrease
the dose by 25% every 1 to 2 weeks. If possible the tapering
process with carbamazepine, phenobarbital and
benzodiazepines should be even slower than this, i.e., 25%
every 2 to 4 weeks. If an exacerbation of seizures occurs
during drug withdrawal, the dose should be increased to the
previous level and then, after seizure control has been
restored, the tapering process restarted using a more
gradual schedule (i.e., decreasing the dose by a smaller
amount each time and allowing a longer time between dose
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decreases).
G. Termination of Antiepileptic Drug Therapy
1. Need for continued AED therapy can be reevaluated when patient has been seizure
free for 2 to 5 years. Once seizure free for 2 to 5 years, studies have shown that 60-
75% of children and 40-60% of adults may be successfully withdrawn frommedication.
2. Factors favoring a low risk for recurrence of seizures after medication withdrawal
include (Annegers et al, Epilepsia 1979; Emerson et al, NEJM 1981; Thurston et al,
NEJM 1982; Callaghan et al, NEJM 1988; MRC Trial Group, Lancet 1991 ):
a. Minimum 2 year seizure free period
b. Normal electroencephalogram
c. Short duration of epilepsy prior to seizures being controlled
d. Few seizures after starting AED therapy
e. Controlled achieved with monotherapy
f. Age of less than 16 years at onset of seizures
g. Presence of absence seizures only
3. Decision should be made on individual basis considering consequences of seizure
recurrence on patient=s employment, education, lifestyle, and driving priveleges.
Although little data is available to indicate the optimal withdrawal rate of AED
therapy or to support a relationship between withdrawal rate and seizure relapse,
most investigators recommend that treatment be withdrawn gradually over a period
of at least three months (Callaghan et al, NEJM 1988; Chadwick et al, Br Med J
1985).
H. Patient Education
The main aim of education in the patient with epilepsy is to provide the patient and/or
their care givers with knowledge needed to allow their active participation in
management of their epilepsy. Goals of education in these patients include providing:
1). An understanding of their disease state;
2). The goals and limitations of drug therapy;
3). How to appropriately manage their disease (i.e., observing and recording seizures
and any changes in seizure activity in diary; types of adverse effects to watch for,
information to record about adverse effects in diary; how and when to report any
problems with adverse effects or seizure control; what to do if miss dose)
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4). An understanding of the concept of a therapeutic plasma concentration range,
steady-state, and relation to regular drug intake (i.e., what occurs when miss dose and
how long will it take once therapy is restarted for plasma concentrations to return to
previous level);
5). An understanding of the importance of compliance with their medication regimen
and what measures or aides can be used to improve compliance. Also since sooner or
later every patient will miss a dose, they should be instructed on how to handle missed
doses. In general, if a single dose is missed, the patient should be instructed to take the
missed dose as soon as possible. If two sequential doses are missed, one should be
taken immediately and the other with the next regular dose. If more than two doses
are missed, patients should contact their physician as the strategy in this situation will
depend on patient=s clinical condition and on the AED.
6). Understanding and recognition of drug related adverse-effects and potential drug
interactions (Who to contact if have questions concerning a potential drug interaction
or adverse effect, What adverse effects to be aware, When to contact their health care
provider);
7). For women of childbearing potential, birth control options and the
risks/complications associated with pregnancy in a woman with epilepsy should be
discussed (see pages 24-26 of The Epilepsy Counseling Guide).
IV. ADVERSE EFFECTS
A. Dose (Plasma Concentration) Related Adverse Effects
1. These adverse effects primarily represent the toxic effects of the AEDs on the
central nervous system, and include somnolence, fatigue, dizziness, vision changes
(double or blurry vision), nystagmus, ataxia (incoordination), tremor, gastrointestinaldisturbances, difficulty thinking, and behavioral disorders. These adverse effects are
dose-related and more prominent at higher AED plasma concentrations. Although
their severity and frequency may vary among agents, the concentration-related
adverse effects are qualitatively similar among the different antiepileptic drugs
(AEDs) and are seen in all patients if large enough doses are given. The occurrence of
these adverse effects end up being the therapy limiting endpoint for most patients.
2. Due to additive neurologic effects of the AEDs, these adverse effects are more
frequent and occur at lower plasma concentrations in patients receiving AED
polytherapy (i.e. more than one AED).
3. The occurrence of these adverse effects, unrelated to dose, is particularly
prominent during initiation of therapy (especially with carbamazepine, ethosuximide,
primidone, felbamate, lamotrigine, tiagabine, topiramate, and valproic acid), but
disappear as tolerance develops. For this reason, therapy with these drugs should be
started with low doses and the dose slowly titrated up to the recommended
maintenance over several weeks.
4. Transient neurotoxicity during the first hours following drug ingestion may relate
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to an excessive fluctuation in plasma concentrations between doses and high peak
plasma concentrations. These peak plasma concentration-related neurologic effects
commonly result from use of inappropriate dosage intervals relative to drug=s half-
life or administration of rapidly absorbed dosage formulations.
5. The occurrence and severity of these neurologic side effects can be minimized by:
a. Initiating therapy at a low dose and slowly increasing thedose
b. Avoiding large dosage changes
c. Restricting therapy to one drug when ever possible
d. Adjusting the administration schedule (e.g., administrationof the largest dose at bedtime, dividing the daily dose into
smaller doses given more frequently)
e. If the occurrence of these adverse effects is primarilyassociated with the time of peak serum concentrations, their
occurrence may be reduced by administering smaller doses
more frequently or switching to a more slowly absorbed
formulation.
f. Reduction in total daily dose.
6. Impairment of Cognitive Function/Behavioral Disorders
a. Impairment of cognitive function (i.e., difficulty thinking)
and behavioral disorders are the adverse effects that mostsignificantly impact on the patient=s quality of life. Factors
contributing to these problems in patients with epilepsy
include the disease state, psychosocial stresses, and AED
therapy.
b. Adverse effects on cognitive function and behavior (i.e.,
hyperactivity, irritability, sleep disturbances, altered mood,
depression) have been reported with all of the AEDs. The
severity of these effects is increased with higher plasma
concentrations and polytherapy.
c. Differential effects among the various AEDs have not beenapparent in controlled studies, with the exception of
phenobarbital and the benzodiazepines. Phenobarbital
appears to decreases cognitive performance to greater extent
than other AEDs in both adults and children. Barbiturates
have greatest effect on behavior, including hyperactivity
which may be seen in 10-50% of children receiving
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phenobarbital. Newer AEDs, such as gabapentin and
lamotrigine, appear to have minimal effects on either
cognitive function or behavior.
d. Management: recognize that these adverse effects may occur
with any of AEDs, restrict therapy to lowest effective dose
and avoid polytherapy, particularly with barbiturates
B. Idiosyncratic (Hypersensitivity) Adverse Effects
1. All of the current AEDs, with the exception of some of the newer AEDs
(gabapentin, topiramate, tiagabine), have been associated with the occurrence of rare,
but serious idiosyncratic reactions, including aplastic anemia, skin rash,
hepatotoxicity, pancreatitis, lupus-like reaction, and exfoliative dermatitis/Stevens-
Johnson syndrome. These reactions are generally rare (about 1 in 20,000 to 50,000
newly treated), unpredictable, non-dose related and usually occur during the first few
months of therapy.
2. Previous recommendations for routine monitoring of blood and urine analyses
during AED therapy were primarily designed to detect these reactions. However,
because of their rare occurrence, the frequent occurrences of transient and clinically
insignificant changes in lab indices during chronic AED therapy, and the fact that
clinical symptoms are usually present before lab testing reveals any abnormalities;
the more recent recommendations given in section III. D.3. have been adopted.
3. Most important approach to monitoring for these serious idiosyncratic effects is
close clinical monitoring of the patient and education of the patient and family about
the symptoms that may indicate serious adverse effects and the importance of
reporting these immediately to their physician.
a. Severe dermatologic or hepatic reaction withcarbamazepine, lamotrigine, phenytoin, phenobarbital,
primidone: rash and fever
b. Valproic acid induced hepatotoxicity or pancreatitis: nausea,vomiting, lethargy, loss of seizure control, jaundice, coma
c. Aplastic anemia/granulocytopenia: abnormal bruising orbleeding, persistent infection
4. Proposed Mechanism For Idiosyncratic Adverse Effects With Heterocyclic AED
Recent studies suggest that the idiosyncratic (hepatotoxicity, rash, pseudolymphoma,
aplastic anemia) and teratogenic adverse effects occurring with the heterocyclic AEDs
(i.e., carbamazepine, lamotrigine, phenytoin, phenobarbital, primidone ) may result
from accumulation of toxic arene oxide metabolites of these drugs. The accumulation
of arene oxide metabolites results from genetic defect of drug metabolism and is
enhanced by polytherapy. These AEDs are metabolized by hepatic cytochrome P-450
monoxygenase to a chemically reactive intermediate metabolite (arene oxide) which is
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then rapidly detoxified by epoxide hydrolase to an inactive hydroxylated metabolite.
The predisposition of certain patients to develop idiosyncratic toxicity with these
drugs appears to be due to a genetic or drug-induced (i.e., valproic acid) reduction in
epoxide hydrolase activity allowing accumulation of the toxic arene-oxide metabolites.
Additionally enzyme induction of monoxygenases by other concurrent AED (such as
carbamazepine, phenobarbital, phenytoin, primidone) serves to further increase thelevels of the reactive arene oxides.
5. Skin Rash
Skin rash is the most common hypersensitivity reaction with the AEDs and is seen in
5-15% of patients receiving carbamazepine, ethosuxmide, lamotrigine, phenytoin, and
phenobarbital. Onset of rash is usually within first 1-3 weeks of therapy and is
reversible on discontinuing the causative agent. Although a mild morbilliform rash is
most common, skin reactions may rarely progress to more severe forms, such as
exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis. The
presence of fever, eosinophilia, desquamation, mucus membrane ulceration, and
painful dermatitis may serve to differentiate between the benign and more seriousskin reactions. Of the current AEDs, skin rash is only rarely reported with valproic
acid, gabapentin, felbamate, topiramate, and tiagabine.
The occurrence of skin rash with lamotrigine therapy is increased by concurrent
valproic acid therapy, a high starting dose, and a rapid dose escalation schedule when
initiating therapy. To minimize the occurrence of rash with lamotrigine, therapy
should be started at a very low dose, particularly if already receiving valproic acid,
and slowly increased into the effective dose range over 1-3 months.
6. Hepatotoxicity
a. Remember: it is not unusual (2 to 40% of patients) to seetransient elevated serum transaminases and alkaline
phosphatase levels without any clinical symptoms in patients
on AED (particularly children). These observations will in
the vast majority of cases resolve on continued therapy and
require no therapeutic intervention. It is important that
these cases be differentiated from the rare but more severe
hepatotoxicity observed with AED treatment: delayed
hypersensitivity (seen with PHT, Pb, CBZ, Pr) and
irreversible hepatic coma (VPA).
b. Delayed Hypersensitivity Reaction
1. Reported with all of the heterocyclic AEDs (i.e.,carbamazepine, lamotrigine, phenytoin, phenobarbital,
primidone). Mechanism thought to be an idiosyncratic
metabolic abnormality in susceptible patients.
2. Onset in majority of patients within first 6 weeks of therapy.
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3. Elevated liver enzymes accompanied by signs and symptoms
of hypersensitivity: rash (86%), fever (84%),
lymphadenopathy (68%), jaundice (54.5%), hepatomegaly
(52%), eosinophilia (77%). (Oxley et al; 1983).
4. 38% of cases may develop fatal hepatic necrosis, multiorganfailure, disseminated intravascular coagulation.
5. Requires discontinuation of therapy.
a. Valproate Hepatotoxicity
1. Usually occurs during first 6 months of therapy.
2. Proposed mechanism: biochemical defect in fatty-acid
metabolism, which is accentuated by an enhanced
production of toxic valproic acid metabolites, which may be
increased by concurrent therapy with enzyme-inducingAEDs, and concurrent disease states.
3. Risk factors for development of valproate hepatotoxicity
include young age and use of polytherapy. Presence of other
neurological disorders, biochemical diseases, or preexisting
liver disease further increase risk. Highest risk of hepatic
fatality is in patients < 2 years of age and on polytherapy.
Risks for development of fatal hepatic failure range from
1/500 in children < 2 y/o on polytherapy to 1/37,000 for
monotherapy patients.
4. Prodromal symptoms: sudden loss of seizure control,malaise, lethargy, drowsiness, weakness, vomiting, anorexia
and/or jaundice. In most cases, routine monitoring of liver
function tests will be of little value in detecting onset of acute
toxicity.
5. Prevention
a. Avoid administering VPA as part of polytherapy regimen tochildren < 3; unless either monotherapy has failed or
potential benefits of polytherapy merit risk.
b. Avoid administering VPA to patients with preexisting liverdisease and/or a family history of childhood hepatic disease.
c. Administer VPA in as low a dose as possible for seizurecontrol
d. Avoid concomitant administration of valproate and
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salicylate,
e. Monitor clinically for such symptoms as vomiting, headache,edema, jaundice, or seizure breakthrough, especially after
febrile illness. If such symptoms develop, VPA therapy
should be discontinued until a definitive diagnosis is made.
Patient should be made aware of these symptoms and what
to do if occur, when initiated on VPA. Greater physician and
patient awareness of the primary risk factors have resulted
in a decrease incidence of fatal VPA hepatotoxicity from
0.93/10,000 in 1978-84 to 0.20/10,000 in 1985-86.
a. Felbamate : Acute hepatic failure with felbamate, 16 casesreported after introduction between 1/94 to 12/94.
Mechanism unknown. Has resulted in severe restrictions
being placed on use of drug.
7. Aplastic Anemia/Agranulocytosis
Although commonly associated with carbamazepine, serious hematological reactions
(i.e., aplastic anemia and agranulocytosis) have been reported with all of the AEDs,
except gabapentin, lamotrigine, topiramate, and tiagabine. The frequency of aplastic
anemia with carbamazepine has been estimated at 1 in 200,000 patients. In contrast,
to the extremely rare occurrence with carbamazepine and the other AEDs, thirty
cases of aplastic anemia were reported with felbamate from 1/94 to 12/94, which
represents an approximate frequency of 1 in 2000 patients.
Routine monitoring of CBCs is usually of little value in detecting the onset of aplastic
anemia. The most important approach is to clinical monitor the patient for the
occurrence of any signs or symptoms indicative of a serious hematologic reaction,
including bruising, bleeding, and persistent infection.
C. Chronic (Systemic) Adverse Effects
1. Long-term AED therapy may lead to a variety of chronic adverse effects, including
connective tissue, endocrine, GI, hematologic, and neurologic disorders. Chronic AED
toxicity tends to be drug specific and is not directly related to AED serum
concentration. While not usually life threatening, these chronic adverse effects may
have a significant impact on the patient's quality of life. Many of these adverse effects
can be avoided or minimized by appropriate preventative measures. Factors that may
predispose a patient to chronic AED toxicity include a long duration of therapy,polytherapy, extended administration of high dosages, repeated or prolonged episodes
of acute toxicity, poor diet or hygiene, and institutionalization.
2. Neurological
a. Chronic Cerebellar Degeneration (Encephalopathy)
1). Primarily seen in patients receiving prolonged (> 5-10y) phenytoin treatment with
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high serum concentrations and/or dose. Similar syndrome also reported to rarely
occur with primidone and phenobarbital.
2). Characterized by confusion, delirium, muscular hypotonia, choreoathetoid
movements, orofacial dyskinesias.
3). May improve in some patients following reduction in dose and/or discontinuationof phenytoin.
4). Related to chronic degeneration of purkinje cells in cerebellum; actual role of
phenytoin in this disorder controversial since most patients also have long history of
uncontrolled generalized tonic-clonic seizures.
a. Peripheral Neuropathy- reported in approximately 8.5-18%of patients receiving long term phenytoin therapy at high
doses. Primarily manifested as sensory loss. May or may not
improve on decreasing dose. May respond to folate
supplementation. Also has been reported withcarbamazepine and barbiturates.
3. Gastrointestinal
a. Increased weight gain - Reported for valproic acid (VPA),
primarily in children. Usually reverses with continued
therapy. If not, consider reduction in caloric intake, dose
reduction or discontinuation of therapy. Mechanism
unknown. In the recently completed VA Cooperative study
in adult epileptics, incidence of a large weight gain (>12 lbs/
5.5 kg) with VPA was 20 % overall and 13 % after 12
months of therapy.
b. Anorexia and weight loss (>10 kg) is reported in 5-15% ofpatients receiving felbamate. Mechanism unknown. Usually
reversible with continued therapy. If persists, the options
include attempting to increase patient caloric intake,
reducing the felbamate dose, or discontinuing therapy.
4. Hematological
a. Leukopenia, thrombocytopenia and various anemias havebeen reported in isolated cases with the all the AED, except
gabapentin and lamotrigine. A transient and/or dose-
dependent leukopenia is seen in 5-10% of patient receiving
carbamazepine. In most cases, this leukopenia is clinicaaly
insignificant and requires no action. Presence of persistent
leukopenia (WBC
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calls for discontinuation of carbamazepine.
b. Neonatal Coagulation Defects
1). Seen in infants born to mothers on phenobarbital, primidone, carbamazepine
and/or phenytoin. Onset of this hemorrhagic disorder is usually within the first 24
hours after birth and consists of hemorrhage from atypical sites such as pleural andabdominal cavity. This is in contrast to hemorrhagic disease of the newborn which
does not develop until 2 to 5 days postpartum and where bleeding is more superficial.
2). Mechanism thought to be competitive inhibition of Vitamin K metabolism in fetal
liver preventing production of vitamin K dependent clotting factors.
3). Management:
a). Mothers receiving antiepileptic drugs should avoid other drugs with adverse
effects on hemostatic system during last trimester (i.e., aspirin, indomethacin,
thiazides, promethazine).
b). Consider cesarean section if difficult or traumatic delivery is expected.
c). Mother receiving AED should be given oral Vitamin K1 20 mg/day the last 2 to 4
weeks of pregnancy
d). Cord blood should be submitted for immediate clotting studies and fresh frozen
plasma given if diminished vitamin K dependent factors are found.
e). Infant should be given 1 mg IV phytonadione immediately after birth.
f). The neonate should then be monitored carefully and should receive an exchange
transfusion at the first sign of development of hemorrhage.
a. Megaloblastic Anemia
1). Occurs in 0.15-0.75% of epileptic patients on AED, primarily with phenytoin but
also reported with Pb, Pr and CBZ.
2). Mechanism appears to be due phenytoin-induced malabsorption of dietary folate
and/or induction of metabolism.
3). Readily responds to treatment with exogenous folic acid 1 to 5 mg/day.
4). Not uncommon to see subclinical macrocytosis and/or low serum folate levelswithout accompanying signs of megaloblastic anemia (1 to 30% of patients on
phenytoin); present recommendations are not to treat these patients with folate.
a. A dose-dependent thrombocytopenia and/or plateletdysfunction (due to inhibition of platelet aggregation) has
been reported infrequently in patients on valproic acid. This
side effect is probably rare or at least has little clinical
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significance. Although regular monitoring is probably not
warranted, a baseline platelet count should be obtained in
patients starting on VPA. As a precaution, patients on VPA
prior to surgery should have a platelet count and bleeding
time performed.
5. Endocrine
a. Osteomalacia
1). Primarily a biochemical disorder with decreased concentrations of Vitamin D and
calcium, rarely associated with the development of clinical disease.
2). Attributed to increased hepatic metabolism of vitamin D and/or inhibition of
calcium absorption. Has been associated with phenytoin, phenobarbital, primidone
and carbamazepine.
3). Risk factors associated with the development of clinical disease include: poor
dietary intake of vitamin D, low exposure to sunlight, drug dose and duration,
multiple anticonvulsants and male sex.
4). Treatment: 4000 IU vitamin D3/mm3 BSA per day for 4 months, then maintenance
therapy of 1000 IU/day.
a. SIADH
1). Reported primarily in elderly patients on carbamazepine. Water retention with
hyponatremia; clinically manifested as headache, mental confusion, dyspnea, and
acute loss of seizure control after prolonged carbamazepine treatment.
2). Mechanism unknown; in patients in whom it occurs, it appears to be related to
serum concentration and may improve with decrease in dose. Baseline urinalysis and
serum sodium should be obtained in patients prior to starting carbamazepine with
follow up tests done in patients with occurrence of above clinical symptoms. Often
mistaken for acute carbamazepine toxicity, should be considered in elderly patients
complaining of above symptoms.
a. Hyperglycemia: an uncommon adverse effect reported for
phenytoin; related to phenytoin impairment of normal
insulin response to glucose. For most epileptic patients of no
clinical significance, however should be kept in mind when
phenytoin being used in diabetic patients. To preventcomplications in these patients, phenytoin should be used in
lowest effective dose.
6. Cardiac
a. Carbamazepine: Cardiac conduction disturbances (2nd or3rd degree A-V block) have been rarely reported with
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carbamazepine. Reversible on discontinuation. Most
important risk factor appears to be advanced age. Elderly
patient starting on CBZ should have EKG performed before
and after initiation of therapy.
b. Intravenous Phenytoin: Ventricular arrhythmias,
conduction disturbances, and hypotension may occur
following IV phenytoin administration. Solvent, propylene
gylcol, in parenteral solution appears to be contributing
factor. Occurrence related both to rate of administration
and patient age (i.e., more common in elderly patients).
7. Connective Tissue Disorders
a. Gingival Hyperplasia
1). Observed in up to 50% of patients on chronic phenytoin therapy.
2). Proposed mechanism: alteration of connective tissue repair process and decrease
in salivary levels of IgA. Initial tissue damage may be related to accumulation of
arene oxide metabolites as severity worse in patients on polytherapy.
3). Severity may be reduced by careful oral hygiene.
a. Hirsutism, acne, hyperpigmentation, and coarsening offacial features- not uncommonly observed in children and
young adults on chronic phenytoin therapy. Incidence of
facial hirsutism reported up to 30% in young females.
b. Alopecia- Reported in 2-12% of patients on valproic acid;characterized by temporary thinning of hair with curly orwavy regrowth. Has not been shown to be dose related
(although some studies have reported that it occurs more
commonly in patients on high doses) and usually resolves in
2-6 weeks without any adjustments in VPA therapy
required. Reversible on discontinuation of drug.
c. Dupuytren's Contractures: characterized by palmar
nodules, frozen shoulder, generalized joint pain. Although
first reported with AEDs in 1925, the 1985 VA monotherapy
trial was first study to show direct association with
phenobarbital and primidone therapy. Seen after at least 6
months of therapy with Pb or Pr and reversible on D/C.
Incidence 5-10% with an increasing incidence longer
patients on drug.
8. Teratogenicity
a. Expected incidence of congenital malformations (Browne,
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1983):
o 2-3% general population
o 4-5% children born to mothers with epilepsy not taking
AED
6-11% children born to mothers with epilepsy taking AED; an incidence similar to
that in untreated mothers has also been reported in offspring of epileptic fathers.
a. Present data does not support a specific teratogenic effectfrom AED, but indicate that congenital abnormalities that
occur normally in epileptic patients occur more frequently
with use of AED. Present data supporting an association
between AED exposure and development of malformations
include:
1). higher malformation rates in children of treated mothers as compared to
untreated mothers with epilepsy
2). higher AED serum concentrations found in serum of mothers with malformed
children than mothers of healthy children (Dansky et al, Neurology 3:15, 1980)
3). higher malformation rates seen in infants exposed to polytherapy than those
exposed to monotherapy during gestation (Lindhout et al, Epilpesia 25:77, 1984;
Kaneko et al, Epilepsia 29:459,1988). Both the Lindhout and Kaneko studies indicate
that the most teratogenic AED combinations are those with VPA plus one or more
enzyme inducing AEDs (PHT, Pb, Pr, CBZ).
4). higher malformation rates are not seen in infants exposed to maternal seizuresduring gestation than in infants whose mothers had no seizures
a. With the exceptions of trimethadione and valproic acid,recent studies do not indicate a difference among different
AEDs in either the incidence or type of malformations
observed.
b. Primary abnormalities seen: cardiovascular malformations(2.0%) and cleft lip/palate (1.8%), Skeletal abnormalities
(1.0%), hypospadias (0.5%), dysmorphia with
developmental retardation (0.5-1%). Incidence of neural
tube defect (spina bifida) has been reported as 1-2% forinfants exposed to valproic acid in utero and 0.5-1% for
infants exposed to carbamazepine.
c. "Fetal AED syndrome" is manifested by cranial facialanomalies, dysmorphic nasal features, epicanthal folds, wide
mouth, prominent lips, digit hypoplasia and mental
retardation. Although at one time primarily associated with
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phenytoin use, more recent studies show that incidence of
this syndrome with phenytoin is no different than with the
other AED.
d. Mechanisms of AED Teratogenicity
1). AED-induced folate deficiency
2). Binding of certain AED due to chemical properties as weak acids (i.e.,VPA) to fetal
tissue
3). Increased accumulation of arene oxide metabolites of AED and/or decreased
activity of epoxide hydrolase activity
a. Management of Epilepsy in Pregnancy
Refer to Prepregnancy Counseling Guidelines for Women with Epilepsy on page 25 of
the Epilepsy Counseling Guide.
V. DRUG INTERACTIONS
A. Pharmacodynamic Interactions
1. Enhance AED Neurotoxicty:Concurrent use of other AEDs (polytherapy), alcohol,
antidepressant, antihistamines, antipsychotics, benzodiazepines, narcotic analgesics,
and sedative hypnotics may result in the occurrence of concentration-related
neutotoxicity at lower than expected plasma concentrations.
2. Drugs Antagonizing Anti-Seizure Effect of AEDs: bupropion, clozapine, imipenem-
cilastin, isoniazid, reserpine, tricyclic antidepressant, theophylline and
cocaine/amphetamines may lower the seizure threshhold
B. Pharmacokinetic Drug Interactions (see Tables 3A and 3B)
1. Interference with absorption
2. Reduction in plasma protein binding
3. Enhancement/Inhibition of hepatic metabolismVI. SPECIFIC DRUG THERAPY FOR EPILEPSY
Note: Information listed below is based on instructor=s experience and review of
literature. Indications and dosages may therefore differ from those found in drug=s
FDA approved product information.
A. Phenytoin (DilantinR) (PHT)
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Indications: simple or complex partial seizures, primary or secondarily generalized
tonic-clonic seizures, convulsive status epilepticus
Mechanism: blockade or inactivation of neuronal sodium channels, possible action on
calcium conductance
Target Plasma Concentration Range: 10-20 mg/mL
Half Life: 7-42 hours (due to non-linear kinetics dependent on plasma concentration)
Time to Steady-State: 4 - 21 days
Adverse Effects
Concentration Dependent: nystagmus, double-vision, blurred vision, incoordination,
drowsiness, dizziness, headache
Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative
dermatitis/Stevens-Johnson, Lupus-like reaction
Chronic: gum hypertrophy, acne, hirsutism, peripheral neuropathy, chronic
cerebellar damage, megaloblastic anemia, osteoporosis, fetal vitamin K depletion.
Dosage: Maintenance Dose-4-6 mg/kg/day (300-500 mg/day) in adults, 4-10 mg/kg/day
in children. Initiation of therapy: Therapy with phenytoin can usually be initiated at
the recommended maintenance dose. Generally therapy is started at a dose of 4-5
mg/kg/day (or 300 mg/day) in adults and 6-8 mg/kg/day in children < 12 years.
Following initiation of therapy, steady-state is not achieved for 1-3 weeks because of
wide variation in pharmacokinetics among individuals and non-linear kinetics of
drug. Due to saturable hepatic metabolism, subsequent dose adjustments should be
limited to 30-100mg/day increments once serum concentrations are above 7.5 ug/ml.Administer in 1-2 daily doses.
Available Dosage Forms:
a. 30mg and 100 mg capsules as phenytoin sodium
b. 50 mg chewable tablet, 30 mg/5ml and 125 mg/5 ml oralsuspension with amount expressed as phenytoin acid
c. 50 mg/ml phenytoin sodium injectable solution for IV useonly
d. 50 mg phenytoin sodium equivalents/ml fosphenytoin
sodium injectable solution for IV and IM use
Advantages: first line agent for partial seizures, inexpensive, once or twice daily
administration, availa
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