Drug Treatment in Children

John M. Pellock

Douglas R. Nordli Jr.

Olivier Dulac

Introduction

Childhood epilepsy differs from that seen in adults because of age-related seizures, the etiology of seizures in children, the presence of both benign and malignant epilepsy syndromes, and the frequent concomitant presence of neurologic abnormality, mental retardation, or behavioral difficulties.³¹ All of these factors have important implications for treatment selection. In addition, children respond differently to antiepileptic drugs (AEDs), with regard to both efficacy and side effects. For those with lesional epilepsy, seeming brain plasticity offers a special opportunity for early surgical intervention. This chapter concentrates primarily on how the medical treatment and evaluation of childhood epilepsy differ from those in adults.

Diagnostic Considerations

Seizures should be treated acutely, and their cause should be determined. If they recur, they should be carefully investigated before chronic therapy is initiated. Febrile seizures or those that occur with minor trauma and those associated with or following sleep deprivation all represent types of seizures that may not go on to be recurrent and, therefore, infrequently need chronic antiepilepsy drug therapy.³⁰ Neonatal seizures, however, are usually symptomatic of significant or longer-lasting central nervous system (CNS) derangements.³³ Besides the varying etiologies of neonatal seizures requiring extensive evaluation, the semiology of seizures may be quite different from that seen in children of older age and in adults.

In contrast to adults, focal seizures in the very young do not necessarily imply the presence of a focal structural lesion or even a localization-related epilepsy. Indeed, disorders that confer a diffuse susceptibility to seizures, like Dravet syndrome, for example, can express themselves with multifocal seizures. This phenomenon is important to consider because treatment of focal seizures with drugs often used as first choice in adults (carbamazepine, phenytoin, lamotrigine, etc.) can actually exacerbate the seizures, worsen myoclonus, or both. Therefore, although the seizure type is an important consideration in the selection of treatment, the epilepsy syndrome is even more important.

Another important difference between children and adults is the presence of infantile spasms as a fairly unique seizure type. Although this characteristically presents between 6 to 9 months of age, it may occur outside this age range and may be preceded by the presence of focal seizures.²¹ Narrow-spectrum agents that are commonly indicated to treat focal seizures may make spasms worse.²⁸ For these reasons, broader-spectrum agents may be superior for younger children with multifocal seizures, mixed seizure disorders including focal seizures, and focal seizures coexisting with infantile spasms.

In other children with seizures, either no chronic therapy or AED treatment for only a limited time may be needed because of the benign character of a particular epilepsy syndrome.²⁰ Examples of these benign syndromes include febrile seizures and benign epilepsy with centrotemporal spikes. In the condition of febrile seizures, the workup is simply to ensure that meningitis is not present at the onset. In the case of absence epilepsy, recognition of the syndrome allows one to tailor the evaluation to the physical exam—including hyperventilation—and then to proceed with the electroencephalogram (EEG). Rarely should imaging studies be performed in these children unless there are other significant findings or unless neurologic abnormality is present. In those with classic childhood absence, treatment with a specific drug such as ethosuximide, valproate, or lamo-trigine is given because of the multiple recurrent daily seizures for a limited time because most children need to be treated for only approximately 2 years. In the case of benign epilepsy with centrotemporal spikes, both evaluation and treatment are also tailored by realization of this syndrome. The classic clinical description of nocturnal or early-morning seizures that may have a focal component and EEG that clearly shows the centrotemporal spikes makes the diagnosis. Some authorities question whether these seizures should be treated at all with anticonvulsants, but others would treat for a limited period of time, perhaps 2 years.¹⁰^,²² In the case of the encephalopathic epilepsies in children, multiple comorbidities exist, and one must consider not only seizure types and epilepsy syndrome, but also the effect of medications on the child’s performance and behavior. Deterioration of function or progression of the epilepsy should always make one suspect a progressive or degenerative condition rather than a static condition. For example, in some children with ceroid lipofuscinosis, early diagnosis of Lennox-Gastaut syndrome may have been made, but as the child continues to lose milestones and the ability to walk or even crawl, it is clearly evident that this is a degenerative process. In addition, at initiation, if the predominant ictal type is myoclonic seizures, the diagnosis of Lennox-Gastaut syndrome should be questioned because its predominant seizure types are axial tonic, atonic, and atypical absence seizures.¹

The pediatric epilepsies are a conglomeration of a number of conditions or syndromes, each of which must be investigated and treated according to associated hallmark symptoms. Children may manifest a single syndrome or may evolve through different epilepsy syndromes as their seizure characteristics change with maturation.⁸^,²²^,³¹ Understanding this clinical evolution and the required pharmacokinetic changes that occur during childhood sets pediatric epilepsy apart as a true special consideration.

The etiology of childhood epilepsy significantly varies from that seen in adults.¹⁴^,³¹ Whereas lesional epilepsy is much more common in adults and genetic or idiopathic epilepsy is less common, the reverse is true in children. The highest incidence of hereditary or genetic epilepsy has its onset during childhood.
Mid-childhood may be the most common age for these syndromes to occur, with an extension of onset age up to late adolescence. On the other hand, whereas strokes and tumors increasingly are noted as the cause of epilepsy in older adults, they rarely cause epilepsy in younger children. Neoplasia is responsible for only approximately 1% of epilepsy in children. The incidence of vascular disease as an etiology of childhood epilepsy depends on the population being examined. An overall figure of 5% is given by Hauser,¹⁴ but in populations with a greater percentage of black individuals, more children will have epilepsy associated with sickle cell anemia–related strokes. Nevertheless, the proportion will still be far less than that seen in adults, in whom cardiovascular disease appears in much higher proportions of the population. Central nervous system malformations and migrational errors are a cause of epilepsy more commonly recognized in children.

Although far more uncommon, nearly all inherited metabolic disorders responsible for seizures will present in childhood, and the majority are expressed in infancy.

In summary, the evaluation and treatment of epilepsy in children must consider the most likely syndromes and their etiologies to enhance diagnostic and therapeutic efficiency. The diagnosis of epilepsy syndromes and their associated treatments are discussed fully in other portions of this text. Here, we cover some general themes regarding pediatric epilepsy treatment.

Acute Symptomatic Seizures

Acute symptomatic seizures are relatively common in childhood. Epidemiologic studies suggest, for example, that >100,000 children in the United States each year present with febrile seizures.³¹ If they are prolonged, these seizures need to be terminated, but there the risk–benefit ratio of subsequent prophylaxis is considered to be so unfavorable that continued treatment outside of the acute period is not recommended in most children.

Idiopathic Localization-Related Epilepsies

Some authors consider these disorders to fall into a spectrum in which the clinical and electrographic presentation is, in part age dependent but also variable in terms of clinical severity and associated comorbidities. For the most part, treatment need not be automatic, and, in fact, it should probably be reserved for those children with persistent seizures that negatively affect the child’s quality of life. Expert opinion favors carbamazepine or oxcarbazepine as the drug of first choice.³⁴ See Table 1. An important subgroup of children may actually worsen with drug treatment, particularly with sodium channel blockers.²⁸

Symptomatic Localization-Related Epilepsies

Nearly all medications approved for use by the Food and Drug Administration for therapy of refractory partial seizures in adults are used for the same indication in children, although only a subset have been formally approved for this use. See Table 2.¹²^,¹³

Generalized Idiopathic Epilepsies

These disorders respond well to agents that cover a broad spectrum of seizures (Fig. 1). In addition to the epilepsy syndrome, the types of seizures will influence treatment selection. For example, patients with idiopathic generalized epilepsies with prominent absence seizures will need treatment with an agent that covers absence seizures. Valproate efficacy is established, but adverse events require consideration of other medications, particularly in female adolescents.³⁴

Generalized Symptomatic Epilepsies

Agents that cover a broad spectrum of seizure types are commonly used. In addition to the epilepsy syndrome and seizure types, comorbid features are particularly important to consider in this group. These children may be particularly sensitive to the added impairments caused by behavioral disorders, cognitive impairment, cerebral palsy, and learning disabilities. In addition, they may be more vulnerable to adverse events because of limited cerebral reserves and the common need for polytherapy to control their seizures.

Genetically Determined Metabolic Diseases

As mentioned earlier, genetically determined metabolic diseases should be considered when children do not fit into one of the broad groups of epilepsies described previously. They often present early in life, often in etiologically nonspecific ways that make diagnosis challenging. Sometimes, there are useful clues that help to identify the particular disorder. There may be particular physical features, constellation of symptoms, or unique EEG features. In the majority of cases, however, these disorders present as one of the age-related but etiologically nonspecific syndromes that could broadly be considered as epileptogenic encephalopathies. If the metabolic derangement is so severe that the patient presents shortly after disconnection from the maternal–fetal homeostatic mechanisms, then young infants may demonstrate severe disturbances of diffuse cerebral dysfunction on EEG including multifocal sharps, appearance of dysmature features, and extreme discontinuity to the point of burst-suppression patterns. This could appear as early myo-clonic epilepsy as described by Aicardi, early infantile epileptogenic encephalopathy, or Ohtahara syndrome. Prototypic etiologies include nonketotic hyperglycinemia, syndromes with severe lactic acidosis, and urea cycle defects, among other conditions. They may have a variety of primitive seizure types, including multifocal seizures, myoclonus, and tonic postures. If the disturbance becomes manifest later in infancy, then infantile spasms will be a prominent feature with concurrent hypsarrhythmia. Etiologies here include peroxisomal disorders, pyruvate dehydrogenase deficiency, pyruvate carboxylase, and other conditions. Later expressions may show diffuse slowing on the EEG, the appearance of multifocal spikes, and sometimes development of well-organized generalized spike-wave discharges with concurrent generalized seizures, as is the case with myo-clonus epilepsy associated with ragged-red fibers (MERRF), the later expression of glucose transporter type 1 deficiency syndrome (GLUT-1 DS), and the sialodoses, to name a few. These disorders may thus fall into the broad group of symptomatic generalized epilepsies, or epilepsies with both focal and generalized features (see later discussion). Treatment should primarily be aimed at correction of the metabolic defect, wherever possible. When that is not possible, and antiepileptic medication is used, then care should be taken to avoid agents that might potentially exacerbate the underlying condition.

Recognition of metabolic disorders may have several important treatment ramifications. First, some of these disorders have specific treatments, which if administered promptly can result in strikingly good outcomes (Table 3). Examples of this include the B6-responsive epilepsies, central creatine deficiency, pyridoxal phosphate–responsive conditions, and phenylketonuria (PKU) deficiency. Second, these disorders are notoriously

refractory to standard antiepileptic treatment, and identification of the cause can be an important factor guiding the expectations of treatments. Third, there can be severe adverse effects peculiar to certain conditions and treatments (Table 4). Patients with pyruvate carboxylase deficiency, for example, often present with intractable seizures, which might prompt the consideration of alternative treatments. Administration of the ketogenic diet, however, could have lethal consequences, and adrenocorticotropic hormone (ACTH) can worsen spasms in this condition.

Table 1 Comparison of Recommendations for the Treatment of Pediatric Epilepsy

Seizure type or epilepsy syndrome	Pediatric Epilepsy Consensus Survey	ILAE	SIGN	NICE	French study^a	Approved by U.S. Food and Drug Administration
Partial-onset	OXC, CBZ	A: OXC B: none C: CBZ, PB, PHT, TPM, VPA	PHT, VPA,CBZ, LTG, TPM, OXC, VGB, CLB	CBZ, VPA,LTG, OXC,TPM	OXC, CBZ,LTG (adult men)	PB, PHT, CBZ, OXC, TPM
Benign epilepsy with centrotemporal spikes	OXC, CBZ	A, B: none C: CBZ, VPA	Notspecifically mentioned	CBZ, OXC,LTG, VPA	Not surveyed	None
Childhood absenceepilepsy	ESM	A, B: none C: ESM, CBZ, VPA	VPA, ESM,LTG	VPA, ESM,LTG	VPA,LTG	ESM, VPA
Juvenile myoclonic epilepsy	VPA, LTG	A, B, C: none	VPA, LTG,TPM	VPA, LTG	VPA, LTG	TPM
Lennox-Gastautsyndrome	VPA, TPM, LTG	Not reviewed	Notspecifically mentioned	LTG, VPA,TPM	Not surveyed	FLB, TPM, LTG
CBZ, carbamazepine; CLB, clobazam; ESX, ethosuximide; FBM, felbamate; ILAE, International League Against Epilepsy; LTG, lamotrigine; NICE, National Institute for Health and Clinical Excellence; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; SIGN, Scottish Intercollegiate Guidelines Network; TPM, topiramate; VGB, vigabatrin; VPA, valproate. ^a Reproduced from French JA, Kanner J, Bautisa B., et al. Efficacy and tolerability of the new antiepileptic drugs. In: Treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62;1252–1260, with permission. Source: Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion. J Child Neurol. 2005;20:S1–S56.

Table 2 New antiepileptic drugs for refractory epilepsy. level A or B recommendations

Drug	Partial adult (adjunctive)	Partial (monotherapy)	Primary generalized	Partial 2° generalized	LGS
GBP	Yes	No	No	Yes	No
LTG	Yes	Yes	No	Yes	Yes
TPM	Yes	Yes^a	Yes (GTC only)	Yes	Yes
TGB	Yes	No	No	No	No
OXC	Yes	Yes	No	Yes	No
LEV	Yes	No	No	No	No
ZNS	Yes	No	No	No	No
GBP, gabapentin; GTC, generalized tonic–clonic; LEV, levetiracetam; LGS, Lennox-Gastaut syndrome; LTG, lamotrigine; OXC, oxcarbazepine; TGB, tiagabine; TPM, topiramate; ZNS, zonisamide. ^aNot approved by the U.S. Food and Drug Administration. Source: Reproduced from French JA, Kanner J, Bautisa B, et al. Efficacy and tolerability of the new antiepileptic drugs. I: Treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252–1260, with permission.