New Drugs in the Treatment of Epilepsy in Children

New Drugs in the Treatment of Epilepsy in Children Elizabeth J. Donner, MD and O. Carter Snead, III, MD

From the Division of Neurology and Program in Brain and Behavior, Hospital for Sick Children, Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to: Dr. Elizabeth J. Donner, Division of Neurology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada. E-mail: [email protected]. Curr Probl Pediatr Adolesc Health Care 2005;35:398-419 1538-5442/$ - see front matter © 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.cppeds.2005.09.004

few basic definitions are in order. A seizure is defined as an episodic behavioral event caused by the paroxysmal discharge of an aggregate of neurons in the brain. A seizure is always involuntary and has a distinct beginning and end. For clinical convenience the seizure may be divided into the aura, or warning, the ictus, or seizure proper, and the postictal state, or altered behavioral state following the seizure proper. In fact, the aura is due to a paroxysmal discharge of neurons in that part of the brain that subserves the sensation that the aura consists of and therefore the aura is a seizure. The clinical manifestation of a seizure, or what it looks like, is called the seizure semiology. The seizure semiology is determined by two things: the location in the brain of the paroxysmal firing neurons, and the connections that these neurons make to other neurons throughout the brain. Epilepsy is defined as a disorder characterized by spontaneous, recurrent seizures. The term has no inferences or meaning relative to ease of control, type of seizure, outcome, or any coexisting comorbidities such as cognitive impairment. Electroencephalography (EEG) is a diagnostic procedure that measures the electrical field potentials generated by several cortical neurons. The neuronal paroxysmal discharge that typifies seizures or a predisposition to seizures is recorded in the EEG as a paroxysmal electrical event, termed a spike, spike-and-wave, or sharp wave. An antiepileptic drug, also known as an anticonvulsant drug, is a compound that, when given chronically and in appropriate dosages, will prevent the recurrence of seizures in a patient with epilepsy. Medically refractory epilepsy refers to that where the seizures are not controlled by at least two different antiepileptic drugs given in appropriate dosages and with therapeutic drug levels in the blood. Before 1993, the drugs available to physicians who care for children with epilepsy were phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuximide, and the benzodiazepines. Of the latter group,

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pilepsy is a chronic condition which affects almost two million people in the United States, with the greatest incidence in young children and the elderly. Up to 3% of the population will have epilepsy at sometime in their life.1 While the goal of seizure management is complete control of seizures with little or no adverse effects, only about 60% of patients become seizure-free with treatment with a single antiepileptic drug (AED). Approximately 30 to 40% of patients will continue to have seizures despite the use of AED either alone or in combination.2 The economic aspects of epilepsy in children are considerable and differ from that in adults. These differences relate to the social and emotional impact of this chronic illness, as well as the developmental and cognitive comorbidities, incidence of refractory epilepsy in children, hospital admissions, and diagnostic tests. Children have access to medical services only with the help of a caregiver, which may result in lost work days or underemployment. Similarly, the special child care needs of children with epilepsy may require one caregiver to stay at home with the child, impacting the ability to work outside the home. The mean annual cost per child with epilepsy in the United States has been estimated to be $1853 for a child with seizures that are controlled and $4950 for a child with medically refractory epilepsy. Hence, seizure control is associated with a significant reduction in the economic costs of epilepsy.3 This article will provide a comprehensive overview of the newer AED. Before embarking on this task, a

E

Vigabatrin Felbamate Gabapentin Lamotrigine Topiramate

Pregabalin Fosphenytoin Tiagabine Zonisamide Levetiracetam Oxcarbazepine

Clobazam Carbamazepine Clonazepam Valproic Acid Ethosuxamide Diazepam Phenytoin Phenobarbital Bromide

1850

1900

1920

1940

TABLE 1. Characteristics of the ideal AED

Characteristics of the ideal AED Broad spectrum Safe No drug–drug interaction Long half-life No cognitive side effects Use-dependent mechanism Alters natural history of epilepsy

TABLE 2. AED and hormonal contraception

1960

1980

2000

FIG 1. History of antiepileptic drug development.

clonazepam, while available for some time, has never found common usage as a first-line drug because of its sedative properties and the development of tolerance. Nitrazepam is used in Canada, but has properties similar to that of clonazepam and is not widely used. The other benzodiazepine, clobazam, is not available in the United States, but is used widely in Canada. It has a broad spectrum of effectiveness against both partial and generalized seizures, in both adults and children.4 These “traditional” AED have the advantage of familiarity; however, there is much room for improvement given the fact that many patients are left with ongoing seizures and intolerable side effects. Since 1993, 10 new AED have been approved by the US Food and Drug Administration (FDA) and, as a result, the treatment options for children and adults with epilepsy have been expanded considerably (Fig 1).

AED that do not interfere with hormonal contraception

AED that interfere with hormonal contraception

Benzodiazepines Vigabatrin Zonisamide Tiagabine Lamotrigine Gabapentin Levetiracetam Valproate Ethosuximide

Felbamate Oxcarbazepine Topiramate Phenobarbital Phenytoin Carbamazepine Primidone

The Ideal AED

In broad terms, the new AED have comparable efficacy when compared with the traditional AED. Efficacy is determined by RCT trial and required for drug regulatory purposes, but is not sufficient to determine optimal treatment. While efficacy is the ability to produce the desired effect of seizure control, effectiveness is a combined measure of efficacy and tolerability. The new AED offer improved pharmacokinetic profiles, fewer side effects, and fewer drug– drug interactions, resulting in superior effectiveness when compared with the traditional AED, thus making their use in children especially attractive.

In reviewing the new AED, indeed when considering the older drugs, it becomes apparent that while some drugs have some characteristics of the ideal AED, such an anticonvulsant drug does not yet exist (Table 1). A key feature of the ideal AED is a broad spectrum of anticonvulsant activity in which the drug is effective against all seizure types in children, including seizures that are rare in adults, such as infantile spasms, absence seizures, and the myoclonic epilepsy syndromes. Valproic acid (VPA) does meet this criterion. The ideal drug should also be completely safe and have no drug– drug interaction so that it could be given in any situation and not disrupt other pharmacotherapy, including oral contraceptives (Table 2). Gabapentin meets these criteria. A very long half-life would allow for the ideal AED to be given only once a day. Phenobarbital, with its half-life of 96 hours, fits this criterion the best. The ideal drug would have no cognitive or behavioral side effects; unfortunately, no existing drug fits this criterion because all AED have the potential to induce serious cognitive and behavioral side effects. The ideal AED would have a use-dependent mechanism, in which the drug is dormant in the interictal state and activated by the epileptogenic process. There is no compelling evidence that any of the drugs, new or old, have such a use-dependent mechanism. The ideal AED would

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Efficacy versus Effectiveness

Seizure

Generalized

Convulsive

Non-convulsive

Focal/Partial

Simple

Complex

FIG 2. Clinical classification of epileptic seizures.

have no teratogenic effects. Finally, the ideal AED would affect the fundamental epileptogenic process and thus alter the natural history of epilepsy. As discussed in some detail below, all of the currently available AED do not alter the natural history of epilepsy, but rather provide symptomatic relief against seizures.

Classification of Seizures and Epilepsy Syndromes

those in which the first clinical change of the seizure and the ictal EEG pattern are consistent with bilateral hemisphere origin. This pattern is distinguished from partial or focal seizures characterized by seizure semiology or findings at investigation that demonstrate a localized brain origin of the seizures. Generalized seizures may then be divided into convulsive and nonconvulsive seizures, based on the semiology of the ictus. Focal seizures may be classified as simple, if consciousness is maintained, or complex, if consciousness is altered. Identification of epilepsy syndromes is particularly relevant in pediatrics, as most of these conditions present in childhood and syndrome identification may help to guide diagnostic and genetic tests, direct treatment, inform prognosis, and provide insight into pathophysiologic mechanisms. A classification of epilepsy syndromes is presented in Figure 3. Syndromes may be divided into generalized and focal syndromes and then further classified as idiopathic, symptomatic, or probably symptomatic/cryptogenic. Idiopathic refers to syndromes with no underlying etiology that are often genetic and/or age-dependent. Symptomatic syndromes are those in which seizures are a result of one or more identifiable structural brain lesions. Probably symptomatic or cryptogenic is used to define syndromes that are believed to be symptomatic; however, no etiology has been identified.

The first step in the selection of an AED is proper characterization and classification of the seizures and, when possible, epilepsy syndrome. An epilepsy syndrome is a set of related symptoms, defined on the basis of seizure type, seizure location in the brain, EEG features, age of onset, related symptoms, and sometimes, etiology. The classification of seizures and epilepsy syndromes is an ongoing process. The International League Against Epilepsy (ILAE) has made major contributions to this field through the Commission on Classification and Terminology. The original contribution, published in 1981, has provided common terminology and an organizational framework for physicians in the care and treatment of patients with seizures and epilepsy.5 In 1989, the Commission proposed revisions to the original classification; however, the basic system remained unchanged.6 In 2001, the ILAE Commission weighed in again with a new Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy.7 This model introduces a new standardized approach to the description of patients with seizures, using five axes: ictal phenomenology, seizure type, syndrome, etiology, and impairment. Despite changes in the approach to classification and terminology, a clinical classification of epileptic seizures is helpful to the physician treating children with epilepsy. A commonly employed classification is presented in Figure 2. Generalized seizures are defined as

To understand the pathogenesis of epilepsy, it is necessary to grasp the fundamentals of neurotransmission in the brain (Fig 4). Neurotransmission consists of the translation of an electrical signal to a chemical signal back to an electrical signal in a single neuron. The electrical signal is the wave of depolarization that sweeps down the axon to the dendrites. This results in release of a chemical, or neurotransmitter, into the synaptic cleft that separates the presynaptic neuron, from whence the neurotransmitter was just released, to the postsynaptic neuron, the cell on which the just released neurotransmitter is poised to act. The neurotransmitter attaches itself to a specific recognition protein, the neurotransmitter receptor, in the postsynaptic neuronal membrane and this results in either an altered ion flow (ionotropic receptor) or a cascade of

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Pathophysiology of Seizures and Epilepsy Neurotransmission

Epilepsy Syndromes Generalized

Focal

Symptomatic Epileptic Encephalopathies

Idiopathic

Idiopathic

Symptomatic

Benign Myoclonic Epilepsy of Infancy

Early Myoclonic Encephalopathy

Benign Familial Infantile Seizures

TLE with MTS

Childhood Absence Epilepsy

Early Infantile Epileptic Encephalopathy

BECTS

Rasmussen Encephalitis

West Syndrome

Early-onset Occipital Epilepsy

Migrating Partial Epilepsy of Infancy

Juvenile Absence Epilepsy

Severe Myoclonic Epilepsy of Infancy

Late-onset Occipital Epilepsy

Juvenile Myoclonic Epilepsy

Myoclonic Astatic Epilepsy

GEFS+

Lennox Gastault Syndrome

Epilepsy with GTC on Awakening (only)

Landau-Kleffner Syndrome

Epilepsy with Myoclonic Absence

Epilepsy with CSWS

Progressive Myoclonic Epilepsies

FIG 3. Classification of epilepsy syndromes. GTC ⫽ generalized tonic clonic. CSWS ⫽ continuous spike and wave in sleep. TLE ⫽ temporal lobe epilepsy. MTS ⫽ mesial temporal sclerosis. GEFS⫹ ⫽ generalized epilepsy with febrile seizures plus. BECTS ⫽ benign epilepsy of childhood with centrotemporal spikes.

A fundamental tenet that is critical to the understanding of the pathogenesis of seizures, epilepsy, and the

mechanisms of action of antiepileptic drugs is that epileptogenesis, the pathogenesis of epilepsy, is distinct from seizurogenesis or ictogenesis, the pathogenesis of seizures. In human epilepsies, the initial seizure may be triggered by an acute event such as traumatic impact injury or ischemic insult, or result from a preexisting brain dysfunction.8-10 Hence, epilepsy often is an emergent phenomenon that results from a variety of brain malformations or pathologies. In fact, the spontaneous recurrent seizure that characterizes epilepsy is the end result of a neurobiological cascade of epileptogenesis about which we know very little11,12 (Fig 5). Animal models used to study seizures rarely provide adequate models of human epileptogenesis, because the genetic or acquired insults that trigger this epileptogenic cascade in humans is not present in experimental animals where the epileptogenic trigger is typically status epilepticus, usually in a normally formed adult rat brain.13 The exception to this is absence epilepsy, which is well modeled in animals.14 The lack of clinically relevant animal models of epilepsy is important because the development of effective new AED are dependent on the availability

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second messenger events (metabotropic receptor) with a resultant translation back to an electrical signal, the hyperpolarization of the postsynaptic membrane and inhibition, or depolarization of the membrane and excitation. There is a very complex and intricate cascade of molecular events that are operative in this process, but they are beyond the scope of this discussion. However, we will discuss the major excitatory neurotransmitter in the brain, glutamate, and the most ubiquitous inhibitory neurotransmitter, ␥-amino butyric acid (GABA), because these two neurotransmitters play a major role in the pathogenesis of seizures. As well, GABAergic and glutamatergic mechanisms are frequent targets for the mechanisms of action of antiepileptic drugs (Fig 4). In children, neurotransmission is confounded by the process of development as manifested by synaptogenesis, circuitry formation, and brain plasticity, all of which work in concert to alter brain function in both normal states and abnormal states such as epilepsy.

Pathophysiology of Epilepsy

Developmental, Genetic and Environmental Factors

Seizure-induced Plasticity, Apoptosis and Neurogenesis

SEIZURES

Age of Child

EVENT

CASCADE OF CRITICAL MEDIATORS

AED

FUNCTIONAL CHANGE IN BRAIN

Transcriptional Changes

EPILEPSY

Behavioral and Cognitive Problems

EPILEPTOGENESIS FIG 5. Epileptogenesis. The process of epileptogenesis entails a cascade of transcriptional changes in brain triggered by an interaction of genetic and environmental factors at a specific point in time. The neurobiological results of these transcriptional changes can be quite varied and include plasticity, apoptosis, and further neurogenesis. Clinically, epilepsy may be but one of many outcomes. (Modified from Cortez and coworkers, 2005.12)

not alter the neurobiology of epileptogenesis or to alter the natural history of epilepsy.15,16 For this reason there is some imperative to think differently about the modeling of epilepsy.

Pathophysiology of Seizures

of such models. All currently available drugs were developed using animal models of seizures, not epilepsy; therefore, in keeping with the currently accepted theoretical construct of epileptogenesis, these drugs are anticonvulsant, not antiepileptogenic.15 Indeed, the term “antiepileptic drug” is a misnomer. These drugs suppress seizures and provide effective symptomatic therapy for epilepsy; however, they do

The seizure is the end result of the epileptogenic process (Fig 5). With the exception of absence seizures, a seizure results from an excess of excitation over inhibition in the brain. When a critical number of neurons synchronously depolarize and generate action potentials, a seizure is initiated. The hallmark of this synchronous discharge of neurons where there is an epileptic focus, ie, a partial seizure, is the paroxysmal depolarizing shift (PDS), which is a large sustained, glutamate-mediated, depolarization of the neuron (Fig 6). This long depolarization triggers a train of action potentials and is followed by a large GABA-mediated hyperpolarization that serves to limit the duration of the discharge. The PDS corresponds to an epileptic spike on the EEG. The spike is typically an interictal phenomenon, ie, between seizures. During a seizure, the epileptic neurons undergo a prolonged depolarization with a continuous burst of action potentials without an intervening repolarization. An EEG during this event shows continuous spikes and the associated seizure semiology is a tonic seizure. The large GABA-mediated inhibitory potential occurs

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FIG 4. Actions of antiepileptic drugs at excitatory and inhibitory synapses. Although not depicted in the diagram, several antiepileptic drugs have an effect on L-type high-voltageactivated calcium channels. The significance of this to neuronal excitability is unclear. AMPA ⫽ ␣-amino-3-hydroxy-5-methyl-4isoxazoleproprionic acid; GABA-T ⫽ GABA aminotransferase; GAD ⫽ glutamate decarboxylase; HVA ⫽ high-voltageactivated; LEV ⫽ levetiracetam; NMDA ⫽ N-methyl-Daspartate. Reproduced with permission from Sankar and Holmes, 2004.109

FIG 6. Diagram of cellular events corresponding to behavioral and electroencephalographic changes during the interictal and ictal periods. The bottom diagram demonstrates the PDS, a large and prolonged depolarization with generation of action potential spikes (arrow) (VM is the voltage across the membrane). The horizontal bars at the bottom of the figure represent the period during which the particular channel is open (gNa⫹, gCa2⫹, gK⫹ refer to conductances of the ions across the membrane); the beginning of the bar indicates the opening of the channel and the end of the bar indicates its closure. At the onset of the PDS, the AMPA channel opens, which allows Na⫹ to enter the cell and begin the process of depolarization. The NMDA channel then opens allowing both Na⫹ and Ca⫹ to enter. Following depolarization, there is opening of the K⫹ and activation of GABA channels with Cl⫺ entering the cell. Both the influx of Cl⫺ and efflux of K⫹ lead to hyperpolarization on the cell. The PDS corresponds to a spike or sharp wave on the EEG (top of diagram). During an actual seizure (ictus), there is a failure of adequate inhibitory mechanisms and no hyperpolarization following the PDS occurrence. This prolonged depolarization with action potentials corresponds to the tonic phase of the seizure. When inhibition is reinitiated, there are brief periods of depolarization followed by hyperpolarization. This period corresponds to the clonic phase of the seizure. (Modified from Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. McGraw-Hill, 2000, with permission. .9Reprinted with permission from Holmes and Ben-Ari, 2001.17)

and alternates with rhythmic glutamate-mediated PDS. During this alternating pattern, the EEG demonstrates generalized spike-and-wave discharges and the associated seizure semiology is a clonic seizure (Fig 6). The mechanism by which the spike transitions to the seizure is unknown, as is the mechanism by which the seizure ultimately stops.17,18 The fundamental underlying mechanisms of absence seizures differ significantly from that described above and have been delineated as well as any mechanism of human epileptogenesis.1,19 Absence seizures represent a perturbation of normal oscillatory neuronal rhythms generated by the thalamocortical circuitry in the brain. In absence seizures, GABA-mediated inhibition and low-voltage activated or T-type calcium current activity becomes phase locked with glutamate-mediated excitation within thalamocortical circuitry with result-

ant abnormal oscillatory rhythms that characterize absence seizures.19,20 Hence, unlike primary generalized epilepsy as manifested by generalized tonic, clonic, or tonic– clonic seizures or partial seizures, all of which are caused by an increased glutamatemediated excitation in the brain, absence seizures are caused by increased GABA-mediated inhibition within thalamocortical circuitry.14 Finally, it should be noted that the pathophysiology of both seizures and epilepsy are dependent on developmental stages of brain function and, in some instances, on gender. For example, GABA, which is most often referred to as an inhibitory neurotransmitter, has been demonstrated to have major excitatory properties in early postnatal brain development in experimental animals. These developmental changes are dynamic and responsible for the fact that the

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TABLE 3. Factors that distinguish epilepsy in children

Factors that distinguish epilepsy in children The immature brain is more susceptible to seizures. Pharmacokinetics are unique in children. Comorbid cognitive and behavioural conditions are common. Children present with seizure types and syndromes not seen in adults.

immature brain is more susceptible to seizures, but less vulnerable to seizure-induced brain injury.17

The Care of Children with Epilepsy Epilepsy in children is unique for several reasons (Table 3). First, the immature brain is more susceptible to seizures. This is indicated by the fact that the highest incidence of seizure is in the first decade of life and that most epilepsy syndromes begin in childhood. Animal models of epilepsy further demonstrate that the immature brain is more susceptible to seizures, likely related to the slow development of inhibitory circuits in the face of rapidly developing excitatory circuits.17,21,22 Second, pharmacokinetics are unique in children. Drug clearance is highest in neonates, up to four times that of adults. Drug clearance then declines with age, reaching adult values in adolescence. This can result in the need for more frequent monitoring of drug levels and alterations in dose in children.23 Third, children present with seizure types and syndromes not seen in adults. Infantile spasms are an excellent example of an age-related seizure type that may present in association with a variety of underlying brain disorders. Childhood absence epilepsy is a wellcharacterized epilepsy syndrome that presents at school age and usually resolves by adulthood. Finally, comorbid cognitive and behavioral conditions are very common in children. Conditions such as attention deficit and hyperactivity disorder, autism, and mental retardation are more common in children with epilepsy.24,25 These conditions may complicate the initial diagnosis of epilepsy in children and often require consideration when selecting an AED.

TABLE 4. Historical features in the initial evaluation of a seizure

Historical features in the initial evaluation of a seizure I. Clinical features of the seizure a. Was there any warning (aura)? b. Where did the seizure begin? c. What did the seizure look like? d. How long did it last? e. Any urinary or fecal incontinence? f. Was consciousness impaired during the seizure? g. Was there impairment of mental or motor function before or after? II. Antecedent events a. Drug ingestion b. Febrile illness c. Head trauma III. Family history of seizures IV. Developmental history

Initial Evaluation of a Child with Seizures

they are acute or of recent onset, is to obtain a careful history of the event. Seizures are divided into the aura and ictus for clinical convenience. The aura is caused by a paroxysmal discharge of neurons, and the symptoms of the aura are related to the area of the brain that is activated. Hence, the aura is actually a simple partial seizure. In young children, specific questioning may be required to elicit information about the aura. Although the aura in some children may be one of fear, this should not always be the case. It may be that the aura is something else that frightens the child. The observed symptoms may appear to be fear. The clinical ictal event, including onset, offset, and presence or absence of incontinence, should be carefully described by the caregiver and, when able, the child. In addition, the description of a postictal state is important in terms of ascertaining whether or not the event was really a seizure and in separating absence seizures from complex partial seizures. Antecedent events are an important part of the history. These include fever, drug ingestion, and head trauma. Family history is also important since a strong positive family history of seizures may have prognostic implications for future seizure control and recurrent seizures. A careful developmental history should be obtained, since children with preexisting neurologic or developmental abnormalities may do more poorly than normal children in terms of future seizure control. The critical features to elicit on history are presented in Table 4.

History

Physical Examination

As with any diagnostic problem in medicine, the initial approach to the patient with seizures, whether

A careful physical and neurologic examination should be conducted in all patients. There may be

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marked changes in the neurologic examination during the postictal period, following a seizure. Therefore, if focal findings are noted in the postictal period, the child should be reexamined periodically until the postictal period is over to monitor for resolution of the findings.

Laboratory Evaluation

TABLE 5. Diagnostic studies in the evaluation of epilepsy

Diagnostic studies in the evaluation of epilepsy 1. Blood chemistry (exclude treatable cause) a. Glucose b. Blood urea nitrogen, creatinine, calcium, phosphorus, electrolytes if indicated by clinical circumstance only II. EEG Controversial after first seizure, but indicated after recurrent or prolonged seizures III. Lumbar puncture Indicated if fever accompanies seizure, otherwise usually not IV: CT or MRI (preferable) scan a. Focal (partial) seizure b. Prolonged (15 minutes) seizure c. Focal EEG abnormality d. Focal finding on neurologic examination before (preexisting), during, or after seizure e. Age of onset 15 years or older

The object of the initial laboratory evaluation should be to rule out causes of seizures requiring acute treatment. The only laboratory test that is mandatory following a seizure in the acute period is serum glucose to rule out hypoglycemia. Other studies such as electrolytes, calcium, phosphorus, and magnesium are not indicated in the absence of clinical features suggestive of abnormalities. A generalized convulsive seizure may result in hyperglycemia, leukocytosis, and lactic acidosis secondary to massive autonomic discharge. These findings, if present, should be recognized as a result rather than the cause of a seizure. Other laboratory studies, such as tests for inborn errors of metabolism and intoxication, are predicated on the history, characteristics of the seizure, family history, and physical examination. Infantile spasms and simple partial seizures in particular may be symptomatic of a number of congenital, acquired, or progressive neurologic diseases. The use of EEG after a first seizure remains controversial. The American Academy of Neurology (AAN) practice guidelines recommend an EEG be performed after the first unprovoked seizure in a child; however, other publications have disagreed.26,27 For recurrent or prolonged seizures an EEG is certainly indicated. EEG may help to identify the etiology of seizures or an epileptic syndrome, which may inform treatment and prognosis. A lumbar puncture is often indicated in children with seizures and fever. Simple, uncomplicated febrile seizures in children older than 18 months of age do not require a lumbar puncture; however, the procedure should always be considered. It is axiomatic in medicine that fever plus seizure equals meningitis unless proved otherwise. Conversely, if there is no fever, a lumbar puncture is rarely indicated in the evaluation of a seizure disorder, unless it is to evaluate for rare metabolic conditions. MRI is preferred over CT scanning for seizures because of the false-negative rate of the latter, particularly for cortical dysplasia, which may be responsible for a variety of epileptiform disorders.

The diagnosis of a generalized convulsive seizure is usually fairly simple, particularly with a good history or when seen by a member of the health care team. However, difficulties in diagnosis may arise when the history is not of a generalized movement, but of some episodic behavior, such as staring, rage, or some other paroxysmal abnormality. In this setting, history is of paramount importance. One should attempt to ascertain if the behavior is situational or spontaneous, specifics of the onset and offset of the event, whether the patient has incontinence or an alteration of consciousness during the event, and whether there is a postictal state. The differential diagnosis of such a paroxysmal behavioral event usually includes generalized absence seizures, complex partial seizures, and nonepileptic seizures. The differentiation of complex partial and absence seizures is critical, as the AED choice is predicated on the seizure type since drugs effective against partial seizures may exacerbate generalized absence seizures. Furthermore, neuroimaging is indicated in the evaluation of partial seizures but not for generalized absence seizures. A careful history and an EEG are usually sufficient to arrive at a diagnosis. Absence seizures are characterized by the three following features: (1) brevity: they rarely last longer than 30 seconds and never longer than 1 minute; (2) the absence of an aura; and (3) the absence of a postictal state. Conversely, complex partial seizures are more prolonged, lasting minutes, and have an aura and a postictus. It may be helpful to ask the child

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The use of diagnostic studies in the evaluation of seizures and epilepsy is summarized in Table 5.

Differential Diagnosis

TABLE 6. Factors that distinguish typical absence and complex partial seizures

Absence seizure

Complex partial seizure

Short duration, usually less than 30 seconds No aura No postictal period

Longer duration, usually several minutes Aura often present Postictal fatigue, confusion, or emotional change often present Less frequent

May cluster or occur frequently through the day

TABLE 7. Evidence for true seizure

Evidence for true seizure 1. Paroxysmal symptoms 2. Clear impairments of motor function or sensorium associated with ictus 3. Urinary or fecal incontinence 4. Electrographic correlate, may require EEG video monitoring

about the presence of an aura, specifically, if they were frightened immediately before the onset of the seizure or confused immediately afterward (Table 6). The list of nonepileptic episodic disorders in children is long. Many are difficult to differentiate from true seizures (Table 7). Video-EEG monitoring may be indicated to differentiate nonepileptic from epileptic seizures.

The Treatment of Epilepsy in Children Childhood is a vulnerable time developmentally, socially, and cognitively. The reasons for the treatment of epilepsy in children encompass many factors.

Brain Damage

Progression of Seizures and Epilepsy The concept that “seizures beget seizures” is longstanding and controversial.16 The experimental paradigm used to support this hypothesis is the kindling model of partial seizures. Kindling is the phenomenon in animal models of epilepsy whereby repeated application to the brain of a chemical or electrical stimulus that is initially weak and subthreshold for seizure, in the end, produces a seizure. Hence, an epileptogenic focus is “kindled in the brain.” Although there is considerable experimental evidence to support the idea that seizures induce more seizures, whether kindling is a clinically relevant phenomenon in humans is uncertain.12 Gowers was the first to put forth this concept in 1881 when he wrote that “The tendency of the disease [epilepsy] is toward self-perpetuation; each attack facilitates the occurrence of the next by increasing the instability of the nerve elements.”16 However, the clinical data do not appear to support this idea.16,27 Half or fewer patients with first seizures have a second seizure. Furthermore, if seizures beget seizures, then successful treatment of seizures should improve the natural history of epilepsy; however, this is not the case.16,28 Epilepsy does occur after prolonged status epilepticus in humans, but this is more akin to the frank brain injury induced in the animal models of seizure-induced neuronal damage following prolonged seizures.29,30 The relevance of this phenomenon to garden-variety epilepsy is not at all clear.

Effect of Seizures on Learning and Cognition While it is difficult to differentiate the effects of seizures, AED treatment, and underlying neuropathology on the cognitive profiles of children with epilepsy, there is no doubt that children with epilepsy are at risk for learning difficulties. There is increasing evidence that even conditions once believed to be “benign” are associated with attention and learning disorders.31-33 Furthermore, in adults, cognitive problems have been shown to progress over time in individuals with temporal lobe epilepsy.34

In some patients, frequent seizures appear to cause progressive neurologic impairment and structural lesions, such as hippocampal atrophy, which may progress over time. Indeed, it has long been known that seizures are associated with brain damage and neuronal cell loss in children.12,17 There is a major developmental confound in considering the correlation between cell death and seizures. The immature brain is more susceptible to seizure generation, but less vulnerable to seizure-induced brain injury.17 One possible reason for the lower seizure threshold of developing brain may lie in the differential expression of the excitatory ionotropic receptors, NMDA and AMPA, and the GABA inhibitory ionotropic receptor. Early in development, GABA has been shown in experimental adults to be excitatory rather than inhibitory.

Even when seizures are controlled, people with epilepsy attain lower educational levels, are less likely to marry, and are more often unemployed.35 Measures of health-related quality of life in children with epilepsy demonstrate increased problems with mental

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Quality of Life

health, social roles, and self-esteem when compared with healthy children.36 Even when compared with children with other chronic illnesses, such as asthma, children with epilepsy display more school and social problems.37

Morbidity and Mortality Accident rates are increased in people with epilepsy, although not only related to seizures. Minor injury related to seizures, including bumps, bruises, and lacerations of the head, are relatively common, while more serious injuries are fortunately rare.38 Increased mortality in people with epilepsy has been consistently reported.39 Children with epilepsy are reported to have a 13 times higher risk of death when compared with the general population; however, much of this may be attributed to the disease underlying the epilepsy.40 While deaths in epilepsy may be related to the underlying cause of the epilepsy or the effects of an acute seizure, there is also the condition of Sudden Unexplained Death in Epilepsy (SUDEP), which is poorly understood. The largest study of SUDEP in children demonstrated a minimum incidence of 2 deaths per 10,000 years of epilepsy.41

When to Treat Seizures

TABLE 8. Basic principles in the medical treatment of epilepsy (Modified from Beyenburg et al, 2004108)

Basic principles in the medical treatment of epilepsy Determine the need for AED treatment (more than one unprovoked seizure) Determine seizure type and epilepsy syndrome and chose appropriate first line AED Increase AED to appropriate dose for body weight If seizures continue and drug levels are available for the drug you have chosen, check levels and adjust to therapeutic levels — 70% of patients will respond at this point and become seizure free If seizures continue in the face of maximally tolerated doses of the first AED, add a second drug and go through the same process — another 5% will respond and become seizure free If the child is seizure free on two drugs, consider tapering the first one tried If seizures continue in the face of two AED, the child is now officially medically refractory and should be considered for epilepsy surgery if there is a lesion or the seizures are localization related. Additional AED may be added on, but the success rate is 1% or less. If the child continues to be refractory and is not a candidate for resective surgery, other alternative therapies, ie, the ketogenic diet, or vagal nerve stimulation, should be considered.

TABLE 9. Exacerbation of specific seizure types by AED

AED

Seizure type exacerbated

CBZ OCZ PHT PB LTG TGB

Absence, atonic, myoclonic Atonic, myoclonic Absence, atonic, myoclonic Absence, atonic Myoclonic, absence Absence

The impetus to treat epilepsy is evident. If the child has presented in status epilepticus, has recurrent seizures, or has a strong family history of seizures, there is little doubt that anticonvulsant drug treatment is indicated. The need for AED treatment is less certain in the child who has had only one seizure. The literature reports a 30 to 70% recurrence rate of seizures in patients who experience a single seizure.42-45 A prospective study in children found the cumulative risk of seizure recurrence after a first unprovoked seizure to be 6% at 12 months, 36% at 24 months, 40% at 36 months, and 42% at 48 months.45 In children with an idiopathic first seizure, abnormal EEG was a predictor of recurrence. A positive family history was a predictor only in children with a history of prior febrile seizure or partial seizure. These data suggest that epilepsy is unlikely to develop in the majority of patients after a single seizure. Therefore, treatment would not seem to be indicated after a single seizure. The AAN has published a practice parameter that reiterates this, stating that AED treatment

following the first unprovoked seizure is not indicated for the prevention of epilepsy but may be considered in circumstances where the benefits of reducing the risk of a second seizure outweigh the risks of pharmacologic and psychosocial side effects.46 The basic principles of the medical treatment of epilepsy in children are outlined in Table 8. Once it is determined that drug treatment for epilepsy is indicated, there are multiple considerations in choosing an AED. The most critical factor is the type of seizure or epilepsy syndrome, particularly because certain AED are known to exacerbate specific seizure types (Table 9). Issues of pharmacokinetics, side effect profile, and drug– drug interactions also play a significant role in drug selection. Considerations in the selection of AED are listed in Table 10.

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CBZ, carbamazepine; OCZ, oxcarbazepine; PHT, phenytoin; PB, phenobarbital; LTG, lamotrignine; TGB, tiagabine.

TABLE 10. Considerations in the selection of antiepileptic drugs

Considerations in the selection of antiepileptic drugs Seizure type or epilepsy syndrome Side-effect profile Mechanism of action Drug interactions Pharmacokinetic profile Ease and speed of drug initiation Need for laboratory monitoring Cost

Development of New AED On its approval in 1993, felbamate (see below) was the first drug to be brought to market in the United States since the introduction of valproic acid in 1978. Following the release of felbamate, a number of additional new drugs were approved over the next 12 years (Fig 1). The reason for this relative flood of new AED in the last 10 years was the development of the AED screening program by the National Institutes of Health (NIH) in the United States. Historically, AED have been discovered by serendipity, although with the advent of new understanding about mechanisms of epileptogenesis, we can expect to see more designer drugs targeted at a specific mechanism. At the present time, any new drug suspected of having clinical potential as an AED can be tested in a host of animal model screens set up by the NIH designed to predict anticonvulsant activity against particular seizure types.15 The routine screening of compounds for anticonvulsant activity begins with evaluating the ability of the test agent to protect adult rodents against seizures in the maximal electroshock model and the threshold pentylenetetrazol chemoconvulsant model. Screening for toxicity generally involves the rotarod test, a test of motor coordination rather than cognition or memory. These screening paradigms are used to calculate the therapeutic index, a ratio of the toxic dose to effective dose. A high ratio indicates promise for the market and leads to more careful preclinical screening in other animal models that use adult male rodents with normal brains. If the therapeutic promise is verified, and particularly if a broad anticonvulsant spectrum is found, then the drug will progress to teratogenic testing in animals. If there is no, or limited, potential for teratogenicity, clinical pharmacokinetic and toxicological testing is undertaken in Phase 1 trials. Finally, if the putative AED passes these hurdles, clinical efficacy testing begins, usually as add-on

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treatment in adult patients with medically refractory localization-related epilepsy. These drugs are tested in children only after efficacy is shown in adults. Hence, the majority of AED used in childhood epilepsy were developed in adult animals for adult patients.

Mechanisms of Action of Antiepileptic Drugs At the outset it should be reiterated that “antiepileptic drug,” although accepted nomenclature for these compounds, is a misnomer. As discussed above, these drugs are antiseizure or anticonvulsant, but do not alter the natural history of epilepsy in any way.16 The AED provide purely symptomatic treatment for seizure suppression and therefore are not truly antiepileptic. To exert anticonvulsant activity, a drug must act at one or more target molecules in the brain that are involved in seizuregenesis. Currently there are no drugs that target the cascade of signaling changes in the brain that represent the epileptogenic process (Fig 5). Rather, virtually all of the available AED, both old and new, are aimed at the end result of epileptogenesis, the seizure. This is generally accomplished by modifying the bursting properties of neurons and reduction of synchronization in both localized and generalized neuronal circuits. To achieve these aims, these drugs target one or more molecules in the brain, virtually all intended to either enhance GABA-mediated inhibition or decrease glutamate-mediated excitation, with the noted exception of absence seizures, where the target is more thalamocortical circuitry.47 These targets include ion channels, neurotransmitter transporters, and neurotransmitter metabolic enzymes. The targets of specific AED are summarized in Table 11 and Figure 4 and are discussed under each AED reviewed below.

New Drugs in the Treatment of Epilepsy in Children As mentioned above, in the past 10 years, 10 new anticonvulsant medications have been brought to market in the United States (Table 12). The advent of these medications has been encouraged by the suboptimal performance of the traditional AED. The new AED offer equal efficacy to the traditional AED with improved tolerability, pharmacokinetic properties, and side effect profiles. With many new medications available, the clinician treating children with epilepsy must be well versed in the application of these drugs to their

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TABLE 11. Antiepileptic drugs and their molecular targets (Reproduced with permission from Rogawski and Loscher, 200447)

Drug Predominant sodium Phenytoin Carbamazepine Oxcarbazepine Lamotrigine Zonisamide

Sodium channels*

Calcium channels*

GABA system*

Glutamate receptors*

(and calcium) channel activity INaF, INaP INaF INaF INaF HVA INaF T-type

Partial seizure

GTC seizure†

Absence seizure†

Myoclonic Infantile seizure† spasms†,†

⫹ ⫹ ⫹ ⫹ ⫹

⫹ ⫹ ⫹ ⫹ ⫹

⫺ ⫺ ⫺ ⫹ (⫹)

⫺ ⫺ ⫺ (⫹/⫺) (⫹)

⫹ ⫹ ⫹ ⫺

⫹ ⫹ ⫹ ⫺

⫹ (⫹) (⫹) ⫹

⫹

⫹ ⫹

⫹ (⫹)

⫺ (⫹)

⫹

⫹

⫺

⫹ ⫹

⫹ ⫹

⫹ ⫺

⫹

⫹

LennoxGastaut†

(⫹)

⫹ (⫹)

(⫹)

(⫹) ⫹ ⫹

⫹

(⫹) (⫹)

Mixed, complex, or poorly understood actions Valproate Felbamate Topiramate Ethosuximide

INaF? INaP? INaF INaF, INaP INaP?

T-type? HVA HVA T-type

Gabapentin Levetiracetam§

HVA (␣2␦) HVA

Phenobarbital

HVA

GABA-mediated mechanisms Benzodiazepines Vigabatrin Tiagabine

1 GABA turnover NMDA GABAA R KA/AMPA GABAA R 1 GABA turnover Reverses DMCM AMPA GABAAR GABAAR GABAT GABAtransporter

(⫹)

⫺ (⫹)

⫹ ⫺

‡A catastrophic epilepsy syndrome usually beginning in the first year of life in which there are typically “jackknife spasms” (myoclonic seizures involving the muscles of the neck, trunk, and limbs, with nodding of the head and stiffening of the arms) and a disorganized cortical discharge termed hypsarrhythmia. *Molecular targets. Not all molecular targets are shown; additional targets are discussed in the text. †Clinical efficacy of drugs on symptoms. Clinical evidence: ⫹ indicates controlled trials or several open-label trials and general acceptance of utility; parentheses indicate less extensive base of evidence. ⫺ indicates evidence of lack of efficacy or worsening. §Levetiractam binds with high affinity to synaptic vesicle protein 2A (SV2A), a ubiquitous 90-kDa protein that is associated with synaptic vesicles and is believed to participate in the regulation of Ca2⫹- dependent neurotransmitter release: SV2A-knockout mice exhibit seizures130. AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, ␥-aminobutyric acid; GABAAR, GABAA receptor; GTC, generalized tonic-clonic; HVA, high voltage activated: INaF, fast sodium current: INaP, persistent sodium current: KA, kainate; NMDA, N-methyl-D-aspartate. DMCM (methyl-6,7-dimethoxy-4-ethyl-␤-carboline-3-carboxylate) is a negative allosteric modulator of GABAA receptors. Adrenocorticotropic hormone and prednisolone are recognized treatments for infantile spasms. Lamotrigine is also effective in myoclonic astatic epilepsy, but causes worsening of other forms of myoclonic epilepsy. Gabapentin has been associated with focal myoclonus.

Felbamate gained approval for use in the United States in 1993, making it the first new AED to come to

market in 15 years. Initially, no serious adverse effects were recognized. Unfortunately, within the first year of approval, with about 100,000 exposures, two major, life-threatening adverse side effects emerged: aplastic anemia and hepatic failure. While the latter complications seemed to occur in conjunction with felbamate polytherapy, the former was far more serious because it seemed to have the potential to occur with felbamate monotherapy and because it was more deadly. Reports suggested that felbamate-related aplastic anemia was idiopathic and occurred most commonly in adult women. Few children under the age of 14 have been reported with this complication. The incidence of aplastic anemia with felbamate may be as high as 1:8000.48 Felbamate remains on the market in the US but with a black box warning for aplastic anemia and hepatic failure and is not considered a first-line anticonvulsant medication.49 Rather, this drug is restricted to only the most intractable patients with epilepsy and can be admin-

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TABLE 12. New AED in the last 10 years

New AED brought to the market in the last 10 years Felbamate* Fosphenytoin Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Vigabatrin† Zonisamide *Felbamate is not considered first-line therapy. †Vigabatrin is not approved for use in the United States.

patient population. The new AED and their use in children will be reviewed in the remainder of this article.

Felbamate (Felbatol©)

istered only by a neurologist. Felbamate is not available in Canada or Europe. The production of a reactive metabolite, atropaldehyde, has been hypothesized as the toxic intermediate resulting in both liver failure and aplastic anemia. There is no predictive test for aplastic anemia with felbamate. Since 1994, it is estimated that 8000 to 10,000 patients are treated annually with felbamate. Two additional cases of aplastic anemia have been reported since the initial cases occurred. To date, there have been no additional reports of liver failure.50 Felbamate is a congener of the muscle relaxant meprobamate and has been shown to have efficacy in Lennox–Gastaut syndrome and partial seizures in children.51,52 Felbamate has a broad spectrum, perhaps analogous to that seen with VPA, with activity against generalized convulsive, partial, and absence seizures.53 A number of different mechanisms of action for felbamate have been proposed.49 These include sodium channel blockade, calcium channel blockade, and antagonisms of NMDA and AMPA receptors. One disadvantage of felbamate is the short half-life, requiring three times a day dosing. Furthermore, its route of elimination is over 90% hepatic, resulting in major interactions with other AED. This proved to be a significant problem since felbamate was used almost exclusively as an add-on drug in intractable epilepsy, as is any new AED when it first appears on the market. Felbamate was associated with a 30% decrease in carbamazepine with a concomitant increase in carbamazepine metabolites. In addition a 20 to 50% increase in phenytoin levels and a 25 to 50% increase in valproic acid levels were observed to occur when these drugs were used with felbamate. Felbamate is supplied as 400- and 600-mg tablets and in an oral suspension of 600 mg/5 mL. Think Felbamate. Think Felbamate only for children with severe, medically refractory seizures associated with Lennox–Gastaut syndrome who have failed treatment with all other drugs indicated for that disorder.

rapidly and totally converted to phenytoin; 1.5 mg of fosphenytoin yields 1 mg of phenytoin. The anticonvulsant properties of fosphenytoin are fully attributed to phenytoin, which acts at the voltage-gated sodium channel. To avoid confusion, fosphenytoin is packaged in phenytoin equivalents (PE) and is ordered from the hospital pharmacy in that way. It may be used intravenously or intramuscularly. Fosphenytoin is most commonly used in the treatment of status epilepticus or as a substitute for oral phenytoin. Intravenous administration results in a reduced incidence of pain and burning at the infusion site compared with phenytoin, and the cardiac effects that are associated with phenytoin have not been reported with fosphenytoin.54 For these reasons, fosphenytoin has become the standard of care in many institutions. The high cost of fosphenytoin, when compared with phenytoin, has prompted some discussion of the cost benefit of this drug.

Gabapentin (Neurontin©)

Fosphenytoin is a prodrug of phenytoin, which was developed to avoid the adverse effects associated with the parenteral administration of phenytoin, ie, local pain after intravenous and more serious adverse effects such as cardiovascular complications. Fosphenytoin is

Gabapentin was approved in 1993 and is indicated as adjunctive therapy for partial seizures with and without secondary generalization in patients 3 years and older. It is effective for some children with refractory partial seizures.50 Gabapentin is also frequently prescribed for neuropathic pain. Gabapentin is structurally related to the inhibitory neurotransmitter GABA; however, it does not bind to GABA receptors. It is known to inhibit glutamate synthesis, potentiate GABA release, and act as a weak inhibitor of GABA transaminase. Gabapentin may also act as voltage-gated calcium channels. Despite these experimental observations, the precise anticonvulsant mechanism of action is not known.55 This drug was initially considered to be of low potency; however, this appears related to the low doses used when the drug first became available. Clinical practice has demonstrated good efficacy against partial seizures at higher doses. A doubleblinded, placebo-controlled study of gabapentin as add-on therapy in children with refractory partial seizures demonstrated superior efficacy in controlling partial seizures and secondarily generalized seizures when compared with placebo with good tolerability, and these results have been replicated.56 Gabapentin has also been proven effective as monotherapy in the control of seizures associated with benign epilepsy of childhood with centrotemporal spikes.57,58

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Fosphenytoin (Cerebyx©)

One of the major advantages of gabapentin is that it is 100% excreted unchanged via the kidneys and therefore has virtually no drug– drug interactions. It is easy to use as an add-on drug, or in children on chemotherapy or other medications for which drug interactions would not be tolerated, as well as in children with liver function impairment. The side effects are mild, usually related to somnolence. Weight gain has also been reported. No serious life-threatening adverse effects have been identified.49,55,56,59 The dose of Gabapentin is 20 to 50 mg/kg/d, with doses of up to 90 mg/kg/d reported. With a short half-life of 5 to 7 hours, this drug must be given in three divided doses. Gabapentin is supplied as 100-, 300-, or 400-mg capsules, 600- or 800-mg tablets, or in an oral suspension containing 250 mg/mL. Think Gabapentin. Think Gabapentin for children with partial seizures who need a drug with few side effects and no drug interactions.

Lamotrigine (Lamictal©) Lamotrigine was approved in 1994 for use as an adjunctive treatment in adults with partial onset seizures. It has now been approved for adjunctive therapy for partial seizures in children aged 2 years or older, as well as monotherapy in adults with epilepsy when converting from valproic acid therapy and in children with generalized seizures associated with Lennox– Gastaut syndrome.49,58 Lamotrigine exerts its anticonvulsant effects through voltage- and use-dependent blockade of voltage-dependent sodium channels and inhibition of highvoltage activation Ca2⫹ currents possibly through inhibition of presynaptic N-types Ca2⫹ channels.60 Lamotrigine has been shown to be effective as add-on therapy of refractory partial and generalized seizure in children.61,62 This drug is considered to have a broad spectrum of action, analogous to valproic acid, effective in partial seizures as well as a variety of generalized epilepsies including absence seizures and myoclonic seizures. It has been proven effective in Lennox–Gastaut syndrome and is commonly used in childhood absence epilepsy as well.63 Lamotrigine is known to produce a skin rash in up to 5 to 10% of patients. These rashes have the potential to be severe and life-threatening and Stevens Johnson syndrome may occur rarely. Severe rash occurs more often in children; up to 1% incidence has been reported.64 The risk of rash is related to the dose and the speed of titration, which necessitates low starting

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doses and slow titration. Other risk factors for development of serious rash are younger age and concomitant use of valproic acid, discussed below. Additional side effects include dizziness, headache, ataxia, and diplopia. Lamotrigine may worsen myoclonic seizures, although it may also help them. Lamotrigine is metabolized by the liver and therefore sensitive to interactions with other drugs that induce hepatic enzymes. Lamotrigine generally does not cause pharmacokinetic interactions; however, it has been associated with a 25% decrease in levels of valproic acid. Hepatic enzyme inducers such as carbamazepine and phenytoin will decrease the half-life of lamotrigine to 15 hours, which may require dosing alterations. The most important interaction to note is that the half-life is very prolonged, 60 hours, when lamotrigine is used in combination with valproic acid.65 The elevated lamotrigine levels which occur when used in conjunction with valproic acid significantly increase the risk of skin rash and care must be taken when using these drugs in combination. To reduce the risk of severe skin rash, a long slow titration of dose is required when used alone or in combination with other AED.49 Oral contraceptives are associated with a 50% reduction of the mean-steady state plasma concentration of lamotrigine.59 The dose of lamotrigine is 1 to 10 mg/kg/d in children and 3 to 15 mg/kg/d in infants. Lamotrigine has a long half-life which permits once or twice a day dosing. The half-life when used in monotherapy is 24 hours and decreases to 15 hours when used in polytherapy with drugs that induce hepatic enzymes. Lamotrigine is supplied as 25-, 100-, 150-, and 200-mg tablets and 2-, 5-, and 25-mg chewable tablets. Think Lamotrigine. Think Lamotrigine for children and adolescents with myoclonic or absence seizures who want to avoid possible adverse effects of valproic acid (VPA) (weight gain, polycystic ovary syndrome) and in young children on phenobarbital, in whom you need to avoid potential hepatic dysfunction of adding VPA (but consider rash risk!).

Oxcarbazepine (Trileptal©) Oxcarbazepine was approved by the FDA in 2000 and is indicated for use as monotherapy or adjunctive therapy for partial onset seizures in patients aged 4 years or older. It is an analog of carbamazepine that was designed to have similar efficacy and fewer adverse effects due to the lack of formation of car-

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bamazepine’s toxic metabolite, carbamazepine 10, 11 epoxide.66 Oxcarbazepine and its active metabolite, 10-monohydroxyderivitive, limit high-frequency neuronal firing by blocking voltage-dependent sodium channels. As well, the metabolite produces a reversible dose-dependent decrease in high-voltage activated calcium currents and reduces glutamatergic neurotransmission.50 Oxcarbazepine has been evaluated as adjunctive and monotherapy for partial seizures. Studies in adults show similar efficacy to phenytoin, carbamazepine, and valproic acid in patients with newly diagnosed partial onset epilepsy, with fewer adverse effects.67 A randomized controlled study in children showed equal efficacy to phenytoin, but better tolerability.68 There is little evidence to suggest that seizures that are not responsive to adequate therapy with carbamazepine will respond to oxcarbazepine, although switching to oxcarbazepine may improve tolerability and carry a higher financial cost. Oxcarbazepine is rapidly metabolized to its active metabolite, the 10-monohydroxy derivative. Metabolism is hepatic; however, there is no altered pharmacokinetics in the presence of hepatic or renal dysfunction. The autoinduction seen with carbamazepine does not occur with oxcarbazepine. Similarly, oxcarbazepine has significantly fewer drug interactions than carbamazepine. Oxcarbazepine does not induce the cytochrome P450 system as seen with carbamazepine. It does affect the CYP3A subfamily and consequently may lower oral contraceptive levels.69 A further advantage of oxcarbazepine is fewer and less severe side effects than carbamazepine. Skin rash is less frequent; however, 25% of patients who experience a rash from carbamazepine will develop a similar reaction to oxcarbazepine, which necessitates that care be taken in patients with a history of severe skin reaction to carbamazepine. There have been no significant changes in white blood cell counts or liver enzyme levels in clinical trials of oxcarbazepine.59 The more common adverse effects of oxcarbazepine are dose related and consist of dizziness, diplopia, nausea, somnolence, and ataxia. A potentially serious adverse effect is hyponatremia, which may be clinically significant in up to 2.5% patients, although it is reported to be more rare in children. Serum sodium levels should be monitored when clinically indicated.70 Oxcarbazepine is dosed at 10 to 30 mg/kg/d divided in bid dosing. Patients may be directly switched from

carbamazepine to oxcarbazepine using a ratio of 1.5:1 oxcarbazepine:carbamazepine for doses up to 1500 mg/d of carbamazepine and 1:1 for higher daily doses.71 Oxcarbazepine is supplied as 150-, 300-, and 600-mg tablets and in an oral suspension containing 300 mg/5 mL. Think Oxcarbazepine. Think Oxcarbazepine for partial seizures in patients who may not tolerate the hematologic and hepatic side effects of carbamazepine and can afford the extra cost.

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Pregabalin (Lyrica©) Pregabalin is the newest AED to come to market in the United States, approved in 2005 for adjuvant therapy of partial seizures in adults. It was previously approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia in late 2004. This drug is a structural analog to GABA, but functionally unrelated. It is thought to exhibit its anticonvulsant activity by binding to the alpha-2-delta subunit of the voltage-gated calcium channel.72 Pregabalin is stated to have very rapid absorption, with steady-state serum levels achieved within 48 hours, which may prove to be a favorable pharmacokinetic property. It is excreted virtually unchanged by the kidneys and does not induce or inhibit liver enzymes.72 Pregabalin has been demonstrated to be more effective than placebo as add-on therapy in patients 12 years of age and older with refractory partial seizures with or without secondary generalization.73 Dosing in clinical trials ranged from 150 to 600 mg per day in adults. Dosing recommendations are not available for children and there is no significant experience with this drug in children to date. Pregabalin is supplied in 25-, 50-, 75-, 100-, 200-, 225-, and 300-mg tablets. Think Pregabalin. As the newest drug on the market, keep apprised of any new evidence about efficacy and tolerability of pregabalin in children.

Levetiracetam (Keppra©) Levetiracetam was approved in 1999 for the adjunctive treatment of adults with partial-onset seizures. Levetiracetam is a pyrolidone, similar to piracetam. The mechanism of action of levetiracetam is unknown but of considerable interest since there are some experimental animal data to suggest that this drug might actually have antiepileptogenic as well as anticonvulsant properties.74 Recently, it has been proposed that levetiracetam might

affect fundamental mechanisms of neurotransmission by binding to a novel protein binding site, SVA, which is an integral membrane protein present on synaptic vesicles.75 While clinical trials have focused on adjuvant therapy in partial seizures, there is experimental evidence from animal models that levetiracetam is also effective against absence seizures.59 Anecdotal evidence suggests efficacy in atypical absence seizures. Open label trials in children have demonstrated good efficacy and tolerability in refractory mixed seizure disorders.76,77 A prospective, open-label study has provided preliminary evidence for the anticonvulsant efficacy of levetiracetam in the pediatric population against a number of different seizure types with 46% of the patients showing a seizure frequency reduction of more than 50% to treatment. The maximal dose in that study was 60 mg/kg.78 Levetiracetam is excreted primarily by the kidneys, with minimal hepatic metabolism. It is not affected by hepatic enzyme-inducing AED and does not affect the metabolism of other AED. Levetiracetam is generally considered to be quite safe, with no severe adverse effects noted. Somnolence, asthenia, and common infection were the most frequent side effects noted in clinical trials and were not dose related. The most significant adverse effect is behavioral, such as anxiety and agitation. Psychotic symptoms have also been reported in children.79 These behavioral effects appear to be reversible with discontinuation or dose adjustment of the drug. The pediatric dose is 10 mg/kg/d to start with a gradual increase to a maintenance dose of 60 mg/kg/d. Levetiracetam is supplied as 250-, 500-, and 750-mg tablets. Think Levetiracetam. Think Levetiracetam for refractory partial or atypical absence seizures in children without preexisting behavioral issues.

Tiagabine (Gabitril©)

Tiagabine has been implicated in episodes of atypical absence status epilepticus.59,81,82 Although the validity of this phenomenon has been challenged, the exacerbation of experimental absence seizures by GABAergic agonists, including direct GABAA or GABAB receptor agonists and indirect GABA agonists, such as GABA transaminase inhibitors (eg, vigabatrin) and GABA uptake inhibitors, such as tiagabine, is well established.14,83 Concentric field defects similar to those associated with vigabatrin treatment, another drug that increases synaptic concentrations of GABA, have not been shown to occur with tiagabine.84,85 Tiagabine undergoes hepatic metabolism via the cytochrome P450 system. The half-life is 5 to 8 hours, which is reduced to 2 to 3 hours in patients also taking hepatic enzyme-inducing AED; therefore, the potential for drug interactions exist. Conversely, tiagabine does not inhibit or induce hepatic enzymes and therefore does not affect the concentration of other drugs. The elimination of tiagabine is nearly doubled in children.86 The most common side effects of tiagabine are dose-related somnolence, confusion, ataxia, and dizziness, which may be reduced with more frequent dosing schedules.49 In children 12 years of age and older, on an enzymeinducing AED, the starting dose of tiagabine is 4 mg/d, to increase by 4 mg weekly to a maximum of dose of 56 mg/d. Significantly lower doses are recommended in patients not taking an inducing AED. Tiagabine is supplied as 2-, 4-, 12-, and 16-mg tablets. Think Tiagabine. Think Tiagabine for adolescents with refractory partial seizures and no history of generalized spike and wave discharges on EEG.

Topiramate (Topamax©)

Tiagabine was approved in 1997 for adjunctive treatment of partial seizures in patients 12 years of age and older. Tiagabine offers a novel mechanism of action, selective inhibition of GABA reuptake into neurons, and glia, which enhances GABA-mediated inhibition. Modest efficacy has been demonstrated in several randomized controlled trials of adjuvant treatment in partial seizures in adults, when compared with placebo and carbamazepine or phenytoin. Monotherapy trials have shown promising results in adults. Pediatric studies have been small but suggested modest efficacy; further pediatric trials are needed.49,80

Topiramate has been available in the United States since 1997, when it was approved for use as adjunctive therapy for patients ⬎2 years of age with primary generalized tonic-clonic seizures, partial-onset seizures, or seizures associated with Lennox–Gastaut syndrome. Topiramate is also used for migraine prophylaxis. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate

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possible cognitive effects, and when you want to avoid hepatic metabolism.

subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.87-92 Topiramate appears to have no effect on NMDA receptor function.93 Topiramate has demonstrated efficacy in placebocontrolled trials in partial onset seizures in children, Lennox–Gastaut syndrome, and infantile spasms.94-97 A recent open prospective trial demonstrated efficacy and tolerability in children less than 2 years of age.98 Topiramate has not been associated with any lifethreatening adverse events; however, there is a risk of serious hyperchloremic, nonanion gap metabolic acidosis (lowering of serum bicarbonate levels) for which measurement of baseline and periodic serum bicarbonate levels is recommended. Renal stones may occur. Oligohidrosis and hyperthermia occurs most often in hot weather and has been reported in children. In adults, acute myopia and secondary angle closure glaucoma may occur. The most significant adverse effects in clinical use relate to cognitive dysfunction. In children, this may present as deterioration in school performance, reduced use of language, or reports of poor attention. Somnolence may contribute to this problem and may be reduced by starting at a low dose (1 mg/kg/d) and increasing slowly. Anorexia can also be a significant adverse effect of topiramate and may require discontinuation of the drug in small children with weight loss. This drug has a long half-life of 10 to 23 hours and is given in one to two divided doses. Topiramate is excreted unchanged via the kidneys. The plasma concentration of topiramate is reduced by 50% by hepatic enzyme inducers such as phenytoin and carbamazepine. However, topiramate has little effect on steady-state concentrations of phenytoin, carbamazepine, and valproate. Topiramate may reduce the effectiveness of oral contraceptives. The dose of topiramate in children is 6 to 8 mg/kg/d and the usual adult dose is 200 to 600 mg/d. Doses of up to 30 mg/kg/d have been reported. Younger patients require higher doses of topiramate to achieve serum topiramate concentrations comparable to adults.99 Topiramate is supplied as 25-, 50-, 100-, and 200-mg tablets and 15- and 25-mg sprinkle capsules, which may be swallowed whole or opened and sprinkled onto soft food. Think Topiramate. Think Topiramate for primary generalized seizures, including absence and myoclonic seizures, in children who need to avoid the adverse effects of VPA, for children who may tolerate the

Vigabatrin was initially licensed in 1989; however, it has never been approved for use in the United States. Recently it has fallen into disfavor in Europe and Canada as well, because of the association with visual toxicity in the form of irreversible constriction of the visual fields.100 The reason to consider this drug here is because it has been shown to be effective against infantile spasms in children and is used widely in this regard. A recent practice parameter on the treatment of infantile spasms determined that vigabatrin is only possibly effective in infantile spasms, due to the fact that most of the evidence for the therapeutic efficacy of vigabatrin in this regard comes from uncontrolled clinical trials.101 However, due to the potential risk of more severe adverse effects with adrenocorticotropin hormone, the other common treatment for infantile spasms, most clinicians consider vigabatrin to be the first-line treatment. There are further studies in children with tuberous sclerosis, suggesting that vigabatrin may be particularly effective for infantile spasms in this population.102 Vigabatrin is an irreversible inhibitor of the enzyme responsible for the catabolism of the major inhibitory neurotransmitter in brain, GABA. It is therefore thought to act by raising the level of the inhibitory neurotransmitter, GABA, in the brain, thereby increasing the threshold to seizures. The most significant adverse effect of vigabatrin is retinal toxicity, manifesting as concentric visual field defects, which has been reported in up to 40% of adult patients on vigabatrin treatment. This finding has also been reported in children. Due to the high reported incidence of retinal toxicity, routine ophthalmologic screening is recommended in all children treated with vigabatrin. There is evidence that electroretinography may detect further abnormalities in children with infantile spasms treated with vigabatrin.103 In fact, there is some evidence that children with infantile spasms on vigabatrin may have compromised visual function which predate vigabatrin therapy and may be more due to the infantile spasms than the drug.100 More minor side effects include somnolence, which may be dose related. Vigabatrin is eliminated by the kidneys and is not an enzyme inducer. The only notable drug– drug interaction of vigabatrin is that it may be associated with a decrease in phenytoin levels.

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Vigabatrin (Sabril©)

The dose of vigabatrin in infantile spasms is 100 to 150 mg/kg/d. The half life is 5 to 11 hours and may be given once or twice daily. Vigabatrin is supplied as 500-mg tablets or 500-mg sachets which may be dissolved or sprinkled on food. Think Vigabatrin. Think Vigabatrin for the treatment of infantile spasms, with careful ophthalmologic monitoring.

increased every 2 weeks to a maximum dose of 12 mg/kg/d.59 Think Zonisamide. Think Zonisamide in refractory seizure disorders, partial or generalized, and particularly in myoclonic seizures.

Zonisamide (Zonegran©) Zonisamide has been in widespread use in Japan since 1989 and gained approval in the United States in 2000 for use in partial onset seizures. Despite this indication, there is evidence that Zonisamide has a broad spectrum of anticonvulsant properties and is said to be very effective in generalized seizures, especially myoclonus. The mechanisms by which zonisamide is anticonvulsant are unknown. This drug has been shown to have multiple pharmacological actions that may contribute to its anticonvulsant effect. It blocks voltage-sensitive sodium and voltage-dependent calcium T-type channels, enhances GABA release, blocks the potassium-evoked glutamate response, and reduces glutamate-mediated synaptic excitation.104 Controlled trials have demonstrated the efficacy of this drug against partial seizures in adults.105 A number of open-label studies suggest that the drug has a broad spectrum of efficacy, including primarily generalized seizures, absence seizure, myoclonic seizures, and possibly infantile spasms. Favorable responses have been noted in progressive myoclonic epilepsy.106 Zonisamide undergoes hepatic metabolism via the cytochrome P450 system. The half-life is long, 50 to 70 hours, and reduced to 30 hours with concomitant use of enzyme-inducing AED. Zonisamide does not alter the metabolism of other AED.59 The side effects are dose related and consist of dizziness, ataxia, and anorexia. Zonisamide was reported to cause renal stones in an early study; however, this was not replicated in later trials. Hyperthermia and anhidrosis has been reported in children. Severe skin rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis were seen in postmarketing experience in Japan; however, these serious skin reactions have not been seen in the United States and Europe.59 Zonisamide is a sulfonamide derivative and its use is contraindicated in patients with sulfonamide allergy.49 Zonisamide is available in 25-, 50-, and 100-mg capsules. The recommended starting dose in children is 2 to 4 mg/kg/d dosed once or divided twice daily,

In a review of the new anticonvulsant drugs, it is imperative to state that there is no evidence that any of the new AED are more efficacious than the traditional older AED. What these new drugs offer is improved pharmacokinetic profiles and fewer drug– drug interactions. The new AED do come with a larger price tag; however, this higher cost may be offset by improved clinical outcome. In 2004, the American Academy of Neurology (AAN), in conjunction with the American Epilepsy Society (AES) and the United Kingdom based National Institute for Clinical Excellence Committee (NICE), independently produced guidelines for the use of the new generation of AED. Both the AAN and the NICE guidelines acknowledge that the new AED appear to have similar efficacy to the older AED, but better tolerability and that there is insufficient evidence to compare the efficacy among the newer AED. The guidelines diverge in their recommendations for the use of new AED in the treatment of new-onset epilepsy. The AAN guidelines recommend that the new drugs, lamotrigine, gabapentin, topiramate, and oxcarbazepine, be considered along with the older drugs for first-line treatment in new-onset partial epilepsy. The NICE guidelines recommend that new AED be considered first-line in specific clinical settings, including women of childbearing age and when there are concerns about drug interactions. The recommendations are summarized in Table 13 and well reviewed by Beghi.107 It is critical to note that evidence-based recommendations are dependent on the available evidence in the literature. Thus, the absence of a recommendation for a certain AED does not imply that it is not effective in that clinical situation, but may reflect an absence of available evidence due to ongoing clinical trials or other factors. The clinician may select an AED based on side-effect profile, pharmacokinetic properties, and risk of teratogenicity in contradiction to these guidelines (Table 10). Recommendations for when to consider the use of a new AED in children with epilepsy are found in Table 14. AED choice by seizure type is presented in Figure 7.

Curr Probl Pediatr Adolesc Health Care, November/December 2005

415

Conclusions

TABLE 13. Summary of the US and UK guideline recommendations for use of the new AED (Reproduced with permission from Beghi, 2004107)

Drug

Newly diagnosed epilepsy Partial, mixed

Felbamate* Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Tiagabine Topiramate Vigabatrin§§ Zonisamide

Refractory epilepsy

Absence

Partial monotherapy

Partial

Idiopathic generalized

US

UK

US

UK

US

UK

US

UK

US

No Yes§ Yes§ No Yes No Yes§ NA No

NA No Yes储 No Yes¶ No Yes¶ No NA

No No Yes§ No No No No NA No

NA No Yes储 No No No No No NA

Yes† Yes Yes Yes Yes Yes Yes NA Yes储储

NA Yes¶ Yes** Yes†† Yes¶ Yes储 Yesⴱⴱ Yes NA

Yes No Yes No Yes No Yes§ NA No

NA No Yes No Yes¶ No Yes¶ No NA

No No No No No No Yes‡‡ NA No

UK NA No Yes** No No No Yes‡‡ⴱⴱ No NA

Symptomatic generalized US

UK

Yes‡ No Yes No No No Yes NA No

NA No Yes*ⴱ No No No Yesⴱⴱ Yes¶¶ NA

None of the new drugs is recommended as first choice in newly diagnosed epilepsy by the UK guidelines (see text). NA ⫽ not available. *Patients unresponsive to standard drugs in whom the risk/benefit ratio supports use. †Only patients ⬎18 years. ‡Only patients ⬎4 years with Lennox-Gastaut syndrome. §Indication not approved by FDA. ¶Only patients ⱖ6 years. 储Only patients ⱖ12 years. **Only patients ⬎2 years. ††Only patients ⱖ16 years. ‡‡Only generalized tonic-clonic seizures. §§In the UK the indications are limited to adjunctive use after failure of all other appropriate drug combinations. ¶¶Only West-syndrome. 储储Only adults.

TABLE 14. Recommendations for the use of new AED in children

When to consider a new AED in children Established drugs have failed Most appropriate older drug is contraindicated Older drug interacts with other medications, including oral contraceptives. Older drugs are poorly tolerated Liver disease Mid-late adolescent females

Partial Seizures Simple

Complex

Generalized Seizures Secondary Generalized

GTC Tonic Atonic Myoclonic Absence Infantile Spasms

PHT. PB CBZ, OXC GBP, LEV

ESM

VGB ACTH

Acknowledgments: This work was supported in part by the Bloorview Children’s Hospital Foundation. VPA, LTG, TPM, ZNS, (FBM)

FIG 7. AED choice by seizure type.

On the horizon There are some AED currently in use outside of North America, but not yet available in the US or Canada that may be efficacious in childhood epilepsy.

416

These include sulthiame (Ospolot), which has been shown to be useful in benign epilepsy of childhood with centrotemporal spikes (BECTS), and stiripentol, which is said to be particularly efficacious in severe myoclonic epilepsy of infancy.59 There are also several new AED currently in preclinical development, some of which have novel mechanisms of action including actions at the ␣2-noradrenergic receptor in the brain and stabilization of neuronal membrane excitability via action on potassium currents.50 However, no drug to date appears to offer antiepileptogenic properties. Real relief for children with epilepsy and their families will have to await the development of truly antiepileptogenic drugs.

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