Epilepsi at Web

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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-%20PATHOPHYSIOLOGY


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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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