New anticonvulsants in pediatrics: Carbamazepine and valproate

NEW ANTICONVULSANTS IN PEDIATRICS: CARBAMAiEPINE AND VALPROATE

Epilepsy is a common chronic neurologic disorder that affects 0.5% of the pediatric population. Although children with epilepsy may enjoy normal lives, several obstacles may impede their functioning and well-being: 1. They have a chronic neurologic disorder. 2. Their lives may be repeatedly interrupted by unannounced, unwanted, unexpected seizures during which normal control of some or all brain function is temporarily lost. 3. They may harbor an underlying CNS disorder (for example, a structural brain malformation) responsible for functional impairment beyond the seizures themselves. 4. They are the focus of society’s biased attitudes and adverse opinions that isolate and socially restrict them. 5. Over the years, repetitive seizures may produce unwanted changes in brain activity expressed as alterations in mood, personality, or cognition that may further hinder or socially retard them. 6. Children with epilepsy chronically consume anticonvulsant medications to eliminate or control their seizures. To achieve the intended biologic effects, anticonvulsants must penetrate the bloodbrain barrier, enter the tissues of the CNS, and alter brain function by changes in the neurophysiologic properties of nerve cells such as ion transport or synaptic activity. Although these neurophysiologic changes reduce the risk of seizures, they may simultaneously disturb other brain functions and depress alertness or alter mood, memory, sleep, and cognitive abilities. In addition to the direct CNS side effects of anticonvulsant medication, chronic administration may cause physical somatic disturbances in the form of hypersensitivity reactions, cosmetic changes, bone marrow depression, and liver dysfunction. Physicians who are responsible for the care of children with epilepsy have little or no control over many of the factors that bear adversely on their patients’ lives and well-being. However, prescribing anticonvulsant medications is in the hands of the physician. The primary tasks facing the clinician are (1) the decision to begin anticonvulsant treatCur-r Probl Pediatr,

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ment, (2) the choice of the drug(s), (3) the selection of the dosage, and (4) monitoring for physical, neurologic, and cognitive side effects. There is no single perfect anticonvulsant medication that achieves total seizure control for all patients yet generates no systemic or neurologic side effects. The search for better anticonvulsants thus continues. This review highlights two recent additions to the medical armamentarium in the treatment of epilepsy: carbamazepine and valproate. These two medications have rapidly gained enormous popularity among neurologists, pediatricians, and those involved in the care of patients with epilepsy; therefore it seems appropriate to review clinically relevant information regarding the selection, dosing, initiation, maintenance, and monitoring of these drugs. Since the care of patients with epilepsy includes more than merely prescribing and renewing anticonvulsant drugs, the use of carbamazepine and valproate should be approached within a larger, comprehensive perspective on the recognition and treatment of seizure disorders. Before reviewing the specific clinical properties of carbamazepine and valproate, we will first consider a broader foundation, a contemporary scheme of epilepsy. THE

MODERN

Seizures

PICTURE

OF EPILEPSY

Versus Epilepsy

The word “seizure” means literally “a grabbing hold of.” Many diseases or conditions can cause abrupt attacks of disordered brain function, causing a sudden change in an individual’s consciousness, behavior, motor activity, or sensation. The diagnosis of epilepsy is reserved for a condition of recurrent (two or more) attacks of altered brain function (seizures) which are due to excessive neuronal electrical discharges in the cerebral cortex. Thus, epilepsy represents the ongoing enhanced susceptibility (“lowered seizure threshold”) to recurrent abnormal attacks of disturbed brain function. The recurring seizures are the clinically visible or outward signs of the epilepsy. The purpose of treatment with anticonvulsant medication is to reduce or eliminate the outward signs of epilepsy-the seizures themselves. There is little evidence that anticonvulsant treatment . affects the natural history of the underlying epilepsy. Two important principles immediately emerge from the foregoing remarks. First, not all patients with recurrent abnormal attacks have epilepsy. It is just as important for clinicians to recognize what is not epilepsy as to recognize what is epilepsy. Many nonepileptic conditions can recur repeatedly and produce attacks or “seizures” that may be confused with the signs of genuine epilepsy. Syncope,

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cardiac arrhythmias, the consumption of illicit drugs, hypoglycemia, migraine, narcolepsy, and gastroesophageal reflux are a few examples of episodic or “paroxysmal” medical disorders that can mimic epilepsy. If the abnormal attacks brought on by such conditions are not recognized as nonepileptic events the clinician may erroneously treat them with anticonvulsants. Naturally, such treatment will ultimately fail, but in the interim it may lead to increasing dosages of an anticonvulsant drug or to the use of multiple drugs (polypharmacy). The first principle of treatment is to be sure that the condition represents genuine epilepsy and not some masquerade. Appendix 1 briefly outlines such conditi0ns.l Solitary

Seizure

The second major diagnostic feature of epilepsy is the presence of two or more unprovoked seizures. The goal of drug treatment is to reduce or eliminate further attacks and possible coincident ictal brain damage.’ Seizure frequency varies widely among the epileptic population from two in a lifetime to numerous episodes each day. The clinical situation in which an individual patient has experienced a single or solitary epileptic seizure represents a unique case; the diagnostic label “epilepsy” does not apply. Many clinicians prefer to await the appearance of a second attack before committing the patient to chronic anticonvulsant medication3 Although the exact risk of recurrence after a solitary epileptic seizure is uncertain (and probably depends on factors such as the patient’s age, family history of epilepsy, potential etiology, clinical seizure type, and the results of the EEG examination), perhaps as few as 259640% of those with solitary seizures develop recurrent seizures (epilepsy).4-8 The clinician must discuss the advantages and disadvantages of drug treatment with the family before making a final decision. In many cases the child may be better off without treatment. Even if no chronic treatment is prescribed, patients with solitary unprovoked seizures deserve the same careful medical and neurologic evaluation as those with recurrent seizures. Some recurrent epileptic seizures are provoked and arise from intercurrent medical illnesses and do not automatically require longterm drug administration. For example, seizures may complicate the course of hyponatremia or acute viral encephalitis.’ While correcting the underlying medic+ condition, physicians may order a short course of anticonvulsant therapy for added protection, but such therapy may be quickly stopped once the transient medical condition has passed. Appendices 2 and 3 include some medical conditions that may feature epileptic seizures as a transient sign of concurrent brain dysfunction. Curr Probl Pediatr,

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The Decision

to Begin

Anticonvukants

The recommendation to begin chronic anticonvulsant medication should occur after it is reasonably certain (1) that the patient’s atmechanism (and are not tacks are founded on a specific epileptic due to migraine, breath-holding attacks, cardiogenic syncope, etc.), (2) that the episodes are recurrent and future attacks are likely to arise, and (3) that the epileptic seizures do not reflect a transient sign of neurologic involvement in the context of a medical illness. Choice

of an Anticonvulsant

The choice of a specific drug for the treatment of epilepsy is largely determined by the type of habitual seizure the patient experiences. Thus, before one can thoughtfully and rationally prescribe any antiepileptic medication, including carbamazepine and valproate, the patient’s recurrent epileptic seizures should be characterized and classified on the basis of a careful historical description of the attack, integrated with the results of the physical and neurologic examination and EEG. Classification

Most types of tient in veal that due to:

of Seizures

individuals with epilepsy have only one or relatively few clinical seizures. An initial investment of time with the paelucidating a description of the seizures will commonly rethe “different” seizure types the patient reports are actually

1. Different durations of seizures 2. Different intensities or severities of seizures 3. Different environments or behavioral states (seizures occurring during sleep or wakefulness) 4. Different “automatisms” during some seizures (for example, during complex partial or petit mal seizures) 5. Different intensities or durations of the postictal period 6. The presence or absence of physical injury following a seizure . 7. Different recollections of parts of the seizure The clinician should not be sidetracked by variations on a common theme of the patient’s habitual seizures. It is nevertheless true that some patients have seizures of multiple types. For example, about 30% of patients with classic petit mal seizures also have grand mal seizures .l” Individuals with the Lennox-Gastaut syndrome often have multiple distinctive seizure types which require an individually tailored anticonvulsant regimen. 142

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Revised

International

Classification

of Epileptic

Seizures

In 1981, the classification of epileptic seizures was updated and revised by the International League Against Epilepsy to incorporate and reflect an improved understanding of the electroclinical foundation of observed seizures.** Although there remains a large number of subtypes of seizures, the new classification broadly divides seizures into two major varieties: partial and generalized seizures. PARTIAL SEIZURES A seizure is considered partial if it involves a limited or restricted amount of cerebral cortex. A partial seizure is confined or localized to a relatively discrete focus (hence the terms “local” or “focal” seizures). The remainder of the cortex is not involved in the excessive, synchronized electrical neuronal discharging (Fig 1). The clinical expression of a partial seizure depends on the area of the brain in which the excessive neuronal discharges arise. For example, partial seizures involving the motor strip will likely give rise to a disturbance in movement (clonic jerking, shaking, posturing, etc.). Partial seizures arising in the occipital lobe will likely provoke visual hallucinations or disturbances. Simple partial seizures are those in which there is no disturbance of consciousness. Simple partial seizures remain sufficiently contained or confined so as not to interfere with memory, consciousness, awareness, or responsiveness. CompZe)c partial seizures are focal seizures that do impair consciousness. This often (but not always) occurs after the localized seizure spatially involves parts of both hemispheres and disrupts the cortical networks that collectively subserve consciousness.‘2 The most common site of origin of complex partial seizures is the temporal lobe. However, since a complex partial seizure may arise from any lobe of the brain, the terms “temporal lobe seizure,” “limbic seizure,” and “psychomotor seizure” have been abandoned in favor of the more generic term “complex partial seizure.” The new classification of seizures also recognizes the existence of a possible evolution through different seizure types. Consider the following scenario as an example: Patient: “Sometimes I have an odd feeling-it starts in my belly and rises up to my throat. It’s hard to describe. I don’t know what will happen next. Sometimes they fizzle out. Sometimes I just “lose it” and pass out. Witness of seizure: “When he gets that way, he has a funny far-away look in his eyes. He doesn’t answer me if I speak to him. He’ll fumble with his pencil or whatever is in his hand and keeps swallowing hard. They usually end at that point but twice I saw him have a hard convulsion at the end.” Physician’s analysis: The patient is describing a warning or “aura.” The aura itself is a simple partial seizure (the patient retains consciousness, remembers the experience and can recall its content). The termination of the Cur-r Probl Pediatr,

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Simple Partial Seizure B

Complex Partial Seizure C

Petit Mal Seizure D

Grand Mal Seizure 144

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FIG 1. A, simple partial seizure, confined to the left motor strip. During the seizure, there is a limited EEG disturbance with localized spikes and postictal slowing in the left central region. The patient is aware of the attack and maintains consciousness during clonic jerking that involves the right hand and arm. B, complex partial seizure, confined to the left frontal and temporal brain regions. During the seizure, there is a limited EEG disturbance with localized spikes and postictal slowing in the left frontal-temporal EEG leads. The patient loses consciousness and awareness and shows forced deviation of the head and eyes to the right. C, petit mal seizure. This submaximal generalized nonconvulsive seizure simultaneously involves all regions of both hemispheres. During the seizure, bilateral synchronous and symmetric 3/set spike-wave discharges occur. The patient loses awareness and appears undirected. Purposeful activity stops and a spoon falls from the victim’s hand. D, grand mal seizure. This maximal generalized convulsive seizure simultaneously involves all regions of both hemispheres. During the initial tonic phase of the seizure, widespread bilateral repetitive spiking occurs. The clonic phase of the clinical seizure begins as slow waves interrupt the train of spikes.

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aura marks the end of the simple partial seizure. After the simple partial seizure enlarges it evolves into a complex partial seizure and the patient suffers an impairment of consciousness and mentally “loses it.” In the disturbed clouded consciousness of the complex partial seizure, pointless semiautomatic behavior surfaces.13 Further evolution can occur if the complex partial seizure spreads maximally and ultimately involves both hemispheres and culminates in a generalized tonic-clonic seizure. In this example,

the patient’s attack evolved from a simple partial seizure to a complex partial seizure and ultimately to a generalized tonic-clonic seizure. GENERALIZED SEIZURES The newly revised classification

of seizures defines a primary generalized seizure as one in whichporn the onset the clinical and EEG manifestations indicate simultaneous, widespread, bilateral epileptic neuronal discharges (see Fig 1). The whole cerebral cortex behaves in a volatile, hyperexcitable fashion. The clinical manifestations of generalized seizures reflect their diffuse bilateral appearance on the brain surface: (1) consciousness may be lost from the onset, and (2) if motor manifestations occur, they arise bilaterally and reasonably symmetrically. The intensity or penetration of the synchronous bihemispheric discharges can be maximal and generate the full fury of the tonic-clonic seizure or submaximal and give rise to incomplete clinical expressions of generalized seizures in the forms of lesser motor or mental impairments such as myoclonic or absence generalized seizureI originates seizures. In contrast, a secondarily as a focal seizure or as a milder form of a generalized seizure which builds and culminates in the complete generalized tonic-clonic seizure. Generalized seizures may also be classified as convulsive or nonconvulsive seizures. The term “convulsion” implies forceful involuntary contractions of the voluntary musculature. The familiar grand mal seizure is the prototype of the convulsive generalized seizure. On the other hand, an absence attack, representing a simple petit mal seizure, lacks forceful muscle contractions; it is a nonconvulsive generalized seizure. Clinicians also distinguish between generalized seizures that have a genetic or idiopathic basis (“primary” epilepsy) and those that have a definable tangible etiologv such as perinatal brain damage, tuberous sclerosis, or brain tumor (“secondary” epi-

lepsy). Relationship Much

curred

progress

Seizure

in the basic

Type and nerve

in the past 15 years. There

fundamental 146

Between

pathophysiology

Choice

of Drugs

of epilepsy has ocare important differences in the

of focal

cell biology

and generalized

seizures.

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The 1987

disturbed synaptic potentials, membrane behavior, and neuronal events responsible for the excessive uncontrolled firing of cortical neurons differ between focal and generalized seizures.15 Generalized seizures are not simply a more extensive version of an abnormal process that is spatially contained in partial seizures;l’ they are inherently different kinds of abnormal electrophysiologic events. The response of partial and generalized seizures to anticonvulsant drugs may vary widely. The correct classification of the epileptic seizure allows the clinician to chose drugs that are best tailored to the patient’s needs and are most likely to offer maximal protection against seizure recurrences .I7 EEG in Patients

With

Suspected

Epileptic

Seizures

The EEG is the most commonly used objective test to supplement the history and physical examination of the patient with suspected seizures. The basis of the test is the recording of the summated extracellular electrical potentials which, when recorded from the scalp surface, arise solely from the cerebral corte)c. Surface EEG records do not directly measure electrical activity originating from “deep” structures such as the thalami, basal ganglia, or midbrain. Since epileptic seizures are founded on the repetitive, excessive uncontrolled firing of cortical neurons, the EEG is ideally suited to evaluate patients with suspected epilepsy. In patients with de$nite epilepsy, interictal EEGs may be normal or may reveal specific or nonspecific abnormalities. Nonspecific EEG abnormalities include excessive focal or diffuse slowing or disorganization of the back: ground cerebral electrical activity. These nonspecific EEG abnormalities may also occur in nonepileptic individuals and do not substantially support or refute the clinical suspicion of epilepsy. The value of the routine EEG examination is the recognition of the specific distinctive signature of the epileptic process-spikes and sharp waves. The EEG “spike” appears as an extremely rapid voltage surge of a population of neurons in the cerebral cortex (Fig 2). This arises from unstable neuronal depolarizations and abrupt synchronized discharges of the “epileptic neuronal pools.” The surface EEG “spike or sharp wave” (fast transients) thus represents the distinctive electrographic expression of the epileptic process. It is important to distinguish between ictal (during the seizure) and interictal (between seizures) EEG recordings. By their nature, seizures are episodic disturbances. Routine EEGs obtained in clinical practice are usually recorded between seizures, and only occasionally and by accident will the patient actually have a seizure while the scheduled 40-minute test is in progress. Thus, for the vast majority of patients with epilepsy, EEGs are recorded interictally and Cum Probl Pediatr,

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T3-F7 F7-FPl FPkFP2

FIG 2. Spikes and sharp waves (arrows) are the distinctive interictal EEG sign of epilepsy. Their presence signifies that some cortical neurons are unstable and prone to rapid spontaneous synchronized depolarization.

the test does not absolutely confirm the clinical suspicion of epilepsy. Sensitivity

and Specificity

(by recording

an actual seizure)

of the EEG in Epilepsy

SENSITIVITY Because of the large sampling error that is involved with the random scheduling and recording of routine EEGs, it is not uncommon or surprising to record normal or nonspecifically abnormal tracings in patients with an unequivocal clinical diagnosis of epileptic seizures. In fact, the first EEG recorded in patients with an undisputed clinical diagnosis of epilepsy will be “positive” (that is, display distinctive epileptiform activity such as spikes or sharp waves) in only slightly more than half of cases.18 Even if several EEGs are obtained to increase the chances of capturing the specific signature of epilepsy, it is possible that all or most of a patient’s routine interictal recordings will remain normal or nonspecifically abnormal. Therefore, to enhance the yield of the routine EEG, the clinician may consider a variety of provocative maneuversl’: 1. Repeat the EEG (obtain serial tracings). The longer the patient is studied, the greater the opportunity of discovering by chance specific and useful information. 2. Record the EEG as soon as possible after a clinical seizure. There is a greater likelihood of obtaining an “epileptically positive” EEG in the first 7 days after a seizure than beyond the seventh day. 3. Try to tailor the EEG to the patient’s individual circumstances. For example, if the patient’s habitual seizures occur in the early morning, schedule the EEG for an early part of the day. 148

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4. Record the EEG during wakefulness and sleep. Sometimes epileptic EEG activity will be confined to sleep or to the transition period between wakefulness and sleep. There is no substantial difference in the yield of “epileptiform activity” in EEGs recorded during natural sleep and those recorded during sleep induced by hypnotic agents such as chloral hydrate. 5. In children older than 10-12 years, sleep deprivation per se can be provocative and sufficiently stress the child to encourage the appearance of definite EEG epileptiform activity.. 6. In the vast majority of cases, the consumption of anticonvulsant medication does not materially influence the rate of interictal “positive” EEGs. There are exceptions, which will be discussed later. Thus, it is usually not necessary or advisable to withhold the patient’s medications prior to an EEG examination. SPECIFICITY OF EPILEPTIFORM EEG ACTIVITY Many physicians are surprised to learn that in a small percentage of healthy nonepileptic children and adults, definite epileptiform activity can be recorded on routine EEGs. It is estimated that 2%-3% of healthy children will display the findings of definite spikes or sharp waves on routine recordings.1s’20 These epileptiform abnormalities might have been discovered by accident when the child volunteered as a healthy control subject in an EEG population study or underwent the EEG as part of an evaluation for an unrelated problem such as a behavioral disturbance or headache. The significance of these unexpected epileptiform abnormalities is not entirely clear. They often represent an inherited or sporadic EEG trait that does not correlate with an enhanced risk of clinical seiabnormalities can also arise in the zures .21-23Transient epileptiform context of some medical illness which predispose to seizures, such as uremia, hypocalcemia, or withdrawal from ethanol or benzodiazepine drugs .24 THE ROLE OF EEG IN EPILEPSY The diagnosis of epilepsy is a clinical one. If the clinician has not heard a convincing story indicating that the patient’s abnormal attacks are epileptic in nature, it is probably wisest not to let the EEG decide the diagnosis. After all, patients with definite epilepsy only have a 50% incidence of definite epileptiform EEG abnormalities in their first EEG. Conversely, 2%-3% of nonepileptic children will display an incidental epileptiform EEG abnormality that has no bearing on the complaint for which the test was performed. For these reasons a routine interictal EEG can only help support or refute the clinical diagnosis of suspected seizures. It should not be the sole basis for the diagnosis (Table 1). The diagnosis of epilepsy can be unequivocally confirmed by an Curr Probl Pediatr,

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TABLE

1.

Role of EEG in Evaluating

Patients With

Seizures

Help support or refute the clinical diagnosis of epilepsy Distinguish between focal onset and generalized seizures Classify the type of seizure disorder Recognize certain clinical-EEG syndromes Suggest drug therapy of choice Formulate a neurologic prognosis

EEG only if the suspicious behavior in question happens to occur while the test is in progress and the EEG shows an electrographic seizure. This is a relatively rare event during randomly scheduled EEG recordings and does not occur in the overwhelming majority of patients in whom seizure disorders are successfully and accurately diagnosed and managed. If the routine interictal EEG does not unequivocally establish a diagnosis of epilepsy, what good is it? The principal value of the test is to reveal the mechanism of the seizure disorder by determining the spatial distribution of the epileptifon-n activity (see Fig 1). The key question is often whether the seizures represent a generalized or focal mechanism of epilepsy. Since this information may not be reliably established clinically, the EEG is ideally suited to disclose this vital information and does materially influence the choice of an anticonvulsant drug. By revealing to the clinician the mechanism of interictal epileptiform activity, the EEG allows a more rational choice of anticonvulsants to be made. One of the best examples of this is the seizure which features an “absence’‘-a temporary interruption. of mental processes. The patient appears blank, “dreaming or staring” and unresponsive. In this clouded mental state, purposeless semicoordinated behavior (automatism4 may surface. If the patient’s EEG shows “generalized three-per-second regular spike-slow wave discharges” (Fig 3) the diagnosis is classic petit mal epilepsy and appropriate medication, including ethosuximide and valproate, may be prescribed, with a good chance of success. Alternatively, if the EEG reveals a “temporal lobe focus” or an actual temporal lobe seizure (Fig 41, the first-line choice of treatment would include carbamaze. pine. Information from the EEG can be exploited to interpret more comprehensive aspects oft the patient’s seizure disorder. There are a number of epilepsy syndromes (for example, petit mal, rolandic, and benign occipital epilepsy, infantile spasms with hypsarrhythmia, and Lennox-Gastaut syndrome) which can be established by integrating the clinical and EEG findings. Recognition of such specific epilepsy syndromes is helpful to understand the patient’s prognosis for seih 150

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FIG 3. lctal EEG during a classic petit mal seizure. The tracing was recorded during hyperventilation in a 4-year-old child with attacks of unresponsive staring. At the onset of the seizure (arrows) both hemispheres show a dramatic change with the appearance of regular spike-slow wave discharges which repeat at a rate of 3/set.

F7-T3

FP2 - F8w F8 - T4d ,Is15o)lv

T4 - T6~ T6 -020 Y

I

FIG 4. lctal EEG during a complex partial seizure of temporal lobe onset. Repetitive spiking (aris confined to the left temporal lobe and replaces the normal cerebral electrical patterns there.

rows)

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zure control, the risk of associated mental ence of possible genetic influences.

retardation,

and the pres-

NEW ANTICONVULSANTS Major advances in the treatment of epilepsy have awaited the discovery and development of new and better antiepileptic agents.25 Although in Biblical times it was recognized that fasting might transiently lessen the severity of seizures, it was not until the second half of the 19th century that a pharmacologic agent with specific antiepileptic effects became available. Sir Charles Locockz6 administered potassium bromide to his epileptic patients in the belief that it would lessen their masturbation-according to the prevailing notions of his day, the major cause of seizures. The remarkable success of bromides paved the way for the subsequent synthesis of phenobarbital in 1912, phenytoin in 1938, and the eventual introduction of trimethadione in the 1940s ethosuximide in the 195Os, carbamazepine in the 1960s and valproate in the 1970s. Just as epilepsy is not a homogeneous condition with uniform etiologv, pathogenesis, outcome, and clinical expression, so too the treatment of its various seizure types is not uniform. The therapeutic stockpile of the physician is made up of families of anticonvulsant drugs in which members of the same group are largely focused on the control of specific types of seizures (Table 2). The chemical and pharmacologic differences of the various families provide alternative methods of attacking different seizure types. Anticonvulsants with unique chemical structures are especially welcome since they provide a new twist or fresh approach to attack the old problem of epilepsy. In this vein, both carbamazepine and valproate are chemically novel anticonvulsant drugs and furnish a different pharmacologic perspective in symptomatically subduing the epileptic seizure. CARBAMAZEPINE

Background Carbamazepine is a dibenzazepine derivative, a structural congener of the tricyclic antidepressant imipramine (Fig 5). It was originally introduced in Europe in 1962 for use as an anticonvulsant. In 1968 the U.S. Food and Drug Administration permitted marketing of the drug (proprietary name: Tegretol) for relief of pain due to trigeminal neuralgia. Carbamazepine was approved for the treatment of epilepsy in adults in 1974, and for children aged 6 years and older in 1979. Carbamazepine has been widely embraced by neurologists and epileptologists as a drug of first choice for many seizure types. 152

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TABLE

2.

Families

of Anticonvulsant

Drugs

FAMILY

GENERIC

Barbiturate

Phenobarbital Methylphenobatbital Primidone Phenytoin Methoin (mephenytoin) Ethotoin Phenacimide Carbamazepine Ethosuximide Phensuximide Methsuximide Trimethadione Paramethadione Diazepam Nitrazepam Clonazepam Clorazepate Lorazepam Valproic acid Divalproex sodium

Hydantoin

Dibenzazepine Succinimides

Oxazolidinediones Benzodiazepine

Valproate

NAMES

TRADE

NAMES

Luminal Mebaral Mysoline Dilantin Mesantoin Peganone Phenurone Tegretol Zarontin Milantin Celontin Tridione Paradione Valium Mogadon Clonopin Tranzene Ativan Depakene Depakote

MISCELLANEOUS

Triple bromides ACTH/corticosteroids’72 Chloral hydrate’73 Acetazozamide174 Paraldehyde Imipramine’13

Whereas some physicians initially reserved carbamazepine for use in cases refractory to conventional drugs (such as phenobarbital and phenytoin), most who have acquired experience with it now prescribe it as the initial treatment for many types of seizures. Early fear of an unacceptable risk of hematologic toxicity was unfounded and greatly exaggerated. The medical and neurologic communities have just recently begun to acknowledge and confront the problems generated by the chronic consumption of anticonvulsants. Physicians have developed an alertness and sensitivity to the subtle systemic, neurologic, and cognitive side effects imposed by chronic anticonvulsant drug consumption. Drug therapy can become an important (and remediable) obstacle to the full realization of personal development and fulfillment in the epileptic child and adult. Because of carbamazepine’s safety, effectiveness, freedom from physical side effects, and comparative lack of neurologic, cognitive or mood disturbances it has enCum Probl Pediatr,

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I

CONH2 FIG 5. Chemical structure of carbamazepine.

joyed a rapid acceptance and enthusiastic following among neurologists and those specializing in the treatment of epilepsy. Before physicians change their prescribing patterns and expand their working selection of anticonvulsants beyond the standard ones such as phenytoin and phenobarbital, they must first establish a sufficient level of confidence in, comfort with, and understanding of the new agents. Since there is growing public awareness and concern regarding the chronic use of any drug in children, particularly drugs that may affect brain function, physicians must be well informed and accept their responsibility to provide the drug treatment that allows the best seizure control and a clear sharp mind. Mechanism

of Action

The precise mechanism by which any of the anticonvulsant drugs stop seizures is not known with certainty. Since the term, “epilepsy” embraces a heterogeneous collection of seizure disorders, it is surely true that more than one type of functional disturbance underlies the epileptic brain’s tendency toward an abnormal, uncontrolled, excessive synchronized firing of neurons. Simplistically, a seizure might arise from intrinsic neuronal instability or extrinsic excessive excitation and/or inadequate inhibition. Antiepileptic drugs may control seizures by restoring membrane stability, or a “normal balance” between extrinsic excitation and inhibition. Carbamazepine may dampen unusual excitation by diminishing the conduction of sodium ions (Na+) across the nerve cell membrane, reducing the intracellular level of the cyclic nucleotide CAMP and elevating brain levels of serotonin. Inhibition may be encouraged by retarding the turnover of the inhibitory neurotransmitter y-aminobutyric acid (GABA).27J28 It is not known which of these disparate effects, if any, are responsible for the clinically observable seizure contr01.2g 154

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Indications

for

GENERALIZED

Use of Carbamazepine

SEIZURES

Seizures.-Carbamazepine is a drug of first choice for general tonic-clonic seizures (the traditional major motor or grand mal seizure). Its*effectiveness is equal to that of phenytoin and phenobarbita13’ However, because of the cosmetic, sedative, or behavior-altering properties of phenobarbital and phenytoin, they are considered secondary choices for many patients with grand mal seizures .31 Carbamazepine is effective for both primary and secondarily generalized tonic-clonic seizures. Primary generalized seizures imply that from the onset, the ictus begins as a tonic-clonic seizure; it does not evolve from a preceding lesser seizure. Primary tonic-clonic seizures are much less common than previously believed.32 Generalized tonic-clonic seizures that are genetically inherited or result from drug or alcohol withdrawal are examples of primary generalized seizures. Most generalized tonic-clonic seizures begin as other seizure types and gradually build in intensity, evolving into the major motor seizure. Thus, careful history taking or the clinical observation of seizures, sometimes supplemented by video-EEG monitoring, may reveal that the attack actually started as a clonic seizure then blossomed and culminated in a grand mal attack. Similarly, generalized absence seizures (petit mal seizures) could commence as a blank stare with repetitive eye blinking and climax as a generalized tonicclonic seizure. Secondarily generalized seizures begin as focal seizures (perhaps arising from a relatively “silent” cortical area such as the right frontal lobe). Indeed, the effectiveness of both carbamazepine and phenytoin in treating generalized seizures may reside in the fact that both drugs are very effective for partial seizures, and many grand mal seizures actually represent secondary generalization from lesser types of seizures. Some patients with generalized tonic-clonic seizures may be unresponsive to monotherapy treatment with carbamazepine or phenytoin alone. Fortunately, carbamazepine and phenytoin may be administered together, and the combination produces seizure control which is superior to that achieved with either agent by itself.33 Tonic-Clonic

Myoclonic Seizures.Carbamazepine has been reported to exert a favorable effect on some myoclonic seizures.34 It is not, however, a first-line drug for such* seizures. 7’ypes of Generalized

Seizures.-AssENcE.-Carbamazepine appears to offer little or no help in controlling the generalized sence (classic petit mal) seizure.

ab-

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Other

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FEBRILE sEizuREs.-Phenobarbital is the mainstay of treatment for simple febrile seizures when the decision has been made that it is appropriate to treat an affected child. Yet some children do not respond to phenobarbital alone. In the case of phenobarbital failure, carbamazepine does not help in reducing the risk of future recurrences .35r36

-In general, carbamazepine has not been helpful in either reducing the number of clinical attacks or modifying the EEG hypsarrhythmia in patients with infantile spasms. Although there are occasional reports of the effectiveness of carbamazepine given empirically for the treatment of infantile spasms after conventional drug therapy (ACTH or prednisone) failed, such sporadic success does not warrant its widespread use as a first-line drug. INFANTILESPASMS.

SYNDROME.-This epilepsy syndrome represents a multifaceted neurologic disorder featuring: (1) A variety of clinical seizure types, some of which are unique to the Lennox-Gastaut synseizure types (for example, drome. Patients may have “standard” generalized tonic-clonic seizures, simple or complex partial seizures) but also display distinctive seizures that are uncommon outside the circle of the Lennox-Gastaut syndrome. Atonic seizures (an abrupt loss of postural tone) and pure tonic seizures (a sudden increase in muscle tone which obliges a rapid distortion of posture) are examples of these unique seizure types. “Atypical” absence seizures may also occur. Compared to typical or classic petit mal absence, atypical absence is more gradual in its onset and offset and may feature more prominent motor manifestations such as loss of tone or myoclonic jerking. As a result the patient drifts into and out of unresponsiveness rather than showing the crisp “switching on and off” of consciousness in classic petit mal seizures. (2) Patients with Lennox-Gastaut syndrome have a high incidence of structural brain pathology, often the result of identifiable injuries such as birth asphyxia, trauma, or meningitis. There is consequently a high incidence of mental retardation and physical signs such as cerebral palsy, blindness, or microcephaly. (3) The EEG may show “slow spike whose repetition rate (l-2% Hz) is visibly and wave complexes” slower than ~-HZ discharges of classic petit mal epilepsy. The interictal EEG background is also excessively disorganized and shows focal, multifocal or dilfuse slowing. It is obvious that the Lennox-Gastaut syndrome embraces a complex and heterogeneous collection of patients with seizures of different etiologies and types, different EEG findings, and different associated neurologic disabilities. The treatment of seizures in this group is frequently frustrating and disappointing. Anticonvulsant regimens need to be tailored to the individual needs of the patient. Thus, if LENNOX-GASTAUT

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the patient’s principal attack is simple partial, complex partial or generalized tonic-clonic seizure, carbamazepine may work well. However, the brunt of the incapacitating seizures in this group may be the so-called minor motor seizures (a collective term for the unusual array of distinctive Lennox-Gastaut syndrome seizure types such as the atypical absence or atonic seizure), and few drugs, including carbamazepine, are consistently helpful for these. In combination, carbamazepine and valproate may control seizures in about one third of patients with mixed seizure types in the LennoxGastaut syndrome .37 PARTIAL SEIZURES Carbamazepine is the drug of first choice for simple and complex partial seizures. It is as effective as phenytoin in reducing or eliminating seizures that are local in origin, whether or not they proceed to secondary generalization. Because these two first-line drugs are so comparable in efficacy, the actual choice of the specific agent is usually determined by other considerations.38 As the chosen anticonvulsant will be administered for a minimum of 2 to 4 years and possibly for a lifetime, great attention must be paid to subtle side effects that may insidiously accumulate. The threat of phenytoin’s unwanted physical, cosmetic, and cognitive side effects has largely prompted the surge of enthusiasm for carbamazepine, which is better tolerated by many patients.17

Use of Carbamazepine in the General Epileptic Population Epilepsy is a broad diagnostic term that embraces many different clinical seizure types. Since generalized convulsive seizures (whether primary or secondarily generalized) and partial seizures (simple or complex) collectively account for three fourths of seizure disorders, it is clear that a majority of epileptics are candidates for treatment with carbamazepine. AGE GROUPS APPROVED BY THE FDA The use of carbamazepine was approved for the treatment of seizures in a stepwise fashion. First it was officially sanctioned only for adults, then for children aged 6 years and older. This will probably soon be officially expanded to adults and children aged 2 years of age and older. Although not officially sanctioned for use in infants and young children, carbamazepine has been in actual clinical use for years, and there are no known specific contraindications to its use in children .3M1 Indeed, the success of carbamazepine in the treatment of focal seizures may be especially good in very young patients.40 CarCurr Probl Pediatr,

March 1987

lS7

bamazepine has been used successfully in newborn infants as well.42 It is desirable to use a drug such as carbamazepine in infants and young children in whom the sedative, behavioral, and cognitive drawbacks of standard drugs such as phenobarbital and phenytoin may be especially unwanted. Pharmacologic

Properties

of Carbamazepine

FORMULATION

Carbamazepine is formulated as a scored ZOO-mg tablet and a scored (chewable) 100-mg tablet. Dosage increments of 50 mg, 100 mg, 150 mg, or 200 mg are thus possible. Although there are no commercially available suspensions in the United States, some individual pharmacies will custom prepare them.43 There is no formulation of carbamazepine for intravenous or intramuscular injection. The chemical properties of carbamazepine make it unlikely that a parenteral form will soon become available. ABSORPTION

AND

BIOAVAILABILITY

Carbamazepine is absorbed relatively slowly from the gastrointestinal (GI) tract after an oral dose.44 The half-time of absorption (length of time for one-half the administered dose to be absorbed) varies considerably among individuals, with average values ranging from 1 to 7 hours. In general, peak plasma values of carbamazepine occur between 4 and 8 hours after ingestion, but peaks as late as 2432 hours have been occasionally reported.45 The speed of absorption may be slightly modified by the formulation and diet. Carbamazepine administered as a specially prepared suspension may be absorbed faster than the commercially available tablets. The consumption of food with carbamazepine causes no delay in absorption. In fact, food may improve its absorption rate.46 Carbamazepine is incompletely bioavailable. About 85% of each consumed dose becomes biologically available. Up to 15% of a single dose may be recovered unchanged in the feces, and about 2% passes unmodified in the urine.45 DISTRIBUTION

TO THE

BODY

Once carbamazepine is absorbed into the bloodstream from the GI tract, it is rapidly and relatively uniformly distributed to the body organs and tissues, with higher concentrations in the brain, liver, and kidney.44 About 75% of circulating carbarnazepine is bound to plasma proteins. The fraction of unbound carbamazepine (that portion available for delivery to the tissues of the brain)47 is independent of the actual serum drug concentration up to 30 pg/ml.44 Incidentally, the relatively high rate of plasma protein binding makes carbamazepine removal by hemodialysis or peritoneal dialysis theoret158

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ically ineffective for treatment of serious overdose.48 In contrast, the lower fraction of protein binding in hepatic disease appears to have little clinical import. The concentration of carbamazepine in body fluids and organs parallels the plasma concentration. Differences of carbamazepine concentration in body fluids (e.g., cerebrospinal fluid, saliva, breast milk) and plasma can be attributed to differences in their protein content. Brain carbamazepine concentration also parallels plasma concentration. This is relevant since in experimental animal models of epilepsy (electroshock seizures in the rat), protection against seizures depends on brain tissue carbamazepine concentrations.45 ELIMINATION The majority of a consumed dose of carbamazepine is eliminated by biotransformation. Hepatic biotransformation of carbamazepine leads to the generation of seven distinct metabolites, of which one (carbamazepine 10,11-epoxide) possesses inherent anticonvulsant activity. These metabolites are also excreted in the urine.““ Repeated doses (chronic administration) of carbamazepine lead to a significant increase in its clearance rate. Carbamazepine is a potent metabolic inducer and quickly stimulates its own metabolism, thus increasing its metabolic clearance from the body. In the rat, carbamazepine autoinduction involves several catabolic pathways which are “turned on,” including the activity of the liver cytochrome P-450, NADPH cytochrome reductase, and N-demethylase.44 The clinical impact of carbamazepine’s self-inducing property is that its elimination half-life is longer in the first weeks of treatment and significantly decreases to a chronic shorter value thereafter. This characteristic of carbamazepine will only be important at the onset of treatment .4g CARBAMAZEPINE’S ELIMINATION HALF-LIFE (TX) Because of its ability to produce autoinduction of liver microsomal enzymes, the value of carbamazepine’s elimination half-life depends on whether it is administered as a solitary dose or as repetitive doses in the context of chronic drug treatment. healthy individuals who have been adminSingle dose- Tl/z.-In istered a solitary dose of carbamazepine, the elimination half-life varies from 18 to 55 hours. A typical value is 36 hours.44 In individuals consuming onZy carbamazepine, the first effects of autoinduction may arise as early as 2-4 days. The full and constant expression of autoinduction may require 20-30 days. In epileptic patients whose liver microsomal enzymes may already be “turned on” by other antiepileptic drugs, shorter periods might be anticipated for a plateau of autoinduction. Because Repetitive

Doses-l?&--

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159

of autoinduction, the elimination half-life may fall from an initial higher value to a chronic lower value. In adults, chronic carbamazephe administration typically produces TX values in the range of 10-25 hours. In children, chronic carbamazepine administration produces a half-life in the range of 7-20 hours.44J4g For practical purposes a T1/ value of 12 hours is often cited. Given this approximate value, the expected time to produce steady-state blood levels with chronic carbamazepine administration is at least 3-6 days. RELATIONSHIP LEVEL

BETWEEN

CARBAMAZEPINE

DOSE AND

DRUG

The “ideal” dose of any anticonvulsant drug is the smallest amount of medication that satisfactorily controls the patient’s seizures and yet does not precipitate dose-related drug side effects. In practice most physicians begin with a small introductory dose and gradually escalate the amount until seizures abate or intolerable side effects intervene. Although the ideal dose of an antiepileptic drug will vary among individuals, a few general guidelines

applyOlder Adolescents and Adults.-” typical total carbamazepine dose of 1,000 mg/day will be comfortably tolerated by most adolescents or adults. If it is necessary to further increase the dose, increments of 100 mg, introduced not more often than every 4 days, may be given. Total daily dosages of 1,400 mg are not uncommon, and some individuals may tolerate even higher amounts. Children. -A typical total carbamazepine dose for children is lo20 mg/kg/day. This, however, is not the starting dose, ‘Dosages in excess of 30 mg/kg/day increase the risk of overmedication in many children. Obviously a heavy youngster would not be given a total daily dose larger than the usual adult guidelines just defined (i.e., 1,000-1,400 mgday). EXAMPLE: CHOOSING CAHBAMAZEPINE

AND

INITIATING

TREATMENT

WITH

History

.

The patient is a 7%year-old, %-pound boy with a previous history of Hemophilus infruenzae meningitis at age 3 years which resulted in a borderline IQ and a mild right hemiparesis. The parents have witnessed

three episodes of abrupt unresponsive mild muscular mouth. 160

twitching

around

staring, cessation of speech, and

the right

eye and the right

corner

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of the

March 1987

Clinician’s

Analysis

Question 1: What is responsible for this patient’s attacks? Decision 2: A clinical diagnosis of an epileptic mechanism (complex partial seizures featuring an alteration of consciousness with clonic motor activity) would best fit the context of the history and the description of the attack. These episodes simply do not resemble syncope, behavioral tantrums, or other paroxysmal events that are sometimes mistaken for epilepsy. Since the patient had had three stereotyped events, they are repetitive and not isolated or solitary seizures. The patient should rightfully receive the clinical diagnosis of “epilepsy,” reflecting the presumed nature and recurrence of the seizures. A clinical decision is then made to start the patient on an anticonvulsant medication. Question 2: What is the mechanism of this patient’s seizures? clinical characteristic of this patient’s seizures Decision 2: The fundamental is loss of consciousness. This could represent either a complex partial seizure or a generalized (petit mal) seizure. However, the presence of definite focal clonic twitching of the right facial musculature strongly argues against the diagnosis of classic petit mal seizure. An EEG performed during wakefulness and sleep recorded spikes in the left anterior temporal lobe. The EEG thus supported the clinical diagnosis of epilepsy and further corroborated the impression that the seizures were of partial origin, probably arising from a “temporal lobe focus.” Question 3: Now that the clinical decision to begin treatment with an antiepileptic drug has been made, what are the therapeutic options currently available? Decision 3: Barbiturates and phenytoin are the traditional mainstays of treating childhood seizures. However, phenobarbital, methylphenobarbital, and primidone are sedating and may introduce important long-term behavioral and cognitive side effects which could encumber the patient. The chronic consumption of phenytoin introduces cosmetic and physical side effects and also has measurable mental and cognitive side effects. After discussing the therapeutic options with the parents, the physician decides to start a trial of carbamazepine monotherapy. Question 4: How should carbamazepine treatment be initiated? STEP 1: CHOICE

OF TOTAL

DAILY

DOSE

The target total daily dose for maintenance treatment is approximately 20 mgkg. The patient weighs 55 pounds (25 kg). A total daily dose of about 500 mg will be reasonable, Comment.-The patient had consumed no prior drugs, so hepatic metabolic enzymes are not yet induced or “turned on.” The initial drug elimination half-life will be significantly longer than that which will ultimately result 2-4 weeks into therapy after autoinduction has peaked. Starting the

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full dose of 500 mg from the beginning and early signs of overmedication. STEP 2: DIVIDING

THE TOTAL

would

DAILY

probably

produce

intolerance

DOSE

First Week.-The initial dose should be 5-10 mg/kg and given after dinner (250 mg for the patient in the example). Although this is a small introduc-

tory dose, carbamazepine’s initial long half-life permits fair blood levels to develop quickly. Peak blood levels will not occur until approximately 5 or more hours after dinner so the child may be near bedtime or asleep when this occurs. Taking the dose with meals may reduce the risk of local gastric irritation but does not substantially alter the speed or bioavailability of the drug. Second

Week.-A

to the dinnertime

dose of 5 mgkg dose of 10 mgkg.

is introduced

at breakfast

in addition

Third Week.-The dosage is escalated to 5 mg/kg at breakfast and lunch and 10 mg/kg at bedtime. At this point autoinduction effects are stable and maximal. A representative total daily dose of 20 mg/kg is given, divided into three separate doses taken with meals. The largest dose is given closest to bedtime. serves as a general example of chasing a dose and gradComment .-This ually implementing it. This outline does not suit all patients and clinical situations. Doses may be increased every 2-4 days rather than weekly. If seizure control is established at a low dose, there may be no need to increase the dose.

BLOOD

LEVELS

There is a general correlation between the administered dose of carbamazepine and the steady-state blood level ultimately achieved. Although the correlation between dose and blood level is statistically significant, there is no mathematical formula that reliably predicts blood levels on the basis of dose size for body weight in individual patients. Large individual metabolic differences produce scattered values of serum drug levels at any given mg/kg dosage. It is a generally true clinical experience that for many individuals seizure control depends on the anticonvulsant’s blood level. A low drug dose (and low blood level) may achieve some success in reducing seizures, but a medium or higher dose might be required for further or complete reduction of seizures. Conversely, seizure control may worsen if the drug dose and level fall below a critical threshold. Unwanted dose-dependent drug side effects may also appear or worsen with escalating drug dosages in parallel with seizure control. The routine clinical availability of laboratory anticonvulsant measurements has led to the concept of the therapeutic range of serum drug levels. The measurement of drug levels is never a sub162

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Pediatr,

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1987

stitute for sound and experienced clinical judgment but rather furnishes the clinician with some objective landmarks to help assess the patient’s drug status. Drug levels are therapeutic guidelines, not legal barriers that must be strictly or blindly obeyed.5*52 LOWER

THERAPEUTIC

‘RANGE

The lower therapeutic level of an anticonvulsant indicates the minimum drug level that many, but not all, patients require to achieve some seizure control. Thus, if a patient consumes a typical daily maintanence dose of a drug but seizures persist, measurement of a serum level that falls below the recommended lower limit may explain the poor seizure control. Some fortunate patients may achieve total seizure control at a maintenance drug dose that produces blood levels below the usual therapeutic range. Treat the patient and not the blood level. EXAMPLES E,xample A

A d-year-old

child had five focal seizures over a 3-week period while awake. The attacks produced a peculiar sensory alteration on the tongue (“it feels like a bunch of grapes on my tongue”) followed by 2 minutes of twitching of the right facial musculature. One year previously a solitary nocturnal generalized seizure had occurred. Her examination was normal and her EEG showed a well-defined right sylvian focus. The family history was positive for seizures in an older brother and the patient’s father. A clinical diagnosis of benign rolandic epilepsy was made. It was decided that a CT scan was not obligatory. Carbamazepine monotherapy was begun. After 1 week of treatment with carbamazepine (10 mg/kg/day), two more seizures occurred. The total daily dose was increased to 15 mg/kg/day. No further seizures occurred. A steady-state determination of serum drug level yielded a carbamazepine level of 5 ~.l,g/cc. Since the patient required only 15 mgday for clinical seizure control the dose was not increased.

E:ample

B

A l&year-old girl had infrequent daytime generalized seizures that recurred about every 5 months. After the first seizure she was started on phenobarbital at a local emergency room. The infrequent seizures continued despite escalating doses and blood levels of phenobarbital, which eventually resulted in obvious sedation and declining school performance. The decision was made to switch to carbamazepine. An initial dosage of 10 mg/kg/day was given. Because the mother had heard that carbamazepine was usually reserved for difficult cases and was “high potency,” she resisted further increases in the dose. After all, her child was not having any immediate seizures. At that time the serum drug level showed a subtherapeutic value of 3.8 pg/cc. Because the infrequency of the clinical seizures made it diffiCur-r Probl Pediatr,

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163

cult to titrate clinical seizure response against the administered carbamazepine dose, the physician recommended that the dose be further increased so that the patient’s blood level at least fell into the minimum therapeutic range.

UPPER THERAPEUTIC RANGE The value of defining an upper therapeutic range is to identify a drug dose that may result in unwanted dose-related side effects. Some acute drug side effects are not dose dependent but represent all-or-none “idiosyncratic” reactions. Anaphylactic reactions, skin rashes and aplastic anemia are examples of dose-independent drug reactions. In general, dose-related anticonvulsant side effects appear at higher drug levels and worsen as the dose increases. The patient then commonly complains of feeling overmedicated, intoxicated, or drunken, with drowsiness, fatigue, headache, gait unsteadiness, or “fuzzy” thinking. The upper therapeutic level indicates a serum drug level at which many but not all patients may begin to experience unwanted dosedependent side effects. The upper range is a general guideline and is not an absolute therapeutic barrier. Some patients will experience side effects below the upper limit. Others experience no obvious adverse effects even after the upper limit is clearly exceeded. Knowledge of the upper therapeutic range is especially valuable for treating patients with medically refractory seizures. Patients with poor medication responses should be tried on the maximum amount of drug tolerated. Generally their measured drug levels should be near the upper end of the therapeutic range. EXAMPLES Example A A 15-year-old girl began having complex partial seizures and rare generalized seizures 3 months after a contusion caused by a head injury in a field hockey game. During a complex partial seizure she would stop speaking, appear confused and disoriented, and fumble with her hands and possessions. Although the complex partial seizures recurred as often as twice per week, she had a total of only six grand mal seizures. She was first treated with primidone, chosen by the neurosurgeon who cared for her closedhead injury. This led to a modest improvement in seizure control but she experienced notable irritability, insomnia, and poor school performance. After the neurosurgeon died of a stroke, the family sought other neurologic care. Carbamazepine was initiated slowly and increased to three daily doses. Primidone was tapered and stopped. At that time the patient first complained of diplopia and dizziness, especially a few hours after the evening dose. Even when the total dose was divided into four small doses, the

164

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side effects persisted. A blood level drawn at 5 P.M. (chosen to coincide temporally with the side effects) was only 6.2 [email protected] that blood level she had only a modest improvement in her seizure control. Comment.-This patient was unusually sensitive to carbamazepine and experienced dose-dependent CNS side effects (diplopia and dizziness) at a drug level that most individuals would be able to comfortably tolerate. An attempt was made to maintain a constant total daily dose but to reduce the amount of the individual doses. The patient bravely tolerated the situation for several months, hoping to eventually “adjust,” but this never happened. In this patient, the upper therapeutic range was significantly different from the usually cited value of 12 pg/cc. E&le B A i’-year-old boy in otherwise good health developed generalized major motor seizures 2 months before presentation. The child was thoroughly evaluated by his physician and started on phenobarbital, which did not control the seizures despite good blood levels. The child was referred to a neurologist for seizure management. Carbamazepine was prescribed and phenobarbital was continued until adequate carbamazepine levels were established. The phenobarbital was then tapered and discontinued over 6-8 weeks. At a carbamazepine drug level of 9 l.rg/cc there was an estimated 50% reduction in seizure frequency. An increase in drug dosage generated morning trough serum drug levels in the range of 11-12 pgkc. The increased dosage was accompanied by further improvement in seizure control, so that about 80% of seizures were controlled. Since the patient had no signs or symptoms of drug intoxication, another dose increase was prescribed which yielded a drug level of 14.8 I.~g/cc. Only a modest improvement in seizure control resulted from this increment and the patient was maintained at that level. Comment.-The upper therapeutic range may be exceeded if the patient enjoys additional benefits of seizure control and does not pay the price of dose-related drug side effects. It is surprising how well some individuals tolerate carbamazepine levels of 13, 14, 15, or 16 p&/cc. However, if the dose increase fails to improve seizure control, it is reasonable to return a lower drug dose. There is no reason to use more drug than is necessary to achieve a given level of seizure control. THERAPEUTIC BLOOD LEVEL RANGE OF CABBAMAZEPINE ranges” for carbamazepine are reported Many “therapeutic

in the the upper and

medical literature. Although they generally overlap, lower borders commonly differ (Fig 6) .53J54 The variance in redorted laboratory values may reflect the patients’ different ages and seizure types, or differences in methodology or the time of day the blood specimens were drawn. No reported values represent “the best range.” What is important is knowledge of the general features of the therapeutic range and clinCurr

Probl Pediatr,

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165

Lower Therapeutic Level

4

5

6

7

Blood concentration

8

9

IO

of carbamazeptne.

11

12

pgl’cc

L

FIG 6. Range of reported therapeutic values of carbamazepine. thor.

For references, contact the au-

ical experience with their interpretation. In practice, a few elementary suggestions will enhance the usefulness of blood level determinations for anticonvulsant drugs: 1. Whenever possible, use the same clinical laboratory to perform serial blood tests. Ideally the laboratory has established skill and experience in the determination of anticonvulsant blood level measurements. 2. Draw the blood sample in the early morning to measure a drug trough level. This practice is more important for medications with short half-lives, such as carbamazepine and valproate. The hour-to-hour fluctuations in the serum levels of long half-life anticonvulsants such as phenobarbital are relatively small. If it is not possible to measure serum drug levels in the early morning, a consistent time should be chosen so that trends may be more easily compared between different doses. INTERACTION BETWEEN CARBAMAZEPINE AND OTHER ANTICONVULSANTS Patients with epilepsy may consume more than one anticonvulsant medication (polytherapy or polypharmacy) for a variety of reasons. They may have refractory seizures or multiple seizure types, or they may simply have been started on two drugs for a single seizure type (a practice that is now generally discouraged).55 Drug interactions between anticonvulsants may result in changes in serum level (higher or lower) and eventually clinical response in the forms of altered seizure control, or may produce dose-related side effects. There are many avenues by which drug interactions may occur: mutual displacement from circulating protein binding sites, competition for CNS preceptor sites, changes in hepatic biotransformation 166

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due to activation of catabolic pathways, or competition for renal elimination. Table 3 describes some possible changes in drug ZeveZs between carbamazepine and other antiepileptic drugs.44, 45j4g Efiects

of Carbamazepine

on the EEG

It is an interesting observation that the administration of an antiepileptic drug does not usually restore to normal the epileptifotm patterns recorded on the interictal EEG. Anticonvulsants are intended to treat the symptoms of epilepsy by reducing or eliminating the clinical seizures. They often do not correct the underlying electrophysiologic disturbance which expresses the enhanced tendency for seizures. For most types of seizures treatment with antiepileptic drugs does not reduce the yield of “epileptiform” EEG abnormalities in the interictal tracings.18 Two major exceptions exist: petit mal seizures and infantile spasms. In these specific seizure types successful anticonvulsant therapy may stop the seizures and normalize the EEG recording. At the usual clinical dosages and levels of carbamazepine, there is no important effect on the ongoing background cerebral electrical activity. This contrasts sharply with the effects of barbiturates and benzodiazepines, which commonly introduce obvious background TABLE

3.

Interactions Antiepileptic

Between Drugs

Carbamazepine

A. Changes in Anticonvulsant Carbamazepine is Added Re&nen

and Other

Blood Levels After to the Established

ESTABLISHED DECREASED

DRUG

Phenytoin Primidone Valproic acid Clonazepam Ethosuximide

LEVEL

UNCHANGED

LEVEL

*

0 0 0 0

0 0

B. Changes in Carbamazepine Blood Levels After Addition of Other Antiepileptic Drugs DRUG

ADDED

TO

CARBAMAZEPJNE

DECREASED

Phenytoin Phenobarbital Primidone

0 0 0

Clonazepam Carbamazepine

Cur-r Probl Pediatr,

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1987

LEVEL

UNCHANGED

LEVEL

0 0 l

0

167

changes in the form of fast rhythms (beta activity). Phenytoin at therapeutic or supratherapeutic levels can produce slowing of the alpha activity or introduce generalized slowing. At standard blood levels, carbamazepine has no visible effects on the EEG. At excessive blood levels it can cause a clinical encephalopathy (lethargy, stupor, ataxia, etc.) and diffuse slowing of the brain rhythms. Although carbamazepine does not erase the interictal traces of epilepsy from the EEG, it is not altogether without effect. It may cause subtle alterations in the amplitude, morphology, and “sharpness” of epileptiform transients in partial seizures.56 In some patients with complex partial or generalized seizures a paradoxical increase in the abundance of spike wave discharges can sometimes be seen.57J58 Response of the Clinical

Seizure

Disorder

to Carbamazepine

IMPROVED SEIZURE CONTROL A reduction or complete elimination of seizures is expected in many individuals administered carbamazepine if they have been properly diagnosed and treated. If seizures respond favorably to carbamazepine, the clinician should seriously consider whether other antiepileptic drugs may be slowly tapered and withdrawn to institute monotherapy rather than continue unnecessary polyphannacy. UNCHANGED SEIZURE CONTROL If a patient exhibits absolutely no change in seizure control in response to carbamazepine, the clinician may wish to reevaluate the patient by asking the following questions: 1. Does the patient have genuine epilepsy or some other basis for the unwanted repetitive attacks? The real question is often whether the seizures are “pseudoepileptic,” “psychogenic,” or “hysterical seizures .” There are no perfect or absolute criteria to prove this suspicion. It may be helpful to refer the patient to a neurologist or a regional comprehensive epilepsy center where prolonged and intensive EEG monitoring may help clarify the diagnosis.17p5g 2. Has the patient’s genuine epilepsy been misclassified and the wrong family of antiepileptic drugs administered? In practice a common pitfall is to confuse absence attacks due to complex partial seizures with petit mal seizures. The former may respond promptly to carbamazepine; the later typically will respond to ethosuximide, valproate, clonazepam, clorazepate, and others. 3. Does the patient have a progressive or degenerative neurologic disorder as the cause of unresponsiveness to drug treatment? All patients with epilepsy deserve occasional reevaluation regarding the etiologic diagnosis, especially if seizure control is inadequate or deteriorates. * 168

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A S-year-old boy with tuberous sclerosis began having stereotypic complex partial seizures. They occurred about three times per week and were initially controlled with phenytoin alone. His initial evaluation included a CT scan which displayed only typical periventricular calcifications. After excellent seizure control for 2 years the habitual seizures returned and did not subside until carbamazepine was substituted for phenytoin. Within a year a new type of seizure surfaced and continued despite additional dose increases. Magnet resonance (MR) imaging was then performed and revealed a large frontal lobe tuber. The tuber was not visible on a simultaneously obtained CT scan. One year later the MR imaging examination was repeated and showed additional tubers scattered in other brain regions.

EXACERBATION OF SEIZURE CONTROL Anticonvulsant drugs are administered by the physician with the intention and expectation of reducing clinical seizures. Their very name (“against convulsions”) implies the anticipation of a reduced seizure abundance or, at worst, no effect at all. Nevertheless one occasionally experiences in clinical practice a patient whose seizures may paradoxically worsen when certain antiepileptic drugs are given. All major antiepileptic drugs have been reported to rarely exacerbate some kinds of seizures. Phenobarbital may worsen petit mal seizures .60 Phenytoin may cause deterioration of seizure control at standard or excessive serum drug concentrations.61~62 Valproate may, rarely, precipitate petit mal status when co-administered with clonazepam. Carbamazepine has also been associated with an unwanted rare deterioration in clinical seizure control, especially myoclonic seizures Y3164 Most affected individuals have a generalized epilepsy. The clinician should always be aware of the possibility of a paradoxical seizure exacerbation when using carbamazepine or other types of anticonvulsants. Signs

and

Treatment

of Drug

Overdose

The signs of a deliberate or accidental acute carbamazepine overdose principally reflect its fundamental tricyclic structure. Drowsiness, coma, nausea, vomiting, seizures, agitation, tremor, mydriasis, cyanosis, flushing, and cardiac arrhythmias should be anticipated.“5 Treatment of an acute overdose should incorporate the following: (1) general medical suppdrtive measures including management of airway, ventilation, cardiovascular monitoring, and thoughtful attention to electrolyte balance, nutrition, and nursing care; (2) reduction of further GI tract absorption by removing any undigested tablets by gastric lavage; and (3) the use of activated charcoal to capture any unabsorbed drug. No study has shown the efficacy of hemodialysis Curr Probl Pediatr,

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or peritoneal dialysis in removing important quantities of carbamazepine, possibly due to its protein binding. Hemoperfusion has been is excreted reported.“6 Since only a small fraction of carbamazepine unmetabolized in the urine, forced diuresis is also probably not an important detoxification route. The use of physostigmine may be cautiously considered if important cardiac arrhythmias (bradycardia) develop .48 If the patient receives adequate medical treatment and does not suffer any serious degree of ischemia or hypoxia, complete recovery is anticipated. Side Ej@cts of Carbamazepine Despite the obvious efficacy of carbamazepine as a powerful new antiepileptic drug, early enthusiasm for its widespread use was dampened by reports of serious or fatal hematologic toxicity. Indeed, in the product information section of the Physicians’ Desk Reference one is greeted by a bold warning, mandated by the FDA, describing the potential hazards of carbamazepine therapy and outlining a complicated, time-consuming, and expensive regimen of recommended blood test monitoring.“7 As will be discussed, this early concern for hematologic toxicity was greatly exaggerated. In the context of other antiepileptic drugs, carbamazepine is a safe and well-tolerated medication. The perspective of time and clinical experience has shown that serious side effects are rare and the initial alarm was unfounded. It is carbamazepine’s safety coupled with its effectiveness and its documented superior freedom from cognitive side effects that has rightly earned this drug its niche as the drug of choice for so many different seizure types. After all, anticonvulsants are consumed daily by patients with epilepsy. Epileptic children are perpetually exposed to their drug’s potential mental or cognitive side effects. It makes good clinical sense that a drug of choice should be safe, effective, and as free as possible from systemic, neurologic, behavioral, and cognitive side effects. SYSTEMIC SIDE EFFECTS anemia is recognized by the presence Aplastic Anemia. -Aplastic of pancytopenia due to markedly reduced bone marrow production of leukocytes, platelets, and red blood corpuscles. This potentially fatal disorder may arise idiopathically, in the context of systemic illnesses (e.g., malignancies or infections) or due to physical agents (e.g., radiation), chemicals (e.g., industrial use of carbon tetrachloride), and drugs. Antiepileptic drugs associated with aplastic anemia include phenytoin, primidone, and carbamazepine. The collective experience with aplastic anemia and carbamazepine administered for epilepsy or trigeminal neuralgia has been ex170

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tensively reviewed by Pisciotta.68 Until 1982, 22 cases of aplastic anemia associated with carbamazepine were reported. Ordy four of the patients were in the pediatric age group (aged 2, 5,17, and 18 years). Carbamazepine-induced aplastic anemia has caused 13 known fatalities, including two deaths in children (aged 15 and 18 years). Of all 22 patients who developed aplastic anemia, carbamazepine was considered the probable cause of the bone marrow suppression in only three. The relationship between the drug and the hematologic toxicity was blurred in the other patients, who were taking other drugs associated with aplastic anemia or who harbored systemic illnesses that could have yielded the same results. Hart and Easton6’ calculated a prevalence rate of less than ~50,000 on the basis of 20 cases of aplastic anemia in 1981 and an incidence rate of 0.5 cases per 100,000 population per year. On the basis of this information, the association between aplastic anemia and carbamazepine must be considered extremely uncommon and fatalities definitely due to carbamazepine a distinct rarity. Leukopenia (Neutropenia or Agranulocytosis).-Transient or persistent reduction in the white blood cell (WBC) count is usually a clinically innocent laboratory observation that occasionally occurs during carbamazepine treatment. It is estimated that in the first month of carbamazepine treatment, a mild transient leukopenia may develop in 10% of patients and resolve spontaneously despite continued treatment. The finding of isolated leukopenia does not presage the appearance of frank aplastic anemia.6g In s%-17% of patients on a long-term regimen of carbamazepine a persistent leukopenia may appear after the first weeks of treatment, continue as long as treatment is maintained, and completely resolve after discontinuation of the drug. There is no simple relationship known between the magnitude of isolated leukopenia and the total daily dose of carbamazepine. The leukopenia is almost always without clinical effects, although an extreme reduction in WBC count can cause an inadequate absolute neutrophil count that could expose the patient to an enhanced risk of infection. Although it has been suggested that children are less likely than adults to develop leukopenia, Silverstein et al.” and Pellock et al.‘l have reported that transient leukopenia (WBC count < 4,000/mm3) occurred in 27 of 200 (13.5%) pediatric patients and persistent leukopenia remained in 2% of the treated population. No clinical problems arose with affected children, although a clinical decision to stop treatment was made in three children. Similarly, leukopenia developed in 13 of 225 (5.8%) patients treated by Livingston et al. but reverted after treatment was terminated. Routine Hematologic Surveillance.-Confronted with these facts, how does the practicing physician reconcile the rarity of serious blood dyscrasias with the manufacturer’s recommendation for mulCum Probl Pediatr,

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171

tiple blood tests at frequent regular intervals during therapy? The annual cost of the recommended blood tests to the individual patient is enormous. In 1982, Hart and Easton6’ estimated that the collective laboratory costs of the 200,000 patients in the nation who take carbamazepine would annually exceed $3OO,OOO,OOO. Two principal issues should be considered in implementing a regimen for routine hematologic suIveillance6’: 1. What is the frequency of the abnormal condition for which the routine laboratory monitoring is being conducted? Even with fastidious blood tests it would require a generous portion of pure luck to discover any rare condition early. 2. Does medical evidence indicate a real improvement in the patient’s outcome if the abnormal condition is detected early and therapy is changed? The frequency of transient isolated leukopenia in which the WBC count declines early during carbamazepine treatment suggests that laboratory monitoring may successfully identify many cases. However, therapy is usually unnecessary since the condition is innocent and self-limited. Even persistent Zeukopenia is usually asymptomatic and rarely requires a change in dose or discontinuation of the drug. Since isolated (transient or persistent) leukopenia does not appear to evolve into aplastic anemia, there is little medical evidence to suggest that hematologic monitoring realistically changes medical management . Potentially fatal aplastic anemia does not cluster in the early months of treatment but may arise at any time in the first year of treatment or later. There are no early unique clinical or laboratory signs of this rare idiosyncratic drug reaction and no specific treatment exists. For many patients the condition is irreversible and rapidly fatal even if the offending drug is stopped. For these reasons many physicians who commonly use carbamazepine consider meticulous hematologic monitoring a futile, wasteful, and expensive practice. This opinion is reflected in the wide variations in neurologists’ actual practice. Some go strictly “by the book.” Most have adopted their own style of intermediate level of hematologic monitoring. Many do little or no hematologic monitoring. Table 4 outlines some different proposals for routine hematologic monitoring. skin rashes have occasionally been reported due to carbamazepine administration.” Mild nonspecific abnormalities such as simple erythematous rashes, photosensitivity, or pruritic reactions may not necessitate discontinuing treatment. More serious conditions such as exfoliative dermatitis, Stevens-Johnson syndrome, or any lupus-like syndrome require at least temporary cessation of treatment. A systemic hyperSkin

172

Rash

and

Hypersensitivity

Reactions.-Various

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TABLE

4.

Hematologic

Monitoring

During

Carbamazepine

Administration

CARBAMAZEPINE’S BMOD SAMPLING

MANUFACTURER: TIME

CBC/

PL~TJRETICJIR~N

X X X X X X X X X X X X X X X X X X X (every mo.)

Pretreatment Wkl wk2 wk3 wlz4 wk5 Wk6 wk7 wlz8 wk9 M/k 10 wk 11 wk12 MO. 4 MO. 5 MO. 6 MO. 7 MO. 8 MO. 9

HART

AND

EASTON6’:

CBdPL4TELETS

SILVERSTEIN

ET AL.“:

HgB, Hct, WC,

PL4T.

X X X X X

X

X (every 4 mo.)

X (every 3 mo.)

X

Year3

sensitivity reaction featuring rash, purpura, adenopathy has been reported.”

eosinophilia,

and lymph-

Hepatic Dysfunction.Hepatic toxicity may occur with any antiepileptic drug. Routine surveillance by means of liver function tests in patients administered carbamazepine reveals occasional mild elevations of SGOT, SGPT, and alkaline phosphatase unassociated with clinical signs. Mild stable elevation of liver function test values with perserved hepatic synthetic functions (albumin and blood clotting factors) does not require a change in treatment. Fatal carbamazepine hepatic toxicity has occurred but is extraordinarily rare.73t 74 Cardiac Arrhythmias.-There are rare reports of disturbances of cardiac rhythm in patients administered carbamazepine. The physician should be especially alert to the possibility of tachycardia developing if the patient has a known disturbance of cardiac rhythm or congenital or acquired heart disease.75 Gastrointestinal Intolerance. -Anorexia, weight loss, and diarrhea are occasional and usually transient GI disturbances encountered Cur-r Probl Pediatr,

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173

early during carbamazepine treatment. GI side effects may also appear after a major dosage increase. Patients usually develop full tolerance to these transient side effects. altering hypothalamic osmoreceptor function and increasing arginine-vasopressin release, carbamazepine may rarely provoke the inappropriate secretion of antidiuretic hormone (ADH). The physiologic results are the renal retention of free water and a reduction in the concentration of serum sodium. These results are clinically negligible in most adults and children. Symptoms resulting from hyponatremia may include headaches, dizziness, drowsiness, and confusion, which could be mistaken for signs of direct drug toxicity.761 77 Inappropriate

Antidiuretic

Hormone

Secretion.-By

NEUROLOGIC SIDE EFFECTS In the first several weeks of treatment dose-related neurologic side effects are mild and not unexpected. They usually fade with the passage of time (Table 5). DipZopia.-Double vision is probably carbamazepine’s most commonly observed single neurologic side effect. It results from a pharmacologic decomposition of fused binocular vision. Double vision may persist for a few minutes to a few hours. When it occurs, it tends to begin within a few hours of an administered dose. The patient usually reports horizontally separated images that are abolished by occluding either eye. Diplopia tends to occur at the onset of treatment, after major dose increases, or if the dosage is maintained at the upper end of the therapeutic range. However, some patients may complain of diplopia even at intermediate serum drug concentrations. The concomitant administration of other antiepileptic drugs, particularly phenytoin, may increase the likelihood of this drug reaction. Diplopia may be curtailed by redistributing the dosage and amounts of the drug or by reducing the total daily dose. Involuntary

occurred

Movements.-

in association TABLE

Tremor and asterixis have occasionally with carbamazepine use. In brain-damaged

5.

Common Transient Neurologic Effects of CarbamazerGne General Fatigue Drowsiness Diplopia Ataxia Slurred speech Headache

174

Dose-Related

Side

Anticholinergic Blurred vision Dryness of mouth Urinary frequency

and urgency

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1987

children (those whose seizures resulted from tangible CNS insults such as microcephaly, cerebral palsy, etc.), dystonic reactions have been reported in the early phases of treatment and gradually subside within a few weeks after discontinuation of the dr~g.‘~’ It has been speculated that carbamazepine’s property as a dopamine antagonist could be responsible for the extrapyramidal side effects. Withdrawal Seizures.-Seizures may follow the termination of any antiepileptic drug if the underlying epilepsy has remained active and the seizures have only been pharmacologically suppressed by the anticonvulsant drug. Specific withdrawal seizures (generalized seizures precipitated by the act of abruptly withdrawing a drug) may follow the discontinuation of phenobarbital, primidone, and benzodiazepines. Withdrawal seizures have not been attributed to carbamazepine termination alone.”

of Higher

of the most exciting recent concepts in the treatment of epilepsy is the recognition and confrontation of the problem of drug-induced cognitive or mental side effects.81’” Although a sizable number of efficacious drugs are available to the clinician, they are variably tolerated by patients in terms of their systemic and neurologic side effects. Physicians have taken a long time to acknowledge that part of epilepsy’s morbidity is iatrogenic in that anticonvulsants are CNS active substances that generate subtle and unwanted behavioral and cognitive side effects. Patients take antiepileptic drugs every day and are constantly exposed to potential CNS side effects. For most individuals with epilepsy, seizures are short-lived and relatively infrequent events. Occasionally, the treatment of epilepsy can be worse than the seizures if the mental effects of the anticonvulsants are especially pronounced.83 Historically, physicians have noted disturbances in behavior, mood, and alertness in epileptic patients treated with drugs. Most physicians attributed these unpleasant side effects to the seizures themselves, social isolation, brain injury antedating the epilepsy, or perhaps a familial behavior disturbance inherited along with the seizure disorder. It has taken much careful clinical investigation to accept the honest conclusion that significant disability from epilepsy may actually arise from the medication prescribed to treat it. Some antiepileptic drugs may simply dull the keen sharpness of the human mind and slow and disrupt the normal speed and accuracy of skilled mental processes. The nefarious mental effects of antiepileptic drugs may be broadly separated into four categories. Disturbances

Cortical

Function.-One

1. Sedation, manifesting as fatigue, drowsiness, or subarousal 2. Behavior, displayed as hyperactivity, irritability, tantrums, outbursts, aggressiveness, or sleep disturbances Cur-r Probl Pediatr, March 1987

176

3. Mood, appearing as depression, dysphoria, or emotional lability 4. Cognitive functions, objectively measured in terms of intelligence quotients (IQ scores), memory, recall, speed and accuracy of mental processes, attention span, and sensorimotor functions such as the rapid and accurate execution of fine motor activity Antiepileptic drug-induced higher cortical dysfunction is unwanted at any age but is especially undesirable in children. Childhood is life’s foundation, and the intrusion of unnecessary drug-induced behavioral or cognitive disturbances amidst the normal turmoil of youth may undermine the prospects for an independent, adjusted, and successful adulthood. There are at least three major factors that generally influence the type and magnitude of drug-related cognitive side effect?: 1. The drug itself: Some antiepileptic drugs have more propensity than others for generating mental side effects. 2. Drug dosage and serum concentration: In general, unwanted drug side effects are more likely to appear or are more noticeable at higher dosages and serum levels than at lower levels.85 3. Polypharmacy: There is little evidence that polytherapy is better than monotherapy. The practice of simultaneously administering multiple drugs for seizure control may generate a net mental disturbance that exceeds the side effects of the individual drugs alone. Although it is sometimes necessary to use more than one agent, neurologic side effects of multiple drugs may be additive and may appear even when concentrations of individual drugs fall within the “therapeutic range.” Carbamazepine and Higher Cortical Function.-There is no perfect antiepileptic drug. Behavioral and neurologic side effects have been reported for all drugs, including carbamazepine.87 It is the documented superiority of carbamazepine, relative to many comparable antiepileptic drugs, that makes it such a desirable and useful addition to the treatment of pediatric and adult epilepsy.88j8g Careful quantified psychological and cognitive studies in healthy volunteers document a clear superiority of carbamazepine over barbiturates and phenytoin. Some studies have even shown an improvement in mood (positive psychotropic effects) separate from intellectual clarity. These salutary effects are present in children as well as adults .“j ” Carbamazepine

in Children:

Summary

Carbamazepine is a relatively recent addition to the collection of therapeutic agents that can be employed for patients with epilepsy. 176

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1987

Because it is so effective for simple partial, complex partial, and generalized tonic-clonic seizures it may be indicated for as many as 75% of all epileptic patients. Although not yet officially approved by the FDA for administration to children under 6 years old, in actual clinical practice it is employed for patients of all ages, from neonates to the elderly. The early impression of common, serious, or fatal hematologic reaction was overrepresented and exaggerated. Carbamazepine appears to be as safe as other antiepileptic drugs. The manufacturer’s recommendation for frequent hematologic monitoring, mandated by the FDA, appears excessive and unreasonable and probably does not substantially lessen the risk of rare serious hematologic toxicity. Routine hematologic monitoring is greatly modified by many neurologists in clinical practice. The outstanding feature of carbamazepine, and one that cannot be overemphasized, is its established superior freedom from chronic neurologic, mental, cognitive, and mood side effects. It is exactly this trio of efficacy, safety, and superior tolerance by patients that has rightly earned carbamazepine its reputation as the drug of choice among so many neurologists. VALPROATE Background Valproic acid is a short-chain fatty acid whose existence as a simple chemical agent was known since its synthesis by Burton in 1881 .g2 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.g3 The experimental paradigm studied a variety of potential anticonvulsants dissolved in valproic acid for potential protection against an animal model of generalized seizures (provoked by the administration of the convulsant drug pentylenetetrazol). Clinical trials were soon carried out in Europe, and valproate was eventually approved by the FDA for use in the United States in 1978. Valproic acid is the chemical name for a colorless liquid compound n-propylpentanoic acid (dipropylacetic acid). Its chemical structure lacks a ring moiety or nitrogen atom and is absolutely unique among existing anticonvulsants (Fig 7). Its chemical structure resembles that of endogenous fatty acids. Mechanism

of Action

The exact mechanism by which effect is unknowng4 Most models Cur-r Probl Pediatr,

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1987

valproate exerts its antiepileptic that have studied its protective 177

CH3-CH2-CH2

0 \

CH3-CH2-CH2

/

CH-C

/ \

OH

FIG 7. Chemical structure of valproic acid.

effects have focused attention on the inhibitory neurotransmitter gamma aminobutyric acid (GABA). Valproate may increase GABA or cooperate with GABA in the exertion of enhanced postsynaptic inhibition. It has been suggested that by competitive inhibition of GABA’s degradative enzymes in the tricarboxylic acid cycle (GABAtransaminase and semialdehyde dehydrogenase), valproate effectively increases whole brain GABA content, thereby enhancing cortireduces seizures, which are physiocal inhibition.g5 This ultimately logic events of excessive neuronal excitation. Conflicting evidence on the effect of valproate on whole brain GABA has led to a refined concept that GABA’s effects need only occur in critical glial or axonal regions such as synapses. Perhaps increased GABA activity in powerful inhibitory control centers such as the substanta nigra plays a role in seizure suppression.g6 Other hypotheses are under consideration.28 Valproate may exert a direct influence on neuronal membranes and allows an increase in the conductance of the potassium ion (K+), accompanied by hyperpolarization of the membrane potentialg7 However, none of the proposed mechanisms satisfies all the observed experimental findings . Indications

for

Use

GENERALIZED SEIZURES The accidental discovery of valproate’s anticonvulsant properties occurred against the backdrop of a model of generalized seizures precipitated by the proconvulsant drug pentylenetetrazol. The subsequent years of experimental study and clinical experience have affirmed its dominant and ubiquitous role in the treatment of virtually all forms of generalized epilepsies, especially petit mal and its section of the variants.g8~ gg Indeed, although the product infdrmation Physicians’ Desk Reference67 lists under indication for valproic acid therapy in the treatment of simple and use: “sole and adjunctive complex absence seizures . . . [and] . . . adjunctively in patients with multiple seizure types which include absence seizures,” the clinical practice and published clinical experience of the treatment 178

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Pediatr,

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1987

of epilepsy reveal a far wider scope of application. Indeed, valproate stands alone in its exceptionally broad spectrum of activity. Petit MaZ Seizure and Its Variants-To many clinicians the term “petit mal” connotes a fairly stereotypic variety of generalized seizure characterized by a blank facial stare, unresponsiveness (absence), and perhaps repetitive eye blinking (usually at three blinks per second!) which is exquisitely time-locked to the generalized three-per-second EEG spike and wave discharges. In the past decade detailed analysis of many attacks of petit mal seizures captured by time-synchronized video-EEG monitoring have revealed the clinical heterogeneity of this disorder and detailed the distinguishing aspects of its various subtypes (Table 6j.l” In each petit mal variant, the most prominent feature of the attacks is absence (unresponsiveness), and secondary features may include mild tonic, atonic, autonomic, or myoclonic components. It may come as a surprise that pure absence (unresponsive staring associated with no other clinical feature) is the least common petit mal variant. Some form of automatism occurs frequently in petit mal seizures, especially if the electrographic seizure lasts long enough for semiautomatic behavior to fill the void left by the departed consciousness. It is no wonder that “temporal lobe” and “petit mal” seizures are so easily confused. As a group, petit mal seizures are relatively uncommon and collectively account for 2%-11% of the epilepsies.l” (A far more common form of seizure disorder is benign rolandic epilepsy, which has received surprising little attention by pediatricians and neurologists in the United States.) The treatment of choice for simple or complex petit mal seizures for several reasons: (1) it is effecremains ethosuximide (Zarontin),“l tive, (2) it is generally well tolerated and safe, (3) twice-a-day dosages are usually adequate, and (4) it is relatively inexpensive. If treatment of petit mal seizures is unsuccessful with ethosuxidrug choices are available and inmide or valproate,loz additional clude clonazepam, methsuximide, and trimethadione. Valproate is as effective as ethosuximide in controlling clinical attacks of absence seizures and in erasing the ~-HZ spike-slow wave of ethosuximide and discharges from the EEG.lo3j lo4 A combination valproate may benefit patients whose petit mal seizures are refractory to each individual agent.lo5 TABLE Subtypes

6. of Petit Mal Seizures

Simple petit mal: Complex petit mal:

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1987

Absence with no associated motor phenomena Absence with automatisms; absence with mild clonic, tonic, atonic, or autonomic components

179

Generalized tonic-clonic seizures may accompany simple or complex petit mal seizures. Indeed, about 30% of patients with petit mal seizures eventually will experience one or more grand mal seioptions. Many clinicians zures .I0 There are then two therapeutic prefer valproate monotherapy, which, owing to its broad spectrum of action, usually will control both seizure types. Another option is polytherapy with ethosuximide and a “grand mal drug” (e.g., carbamazepine, phenytoin, or phenobarbital). Myodonic Seizures. -Valproate is a drug of first choice for myoclonic seizures. The generic term “myoclonus” refers to a very rapid muscle contraction or twitch. The resulting movement is quick and shock-like. Myoclonic movements may occur as solitary events. When they recur repetitively they generally lack the sterotypic rhythmicity of clonus. Myoclonic movements can represent (1) normal physiologic body events (e.g., the familiar sleep startle or jump), (2) abnormal but nonepileptic movements (e.g., post-anoxic action myoor (3) a form of epilepsy-myoclonic seizures. clonus,106 The term “myoclonic seizure” assumes an epileptic basis for the quick shock-like muscle twitch. The EEG generally displays a spikeslow wave involving the motor cortex immediately prior to the muscle twitch. As a group, myoclonic seizures are relatively uncommon and represent only a small percentage of the epilepsies.g”‘lOO They are noteworthy, however, for their possible association with serious underlying neuropathology or degenerative conditions and their resistance to treatment. In approaching the patient with myoclonic seizures, a series of questions will help focus the workup, treatment, and understanding of the patient: Question 1: Does the patient have a normal clinical neurologic examination? and clinically normal, Answer 1: If the patient is intellectually epileptic myoclonus often represents a fragment of other clinical seizure types such as absence or tonicclonic seizure. If the myoclonus is not a fragment of another seizure type, the patient may have a pure myoclonic epilepsy. Pure myoclonic seizures may occur in Lennox-Gastaut syndrome, but many of those patients have abnormal neurologic examinations. In healthy adolescents pure myoclonic seizures may appear as massive muscular shocks. They may additionally have separate petit mal or grand mal seizures. This form of epilepsy is exquisitely sensitive to treatment with valproate.107J lo8 or neurologQuestion 2: If th e patient is not normal intellectually ically, does the patient’s clinical course suggest a static encephalopathy? 180

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1987

Myoclonic seizures may occur as a consequence of infantile hemiparesis or the Lennox-Gastaut syndrome. Some of these will be responsive to valproate.37 Question 3: If the patient is not normal intellectually or clinically, does the patient’s course suggest a progressive encephalopathy with evolving ataxia, cerebral signs, dementia, or other evidence of deterioration? The constellation of myoclonic seizures and an evolvAnswer 3: ing organic brain syndrome should warrant a search for progressive disorders such as subacute sclerosing panencephalitis, Ramsey-Hunt syndrome, or an inborn error of metabolism such as the Lafora body disease. Although myoclonic seizures may be treatment resistant in the setting of a degenerative CNS disorder, valproate would remain the first choice.100 Alternatives include the benzodiazepams, barbiturates, carbamazepine, phenytoin, or a ketogenic diet.*”

Answer

2:

Seizures.-Valproate is the drug of choice for atonic seizures. The predominant clinical manifestation of an atonic seizure is an abrupt loss of tone. The resulting precipitous fall is commonly called an epileptic drop attack (if the seizure is very brief) or atonic absence (if the seizure is longer and gives rise to an unconscious fallen victim). Such pure atonic seizures are typically refractory to treatment. Valproate is the most effective drug for these difficult to treat seizuresfo3 ‘loJ *I1 Clonazepam is commonly a secondary choice but can also exacerbate the seizures in some individuals112 The unexpected success of imipramine (Tofranil) has been reported in a few children.lf3 A mild, more gradual loss of postural tone may occur with some petit mal seizures. These may appear as mild sagging of the head or buckling of the knees. Such relatively minor atonic features are much less frequently associated with damage to teeth, eyes, jaws, or face and do not merit inclusion in the category of atonic seizures. Atonic

Seizures.-Generalized tonic-clonic seizures (major motor or grand mal) are most widely treated with carbamazepine, phenytoin, and phenobarbital. There is good evidence, however, that valproic acid is equally effective.g6t114 Those generalized seizures which are reflexly precipitated by sensory input (light, startle, noise, etc.) are controlled by @proate better than by other anticonvulsants. In patients whose grand mal seizures coexist with petit mal seizures, valproate monotherapy is considered superior to polytherapy by many. Some clinicians consider valproate to be the drug of choice for traditional grand mal seizures.g6 Tonic-Clonic

Febrile

phylactic

-The drug treatment

Seizures.

Cum Probl Pediatr,

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1987

clinician who elects to begin chronic for simple or complex febrile seizures

procon181

fronts a rather limited choice. The mainstay of continuous treatment is phenobarbital. Although phenobarbital is safe and effective, the relatively high incidence of unwanted behavioral disturbances extracts a high price in side effects for some children and their families. Not surprisingly, primidone offers a roughly comparable degree of protection and side effects and has no real advantage over phenobarbital. Phenytoin is not effective in protecting infants from recurrences of febrile seizures even if serum levels are adequately maintained in young infants. Carbamazepine does not offer any protection in cases where phenobarbital failed. Several studies have shown that valproate is comparable to phenobarbital in the prophylaxis of febrile seizure recurrences. A serum level of 60-80 P&C generally correlates with seizure protection.*15 The major advantage of valproate over phenobarbital is the lower risk of behavioral disturbances. For most clinicians this advantage is outweighed by the possibility of hepatotoxicity since many children treated for febrile seizures are in an age group that is at highest risk for hepatic damage. On balance, because of their extremely benign nature, febrile seizures should rarely be treated with any drug. Infantile Spasms.-Infantile spasms are an age-specific, highly characteristic clinical seizure that may arise de novo or materialize in the aftermath of serious, diffuse or multifocal brain injuries such as asphyxia, trauma, intrauterine infection, or intracranial hemorrhage. The clinical seizure appears as myoclonic spasms in flexion, extension, or mixed flexion-extension (Salaam attacks) and is often but not invariably accompanied by a highly abnormal, disorganized, chaotic EEG pattern called hypsarrhythmia. Hypsarrhythmic debetween seizures. scribes the appearance of the EEG background During the actual seizure, different ictal patterns arise. When infantile spasms start unexpectedly in a previously healthy child, the long-term developmental and neurologic outcome appear to be improved if seizure control and normalization of the EEG are successful. Many physicians consider ACTH and/or prednisone as the drug(s) of choice.‘16 These drugs may stop clinical seizures and improve or normalize the EEG. Although some conventional anticonvulsant drugs may offer a partial remedy with reduced seizure frequency, they do not seem to fundamentally alter the infrastructure of the disorder. Some have reported success with benzodiazepam (usually nitrazepam, which is not readily available in the United States) .l17 Valproate has also been given for clinical control of infantile spasms and is clinically useful in some individuals.” Since standard medical therapy frequently falters, unusual and unapproved approaches to treatment are sometimes used,‘l’ such as methysergide . 182

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PARTIAL SEIZURES Valproate is not presently considered an adequate initial or sole drug in the treatment of simple or complex partial seizures. However, in open drug trials employing valproic acid as adjunctive therapy, improved partial seizure control occurred in an appreciable percentage of treated patients.l’“’ I19 STATUS EPILEPTICUS Phenytoin, diazepam, and phenobarbital are usually considered the drugs of choice in most forms of convulsive status epilepsy. A role for valproate has been suggested by some who have administered it rectally or by nasogastric tube.120-122 Pharmacologic

Properties

of Valproa te

FORMULATION Valproic acid is available for oral ingestion as a liquid enveloped in a soft gelatinous capsule. The capsules cannot be chewed or mixed with food because of local oral irritation from the acidity. The capsules can be frozen and cut in sections if necessary. The sodium salt of the parent acid (sodium valproate) is available as a syrup. An enteric coated tablet of a stable 1: 1 combination compound of valproic acid and its sodium salt reduces local gastric upset and delays the onset of absorption. There is no commercially available IV or rectal formulation in the United States. Although the FDA has not endorsed rectal administration of valproate, some investigators have reported successful use of retention enemas of sodium valproate syrup (mixed 1: 1 by volume with tap water) for seizure contro1.122 ABSORPTION AND BIOAVAILABILITY Valproate administered in soft gelatinous capsules is rapidly absorbed from the GI tract. Peak plasma concentration (C,,) occurs within 4 hours after an administered dose. Between 68% and 100% of an administered dose is bioavailable.123 Only a small amount (3%7%) is excreted unchanged in the urine. Sodium valproate administered as a syrup is more rapidly absorbed and peak plasma concentrations (C,,) occur between 15 minutes and 2 hours after ingestion. The liquid is only slightly more biologically available (!6%-100%) than the capsule.124 The ingestion of food with either the capsule or the syrup does not reduce bioavailability but delays absorption and helps smooth out the exaggerated peaks and troughs that result from its relatively short elimination half-life. The administration of valproic acid with meals is also encouraged to diminish its local gastric irritant effects. Enteric coated tablets of divalproex sodium delay the onset of Cur-r Probl Pediatr,

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1987

183

drug absorption for about 1 hour. The enteric coating also reduces the incidence of gastric upset, which occurs in about 40% of patients who take standard forms of valproate. Valproate administered by a retention enema as a 1: 1 (volume to volume) mixture of syrup and tap water appears to result in similar bioavailability as an equivalent-sized oral dose. The appearance of peak serum levels, however, may be modestly delayed.lz2 DISTRIBUTION

TO THE

BODY

Circulating valproate is 80%-95% bound by plasma proteins, mostly albumin.125 At blood levels above 90-100 P#CC, saturation of transport binding sites occurs and the percentage of unbound valproate increases to 30% .125Therefore serum levels in excess of 100 l.~g/cc provide relatively more free (unbound) valproate that is available for entry into the tissues of the nervous system. The unbound fraction may also be eliminated more rapidly than the bound fraction.126 Valproate is chiefly distributed to the intravascular and extracellular spaces. There is relatively little accumulation of valproate in the nervous system except in regions that are particularly rich in GABA transaminase activity.llg’ lo3 ELIMINATION HALF-LIFE (TX) Only a small fraction of circulating valproate escapes unchanged in the urine. Most of each dose is eliminated by complex hepatic metabolism, which generates more than ten separate drug byproducts by glucuronidation and fatty acid beta and omega oxidation. These drug metabolic byproducts are then eliminated in, the urine. At least one of valproate’s main metabolites possesses intrinsic anticonvulsant activity.1o5 Valproate is not known to promote its own clearance by induction of hepatic microsomal enzymes.lz7 Valproate is eliminated by linear kinetics and degradative enzyme saturation is not known to occur. Its elimination half-life is short, generally cited as 6-16 hours, and accounts for considerable fluctuations of plasma drug concentrations. In fact, the ratio of peak to trough valproate concentrations may be as high as 2 : 1. Its relatively brief elimination half-life requires dosing three to four times per day. Stable serum concentrations are achieved quickly, however, in as little as 1-3 days. RELATIONSHIP OF DOSE TO BLOOD LEVEL There is a poor correlation between the administered total daily dose and resulting blood levels of valproate. The cause of this variability may be explained by individual differences in pharmacokinetic elimination or absorption rates or the times at which blood specimens am obtained. Since there is no mathematical formula that 184

Cum Probl Pediatr,

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1987

reliably predicts what blood levels will result from a specified dose in individual patients, it is necessary to measure serum concentrations to monitor the blood level from each dose. As discussed previously, the goal of treatment with any antiepileptic drug is the cessation of clinical seizures. Valproate should be given with the same intention. It has been suggested that for some patients, observed seizure control is not tightly linked to serum drug concentrations.128 This uncoupling of the effects of the drug and the circulating concentration suggests that an important factor in successful treatment may relate to drug binding in the CNS rather than simply a critical serum concentration. For children, the manufacturer recommends an introductory dose of 15 mg/kg of body weight. This starting dose may be “too much, too soon,” since some patients experience sedative effects and GI upset. Many physicians prefer to start with a smaller dose, such as 5-10 mg/kg. Each week, the dose can be escalated by 5-10 mgkg until seizure control is achieved or side effects bar further dose escalation. The upper recommended dosage is in the range of 30-60 mg/kg/day. However, some individuals will tolerate larger amounts and enjoy better seizure control at dosages in excess of 60 mg/kg/ day. In adolescents and adults, treatment is usually started at about 510 mg/kg and gradually increased to approximately 20 mg/kg. Typical amounts of drug consumed are then 1,500-2,000 mg/day. For adults and children the total daily dose of valproate is divided into three or four smaller doses and administered after meals and at bedtime. Individuals who are simultaneously taking other antiepileptic drugs (polytherapy) may require a higher milligram per kilogram dose than if valproic acid is given alone as monotherapy.37112g EXAMPLE: CHOOSING VALPROATE

AND

INITIATING

TREATMENT

WITH

History A 15-year-old, previously healthy young man is being evaluated for recurrent grand mal seizures. He had a first grand mal attack at age 13, during summer camp. The seizure occurred at 6 A.M. He had stayed awake until 3 A.M. the night before telling stories and “horsing around” with his fellow campers. He was evaluated by the camp physician but no treatment was started. His second seizup occurred 1 year later during football camp. This seizure occurred in the early morning, and again after he stayed up unusually late. He was referred to a neurologist. His evaluation included an EEG, which displayed generalized ~-HZ spike-slow wave discharges and periods of unresponsiveness (absence) without any other clinical signs. In retrospect, his mother had noted occasional brief lapses, but it had not occurred to her that these could be seizures. She then volunteered that he was “nerCurr Probl Pediatr,

March

1987

186

vous and jumpy” in the morning, most noticeably during breakfast, and had quick shock-like movements and occasional twitches in his face. Once a spoon filled with cereal was tossed across the table. Physician’s

Analysis

By history this is a healthy, intelligent youngster with the recent onset of generalized seizures in the forms of occasional grand mal seizures (possibly precipitated by the stress of sleep deprivation), absence, and myoclonic seizures which clustered in the early morning just after awakening. He may be classified as having juvenile myoclonic epilepsy (impulsive petit mall. After discussion with the family a trial of valproate was selected since its wide spectrum of activity could abolish all the patient’s clinical seizure types using monotherapy. Furthermore, at his age the risk of serious liver toxicity is very low. STEP 1: CHOOSING

A TOTAL

DAILY

DOSE

Although only 15 years old he was a large athletic young man who weighed 195 pounds (89 kg). If the “pediatric goal” of 30-60 mg/kg/day of valproate were chosen he would be taking 2,600-5,300 mg/day, probably an excessive amount. Instead, his goal would be in the adult range of 20 mg/ kg/day, yielding a total daily dose of about 1,750 mg. Since the early morning seemed to be a time of special vulnerability, it was decided to make the bedtime dose relatively large, so as to provide extra coverage in the morning before breakfast. INITIATION

OF TREATMENT NO. OF 250 MG CAPSULES BREAKFAST

First week: Second week: Third week:

EVALUATION

5 m&3 15 mgkg 20 mg/kg

445 mg (500 mg) 1,335 mg (1,250 mg) 1,780 mg (1,750 mg)

0 1 2

LUNCH

0 1 1

OF VALPROATE

DINNER

BEDTIME

0 1 2

2 2 2

OF TREATMENT

The first blood level determination, made 5 days after he was given the full target dose of 20 mg/kg/day, yielded a morning predose trough level of 58 P&/cc. There had been no grand mal or simple absence seizures in the morning, but he was still “nervous and jumpy” shortly after awakening. His dose was then increased by one more capsule given at bedtime. His total daily dose was then eight capsules (2,000 mg) or 22 mg/kg/day. His mother subsequently reported that his sharp muscle jumps had entirely disappeared in the morning. 186

Cur-r Probl Pediatr,

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1987

ONGOING

TREATMENT

In an effort to ensure compliance in this active adolescent, a decision was made to simplify the drug regimen. An equivalent dose of the entericcoated tablets was substituted for the capsules. BREAKFAST

LUNCH

BEDTIME

3 tablets (750 mg)

2 tablets (500 mg)

3 tablets (750 mg)

There was no change in seizure control, and that regimen appeared to be the best for the patient. Since tolerance to the antiepileptic effects of valproate is rare, the clinician did not expect to make more than minor dosage adjustments according to seizure control and body weight. BLOOD

LEVELS

It has been difficult to establish a relationship between valproate serum concentrations and either seizure control or drug side effects. As a result, different but overlapping therapeutic ranges have been reported (Fig 8). Most clinicians have found that patients generally require a trough serum level of 50 pg/cc to enjoy seizure control. Some patients can tolerate levels of 150 pg/cc before dose-dependent drug side effects occur.124 INTERACTIONS BETWEEN ANTICONWLSANTS

VALPROATE

AND

OTHER

Interactions between valproate and other antiepileptic drugs are common. The magnitude of these effects can be large and responsiLower Therapeuk Level

Upper Therapeuk Level

I-llll I

I v----------------1 t------l Illi-1

I

I

I

I

I

t---------------i /

40

/

50 60

1 I

I I

70

80

I I

I

1 I

, I

, I

1 I

I /

/

I I

90 100 110 120 130 140 150 160

Blood concentration

of valproate, pg/cc

FIG 8. Range of reported

therapeutic

Curr Probl Pediatr,

March

1987

values of valproate.

For references,

contact

the author. 187

ble for significant clinical changes in the forms of drug intoxication or altered seizure control (Table 7). When valproate is added to an antiepileptic drug regimen that includes phenobarbital the physician should anticipate an increase in serum phenobarbital levels with possible clinical signs of overmedication such as lethargy or ataxia. A typical blood level increase of 30% is common, but increases as high as 50% above the previous baseline have been encountered. Increased phenobarbital levels stem from an inhibition of phenobarbital metabolism.130 Valproate does not retard its renal excretion. A similar interaction sometimes occurs between valproate and primidone. There are more complex effects when valproate is added to an established phenytoin regimen. 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 phenytoin. On balance, the concentration of unbound drug changes little. If the fall in total serum phenytoin concentration is not accompanied by deterioration in clinical seizure control, it may not be necessary to increase the phenytoin dose.lz6 The displacement of phenytoin from its binding sites may also

TABLE

7.

Interactions

Between

Valproic

A. Changes of Anticonvulsant Added

to the Established

ESTABLISHED

DRUG

DECREASED

Phenytoin Carbamazepine Clonazepam Phenobarbital Primidone Ethosuximide

DRUG

ADDED

LEVEL

UNCHANGED

LEVEL

Drugs Acid is

INCREASED

LEVEL

0 0 0 0 0 0

Acid Levels After Addition

of Other

TO

ACID

Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Clonazepam

188

Blood Levels After Valproic Regimen

0

B. Changes in Valproic Antiepileptic Drugs VALPROIC

Acid and Other Antiepileptic

DECREASED

LEVEL

UNCHANGED

LEVEL

0 0 0 0 0 0 Cur-r Probl Pediatr,

March

1987

allow signs of drug intoxication to develop while blood level remains in the therapeutic range.131

the measured

INTERACTIONS WITH NONANTICONWLSANTS Drugs that are highly bound to circulating

proteins, such as aspirin and phenylbutazone, may displace valproate, but the clinical significance of this has not been demonstrated. Eflects

of Valproate

on the EEG

At customary clinical doses and serum levels of valproate monotherapy, little or no change occurs in the background cerebral electrical activity. Occasional patients display an unusual sensitivity to valproate and develop a mild reversible encephalopathy (lethargy progressing to coma) that may or may not be accompanied by hyperammonemia and the development of a diffusely slowed and disorganized EEG. In successfully treated simple and complex petit mal seizures, the classic EEG hallmark of the three-per-second generalized spike-slow wave discharges may be partially or completely erased by valproate .13’Clinical seizure control parallels the disappearance of the epileptiform activity from the tracings. Indeed, one might argue that the dosage of valproate should be titrated against clinically apparent seizures and the abundance of spike-wave discharges on the EEG rather than on the serum blood concentrations of the drug. Parado;uical

Seizure

E,xacerbation

by Valproate

Rare instances of petit mal status (absence status) have been reported when valproate and clonazepam are co-administered. The simultaneous use of these agents is not contraindicated. Indeed, some clinicians have reported a successful combination of these two drugs .133-136 When the serum level of valproate exceeds 150 kg/cc a rare syndrome of worsened seizure control, confusion and disturbed behavior may occur. 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.137 Owing to the rapid and relatively complete GI 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 Cum Probl Pediatr,

March

1987

189

the high percentage of circulating protein binding, hemodialysis or peritoneal dialysis will probably not speed recovery by substantially reducing the total body drug burden.138 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.

Adverse Drug Side Eflects In 1982 the Committee on Drugs of the American Academy of Pediatrics published a statement that summarized the indications, and adverse side effects of valproic pharmacologic properties, acid.13’ Their recommendation included the opinion that “valproic acid is not the first drug of choice for most patients with seizures. . . . Whenever possible . . . current standard therapy should That reservation was based on their current be used initially.” knowledge of serious or fatal reactions involving the liver and pancreas. Fortunately, important new data have since become available that more clearly define the risk factors for fatal hepatotoxicity. Consequently, the clinician may now identity with sharper focus those patients who may face an unacceptable risk of serious drug reactions. SYSTEMIC SIDE EFFECTS

Fulminan t liver failure. -The

association between valproate and acute hepatic failure was first reported in 1979,1 year after the drug was first released in the United States.14’ Since then additional cases have occurred and the manufacturer and FDA have issued a product w-ing.141’ 14’ The illness may manifest clinically with subtle symptoms such as lethargy, vomiting, altered behavior, and worsened seizure control, accompanied by the signs of facial edema, ascites, and jaundice proceeding to overt hepatic failure. Abnormal laboratory values can include elevated SGOT and bilirubin with prolonged prothrombin time. Pathologic examination of the liver may feature aspects of direct hepatocellular damage and inflammation (a “hepatitis” picture). This fatal reaction tends to occur within the first 6 months of valproate treatment. It is independent of the size of the administered dose and may progress despite discontinuation of the drug. The demographics of fatal hepatotoxicity have recently been clarified by Dreifuss and Santilli (Table 8).143 YOUNGER.-The primary risk group of fulincluded children up to 2 years of age. In that

CHILDREN AGED 2 YEARS AND

minant 130

liver failure

Cum Probl Pediatr,

March

1987

TABLE

8.

Rate of Hepatic or Polytherapy

Fatality by Age Group (1978-19&I)*

in Patients

Receiving

Valproate

MONOTHERAPY

POLWHERAPY

TOTAL AGE GROUP

(YFt)

o-2 3-10 11-20 2140 41+

Monotherapy (total) Polytherapy (total) Combined total

RATE

PATIENTS

DEATHS

7,025 35,593 51,951 59,107 34,145 187,821

1 4 0 0 0 5

PER

10,000 1.42 1.12 a 0 0

TOTAL

RATE PER

PATIENTS

DEATHS

10,000

7,889 39,975 58,348 66,386 38,351

1.5 7 5 4 1

0.86 0.60 0.26

210,949

32 37

1.52 0.93

19.01l1/5001

1.75

0.2711/37,000l 398,770

*From Dreifuss FE, Santilli N: Valproic 36k.uppl 11:175. Used by permission.

as Monotherapy

acid hepatic

fatalities:

Analysis

of US, cases. Neurology

1165001

1986;

age bracket those who received valproate monotherapy had a 1.42 per 10,000 incidence of fatal hepatic failure. Children treated with a combination of valproate and one or more other anticonvulsants (polytherapy) had a disproportionately high risk of hepatic failure with an incidence of z in 500. 3-10 -S.--In this age group the risk of fatal liver reactions was 1.12 per 10,000 for valproic acid monotherapy and slightly higher (1.75 per 10,000) for polytherapy. CHILDREN

AGED

11 YEARS AND OLDER .-No hepatic fatalities have been reported in patients older than 10 years treated with valproate monotherapy. In patients treated with valproate polytherapy the risk was 0.613 per 10,000. These data clearly indicate that the primary risk of fatal hepatic reaction is in children under age 2 years on polytherapy. Furthermore, there is a higher risk for polytherapy than monotherapy in the other age groups. PATIENTS

AGED

Monitoring Liver Function.-Physicians are advised to monitor hepatic function carefully and regularly in patients on valproate. It has not yet been determined whether early termination of valproate in the course of hepatic necrosis will prevent progression of the disease or improve the patient’s chance for survival. Valproic acid should be not be given to patients with inborn errors of metabolism or preexisting liver disease. contrast to the very unTransient Increase in Liver Enzymes.-In common appearance of fulminant hepatic failure, biochemical evidence for mild hepatic dysfunction is more frequent. SeriaJ measurements of liver function in asym~tomatic individuals reveal elevated Curr Probl Pediatr,

March

1987

191

liver enzyrnes in 5%-30% of patients treated with valproate. The magnitude of elevation roughly correlates with the size of the dose. Liver enzymes normalize after the dose is lowered.142’144 Asymptomatic mild elevation of liver function tends to occur in the first few months of treatment. It is dii%cult to prospectively distinguish those individuals who will continue to follow an innocent clinical course and those who are in the early phase of a progressive serious hepatic failure. The clinician should seriously consider terminating treatment if (1) clinical signs of hepatic disease appear (e.g., malaise, jaundice, or edema), (2) the SGOT elevation exceeds three times the usual upper limit,lz4 or (3) hepatic synthetic function falters (hypoalbuminemia or prolonged prothrombin time or partial thromboplastin time. Hyperammonemia in Asymptomatic Patients with Normal Liver function .-Mild increases in blood ammonia levels in healthy asymptomatic individuals taking standard doses of valproate may occasionally occur. Coincident liver function tests are usually normal. There may be a higher risk of hyperammonemia if valproate polytherapy is used.145J146 Encephalopathy Due to Hyperammonemia with Normal Liver Function.-Some patients on standard doses and levels of valproate develop a toxic encephalopathy that is due to clinically significant hyperammonemia. Other liver function indices are normal or minimally increased. The clinical presentation is characterized by vomiting and lethargy, proceeding to coma in some cases. This complication has been reported in otherwise well individuals and rarely in patients with inborn errors of urea cycle metabo1ism.147-14g Reye-Like Syndrome.-A rare Reye-like illness has been reported during valproic acid administration.146 The clinical presentation features progressive constitutional signs (anorexia, vomiting, fever) and lethargy deepening to coma. The biochemical profile includes hyperammonemia, abnormal liver enzyme levls, and prolonged bleeding times, Fatty infiltration of the liver and kidneys, similar to the pathologic alterations seen in classic Reye syndrome, has been found. Investigators have speculated that valproate might sometimes behave like some fatty acids that can experimentally induce a Reyelike syndrome in rats. ACUTE PANCREL4TITIS Valproate has recently been added to the list of drugs capable of producing serious or fatal acute hemorrhagic pancreatitis. However, the incidence is extremely low. The principal clinical presentation includes abdominal pain, distention, and tenderness on palpation, with major increases in serum amylase levels.151~*52 192

Curr

Probl

Pediatr, March

1987

COAGULOPATHY The clinician should be aware of the possibility of a clinically significant bleeding diathesis developing in patients taking valproate. Patients should be advised to report any unusual bruising or bleeding, especially if they- are already taking drugs such as aspirin or warfarin. If elective surgery is anticipated, coagulation status should be evaluated prior to the operation. Valproate has a complex effect on the hemostasis mechanisms. The absolute platelet count can be depressed and platelet behavior disturbed, as indicated by impaired platelet adhesiveness and aggregation.‘“” By an independent mechanism the prothrombin and partial thromboplastin times can also be prolonged.105J11g GASTROINTESTINAL The most common side effects of valproate administration are referred to the GI system in the form of anorexia, nausea, and vomiting.15” Intolerance often develops early during treatment or after a substantial dose increase. Up to 40% of patients who take non-enteric-coated valproate will complain of GI upset. These effects are usually transient and respond to lowering the dose, administering the dose after meals or with milk, or the use of “enteric-coated” pills. 105,119 The chronic consumption of valproate can occasionally lead to a lasting change (increase or decrease) in appetite that may ultimately result in substantial weight gain or loss. HAIR Changes in hair texture (coarsening or curling) and mild hair loss occur in 0.5%4% of patients treated with valproate. Reversible alopecia is usually short-lived and rarely requires a change in dosage.124 TERATOGENICITY Valproate crosses the placental barrier and produces significant concentrations in the fetus and newborn infant. A variety of teratogenie effects have been found in offspring of rabbits and mice given valproic acid during gestation. Spina bifida in human newborns may occur with excessive frequency if valproic acid is administered during the first trimester of the pregnancy.155J’56 LABORATORY TESTS Valproate is chemically a short-chain fatty acid. After hepatic oxidation it is converted into a ketone body, which may be responsible for the false positive appearance of urinary “ketones” on laboratory testing. Similarly, its metabolites can generate false positive laboratory tests for some organic acids.124 Curr Probl Pediatr,

March

1987

X93

NEUROLOGIC

SIDE EFFECTS

Withdrawal.Withdrawal the abrupt discontinuation

seizures have not been reported of valproic acid.

after

Vigilance.-Sedation during the initial stages of valproate treatment is usually mild and transient and requires no specific intervention,157 More marked disturbances in consciousness have also been described. Probably the most frequent cause of excessive sedation is the pharmacokinetic or pharmacodynamic interaction between valproate and other anticonvulsants, especially phenobarbital and primidone. Valproate-induced hyperammonemia may also induce an encephalopathy. Pathologic lethargy can be seen in severe valproate overdose or as an idiosyncratic effect at therapeutic blood levels. Generalized slowing of the EEG may occur, but other blood tests, including liver enzymes, ammonia, and levels of other antiepileptic drugs, may be normal.154 .-Since valproate is the newest addition to the arsenal of antiepileptic drugs, there has been less time for clinical and investigational experience to define clearly its impact on behavior and cognition. Most published reports have expressed a very favorable opinion of minimal behavioral or mental side efvalproate for febrile seifects .15’Certainly in children administered zures, there are many fewer behavioral disturbances than in similar children given phenobarbital. With the clear understanding that no anticonvulsants are entirely free of mental side effects, valproate currently appears to rank among the best in terms of a low frequency of adverse mental side effects.15g-161 Behavior

and

Cognition

-The administration of excessive valproate has been responsible for the rare appearance of an acute reversible encephalopathy in a few patients. There is no prominent depression of arousal, With the outward appearance of vigilant wakefulness, a gradual decline in intellect, memory, and personality can unfold that reverses to baseline after discontinuation of the drug.‘“’ A chronic dementialike illness has also been reported.163 Delirium.

-A tremor may appear in patients chronically adminisfor valproate to enhance or tered valproate.1”4 It is not uncommon introduce an exaggerated “physiologic,” “benign” or “essential” tremor. The magnitude or amplitude of the tremor roughly parallels the serum valproate levels. If necessary, the tremor can be ameliorated by the administration of propranolol.1”5 Other involuntary movements have also rarely been reported, such as myoclonus or asterixis.166 Tremor.

194

Curr

Probl Pediatr,

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1987

Valpruate

in Children:

Summary

Valproate is the most recent addition to the medical treatment of childhood epilepsy. It is unique in its chemical structure and in its extremely broad spectrum of activity, especially among the generalized epilepsies. Valproate is currently approved by the FDA for the treatment of petit mal seizure and its variants. In actual clinical practice, valproate is widely employed for many types of generalized seizures, including isolated grand mal seizures. Some patients with primary generalized epilepsy have multiple types of clinical seizures (for example, tonic-clonic, absence, and myoclonic seizures). For these patients, valproate monotherapy is an especially attractive choice, as (1) a single agent with broad-spectrum coverage may control all of the patient’s clinical seizure types, (21 a lower total dose of drug is required for monotherapy compared to polytherapy, (3) cognitive and behavioral side effects of valproate monotherapy are minimal, and (4) valproate monotherapy is safer than polytherapy with respect to liver toxicity. Valproate is also a first drug of choice for juvenile myoclonic epilepsy and some of the minor motor seizures encountered in the Lennox-Gastaut syndrome. Valproate is generally well tolerated by most individuals. The most common side effect, GI upset, can usually be ameliorated by administering the dose with meals or switching to the enteric-coated tablets, divalproex sodium. The Committee on Drugs of the American Academy of Pediatrics” considered valproate to have only minimal adverse effects on cognitive performance and behavior. Fortunately, clinical experience has permitted the identification of patients who are at an unusually high risk for serious or fatal hepatotoxicity: children under 2 years of age on valproate polytherapy. This new information allows the clinician to select patients in whom valproate can be safely administered with confidence. WITHDRAWAL

OF

ANTICONVULSANT

DRUGS

Epilepsy is not a life-long condition for many affected children. The biologic factors that regulate and modify the clinical expression of seizures remain largely obscure. It is frequently difficult to accurately forecast how many seizures an individual will have or when spontaneous remissionsof the seizure disorder might occur. The question of withdrawal of antiepileptic drugs is raised after the patient has enjoyed a completely seizure-free existence for an extended period: Is the patient “cured” of epilepsy? Or is the patient in temporary symptomatic remission only while anticonvulsants are taken? Curr Probl Pediatr,

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1987

195

The modern perspective on the medical management of seizure disorders focuses heavily on the patient’s quality of life and freedom from unwanted mental side effects caused by some antiepileptic drugs. Just as one goal of epilepsy treatment is use of the lowest dose and the fewest drugs required for seizure control, it is similarly desirable to administer anticonvulsants only as long as necessary, and to discontinue treatment when possible. The task is not an easy one since there is no universal consensus on how long drugs should be continued and which patients are the best candidates for discontinuing therapy. Despite the lack of uniform agreement a number of factors appear to be clinically pertinent167-170: 1. The class$ication of the epilepsy or seizure iype. Some types of seizures are more likely to persist than others. For example, complex partial seizures of temporal lobe origin have a worse prognosis than simple grand mal seizures. Conversely, the syndromes of benign rolandic epilepsy and classic petit mal epilepsy generally connote a favorable outcome.171 2. The severity of the seizure disorder. Clinicians gauge the severity of a seizure disorder in several ways: (a) Mixed seizure disorders have a worse prognosis than simple seizure types. (b) The duration of therapy prior to seizure control is another measure of disease severity. Patients who require 6 or more years of anticonvulsant treatment before seizures are controlled are at higher risk for relapse than those whose seizures are controlled within 1 or 2 years. {c) Patients who require high doses of multiple drugs to achieve seizure control are more likely to relapse than those who require low doses of a single drug. (d) Patients with a greater number of seizures or a higher frequency of seizures prior to control are also considered to be at higher risk. 3. The presence of coincident brain damage. Individuals with epilepsy who have indications of widespread brain patholom, as evidenced by the presence of mental retardation, motor abnormalities (for example, hemiparesis) microcephaly, etc., face a greater risk of relapse after withdrawal than those who are well apart from their seizures. Although the age at onset of seizures is not per se a powerful independent predictor of relapse risk, onset in the first 6 months of life may indicate the presence of a “symptomatic” epilepsy in the setting of organic brain disease. Patients with progressive or degenerative CNS disorders that feature recurrent seizures have a high relapse rate if drugs are stopped. 4. The EEG e,xamination. Just as the EEG examination cannot absolutely identity all individuals who do or do not have epilepsy, there are limitations to its use in predicting relapse after withdrawal of antiepileptic drugs. Some individuals will relapse despite a normal EEG prior to drug withdrawal. Many individuals with persistent epileptiform ‘ISEG abnormalities will remain in remission after their drugs are discontinued. It is recognized that the EEG trait of epilep196

Curr Probl Pediatr,

March

1987

tiform activity may outlive the patient’s clinical seizure disorder. Although the EEG may not predict the success of drug withdrawal for individual patients, it is generally believed that there is a higher risk for relapse in a population of children with bountiful epileptiform EEG activity compared to those who have no or rare traces of epilep’ tiform EEG activity. Selecting patients for withdrawal from antiepileptic the physician’s skill in the art of medicine. A seasoned ment must be made with limited scientific facts after eration of the patient’s entire clinical circumstances. relapse occurs (seizures that do not simply represent result of drug withdrawal), treatment should usually no relapse occurs, the patient is considered effectively lepsy and may enjoy an anticonvulsant-free life.

drugs requires medical judgcareful considIf a genuine the immediate be restarted. If cured of epi-

SUMMARY The majority of patients with epilepsy have their first seizure during childhood and are first evaluated and diagnosed by their pediatrician. For many patients the medication selected by the pediatrician will be taken for an extended time period, perhaps even for a lifetime. The first job of the pediatrician is to be sure that the patient’s recurrent attacks represent genuine epilepsy and not some other paroxysmal medical disorder such as migraine or cardiac arrhythmias. Epileptic seizures are then classified by a careful clinical description of the attacks in conjunction with the results of the physical and EEG examinations. Based on all of the information at hand, the clinician chooses the drug that is most likely to reduce or eliminate further seizures without exposing the child to unnecessary medical risk or behavioral-cognitive adverse effects. In properly selected patients, both carbamazepine and valproate are safe, physically well tolerated, and less likely to provoke chronic mental side effects than the pediatrician’s “traditional” choices: phenobarbital or phenytoin. Although carbamazepine and valproate have been widely acclaimed by neurologists and epileptologists, practicing pediatricians have heretofore been less likely to initiate treatment with these drugs. Yet pediatricians have something of priceless value to offer the child with epilepsy: seizure control and a clear mind. The information in this monograph should assist the practicing pediatrician in the rational choice, initialion, and follow-up of treatment with these two excellent anticonvulsants.

Acknowledgments The author thanks Karen Ott who Cella who typed the manuscript. Curr

Probl

Pediatr, March 1987

prepared

Figure

1 and

Linda 197

APPENDIX l.-PAROXYSMAL MEDICAL AND NEUROLOGIC CONDITIONS THAT MAY MIMIC EPILEPSY A. Lose or Alteration

of Consciousness

EPlLElTIC

Generalized Complex

seizures

partial

B. Behavioral

REFERENCES

Simple syncope tvasovagal syncope) Cardiogenic syncope; sick sinus syndrome, prolonged QT interval syndrome, left atria1 ball valve, mitral or aortic valve stenosis, asymmetric septal hypertrophy, tetralogy of Fallot “spells” Cardiovascular reflexogenic syncope: carotid sinus message, deglutition, cough, micturition, orthostatic syncope Hyperventilation Migraine “Blue” breathholding attacks “White” breathholding attacks (pallid infantile syncope, reflex anoxic “seizures”) Pseudoepileptic seizures (pseudoseizures, hysterical seizures)

175 176, 177

178

179 180,181

182, 183

Disturbances REFERENCES

EPILEPTIC

NONEPILEITIC

Petit mal, complex partial seizures, nocturnal epilepsylm’lw

Drug toxicity Hypoglycemia Acute migrainous confusional states Transient global amnesia Narcolepsy (automatic behavior syndrome) Non-REM dysomnias tpavor nocturnus, somnambulism, somnilquy) Episodic dysconttol syndrome Acute psychotic behavior

C. Stereotyped

198

seizures

NONEPILEFlW

Motor

186 187 188 189

190

’

Activity

EPILEFRC

NONEPILEFITC

REFERENCES

Automatisms with petit mal or complex partial seizures Myoclonic seizures

Masturbation in female infants Shivering or shuddering attacks Stereotypies or stereotypic behaviors in childhood Autism

191 192 193

Cwr

Probl Pediatr,

March

1987

Simple partial

D.

(motor)

Disturbed

Body

seizures

Tone

and

Paroxysmal movement disorders Rumination syndrome Head rocking and banging Hemifacial spasms Benign tics Benign myoclonus of infancy Complex tics in Guilles de la Tourette syndrome

194

195 196

Posture

EPILEPnC

NONEFILEF’TIC

REFERENCES

Tonic, atonic, adversive, inhibitory, or “hemiplegic” seizure

Paroxysmal torticollis in infancy Cataplexy Vertebrobasilar transient ischemic attacks (TIAsl Gastroesophageal reflux (infants1 Colloid cysts of third ventricle Paroxysmal hemiparesis

197 198 199

E.

Sensory

202

Alterations

EPILEPIK

NONEPILEFTIC

Simple somatosensory seizures Complex partial seizures

Hyperventilation [numbness) TlAs Migraine Benign paroxysmal vertigo of childhood

APPENDIX

2.-ETIOLOGIES

OF

REFERENCE

203

SEIZURES

EXAMPLES

CATEGORY

Neonatal

200, 201

insults

Trauma Post trauma Vascular Immunologic infection Neurocutaneous

syndrome

Chromosomal disorder Hypoxia-ischemia Cerebral dysgenesis Tumor Curr Probi Pediatr,

March

1987

Asphyxia, trauma, hemorrhage, meningitis, TORCH infections Contusion, cortical laceration, penetrating missiles, depressed fracture Impact seizure, early and late onset posttraumatic epilepsy Stroke, polycythemia, arteriovenous malformation, arteritis, hemorrhage Post- or pat-a-infectious encephalopathy; post immunization Meningitis, encephalitis, abscess, endocarditis, subdural empyema, SSPE Neurofibmmatosis, Sturge-Weber syndrome, tuberous sclerosis Down’s syndrome Cardiac arrest, near-drowning Holoprosencephaly Primary brain tumor, metastatic malignancy

199

EXAMPLES

CATEGORY

Inborn

errors of metabolism

Neurodegenerative Systemic conditions

METABOLIC

syndrome, malignant See Appendix 3

3.-TOXIC-METABOLIC

DISORDERS

Hyponatremia Hypernatremia Hypocalcemia Hypomagnesemia Hypoglycemia Nonketotic hyperosmolar

hyperglycemia Hyperthyroidism Uremia Liver failure

porphyria,

Burn encephalopathy, heat stroke, Reye’s

Toxic-metabolic

APPENDIX

Phenylketonuria, acute intermittent pyridoxine dependency Batten’s disease, Alper’s disease hypertension

CAUSES

OF SEIZURES

DRUGS

SUBSTANCES

WITHDRAWAL

Anticholinergics Antihistamines

Boric acid

Alcohol

Brucine Ethylene

Barbiturates Diazepam Narcotics

Antipsychotics Cocaine Isoniazid Lidocaine Lithium carbonate Methaqualone

glycol

Lead Mushrooms Organophosphates

Strychnine Thallium

Methylphenidate Narcotics Penicillin Phencyclidine Phenylethanolamine

Physostigmine Prostaglandin Salicylate Theophylline Tricyclic antidepressants

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