Antiepileptic Drugs, 5th Edition

General Principles

11

Use of Antiepileptic Drugs in Children

Olivier Dulac MD

Professor, Department of Pediatric Neurology, University of René Descartes, Paris, France

Managing epilepsy in the neonate and child requires an understanding of the unique biochemical and pharmacologic characteristics of this age range. Accurate classification of seizures and identification of epilepsy syndromes, coupled with a thorough neurologic assessment to define etiology, and a comprehensive assessment of the patient's health and social situation are essential to good treatment. Effective management also requires communication with the patient's parents, to ensure that they understand the goals of the treatment, which depend of the type of epilepsy and its prognosis, the side effects of medications, the diagnostic process, and treatment monitoring strategies. Parents need to have realistic expectations regarding seizure control, and they must understand the need to try drugs in sequence. After each prescription is written, a leaflet giving the main characteristics of the drug prescribed, focusing on the usual dose administered, the first signs of potential side effects, and the concurrent medications that are contraindicated or need special attention, should be given to the parents and read to them. The child's parents also need to know from the onset of treatment what the criteria for cessation of treatment will be. “Treatment for life” does not exist, despite frequent claims to the contrary, including those made by the medical profession.

CHARACTERISTICS OF EPILEPSY IN NEONATES AND CHILDREN

The first peak of incidence of epilepsy is in the first decade of life (1). In one cohort, the incidence was 120 per 100,000 in the first year of life (2), decreasing to 40 per 100,000 for the remainder of the first decade. The most common identifiable cause is either prenatal or a consequence of acute circulatory failure (3). However, for more than three-fourths of children with epilepsy, the cause cannot be determined. Seizures are more likely to be occasional and the result of acute brain damage in the newborn than in the infant and in the infant than in the child.

The type of seizures observed in adults may also occur in children. Partial seizures may be observed from the very first months of life (1,4). Some types of seizures are specific to the newborn period and infancy. For example, clusters of spasms are rarely observed after 1 year of age (5), although they may occur later (6), even without the expected hypsarrhythmic electroencephalographic (EEG) pattern (7). Many children have several types of seizures; one epidemiologic study reported more than 1.6 seizure types per patient <10 years old (1). Seizures are not the only expression of epilepsy in children, however. Motor and cognitive functions may be affected, and some patients with a form of epilepsy that produces speech disorders, the Landau-Kleffner syndrome, never have seizures.

Some types of epilepsy are age specific. The combination of specific seizure types, cognitive and motor characteristics, and EEG patterns, beginning within a specific age range, serves to define epilepsy syndromes that are age related and depend partly on particular stages of brain cortical maturation. This concept is of critical importance because the cause is unknown in most children (8).

Intractability of epilepsy is correlated with educational difficulties. More than 60% of patients with seizures persisting for >2 years after onset fail in school, compared with a 25% rate of failure among those patients with rapid seizure control (9).

EFFECTS OF ANTIEPILEPTIC DRUGS ON THE CLINICAL PATTERN

The selection of an antiepileptic drug (AED) for a specific patient is usually based on clinical observation, because controlled data do not apply to individual patients. Carbamazepine (CBZ) is often considered more effective to treat

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partial seizures than generalized seizures, whereas the reverse is true for valproate (VPA) (10, 11, 12). However, one randomized trial in children with newly diagnosed partial or generalized Torric-Clount seizures failed to disclose any difference in efficacy of both compounds, whatever the seizure type, partial or generalized (13).

AEDs may modify the clinical pattern of seizures by (a) controlling the type of seizures experienced by the patient or (b) changing the type of seizures. For example, in a given patient, a drug may result in control of secondarily generalized seizures, including epileptic spasms, whereas simple or complex partial seizures remain unaffected (14). This response may be clinically relevant because generalized seizures are more incapacitating than partial seizures from the cognitive point of view (15). An additional seizure pattern may emerge as a result of adverse effects of the AEDs, and it may worsen of the patient's condition, as may occur in the case of (a) tonic status epilepticus in patients with Lennox-Gastaut syndrome who are treated with benzodiazepines (16) or (b) myoclonic status in patients with myoclonic epilepsy who are treated with CBZ or vigabatrin (VGB) (14). Thus, the choice of a drug must be governed not only by seizure types but also by the identification of any specific epilepsy syndrome. Although this may be difficult at onset of the seizure disorder, when the diagnosis remains uncertain, it soon becomes feasible because, in one epidemiologic study of prevalence, proper syndromic diagnosis could be established in >90% of cases with established epilepsy (17).

ANTIEPILEPTIC DRUG EFFICACY IN EPILEPSY SYNDROMES

The occurrence of seizures requires identification of other potentially related clinical characteristics to define the epilepsy syndrome. A specific seizure type may be associated with several epilepsy syndromes, each having a different response to AED treatment. For example, simple partial seizures appear to respond differently to treatment, depending on whether the seizures are the result of a brain lesion or of a condition such as benign partial epilepsy with centrotemporal spikes (BPECTS). Although preliminary observations suggest that CBZ is more effective than VPA in patients with symptomatic partial epilepsy, both drugs are associated with the same rate of efficacy in patients with BPECTS (10). An AED may improve seizure control in some epilepsy syndromes, whereas it may worsen seizure control in others. Some specific responses to drugs may be expected with some of the epilepsy syndromes (18, 19, 20). For example, CBZ may worsen continuous spike waves in slow-wave sleep (21). Table 11.1 shows those drugs that are more likely to be dangerous in specific epilepsy syndromes.

The diagnosis of a specific epilepsy syndrome is challenging. Although the patient may have specific seizures from the onset, the characteristic EEG pattern necessary to establish the diagnosis may not be observed for some time, and early diagnosis may not be possible. A patient with seizures that are typical of those observed in BPECTS may not have centrotemporal spikes on a given EEG. Patients with myoclonic-astatic epilepsy (22) are commonly thought to have Lennox-Gastaut syndrome. In severe myoclonic epilepsy of infancy (Dravet's syndrome) (23,24), the observation of myoclonic jerks and spike-wave discharges on the EEG will be delayed for several years. Alternating unilateral seizures may, at the onset, be thought to result from focal epilepsy. However, patients with focal epilepsy may have generalized seizures when the condition starts during the first year of life, with focal seizures appearing later (25).

TABLE 11.1. POTENTIAL AGGRAVATION IN VARIOUS EPILEPSY SYNDROMES

   

PB

CBZ

VGB

PHT

LTG

Idiopathic generalized epilepsy

 

+

+

   
 

Absences

+

+

+

+

 
 

Dravet's syndrome

+

+

+

 

+

Epileptogenic encephalopathies

         
 

Continuous spike-waves in sleep

+

+

+

+

 
 

Infantile spasms

+

+

 

+

 
 

Lennox-Gastaut syndrome

+

+

+

   

PB, phenobarbital; CBZ, carbamazepine; VGB, vigabatrin; PHT, phenytoin; LTG, lamotrigine.

An epileptic syndrome may have a clinical pattern evolving through several stages, each with a different response to AEDs. Both VPA and the benzodiazepines are effective at the onset of Dravet's syndrome. By the age of 3 to 4 years, phenytoin (PHT) and VGB may have become effective, possibly because episodes of status epilepticus have produced additional epileptogenic brain injury (23). Accumulating evidence indicated that some disorders currently considered specific epilepsy syndromes are, in fact, heterogeneous. A syndrome with different causes may have different responses to treatment. This is best illustrated by infantile spasms that have a better response to VGB than to steroids when the spasms are caused by tuberous sclerosis (26), but they may fail to respond to VGB monotherapy when they are cryptogenic with negative neuroradiology but psychomotor delay before the first spasms (27). Thus, an etiologic diagnosis, in addition to identification of the syndrome, is required whenever possible before any treatment decision is made.

Precise identification of the epilepsy syndrome is often difficult during the first weeks or months of the disease. Thus, it is often wise to administer a compound that has a relatively large spectrum of activity and that is not known to cause syndrome specific worsening, particularly VPA.

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Before marketing new compounds for epilepsy, some data should be available regarding not only efficacy but also potential harm in the various specific syndromes of childhood epilepsy. Regarding efficacy, controlled trials need only small numbers of patients when they select patients with one given epilepsy syndrome and eventually one type of origin. Thus, it was possible to demonstrate the efficacy of VGB in infantile spasms, whatever the cause (28), with <50 patients and in those with epilepsy resulting from tuberous sclerosis with only 22 patients (29). It was also possible to show the efficacy of stiripentol combined with clobazam and VPA in Dravet's syndrome with only 41 patients (30).

TOLERABILITY OF DRUG THERAPY

Several of the AEDs have age-specific adverse effects, particularly in patients with associated metabolic abnormalities. Acute hepatic failure is 30 to 100 times more frequent in infants than in adults (31, 32, 33, 34, 35, 36, 37, 38, 39). Infants <2 years of age are in the most vulnerable group for the occurrence of inborn errors of metabolism, which predispose to VPA hepatotoxicity, and these infants are in the age group of patients in need of VPA therapy (31, 32, 33,39, 40, 41). VPA is more likely to be used in polytherapy in infants than in adults. For example, acetylsalicylic acid often used to be administered for fever in infants, and the combination of this drug with VPA in the presence of fever seems to be particularly strongly associated with drug-induced Reye-like hepatic failure (34,42). Drug interactions between macrolides and CBZ have been most commonly reported in children (35,43). Ethosuximide may cause hallucinations in adolescents (36,44). Whether this effect of ethosuximide is the result of age-related specific effects of AEDs or, alternatively, a specific age-related characteristic of the epilepsy for which this drug is administered remains unclear because treatment of absence epilepsy with high doses of ethosuximide is required in adolescents. Skin rash associated with lamotrigine (LTG) is more common when the drug is used in combination with VPA (37,45). This type of drug combination is effective in patients with generalized epilepsy, a common type of epilepsy in childhood (38,46). Thus, the cause of epilepsy may contribute to the occurrence of side effects of AEDs in children.

ANTIEPILEPTIC DRUGS AND COGNITIVE FUNCTIONS IN PEDIATRIC PATIENTS

Behavior and cognitive functions are affected by preexisting brain injury coupled with psychological isolation (31,32,39,40). Seizures, frequent spike-wave activity, and AED effects may all exacerbate these problems, and distinguishing the leading cause of cognitive disorder is often challenging. Half the children exhibit fluctuations of cognitive functions and behavior over periods of a few months (33,41). However, some epilepsy syndromes in infants and children are associated with marked mental deterioration within a few weeks. This finding applies particularly to patients with generalized paroxysmal activity, whether primarily or secondarily generalized, with the epilepsy syndromes unclassified as either partial or generalized. In partial epilepsy, the type of cognitive deficit depends of the topography of the epileptogenic focus (34,42).

Toxic circulating levels of AEDs may alter intellectual functioning. Cognitive disorders are easily overlooked, as shown in studies of school-age children treated with phenobarbital (PB) (35,36,43,44) or CBZ (37,45). PB-induced depression may be overlooked (38,46). These complications of treatment are of particular concern because children are rapidly developing cognitive functions. Cognitive impairment caused by drugs may abate within a few weeks after beginning treatment. Polypharmacy and underlying poor neuropsychological functioning increase the risk of developing behavioral side effects. In addition, the use of several drugs may alter a patient's ability to develop tolerance to cognitive alterations when compared with the use of monotherapy. Observational data and standardized tests are not available regarding cognitive test performance in children <6 years of age who are treated with AEDs.

PHARMACOKINETICS

The effect of a drug on a target organ is determined by the drug concentration at the site of action. Both seizure control and toxic effects depend on the quantity of circulating free drug not bound by plasma proteins that is in equilibrium with brain water. Commonly available methods for monitoring serum levels of AEDs measure total drug levels. Although monitoring total plasma levels provides useful information in most instances, this may not be the case for highly protein-bound drugs when the ratio of unbound to free drug is altered. PHT, VPA, and CBZ are highly bound to proteins. Any changes that alter protein binding could influence the relationship between total drug concentration and clinical effect.

In neonates and very young children, albumin, globulins, and circulating glycoproteins are reduced in concentration (47), thus limiting the capacity for protein binding by AEDs. Further, high levels of free fatty acids and bilirubin are capable of displacing some AEDs from protein binding sites (48,49).

In the newborn, permeability of the blood-brain barrier to small molecules is increased, resulting in increased extracellular volume. Because cerebrospinal fluid production is diminished, the sink effect is reduced, with increasing drug concentrations in brain extracellular fluids (50). The factors causing variable rates in central nervous system concentration

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include the negative log of dissociation constant of a drug, cerebral blood flow, and acid-base equilibrium (51).

Gastrointestinal System

AED absorption is delayed in the newborn. This pattern is caused by several factors, including achlorhydria. Stomach acid secretion increases during the first 20 to 30 months of life. Absorption also is affected by erratic and prolonged gastric emptying, a pattern that persists until 6 to 8 months of age (52). The principal factor affecting drug absorption is immaturity of the intestinal mucosa (53). These changes cause variable bioavailability of PHT (54,55). In contrast to the situation in neonates and very young children, drug absorption may be more rapid in children than in adults. This change causes a higher peak concentration of drug, with a subsequent increase of dose-related adverse effects (56). For example, CBZ syrup causes somnolence within 1 hour of dosing; this drug formulation should be given in divided doses throughout the day (57).

Conversely, age has little effect on rectal absorption of the AEDs (58,59). It is the formulation that may affect rectal bioavailability and absorption velocity. Liquid formulations are more rapidly absorbed than suppositories. This is particularly relevant for diazepam when one is treating a patient with a prolonged seizure or status epilepticus.

Parenteral Routes of Administration

The intramuscular route of administration is not reliable, particularly in acute conditions in which the patient's cardiovascular function is altered. As for the intravenous route, most formulations are developed for adults, and concentrations are too high for proper administration in small children. Thus, the drug needs to be diluted, with a risk of error.

Changes in Body Composition

The distribution in the body depends of the size of the various compartments, the relative liposolubility and hydrosolubility of the compound, and its binding to plasma proteins. In the first year of life, the extracellular water represents a higher proportion of body weight than in adults. Until puberty, the lipidic compartment comprises a bigger proportion of body weight than in the adult. Drug binding to plasma proteins is weaker in the first year of life than later in life because the concentrations of albumin and α1-glycoprotein are low.

The bigger volume of distribution of drugs in the newborn explains the need for an increased loading dose, compared with adults, to reach the same blood level. It also explains in part the longer half-life.

Hepatic Function

Clearance of an AED from the plasma is influenced by the capacity of the liver to metabolize the drug. Because drug clearance determines steady-state drug concentrations, any age-related alteration in clearance by the liver will affect observed serum drug concentrations. One key variable is the rate of elimination of an active metabolite as compared with the elimination of the parent drug. This relationship can cause symptoms of toxicity because a metabolite may not be eliminated rapidly, whereas the serum level of the parent drug appears unchanged.

Some, but not all, metabolic pathways are reduced in the newborn, with reduced plasma clearance. The requested dose per body weight is therefore lower than in adults to reach the same plasma level. Drug metabolism may be modified in favor of the most mature pathway (60). For example, diazepam, which in adults is desmethylated by cytochrome CYP2C into nordiazepam and then is hydroxylated by cytochrome CYP3A into oxazepam before glycuronic acid conjugation and urine elimination, accumulates in the newborn as nonglucuronated oxazepam and nordiazepam because of the immaturity of glucuroconjugation.

The rate of metabolism by liver microsomes is influenced by drug exposure (61). PB (62), PHT (63), and CBZ (80) induce hepatic metabolism. Conjugation with glucuronic acid is significantly reduced until 18 to 24 months of age. Inefficient oxidative plasma clearance endures until the second or third week of life. After that time, there is a gradual increase in the rate of drug metabolism, which, over a period of weeks to months, reaches rates considerably higher than those in adults (56). For this reason, the dosage requirements in milligrams per kilogram for most AEDs are higher in children than in adults.

Renal Function

Filtration reaches the adult rate at the end of the first month of life and tubular function within the second month. This feature may be relevant for drugs that are mainly eliminated by the kidney, such as VGB, gabapentin, and primidone.

SPECIFIC DRUGS

Phenytoin

Data regarding bioavailability of PHT in the newborn are conflicting, with poor absorption reported by some authors (55), but not confirmed by others (64). This point is important when one is attempting oral treatment after intravenous administration for status epilepticus, however, because impaired bioavailability interferes with the switch to oral treatment. The drug's half-life is longer in the neonate (15 to 105 hours) and shorter in infants (2 to 7 hours) than it is in adults (24 to 48 hours). Nonlinear pharmacokinetics causes the therapeutic index to be narrow, because mild alteration in the dose may produce major changes in the blood level with a high risk of intoxication or loss of

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efficacy. Therefore, at onset of treatment, monitoring of plasma level is critical to prevent side effects and to determine the rate of dosage increase. In addition, the plasma level of the drug should be monitored until the proper steady state has been reached.

A review of the charts of 80 infants aged up to 20 months who were receiving PHT showed that, if properly monitored, this compound is very efficient when it is administered intravenously for status epilepticus. However, when the drug was given orally, it was difficult to determine the appropriate dose and to maintain the patient at a given plasma level for a clinically relevant period (65). Fewer than 10% of patients in this series benefited from the drug given orally. Thus, in practice, oral administration of PHT is not recommended in infancy.

A model for loading of patients with status epilepticus has been developed (66), and the plasma level is correlated with efficacy and side effects, including a paradoxical increase in seizure frequency with high blood levels. Dilantin (the trade name for the parenteral formulation of PHT) must be diluted in a large amount of physiologic saline to avoid precipitation in the tube. When the drug is given orally by gastric tube to children who cannot swallow tablets because they are unconscious, bioavailability may be poor, and blood levels should therefore be monitored (67).

The newborn babies of mothers treated with PHT are prone to develop neonatal hemorrhage that should systematically be prevented with vitamin K1, given to the mother during the last month of pregnancy and to the baby at birth. Many children, particularly those with mental disability, have problems with gingival hypertrophy and hypertrichosis.

Fosphenytoin

Fosphenytoin is the phosphatase ester of PHT; thus, it is a prodrug of PHT that is changed into PHT by esterases. It is soluble in water, and its pH is lower than that of PHT, features that permit both intravenous and intramuscular administration in the adult. Unfortunately, very few data are available on children, and they mostly concern children between 5 and 18 years of age, with findings similar to those in adults. Very few data are available on children <5 years old (68). Only four infants have been reported, and PHT blood levels between 10 and 20 µg/kg could not be reached in these patients (69).

Valproate

Age-related changes in pharmacokinetics of VPA should be anticipated because of the high percentage of drug that is protein bound and its metabolic route of elimination (70). Dehydrogenation of VPA results in the formulation of 2-ene, 3-ene and 4-ene VPA compounds. The 4-ene metabolites are highest in infants and decline with age. The 2-ene compound has antiepileptic potency (71). VPA binds to albumin at high- and low-affinity sites. This binding is saturable, and thus the free fraction increases with dose.

VPA interferes with the metabolism of several AEDs, including LTG, CBZ, PB, PHT, and felbamate (FBM), as well as with drugs other than AEDs, and so the dose of the concomitant medication needs to be reduced. The drug's half-life is 60 to 100 hours in newborns and 10 to 15 hours in children.

VPA-associated hepatic failure is of major concern when one is selecting this drug for infants and young children. It appears to be age related, with a higher risk in infants treated with polytherapy (39). The hepatic failure occurs within the first 6 months of VPA treatment, and it begins with vomiting, increased seizures, and drowsiness. At this stage, cessation of treatment after measuring prothrombin and transaminase levels may prevent a fatal outcome (72). The risk of hepatotoxicity may be influenced by the need to use the drug in a group of patients who may be either (a) selectively vulnerable because of underlying disease or (b) at risk because of unidentified metabolic abnormality (41). One specific disorder, the hepatocerebral syndrome of Alper, produces intractable epilepsy and hepatic failure, occasionally causing attribution of hepatic failure to VPA. Monitoring strategies in children, including regular or scheduled measurement of blood chemistry studies, fail to detect hepatic dysfunction, and thus communication with parents or caregivers regarding the clinical state of the patient is the best defense against abnormalities in hepatic function (70).

Pancreatitis also has a peak of incidence in association with VPA therapy in childhood (73). Stomach ache, nausea, and anorexia are frequent in patients taking the solution or syrup formulations, unfortunately the only two available for infants and young children.

Dose escalation should be progressive, over 10 to 14 days, to prevent the occurrence of confusion and drowsiness. The parenteral administration of VPA is useful when oral administration is not possible because of gastrointestinal disorders or surgical intervention. However, this drug has not been studied extensively for use in status epilepticus.

Carbamazepine

CBZ is insoluble in aqueous solution, and it behaves as a neutral lipophilic substance (74). It is biotransformed into CBZ-10,11-epoxide (75, 76, 77). The epoxide is formed at the 10,11 double bond on the azepine ring, catalyzed by the hepatic monoxygenases (78). The epoxide is then hydrated by the microsomal epoxide hydrolase (79). Because of solubility problems, gastrointestinal absorption of CBZ is both slow and unpredictable (80). Bioavailability is variable and unpredictable in neonates and infants (81). The elimination half-life varies greatly with age (80,82,83). After establishment

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of autoinduction, it is < 10 hours in children and even shorter in infants. To overcome excessive fluctuation in plasma levels, a controlled-release formulation has been developed. Unfortunately, this formulation is not suitable for infants and young children, the age group for which it would be the most useful because it is the age at which the half-life is the shortest and peak-related side effects are the most prominent.

CBZ has problematic drug interactions with other AEDs and with various other medications as well. Enzyme inducers cause a fall in blood CBZ levels. Inhibition of the activity of epoxide hydroxylase, as occurs with VPA concomitant medication, increases the concentration of the epoxide (84). Both CBZ and the epoxide have antiepileptic properties (85,86). However, compounds such as stiripentol that inhibit the transformation of CBZ into the epoxide at the cytochrome P450 level permit better tolerability of high levels of CBZ with better antiepileptic effect (87).

CBZ is bound to albumin at 65% to 85%. CBZ-10,11-epoxide is also protein bound, but by a lesser percentage (88). The starting dose is 5 mg/kg, going to 10 to 20 mg/kg by 2- to 3-mg/kg increments every week. Infants require up to 30 mg/kg (37,89).

Diplopia is a common concentration-dependent side effect. Treatment with CBZ may be associated with transient somnolence after use of the syrup. This effect is the result of the combination of rapid absorption and short half-life that requires higher doses by body weight in infants than in adults. Nystagmus, vertigo, headache, and ataxia may occur (90,68). These side effects disappear when the dose is reduced, and they tend to decrease after 2 to 3 weeks of treatment, probably as a result of autoinduction. The most severe reactions are hematopoietic, hepatic, renal, and skin reactions (90). The incidence of a rash may be up to 10% (10), but it may be reduced by slow titration when starting the drug. However, Lyell's syndrome does occur, and the outcome is very severe. Hyponatremia is rarely, if ever, a problem in children. CBZ toxicity resulting from an interaction with the macrolide antibiotics, including josamycin, needs to be anticipated because use of this class of antibiotics in children is so common, particularly in school-age children.

In the newborn born of a mother treated with CBZ, there is a risk of vitamin K deficiency requiring vitamin K supplementation. The risk of seizure exacerbation is probably the most difficult problem to handle in infants and children. Myoclonus in patients with idiopathic generalized epilepsy (91), absence and atonic seizures (92) in children, infantile spasms (93,94), and spike activity, particularly during sleep (21), may all be accentuated or triggered by CBZ.

Oxcarbazepine

Oxcarbazepine (OXC) is a derivative of CBZ that has similar efficacy but better tolerability, particularly in children. Its hepatic metabolism converts it into the monohydroxy derivative of OXC. The metabolic interactions of OXC are very limited. The drug's half-life is in the adult range in children ≤5 years of age, but it is significantly lower in younger children and infants (unpublished data). The incidence of skin rash is four times lower than with CBZ. Hyponatremia may be an issue in children (95). No effect on growth has been observed (96). No soluble formulation is currently available.

Like CBZ, the drug has been shown to be effective in partial epilepsy in children (97, 98, 99, 100). Its efficacy was similar to that of PHT in a controlled study (101). As with CBZ, there is a risk of increased seizures, particularly myoclonic and absence seizures, infantile spasms, and conditions characterized by major spike-wave activity, although the effect in partial epilepsy is similar to that in patients with mental retardation (102).

Felbamate

FBM has a complex hepatic metabolism, with clinically relevant metabolic interactions with CBZ, VPA, PB, and PHT. Inducing compounds reduce FBM's half-life by 30%, whereas FBM reduces the clearance of PB, PHT, and VPA but increases the clearance of CBZ. CBZ E levels are increased by FBM.

Bone marrow failure and hepatic failure are the major concerns. Thirty-four patients with FBM-associated aplastic anemia have been reported, with 13 known fatalities. No case of bone marrow failure has been observed in children <13 years of age, but exposure in the lower age groups has been limited. Hepatic failure is lethal in one-third of cases, the overall risk is similar to that associated with VPA, and children <5 years of age have been affected (103). The identification of a reactive metabolite, atropaldehyde, and human leukocyte antigen studies suggest that high-risk patients may be identified. One should monitor transaminases and blood cell counts, every 2 weeks at onset and for several months, then less often. A few cases of anaphylactic reactions and other idiosyncratic reactions including Stevens-Johnson syndrome have been recorded.

FBM has been shown to be effective in double-blind studies both in pediatric partial epilepsy and in adults and children with Lennox-Gastaut syndrome. The combination with VPA may be particularly useful, with a mean decrease in seizure frequency of 60% and a 40% decrease in the frequency of drop attacks in one series when VPA was added to FBM (104). Improved behavior has also been reported, as a result of reduced seizure frequency (105). The main indication is therefore for children with Lennox-Gastaut syndrome, provided they respond clearly within the first 2 or 3 months of treatment. A few clinical observations have mentioned an effect in infantile spasms (106), but if this is the case, the effect is mild.

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Lamotrigine

LTG is metabolized by the liver. Its half-life is decreased by enzyme-inducing concomitant medication and is increased by VPA. These interactions are clinically relevant, for example, with a risk of the loss of antiepileptic activity if VPA is removed without modifying the LTG dose. The incidence of the major side effect, skin rash, is increased by the combination with VPA and with rapid titration. Titration must be particularly slow in combination with VPA, starting with a maximum of 0.2 mg/kg for the first 2 weeks, then 0.5 mg/kg for the next 2 weeks, then 2 mg/kg for another 2 weeks before the usual dose of 2 to 5 mg/kg can be reached. Conversely, the combination with VPA may be more effective in some patients than LTG monotherapy. The reason for this enhanced effect is not restricted to metabolic interactions with raised plasma LTG levels, but it may include a pharmacodynamic effect, yet to be elucidated (46). Tolerance is good, with headache and nausea occurring mainly if titration is too rapid. A combination with CBZ is reported to be poorly tolerated, even with moderate doses and blood levels of CBZ, and it results in side effects usually encountered in patients receiving high doses of CBZ (107). Again, a pharmacodynamic phenomenon may be the cause.

Generalized epilepsies, namely, Lennox-Gastaut syndrome and absence epilepsies, are the best indications for this drug (45), although some patients with infantile spasms may occasionally benefit, at the point at which the condition has become Lennox-Gastaut syndrome (108). Efficacy has also been demonstrated in a doubleblind study of children with partial epilepsy (109). The combination with VPA may be useful in this setting. Moreover, a double-blind study has shown the efficacy of this drug in Lennox-Gastaut syndrome (110). In this case, a paradoxical increase in seizure frequency with high doses of LTG has occasionally been observed (not published). Regarding myoclonic astatic-epilepsy starting after the age of 2 years, with major slow spike-wave activity, several clinical observations suggest good efficacy of LTG if it is given early in the course of the disorder. Conversely, LTG has worsened >80% of patients with severe myoclonic epilepsy in infancy, a disorder that is characterized by recurrent convulsive seizures beginning in the middle of the first year of life and often triggered by fever (19). This finding may seem paradoxical because this generalized epilepsy shares a major myoclonic component with myoclonic-astatic epilepsy.

Improved cognitive function has been claimed in patients with Lennox-Gastaut syndrome, but it remains difficult to determine whether the improvement is indeed the result of some psychotropic effect independent of the control of seizures. Patients with infantile and juvenile ceroid lipofuscinosis have been shown to benefit from this compound, in nonblinded conditions (111).

Vigabatrin

VGB is an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase. It increases the concentration of GABA in the synapse, and this is the supposed mode of the antiepileptic action. The drug is not metabolized by the liver, but it is excreted by the kidneys, and the dose should be reduced when the patient has low creatinine clearance (112). Titration can be rapid, with good tolerability.

Side effects are mild in infant and children. Hyperactivity may occur, especially in children who have a history of hyperactivity or mental retardation, and it disappears when the dose is reduced (113). Increased body weight occurs rarely, but the weight gain in these patients may be very marked. The most impressive side effect, visual field defects, was discovered almost 10 years after the drug reached the market, with several hundred thousand patient-years of treatment completed. One-third of the patients have the defect on visual field testing, but only a few patients have a clinical complain that leads to the investigation (114).

The drug is particularly effective in infantile spasms, especially in patients with tuberous sclerosis and focal cortical dysplasia (in preparation). Efficacy in infantile spasms has been established in one double-blind placebo-controlled study (115), as well as in two randomized studies comparing the compound to either adrenocorticotropic hormone or hydrocortisone (29,116). The latter study exclusively included patients with tuberous sclerosis. In this particular disease, cessation of spasms may be followed by the occurrence of focal seizures. In these cases, however, major improvement of cognitive function has been reported, despite the persistent focal seizures, and patients reach a cognitive level similar to that of patients who experienced only focal seizures starting in the same age range (15). For all these studies, VGB was administered as the first-line drug. The number of patients included in each study was very small, and freedom from seizures was the end point, thus demonstrating high specificity of this compound in this type of epilepsy. In infants with spasms, the drug is currently used as first-line therapy in most European countries (27,117,118). At a dose of 100 to 150 mg/kg, the drug is active in >65% of patients with cryptogenic cases and >55% of patients with symptomatic cases, with one-third of the latter experiencing relapse, whereas this is very uncommon in cryptogenic cases. One major issue is the appropriate duration of treatment in responders, a duration that probably depends on the cause of the seizures: 6 to 12 months in patients with cryptogenic cases, but longer in tuberous sclerosis, in which the risk of recurrence is higher. The addition of steroids in nonresponders raises the proportion of responders to nearly 100% of patients with cryptogenic cases. In older patients, however, who have not received the drug within the first 2 to 3 years of the disease, VGB is much less effective. Increased seizures have even been reported in patients who have developed the patterns

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of Lennox-Gastaut syndrome (14). In patients with tuberous sclerosis, this contrast is even more striking. Patients >4 years old who have persistent infantile spasms may note a worsening of their condition with the occurrence of major hyperactivity, after the introduction of VGB.

The administration of VGB is more troublesome in patients with partial epilepsy, given the lack of valuable data regarding retinal function in this age range. Nevertheless, the drug has been shown to be effective in a randomized double-blind withdrawal trial (119). Patients with severe partial epilepsy not responsive to other drugs usually effective and patients for whom a rapid decline in cognitive function related to frequent seizures requires a compound with a possibly rapid titration should be tried on VGB at the dose of 40 to 80 mg/kg (120). Indeed, within a few days, too short a period for retinal toxicity to appear, the eventual benefit can be observed, or the drug can be discontinued. Finally, absence seizures and myoclonic epilepsy may be worsened by VGB (14).

Topiramate

Topiramate (TPM) is poorly protein bound; it is moderately metabolized (30%) in monotherapy but metabolized more thoroughly in polytherapy with enzyme-inducing compounds (50%). The kidney mainly excretes it. Thus, the dose needs to be reduced when renal clearance is <60 mL/min/1.73 m2. The clearance of TPM is higher in children than in adults, and, consequently, plasma TPM concentrations in children are about 30% lower than those found in adults receiving comparable dosages (120). Kidney stones occur rarely, if at all, in children. Poor appetite and weight loss are frequent. Modified mood with some kind of depression with hallucinations may occur, especially at the onset of treatment, when the dose titration is too rapid. Cognitive dulling was observed in 41% of patients in one series, and 31% stopped treatment because of drug intolerance (121). The incidence reaches 54% in mentally handicapped children (122). Factors that increase the risk of behavior disorders are mainly a history of such disorders and LTG concomitant medication (123). Ataxia and coordination disorders may also occur. With high doses, speech difficulties may affect the child; this is quite specific to TPM (124). Case reports mention central hyperventilation related to the administration of TPM because of its inhibitory action on carbonic anhydrase (125). TPM may inhibit the metabolism of PHT.

TPM has been shown to be effective as add-on drug in refractory partial epilepsy in children from the age of 4 years (126): given a mean 10 mg/kg at maintenance, 14% children became seizure free, and 57% had a >50% decrease in seizure frequency. In generalized tonic-clonic seizures, TPM was also effective, with 44% of children aged 3 to 16 years having a >75% decrease in seizure frequency when they received 1 to 16 mg/kg (mean, 7 mg/kg), but no clue was given regarding the syndromic form in these patients (127). Patients with Lennox-Gastaut syndrome experienced a moderate effect; a double-blind study showed a 14% decrease in seizure frequency (128), and in open follow-up with 10 mg/kg, 15% became free of drop attacks, and 55% had a >50% decrease in drop attacks (97). However, the clinical relevance of incomplete responses in patients with daily seizures remains to be established. Fewer than a dozen patients with infantile spasms who had not received VGB were given TPM in very high doses (mean, 29 mg/kg, ≤50 mg/kg), and four of 11 became seizure free (97). TPM was claimed to be effective in five children with Angelman's syndrome (129). One case with dramatic improvement of progressive myoclonic epilepsy is on record (122). In practice, the initial dose should be no more than 0.5 to 1 mg/kg/day for 2 weeks, followed by increases every other week, usually up to 5 mg/kg.

Gabapentin

Gabapentin is readily absorbed, and it is neither protein bound or metabolized by the liver. Thus, it has no significant metabolic interactions. Excretion is mainly through the kidney. Hyperactivity may be an issue, mainly for patients who have mental retardation or a history of hyperactivity (130).

This drug has an effect on partial epilepsy in children, but the only study performed failed to demonstrate any effect in the newborn (although these patients had very severe cases). The efficacy in childhood partial epilepsy is very mild; in a double-blind placebo-controlled trial, no difference in the number of responders could be identified, and only three patients became seizure free compared to one in the placebo group (115). In one series, only three of 52 children with uncontrolled partial seizures benefited in the long term (131). A controlled study failed to demonstrate an effect in childhood absence epilepsy (132).

Ethosuximide

In children, ethosuximide has a long half-life of 30 hours, and this permits a single daily dose at night. Bone marrow toxicity, which is very rare, cannot be predicted by hematologic monitoring. Ethosuximide is indicated in absence seizures and myoclonus, and some patients with epileptic encephalopathy and continuous spike waves in sleep may benefit.

Phenobarbital and Primidone

PB causes insidious cognitive and behavioral effects (133). Vining et al. (35) compared results of cognitive tests in 28 children with febrile seizures who were treated with PB with results in control subjects who were treated with VPA. PB

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caused significant difficulties in full-scale and performance intelligence quotient, contraction praxis, attention, mood, and the ability to finish a task. Farwell et al. (36) performed serial assessments of cognitive performances of children treated prophylactically for febrile seizures with PB. These investigators found cognitive decline in patients receiving PB. Hyperactivity in response to PB administration may be insignificant, or it may occur in as many as 42% of patients. Occasionally, dose reduction of PB may result in improvement of hyperactivity or disordered sleep that was not identified as being caused by PB. PB-induced hyperactivity does not appear to correlate with PB blood levels (35). Rash complicates PB treatment in 1% to 3% of patients; exfoliative dermatitis may occur rarely. Rickets has occurred among disabled children with pigmented skin who are treated with multiple AEDs. Dependency to PB may develop; withdrawal symptoms of anxiety, somnolence, tremor, and convulsions with possible seizure exacerbation may occur. Attacks of acute intermittent porphyria may be precipitated by administration of drugs causing enzyme induction, including PB. Primidone is poorly tolerated in children because of associated somnolence and drug-induced hyperactivity.

Benzodiazepines

Diazepam is an important drug for the treatment of convulsive status epilepticus. The drug is highly protein bound; the metabolite desmethyldiazepam is also active. In the newborn, it has slow catabolism, with a half-life ranging from 40 to 400 hours. Therefore, the drug and its active metabolites accumulate, producing hypotonia and breathing difficulties. The drug is absorbed rectally in infants and children (58,59), more rapidly as a solution than as a suppository. Rectal administration of the solution is useful for infants and children experiencing convulsive status epilepticus because parents administer the drug rectally. However, intravenous administration reaches blood levels sufficient to stop status epilepticus more rapidly, and it is preferred whenever possible.

Clonazepam is useful intravenously for the treatment of status epilepticus. Clonazepam produces hypotonia, somnolence, and ataxia. For the oral treatment of epilepsy in infants and children, it should therefore not be the benzodiazepine of first choice.

Clobazam is certainly the benzodiazepine of choice for the oral treatment of chronic epilepsy in infants and children. It is relatively well tolerated, and the usual side effects encountered with the other compounds of the group, namely, somnolence, hypotonia, and ataxia, are much less frequent with clobazam, although some children become irritable and aggressive. Absorption is rapid and reaches maximum concentration within 2 hours. Protein binding is 85%, and there is complete metabolic transformation through cytochrome P450 into desmethylclobazam, which is active and has a longer half-life (50 hours) than clobazam (20 hours). The steady state is reached within 10 days.

Lorazepam is commonly used in infants and children for the treatment of status epilepticus. It may be more efficient than diazepam, particularly by rectal administration (134).

Tiagabine

Tiagabine (TGB) is an inhibitor of GABA reuptake. Therefore, it increases the concentration of GABA in the synaptic cleft. Few data are available in children. The pharmacokinetics of TGB after a single 0.1 mg/kg dose was studied in 25 children receiving concomitant medication (135). Areas under the curve were significantly higher (.002), and clearance values were significantly lower (p >.02) in children comedicated with VPA compared with children taking enzyme inducers such as CBZ and PHT. Moreover, the half-life of TGB was twice as long in patients taking VPA compared with patients receiving enzyme inducers. When adjusted for body surface, kinetic parameters in children were similar to those found in historical adult controls receiving comparable comedication. However, when adjusted for body weight, clearance values were higher in children than in adults.

Ascending doses of TGB (0.25 to 1.5 mg/kg/day) were added to previous medication in 52 children >2 years old (136). The median reduction in seizure frequency for patients with partial seizures was 33%, whereas there was no change for those with generalized seizures. A single patient with pharmacoresistant epilepsy and multifocal spikes experienced total seizure control (137). In 14 patients with both seizures and spastic tetraplegia, TGB was given at the starting dose of 0.1 to 0.2 mg/kg/day and was increased to 1.1 mg/kg (138). Half of the patients experienced improved tone, strength, coordination, range of motion, and relaxation of extremities, with less ataxia and wobbling.

The main side effects of TGB affect the central nervous system: asthenia, nervousness, dizziness, and somnolence. Like other GABAergic drugs, TGB has the potential to worsen myoclonus and absence seizures. In addition, it may precipitate nonconvulsive status epilepticus. Two patients experienced status epilepticus in one series (136). One 12-year-old child with perisylvian microgyria developed frontal lobe status after 1 week of total seizure control, at the dose of 1 mg/kg, with disappearance of status epilepticus after the dose was decreased by 25% (139).

In view of the evidence reviewed earlier, the use of TGB in children should be restricted to resistant partial epilepsy, and consideration should be given to the risk of nonconvulsive status epilepticus.

Zonisamide

Some authors believe that zonisamide (ZNS), added to clonazepam and VPA or a barbiturate, can reduce the cascade

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of myoclonia in progressive myoclonus epilepsies for ≥2 years, but relapse may occur thereafter (140). Of 11 patients with infantile spasms resistant to vitamin B6 who were receiving ZNS, four responded with cessation of spasms and hypsarrhythmia, at 4 to 5 mg/kg/day, but half had a relapse (141). At 4 to 20 mg/kg, ZNS was effective in both patients with cryptogenic cases and in 28% of the symptomatic cases, but again, half the patients had a relapse (142). Kishi et al. (143) found that ZNS is useful for patients with atypical infantile spasms, when steroids cannot be administered. One patient with epileptogenic encephalopathy had an excellent response to ZNS (144). The effect of ZNS add-on therapy was weaker in patients with intellectual disability (41% of patients experiencing a >50% seizure decrease) than in those without intellectual disability (67% responder rate; p < .01); in monotherapy, tolerability was also poorer in patients with intellectual disability (145).

In two children aged 1 and 3 years, ZNS induced behavior disorders at plasma ZNS levels within or even lower than the therapeutic range (146). One 2-year-old child exhibited fever and oligohidrosis resulting from abnormal perspiration, with acute chorea, tremor, and cogwheel hypertonia that disappeared within 2 weeks of cessation of the drug (147). Acetylcholine stimulation testing may be helpful in predicting this complication, with a sensitivity of 1 and a false-positive rate of 0.67 (148). Three patients were reported withurinary lithiasis; alkaline urine and hypercalciuria seem to be predisposing factors (149).

The indications of ZNS are still to be identified on the basis of controlled trials, particularly for infantile spasms, in which a comparison should be done with VGB. Parents should be aware of the risk of perspiration abnormalities and nephrolithiasis.

CONCLUSION

In addition to proper pediatric formulation, four sets of pediatric data should be collected early in the development of new compounds, to optimize the benefit:risk ratio as soon as possible: pharmacokinetics, tolerability, pediatric syndrome-specific potential of worsening, and, eventually, efficacy in pediatric-specific epilepsy syndromes. Whether duplicating in children the efficacy controlled studies already performed in adults for types of epilepsy observed in both adults and children are clinically relevant and ethically sound remains to be established.

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