Valproate : An update—the challenge of modern pediatric seizure management

Robert Ryan Clancy, M.D., received his B.S. degrees in mathematics and chemistry at Georgetown University and completed his medical degree at Johns Hopkins University. His residency training included general pediatrics at Johns Hopkins Hospital and adult and pediatric neurology at Stanford University Hospital, where he also completed an electroencephalography fellowship. He is presently Associate Professor of Neurology and Pediatrics at the University of Pennsylvania School of Medicine and a senior physician at The Children’s Hospital of Philadelphia. He is Medical Director of the Children’s Hospital EEG laboratory and Co-director of the Philadelphia Regional Pediatric Comprehensive Epilepsy Clinic. His research and clinical interests focus on epilepsy, EEG, and neonatal neurology. 166

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VALPROATE: AN UPDATE -THE CHALLENGE OF MODERN PEDIATRIC SEIZURE MANAGEMENT

More than 2 million Americans1 in 100 -have epilepsy. In children, the prevalence of epilepsy is even higher; figures of 2% to 3% are commonly cited. Epilepsy is predominantly a pediatric disorder, with more than 75% of all cases surfacing by the 18th birthday. Our ignorance about this condition has been gradually eroded by diligent clinical and basic laboratory investigations during the past 2 decades. Social and medical attitudes and clinical strategies for patient care have evolved to reflect new scientific insights into seizure disorders. The elevation of the study of epilepsy from the mystical occult of yesteryear to a medical-neurologic discipline has dispersed much of the myth and misunderstanding that still lingers about the “falling sickness.” Passages in the Bible (Mark 9:14-29) recount how those “possessed” with epilepsy would find some relief by prayer andfasting, an ancient clue to the beneficial effects of ketosis and acidosis in reducing seizure frequency. In essence, an endogenous therapy for seizures had been discovered. The first genuinely effective drug for epilepsy was potassium bromide, introduced in the mid-1800s. The passage of 80 more years gave us only two more agents that became the traditional mainstays of seizure management: phenobarbital and phenytoin. These agents have served us well until modern times. Since then, about 15 or 16 new agents have been added to the therapeutic arsenal. Many more drug candidates are sought now and several investigations have reached open clinical trials in the United States and Europe. Valproate has been available for about 10 years to the practicing pediatrician. It is a superb medication and the most valuable recent addition to the ranks of the antiepileptic drugs (AED). Physicians are typically cautious about changing their prescribing practices. Nonetheless, contemporary epileptologists and neurologists have found valproate extremely useful in the management of epilepsy. Most children with epilepsy can be successfully recognized, diagnosed, Curr

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and treated by a knowledgeable pediatrician or family physician. lndeed, these clinicians are responsible for the majority of seizure management and the initial selection of drug treatment. This monograph is intended to provide the practitioner with a broad perspective of valproate and its role in seizure management. As an update, it will discuss new perspectives and insights that have appeared since this agent was last reviewed in Current Problems in Pediatrics.’ In order to understand the role of valproate in epilepsy, we will first review modern concepts of epilepsy and the “minimalist” approach to managing seizures. BACKGROUND In the most general use of the term, a seizure is a sudden attack of illness.’ Patients and physicians may loosely talk about “seizures,” “spells, ’ “attacks,” or “events” when referring to an abnormal episode that begins abruptly or paroxysmally. In this generic way, a seizure can refer to a wide variety of alterations of body function. Thus, one could properly use the term in phrases such as “the patient was seized with pain” or “his mind was seized with fear.” Most of the time, however, the term seizure is closely associated with epilepsy. Through frequent usage, “epileptic seizure” has been abbreviated to just “seizure” with the unspoken understanding that the moving force that underlies the attack of altered brain function is excessive electrical firing of neurons in the brain. Historically, the nomenclature describing epilepsy and epileptic phenomena has been applied inconsistently or in vague, imprecise ways resulting in substantial confusion and controversy. In the following discussion, seizures will connote those attacks based on a specific epileptic mechanism. EPILEPTIC SEIZURES Epileptic seizures are clinical manifestations, expressed as transient signs or symptoms of altered brain function, triggered by the epileptic mechanisma self limited but excessive, repetitive, hypersynchronous electrical discharging of the neurons in the cerebral cortex. Epileptic seizures will differ in their clinical appearance depending on the part or parts of the brain involved with the unnatural cortical electrical activity. The clinical signs of epileptic seizures are protean but broadly divisible into a limited number of categories: alteration of consciousness, behavior, posture, tone or motor activity, sensation, and autonomic function. As already implied, epilepsy is not the only condition that can 160

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bring about sudden attacks or paroxysms of altered brain function expressed as altered consciousness, behavior, posture, sensation, or autonomic function.” Table 1 provides a general overview of clinical conditions that sometimes raise the suspicion of epilepsy because of similar presenting signs or s-ymptoms. CLASSIFI(=ATION GENERALIZED

OF EPILEPTIC SEIZURES-PARTlAL

AND

Not too long ago, the classification of epileptic seizures found in many neurology textbooks was a fairly obtuse monument of Latin terminology with arbitrary lumping and splitting of seizure types. TABLE

1.

Events

That

Nature

of Uisturbance

Mav

Simulate

Epilepsv

Alteration of consrlousness

Epileptic

Nonepileptic

Grand mal, petit mal and complex partial

Syncope Hyperventilation Migraine Breath holding Narcolepsy Pseudoseizures Drug reactions Hypoglycemia Migraine Parasomnias Episodic rage Narcolepsy Transient amnesia Autism Shuddering attacks Masturbation Rumination Head rocking Hemifacial spasms Multiple tics Pamxysmal movement

S&WI-3

Change

of behavior

Stereotyped

motor

b”ci.v

Disturbed

Petit mal, complex partial and nocturnal seizures

activity

tone

Automatisms from complex partial “P petit mal seizures; myoclonic seizures

and

posture

Sensory

(‘w-r

Tonic, atonic, axial, adversive, inhibitor?/ and hemiplegic seizures

alteration

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Gastruesophageal reflux Esophageal spasm ‘Torticollis Cataplexy Transient ischemia Hyperventilation Migraine Benign paroxysmal vertigo Transient ischemia

169

f‘l.

_

_’ ’

‘\j

PARTIAL

I \

*

,

I

_-

TIME 1 SECOND

FIG 1. All seizures are broadly divisible Into two types: partial and generalized. In partial seizures the abnormal epileptic activity begins In a limited area of the brain and the other regions are not affected. In generalized seizures the ictal activity awes synchronously and symmetrlcally In all areas of both hemispheres.

With the present widespread use of video-electroencephalographic (EEGI monitoring, there has been a growing appreciation that there are fundamentally just two types of seizures: partial and generalized (Fig 1). In a partial seizure, the abnormal excessive repetitive neuronal firing begins in a limited patch of the cortex. At the onset, other brain regions are not involved. The seizure may remain localized OI spread. A partial seizure that does not produce a change or alteration of consciousness is termed a “simple” partial seizure. A partial seizure extensive enough to involve parts of both hemispheres and disrupt the neuronal pathways that serve “consciousness” is called a “complex” partial seizure. The term “complex” refers only to the change of consciousness. It does not imply complicated experiences such as formed visual hallucinations. Complex partial seizures may first arise in any part of the brain. Consequently, the term “temporal lobe seizure” is considered outdated. Likewise, the terms “psychomotor” and “limbic” seizure have fallen out of favor.

In a generalized seizure, the cortex from both hemispheres displays the excessive neuronal firing from the onset. At the beginning of the attack, the epileptic process is symmetrical (both hemispheres are evenly affected) and synchronous (the excessive neuronal discharging is orchestrated such that the spiking is simultaneous or in “s-ynch)’ between comparable, homologous areas of both hemispheres]. Since both hemispheres are involved from the onset, there is often some loss or change of consciousness from the inception of the attack. Similarly, if motor activity appears, it is typically bilateral and relatively symmetric; however, a slight imbalance of the motor expression of a generalized seizure may occur, producing rotation of the trunk, turning of the head, or conjugate eye deviation to one side when one hemisphere mildly overpowers the other. IWOLLITION

OF PARTIAL

SEIZURES

At the onset of a partial seizure, the ictal electrical disturbance is confined to a limited or restricted “focus” in the cortex. However, some partial seizur+ ma-v spread from their place of origin to more distant sites and eventually culminate in a full-blown grand mal (tonic-clonic1 seizure (Fig 21. The process can be schematically depicted as simple partial seizure + complex partial seizure -+ generalized tonic-clo~iic seizure. The word “aura,” originally meaning “breath” or a “breeze of air,” refers to the subjective warning experience that iieralds the onset of the main event or ictus. An aura might be experienced as a rising epigastric sensation, a sense of fear, a forcetl mental idea, or a sensory hallucination such as an odd taste, smell. or body sensation. It is, in reality, a simple partial seizure that the patient later recalls since consciousness is not lost during the experience. If this simple partial seizure spreads to involve both hemispheres and disrupts the neuronal networks of consciousness, there is a change in the level of alertness. The patient will usually have limited, inaccurate, or no recall for subsequent events, and the seizure, b-v definition, has evolved into a complex partial seizure,

SEIZURE EVOLUTION SIMPLE COMPLEX PARTIAL + PARTIAL SEIZURE SEIZURE

4

GENERALIZED TONIC-CLONIC SEIZURE

FIG 2. Video-EEG SetLures

monltorlng

has demonstrated

that

partlal

setzures

can

evolve

Into generalized

This evolutionary process may be counteracted by cortical inhibition, a neurophysiologic defensive response that quenches the aggressive spread of excitation, the fundamental force behind a seizure. If not, the entire cortex may become engulfed in the epileptic process, resulting in a generalized tonic-clonic seizure. MEChXNlSMS

OF EPILEPSI

The resting neuron maintains an electrical voltage or potential across the cell membrane. This transmembrane potential is generated by energy dependent ion pumps that create an electrochemical gradient between the interior of the neuron and the extracellular space (Fig 3). When excitatory neurotransmitters (e.g., glutamate, aspartate) impinge upon their target receptors, the transmembrane potential increases and approaches the threshold for firing the allor-none action potential.4 Inhibitory neurotransmitters (e.g., gamma aminobutyric acid [GABA]) do the opposite. When they impinge on their target receptors of the neuron, there is an increase or hyperpolarization of the transmembrane potential, removing it further from the critical threshold value for generating the action potential and thus inhibiting or reducing neuronal firing. In epilepsy, an unstable transmembrane potential results in excessive excitability (excitation vs. inhibition) and a synchronized collective firing of groups of neurons. A seizure could thus arise from excessive excitation or synchronization of neuronal firings and/or from inadequate inhibition or desynchronization of neuronal firing. In the setting of partial epilepsy, the epileptic “focus” usually refers to the area of cortex, identified by the EEG, as the principal site of interictal “potentially epileptogenic discharges.” In partial seizures, these changes in electrical excitation and synchronization are confined to a limited epileptogenic zone which serves as the ictal birthplace.” There are probably two factors that must exist for a generalized seizure.’ First, cortical hyperexcitability must be diffuse: all regions of the cortex must be capable of excessive excitation in response to ordinary, mundane afferent stimulation. Second, there must be a mechanism, a set of controls or pathways, that orchestrates the diffuse cortical hyperexcitability into a cooperative, harmonized, synchronous electrical response. There ale known neural pathways that serve similar purposes during normal functioning. For example, the ascending reticular activating system (AIMS), which includes parts of the thalamus and midbrain, ordinarily defines the behavioral state or tone. Normal awakening from sleep is achieved within the arousal locus of the sleep center in the ARAS, which diffusely projects to both hemispheres and alerts or awakens the cortex. It is believed that these same pathways are subverted in generalized epilepsy as

DENDRITE

V PYRAMIDAL

1

/’

NEURON A X 0 N

-70

mV

FIG 3. There IS a transmembrane potential or voltage difference between the Interior of the dendrtte and the extracellular space. At rest, this difference IS -70 mllllvolts. The all-or-none action potential results when the resting membrane potential is Increased to the threshold for flnng.

the means to achieve the cohesive synchronization of the diffusely hyperexcitable cortex. Although in principle seizures result from abnormal excitation and synchronization, there are specific biologic differences between partial and generalized seizures, in the pathologic behavior of the nerve cells, neuromodulators, neurotransmitters, neuroreceptors, and supporting glial cells. Indeed, the terms “partial” and “generalized” describe only the most general characteristics of the seizure, and there are actually many distinctive subtypes of both. The AEDs display a wide variety of effects that have been empirically discovered to offer beneficial protection against epileptic seizures. The precise biochemical basis of the desired pharrnacotherapeutic effects are not known with certainty in many instances. Consequently, seizures must be carefully classified in order to choose most intelligentlv the drug best suited to help the patient. ACU’I’E ,+cute

SEIZL’RE

VS. CHRONIC

EPILEPSY

VS. SOLIWRY

Seizure

There are many acute medical or neurologic ture transient epileptic seizures as a nonspecific Curr

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conditions that feasign of neurological 171.

TABLE Examples

2. of Conditions

Water and Electrol-yte H.yponatremia Hvpernatremia H.ypocalcemia H-ypomagnesemia

‘That Imbalance

Metabolic Disturbances Umrnia Pyridoxine deficiency Porphyria Reye’s syndrome Hypoglycemia Hypothyroidism Hyperthyroidism Hepatic failure Inborn errors of metabolism

Feature

Acute

Seizures

Collagen Vascular Disorders Lupus eythematosus Periarteritis nodosa Rheumatoid disease Sjijgren’s s”yndrome

Drug Withdrawal Alcohol Rarbiturates Renzodiazepines

Drugs/Substances Cocaine Amphetamines Lead Isoniakda ‘I‘heophyllinc:

Neurologic Global

Disorders asph.yxia

Stroke

Meningoencephalitis Hemorrhage ‘I‘rauma

dysfunction (Table 2). For example, a seizure may occur in hyponatremic dehydration. However, it is simply an immediate result of a metabolic imbalance. The seizure would not have occurred except for the unwanted lowering of the serum sodium level. There is no intrinsic neurologic disturbance with abnormal neuronal excitability or synchronization. Normalization of the serum sodium removes the cause of the seizures. In practice, many physicians administer AEDs briefly to bolster protection against further seizures until the temporary medical or neurologic illness has passed. Long-term AED treatment is not desirable and is usually not indicated. It is reasonable to taper and discontinue AEDs in this setting when electrolyte homeostasis is restored or other causes of acute seizures are corrected. There may be some circumstances in which acute seizures accompanying serious neurologic illnesses such as meningitis, intracranial hemorrhage, stroke, or closed head trauma could serve as the foundation for later chronic epilepsy. There are no simple uni\rersal rules that apply in all of those circumstances, but AEDs may often be discontinued after a thoughtful analysis of each individual case and discussion with the patient and family. Chronic Epilepsy In contrast to acute seizures, which are reactive and directly provoked by intercurrent illness, chronic epilepsy describes the inherent fundamental predisposition of the brain to recurrent attacks of seizures from abnormal cortical excitability and synchronization (Fig 4~. The individual seizures are the outwardly visible signs of the epileptic tendency and occur unpredictably, spontaneously and in the

NONEPILEPTIC

EPILEPTIC

SEIZURES

PSEUDOSEIZURES r MEDICAL OR NEUROLOGIC PARoxsYM (SYNCOPE, NONSYNDROME

CHRONIC

PARTIAL

ETC.!

EPILEPSY

EPILEPSY GENERALIZED

SPONTANEOUS SEIZURE

ACUTE SEIZURE MIGRAINE,

-

CHILDHOOD

-

BENIGN

SEIZURES

SOLITARY I‘ RECURRENT

7

SYNDROME ABSENCE.LENNOX-GASTAUT,

ROlmANDlC

RFNIGN

OCCIPITAL

ETC

FTC

FIG 4. Seizures

and

epilepsy

syndromes

setting of good health. They surface by themselves and do not need an external trigger or provocation. It is true that certain physical stresses (fever, alcohol consumption, a marked lack of sleep, dehydration, or intercurrent illness) can occasionally “lower the seizure threshold” and increase the chance that a seizure will occur in a person already predisposed. There are also some individuals with so-called reflex epilepsy. They too have an inherent predisposition to seizures but require a specific neurologic stimulus to trigger the attack. Examples include photosensitive epilepsy (e.g., flickering lights) or audiogenic seizures brought on by certain sounds. Long-term treatment with AEDs is usually reserved for chronic epilepsy. The medication is intended to prevent or suppress individual seizures and their disruptive consequences. The AEDs are not curative in the same sense that penicillin cures an ear infection. They do not permanently remove the underlying disturbance that serves as the basis of the attacks. Fortunatelv, for many children the underlying tendenc.v for seizures remits with the passage of time, presumably reflecting maturational, developmental, and other heretofore unrecognized ameliorating factors. Solitary Seizures Some children and adults may experience a single epileptic seizure that arises de novo without identifiable extrinsic triggering factors. It is not an acute seizure since it is not the immediate result of

a concurrent stress or illness. Conversely, the term “epilepsy,” defined as a tendency for recurring seizures, is also invalid. The risk of recurrence after a solitary seizure may be influenced by a coexisting neurologic condition such as mental retardation or cerebral palsy, a positive family history of epilepsy, a postictal Todd’s paresis, or the presence of definite potentially epileptogenic discharges on the EEG. A person who has experienced a solitary seizure deserves a careful and thoughtful medical and neurologic evaluation tailored to the patient’s individual circumstances and the context of the seizure. Opinions vary regarding long-term treatment of a solitary seizure. Some physicians recommend ongoing AED treatment. Today, however, most prefer to await a second seizure before committing the patient to daily AED therapy for a minimum of 2 to 4 years. The risk of a second seizure after the first solitary seizure ranges from 25% to 50% ,7- l2 ROLE OF THE EEG The EEG is the single most useful test to supplement the history and physical examination of children with a suspected seizure disorder. Although the test is useful in many dimensions of this disorder, there are two specific areas where its role is particularly invaluable: the confirmation or remtation of the clinical diagnosis and the recognition of specific electroclinical epilepsy syndromes. Diagnostic Aid We have just discussed the pathophysiologic behavior of cortical neurons in epilepsy. The transmembrane potentials in a small site (the EEG “focus”) or in both hemispheres (generalized) are unstable and prone to spontaneous depolarization. The EEG sign of this phenomenon is the so-called “potentially epileptogenic discharge” (PED) (Fig 5). These are the familiar spike (duration under 70 milliseconds) and sharp wave (duration 70 to 200 milliseconds). They have many aliases and some electroencephalographers refer to them as epileptiform patterns, fast transients, irritative features, or paroxysmal discharges. Nevertheless, all of these terms convey the sense of rapid voltage changes arising from instability of the transmembrane potentials of cortical neurons. Do all patients with epilepsy have such ‘epileptiform features” on their EEG? Do all patients with spikes or sharp waves have epilepsy? What is the specificity and sensitivity of EEGs? The Sensitivity of the EEG The absolute confirmation of a seizure disorder demands that an actual seizure be captured and recorded on an EEG. III most situations, this is impractical or nearly impossible to achieve. Instead,

5

SPIKE

TIME

“,

SHARP

WAVE

1111111,

FIG 5. The most specific electroencephalographic sign of a sezure &order IS the potentially leptogenic discharge (PED). Spikes are very fast fluctuations in the voltage lasting than 70 milliseconds. Sharp waves are slower, lasting 70 to 200 milliseconds.

eplless

most EEGs recorded to evaluate patients with seizure disorders are interictal tracings taken between seizures. All studies of interictal EEGs have reported a sizable percentage of negative studies (false negatives). In fact, only approximately half of the first EEGs recorded on patients with definite epilepsy have specific epileptiform features -spikes or sharp waves.13

Increasing

the Yield

There are a few general maneuvers that enhance nostic information in the interictal EEG.“’

the yield of diag-

1. Serial EEGs.-Some patients with genuine epilepsy lack potentially epileptogenic discharges in their first EEG but will display them on a subsequent tracing. It may therefore be necessary to repeat the test several times before finally observing spikes or sharp waves. 2. Recording during sleep.-A part of the EEG should be recorded during sleep, especially if some or all of the clinical seizures are nocturnal. The EEG lab needs to be informed of your desire to record sleep beforehand, in order to schedule an adequate amount of time for the sleep study. A safe, simple, and effective hypnotic agent such as chloral hydrate can be orallv administered to promote sleep without producing unwanted medication artifact on the EEG. 3. Sleep Deprivation.By contrast, the stress of being deprived of (hrr

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sleep may enhance the appearance of potentially epileptogenic discharges, even if sleep itself is not recorded. Even the healthiest person can have a seizure after extreme sleep deprivation (greater than 72 hours). In a person with epilepsy, the provocation of overnight sleep deprivation may coax forth some reluctant spikes or sharp waves. One of the drawbacks of overnight sleep deprivation is that the EEG recorded the next morning often reflects drowsiness and the EEG background rhythms may seem abnormally “slow.” Since background slowing is not uncommon in epilepsy per se, it might be wise to defer sleep deprivation until the patient’s second or subsequent recording session, when the resting background can be judged in an alert, well rested state. 4. Time of Recording.-Some children have individual times when they appear particularly vulnerable to a seizure, perhaps in the early morning or when awakening from a nap. It makes sense to schedule the EEG during a similar time of the day to exploit this temporal tendency. The highest yield in finding potentiallv epileptogenie discharges is within 1-7 days after the last seizure.‘” Immediately after the seizure itself, the cortex often shows “diffuse postictal slowing,” a relic of inhibitory mechanisms called into play to terminate the seizure. During this postictal slowing, PEDs may also be inhibited and suppressed. For the next 1 to 7 days, however, there is a slight statistical advantage to recording the EEG, since PEDs appear relatively more abundantly then. 5. Hyperventilation.Sometimes 3 minutes of vigorous sustained overbreathing will precipitate an actual petit ma1 seizure. The chance of enhancing other forms of epilepsy is small, so this maneuver is principally directed to petit mal. There is no rule that states one can try hyperventilation only once during the EEG. If you strongly suspect petit mal, ask the EEG lab to perform hyperventilation several times. The Specificity of EEGs More than a few physicians are surprised to learn that PEDs can be recorded in the EEGs of a small percentage of otherwise healthy youngsters who have no personal history of epilepsy (false positives).‘4, l5 Sometimes these children undergo EEG examinations for nonepileptic complaints such as syncope, breath holding, behavioral disorders, school problems, or headaches. Indeed, studies cite about a 2% to 3% rate of “false positive” EEGs. These are tracings that display unequivocal potentially epileptogenic discharges despite an absence of clinical seizures. For this reason, sound clinical judgment and seasoned experience are invaluable in interpreting the meaning of these laboratory findings. It is occasionally necessary to ignore EEG findings as irrelevant to the clinical problem at hand rather than assume epilepsy is the under&ing cause. A PED may also be 178

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found in neurologically abnormal children who have never had a seizure. For example, up to 20% of children with spastic hemiplegic cerebral palsy may have PEDs in the motor area (central or rolandic regions). Some children with peripheral causes of blindness (for example, severe retinitis of prematurity) may eventually develop spikes or sharp slow waves in the occipital cortex. Although it is reasonable to forewarn the parents of these children that there may be heightened risk of future seizures, prophylactic administration of AEDs should be avoided. EPILEPTIC SYNDROMES A syndrome is defined as a set of signs and symptoms that cluster together. There is genuine value in defining epileptic syndromes because of the important insights and useful information that they provide. The following are common findings that define an epileptic syndrome: seizure types, EEG abnormalities, age at onset, family history of epilepsy, associated central nervous system features, natural history, and response to AED therapy (Table 3). To illustrate the value of this approach, let us first examine the simple febrile seizure, even though it is not strictly considered an example of an epilepsy syndrome. Simple febrile seizures are recognized as brief generalized convulsives (seizure type) that occur between 6 months and 5 years (age of onset). The child often has a close relative with febrile seizures (family history). The disorder occurs in an otherwise healthy child heretofore neurologically and developmentally normal (associated central nervous system features). Between the seizures the EEG is normal. When the first febrile seizure occurs before the first birthday, there is a significant chance of future recurrences (natural history. The daily prophylactic administration of phenobarbital may reduce the risk of further febrile seizures Iresponse to treatment).

179

PEDlATRIC SEIZURES AND EPILEPSY SYNDROMES VHLPROATE

TREATABLE BY

Valproate may be indicated in a number of seizure types and pediatric epilepsy syndromes. One of the remarkable features of this antiepileptic drug is its extremely broad spectrum of activity. Valproate exerts its protective effects over a wide range of generalized and some partial seizures. The following outline summarizes only the major epilepsy syndromes of infancy and childhood in which valproate plays a therapeutic role (Fig 6). These conditions will be discussed in the chronological order of their onset during childhood. West Syndrome West Syndrome is composed of the classic triad of: (I) infantile spasms; 12) a highly abnormal EEG pattern known as hypsarrhythmia; and (3) an arrest of psychomotor development.‘” The onset of the clinical seizures is usually between 6 months and

AGE

(YEARS)

25

0

rI! -r---

7~

A

6

C

-----

D EPILEPSY

7 ’i-i

-ITS

E

:

~-~

I

F

G

Ii

I

J

SYNDROMES

FIG 6. Age of onset of ten eprlepsy syndromes responsive to valproate. A = West Syndrome; B = Benign myoclonic epilepsy of infancy; C = Simple febrile seizures; Cl = Epilepsy with myoclonic-astatic seizures; f = Lennox-Gastaut syndrome; F = Childhood absence; G = Generalized tonic-clonic seizures upon awakening; H = Epilepsy with myoclonic absence; I = Juvenile absence; J = Juvenile myoclonic epilepsy, 1230

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1 year of age. Classically, the seizures are rapid myoclonic movements in which the chin, arms, and legs are all flexed unto the trunk. These produce the classic Salaam spells. The spasms these infants undergo are actually quite heterogeneous: some are predominantly extensor and others represent a mixture of flexion and extension. The individual seizures tend to cluster in groups and are most likely to arise when the child awakens in the morning or following a nap. Most of the time, infantile spasms begin in children with clear preexisting brain abnormality such as cerebral dysgenesis, congenital infection, or following severe birth asphyxia. Occasionally, however, the attacks occur in children previously believed to be normal. In those with no demonstrable causes, the term “cryptogenic” is used to describe the idiopathic etiology. Untreated, infantile spasms may occur hundreds of times per day but do eventually fade as the child grows older, or other types of seizures may supervene. The seizures themselves are considered nonspecific from an etiologic viewpoint, but actually are a type of clinical seizure confined to a certain age reflecting the immaturity of the infant nervous system.“” The treatment of choice is the intramuscular injection of adrenocorticotropic hormone (ACTHI which, however, has important side effects, including marked irritability, weight gain, acne, hypertension, and cerebral atrophy as shown on the computed tomography scan. Valproate is the only other agent that in some instances can reduce or eliminate the seizures, and also normalize the EEG. Benign Myoclonic Epilepsy of Infancy This pediatric epilepsy syndrome usually begins in the first or second year of life in heretofore normal children who often have a family history of seizures.17 The clinical seizures are characterized by myoclonus, the sudden brief bursts of generalized synchronous muscle jerking. In light sleep, the EEG may show bursts of generalized spike slow wave discharges. These seizures are commonly well controlled by valproate. No other type of seizures occur during infancy, but in adolescence, generalized tonic clonic seizures may surface. Do not confuse this disorder with benign infantile spasms (also called benign myoclonus of early infancy) in which the seizures resemble infantile spasms, even though the EEG remains normal and no clinical deterioration occurs. Simple Febrile Seizures Although not considered an epilepsy syndrome, this is a common disorder in which recurrent seizures could be treated with valproate in highly selected circumstances. Febrile seizures affect 2% to 5% of children under 5 years of age. A simple febrile seizure has these features: (1) a generalized convulsion; (2) a relatively brief attack (less than 15 minutes); and (3) a solitary event (one attack per 24 hours). Curr

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Simple febrile seizures usually occur early in the course of a febrile illness. This observation relates principally to the cause of the fever and seizure. For example, in meningitis, the seizures may occur several days following the onset of fever and indicate the onset of cerebritis. About 30% of affected children will have a recurrence after the first febrile seizure.‘8 The risk of recurrence is modified by the patient’s age: 50% will recur at least once if the patient’s first seizure occurred before the first birthday. In this age group, there is also a 30% chance of multiple recurrences compared to only an 11% risk of multiple recurrences if the first seizure occurred after 1 year of age. Thus, many physicians do not recommend prophylactic treatment for recurring febrile seizures unless the first febrile seizure occurred before the first birthday. There are several approaches available to febrile seizures, including the continuous daily prophylactic administration of phenobarbital to produce a minimal serum level of 15 Fg/ml. Unfortunately, in this age group, there is a 40% incidence of objectionable adverse behavioral side effects from the barbiturates. Neither carbamazepine nor phenytoin are effective in the prevention of recurrences of febrile seizures. The daily use of primidone (15 to 20 mg/kg/day) is effective but probably has little advantage over phenobarbital. In Europe, the use of valproate to prevent febrile seizures is common but this practice has not been widely adopted in the United States. Although valproate clearly is protective against the recurrence of febrile seizures, children in the age group of highest incidence of febrile seizures (6 months to 5 years) may also be at highest risk of hepatotoxicity from valproate (under 2 years). Epilepsy With Myoclonic Astatic Seizures @loose’s Syndrome) This pediatric epilepsy syndrome usually affects boys between 6 months and 6 years of age.” There is a frequent family history of epilepsy and usually normal development until the onset of the seizures The most common type of seizure is myoclonic. In addition, however, astatic (drop attacks), myoclonic-astatic, absence with clonic and tonic components, and grand ma1 seizures may also occur. At times, long periods of sustained myoclonic and absence seizures are noted. The EEG is characterized by generalized 2 to 3 Hz spike wave or polyspike wave discharge. The course is variable. Although some children appear to emerge perfectly well despite the long period of absence status, others do not fare well and may ultimately blend in with cases of the idiopathic Lennox-Gastaut syndrome. The drug of choice is valproate.

LennoT-Gastaut

Syndrome

The Lennox-Gastaut syndrome ideally describes a fairly stereoin fact, it frequently represents an etiologityped clinical picture”‘; tally heterogeneous group as does the West Syndrome. It is also considered an age-specific expression of seizures in children with important underlying central nervous system disorders. The onset of the seizures in Lennox-Gastaut syndrome usually commences between the ages of 1 and 8 years. The most common forms of seizure in Lennox-Gastaut syndrome are tonic seizures, which appear in 75% or more of those affected. The abrupt increase in tone may affect the trunk, limbs, or all parts of the body and lead to a sudden fall. Atypical absence seizures are another characteristic type of seizure found in a majority of cases. They are rather subtle in their onset and termination and do not have the crisp, clean beginning and end as seen in classic petit mal. They may also be associated with more prominent motor signs such as myoclonic movements of the face or mouth. The coincident EEG shows “slow” spike and slow waves with a repetition rate of less than 2.5 Hz. Other types of EEG abnormalities may be noted, including many focal spikes or sharp waves (multifocal) and generalized bursts of rhythmic fast activity. Other types of seizure seen less often in this syndrome are myoclonic seizures, atonic seizures (loss of tone leading to head nods and drop attacks) and periods of tonic or atonic status. Only about 20% of Lennox-Gastaut syndrome patients are otherwise free of neurologic or developmental handicap. The others have important handicaps including mental retardation, cerebral palsy, and behavioral or mental disturbances such as psychosis. The treatment of Lennox-Gastaut syndrome has always been difficult. Valproate is one of the best drugs, yet it offers incomplete control for many affected individuals. Alternative forms of treatments such as combinations of valproate with benzodiazepines, ketogenic diet, corticosteroids, ACTH, intravenous gamma globulins and neurosurgical section of the corpus callosum have all been employed with some success for the different seizure types within this syndrome .

Childhood

Absence

The hallmark of an absence seizure is a lapse of consciousness or an arrest of awareness. The term historically described the departure of the spirit from the eyes as evidenced in the blank, expressionless stare during the ictus. A pure or simple petit mal seizure consists only as an absence-an arrest of mental activity. With longer absences, there are mild behavioral changes including automatisms or purposeless motor patterns, mild tone changes (slight head flexion or extension), or mild clonic movements such as eye Curr

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blinking at three eye blinks per second.z1-24 These more elaborate absences are called comple)c absence (which should not be confused with the terminology for complex partial seizures, an entirely different entity). In classic petit mal epilepsy, each absence has a succinct onset and termination as. though a switch were thrown on or off. This syndrome rarely begins before age 3 and usually affects children between ages 5 and 7. Untreated, the patient may have clusters of hundreds of seizures per day. Hence, the term “pykno-epilepsy” (Greek, pyknos = frequent). A seizure may be precipitated by hyperventilation for several minutes. The usual EEG finding is the classic three per second generalized spike slow wave pattern. Successful treatment with ethosuximide or valproate not only stops the clinical seizures but erases the abnormal EEG patterns as well. About 30% to 50% of patients with petit mal develop grand mal seizures as well. These can be controlled with valproate but not ethosuximide. The prognosis for petit mal is generally good; only 20% do not enter permanent remission after long-term treatment. Epilepsy With Myoclonic Absence Another recently recognized epilepsy syndrome of childhood is myoclonic absence.25 This may represent a transitional condition spanning the more innocent primary generalized epilepsies (especially childhood absence) with the more malignant secondary generalized epilepsies embodied in the Lennox-Gastaut syndrome. The onset of absence commences between the ages of 7 and 9 years. Multiple seizures occur daily and each absence may be accompanied by forceful, rhythmic myoclonic jerking and tonic muscle contractions. Associated seizures are uncommon. The EEG shows the familiar three per second spike slow wave discharge. The best seizure control may result from combinations of valpmate and ethosuximide or benzodiazepine. In some cases, mental deterioration occurs and ultimately the clinical picture may resemble the LennoxGastaut syndrome more closely than simple childhood absence. Juvenile Absence Another petit mal epilepsy syndrome is juvenile absence.2” Together with childhood absence, these two represent the bulk of the benign primary generalized epilepsies of childhood and account for 15% to 20% of children with epilepsy. The age of onset is older than childhood absence, beginning at or following puberty. Instead of frequent daily clusters of absence seizures that occur in childhood petit mal (pykno-epilepsy) epilepsy, there may be only a single seizure in one day and several days may elapse between seizures. These youngsters are also likely to experience generalized tonicclonic seizures, absence status, and occasional myoclonic jerks. The drug of choice is valproate. 184

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Juvenile Myoclonic Epilepsy This interesting childhood epilepsy syndrome may also be encountered under the name impulsive petit mal of Jan~.‘~’ ” The predominant feature of this disorder is single or repeated myoclonic jerks, often occurring in the morning, beginning between ages 13 and 19, in otherwise healthy normal children. Sometimes the myoclonic jerks recur repeatedly and blossom into a full-blown generalized clonic-tonic-clonic seizure. Indeed, most people with juvenile myoclonic epilepsy have had at least one grand mal seizure and approximately 15% also experience absence. The EEG shows a generalized fast spike-slow wave pattern (4 to 6 Hz). Photic stimulation, but not hyperventilation, may elicit these discharges. Clinical seizures are more likely to occur if the individual is sleep deprived, is unexpectedly awakened from sleep, or consumes alcohol. Some degree of sensitivity to photic stimulation is also present. Valproate is unquestionably the drug of choice for this disorder. The seizures of more than 80% of these individuals are totally controlled with valproate monotherapy. Unfortunately, despite the complete relief from seizures that valproate often provides, there is a very high rate (greater than 90%) of relapse after medication is terminated. For many individuals the seizures may occur throughout their life. Tonic-Clonic Seizures The familiar generalized tonic-clonic seizure is a common, dramatic, and widely recognized type of convulsive seizure (Table 41. It can occur acutely in the nonepileptic individual who is suddenly stressed by intercurrent medical or neurologic illness. In chronic epilepsy, it may represent the end product of a seizure that began partially and secondarily generalized (see Fig 2) or it can be generalized from the onset.” There is a newly described syndrome of grand mal epilepsy expe-

TABLE Generalized

4. Tonic-Clonic

Seizures

Acute (reactive) seizure Febrile seizures Partial seizunz with secondary generalization Primary and secondar?/ generalized syndromes Childhood and juvenile absence Juvenile myoclonic epilepsy tiTCS upon awakening Lennox tiastaut syndrome Isolated, nons,yndmmic GTCS

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rienced upon awakening that overlaps with childhood petit mal, juvenile absence, and juvenile myoclonic epilepsy. In this syndrome, generalized tonic-clonic seizures appear primarily after spontaneously awakening or interruption of sleep. A variety of medications are effective in grand mal .epilepsy, but AEDs such as valproate and carbamazepine are considered drugs of choice because of their well established efficacy and a lower risk of mental side effects, factors to be discussed later. There is no single “syndrome” of generalized tonic-clonic seizures.‘” Only about 10% of people with epilepsy have only grand-mal seizures. Whenever generalized tonic-clonic seizures coexist with other seizure types (such as absence in petit mall, the patient’s epilepsy syndrome is classified according to those other species of seizures. In other instances, acute seizures reflecting a reaction to an abrupt illness, on a partial seizure that secondarily generalizes, or the coexistence of multiple seizure types that occur in childhood absence is the setting in which tonic-clonic seizures occur. THE PHILOSOPHICAL. AND MANAGEMENT

FRAMEWORK

OF

EPILEPSY

DIAGNOSIS

Like all fields of study, epileptology is undergoing a process of evolution that gradually reshapes our knowledge of and attitudes toward seizure disorders. Medical progress requires the acquisition and interpretation of new information, reexamination of the truth or relevance of the established “conventional wisdom” and a search for more effective and novel forms of therapy. Anyone who has personally witnessed the full fury of a grand ma1 seizure is immediately impressed with the drama and ferocity of the attack. How many times has the doctor heard a parent say, “I was sure my child was dying.” Apart from any supernatural connotations that might still prevail in some minds, seizures were feared because of their potential to cause brain damage or death. Spoons or padded blades were inserted into the mouth to keep the child from swallowing the tongue. The prevailing desire was to stop the seizures at all costs. Seizures are still viewed by the public with relative terror and anxiety. However, there has been a considerable shift in attitude over recent years regarding the nature, significance, and treatment of epi1eps.y. Kemarkable progress has been made in the basic science understanding of the electrophysiologic behavior of normal and “epileptic” neurons and neural networks.“0 On a larger and more human scale, the contemporary medical approach to epilepsy has substantially emerged in a more thoughtful and holistic fashion. These philosophical changes emerged in the context of

society’s growing awareness of and sensitivity many forms of chronic illness, not just epilepsy. ANTIEPILEPTIC

to individuals

with

DRUGS

Folklore is rich and varied with recommendations for treating seizures. In the mid-MOOs, potassium bromide became the first genuine pharmacotherapy regimen.“” Although bromides effectively reduced seizures in some, the price paid was chronic bromide intoxication (bromism) in the form of skin rash, constipation, weight loss, psychosis, and hallucinations. The narrow therapeutic margin of bromides forced the patient to walk a thin line between seizure control and toxicity. But some seizure control was better than none. Although rarely used today, bromides were a giant step in the right direction. Through the 19i’Os, the use of multiple agents (pol.ypharmacy or polUytherapy, was common. Indeed, patients were often started on two drugs after their first seizure (typically phenobarbital and phenytoini and maintained on duotherapy indefinitely, often for a lifetime. After all, it M~S a perfectly logical assumption that two drugs would work better than one. iithout knowledge of the natural history of the various forms of epilepsy, it was impossible to make a well-informed recommendation to discontinue drugs. Furthermore, the consequences of subtle long-term physical, cosmetic or central nervous system side effects of AEDs were ill appreciated, if at all. Even the manner of selecting the medication dosage invited excess. Clinical drug level testing was scarce and age-specific pharmacokinetic data were sketchy. Consequently, the usual clinical practice was to start a drug, gradually escalate the dose until clear intolerance developed, and then reduce the dose by a small amount. All of these approaches made sense at the time and attested to the versatility and ingenuity of the physicians of the day. They did the best they could with all that they had. “Idiosyncratic” is the word that best describes the actual selection of the specific AED used during the “old school” of treatment. Everyone had his or her favorite choice or combinations based on personal experience or anecdotes. Indeed, it is difficult even today to reliably compare the efficacy of drug treatment because of the variable and unpredictable recurrence of seizures, the natural extinction of seizures with time in some forms of epilepsy and the limited duration of follow-up. An anecdote may illustrate how capricious the choice of treatment could be. A prominent academic neurologist once informed me that he had several physicians under his care whom he treated for epilepsy. His recommendation was that medical professionals with epilepsy should not be administered brand

name phenytoin (Dilantinl because of the distinctive orange ring that encircles the capsule. He feared that if colleagues recognized the identity of the drug, it would cause potential embarrassment to the patient. Therefore, he would always prescribe primidone for physicians with epilepsy. Probably the most noteworthy shortcoming of the old school was the lack of recognition of and sensitivity to the neurologic side effects of AEDs. There were other tangible factors to explain the patient’s unwanted mood, behavioral, or concentration deficiencies. How could phenobarbital cause hyperactivity? (Everyone knows it’s a sedative!) The presence of the epilepsy itself, the possible existence of underlying structural lesions, or a personality disorder inherited along with the epilepsy were the presumed basis of these problems. The contribution of iatrogenic factors in the form of the AEDs prescribed was overshadowed, overlooked, or ignored.

The Contemporary

School of Treatment

The Seizure.-Whether or not they voice their concerns, most parents fear that epilepsy causes brain damage. Physicians are quick to reassure them, but a completely honest answer acknowledges that the 1.4. curve in epilepsy is “shifted to the left.” The difficult task is dissecting preexisting pathology in those with symptomatic epilepsy and acknowledging that certain conditions, particularly infantile spasms and the Lennox-Gastaut syndrome, are intimately related to mental deficiency or deterioration. Modern physicians understand that a single seizure, despite its dramatic external appearance, does not harm the brain. Repeated psychometric testing demonstrates stable serial IQ. scores in most epileptic children. Bourgeois et a131 noted that in those epileptic children whose serial 1.4. scores dropped by 10 points or more, excessive medication rather than seizure frequency seemed responsible for the decline. They recommended that total seizure control should not be attempted heedless of overmedication. It must also be honestly acknowledged that individual seizures may cause accidents and be the near occasion of harm. Unexpected seizures can leave the child helpless and vulnerable to dangerous circumstances. Those risks may be reduced by avoiding unsupervised swimming or water sports, climbing at unsafe heights, bicycling amidst heavy traffic, and similar activities. Do seizures beget more seizures? Although serial seizures do not cause a measurable reduction in IQ., there is a justified concern that each seizure facilitates the appearance of the next. This imparts a progressive nature to epilepsy so that with the passage of time, it was feared seizures might become progressively more difficult to

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SECONDARY “MIRROR”

_’

:‘_

STIMULI

SERIAL

STIMULI

CORTICAL AFTERDISCHARGES

SPONTANEOUS SEIZURES

FIG 7. In the experimental model of epilepsy called kindling, repeated electrical strmuli to an area of the brain, the “kindled” area produces cortical afterdischarges. Initially, these afterdischarges are of low amplitude and last only as long as the stimuli. Successive stimuli produce higher amplitude and more sustained cortical afterdischarges. Eventually, spontaneous seizures may occur in the kindled area. Furthermore, a secondary or “mirror” focus could result from a transfer effect and might also result in the spontaneous appearance of serzures.

control. Indeed, some patients with partial seizures arising in the temporal lobe appear to behave in this manner. There is an animal model of experimental epilepsy in which seizures are first induced or kindled” by weak electrical shocks applied to a single brain region”” (Fig 71. At first, local electrical stimulation produces only a momentary cortical response called the afterdischarge. With additional applications of the same shock, the cortical afterdischarges grow in duration and amplitude. Eventually, the same response can be produced by weaker electrical stimuli until the kindled area gives rise to seizures spontaneously. Furthermore, each seizure may propagate along existing neuroanatomical path(‘urr

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ways to homologous areas in the opposite hemisphere. An independent epileptic focus could be seeded at a distant site (the “mirror” focus). The concern is that the mirror focus could spontaneously give rise to seizures independent of the original kindled site. Neither kindling nor the mirror focus have established, proven relevance to human epilepsy. There is little evidence that this experimental model of seizures in animals occurs in children. Nevertheless, the implications are that “small” seizures could “enlarge” to produce a more potent clinical effect and that the influence of the original focus could be extended to a distant independent location where the subsequent seizures might be more difficult to treat. The net concern is that with some individuals, epilepsy can feed upon itself and behave in a progressive fashion. In practical terms, it is desirable to efiect as prompt and thorough seizure control as possible, but extreme measures of aggressive pharmacotherapy do not appear justified. ANTIEPILEPTIC

DRUGS:

EFFECTS

AND

SIDE

EFFECTS

It is often surprising to learn that only minor differences exist in the @xtiveness of phenobarbital, phenytoin, primidone, and carbamazepine in partial and secondarily generalized seizures. The Veterans’ Administration cooperative study randomly assigned newly diagnosed patients with epilepsy to one of these drugs in a doubleblind controlled stuc?V.32 Patients with unsatisfactory seizure control were switched to a second drug. The effectiveness of phenobarbital, primidone, phenytoin, and carbamazepine were compared. The drugs had a similar success rate; no drug emerged as the best agent with respect to seizure control.‘” The measurable differences among the AEDs examined were in the patients’ tolerance of the side effects of treatment. For example, a substantial number of patients refused to continue consuming primidone because they objected to its unwanted side effects. The principal message of the study was that therapeutic superiority reflected a relative freedom from side effects, not seizure control! All the drugs did a comparably good job at controlling the seizures. ‘I’he C~I’LI~ of choice was measured by its acceplance nol its therapeutic potency.

‘l’he ideal AIXI would totally eliminate further seizures without producing unwanted side effects. Because of the comparable efficacy of several agents for many ciiffkrent tUypes of seizures, the choice of treatnlent should reflect a thoughtful understanding of and sensitivity IO the pt~\~sir:al and Ileurotogic side effects of therapy. It is no

surprise that AEDs administered to change brain chemistry and stop seizures can have unwanted secondary effects on the central nervous system. A review of the principal toypes of central nervous system side effects from AEDs follow~.““-“~ Sedation.--:\ common and nonspecific side effect of central nerLOUS system active medication is sedation. The affected individual feels tired and fatigued, lacks the energy and stamina to get through the day, and needs more sleep. The sedation may be more noticeable at the onset of therapy or immediately following an increase of dosage. The real problem is a chronic sense of fatigue, especially \\ith the barbiturates or phen-ytoin. Mood.-Some AEDs produce emotional depression, sadness, OI clysphoria.“x Suicide is a leading cause of death among people with epilepsy and is o\,errepresented among those who consume barbiturates. In one re\realing stud-v in which semistructured psychiatric interviews were conducted to assess the frequency of suicidal ideation, it was noted that those who consumed phenobarbital were significantly more likely to think about their death or have suicidal fantasies. In fact, the authors urged caution in prescribing barbiturates to people with epilepsy if there is a family history of depression or sllicide.‘i!’ Behavior.-‘l‘he manner in which a child conducts his personal activities can be materially influenced by AEDs. Some parents describe a striking change in behavior after medication as though a “Jekyll and Hyde” personality transformation had occurred. Adjectives such as “nasty,” “negative,” “hyperactive,” “demanding,” “aggressive,” ‘I’impossible,” or “oppositional” are plentiful. Children who were once happy, calm, and agreeable can apparently be transformed into aliens with conduct disorders and intolerable behaviors.

,4ttention

and Concentration

The ability to concentrate, pay attention, and focus one’s mental activities may be impaired by some AEDs. Even the brightest child will have difficulty learning if he is consistently distractible, impulsive, and unable to sustain a cohesive train of thought. Consider the following example: Imagine you are given the task of reading a book. Ordinarily the book might be read almost without interruption, one chapter at a time, so that the development of each chapter can be understood and appreciated. Now imagine that the book must be read one paragraph at a time. At the end of each paragraph, you1 attention is diverted to some extraneous distraction. Even the brightest individual would have a harder task to comprehend the book as a whole because of the frequent interruptions and distractions.

Cognition The speed and accuracy of mental processes such as problem solving, logic, calculation, planning, and memory can be dulled under the influence of some AEDs. These disturbances may appear independent of any coincident alteration of vigilance, mood, or attention. It took years for clinicians to acknowledge the mental dulling that can result from acute and chronic AED administration. After all, there were many alternative explanations for these problems, including the immediate effects of repeated seizures or the underlying brain disorder responsible for the epilepsy in the first place. It was not until the 1970s and 1980s that properly conducted studies in healthy volunteers (not patients with epilepsy) demonstrated AEDs’ inherent potential to blunt the intellect. The Relationship Between AEDs and Central Nervous System Side Eflects Three fundamental principles describe the relationship between central nervous system side effects and AEDs: 1. Some drugs have a more favorable profile of central nervous system side effects than others. Although certainly not every individual who consumes AEDs will experience an adverse reaction, the barbiturates and benzodiazepines carry the highest risk. On the other hand, valproate monotherapy is considered to carry one of the lowest risks of neurologic and mental side effects. 2. Side effects are more likely to appear with higher dosages and drug levels. Overmedication will result in blatant signs of drug intoxication, but even in average therapeutic doses children are more likely to do better at the lower end of the dosage range than in the higher end. Even studies with valproate suggest some differences in cognitive function depending on the drug level.402 41 3. Polytherapy is worse than monotherapy. Routine employment of multiple drugs should be avoided if possible. Mental side effects are additive and may appear with drug combinations even though the individual drug levels are well within the therapeutic range.42 Furthermore, the change from polytherapy to monotherapy, especially valproate monotherapy, improves cognitive functioning.4” There are two major situations in which the problem of polytherapy frequently surfaces: refractory epilepsy4’ or multiple seizure types. In children whose seizures are medically intractable there is a strong temptation to keep adding AEDs until seizure control is improved. Occasionally, two drug combinations may work better than any single agent, but there is usually no material advantage to three or more medications. If two-drug therapy does not materially im-

prove seizure control, the regimen should be restored to monotheraw In patients with multiple seizure types, several AEDs may be given to counteract each seizure type. For example, many patients with childhood absence also have grand mal seizures. The polytherapy solution would include ethosuximide (for the absences) and phenobarbital, phenytoin, or carbamazapine for the generalized tonicclonic seizures. A more elegant solution would be valproate monotherapy, which has an excellent chance of success to stop both seizure types because of its broad spectrum of effectiveness. THE “MINIMALIST”

APPROACH TO EPILEPSY

Is there any one recommendation that summarizes the current philosophy of pediatric epilepsy management? Probably the most succinct way to distill the foregoing discussion is the “minimalist” approach to epilepsy. This approach has several key features, which are asked in the following sequence: 1. Do the patient’s attacks represent an epileptic- or nonepilepticbased disorder? Don’t assume that every child who daydreams, falls down, or seems confused has epilepsy. Consider the differential diagnosis of episodic or paroxysmal attacks in children4’ A careful history and physical examination must be obtained and integrated with knowledge of the family history and the EEG examination. When in doubt, it may be advisable to continue careful observation without pharmacotherapy until the nature of the episodes is revealed. 2. Does the patient really need AED treatment for epileptic seizures? In some individuals the seizures are reactive; i.e., occurring in response to acute illness. It is preferable to remove the cause of the seizures than to prescribe AEDs. If AEDs are given, consider discontinuing them soon after the acute illness has resolved. A child may exhibit a solitary unprovoked epileptic seizure. There is not unanimous agreement about treatment of these. Consider awaiting the second attack and not administering AEDs until the diagnostic label “epilepsy” is appropriate. Many children who have a seizure never have a recurrence and don’t need AEDs. 3. What is the lowest dose of the best single drug to get the job done? If the patient is having recurrent epileptic-based seizures, the selection of drugs will depend on the seizure type (partial seizure versus generalized seizure) and whether the entire clinical picture is consistent with a recognized epilepsy syndrome. Monotherapy, the use of a single agent for seizure control, is the usual goal. Why use two or more drugs if a single agent will accomplish the same or a better result?‘” Monotherapy has many important advantages: 11) Curr

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There are fewer systemic and mental side effects. (21 There are no drug-drug interactions. (3) The dosage (mg/kg/dayI of the drug needed to achieve seizure control or a therapeutic blood level may be higher when coadministered with AEDs that induce hepatic catabolic enzymes.47 (41 It is less costly. (5) Seizures may be better controlled by monotherapy without interference from other drugs. It is worthwhile to reemphasize that the “best” choice of a drug for a seizure type reflects the thoughtful comparison of the risk-benefit ratio. Since many drugs are equally efficacious for many seizure types, the selection of an agent is largely dependent on its side eflects. 4. When can AEDs be discontinued? The natural history of seizures varies with the epilepsy syndrome. For example, although valproate is extremely effective in controlling all seizure types in juvenile m.yoclonic epilepsy, there is over a 9OYo relapse rate after medication is discontinued.4X On the other hand, in essentially 100% of patients with typical benign rolandic epilepsy, seizures will stop within 10 years. Empirically, physicians are advised to consider gradual discontinuation of medication when seizure control has been complete for 2 to 4 years. For about 75% of children a 2-year seizure-free period heralds the actual retreat of the seizure tendency.4Y, 5o In the others, removal of therapy represents the withdrawal of needed AEDs. A relapse of seizures then occurs and it is recognized that the seizure disorder is still active and AEDs are reinstituted. At the time of the diagnosis it is never easy to predict how long a given child will require AED treatment.“‘,” It is the responsibility of the physician to tly to choose the agent most likely to succeed without compromising the child. Since some patients will require long-term treatment, the impact of chronic medication must alwaJrs he born in mind. TffE ROLE OF WILPROATE SEIZIIRE MANAGEMENT

IN CONTEMPORARY

PEDIATRIC

Perhaps more than in any other field of medicine, the pediatrician assumes the serious role of patient advocate. In the setting of epilepsy, this means applying a thoughtful, sensitive, and knowledgeable approach to the entire ran+ of problems encountered in pediatric epilepsy. It is not adequate to simply “control the seizures.” instead, one must measure the impact of the diagnosis, the seizures themselves, and the AEDs on the welfare of the entire individual. Childhood is inherently tumultuous. The intrusion of epilepsy amidst the normal commotion of youth is troublesome enough without the added complications of unnecessary drug side effects. In epilepsy, there are many factors that are completely bevond the physician’s control. However, the selection and dosage oi an AELI are entirely the choice of the c:linic%rl. Since epilepsy:?’ is prirnariIy a

disease of childhood, it is the pediatrician who lays the foundation for the patient’s evaluation, education, and treatment. It is the pediatrician who first prescribes the AED that the child may consume daily, for years-even for a lifetime. It is worth knowing which drugs best approach the goals of minimalist intervention: to use the smallest amount of the most effective drug with the least long-term side c:ft’ects and preserve the best quality of life. In just a few years, valproate has been accorded a major role in the management of childhood seizure disorders by epileptologists, neurologists, and pediatric neurologists. As discussed in the next section, valproate is unique in its extremely broad spectrum of activit-v. It is especially useful for all forms of generalized seizures including absence, tonic-clonic, atonic, and m?/oclonic seizures. It is an ideal monotherapy choice since it can control all of these seizure types in one patient. It is as effective as phenytoin and carbamazepine in the treatment of generalized tonic-clonic seizures. It men has a role as adjutant therapy for refractory partial epilepsy. Valproafe is extremely well tolerated and safe in properly chosen patients. The incidence of serious side effects has significantly dropped since physicians have recognized the higher risk of administration to very young patients. The use of the enteric coated divalproex formulation effectively eliminates gastrointestinal upset and allows convenient twice a day dosing in many. However, valproate’s most valuable attraction is its relative freedom from mental side effects. Compared to the other AEDs such as phenytoin, phenobarbital, primidone, and the benzodiazepines, valproate offers a lower risk of sedation, behavioral disturbances, or cognitive dulling. At the present time, valproate is clearly a drug of choice for most forms of generalized epilepsy because: (1) it is very effective; (2) it has a broad spectrum of activity that makes monotherapy a reality, not just a theoretical token; and (3) it has a relative lack of central nervous system side effects. It behooves every clinician who treats children with epilepsy to become familiar with this excellent agent. It is not just the role of the neurologist to initiate treatment with valproate. Every practicing pediatrician can easily learn how to initiate and continue treatment with this superior agent for childhood epilepsy. The remainder of this monograph is intended to convey useful practical information in the administration and monitoring of this drug. VALPROATE HfS’fORY Valproic acid is a short-chain fatty acid whose existence as a simple chemical agent was known since its synthesis by BurZon in 1881.“” Curr

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Its physicochemical properties made it a popular and suitable solvent for the study of other chemicals. Its anticonvulsant virtues were accidentally discovered in 1963 when Meunier et al. chose valproic acid as the solvent vehicle for testing a variety of antiepileptic drug candidates.54 In the experimental paradigm a variety of anticonvulsant candidates dissolved in valproic acid were studied for potential protection against an animal model of generalized seizures (provoked by the administration of the convulsant drug pentylenetetra~011. Subsequent studies of experimental seizures showed valproate’s protective effects against electroshock and audiogenic and kindled seizures. Clinical trials were soon carried out in Europe, and valproate was eventually approved by the Food and Drug Administration (FDA) for use in the United States in 1978. CHEMICAL

STRUCTURE

Valproic acid is the chemical name for a colorless liquid compound, di-iV-propylacetic acid, 2-propylpentanoic acid or 2-propylvaleric acid. Its chemical structure (Fig 8) lacks a nitrogen atom and a ring moiety and is unique among existing anticonvulsants. The chemical structure of valproate resembles a fatty acid and indeed, the body metabolizes it via normal fatty acid degradative pathways. MECHANISM

The hances alters effect GABA

OF ACTION

precise mechanism of valproate’s action is unknown. It enGABA-mediated inhibition, retards rapid neuronal firing, and the excitability of neuronal networkss5 Valproate’s principal is to increase the concentration of GABA in the brain. Both and glycine are the primary inhibitory neurotransmitters in

CH3-

CH3FIG 8. Structure

196

of valprolc

acid

CH2 - CH2 I

0 II

CHI

C I

CH2

OH

CH2-

the central nervous system and operate by opening the cell membrane chloride and potassium channels that hyperpolarize the neuron, removing it further from the critical threshold transmembrane potential needed to fire the all-or-none action potential. There are three ways that valproate could increase the concentration of GABA in the central nervous systems6: (1) interfere with GABA metabolism in the axon terminals; (2) enhanced synthesis of GABA; and 13) change the synaptic release or reuptake of GABA. Separate mechanisms of action of valproate as an anticonvulsant unrelated to GABA may be a primary effect on nerve cell membranes to reduce sodium permeability, decrease in the abundance of the excitatory neurotransmitter aspartic acid and increase in the inhibitory neurotransmitter glycine. Clearly, valproate has multiple central nervous system effects that may bear on its empirically documented antiepileptic properties. The exact mechanism of action still remains to be established. RESPONSE OF SEIZURES TO V!l?OATE USE

AND INDICATZONS

FOR

A “labelled” indication refers to a clinical condition for which a manufacturer is permitted by the FDA to claim efficacy for a drug. An “unlabelled” indication pertains to a treatment-responsive condition for which the manufacturer either has not applied for or received permission to represent that the drug is effective. According to the Physicians’ Desk Reference (44th, edition, 1990) valproate is indicated for use as a sole agent in the treatment of petit mal seizures or as an adjunct in patients with multiple seizures, including petit mal. In actual clinical practice, valproate has a much broader role in the treatment of epilepsy. To be sure, it is extremely effective in petit mal but substantial evidence now exists that defines its effectiveness in most forms of generalized seizures and as an adjunct in refractory partial seizures. ilbsence In patients with absence alone (i.e., without coexisting grand ma1 seizures) ethosuximide is the drug of first choice. It is effective, safe, well tolerated, and inexpensive. Recall that 30% to 50% of children with petit ma1 also have grand ma1 seizures. Valproate is the first choice for those with both absence and generalized tonic-clonic seizures, and in cases of ethosuximide failure. In resistant cases, polytherapy with valproate plus ethosuximide may prove more effective than either drug alone. The efficacy of valproate and ethosuximide is similar, as shown in open therapeutic trials or in studies that directly compare the two drugs57p60 (Table 51. Curr

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TABLE

5.

Absence:

Res~~~ns”

to Tnxitnwznt Valproate No. Patirnts

ShldV

F;thosuximide

No. Resaonders

Responders. “0

No. Patients

NO. Resoondws

RPSpondWS, “I,

Generalized Tonic-Clonic Seizures The first studies of valproate’s efficacy, in the early 197Os, examined its role in open polUytherapy trials. Its therapeutic worth was strongly alluded to in these studies. In later monotherapy studies, excellent results were obtained in all forms of generalized seizures. At about that time, it was realized that seizure control actually improved when many patients were converted from pokytherapy to monotherapy. Valproate monotherapy is considered a drug of first choice for all forms of primary generalized epilepsies in Europe.“O Several studies have compared the effectiveness of valproate to other antiepileptic drugs commonly employed in generalized tonic-clonic seizures (Table 61. No significant difference in the rate of successful treatment was found between valproate and any of these other drugs.“oPGJ

TABLE Tonic-Clonic

6. Seizures:

Response

to ‘I’reatment

Valpt‘oate NO.

Studv

Patients

NO.

Responders

Comparison Rqxmdws,

90

Drug

No. Patients’

NO. Responders

Drug Responders, “6

Juvenile Myoclonic Epilepsy Patients with juvenile myoclonic epilepsy often display a triad of seizure types: myoclonic, absence, and generalized tonic-clonic seizures. Before valproate, the use of monotherapy or polytherapy with primidone, phenyvtoin, phenobarbital, ethosuximide, and carbamazepine were targeted to one specific seizure type but none of these agents alone could control all of the seizure types.j’ The drug of choice for this disorder is now valproate monotherapy, which controls all seizure types in 88% of affected patients.j”, ” Unfortunately, it appears that the seizure tendency in juvenile myoclonic epilepsy may persist through adulthood. Most individuals will relapse after discontinuation of valproate even if seizures had been totally controlled. Partial Seizures There has been an excessive emphasis on valproate as a drug effective only in generalized seizures. In early reports valproate was described as having limited effect in treating partial epilepsy. It is now recognized that many forms of partial seizures are resistant to AED therapv and the merits of valproate in this context have been reexamined. dtiz.63.GG.67 Several studies of valproate have forced a rethinking of its value in partial seizures (Table 7). Dean and Penry recently reported their results of valproate monotherapy in those who failed or could not tolerate conventional drug therapy such as phenytoin or carbamazepine. A 50% to 100% improvement in seizure frequency occurred in 73% of valproate-treated patients.“7 Seizure control seemed most notable in those whose partial seizures secondarily became generalized. In a related study, the value of carbamazepine-valproate combination therapy in patients

199

with partial seizures uncontrolled with carbamazepine alone was examined. For both short-term (90 days) and long-term (17 months] assessments, there was clear benefit. Fifty-six percent of 100 patients were completely seizure-free or enjoyed more than a 50% reduction in their seizure frequency.? ” A similar result of carbamazepine-valproate was reported by Walker.70 Clearly, valproate has value in partial seizures and its full role waits to be defined by further large scale comparative studies. West

Syndrome

The triad of infantile spasms, a highly abnormal interictal EEG pattern (hypsarrhythmia), and developmental arrest constitute the West syndrome. This is an age-specific disorder that can arise following a number of important early onset encephalopathies such as birth asphyxia, congenital infection, or cerebral dysgenesis. Less commonly the condition is cryptogenic, implying that the specific etiology is not apparent. The traditional mainstay of therapy is the powerful adrenocorticotropic hormone (ACTHI. Unfortunately, therapy is often complicated by important side effects: marked irritability, hypertension, edema, weight gain, gastric ulcer, acne, opportunistic infection, and cerebral atrophy shown by computed tomography scan. Conventional AEDs such as phenobarbital, phenytoin, and carbamazepine have no consistent effect either in reducing the abundance of clinical seizures or improving the markedly abnormal EEG tracing. Observations of clinical response of infantile spasms in 9 of 19 (47%) valproate treated children were reported by Simon and Pemy in 1975.71 Others reported a 20% to 45% response rate.72’7” A well designed prospective study by Siemes et a1.74 examined valproate in 22 untreated infants with infantile spasms and a hypsarrhythmic EEG. After 6 months of high dose valproate therapy, 20 of 22 (91%) were seizure-free. No large prospective study comparing the effectiveness and side effects of valproate vs. ACTH has been reported to date. Febrile

Seizures

One of the most common forms of reactive convulsions in children is febrile seizures. Recurrent febrile seizures are more likelv to occur if the first febrile seizure occurred before the patient’s lfirst birthday. Prophylactic drug treatment is intended to reduce the risk of additional febrile seizures. Only valproate and phenobarbital’“. ‘I+ have demonstrated utility in febrile seizure prophylaxis; neither carbamazepine nor phenytoin offer protection.77,78 However, the value of all forms of prophylaxis has not been universally demonstrated.7” Simple febrile seizures are considered a benign disorder and drug therapy is not routinely started after the first or second seizure. 24M

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1990

Many physicians are reluctant to use valproate condition that occurs in young infants, whose greatest risk of valproate hepatotoxicity.

to treat this benign age makes them at

Status Epilepticus Status epilepticus refers to a fixed and enduring epileptic state. The specific seizure type during status can be tonic-clonic (status epilepticus convulsicus), simple partial (epilepsia partialis continua), absence (spike-wave stupor), complex partial (psychomotor status), or minor motor status as might occur in the Lennox-Gastaut syndrome. The most threatening of these conditions is convulsive status epilepticus, defined as a single grand mal seizure of more than 30 minutes duration or serial seizures between which the patient does not recover. Permanent neurologic sequelae or death can result from extremely long convulsive seizures. The usual mainstay of treatment is intravenous lorazepam, diazepam, phenytoin, or phenobarbital. There is no commercially available intravenous form of valproate so it is not usually considered a drug of choice. Several reports have described its benefits via rectal administration during status epilepsy.80-83 Although rectal administration of valproate or other AEDs is only rarely necessary in status, there are other clinical situations (for example, persistent vomiting, following abdominal surgery, etc.1 in which valproate or other AEDs could be administered rectally.84 VALPROATE FORMULATIOiVS There are four available preparations of valproate available for general use: capsules, liquid, tablets, and a newly released sprinkle formulation. Capsule Each soft elastic capsule of valproic acid (trade name, Depakene capsules) contains 250 mg of liquid valproic acid. The capsule must be swallowed whole, and not chewed, to prevent local mouth irritation. Although this practice may be commonly accepted clinically, the formulation experts don’t recommend this. Liquid Each teaspoon (5 ml) of the sodium valproate syrup (trade name, Depakene syrup) provides the equivalent of 250 mg of valproic acid in the form of its salt-sodium valproate.

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201

Tablet Divalproex sodium (trade name, Depakotel is a stable, coordination compound representing a 1:l molar combination of valproic acid and valproate. The tablets are available in three strengths containing the equivalent of 125 mg, 250 mg and 500 mg of valproic acid. Each tablet is enteric coated, which delays its dissolution until it reaches the small intestine. This dramatically reduces the incidence of gastrointestinal distress. Note that this is not a long acting formulation but rather delayed in onset. Once the tablet is dissolved it has elimination kinetics similar to valproate. To preserve the integrity of the enteric coating, the tablet should not be cut or chewed.

Sprinkle The most recently available formulation is divalproex sodium sprinkles (trade name, Depakote sprinkle capsules).85 Each pullapart capsule contains the equivalent of 125 mg of valproic acid. The capsule could be swallowed whole or opened and sprinkled ovet food. Because the sprinkles are tasteless, palatability is enhanced in young children, the elderly, or anyone who experiences difficulty swallowing whole tablets. Valproate syrup had been the only pediatric formulation previously available but some children did not enjoy its taste or experienced an upset stomach upon consumption. The sprinkle formulation has been demonstrated to have the same bioavailability as the enteric coated divalproex sodium tablets but with improved patient compliance.‘” Investigational formulations of a valproate suppository and injectable form are now undergoing clinical trials.X7-8f)

Absorption The temporal profiles of systemic absorption and the resulting blood levels depend on the formulation and state of fasting (Fig 9). Nevertheless, the bioavailability of each dose exceeds 90% for all of the formulations.“‘-“’ The peak serum concentration (Cmax) occurs more quickly (around 2 hours) if sodium valproate syup is taken in the fasting state. Although peak concentrations can be delayed by several hours (3 to 8 hours) if the dose is taken with meals, the total amount absorbed (bioavailabilityl is unaffected by food consumption. The Cmax with the enteric coated divalproex sodium tablet is usually reached in the fasting state between 3 to 8 hours. Absorption thus takes place in the small intestine. Absorption can be deferred by several more hours when taken with meals. The Cmax of the sprinkle formulation is lower than the other formulations but total bioavailability is the same. The absorption course is spread out more evenly, which avoids the more exaggerated peaks and valleys of the other formulations. 202

Cum

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1990

---I----I

I

I

Divalproex Sodium (Sprinkle) Valproic Acid (Syrup) Divalproex Sodium (Tablets)

I

I

I

I

II

II

45678 Time (Hours) FIG 9. The temporal proflle of blood levels of three formulations of valproate. Dean JC. ,! Cl/n Psychiatry 1989, 506uppl 3):17-22 Used by permwon.)

(From

Penry

JK.

There is presently no commercially available rectal suppository of valproate. If the proper clinical context arises, a retention enema of sodium valproate syrup, mixed 1: 1 (volume to volume1 with tap water can be administered and will produce good bioavailability but slightly delayed absorption. Distribution to the Body At the usual total serum drug levels in the range of 50 pg/ml to 80 ~g/ml, over 90% of circulating valproate is bound to plasma proteins, mostly albumin.“’ Only the remaining 5% to 10% is unbound and free to enter the tissues of the central nervous system to exert its therapeutic elects. When serum levels are above 80 to 90 pg/ml, the protein binding sites become saturated and the free fi-action of untmund drug increases in a nonlinear fashion up to 30% of the total serum level. For example, at a total valproate blood level of 60 pg/ml, 95% may be protein bound, leaving 3 pg/ml of the drug unbound. However, if the total serum concentration is double to 120 pg/ml, only 80% may be bound and the concentration of free dlvg may raise to 24 pg/ml, an eightfold increase.“” \i’alproatr is distributed chiefly to the intravascular and extracellu-

lar spaces. There tion in the brain plentiful.s4

Degradative

is little actual central nervous system accumulaexcept for regions where GABA transaminase is

Metabolism

Although carbohydrates are our main metabolic fuel, fatty acids also play an extremely important role as energy sources. It is estimated that burning fat (fatty acid oxidation) accounts for a substantial percentage of the energy that drives the liver, heart, skeletal muscles, and kidneys. Fatty acids pass through the mitochondrial membrane as esters of the compound carnitine (Fig 10). Ordinarily, fatty acids are degraded by beta oxidation in the liver mitochondria into two carbon units that can enter the Krebs tricarboxylic acid cycle (Fig 11). Beta oxidation refers to the oxidation of the beta carbon on the fatty acid molecule to yield a beta-keto acid. Fatty acids may also undergo oxidation in the cytosol at the omega and omega-1 carbons to form alpha and omega dicarboxylic acids. Valproate appears as a fatty acid to the body’s metabolic machinery. Only a small fraction of circulating valproate escapes unchanged in the urine. The remainder undergoes complex hepatic fatty acid beta and omega oxidation and combination with glucuronide. Al-

HEPATOCYTE CARNlTlNE M ACYLTRANSFERAS~~.\

CYTOSOL MICROSOMAL

CYTOCHROME P-450

i-j ,

BETA / 0xlD;10~!

‘I

! b b

OMEGA-l

OXIDATION

-

VPA

4-ENE-VPA

OXIDATION

1 SUCCINATE 1

4 OMEGA

P-ENE-VPA

KREBS GLUCURONIDATION

TCA CYCLE

P-PGA

VPA-GLUCORONIDE

H 0 N D R I 0 N

FIG 10. Valproate is metabolized in the hepatocyte by the same biochemical mechanisms utilized for processing fatty acids. In the mitochondrion, beta oxidation occurs. In the cytosol the mlcrosomal cytochrome P450 system IS responsible for omega and omega-l oxidation

204

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Pmhl

Pediatr-,

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1990

R - CH2 - (CH2)n OMEGA

- CH2 - CH2 - CH2 - COOH t t I

BETA

1

ALPHA

FIG 11. The generic formula for fatty acids. In fatty acid oxldatlon the molecule is divided into two carbon fragments. This can occur at several sites corresponding to beta or omega oxidatlon.

though about ten separate valproate metabolites are generated, only one possesses anticonvulsant activity in its own right.” It is important to note that many AEDs (phenobarbital, primidone, phenytoin, and carbamazepine) induce the activity of hepatic degradation enzymes. This results in faster elimination from the serum of coadministered AEDs and even other medications such as birth control pills. One important exception is valproate, which does not induce hepatic enzymes. The addition of valproate to an existing AED regimen does not lower the other drug levels by promoting enzyme induction. The metabolism of hormones such as contraceptives is likewise not affected. In fact, valproate can even inhibit some degradative enzymes. For example, a substantial increase in the serum phenobarbital level may occur when valproate is added, because of the inhibition of degradative enzymes.s6 Elimination Half-Life Valproate is eliminated by first order (linear) kinetics. Its estimated half-life (TY& the time required for the serum level to decrease by 50%) depends principally on the patient’s age and the presence of coadministered drugs. In general, children have valproate clearances and distribution volumes one and a half to two times greater than adults on a similar drug regimen.s7 Elimination half-lives range from 10 to 16 hours when given as monotherapy and 8 to 9 hours as polytherapy.s8 The relatively short half-life implies substantial fluctuation of serum levels through the course of the day. The ratio of peak-totrough levels may be as high as 2 : 1. It is therefore advised that blood samples to measure drug concentrations should be drawn at a fixed, standard time with respect to the dose. The ideal drug sampling time would be a trough determination. A steady-state blood drug level may be achieved within five elimination half-lives. In this case 80 hours (3.3 days) will pass before a new equilibrium is reached between drug absorption and elimination. Be aware that the desired pharmacologic effects (seizure control) may require weeks to months after steady state levels are achieved.

The relatively rapid elimination of valproic acid and sodium valproate, particularly with coexisting polytherapy, requires three to four dosages per day. In the setting of monotherapy and divalproex sodium tablets or sprinkles, twice a day dosing has been successfully used without sacrificing seizure control.”

There is no simple mathematical formula that relates valproate’s dosage img/kg/dayJ to a narrow range of blood levels (mcg/mll. The target dose of valproate is usually in the range of 15 to 60 mglkglday. In practice, a much smaller dose is initiated to minimize the early introductory side effects such as gastrointestinal distress or mild sedation. These introductory side effects soon pass and the patient becomes acclimated to the drug (Table 8). By starting with a small amount of valproate and gradually increasing it, the physician can titrate the dose against the observed abundance of seizures. For example, in childhood absence, many seizures occur each day. The correct dose of valproate would be the lowest dose that completely controls all of the seizures without introducing unwanted drug side effects. In this specific case the endpoint of treatment is seizure control, not a preordained serum drug level. The dosage of drug required to achieve a given drug level is usually higher, sometimes substantially higher, in polytherapy.“ In one study,“’ as much as 100 mg/kg/day was needed to achieve therapeu-

TABLE

8.

3 3

I

1

I

AED + VPA

VPA

Treatment FIG 12. One advantage of valproate monotherapy IS the lower dose required to generate serum levels in the therapeutic range. (From Cloyd JC. et aI, Neurology 1985; 35 1623-1627. Used by permission )

tic serum levels (50 to 100 pg) with polytherapy (Fig 1.2). After patients are converted from polytherapy to monotherapy, their dosage requirements may decrease by more than 50% .y7,I”” Blood

Levels

The clinical laboratory determination of the serum concentration of a drug provides guidance for future dose adjustments. The ideal dose of a drug is the smallest amount that controls the seizures without dose-related side effects. The lower therapeutic limit is generally the serum concentration below which seizure control may fail because of inadequate therapy. The upper therapeutic limit is usually the serum concentration above which some individuals begin to experience dose-related side efti~ts. ‘l’he therapeutic range for valproatt: is generally cited as 50 to 100 ~g/ml. Howe\~, there are many exceptions to this rule. Some chilclrvn’s st:izurcs rt:spond favorabl~v to levels below 50 ~g/riil”” while others rr:quirc nluch higher levels for control.“”

TABLE

9.

Effect AED’

on WA

Drue

Added

Level

After

to VPA

Phenobarbital Primidone Pheytoin Carbamazepirw ‘VPA = x4pmate.

Adding

Another

Change

in VPA Level Decrease Decreabe Decrease Decwase

AED = antirpileptic

drug

patic degradative enzyme activity and thereby hasten the elimination of valproate or other drugs added to the existing regimen (Table 9). The effect of other AEDs on valproate can be particularly pronounced in children. The serum level of valproate is lowered by about 50% with the coadministration of phenobarbital, phenytoin, or carbamazepine. Conversely, in children previously receiving polytherapy who discontinued treatment with phenobarbital, pheqytoin, or carbamazepine, valproate serum levels increase from 50% to 122% .loJ Whereas other AEDs induce hepatic degradative microsomal enzyme activity, valproate does not, and may actually cause some metabolic inhibition. As a result, the half-life of other AEDs could be increased when valproate is added, leading to drug accumulation, elevated serum levels, and potentially clinical intoxication. Phenobarbital levels increase from 30% to 80% when valproate is added to the existing therapeutic regimen (Table 10). It is usually wise to anticipate this effect and reduce the administered dose of phenobarbital or primidone before starting the valproate. When valproate is added to an established phenytoin regimen, there are more complex effects. Valproate competes with phenytoin for circulating protein binding sites. Unbound phenytoin is cleared from the body more readily and the measured total serum phenytoin levels may fall, at least transiently. As the valproate dose increases, there is a concomitant rise in the percentage of unbound TABLE Effect

10. on AED

I.r:vel

Mel,

VPA Is Added

pheqytoin. On balance, the concentration of unbound drug changes little. If the fall in total serum pherrytoin concentration is not accompanied by deterioration in clinical seizure control, it may not be necessary to increase the pheqtoin dose.‘“5 The displacement of phenytoin from its binding sites may also allow signs of drug intoxication to develop while the measured blood level remains in the therapeutic range. Valproate affects carbamazepine by displacing it from sites on circulatory protein (carbamazepine is 75% protein bound) and via metabolic inhibition.‘06 The measured increase in the free fraction of drug is a modest 25%, which leads to a slight increase of clearance and therefore, a slight decrease in blood level. Valproate also causes a decrease in the elimination of its main metabolite, carbamazepine10, II-epoxide, which has its own antiepileptic and neurotoxic activity. Therefore, valproate can alter the therapeutic effect of carbamazepine by changing its conversion to an active metabolite. Aside from its significant interactions with other AEDs, attention has also been drawn to the relationship between aspirin and valproate. Aspirin displaces valproate from its circulatory protein binding sites, thus increasing its unbound free fraction, which is cleared faster. Aspirin may metabolically inhibit valproate elimination by beta oxidation, resulting in an increase in its total serum level, and by fostering the promotion of 4ene-valproate, a biproduct with suspected toxicity. These results await confirmation and elucidation. 107-110 Because valproate does not induce drug metabolism, it has an advantage over other AEDs, which causes accelerated catabolism of steroids such as oral contraceptive pills, which in turn might increase the risk of pregnancy. RAMIFICATIONS

OF TREATMENT

Neurologic E@cts of Treatment Valproate monotherapy does not disturb the resting EEG background.“’ With phenobarbital-valproate duotherapy, the barbiturate-provoked fast (beta1 activity in the background can be augmented. In cases of accidental or deliberate intoxication, hyperammonemia, and high valproate levels, the EEG background rhythms may be slow. Valproate can normalize the EEG by “erasing” the three per second generalized, spike slow-wave discharges encoungered in childhood petit mal seizures.112 Likewise, substantial amelioration of the highly chaotic hypsarrhythmic EEG background may be observed in infants with West syndrome who respond favorably to valproate.

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19YO

209

Absence of Withdrawal

Symptoms

There are well described signs and symptoms of medication withdrawal following the discontinuation of some barbiturates, alcohol, and the benzodiazepines. There are no symptoms attributable to the withdrawal of valproate.“?

Seizure Control By their very nature, antiepileptic drugs are intended to reduce 01 eliminate seizures. Nevertheless, there are instances of paradoxical seizure exacerbation by antiepileptic drugs. The Physicians’ Desk Reference contains a warning that in some rare instances, the combined use of valproate and clonazepam may precipitate absence status. While that might be true, recall that some children with certain epilepsy syndromes such as juvenile myoclonic epilepsy, the Lennox-Gastaut syndrome, and myoclonic-astatic seizures are inherently prone to developing absence status. It is difficult to determine whether their seizure disorder or that drug combination was responsible for the status. Indeed, the combination of valproate and a benzodiazepine when needed because of refractory seizures is considered an example of rational pal”ytherapy, especially in the Lennox-Gastaut sUyndrome.““- ‘I7

Tremor Some form of abnormal movements has been occasionally reported in association with all of the major AEDs. These sometimes take the form of dramatic motor activity such as ataxia or choreoathetosis.‘18-1”’ The most common movement disturbance associated with valproate is a mild, dose dependent tremor of the hands that is characteristic of a benign essential or physiologic trem0r.l”’ Tremors are rhivthmic movements around a fixed point. The tremors induced by valproate oscillate with a frequency of 6 to 15 Hz and occur during activities or while sustaining a posture. Although they are bilateral, the dominant hand may be more involved. The amplitude of the tremor is usually low and dose dependent. It rarely limits the patient’s functional ability and is almost never a cause to discontinue treatment. Coadministration of aspirin may worsen it .lf19 A reduced dose may lower the tremor’s amplitude. If that approach is impractical, the use of beta blocking agents such as propranolol is very helpful in controlling valproate tremors.12”

Sedation Sedation may occur at the onset of therapy or following an increase of dose of valproate. It is usually mild, transient, dose related, and fades quickly. More prominent 1ethargV may occur if valproate is coadministered with phenobarbital and drug-drug interactions result in barbiturate intoxication. Lethary can also occur with val-

proate-carbamazepine polytherapy.lz4 Rarely, valproate can induce an acute depression of mental status of obscure etiology with or without elevation of ammonia or related metabolic changes.1z5-1z7 Mental Side Efsects The medical and neurologic communities have only recently come to acknowledge and confront the problems imposed upon children by the chronic consumption of antiepileptic agents.128 Childhood is the stage upon which is fostered the success of independent adult life. It is a serious responsibility of the pediatrician to monitor the patients’ psychosocial progress in addition to their physical and medical well-being.‘“’ Perhaps the most salubrious quality of valproate, and the one that makes it so desirable for use in children, is its relative freedom from mental side effects impacting mood, cognition, behavior, and attention. When valproate is added to existing drug regimen learning tasks are not effected. Only minimal adverse effects on psychological testing have been noted.lR4 A recent double blind crossover study in adults of valproate compared to placebo examined the drug’s potential mental effects.4” A far-reaching battery of psychological tests to measure concentration, memory, speed of perception, motor speed, and decision making was executed. The authors concluded that valproate had a minimal impact on cognitive function. Another prospective study compared the types and frequency of side effects in children receiving phenobarbital, primidine, phenytoin, carbamazepine, and valproate monotherapy.13’ As expected, each drug had its own profile of side effects. For example, behavioral disorders were most common with phenobarbital, digestive disorders with valproate, and gingival hyperplasia-hirsutism with phenytoin. Valproate had one of the most favorable profiles of neurologic and behavioral effects (Fig 13). These and other studies indicate that valproate appears to exert less effect on mental functions than phenytoin and phenobarbital.‘24 In another study,131 the incidence and persistence of adverse drug effects were prospectively examined in adults and children receiving monotherapy. The rate of adverse drug reactions varied with each drug: phenytoin, 33%; phenobarbital, 23%; carbamazepine, 15%; and valproate, 12%. In a related follow-up study’32 the investigators noted that the incidence of side effects in chronic treatment increased for phenobarbital and benzodiazepines and decreased for valproate, carbamazepine, and phenytoin (Fig 14). A landmark study at the Johns Hopkins University Hospital quantitatively compared a comprehensive battery of neuropsychological measures in children who appeared clinically unaffected by the valproate or phenobarbital they were taking.13” Only those children who consumed either drug vet seemed entirely well were included

FIG 13. Neurologic and behavioral dren. PB = phenobarbital; WA = valproate.

side effects with antiepileptic drug (AED) monotherapy In chllPRM = primidone; PHT = phenytoin; 032 = carbamazepine;

in the study. (Children with visible barbiturate side effects, such as hyperactivity, were excluded.) That study demonstrated statistically significant differences between the children administered valproate and phenobarbital. Children enjoyed better cognitive function and behavior on valproate. It is worth reemphasizing that none of the patients had any visible side effects discernible by the parents or the physician in the office. Even though all the patients ostensibly seemed the same, the neuropsychological testing revealed clear, significant differences between the two groups. In 1985 the Committee on Drugs of the American Academy of Pediatrics reviewed the available studies to comment on the detrimental effect some AEDs have on behavior and cognition, and urged that physicians who prescribe AEDs should be familiar with these unwanted side effects.lS4 They recommended that the profile of behavioral and cognitive function of each AED should be considered when selecting a specific agent. Table 11 summarizes the range of side effects that can be induced by AEDs.

212

FIG 14. Persistence phenobarbital; valproate.

of side effects during chronic monotherapy. BZD = benzodiazeplnes; PHT =phenytoin,

AED

CBZ

= antieplleptic drug; PB = = carbamazepine; VP,4 =

THE USE OF VALPROATE IN THE ZNSTITUTIONALIZED MENTALLY RETARDED PATIENT WITH EPILEPSY

AND

Epilepsy is not uncommon among the mentally retarded.135 Up to 40% of the institutionalized retarded consume one or more AEDs. Polytherapy is relatively frequent in the institutionalized, either because of the abundance of refractory seizures or a reluctance to withdraw their medications lest status epilepsy be precipitated. A common management problem among the institutionalized retarded is unacceptable behaviors. These include episodic loss of control or rage attacks, negativism, oppositional behavior, depression, or refusal to participate freely in the daily routines of institutional life. It is not precisely known how much these unwanted behaviors are amplified by the administration of AEDs. Antiepileptic drug pal-ytherapy frequently can be simplified to monotherapy wthout sacrificing seizure control in the institutionalized retardate. 135-138 This can sometimes be accompanied by a gratifying improvement in mood and behavior. PSYCHIATRIC DISORDERS RESPONSIVE TO VALPROATE Although valproate is officially indicated for use in epilepsy, psychiatrists have discovered an important role for it in some forms of Cum

Probl

Pediatr,

April

1990

213

TABLE

11.

Potential

Adverse

Antiepileptic

Drug

Phenobarbital

Phen.ytoin

Carbarnazepine

Clonazepam

Valproate ‘Adapted /‘ediatrm

Effects

of Antieuileotic Behavioral

Drucs’ Effects

Cognitive

Hyperactivity Fussiness Lethargy Disturbed sleep Irritability Disobedience Stubbornness Emotional changes Unsteadiness Involuntary movements Tiredness Difficulty sleeping i\gitation Irritability Emotional lability Irritability Aggression Hyperactivity Disobedience Antisocial beha\eor Drowsiness (especially with phenobarbitali

from AAP Chrrunittee on Drugs: Behavioral 1’385; 7fi:64&647. Used by Permission.

Effects

Neuropsychologic Memory impairment Poor concentration

deficits

Neuropsychologic deficits Impaired attention, problem solving, and visuomotor tasks Impaired task p!1f0mancr

Minimal adverse on psychosocial and

cognitive

effects

effects tests

of anticonvulsant

thewpy

mental disease.13’ Areas of application currently under investigation include anorexia nervosa and cases of manic-depressive psychosis that fail to respond to the drug of choice, lithium carbonate. The subset of patients with rapid mood cycling (more than three attacks per year) appears especially promising.‘40-142 Post has recently described his results in lithium-refractory bipolar illness at the National Institute of Mental Health and noted that valproate and some other AEDs may be successful options or adjuncts to lithium, the traditional mainstay of treatment.143 The biochemical basis of mania is suspected to result from depletion of GABA, the principal inhibitory neurotransmitter in the central nervous system. Valproate augments the activity of GABA by a variety of suspected mechanisms and may account in part for its salutary effects in bipolar illness and acute mania.

214

NONEPILEPTIC NEUROLOGIC RESPOND TO VALPROATE

CONDITIONS

THAT

SOMETIMES

There are unlabelled applications of valproate in neurology beyond epilepsy. Recall that valproate may occasionally induce tremor and rarely other involuntary movements. It may seem paradoxical, yet valproate may ameliorate several types of involuntary movements. Investigators have reported favorable responses to valproate in Sydenham’s chorea,lU myoclonus,‘4s hemiballismus,14” intractable hiccups,14’ and hyperekplexia.lJ8 All of these reports should be viewed as preliminary. RECOGNITION

AND

TREATMENT

OF ACUTE

DRUG

OVERDOSE

Deep coma may result from valproate overdose. General supportive measures are indicated; there is no specific treatment except possibly the administration of an opiate antagonist.149 In view of the rapid and relatively complete gastrointestinal absorption of the drug, the effectiveness of gastric lavage or activated charcoal depends mostly on the amount of time that has passed since the ingestion. Because of the high percentage of circulating protein binding, hemodialysis or peritoneal dialysis will probably not speed recovery by substantially reducing the total body drug burden.15’ Similarly, forced diuresis has little effect in accelerating drug elimination from the body. Recovery is expected even after large overdoses of valproate as long as general medical and nursing care have been maintained during the acute intoxication. Some fatalities have been reported, however. SYSTEMIC Subacute

SIDE

EFFECTS

Hepatotoxicity

important concern to pediatricians who prescribe valproate is I he rare occurrence of a sometimes fatal, idiosyncratic liver toxicity. It is fortunate that the incidence of this disorder is dramatically falling, despite the increased use of valproate by physicians. The decrease is attributed to an increased awareness of high-risk groups and the growing appreciation of the virtues of monotherapy Let ~1s now review our current understanding of this disorder. The association between valproate and acute hepatic failure was first reported in 1979.‘“’ The manufacturer and FDA issued a product \varning when additional cases of bepatotoxicit?/ suspected to have resillt&l from \3lproate Lucre reporled. A systematic review and analysis of these cases LIIJ to 1984 was rx~porlcd 1~ the Amt:rit*an \caclem.v of NWolrt~\~ I!\, I)r~c~ifiiss ancl Santilli in l!)Xli IT’ Ii Wiis An

78

79

80

81

a2

83

84

85

86

83

84

85

86

Year

78

79

80

81

82 Year

FIG 15. Waning incidence of fatalities from hepatic toxicity the epileptic population. (From Dreifuss FE, Langer by permission.)

despite increased use of valproate in FH: Am J Med 1988; 84:34-41. Used

clear that the risk of hepatotoxicity was not homogeneous across all age groups but rather concentrated in young children, particularly those less than 2 years with such medical conditions as mental retardation, developmental delay, congenital abnormalities, or other neurologic diseases and receiving polytherapy. In that patient subset, the rate of fatal reactions was 19 per 10,000. In contrast, there were no fatalities in patients over age 10 years receiving monotheraPY. The study was then extended to include 198.5 and 1986. A nearly fivefold decrease in the overall incidence of hepatic fatality (1 per 49,000) was shown.153 This was remarkable in light of the sharp increase in the overall use of valproate (Fig 15). The recognition of the 216

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1990

high-risk young infant and increased practice of monotherapy were likely responsible for some of the decreased incidence. Schefier et al.154 reported a qualitatively similar experience with valproate hepatotoxicity in West Germany between 1977 and 1986. They also found that most affected patients had received polytherapy and were young, typically under 9 years of age. Clinical within 6 anorexia, dominal

Appearance ofHepatotoxicify.-The majority of cases start months of the onset of treatment. Symptoms such as frank nausea, vomiting, lethargy, malaise, jaundice, edema, abpain, and easy bruising are among the presenting comp~~~~~~~1"3~1"4 Sometimes these constitutional complaints are preceded by an unexplained deterioration of seizure control. Serum measurements of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase, (SGPT), and bilirubin are not particularly good predictors of this disorder. Rather, markers for hepatic synthetic capability such as albumin, total protein fibrinogen, prothrombin PI’), and partial thromboplastin time FIT) are more relevant.‘55 If a patient develops these signs and symptoms with the appropriate laboratory abnormalities, valproate treatment should be discontinued. Hepatotoxicity is not always fatal and drug withdrawal seems to be the most logical step in response to the development of liver disease.ls4 Suspected Etiology.-The relationship between some rare types of liver injury and AED therapy in general is well established. Both phenytoin and carbamazepine may induce fatal hepatocellular necrosis with constitutional signs of a hypersensitivity reaction featuring fever, rash, and lymphadenopathy.155 The specific cause of fatal hepatotoxicity with valproate is uncertain but either a toxic metabolite of valproate or pre-existing inborn error of metabolism in the patient may be responsible. The liver histopathology in valproate hepatotoxicity is dominated by microvesicular steatosis, often with hepatocellular necrosis.15‘j Similar pathologic changes have been described in Reye’s syndrome and Jamaican vomiting sickness. Indeed, patients have been reported whose clinical condition unfolded in a way suggesting a “Reye-like” illness. In both Jamaican vomiting sickness and Reye’s syndrome a toxic fatty acid is suspected to play a key metabolic role in the genesis of liver damage. An aberrant metabolite of valproate oxidation is suspected to play a similar causative role. Recent studies have highlighted the production of a hepatotoxic byproduct of valproate metabolism: 4-ene-valproate. It is chemically similar to the toxic unsaturated fatty acid encountered in Reye’s s-yndrome and Jamaican vomiting sickness and was detected in several patie,lts reported t1.v Scheffner’“4 and others.‘“” Omega-l oxidaCurr

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217

tion of valproate in the cytosol (see Fig 121 leads to 4-ene-valproate. Anything that favors this degradative pathway or inhibits valproate beta oxidation within the mitochondrion potentially promotes an increase in 4-ene-valproate production and hepatotoxicity. This compound induces microvesicular steatosis in laboratory animals and its formation may be promoted by phenobarbital which induces hepatic P450-dependent metabolism. These potentially toxic valproate metabolites might be detectable before the onset of clinical disease.lS7 Some clinically affected children have been reported to recover after the administration of a detoxifying agent UV-acetylcysteine) .158 These studies suggest future possible avenues to explore treatment. Role of Carnitine.Carnitine is an essential cofactor of fatty acid metabolism that is supplied from the diet or endogenously synthesized. It is necessary for the biochemical processing of free long chain fatty acids and their transport into the mitochondrion. Inside the mitochondria, fatty acid undergoes beta oxidation to fuel energy production via the Krebs cycle. Interference with carnitine leads to a buildup of free fatty acids in the cell qytoplasm and cellular dysfunction because of mitochondrial energv deficiency. Carnitine blood levels are reduced in classic Reye’s qyndrome and primary carnitine deficiency can present with a clinical picture resembling Reye’s syndrome. Carnitine levels are sometimes reduced in patients consuming valproate.15Y. Iti” Valproate binds to carnitine for its own transportation into the mitochondrion. Unfortunately, some valproate-carnitine compound is leaked into the urine by the kidneys and may be partly responsible for carnitine depletion and the observed low serum levels.161 There is speculation that carnitine deficiency may play some role in valproate hepatotoxicity. The administration of carnitine to children receiving valproate with hyperammonemia and Reye-like illnesses has led to improvement in some cases.161, 162 It is unknown whether carnitine plays a central role in the genesis of liver toxicity but the implications are important since dietary supplements of carnitine are available and well tolerated.‘“” Fasting and Aspirin Administration.Fasting has an uncertain relationship to valproate hepatotoxicity. Valproate may reduce ketogenesis in fasting children, indicating an impairment of hepatic ketone synthesis by burning fats.lfiJ This underscores the concern that chronically malnourished children, with depleted fat and glycogen stores, may experience cellular energy failure by drug induced inhibition of fatty acid oxidation. The coadministration of valproate and aspirin is generally well tolerated.“‘, ‘lo There are rare instances of transient valproate intoxication because of its displacement from its albumin binding sites. Of theoretical concern is the fact that aspirin is believed to play a role in Reye’s syndrome. Aspirin stimulates omega oxidation, which fa218

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f’roh/

Pdiatr,

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1990

vors the appearance of toxic dicarboxylic acids in Reye’s syndrome. In analogy with this, the unnecessary use of aspirin in children receiving valproate should be avoided when possible. Recommendations.-The specific etiology of hepatotoxicity is unknown. Some children may actually have an inherent cerebrohepatic disorder’fi” or a subtle metabolic anomaly that renders them vulnerable to drug toxicity. In others, the presence of 4-ene-valproate, and! or a low carnitive blood role may be more important. In light of the available clinical knowledge, the following recommendations are offeI.ed’-: 1. Be aware of those patients at highest risk-infants 2 years of age and under on poldytherapy. Carefully weigh the benefits of treatment versus the risk of side effects and seek alternative therapies tirst in very young patients. 2. In children with evidence of inborn errors of metabolism, preexisting liver disease, or a positive family history of childhood liver disease, valproate should be avoided when possible. 3. Be alert to the theoretical risk involved with valproate administration in malnourished or fasting children and those consuming aspirin. 4. The patient and family should be informed that the administration of all AEDs carries risks, including rare instances of fatality. The family should learn the important early signs of hepatotoxicity such as anorexia, nausea, vomiting, lethargy, malaise, bruising, jaundice, or edema and promptly report them. 5. Before starting valproate treatment, baseline blood studies should be performed, including total serum protein, albumin, SGOT, SGR, bilirubin, complete blood count, platelet count, PT, PTT, and fibrinogen levels. Blood tests should be periodically monitored during the period of risk, generally the first 6 months of treatment. 6. Start valproate monotherapy at a low dose and use the smallest amount that controls the seizures. Discontinue treatment if signs and symptoms of hepatotoxicity develop. Elevated Liver Enzvmes and Serum Ammonia Asymptomatic mild elevation of hepatic enzymes occurs in up to 44% of patients treated with valproate.166*167 The patients are clinically well and there are no chemical abnormalities of hepatic synthetic activities. The elevated hepatic enz-ymes may lower following a reduction of the dose. This appears to be a clinically innocent observation and is not indicative of the serious hepatotoxicity just described. As-ymptomatic mild elevation of liver function tests tends to occur in the first few months of treatment. Clinicians should seriously con-

sider terminating treatment if: (1) clinical signs of hepatic disease appear (i.e., malaise, jaundice, or edema); (2) the SGOT elevation exceeds three times the usual upper limit; or (3) hepatic synthetic function falters (i.e., hypoalbuminemia or prolonged PT or PTT). Some patients may also experience mild increases in blood ammonia levels.168’ 16’ This may occur with valproate monotherapy but appears exaggerated with polytherapy. This is usually clinically asymptomatic but in some individuals a toxic encephalopathy may appear featuring lethargy in association with hyperammonemia.

Acute Pancreatitis Valproate has recently been added to the list of drugs capable of producing serious or fatal acute hemorrhagic pancreatitis.‘7”’ I71 However, the incidence is extremely low. The underlying mechanism of this disorder is unknown. The principal clinical presentations include abdominal pain, distention, and tenderness on palpation, with major increases in serum amylase levels.

Gastric intolerance The most common early side effect of valproate is gastrointestinal intolerance in the form of nausea, indigestion, and anorexia. Vomiting and diarrhea occur occasionally. These complaints have been greatly curtailed by the use of the enteric coated divalproex sodium formulation. Wilder reported that 85% of those who were previously gastrointestinally intolerant to valproate could tolerate the enteric coated formulation.‘7z Most of the early gastrointestinal complaints subside in time, and tolerance develops. Chronic or late onset gastrointestinal tract distress can occasionally indicate gastritis in children, especially if feeding difficulties are prominent.173 Fortunately, this responds to routine medical management with agents such as antacids and H, receptor antagonists.

Weight Gain Weight gain has been reported in less than 20% of patients who chronically consume valproate. *74 The mechanism does not appear to be anything exotic such as an altered basal metabolic rate”” but simply an overactive appetite. Patients should be counseled regarding the possibility of weight gain and dietary restrictions applied as needed.

Hair Changes Mild hair loss may occur in 0.5% to 4% of patients chronically treated with valproate. The hair loss is typically diffuse rather than in localized patches. Occasionally, the new hair that appears is altered in texture and described as being more coarse or curly. This

reversible alopecia is usually short lived and rarely requires tinuing treatment or changing the valproate dosage.

Laboratory

discon-

Tests

Valproate is chemically a short chain fatty acid. After hepatic oxidation, it is converted into a ketone body that may be responsible for false positive laboratory tests of urinary ketones. Likewise, false positive laboratory test for some organic acids is possible.g1 Laboratory screen examinations may also show asymptomatic hyperglycinemia and hyperglycinuria.17’, 177 Elevation of high density lipoprotein cholesterol may occur with phenobarbital, carbamazepine, and valproate.“’

Hematologic

E@cts

Valproate does not have prominent hematologic effects; however, complex effects on hemostasis may occur. The absolute platelet account can be depressed, especially during intercurrent viral illplatelet behavior, such as platelet adhesiveness. 1’S,lRo Furthermore, ness and aggregation, may be impaired.‘“’ By an independent mechanism the prothrombin and partial thromboplastin times can also be prolonged.“4, ” These effects are usually only detectable with laboratory measurements of prolonged bleeding times and occasionally the presence of ecchymosis. Frank hemorrhagic complications are rare. Nevertheless, if elective surgery is anticipated, the patient’s coagulation status should be evaluated prior to the operation.

Reproductive

System

Valproate is the only major AED that does not accelerate the hepatic metabolism of the hormones in oral contraceptives; lower hormonal levels could lead to undesired conception. Approximately one third of women with epilepsy experience an increase in their usual seizure frequency during pregnancy or have seizures confined to pregnancy (gestational epilepsy). Convulsive maternal seizures are potentially harmtil or fatal to the fetus. Therefore, it is wise to recommend anticonvulsant treatment during PI-gnancy, usually with a single effective drug. (The anticonvulsant trimethadione is highly teratogenic and absolutely contraindicated during pregnancy.! Epileptic mothers have a twofold to threefold increased risk of having offspring with congenital malformations. The suspicion of drug related mutagenesis or teratogenesis is complicated by evidence that epilepsy per se in the mother or father is associated with a higher risk of fetal malformations. Valproate has been associated with an increased risk of neural tube defects when taken during the first trimester.‘X”, “” The overall risk for any form of neural tube defects is 1% to 2%. In 1983, the

Committee on Drugs of the American Academy of Pediatrics brought this fact to the attention of pediatricians184 and the Centers for Disease Control later warned that valproate should be considered a human teratogen. Other investigators have described a separate congenital malformation syndrome with facial, musculoskeletal, and cardiovascular dysmorphism, ls5- ls8 secondary to valproate use. Women of childbearing age should be counseled regarding these risks. If they do conceive while consuming valproate, they should be offered a careful evaluation of the fetus including alpha-fetoprotein determination and ultrasonic examination so that therapeutic abortion can be considered if desired.

MONOTHERAPY Monotherapy is the goal of seizure treatment with all AEDs and for all seizure types.18y It is easiest to begin treatment with a single agent chosen for the specific seizure type, the patient’s age, and other relevant considerations. If the first monotherapy choice fails, a second agent should be substituted (not added). Only after all monotherapy trials fail should two-drug combinations be attempted. We have already highlighted the many virtues of monotherapy: although seizure control is often not additive when two or more drugs are coadministered, their neurologic and cognitive toxicities may be. Monotherapy is simplar, cheaper, safer, and avoids the many opportunities for multiple drug interactions. Resistant, refractory, or intractable epilepsy is a serious condition that carries very real morbidity and mortality.40’ lso Although the desired theoretical goal of AED treatment is monotherapy, it is a sad reality that some patients do not experience adequate seizure protection with one drug alone and a trial of polytherapy or a “second There are rational or reasonable line” drug becomes appropriate.‘“’ choices for duotherapy. For example, in resistant petit mal, valproate-ethosuximide duotherapy may be helpful. In the Lennox-Gastaut syndrome, valproate-benzodiazepine duotherapy may work better than monotherapy. Valproate may also be a useful adjunct to carbamazepine in some patients with partial seizures. On the other hand, the combination of phenobarbital-primidone is not likely to improve seizure control over either drug used alone.

CONVERSION

FROM

POLYTHERAPY

TO MONOTHERAPY

It is always easiest to start treatment with monotherapy. However, some patients are already consuming multiple AEDs and the goal of

FIG 16. An aigorlthm apy (Frorn

describing Wilder BJ

the conversion EpdepsG 1987

of patients on polytherapy to valproate 28(suppl) l-7 Used by permIssIon )

monother-

approach. Extraneous or second line agents such as acetozolamide are withdrawn first. If valproate monotherapy is the goal of the conversion, its dosage is adjusted to achieve serum levels in the therapeutic range to give adequate seizure protection while the other AEDs ‘are withdrawn. -One by one, the other drugs are gradually tapered and discontinued until monotherapy is achieved. ACKNOWLEDGMENT

The author wishes to express his sincere thanks to Dr. Hee Jung Chung for her valuable help in researching literature for this monograph and Moselle Peace who typed the manuscript. REFERENCES

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